1. EPIDEMIOLOGY OF CANCER DISEASES
The epidemiology of cancer is the study of the factors affecting cancer, as a way to infer possible trends and causes. The study of cancer epidemiology uses epidemiological methods to find the cause of cancer and to identify and develop improved treatments.
This area of study must contend with problems of lead time bias and length time bias. Lead time bias is the concept that early diagnosis may artificially inflate the survival statistics of a cancer, without really improving the natural history of the disease. Length bias is the concept that slower growing, more indolent tumors are more likely to be diagnosed by screening tests, but improvements in diagnosing more cases of indolent cancer may not translate into better patient outcomes after the implementation of screening programs. A related concern is overdiagnosis, the tendency of screening tests to diagnose diseases that may not actually impact the patient’s longevity. This problem especially applies to prostate cancer and PSA screening.
Some cancer researchers have argued that negative cancer clinical trials lack sufficient statistical power to discover a benefit to treatment. This may be due to fewer patients enrolled in the study than originally planned.[3]
The death rate from cancer per 100,000 inhabitants in 2004:
no data
less than 55
55–80
80–105
105–130
130–155
155–180
180–205
205–230
230–255
255–280
280–305
more than 305
Organizations: State and regional cancer registries are organizations that abstract clinical data about cancer from patient medical records. These institutions provide information to state and national public health groups to help track trends in cancer diagnosis and treatment. One of the largest and most important cancer registries is Surveillance Epidemiology and End Results (SEER), administered by the US Federal government.[4]
Health information privacy concerns have led to the restricted use of cancer registry data in the United States Department of Veterans Affairs[5][6][7] and other institutions.[8] The American Cancer Society predicts that approximately 1,690,000 new cancer cases will be diagnosed and 577,000 Americans will ultimately die of cancer in 2012.[9]
Studies: Observational epidemiological studies that show associations between risk factors and specific cancers mostly serve to generate hypotheses about potential interventions that could reduce cancer incidence or morbidity. Randomized controlled trials then test whether hypotheses generated by epidemiological studies and laboratory research actually result in reduced cancer incidence and mortality. In many cases, findings from observational epidemiological studies are not confirmed by randomized controlled trials.
Risk factors: The most significant risk factor is age. According to cancer researcher Robert A. Weinberg, “If we lived long enough, sooner or later we all would get cancer.”[10] Essentially all of the increase in cancer rates between prehistoric times and people who died in
Although the age-related increase in cancer risk is well-documented, the age-related patterns of cancer are complex. Some types of cancer, like testicular cancer, have early-life incidence peaks, for reasons unknown. Besides, the rate of age-related increase in cancer incidence varies between cancer types with, for instance, prostate cancer incidence accelerating much faster than brain cancer.[11]
Over a third of cancer deaths worldwide are due to potentially modifiable risk factors. The leading modifiable risk factors worldwide are:
· tobacco smoking, which is strongly associated with lung cancer, mouth, and throat cancer;
· drinking alcohol, which is associated with a small increase in oral, esophageal, breast, liver and other cancers;
· a diet low in fruit and vegetables,
· physical inactivity, which is associated with increased risk of colon, breast, and possibly other cancers
· obesity, which is associated with colon, breast, endometrial, and possibly other cancers
· sexual transmission of human papillomavirus, which causes cervical cancer and some forms of anal cancer.
Men with cancer are twice as likely as women to have a modifiable risk factor for their disease.[12]
Other lifestyle and environmental factors known to affect cancer risk (either beneficially or detrimentally) include the use of exogenous hormones (e.g., hormone replacement therapy causes breast cancer), exposure to ionizing radiation and ultraviolet radiation, and certain occupational and chemical exposures.[13]
Every year, at least 200,000 people die worldwide from cancer related to their workplace.[14] Millions of workers run the risk of developing cancers such as pleural and peritoneal mesothelioma from inhaling asbestos fibers, or leukemia from exposure to benzene at their workplaces.[14] Currently, most cancer deaths caused by occupational risk factors occur in the developed world.[14] It is estimated that approximately 20,000 cancer deaths and 40,000 new cases of cancer each year in the
Incidence and mortality: In the U.S. cancer is second only to cardiovascular disease as the leading cause of death; in the
Cancer epidemiology closely mirrors risk factor spread in various countries. Hepatocellular carcinoma (liver cancer) is rare in the West but is the main cancer in China and neighbouring countries, most likely due to the endemic presence of hepatitis B and aflatoxin in that population. Similarly, with tobacco smoking becoming more common in various
The leading cause of death in both males and females is lung cancer, which contributes to 26.8% of all cancer deaths. Statistics indicate that between the ages of 20 and 50 years, the incidence rate of cancer is higher amongst women whereas after 50 years of age, the incidence rate increases in men. Predictions by the Canadian Cancer Society indicate that with time, there will be an increase in the rates of incidence of cancer for both males and females. Cancer will thus continue to be a persistent issue in years to come.
Cancer is responsible for about 25% of all deaths in the
· 
Most common cancers in US males, by occurrence.
· 
in US males, by mortality.
· 
in US females, by occurrence
· 
in US females, by mortality[
|
Male |
|
Female |
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|
most common (by occurrence)[16] |
most common (by mortality)[16] |
most common (by occurrence)[16] |
most common (by mortality)[16] |
|
|
prostate cancer (25%) |
lung cancer (31%) |
breast cancer (26%) |
lung cancer (26%) |
|
|
lung cancer (15%) |
prostate cancer (10%) |
lung cancer (14%) |
breast cancer (15%) |
|
|
colorectal cancer (10%) |
colorectal cancer (8%) |
colorectal cancer (10%) |
colorectal cancer (9%) |
|
|
bladder cancer (7%) |
pancreatic cancer (6%) |
endometrial cancer (7%) |
pancreatic cancer (6%) |
|
|
ovarian cancer (6%) |
||||
|
skin melanoma (5%) |
leukemia (4%) |
thyroid cancer (4%) |
non-Hodgkin lymphoma (3%) |
|
|
kidney cancer (4%) |
esophageal cancer (4%) |
Skin melanoma (4%) |
leukemia (3%) |
|
|
oral and pharyngeal cancer(3%) |
bladder cancer (3%) |
ovarian cancer (3%) |
uterine cancer (3%) |
|
|
leukemia (3%) |
kidney cancer (3%) |
liver & intrahepatic bile duct (2%) |
||
|
pancreatic cancer (3%) |
kidney cancer (3%) |
leukemia (3%) |
brain and other nervous system (2%) |
|
|
other (20%) |
other (24%) |
other (22%) |
other (25%) |
|
Incidence of a second cancer in survivors
In the developed world, one in three people will develop cancer during their lifetimes. If all cancer patients survived and cancer occurred randomly, the normal lifetime odds of developing a second primary cancer (not the first cancer spreading to a new site) would be one in nine.[21] However, cancer survivors have an increased risk of developing a second primary cancer, and the odds are about two iine.[21] About half of these second primaries can be attributed to the normal one-in-nine risk associated with random chance.
The increased risk is believed to be primarily due to the same risk factors that produced the first cancer, such as the person’s genetic profile, alcohol and tobacco use, obesity, and environmental exposures, and partly due, in some cases, to the treatment for the first cancer, which might have included mutagenic chemotherapeutic drugs or radiation.[21]Cancer survivors may also be more likely to comply with recommended screening, and thus may be more likely than average to detect cancers.
Epidemiology of breast cancer
Age-standardized deaths from breast cancer per 100,000 inhabitants in 2004.[1]
|
no data <2 2-4 4-6 6-8 8-10 10-12 |
12-14 14-16 16-18 18-20 20-22 >22 |
Worldwide, breast cancer is the most common invasive cancer in women. (The most common form of cancer is non-invasive non-melanoma skin cancer; non-invasive cancers are generally easily cured, cause very few deaths, and are routinely excluded from cancer statistics.) Breast cancer comprises 22.9% of invasive cancers in women[2] and 16% of all female cancers.[3]
In 2008, breast cancer caused 458,503 deaths worldwide (13.7% of cancer deaths in women and 6.0% of all cancer deaths for men and women together).[2] Lung cancer, the second most common cause of cancer-related death in women, caused 12.8% of cancer deaths in women (18.2% of all cancer deaths for men and women together).[2]
The number of cases worldwide has significantly increased since the 1970s, a phenomenon partly attributed to the modern lifestyles.[4][5]
By age group. Breast cancer is strongly related to age, with only 5% of all breast cancers occurring in women under 40 years old. By region: the incidence of breast cancer varies greatly around the world: it is lowest in less-developed countries and greatest in the more-developed countries. In the twelve world regions, the annual age-standardized incidence rates per 100,000 women are as follows: in Eastern Asia, 18; South Central Asia, 22; sub-Saharan Africa, 22; South-Eastern Asia, 26; North Africa and Western Asia, 28; South and Central America, 42; Eastern Europe, 49; Southern Europe, 56; Northern Europe, 73; Oceania, 74; Western Europe, 78; and in North America, 90.[7]
The lifetime risk for breast cancer in the United States is usually given as about 1 in 8 (12%) of women by age 95, with a 1 in 35 (3%) chance of dying from breast cancer.[9] This calculation assumes that all women live to at least age 95, except for those who die from breast cancer before age 95.[10] Recent work, using real-world numbers, indicate that the actual risk is probably less than half the theoretical risk.[11]
The
In the
Breast cancer incidence by age in women (UK) 2006-08
Developing countries: “Breast cancer in less developed countries, such as those in
IT IS GENERALLY UNAPPRECIATED HOW BIG A HEALTH PROBLEM CANCER PRESENTS WORLDWIDE – A CHALLENGE THAT IS GROWING. Each year cancer is newly diagnosed in 9 million people worldwide and it causes 5 million deaths. It is second to cardiovascular disease as a cause of death in developed countries, and overall causes 10% of all deaths in the world. It is usually regarded as a problem of the developed world, but more than half of all cancers are seen in the three-quarters of the world’s population who live in developing countries.
40 million of these deaths are preventable
The answer to this question, “What is cancer?”provides the scientific basis for cancer control. With all of the recent advances in molecular biology which have increased our understanding of the genetic basis of cancer with the description of oncogenes (cancer genes) and the suppressor genes which regulate their expression, the biologic basis of cancer has received most of the attention. But the nature of cancer also has an equally important social aspect which is essential for cancer control.
Neoplasia is a disease process that results in over 100 different malignant diseases that share a common biology and natural history. Any cell in the body that can undergo mitosis or cell division can be affected. Cancer has links to other disease processes. Some infections cause cancer: e.g. schistosomiasis associated with bladder cancer and the liver fluke, Clonorchis sinensis, which causes cancer of the gall bladder. There are also toxic causes: e.g.mesothelioma, a tumor arising in the pleura which lines the thoracic cavity resulting from exposure to asbestos (asbestosis). Despite popular opinion, however, it is unlikely that local trauma is a cause of cancer. As a fundamental disorder of cellular growth and differentiation or development, cancer is essentially a genetic disorder at the cellular level. Most tumors are encapsulated and benign in behavior. Occasionally they may create symptoms from cosmetic or mass effects. In using the generic word “cancer”, however, we are concerned here with malignanttumors that are morphologically abnormal under the microscope. They show uncontrolled growth leading to local invasion with disruption of tissues, and later metastasis or spread to loco-regional lymphatics and later the blood stream. Cancer kills mostly through blood-borne metastasis.
A tumor does not grow freely in its human host as it would in tissue culture. The host puts up a defense, generically called “host resistance”, which resembles defense against infections. There is a homeostatic interaction between the host and tumor cells or microorganisms based on a dynamic balance between them and the host microenvironment in which they grow – an updated version of the seed-and-soil hypothesis. The tumor arises from an abnormality of growth and differentiation based on altered structure, regulation and expression of its genes. The resulting properties of transformation, invasiveness, metastasis, clonality and heterogeneity give rise to its malignantbehavior. But the outcome of its growth still depends on its interactions with host defenses for a net result of progression, dormancy or regression. The process is dynamic and chronic with the balance of host resistance changing with the advancing stage of tumor growth.
Cancer has a characteristic natural history. Healthy cells first become dysplastic showing subtle morphological abnormalities under the microscope which suggest the beginning of transformation. The next step is carcinoma in situ where characteristic abnormalities of both form and proliferation are present but without invasion of the underlying basement membrane that holds them in place in the tissue of origin. This earliest phase is highly curable and is detected with screening programs, such as the PAP smear for cervical cancer. Localized cancer is stage I disease where the tumor exhibits invasion and disruption of local tissues to form a primary lesion. Tumor cells then invade local lymphatics and spread to the regional (stage II) or extended regional (stage III) draining lymph nodes as secondary tumors. Finally tumor cells invade into the blood stream where characteristic patterns of blood-borne metastasis herald the onset of stage IV disease. Particular tumors vary in the extent to which they follow these phases in sequence: melanoma usually has a distinct loco-regional phase, while breast cancer is systemic from the beginning. Staging correlates with survival and provides an essential guide both to prognosis and to the design of treatment plans.
The “gold standard” for a diagnosis of cancer is a histopathological examination by a pathologist on biopsied tumortissue. Unfortunately this is not always done and the diagnosis is made from clinical findings or less. Cancer can be mimicked by many other diseases. Moreover, cancer statistics depend on the accuracy of death certificates, where cancer may not be properly noted as the cause of death. Biologic markers are playing an increasingly important role in cancer management. Most of these markers are not unique for cancer cells, but are shared also by normal cells and may also be overexpressed in benign conditions. Thus markers cannot be used to screen populations to detect cancer.
The biology of cancer has important implications for cancer control. At the cellular level the problem is faulty genetic control; cancer is basically a genetic disorder. But hereditary cancers such as retinoblastoma, are uncommon. Instead the disease is usually acquired from external influences which are, therefore, potentially avoidable. With current methods overall one can expect to prevent theoretically 2/3 but in practice more realistically 1/3 of cancer, and to be
able to cure about 1/3 in a developing country, and closer to 1/2 in a developed country.
As a lifestyle disease, cancer arises out of conditions of life which result in exposures to carcinogens. Such exposures result from two situations: * Where people live * Changes people make in the world
Cancer shows both geographic and temporal variability. There are different patterns of cancer at different places and different times. These patterns relate both to habits and to environmental hazards. Habits: The use of tobacco has resulted in lung cancer in North America and
Viruses: Hepatitis B Virus is associated with liver cancer.
Risk factors for cancer which people create by making changes in their world may be thought of as the price for industrialization. Ionizing radiation: In the latter part of the 19th century over half of certain groups of miners working in the Joachimsthal and Schneeburg mines of
These social dimensions of cancer have important implications for the design of cancer control programming. They stem from behavior patterns that people evolve to meet their biological, psychological and social needs. These patterns, in turn, create a lifestyle which influences cancer incidence. They include the development of addictions to tobacco, drugs and alcohol, the ways in which food is prepared, stored and eaten, and certain risk patterns of personal interaction as with sexual mores. With tobacco, for example, oral cancer predominates where tobacco is chewed, and lung cancer where it is smoked. The changed cancer patterns that accompany the migration of people provides an example of the influence of lifestyle on the occurrence of cancer. When Mexicans migrate to the
Biologic factors in cancer etiology refer largely to the role of four classes of external agents in carcinogenesis: physical, chemical and biological agents, and diet.
Physical Agents: * Ionizing radiation can be background from cosmic rays and earth sources of radioactivity. More important are cumulative exposures from medical diagnostic and treatment procedures, and from commercial and occupational sources. Exposures have also occurred with warfare, as in the atomic bombs dropped on Hiroshimaand Nagasaki in
Because of the widespread nature of the tobacco habit, control of carcinogenesis by chemical agents provides a major basis for cancer control. The process of carcinogenesis by chemicals is subject to both initiation and promotion steps. These carcinogens have a particular chemistry as aromatic electrophiles – chemically very reactive substances often formed as metabolic products.* Some have medicinal sources, such as the use of diethylstilbestrol in pregnancy to avert abortion resulting in vaginal cancer in the daughters.* Others come from habits such as the use of tobacco (oral and lung cancer, and other tumors) or alcohol (head and neck cancers).* Industrial and occupational exposures are also important:
Viruses are responsible for only about 5% of human cancer. But they are much more common causes of cancer in animals, where their experimental study has played a key role in the identification of oncogenes. Both DNA and RNA viruses are implicated. * Hepatitis B virus (HBV) causes primary liver cancer. Vaccination of the children of susceptible populations is used for prevention.* The Epstein Barr Virus (EBV) is implicated iasopharyngeal cancer.* The Human Papilloma Virus (HPV), especially certain subtypes like 16, are associated with cervical cancer. These viruses also cause warts, which are benign tumors. Some parasitic infections are associated with cancer.* Infections with Schistosoma haematobium (schistosomiasis) may be associated with bladder cancer. This parasite enters the skin from water infected by snails. * The liver fluke, Clonorchis sinensis, is associated with cancer of the gall bladder and hepatobiliary ducts.
As a lifestyle factor diet has been shown to play a significant role in the causation of cancer worldwide. But little is known as yet about how it plays its role as a carcinogen. This is currently a very active area of cancer research. There are several studies which show that excessive fat in the diet raises the risk of colorectal and breast cancer, and possibly other cancers as well, such as prostate cancer.
Methods of food preparation and preservation can also create risks. There are studies showing that nitrites are associated with stomach cancer. Other studies are showing that certain broad classes of foods may containprotective substances against cancer. These include certain vegetables (the cruciferous group), whole grain products (fiber) and citrus fruits.
The three major classes of external carcinogens, and perhaps to some extent diet (although how it plays its role is not yet understood), exert their effect through multiple steps involving a final common pathway – the oncogenes. The final result is malignant transformation and then the development through further genomic instability the properties of invasiveness and metastasis.
Lifestyle and the conditions in which people live determine the prevalence of environmental risk factors. Five groupings of these risk factors make up the social factors in cancer etiology.
Click here for a summary of each of the key risk factors that are implicated currently in the causation of cancer.
This slide shows the relative importance of the various risks and causes of cancer. It is based on a study of cancer mortality in the
In developing countries cancer causes about 1 in 20 deaths. The incidence is increasing as living standards improve and life expectancy is prolonged leading to a decline in communicable diseases and an increase innoncommunicable diseases.
In developed countries, cancer is second only to cardiovascular diseases as a cause of mortality and accounts for about 1/4 of all deaths. Three factors contribute to the increase in cancer mortality: *in developed countries deaths from cardiovascular diseases are declining; *the “graying” of the population means that people are living longer and cancer is more frequent in older age groups; and *increasing use of tobacco, mostly as cigarette smoking, during the past few decades has resulted in a greater incidence of related cancers, especially lung cancer. Indeed the increase in smoking in young women is resulting in a rapid rise in the incidence of lung cancer, which in some developed countries is surpassing breast cancer as the commonest cancer in women.
In contrast, perinatal disorders and infections comprise less than 10% of the mortality in developed countries, and it continues to drop.
The basis for the striking contrast in the last two slides between developing and developed countries is the transition phenomenon, which is illustrated here.
The incidence of cancer at various body sites may differ in different countries. Oral cancer is common in
Temporal trends in cancer tend to show epidemics that rise to a peak and then recede over very long time periods of decades. The long time periods hide the epidemic nature of the disease. Projections of incidence, prevalence and mortality are important for planning cancer control interventions.
Cancer impacts not only the patient, but also his or her family and community. In
The economic burden of cancer to a country is shown in this example of a study done in the
Material was taken from the lecture of:
The W.H.O. Collaborating Centre for Cancer Control was founded by Dr. Jerry in 1993 at the Tom Baker Cancer Centre in
2. PRINCIPLES OF CANCER TREATMENT
SURGICAL ONCOLOGY
Surgery is the oldest treatment for cancer and, until recently, was the only treatment that could cure patients with cancer. The surgical treatment of cancer has changed dramatically over the last several decades. Advances in surgical techniques and a better understanding of the patterns of spread of individual cancers have allowed surgeons to perform successful resections for an increased number of patients. The development of alternate treatment strategies that can control microscopic disease has prompted surgeons to reassess the magnitude of surgery necessary. The surgeon who treats cancer must be familiar with the natural history of individual cancers and with the principles and potentialities of surgery, radiation therapy, chemotherapy, immunotherapy, and other new treatment modalities. The surgeon has a central role in the prevention, diagnosis, definitive treatment, palliation, and rehabilitation of the cancer patient. The principles underlying each of these roles of the surgical oncologist are discussed in this chapter.
HISTORICAL PERSPECTIVE
Although the earliest discussions of the surgical treatment of tumors are found in the Edwin Smith papyrus from the Egyptian Middle Kingdom (about 1600 BC), the modern era of elective surgery for visceral tumors began in frontier
The treatment of most tumors depended on two subsequent developments in surgery. The first of these was the introduction of general anesthesia by two dentists, Dr. William Morton and Dr. Crawford Long. The first major operation using general ether anesthesia was an excision of the submaxillary gland and part of the tongue, performed by Dr. John Collins Warren on October 16, 1846, at the Massachusetts General Hospital. The second major development stimulating the widespread application of surgery resulted from the introduction of the principles of antisepsis by Joseph Lister in 1867. Based on the concepts of Pasteur, Lister introduced carbolic acid in 1867 and described the principles of antisepsis in an article in The Lancet in that same year. These developments freed surgery from pain and sepsis and greatly increased its use for the treatment of tumors. In the decade before the introduction of ether, only 385 operations were performed at the
Lists selected milestones in the history of surgical oncology. Although this list does not include all of the important developments, it does provide the tempo of the application of surgery to cancer treatment. [ref: 4] Major figures in the evolution ofsurgical oncology included Albert Theodore Billroth who, in addition to developing meticulous surgical techniques, performed the first gastrectomy, laryngectomy, and esophagectomy. In the 1890s, William Stewart Halsted elucidated the principles of en bloc resections for cancer, as exemplified by the radical mastectomy. Examples of radical resections for cancers of individual organs include the radical prostatectomy by Hugh Young in 1904, the radical hysterectomy by Ernest Wertheim in 1906, the abdominoperineal resection for cancer of the rectum by W. Ernest Miles in 1908, and the first successful pneumonectomy performed for cancer by Evarts Graham in 1933. Modern technical innovations continue to extend the surgeon’s capabilities. Recent examples include the development of microsurgical techniques that enable the performance of free grafts for reconstruction, automatic stapling devices, sophisticated endoscopic equipment that allows for a wide variety of “incisionless” surgery, and majorimprovements in postoperative management and critical care of patients that have extended the safety of major surgical therapy.
Critics who believe that the application of surgery has reached a plateau beyond which it will not progress should remember the words of a famous British surgeon, Sir John Erichsen, who in his introductory address to the medical institutions at University College, said, There must be a final limit to the development of manipulative surgery, the knife cannot always have fresh fields for conquest and although methods of practice may be modified and varied and even improved to some extent, it must be within a certain limit. That this limit has nearly, if not quite, been reached will appear evident if we reflect on the great achievements of modern operative surgery. Very little remains for the boldest to devise or the most dextrous to perform. These comments, published in The Lancet in 1873, preceded most important developments in modern surgical oncology.
THE OPERATION
ANESTHESIA
Modern anesthetic techniques have greatly increased the safety of major oncologic surgery. Regional and general anesthesia play important roles in a wide variety of diagnostic techniques, in local therapeutic maneuvers, and in major surgery. These techniques should be understood by all oncologists. Anesthetic techniques may be divided into regional and general anesthesia. Regional anesthesia involves a reversible blockade of pain perception by the application of local anesthetic drugs. These agents generally work by preventing the activation of pain receptors or by blocking nerve conduction. Agents commonly used for local and topical anesthesia for biopsies in cancer patients, are shown in Tables 15-2 and 15-3. [ref: 5] Topical anesthesia refers to the application of local anesthetics to the skin or mucous membranes. Good surface anesthesia of the conjunctiva and cornea, oropharynx and nasopharynx, esophagus, larynx, trachea, urethra, and anus can result from the application of these agents. Local anesthesia involves injecting anesthetic agents directly into the operative field. Field block refers to injection of local anesthetic by circumscribing the operative field with a continuous wall of anesthetic agent. Lidocaine (Xylocaine) in concentrations from 0.5% to 1% is the most common anesthetic agent used for this purpose. Results from the deposition of a local anesthetic surrounding major nerve trunks. It can provide local anesthesia to entire anatomic areas.
Major surgical procedures in the lower portion of the body can be performed using epidural or spinal anesthesia. Epidural anesthesia results from the deposition of a local anesthetic agent into the extradural space within the vertebral canal. Catheters can be left in place in the epidural space, allowing the intermittent injection of local anesthetics for prolonged operations. The major advantage of epidural over spinal anesthesia is that it does not involve puncturing the dura, and the injection of foreign substances directly into the cerebrospinal fluid is avoided. Spinal anesthesia involves the direct injection of a local anesthetic into the cerebrospinal fluid. Puncture of the dural sac generally is performed between the L-2 and L-4 vertebrae. Spinal anesthesia provides excellent anesthesia for intraabdominal operations, operations on the pelvis, or procedures involving the lower extremities. Because the patient is awake during spinal anesthesia and is breathing spontaneously, it often has been thought that spinal anesthesia is safer than general anesthesia. There is no difference in the incidence of intraoperative hypotension with spinal anesthesia compared with general anesthesia, and there is no clear benefit in using spinal anesthesia for patients with ischemic heart disease. Because patients are awake during spinal anesthesia and can become agitated during the surgical procedure, spinal anesthesia actually can cause more myocardial stress than general anesthesia. The health status of patients with preoperative evidence of congestive heart failure is more likely to be worsened by general anesthesia than by spinal anesthesia. In one series, heart failure developed de novo in 4% of adults over the age of 40 years who were undergoing major surgery, and worsened in 22% of patients who had a history of heart failure. [ref: 6] Spinal anesthesia was not associated with any new or worsened heart failure. Because of local irritating effects of general anesthesia on the lung, it has been suggested that spinal anesthesia may be safer for patients with severe pulmonary disease.
General anesthesia refers to the reversible state of loss of consciousness produced by chemical agents that act directly on the brain. Most major oncologic procedures are performed using general anesthesia, which can be induced using intravenous or inhalational agents. The advantages of intravenous anesthesia are the extremely rapid onset of unconsciousness and improved patient comfort and acceptance. Ultrashort-acting barbiturates such as sodium thiopental, or tranquilizers such as the benzodiazepines or droperidol, are the most frequently used intravenous agents for general anesthesia or for sedation during regional anesthesia. A variety of inhalational anesthetic agents are in clinical use. Nitrous oxide is popular, usually in combination with narcotics and muscle relaxants. This technique provides a safe form of general anesthesia with the use of nonexplosive agents. Two other agents in widespread use are the fluorinated hydrocarbons, halothane (Fluothane) and enflurane (Ethrane). Although they are used frequently, the fluorinated hydrocarbons have a variety of side effects. Halothane depresses myocardial function, reduces cardiac output, causes significant vasodilation, and sensitizes the myocardium to endogenous and administered catecholamines which can lead to life-threatening cardiac arrhythmias. In rare instances, halothane can cause severe hepatotoxicity, which begins 2 to 5 days after surgery. Enflurane also depresses myocardial function but does not appear to sensitize the myocardium to catecholamines and has not been associated with hepatic toxicity. The newest of the halogenated hydrocarbons is isoflurane, which was introduced in 1980. Isoflurane depresses the myocardium less than halothane or enflurane, but it has more potent vasodilatoryproperties.Virtually all general anesthetics affect biochemical mechanisms, including depression of bone marrow, alteration of the phagocytic activity of macrophages, and exhibition of immunosuppressive properties. General anesthetic agents, such as cyclopropane and diethyl ether, are rarely used because of their explosive potential.
Intravenous neuromuscular blocking agents, called muscle relaxants, are commonly used during general anesthesia. These agents are nondepolarizing (e.g., curare), preventing access of acetylcholine to the receptor site of the myoneural junction, or depolarizing (e.g., succinylcholine), acting in a manner similar to that of acetylcholine by depolarizing the motor end plate. These agents induce profound muscle relaxation during surgical procedures but have the disadvantage of inhibiting spontaneous respiration because of paralysis of respiratory muscles.Succinylcholine is short acting (3 to 5 minutes) with a rapid recovery phase. Curare-induced paralysis lasts for 30 to 40 minutes after usual clinical doses of 0.3 to 0.5 mg/kg. Pancuronium has fewer side effects than curare but can induce tachycardia by means of sympathetic stimulation.
DETERMINATION OF OPERATIVE RISK
As with any treatment, the potential benefits of surgical intervention in cancer patients must be weighed against the risks of surgery. The incidence of operative mortality is of major importance in formulating therapeutic decisions and varies greatly in different patient situations. The incidence of operative mortality is a complex function of the basic disease process that involves surgery, anesthetic technique, operative complications, and, most importantly, the general health status of patients and their ability to withstand operative trauma.
In an attempt to classify the physical status of patients and their surgical risks, the American Society of Anesthesiologists has formulated a General Classification of Physical Status that appears to correlate well with operative mortality. Patients are classified into five groups depending on their general health status.
Operative mortality usually is defined as mortality that occurs within 30 days of a major operative procedure. In oncologic patients, the basic disease process is a major determinant of operative mortality.
Patients undergoing palliative surgery for widely metastatic disease have a high operative mortality rate even if the surgical procedure can alleviate the symptomatic problem. Examples of these situations include surgery for intestinal obstruction in patients with widespread ovarian cancer and surgery for gastric outlet obstruction in patients with cancer of the head of the pancreas. These simple palliative procedures are associated with mortality rates of about 20% in most series because of the debilitated state of the patient and the rapid progression of the basic disease.
Mortality caused by anesthetic administration alone is related directly to the physical status of the patient. In a review of 32,223 operations, Dripps and colleagues determined the mortality thought to be related to anesthetic administration alone. It is extremely difficult to differentiate the mortality caused by anesthesia from that resulting from other contributors to operative mortality. However, this analysis indicates that operative mortality due to anesthesia in physical status class 1 patients is extremely low, less than 1 in every 16,000 operations. The anesthetic mortality increased with worsened physical status.
There is considerable evidence that anesthesia-related mortality has decreased in the past two decades, largely because of the development of rigid practice standards and improved intraoperative monitoring techniques. A summary of the specific intraoperative monitoring methods used to achieve improved anesthetic safety is presented in Table 15-7. A study of 485,850 anesthetics administered in 1986 in the United Kingdom revealed the risk of death from anesthesia alone in patients from all ASA classes to be approximately 1 in 185,000. [ref: 9] In a retrospective review encompassing cases from 1976 through 1988, Eichorn estimated anesthetic mortality in ASA class I and II patients to be 1 in 200,200. [ref: 10] These are probably underestimates since underreporting of anesthetic related deaths is a problem in all studies. Most cancer patients undergoing elective surgery fall between physical status I and II; thus, an anesthetic mortality rate of 0.01 to 0.001% is a realistic estimate for this group.
Anesthesia-related mortality is rare, and factors related to the patient’s preexisting general health status and disease are far more important indicators of surgical outcome. A study of the factors contributing to the risk of 7-day operative mortality following 100,000 surgical procedures is shown in Table 15-8. [ref: 13] The 7-dayperioperative mortality in this study was 71.4 deaths per 10,000 cases, and the major determinants of death were the physical status of the patient, the emergent nature of the procedure, and the magnitude of the operation.
Several specific health factors can increase the risks of the operative procedure. Using discriminant analysis, Goldman and colleagues identified nine independent variables that correlated with life-threatening and fatal cardiac complications in patients undergoing noncardiac surgical procedures. By assigning a point value to each variable, a Cardiac Risk Index could be computed.
That separated patients into four categories of risk. The two risk factors most predictive of life threatening complications were the presence of a third heart sound (S(3)) or jugular vein distention (11 points) or a myocardial infarction in the previous 6 months (10 points). A recent myocardial infarction significantly increases the incidence of reinfarction and cardiac death associated with surgery. Significant improvements have occurred as new techniques of anesthetic monitoring and hemodynamic support have been developed.
The impact of general health status on operative mortality is seen when operative mortality as a function of age is analyzed. Palmberg and colleagues studied the postoperative mortality of 17,199 patients undergoing general surgical procedures. The overall mortality rate of patients under 70 years was 0.25%, compared with 9.2% for patients over 70 years. In these elderly patients, the operative mortality rate for emergency operations was 36.8%, compared with 7.8% for elective surgical procedures. The four leading causes of operative mortality that accounted for about 75% of all postoperative deaths in this age group were pulmonary embolism, pneumonia, cardiovascular collapse, and the primary illness itself.
More recently, Hoskings and colleagues reviewed the outcome of surgery performed on 795 patients 90 years of age or older. [ref: 18] Surgery was generally well tolerated. As with younger patients, the American Society of Anesthesiology classification was an important predictor of outcome.
Cancer is often a disease of the elderly, and there is sometimes a tendency to avoid even curative major surgery for cancer in patients of advanced age. In the
ROLES FOR SURGERY
PREVENTION OF CANCER
Because surgeons are often the primary providers of medical care, they are responsible for educating patients about carcinogenic hazards and about direct surgical intervention for the prevention of cancer. All surgical oncologists should be aware of the high-risk situations that require surgery to prevent subsequent malignant disease. Underlying conditions or congenital or genetic traits are associated with an extremely high incidence of subsequent cancer. When these cancers are likely to occur in nonvital organs, it is necessary to remove the offending organ to prevent subsequent malignancy. Examples of diseases associated with a high incidence of cancer that can be prevented by prophylactic surgery. An excellent example is presented by patients with the genetic trait for multiple polyposis of the colon. If colectomy is not performed in these patients, about half will develop colon cancer by the age of 40. By the age of 70, virtually all patients with multiple polyposis will develop colon cancer. It is therefore advisable for all patients containing the mutant gene for multiple polyposis to undergo prophylactic colectomy before the age of 20 to prevent these cancers.
In this situation, as for many of the other familial conditions associated with a high incidence of cancer, the surgeon has a responsibility for alerting the family to the hereditary nature of the disorder and its possible occurrence in other family members. Another disease associated with a high incidence of cancer of the colon is ulcerative colitis. About 40% of patients with total colonic involvement ultimately die of colon cancer if they survive the ulcerative colitis. Three percent of children with ulcerative colitis develop cancer of the colon by the age of 10, and 20% develop cancer during each ensuing decade. Colectomy is indicated for patients with ulcerative colitis if the chronicity of this disease is well established.
Other disorders that require early treatment to prevent subsequent cancers include cryptorchidism and multiple endocrine neoplasia. Cryptorchidism is associated with a high incidence of testicular cancer that probably can be prevented by early prophylactic surgery.
In the past, patients with multiple endocrine neoplasia type IIA (MEN IIA) were screened for the presence of C-cell hyperplasia and calcitonin secretion using pentagastrin stimulation tests to determine the possible need for prophylactic surgery to prevent the occurrence of medullary thyroid cancer. Recent studies using PCR-based direct DNA testing for mutations in the RET protooncogene have shown it to be the preferred method for screening MEN IIA kindreds to identify individuals in whom total thyroidectomy is indicated, regardless of the plasma calcitoninlevels.
A more complex example of the role of surgery in cancer prevention involves women at high risk for breast cancer. Because the risk of cancer in some women is increased substantially over the normal risk (but does not approach 100%), counseling is required. Women in this situation must carefully balance the benefits and risks of prophylactic mastectomy. A careful understanding of the factors involved in increased breast cancer incidence is essential for the surgical oncologist to provide sound advice in this area. Statistical techniques can provide approximations of the risk for patients depending on the frequency of disease in the family history, the age at the first pregnancy, and the presence of fibrocystic disease. For example, a woman with a family history of breast cancer in a sister or mother, who has fibrocystic disease, and is nulliparous or had a first pregnancy at a late age has an 18% probability of developing breast cancer over a 5-year period. [ref: 20] These estimates can be of value in advising women about prophylactic mastectomy.
DIAGNOSIS OF CANCER
The major role of surgery in the diagnosis of cancer lies in the acquisition of tissue for exact histologic diagnosis. The principles underlying the biopsy of malignant lesions vary depending on the natural history of the tumor under consideration. Various techniques exist for obtaining tissues suspected of malignancy, including aspiration biopsy, needle biopsy, incisional biopsy, and excisional biopsy.
Aspiration biopsy involves the aspiration of cells and tissue fragments through a needle that has been guided into the suspect tissue. Cytologic analysis of this material can provide a tentative diagnosis of the presence of malignant tissue. However, major surgical resections should not be undertaken solely on the basis of the evidence of aspiration biopsy. Even the most experienced cytologist can mistake inflammatory or benign reparative changes for malignant
cells. This error is inherent in the uncertainties of an individual cell analysis and, even in the best of hands, provides an error rate substantially higher than that of standard histologic diagnosis.
Needle biopsy refers to obtaining a core of tissue through a specially designed needle introduced into the suspect tissue. The core of tissue provided by needle biopsies is sufficient for the diagnosis of most tumor types. Soft tissue and bony sarcomas often present major difficulties in differentiating benign and reparative lesions from malignancies and often cannot be diagnosed accurately. If these latter lesions are considered in the diagnosis, attempts should be made to obtain larger amounts of tissue than are possible from a needle biopsy.
Incisional biopsy refers to removal of a small wedge of tissue from a larger tumor mass. Incisional biopsies often are necessary for diagnosing large masses that require major surgical procedures for even local excision. Incisionalbiopsies are the preferred method of diagnosing soft tissue and bony sarcomas because of the magnitude of the surgical procedures necessary to extirpate these lesions definitively. The treatment of many visceral cancers cannot be undertaken without an incisional biopsy, but be aware of opening new tissue planes contaminated with tumor by performing excisional biopsies for large lesions. An inappropriately performed excisional biopsy can compromise subsequent surgical excision. When this is a possibility, incisional biopsies should be performed.
In excisional biopsy, an excision of the entire suspected tumor tissue with little or no margin of surrounding normal tissue is done. Excisional biopsies are the procedure of choice for most tumors if they can be performed without contaminating new tissue planes or further compromising the ultimate surgical procedure.
The following principles guide the performance of all surgical biopsies:
1. Needle tracks or scars should be placed carefully so that they can be conveniently removed as part of the subsequent definitive surgical procedure. Placement of biopsy incisions is extremely important, and misplacement often can compromise subsequent care. Incisions on the extremity generally should be placed longitudinally so as to make the removal of underlying tissue and subsequent closure easier.
2. Care should be takeot to contaminate new tissue planes during the biopsy. Large hematomas after biopsy can lead to tumor spread and must be scrupulously avoided by securing excellent hemostasis during the biopsy. For biopsies on extremities, the use of a tourniquet may help in controlling bleeding. Instruments used in a biopsy procedure are another potential source of contamination of new tissue planes. It is not uncommon to take biopsy samples from several suspected lesions at one time. Care should be takeot to use instruments that may have come in contact with tumor when obtaining tissue from a potentially uncontaminated area.
3. Choice of biopsy technique should be selected carefully to obtain an adequate tissue sample for the needs of the pathologist. For the diagnosis of selected tumors, electron microscopy, tissue culture or other techniques may be necessary. Sufficient tissue must be obtained for these purposes if diagnostic difficulties are anticipated.
4. Handling of the biopsy tissue by the pathologist is also important. When the orientation of the biopsy specimen is important for subsequent treatment, the surgeon should mark distinctive areas of the tumor carefully to facilitate subsequent orientation of the specimen by the pathologist. Different fixatives are best for different types or sizes of tissue. If all biopsy specimens are placed in formalin immediately, the opportunity to perform valuable diagnostic tests may be lost. The handling of excised tissue is the surgeon’s responsibility. Biopsy tissue obtained from breast cancer lesions, for example, should be saved for estrogen receptor studies and placed in cold storage until ready for processing.
Surgery also has a role in diagnosing pathologic states in cancer patients that do not directly involve the diagnosis of cancer. Cancer patients often are immunosuppressed by their disease or their treatment and are subject to opportunistic infections not commonly seen in most general surgical patients. Open lung or liver biopsies are often important in diagnosing these lesions adequately and in planning suitable therapy.
Oncologists are becoming increasingly aware of the need for precise staging of patients when planning treatment. Lack of proper staging information can lead to poor treatment planning and compromise the ability to cure patients. Staging laparotomy can be important in determining the exact extent of spread of lymphomas.
In performing accurate surgical staging, the surgeon must be familiar with the natural history of the disease under consideration. The development of ovarian cancer treatment is an excellent example. The tendency of ovarian cancer to metastasize to the undersurface of the diaphragm is a good example of the need to biopsy an anatomic site that would not normally be biopsied by most surgeons. Extensive surgical staging may be required before undertaking other major surgical procedures with curative intent. For example, biopsy of the celiac and paraaortic lymph nodes in patients with cancer of the esophagus is often important so that unnecessary esophageal resections can be avoided.
Placement of radioopaque clips during biopsy and staging procedures is important to delineate areas of known tumor and as a guide to the subsequent delivery of radiation therapy to these areas.
TREATMENT OF CANCER
Surgery can be a simple, safe method to cure patients with solid tumors when the tumor is confined to the anatomic site of origin. Unfortunately, when patients with solid tumors present to the physician for the first time, about 70% already have micrometastases beyond the primary site. The extension of the surgical resection to include areas of regional spread can cure some of these patients, although regional spread often is an indication of undetectable distant micrometastases.
The emergence of effective nonsurgical therapies has had profound impact on the treatment of cancer patients and on the role and responsibilities of the surgeon treating the cancer patient. John Hunter, a brilliant 18th-century surgeon, characterized surgery as being “like an armed savage who attempts to get that by force which a civilized man would get by strategem.”
Although surgery continues to be the most important aspect of the treatment of most patients presenting with solid tumors, modern clinical research in oncology has been devoted to applying other adjuvant “strategems” to improve the cure rates of those 70% who ultimately fail surgical therapy alone.
The role of surgery in the treatment of cancer patients can be divided into six separate areas. In each area, interactions with other treatment modalities can be essential for a successful outcome. Definitive surgical treatment for primary cancer, selection of appropriate local therapy, and integration of surgery with other adjuvant modalities. Surgery to reduce the bulk of residual disease (Examples: Burkitt’s lymphoma, ovarian cancer)
Surgical resection of metastatic disease with curative intent (examples: pulmonary metastases in sarcoma patients, hepatic metastases from colorectal cancer)
Surgery for the treatment of oncologic emergencies
Surgery for palliation
Surgery for reconstruction and rehabilitation
Surgery for Primary Cancer
There are three major challenges confronting the surgical oncologist in the definitive treatment of solid tumors:
Accurate identification of patients who can be cured by local treatment alone
Development and selection of local treatments that provide the best balance between local cure and the impact of treatment morbidity on the quality of life
Development and application of adjuvant treatments that can improve the control of local and distant invasive and metastatic disease
The selection of the appropriate local therapy to be used in cancer treatment varies with the individual cancer type and the site of involvement. In many instances, definitive surgical therapy that encompasses a sufficient margin of normal tissue is sufficient local therapy. The treatment of many solid tumors falls into this category, including the wide excision of primary melanomas in the skin that can be cured locally by surgery alone in about 90% of cases. The resection of colon cancers with a 5-cm margin from the tumor results in anastomotic recurrences in less than 5% of cases.
In other instances, surgery is used to obtain histologic confirmation of diagnosis, but primary local therapy is achieved through the use of a nonsurgical modality such as radiation therapy. Examples include the treatment of
The magnitude of surgical resection is modified in the treatment of many cancers by the use of adjuvant treatment modalities. Rationally integrating surgery with other treatments requires a careful consideration of all effective treatment options. The surgical oncologist must be thoroughly familiar with adjuncts and alternatives to surgical treatment. It is a knowledge of this rapidly changing field that separates the surgical oncologist from the general surgeon most distinctly.
In some instances, effective adjuvant modalities have led to a decrease in the magnitude of surgery. The evolution of childhood rhabdomyosarcoma treatment is a striking example of the successful integration of adjuvant therapies with surgery in the treatment of cancer.
Childhood rhabdomyosarcoma is the most common soft tissue sarcoma in infants and children. Before 1970, surgery alone was used almost exclusively, and 5-year survival rates of 10% to 20% were commonly reported. Local surgery alone failed in patients with rhabdomyosarcomas of the prostate and extremities because of extensive invasion of surrounding tissues and the early development of metastatic disease. The failure of surgery alone to control local disease in patients with childhood rhabdomyosarcoma led to the introduction of adjuvant radiation therapy. This resulted in a marked improvement in local control rates that was further improved dramatically by the introduction of combination chemotherapy with vincristine, dactinomycin, and cyclophosphamide. Long-term cure rates are in the range of 80%. Many other examples of the integration of surgery with other treatment modalities appear throughout this book.
Surgery for Residual Disease
The concept of cytoreductive surgery has received much attention in recent years. In some instances, the extensive local spread of cancer precludes the removal of all gross disease by surgery. The surgical resection of bulk disease in the treatment of selected cancers may well lead to improvements in the ability to control residual gross disease that has not been resected. Studies that suggest the merit of this approach are discussed in Chapters 44 and 35 (Burkitt’s lymphoma and ovarian cancer, respectively).
Enthusiasm for cytoreductive surgery has led to the inappropriate use of surgery for reducing the bulk of tumor in some cases. Clearly, cytoreductive surgery is of benefit only when other effective treatments are available to control the residual disease that is unresectable. Except in rare palliative settings, there is no role for cytoreductive surgery in patients in whom little other effective therapy exists.
Surgery for Metastatic Disease
The value of surgery in the cure of patients with metastatic disease tends to be overlooked. As a general principle, patients with a single site of metastatic disease that can be resected without major morbidity should undergo resection of that metastatic cancer. Many patients with few metastases to lung or liver or brain can be cured by surgical resection. This approach is especially true for cancers that do not respond well to systemic chemotherapy. The resection of pulmonary metastases in patients with soft tissue and bony sarcomas can cure as many as 30% of patients. As effective systemic therapy is developed for the treatment of these diseases, cure rates may increase. Studies have shown that similar cure rates occur in patients with adenocarcinomas when resected metastatic disease to the lung is the sole clinical site of metastases. Small numbers of pulmonary metastases often are the only clinically apparent metastatic disease in patients with sarcomas. However, this is rare in the natural history of most adenocarcinomas. If solitary metastases to the lung do occur in patients with carcinoma of the colon or other adenocarcinomas, then surgical resection is indicated.
Similarly, there is increasing enthusiasm for the resection of hepatic metastases, especially from colorectal cancer, in patients in whom the liver is the only site of known metastatic disease. In patients with solitary hepatic metastases from colorectal cancer, resection can lead to long-term cure in about 25% of patients. This far exceeds the cure rates of any other available treatment.
The resection for cure of solitary brain metastases should also be considered when the brain is the only site of known metastatic disease. The exact location and functional sequelae of resection should be considered when making this treatment decision.
SURGERY FOR ONCOLOGIC EMERGENCIES
As in the treatment of all patients, emergencies arise for oncologic patients that require surgical intervention. These generally involve the treatment of exsanguinating hemorrhage, perforation, drainage of abscesses, or impending destruction of vital organs. Each category of surgical emergency is unique and requires an individual approach. The oncologic patient often is neutropenic, thrombocytopenic, and has a high risk of hemorrhage or sepsis. Perforations of an abdominal viscus can result from direct tumor invasion or from tumor lysis resulting from effective systemic treatments. Perforation of the gastrointestinal tract after effective treatment for lymphoma involving the intestine is not uncommon. The ability to identify patients at high risk for perforation may lead to the use of surgery to prevent this problem. Surgery to decompress cancer invading the central nervous system represents another surgical emergency that can lead to preservation of function.
Surgery for Palliation
Surgical resection often is required for the relief of pain or functional abnormalities. The appropriate use of surgery in these settings can improve the quality of life for cancer patients. Palliative surgery may include the relief of mechanical problems such as intestinal obstruction or the removal of masses that are causing severe pain or disfigurement.
Surgery for Reconstruction and Rehabilitation
Surgical techniques are being refined that aid in the reconstruction and rehabilitation of cancer patients after definitive therapy. The ability to reconstruct anatomic defects can substantially improve function and cosmetic appearance. The development of free flaps using microvascular anastomotic techniques is having a profound impact on the ability to bring fresh tissue to resected or heavily irradiated areas. Loss of function (especially of extremities) often can be rehabilitated by surgical approaches. This includes lysis of contractures or muscle transposition to restore muscular function that has been damaged by previous surgery or radiation therapy.
RADIATION THERAPY
To understand the practice of radiation therapy, one must seek its roots in principles derived from three separate areas. The first is practical radiation physics. This must be understood much as the surgeon understands the use of the equipment available in the operating room and as the internist understands the pharmacologic basis of therapeutics. The basic concepts of physics necessary to consider radiation therapy in the disease-related chapters are introduced in this chapter.
The second important discipline to be understood is cell, tissue, and tumor biology. This chapter describes the fundamental principles of radiation biology and cell kinetics; cell kinetics in relation to chemotherapy and radiation therapy. These two discussions provide the rudiments of cell biology necessary to understand the uses of radiation.
A large clinical experience in radiation use has resulted in certain principles of treatment. These are discussed separately and related to the physical and biologic concepts that may underlie their success.
PHYSICAL CONSIDERATIONS
Only the most important concepts of the physics of ionizing radiation can be discussed in this chapter. If more detailed information is needed, a standard textbook of radiation physics is a more appropriate source of information.
Ionizing radiation is energy that, during absorption, causes the ejection of an orbital electron. A large amount of energy is associated with ionization. Ionizing radiation can be electromagnetic or particulate, and electromagnetic radiation can be considered as a wave and as a packet of energy (a photon). It is the particulate nature of electromagnetic radiation that explains much of its biologic activity. The packet of energy is large enough to cause ionizations, and these are distributed unevenly through tissue. Examples of particulate radiation are the subatomic particles: electrons, protons, alpha particles, neutrons, negative pi mesons, and atomic nuclei. All of these have been experimentally considered or are being used in radiation therapy.
ELECTROMAGNETIC RADIATION
Electromagnetic radiation consists of roentgen and gamma radiation. They differ only in the way in which they are produced: gamma rays are produced intranuclearly, and roentgen rays are produced extranuclearly. In practice, this means that gamma rays used in radiation therapy are produced by the decay of radioactive isotopes and that almost all of the roentgen rays used in radiation therapy are made by electrical machines. Exceptions are roentgen rays produced by orbital electron rearrangements, as in the decay of iodine 125 (**125I), which is a radioactive isotope but produces photons by extranuclear processes. **125I also emits a small number of gamma rays from the nucleus.
The intensity of electromagnetic radiation dissipates as the inverse square of the distance from the source. The dose of radiation 2 cm from a point source is 25% of the dose at 1 cm. The relative prevalence of the three dominant absorption mechanisms of electromagnetic radiation depends on the energy of the radiation. The first is photoelectric absorption, which predominates at lower energies. In this circumstance, the photon interaction results in the ejection of a tightly bound orbital electron. The vacancy left in the atomic shell is then filled by another electron falling from an outer shell of the same atom or from outside the atom. All or most of the photon energy of the transition is lost in this process. Photoelectric absorption varies with the cube of the atomic number (Z**3). This has significant practical implications because it explains why materials with high atomic numbers, such as lead, are such effective shielding materials. It also means that bones absorb significantly more radiation than soft tissues at lower photon energies, the basis for conventional diagnostic radiology.
The second type of radiation absorption is the
The third type of absorption is the pair production process. This type of absorption requires an incident photon energy greater than 1.02 MeV. In this process, positive and negative electrons are produced at the same time.
The fundamental quantity necessary to describe the interaction of radiation with matter is the amount of energy absorbed per unit mass. This quantity is called absorbed dose, and the rad was the most commonly used unit. Absorbed dose is measured in joules per kilogram; another name for 1 joule/kg is the Gray (1 Gray = 100 rad), which is now the recommended unit. The roentgen (R) is a unit of roentgen rays or gamma rays based on the ability of radiation to ionize air. At the energies used in radiation therapy, 1 R of roentgen rays or gamma rays results in a dose of somewhat less than 1 rad (0.01 Gy) in soft tissue.
The different ranges of electromagnetic radiations used in clinical practice are superficial radiation or roentgen rays from about 10 to 125 KeV; orthovoltage radiation or electromagnetic radiation between 125 and 400 KeV; and supervoltage or megavoltage radiation for energies above 400 KeV. There are important differences between these classes. As energy increases, the penetration of the roentgen rays increases (Fig. 16-1), and at supervoltage energies, absorption in bone is not higher than that in surrounding soft tissues, as is the case with lower energies. This is because at supervoltage energies, Compton absorption predominates. Compared with orthovoltage, supervoltageradiation is skin sparing, meaning that the maximum dose is not reached in the skin but instead occurs below the surface. The electrons created in the interaction travel some distance and do not attain full intensity until they reach some depth, resulting in a reduced dose to the skin. With orthovoltage radiation, the skin frequently is the dose-limiting normal tissue.
RADIATION TECHNIQUES
Two general types of radiation techniques are used clinically — brachytherapy and teletherapy.
In brachytherapy, the radiation device is placed within or close to the target volume. Examples of this are interstitial and intracavitary radiation used in the treatment of many gynecologic and oral tumors. Teletherapy uses a device located at a distance from the patient, as is the case in most orthovoltage or supervoltage machines.
Because the radiation source is close to or within the target volume with brachytherapy, the dose is determined largely by inverse-square considerations. This means that the geometry of the implant is important. Spatial arrangements have been determined for different types of applications based on the particular anatomic considerations of the tumor and important normal tissues. An example of isodose distribution around anintracavitary application for carcinoma of the cervix is shown in Figure 16-2. The dose decreases rapidly as the distance from the applicator increases. This emphasizes the importance of proper placement. The applicator pictured is used to treat the cervix, uterus, and important paracervical tissues, while limiting excessive irradiation of the bladder and rectum in front of and behind the tumor.
Historically, the removable interstitial and intracavitary sources used were radium and radon, the latter primarily for permanent implants. Marie Curie, the discoverer of radium, recognized its importance early and championed the medical use of these isotopes. They were important tools in early cancer therapy but now have been largely replaced by manmade isotopes, which overcome most of the disadvantages of the naturally occurring ones.
Initially, even removable isotopes were used by directly applying the isotope, and thereby exposing the operator to significant radiation doses. This problem has largely been circumvented through the use of **137Cs, **192Ir, and **60Co. The first two have a lower energy and are much easier to shield. Afterloading techniques are used for removable implants as often as possible. Receptacles for the radioactive material are placed in the patient in the form of needles, tubes, or intracavitary applicators. When they have been satisfactorily placed they areafterloaded with the radiation sources. Permanent implants are primarily done today with **198Au and **125I. The latter is also used for removable implants. Its low energy makes shielding a simple matter.
Teletherapy isodose depends on inverse-square considerations and tissue absorption. The distribution of radiation depends on characteristics of the machine and the patient. The isodose curve depends on the energy of radiation, the distance from the source of radiation, and the density and atomic number of the absorbing material. The beam of radiation produced in typical radiation treatment may be modified to make isodose distributions conform to the specific target volume, and individually designed shields are used to protect vital normal tissues.
SURVIVAL CURVES
Survival curves plot the fraction of cells surviving radiation against the dose given. Survival is determined by the ability to form a macroscopic colony. The simplest relation can be seen for bacteria in which survival is a constant exponential function of dose. The importance of this exponential relation is that for a given dose increment, a constant proportion, rather than a constant number, of cells is killed. Because of the randomness of radiation damage, if there is on average one lethal lesion per cell, some cells have one lesion, some more than one, and some less than one. Under such circumstances, the proportion of cells that have less than one, that is, no lethal events, is e/**1, or a survival fraction of 0.37. The dose required to reduce the survival fraction to 37% on the exponential curve is known as the D(o). This term is related to the slope of the exponential survival curve. If a smaller dose is required to reduce the survival fraction to 37%, the cells are more sensitive to radiation.
Chemotherapy
Chemotherapy is the use of anticancer drugs to treat cancerous cells. Chemotherapy has been used for many years and is one of the most common treatments for cancer. In most cases, chemotherapy works by interfering with the cancer cell’s ability to grow or reproduce. Different groups of drugs work in different ways to fight cancer cells. Chemotherapy may be used alone for some types of cancer or in combination with other treatments such as radiation or surgery. Often, a combination of chemotherapy drugs is used to fight a specific cancer. Certain chemotherapy drugs may be given in a specific order depending on the type of cancer it is being used to treat. While chemotherapy can be quite effective in treating certain cancers, chemotherapy drugs reach all parts of the body, not just the cancer cells. Because of this, there may be many side effects during treatment. Being able to anticipate these side effects can help you and your caregivers prepare, and, in some cases prevent these symptoms from occurring.
How is chemotherapy administered?
Chemotherapy can be given:
- as a pill to swallow.
- as an injection into the muscle or fat tissue.
- intravenously (directly to the bloodstream; also called IV).
- topically (applied to the skin)
- directly into a body cavity
What are some of the chemotherapy drugs and their potential side effects?
There are over 50 chemotherapy drugs that are commonly used. The following table gives examples of some chemotherapy drugs and their various names. It lists some of the cancer types but not necessarily all of the cancers for which they are used, and describes various side effects. Side effects may occur just after treatment (days or weeks) or they may occur later (months or years) after the chemotherapy has been given. The side effects list provided below do not comprise an all-inclusive list. Other side effects are possible.
As each person’s individual medical profile and diagnosis is different, so is his/her reaction to treatment. Side effects may be severe, mild, or absent. Be sure to discuss with your cancer care team any/all possible side effects of treatment before the treatment begins.
|
Chemotherapy Drug |
Possible Side Effects |
|
carboplatin (Paraplatin) › usually given intravenously (IV) |
› decrease in blood cell counts |
|
cisplatin (Platinol, Platinol-AQ) › usually given intravenously (IV) |
› decrease in blood cell counts |
|
cyclophosphamide (Cytoxan, Neosar) › can be given intravenously (IV) or orally |
› decrease in blood cell counts |
|
doxorubicin (Adriamycin) › given intravenously (IV) |
› decrease in blood cell counts |
|
etoposide (VePesid) › can be given intravenously (IV) or orally |
› decrease in blood cell counts |
|
fluorouracil (5-FU) › given intravenously (IV) |
› decrease in blood cell counts |
|
gemcitabine (Gemzar) › given intravenously (IV) |
› decrease in blood cell counts |
|
irinotecan (Camptosar) › given intravenously (IV) |
› decrease in blood cell counts |
|
methotrexate › may be given intravenously (IV), intrathecally (into the spinal column), or orally |
› decrease in blood cell counts |
|
paclitaxel (Taxol) › given intravenously (IV) |
› decrease in blood cell counts |
|
topotecan (Hycamtin) › given intravenously (IV) |
› decrease in blood cell counts |
|
vincristine › usually given intravenously (IV) |
› numbness or tingling in the fingers or toes |
|
vinblastine (Velban) › given intravenously (IV) |
› decrease in blood cell counts |
Biological Therapy For Cancer Treatment
Biological therapy (also called immunotherapy, biological response modifier therapy, or biotherapy) uses the body’s immune system to fight cancer. The cells, antibodies, and organs of the immune system work to protect and defend the body against foreign invaders, such as bacteria or viruses. Physicians and researchers have found that the immune system might also be able to both determine the difference between healthy cells and cancer cells in the body, and to eliminate the cancer cells.
Biological therapies are designed to boost the immune system, either directly or indirectly, by assisting in the following:
- making cancer cells more recognizable by the immune system, and therefore more susceptible to destruction by the immune system
- boosting the killing power of immune system cells
- changing the way cancer cells grow, so that they act more like healthy cells
- stopping the process that changes a normal cell into a cancerous cell
- enhancing the body’s ability to repair or replace normal cells damaged or destroyed by other forms of cancer treatment, such as chemotherapy or radiation
- preventing cancer cells from spreading to other parts of the body
How does the immune system fight cancer? The immune system includes different types of white blood cells – each with a different way to fight against foreign or diseased cells, including cancer:
- lymphocytes – white blood cells, including B cells, T cells, and NK cells.
B cells – produce antibodies that attack other cells.
T cells – directly attack cancer cells themselves and signal other immune system cells to defend the body.
natural killer cells (NK cells) – produce chemicals that bind to and kill foreign invaders in the body.
monocytes – white blood cells that swallow and digest foreign particles.
These types of white blood cells – B cells, T cells, natural killer cells, and monocytes – are in the blood and thus circulate to every part of the body, providing protection from cancer and other diseases. Cells secrete two types of substances: antibodies and cytokines. Antibodies respond to (harmful) substances that they recognize, called antigens. Specific (helpful) antibodies match specific (foreign) antigens by locking together. Cytokines are proteins produced by some immune system cells and can directly attack cancer cells. Cytokines are “messengers” that “communicate” with other cells.
What are the different types of biological therapies?
There are many different types of biological therapies used in cancer treatment, including the following:
- nonspecific immunomodulating agents. Nonspecific immunomodulating agents are biological therapy drugs that stimulate the immune system, causing it to produce more cytokines and antibodies to help fight cancer and infections in the body. Fighting infection is important for a person with cancer.
- biological response modifiers (BRMs). Biological response modifiers (BRMs) change the way the body’s defenses interact with cancer cells. BRMs are produced in a laboratory and given to patients to:
- boost the body’s ability to fight the disease.
- direct the immune system’s disease fighting powers to disease cells.
- strengthen a weakened immune system.
BRMs include interferons, interleukins, colony-stimulating factors, monoclonal antibodies, cytokine therapy, and vaccines:
- interferons (IFN)
Interferons (IFN) are a type of biological response modifier that naturally occurs in the body. They are also produced in the laboratory and given to cancer patients in biological therapy. They have been shown to improve the way a cancer patient’s immune system acts against cancer cells. Interferons may work directly on cancer cells to slow their growth, or they may cause cancer cells to change into cells with more normal behavior. Some interferons may also stimulate natural killer cells (NK) cells, T cells, and macrophages – types of white blood cells in the bloodstream that help to fight cancer cells. - interleukins (IL)
Interleukins (IL) stimulate the growth and activity of many immune cells. They are proteins (cytokines) that occur naturally in the body, but can also be made in the laboratory. Some interleukins stimulate the growth and activity of immune cells, such as lymphocytes, which work to destroy cancer cells - colony-stimulating factors (CSFs)
Colony-stimulating factors (CSFs) are proteins given to patients to encourage stem cells within the bone marrow to produce more blood cells. The body constantly needs new white blood cells, red blood cells, and platelets, especially when cancer is present. CSFs are given, along with chemotherapy, to help boost the immune system. When cancer patients receive chemotherapy, the bone marrow’s ability to produce new blood cells is suppressed, making patients more prone to developing infections. Parts of the immune system cannot function without blood cells, thus colony-stimulating factors encourage the bone marrow stem cells to produce white blood cells, platelets, and red blood cells. With proper cell production, other cancer treatments can continue enabling patients to safely receive higher doses of chemotherapy. - monoclonal antibodies. Monoclonal antibodies are agents, produced in the laboratory, that bind to cancer cells. When cancer-destroying agents are introduced into the body, they seek out the antibodies and kill the cancer cells. Monoclonal antibody agents do not destroy healthy cells.
- cytokine therapy. Cytokine therapy uses proteins (cytokines) to help your immune system recognize and destroy those cells that are cancerous. Cytokines are produced naturally in the body by the immune system, but can also be produced in the laboratory. This therapy is used with advanced melanoma and with adjuvant therapy (therapy given after or in addition to the primary cancer treatment). Cytokine therapy reaches all parts of the body to kill cancer cells and prevent tumors from growing.
- vaccine therapy. Vaccine therapy is still an experimental biological therapy. The benefit of vaccine therapy has not yet been proven. With infectious diseases, vaccines are given before the disease develops. Cancer vaccines, however, are given after the disease develops, when the tumor is small. Scientists are testing the value of vaccines for melanoma and other cancers. Sometimes, vaccines are combined with other therapies such as cytokine therapy.
Side effects of biological therapies. As each person’s individual medical profile and diagnosis is different, so is his/her reaction to treatment. Side effects may be severe, mild, or absent. Be sure to discuss with your cancer care team any/all possible side effects of treatment before the treatment begins. Side effects of biological therapy, which often mimic flu-like symptoms, vary according to the type of therapy given and may include the following:
- fever
- chills
- nausea
- vomiting
- loss of appetite
- fatigue
Specifically, cytokine therapy often causes fever, chills, aches, and fatigue. Other side effects include a rash or swelling at the injection site. Therapy can cause fatigue and bone pain and may affect blood pressure.
Hormone Therapy For Cancer Treatment
Hormones are chemicals produced by glands, such as the ovaries and testicles. Hormones help some types of cancer cells to grow, such as breast cancer and prostate cancer. In other cases, hormones can kill cancer cells, make cancer cells grow more slowly, or stop them from growing. Hormone therapy as a cancer treatment may involve taking medications that interfere with the activity of the hormone or stop the production of the hormones. Hormone therapy may involve surgically removing a gland that is producing the the hormones.
How does hormone therapy work? Your physician may recommend a hormone receptor test to help determine treatment options and to help learn more about the tumor. This test can help to predict whether the cancer cells are sensitive to hormones. The hormone receptor test measures the amount of certain proteins (called hormone receptors) in cancer tissue. Hormones (such as estrogen and progesterone that naturally occur in the body) can attach to these proteins. If the test is positive, it is indicating that the hormone is probably helping the cancer cells to grow. In this case, hormone therapy may be given to block the way the hormone works and help keep the hormone away from the cancer cells (hormone receptors). If the test is negative, the hormone does not affect the growth of the cancer cells, and other effective cancer treatments may be given.
If the test indicates that the hormones are affecting your cancer, the cancer may be treated in one of following ways:
- treating cancer cells to keep them from receiving the hormones they need to grow
- treating the glands that produce hormones to keep them from making hormones
- surgery to remove glands that produce the hormones, such as the ovaries that produce estrogen, or the testicles that produce testosterone
The type of hormone therapy a person receives depends upon many factors, such as the type and size of the tumor, the age of the person, the presence of hormone receptors on the tumor, and other factors.
Your physician may prescribe hormone therapies before some cancer treatments or after other cancer treatments. If hormone therapy is given before the primary treatment, it is called neoadjuvant treatment. Neoadjuvant treatments help to kill cancer cells and contribute to the effectiveness of the primary therapy. If hormone therapy is given after the primary cancer treatment, it is called adjuvant treatment. Adjuvant therapy is given to improve the chance of a cure.
With some cancers, patients may be given hormone therapy as soon as cancer is diagnosed, and before any other treatment. It may shrink a tumor or it may halt the advance of the disease. And in some cancer, such as prostate cancer, it is helpful in alleviating the painful and distressing symptoms of advanced disease. The National Cancer Institute (NCI) states that although hormone therapy cannot cure prostate cancer, it will usually shrink or halt the advance of disease, often for years.
What medications are used for hormone therapy?
Hormone therapy may be used to prevent the growth, spread, and recurrence of breast cancer. The female hormone estrogen can increase the growth of breast cancer cells in some women. Tamoxifen (Nolvadex®) is a medication used in hormone therapy to treat breast cancer by blocking the effects of estrogen on the growth of malignant cells in breast tissue. However, tamoxifen does not stop the production of estrogen.
Hormone therapy may be considered for women whose breast cancers test positive for estrogen and progesterone receptors.
Drugs recently approved by the US Food and Drug Administration (FDA), called aromatase inhibitors, are used to prevent the recurrence of breast cancer in postmenopausal women. These drugs, such as anastrozole (Arimidex®) and letrozole (Femara®), prevent estrogen production. Anastrozole is effective only in women who have not had previous hormonal treatment for breast cancer. Letrozole is effective in women who have previously been treated with tamoxifen. Possible side effects of these drugs include osteoporosis or bone fractures. Another new drug for recurrent breast cancer is fulvestrant (Faslodex®). Also approved by the FDA, this drug eliminates the estrogen receptor rather than blocking it, as is the case with tamoxifen, letrozole, or anastrozole. This drug is used following previous antiestrogen therapy. Side effects for fulvestrant include hot flashes, mild nausea, and fatigue.
Men who have breast cancer may also be treated with tamoxifen. Tamoxifen is currently being studied as a hormone therapy for treatment of other types of cancer.
With prostate cancer, there may be a variety of medications used in hormone therapy. Male hormones, such as testosterone, stimulate prostate cancer to grow. Hormone therapy is given to help stop hormone production and to block the activity of the male hormones. Hormone therapy can cause a tumor to shrink and the prostate-specific antigen (PSA) levels to decrease.
What are the side effects of hormone therapy?
The following are some potential side effects that may occur with hormone therapy. However, the side effects will vary depending upon the type of hormone therapy that is given. Every person’s hormone treatment experience is different and not every person will experience the same side effects. Discuss the potential side effects of your hormone therapy with you physician.
As each person’s individual medical profile and diagnosis is different, so is his/her reaction to treatment. Side effects may be severe, mild, or absent. Be sure to discuss with your cancer care team any/all possible side effects of treatment before the treatment begins.
For prostate cancer, either the surgical removal of the testes or hormone drug therapy can improve the cancer. Both surgery and drugs may cause the following side effects:
- hot flashes
- impotence
- a loss of desire for sexual relations
- male breast enlargement
For breast cancer, some women may experience side effects from tamoxifen that are similar to the symptoms some women experience in menopause. Other women do not experience any side effects when taking tamoxifen. The following are some of the side effects that may occur when taking tamoxifen:
- hot flashes
- nausea and/or vomiting
- vaginal spotting (a blood stained discharge from the vagina that is not part of the regular menstrual cycle)
- increased fertility in younger women
- irregular menstrual periods
- fatigue
- skin rash
- loss of appetite or weight gain
- headaches
- vaginal dryness or itching and/or irritation of the skin around the vagina
Taking tamoxifen also increases the risk of endometrial cancer (involves the lining of the uterus) and uterine sarcoma (involves the muscular wall of the uterus), both cancers of the uterus. There is also a very small risk of blood clots and stroke, eye problems such as cataracts, and liver toxicities. Tamoxifen should be avoided during pregnancy.
Tamoxifen is used to treat men with breast cancer as well. As each person’s individual medical profile and diagnosis is different, so is his/her reaction to treatment. Side effects may be severe, mild, or absent. Be sure to discuss with your cancer care team any/all possible side effects of treatment before the treatment begins.
Men may experience the following side effects:
- headaches
- nausea and/or vomiting
- skin rash
- impotence
- decrease in sexual interest
Angiogenesis Inhibitors For Cancer Treatment
What is angiogenesis?
§ Angiogenesis, the formation of new blood vessels, is a process controlled by certain chemicals produced in the body. Although this may help iormal wound healing, cancer can grow when these new blood vessels are created. Angiogenesis provides cancer cells with oxygen and nutrients. This allows the cancer cells to multiply, invade nearby tissue, and spread to other areas of the body (metastasize).
§ What are angiogenesis inhibitors and how do they work?
§ A chemical that interferes with the signals to form new blood vessels is referred to as an angiogenesis inhibitor.
§ Sometimes called antiangiogenic therapy, this experimental treatment may prevent the growth of cancer by blocking the formation of new blood vessels. In some animal case studies, angiogenesis inhibitors have caused cancer to shrink and resolve completely.
§ In humans, angiogenesis inhibitors are only used in clinical trials at this time. These drugs are still considered investigational. Research studies are now underway to help scientists learn whether the approach will apply to human cancers. Patients with cancers of the breast, prostate, pancreas, lung, stomach, ovary, cervix, and others are being studied. If the research studies demonstrate that angiogenesis inhibitors are both safe and effective for cancer treatment in humans, these drugs will need approval by the US Food and Drug Administration (FDA) to become available for widespread use.
Hyperthermia For Cancer Treatment
Hyperthermia is heat therapy. Heat has been used for hundreds of years as therapy. According to the National Cancer Institute(NCI), scientists believe that heat may help shrink tumors by damaging cells or depriving them of the substances they need to live. There are research studies underway to determine the use and effectiveness of hyperthermia in cancer treatment.
How is it used? Heat can be applied to a very small area or to an organ or limb. Hyperthermia is usually used with chemotherapy, radiation therapy, and other treatment therapies. The types of hyperthermia described in the following chart:
|
Type of Hyperthermia |
Treatment Area |
Method of Application |
|
local hyperthermia |
Treatment area includes a tumor or other small area. |
or
|
|
regional hyperthermia |
An organ or a limb is treated. |
or
|
|
whole body hyperthermia |
The whole body is treated when cancer has spread. |
|
Are there any side effects? There are no known complications of hyperthermia. Side effects may include skin discomfort or local pain. Hyperthermia can also cause blisters and occasionally burns but generally these heal quickly.
Laser Therapy For Cancer Treatment
The term LASER stands for “Light Amplification by the Stimulated Emission of Radiation.” Laser light is concentrated so that it makes a very powerful and precise tool. Laser therapy uses light to treat cancer cells. Consider the following additional information regarding laser therapy:
– Lasers can cut a very tiny area, less than the width of the finest thread, to remove very small cancers without damaging surrounding tissue.
– Lasers are used to apply heat to tumors in order to shrink them.
– Lasers are sometimes used with drugs that are activated by laser light to kill cancer cells.
– Lasers can bend and go through tubes to access hard to reach places.
– Lasers are used in microscopes to enable physicians to view the site being treated.
How are lasers used during cancer surgery? Laser surgery is a type of surgery that uses special light beams instead of instruments, such as scapels, to perform surgical procedures. There are several different types of lasers, each with characteristics that perform specific functions during surgery. Laser light can be delivered either continuously or intermittently and can be used with fiber optics to treat areas of the body that are often difficult to access. The following are some of the different types of laser used for cancer treatment:
– carbon dioxide (CO2) lasers
Carbon dioxide (CO2) lasers can remove a very thin layer of tissue from the surface of the skin without removing deeper layers. The CO2 laser may be used to remove skin cancers and some precancerous cells.
– Neodymium:yttrium-aluminum-garnet (Nd:YAG) lasers
Neodymium:yttrium-aluminum-garnet (Nd:YAG) lasers can penetrate deeper into tissue and can cause blood to clot quickly. The laser light can be carried through optical fibers to reach less accessible internal parts of the body. For example, the Nd:YAG laser can be used to treat throat cancer.
– laser-induced interstitial thermotherapy (LITT). Laser-induced interstitial thermotherapy (LITT) uses lasers to heat certain areas of the body. The lasers are directed to areas between organs (interstitial areas) that are near a tumor. The heat from the laser increases the temperature of the tumor, thereby shrinking, damaging, or destroying the cancer cells.
– argon lasers. Argon lasers pass only through superficial layers of tissue such as skin. Photodynamic therapy (PDT) uses argon laser light to activate chemicals in the cancer cells.
What is photodynamic therapy? Because cancer cells can be selectively destroyed while most healthy cells are spared, photodynamic therapy (PDT) is useful for the treatment of certain cancer tumors. Photodynamic therapy uses chemicals in the cancer cells that react to the argon light. These chemicals, called photosensitizing agents, are not naturally found in the cancer cells. In PDT, the chemicals are given to the cancer patient by injection. Cells throughout the body absorb the chemicals. The chemicals collect and stay longer in the cancer cells than in the healthy cells. At the right time, when the healthy cells surrounding the tumor may already be relatively free of the chemicals, the red light of an argon laser can be focused directly on the tumor. It hits the tumor and, as the cells absorb the light, a chemical reaction destroys the cancer cells.
Argon lasers can pass through about an inch of tissue without damaging it, so PDT can be used for the treatment of cancers that are close to the surface of the skin. It can also be directed at cancers that are located in the lining of the internal organs, such as:
– in the lungs by using a bronchoscope
– in the esophagus and gastrointestinal tract by using an endoscope
– in the bladder by using a cystoscope
What cancers may be treated with laser therapy?
Lasers are used in surgery for the following types of cancer because they often have a special requirement that only lasers can meet – such as the ability to reach a hard to treat location, apply heat, or cut only a very small area:
vocal cord, cervical, skin, lung, vaginal, vulvar, penile, palliative surgery.
Laser surgery is also used for palliative surgery in cancer patients. The purpose of palliative surgery is to help the patient feel better or function better even though it may not treat the cancer. An example of this type of surgery may involve surgery to remove a growth that is making it difficult for a patient to eat comfortably.
Side effects of photodynamic therapy. The side effects of photodynamic therapy are relatively mild and may include a small amount of damage to healthy tissue. Also, a patient’s skin and eyes are sensitive to light for as long as six weeks or more after treatment is completed. Depending on the area that is treated, patients may experience other temporary side effects. As each person’s individual medical profile and diagnosis is different, so is his/her reaction to treatment. Side effects may be severe, mild, or absent. Be sure to discuss with your cancer care team any/all possible side effects of treatment before the treatment begins.
3. TNM Classification of Malignant Tumours
TNM is a cancer staging system that describes the extent of a person’s cancer.
· T describes the size of the original (primary) tumor and whether it has invaded nearby tissue,
· N describes nearby (regional) lymph nodes that are involved,
· M describes distant metastasis (spread of cancer from one part of the body to another).
The TNM staging system for all solid tumors was devised by Pierre Denoix between 1943 and 1952, using the size and extension of the primary tumor, its lymphatic involvement, and the presence of metastases to classify the progression of cancer.
TNM is developed and maintained by the Union for International Cancer Control (UICC) to achieve consensus on one globally recognised standard for classifying the extent of spread of cancer. The TNM classification is also used by the American Joint Committee on Cancer (AJCC) and the International Federation of Gynecology and Obstetrics (FIGO). In 1987, the UICC and AJCC staging systems were unified into a single staging system.
Most of the common tumors have their own TNM classification. Not all tumors have TNM classifications, e.g., there is no TNM classification for brain tumors.
The general outline for the TNM classification is below. The values in parentheses give a range of what can be used for all cancer types, but not all cancers use this full range.
Mandatory parameters:
· T: size or direct extent of the primary tumor
· Tx: tumor cannot be evaluated
· Tis: carcinoma in situ
· T0: no signs of tumor
· T1, T2, T3, T4: size and/or extension of the primary tumor
· N: degree of spread to regional lymph nodes
· Nx: lymph nodes cannot be evaluated
· N0: tumor cells absent from regional lymph nodes
· N1: regional lymph node metastasis present; (at some sites: tumor spread to closest or small number of regional lymph nodes)
· N2: tumor spread to an extent between N1 and N3 (N2 is not used at all sites)
· N3: tumor spread to more distant or numerous regional lymph nodes (N3 is not used at all sites)
· M: presence of distant metastasis
· M0: no distant metastasis
· M1: metastasis to distant organs (beyond regional lymph nodes)[2]
The Mx designation was removed from the 7th edition of the AJCC/UICC system.
Other parameters:
· G (1–4): the grade of the cancer cells (i.e. they are “low grade” if they appear similar to normal cells, and “high grade” if they appear poorly differentiated)
· S (0-3): elevation of serum tumor markers
· R (0-2): the completeness of the operation (resection-boundaries free of cancer cells or not)
· L (0-1): invasion into lymphatic vessels
· V (0-2): invasion into vein (no, microscopic, macroscopic)
· C (1–5): a modifier of the certainty (quality) of the last mentioned parameter
Prefix modifiers:
· c: stage given by clinical examination of a patient. The c-prefix is implicit in absence of the p-prefix
· p: stage given by pathologic examination of a surgical specimen
· y: stage assessed after chemotherapy and/or radiation therapy; in other words, the individual had neoadjuvant therapy.
· r: stage for a recurrent tumor in an individual that had some period of time free from the disease.
· a: stage determined at autopsy.
1. EPIDEMIOLOGY OF CANCER DISEASES
The epidemiology of cancer is the study of the factors affecting cancer, as a way to infer possible trends and causes. The study of cancer epidemiology uses epidemiological methods to find the cause of cancer and to identify and develop improved treatments.
This area of study must contend with problems of lead time bias and length time bias. Lead time bias is the concept that early diagnosis may artificially inflate the survival statistics of a cancer, without really improving the natural history of the disease. Length bias is the concept that slower growing, more indolent tumors are more likely to be diagnosed by screening tests, but improvements in diagnosing more cases of indolent cancer may not translate into better patient outcomes after the implementation of screening programs. A related concern is overdiagnosis, the tendency of screening tests to diagnose diseases that may not actually impact the patient’s longevity. This problem especially applies to prostate cancer and PSA screening.
Some cancer researchers have argued that negative cancer clinical trials lack sufficient statistical power to discover a benefit to treatment. This may be due to fewer patients enrolled in the study than originally planned.[3]
The death rate from cancer per 100,000 inhabitants in 2004:
no data
less than 55
55–80
80–105
105–130
130–155
155–180
180–205
205–230
230–255
255–280
280–305
more than 305
Organizations: State and regional cancer registries are organizations that abstract clinical data about cancer from patient medical records. These institutions provide information to state and national public health groups to help track trends in cancer diagnosis and treatment. One of the largest and most important cancer registries is Surveillance Epidemiology and End Results (SEER), administered by the US Federal government.[4]
Health information privacy concerns have led to the restricted use of cancer registry data in the United States Department of Veterans Affairs[5][6][7] and other institutions.[8] The American Cancer Society predicts that approximately 1,690,000 new cancer cases will be diagnosed and 577,000 Americans will ultimately die of cancer in 2012.[9]
Studies: Observational epidemiological studies that show associations between risk factors and specific cancers mostly serve to generate hypotheses about potential interventions that could reduce cancer incidence or morbidity. Randomized controlled trials then test whether hypotheses generated by epidemiological studies and laboratory research actually result in reduced cancer incidence and mortality. In many cases, findings from observational epidemiological studies are not confirmed by randomized controlled trials.
Risk factors: The most significant risk factor is age. According to cancer researcher Robert A. Weinberg, “If we lived long enough, sooner or later we all would get cancer.”[10] Essentially all of the increase in cancer rates between prehistoric times and people who died in
Although the age-related increase in cancer risk is well-documented, the age-related patterns of cancer are complex. Some types of cancer, like testicular cancer, have early-life incidence peaks, for reasons unknown. Besides, the rate of age-related increase in cancer incidence varies between cancer types with, for instance, prostate cancer incidence accelerating much faster than brain cancer.[11]
Over a third of cancer deaths worldwide are due to potentially modifiable risk factors. The leading modifiable risk factors worldwide are:
· tobacco smoking, which is strongly associated with lung cancer, mouth, and throat cancer;
· drinking alcohol, which is associated with a small increase in oral, esophageal, breast, liver and other cancers;
· a diet low in fruit and vegetables,
· physical inactivity, which is associated with increased risk of colon, breast, and possibly other cancers
· obesity, which is associated with colon, breast, endometrial, and possibly other cancers
· sexual transmission of human papillomavirus, which causes cervical cancer and some forms of anal cancer.
Men with cancer are twice as likely as women to have a modifiable risk factor for their disease.[12]
Other lifestyle and environmental factors known to affect cancer risk (either beneficially or detrimentally) include the use of exogenous hormones (e.g., hormone replacement therapy causes breast cancer), exposure to ionizing radiation and ultraviolet radiation, and certain occupational and chemical exposures.[13]
Every year, at least 200,000 people die worldwide from cancer related to their workplace.[14] Millions of workers run the risk of developing cancers such as pleural and peritoneal mesothelioma from inhaling asbestos fibers, or leukemia from exposure to benzene at their workplaces.[14] Currently, most cancer deaths caused by occupational risk factors occur in the developed world.[14] It is estimated that approximately 20,000 cancer deaths and 40,000 new cases of cancer each year in the
Incidence and mortality: In the U.S. cancer is second only to cardiovascular disease as the leading cause of death; in the
Cancer epidemiology closely mirrors risk factor spread in various countries. Hepatocellular carcinoma (liver cancer) is rare in the West but is the main cancer in China and neighbouring countries, most likely due to the endemic presence of hepatitis B and aflatoxin in that population. Similarly, with tobacco smoking becoming more common in various
The leading cause of death in both males and females is lung cancer, which contributes to 26.8% of all cancer deaths. Statistics indicate that between the ages of 20 and 50 years, the incidence rate of cancer is higher amongst women whereas after 50 years of age, the incidence rate increases in men. Predictions by the Canadian Cancer Society indicate that with time, there will be an increase in the rates of incidence of cancer for both males and females. Cancer will thus continue to be a persistent issue in years to come.
Cancer is responsible for about 25% of all deaths in the
·
Most common cancers in US males, by occurrence.
·
in US males, by mortality.
·
in US females, by occurrence
·
in US females, by mortality[
|
Male |
|
Female |
||
|
most common (by occurrence)[16] |
most common (by mortality)[16] |
most common (by occurrence)[16] |
most common (by mortality)[16] |
|
|
prostate cancer (25%) |
lung cancer (31%) |
breast cancer (26%) |
lung cancer (26%) |
|
|
lung cancer (15%) |
prostate cancer (10%) |
lung cancer (14%) |
breast cancer (15%) |
|
|
colorectal cancer (10%) |
colorectal cancer (8%) |
colorectal cancer (10%) |
colorectal cancer (9%) |
|
|
bladder cancer (7%) |
pancreatic cancer (6%) |
endometrial cancer (7%) |
pancreatic cancer (6%) |
|
|
ovarian cancer (6%) |
||||
|
skin melanoma (5%) |
leukemia (4%) |
thyroid cancer (4%) |
non-Hodgkin lymphoma (3%) |
|
|
kidney cancer (4%) |
esophageal cancer (4%) |
Skin melanoma (4%) |
leukemia (3%) |
|
|
oral and pharyngeal cancer(3%) |
bladder cancer (3%) |
ovarian cancer (3%) |
uterine cancer (3%) |
|
|
leukemia (3%) |
kidney cancer (3%) |
liver & intrahepatic bile duct (2%) |
||
|
pancreatic cancer (3%) |
kidney cancer (3%) |
leukemia (3%) |
brain and other nervous system (2%) |
|
|
other (20%) |
other (24%) |
other (22%) |
other (25%) |
|
Incidence of a second cancer in survivors
In the developed world, one in three people will develop cancer during their lifetimes. If all cancer patients survived and cancer occurred randomly, the normal lifetime odds of developing a second primary cancer (not the first cancer spreading to a new site) would be one in nine.[21] However, cancer survivors have an increased risk of developing a second primary cancer, and the odds are about two iine.[21] About half of these second primaries can be attributed to the normal one-in-nine risk associated with random chance.
The increased risk is believed to be primarily due to the same risk factors that produced the first cancer, such as the person’s genetic profile, alcohol and tobacco use, obesity, and environmental exposures, and partly due, in some cases, to the treatment for the first cancer, which might have included mutagenic chemotherapeutic drugs or radiation.[21]Cancer survivors may also be more likely to comply with recommended screening, and thus may be more likely than average to detect cancers.
Epidemiology of breast cancer
Age-standardized deaths from breast cancer per 100,000 inhabitants in 2004.[1]
|
no data <2 2-4 4-6 6-8 8-10 10-12 |
12-14 14-16 16-18 18-20 20-22 >22 |
Worldwide, breast cancer is the most common invasive cancer in women. (The most common form of cancer is non-invasive non-melanoma skin cancer; non-invasive cancers are generally easily cured, cause very few deaths, and are routinely excluded from cancer statistics.) Breast cancer comprises 22.9% of invasive cancers in women[2] and 16% of all female cancers.[3]
In 2008, breast cancer caused 458,503 deaths worldwide (13.7% of cancer deaths in women and 6.0% of all cancer deaths for men and women together).[2] Lung cancer, the second most common cause of cancer-related death in women, caused 12.8% of cancer deaths in women (18.2% of all cancer deaths for men and women together).[2]
The number of cases worldwide has significantly increased since the 1970s, a phenomenon partly attributed to the modern lifestyles.[4][5]
By age group. Breast cancer is strongly related to age, with only 5% of all breast cancers occurring in women under 40 years old. By region: the incidence of breast cancer varies greatly around the world: it is lowest in less-developed countries and greatest in the more-developed countries. In the twelve world regions, the annual age-standardized incidence rates per 100,000 women are as follows: in Eastern Asia, 18; South Central Asia, 22; sub-Saharan Africa, 22; South-Eastern Asia, 26; North Africa and Western Asia, 28; South and Central America, 42; Eastern Europe, 49; Southern Europe, 56; Northern Europe, 73; Oceania, 74; Western Europe, 78; and in North America, 90.[7]
The lifetime risk for breast cancer in the United States is usually given as about 1 in 8 (12%) of women by age 95, with a 1 in 35 (3%) chance of dying from breast cancer.[9] This calculation assumes that all women live to at least age 95, except for those who die from breast cancer before age 95.[10] Recent work, using real-world numbers, indicate that the actual risk is probably less than half the theoretical risk.[11]
The
In the
Breast cancer incidence by age in women (UK) 2006-08
Developing countries: “Breast cancer in less developed countries, such as those in
IT IS GENERALLY UNAPPRECIATED HOW BIG A HEALTH PROBLEM CANCER PRESENTS WORLDWIDE – A CHALLENGE THAT IS GROWING. Each year cancer is newly diagnosed in 9 million people worldwide and it causes 5 million deaths. It is second to cardiovascular disease as a cause of death in developed countries, and overall causes 10% of all deaths in the world. It is usually regarded as a problem of the developed world, but more than half of all cancers are seen in the three-quarters of the world’s population who live in developing countries.
40 million of these deaths are preventable
The answer to this question, “What is cancer?”provides the scientific basis for cancer control. With all of the recent advances in molecular biology which have increased our understanding of the genetic basis of cancer with the description of oncogenes (cancer genes) and the suppressor genes which regulate their expression, the biologic basis of cancer has received most of the attention. But the nature of cancer also has an equally important social aspect which is essential for cancer control.
Neoplasia is a disease process that results in over 100 different malignant diseases that share a common biology and natural history. Any cell in the body that can undergo mitosis or cell division can be affected. Cancer has links to other disease processes. Some infections cause cancer: e.g. schistosomiasis associated with bladder cancer and the liver fluke, Clonorchis sinensis, which causes cancer of the gall bladder. There are also toxic causes: e.g.mesothelioma, a tumor arising in the pleura which lines the thoracic cavity resulting from exposure to asbestos (asbestosis). Despite popular opinion, however, it is unlikely that local trauma is a cause of cancer. As a fundamental disorder of cellular growth and differentiation or development, cancer is essentially a genetic disorder at the cellular level. Most tumors are encapsulated and benign in behavior. Occasionally they may create symptoms from cosmetic or mass effects. In using the generic word “cancer”, however, we are concerned here with malignanttumors that are morphologically abnormal under the microscope. They show uncontrolled growth leading to local invasion with disruption of tissues, and later metastasis or spread to loco-regional lymphatics and later the blood stream. Cancer kills mostly through blood-borne metastasis.
A tumor does not grow freely in its human host as it would in tissue culture. The host puts up a defense, generically called “host resistance”, which resembles defense against infections. There is a homeostatic interaction between the host and tumor cells or microorganisms based on a dynamic balance between them and the host microenvironment in which they grow – an updated version of the seed-and-soil hypothesis. The tumor arises from an abnormality of growth and differentiation based on altered structure, regulation and expression of its genes. The resulting properties of transformation, invasiveness, metastasis, clonality and heterogeneity give rise to its malignantbehavior. But the outcome of its growth still depends on its interactions with host defenses for a net result of progression, dormancy or regression. The process is dynamic and chronic with the balance of host resistance changing with the advancing stage of tumor growth.
Cancer has a characteristic natural history. Healthy cells first become dysplastic showing subtle morphological abnormalities under the microscope which suggest the beginning of transformation. The next step is carcinoma in situ where characteristic abnormalities of both form and proliferation are present but without invasion of the underlying basement membrane that holds them in place in the tissue of origin. This earliest phase is highly curable and is detected with screening programs, such as the PAP smear for cervical cancer. Localized cancer is stage I disease where the tumor exhibits invasion and disruption of local tissues to form a primary lesion. Tumor cells then invade local lymphatics and spread to the regional (stage II) or extended regional (stage III) draining lymph nodes as secondary tumors. Finally tumor cells invade into the blood stream where characteristic patterns of blood-borne metastasis herald the onset of stage IV disease. Particular tumors vary in the extent to which they follow these phases in sequence: melanoma usually has a distinct loco-regional phase, while breast cancer is systemic from the beginning. Staging correlates with survival and provides an essential guide both to prognosis and to the design of treatment plans.
The “gold standard” for a diagnosis of cancer is a histopathological examination by a pathologist on biopsied tumortissue. Unfortunately this is not always done and the diagnosis is made from clinical findings or less. Cancer can be mimicked by many other diseases. Moreover, cancer statistics depend on the accuracy of death certificates, where cancer may not be properly noted as the cause of death. Biologic markers are playing an increasingly important role in cancer management. Most of these markers are not unique for cancer cells, but are shared also by normal cells and may also be overexpressed in benign conditions. Thus markers cannot be used to screen populations to detect cancer.
The biology of cancer has important implications for cancer control. At the cellular level the problem is faulty genetic control; cancer is basically a genetic disorder. But hereditary cancers such as retinoblastoma, are uncommon. Instead the disease is usually acquired from external influences which are, therefore, potentially avoidable. With current methods overall one can expect to prevent theoretically 2/3 but in practice more realistically 1/3 of cancer, and to be
able to cure about 1/3 in a developing country, and closer to 1/2 in a developed country.
As a lifestyle disease, cancer arises out of conditions of life which result in exposures to carcinogens. Such exposures result from two situations: * Where people live * Changes people make in the world
Cancer shows both geographic and temporal variability. There are different patterns of cancer at different places and different times. These patterns relate both to habits and to environmental hazards. Habits: The use of tobacco has resulted in lung cancer in North America and
Viruses: Hepatitis B Virus is associated with liver cancer.
Risk factors for cancer which people create by making changes in their world may be thought of as the price for industrialization. Ionizing radiation: In the latter part of the 19th century over half of certain groups of miners working in the Joachimsthal and Schneeburg mines of
These social dimensions of cancer have important implications for the design of cancer control programming. They stem from behavior patterns that people evolve to meet their biological, psychological and social needs. These patterns, in turn, create a lifestyle which influences cancer incidence. They include the development of addictions to tobacco, drugs and alcohol, the ways in which food is prepared, stored and eaten, and certain risk patterns of personal interaction as with sexual mores. With tobacco, for example, oral cancer predominates where tobacco is chewed, and lung cancer where it is smoked. The changed cancer patterns that accompany the migration of people provides an example of the influence of lifestyle on the occurrence of cancer. When Mexicans migrate to the
Biologic factors in cancer etiology refer largely to the role of four classes of external agents in carcinogenesis: physical, chemical and biological agents, and diet.
Physical Agents: * Ionizing radiation can be background from cosmic rays and earth sources of radioactivity. More important are cumulative exposures from medical diagnostic and treatment procedures, and from commercial and occupational sources. Exposures have also occurred with warfare, as in the atomic bombs dropped on Hiroshimaand Nagasaki in
Because of the widespread nature of the tobacco habit, control of carcinogenesis by chemical agents provides a major basis for cancer control. The process of carcinogenesis by chemicals is subject to both initiation and promotion steps. These carcinogens have a particular chemistry as aromatic electrophiles – chemically very reactive substances often formed as metabolic products.* Some have medicinal sources, such as the use of diethylstilbestrol in pregnancy to avert abortion resulting in vaginal cancer in the daughters.* Others come from habits such as the use of tobacco (oral and lung cancer, and other tumors) or alcohol (head and neck cancers).* Industrial and occupational exposures are also important:
Viruses are responsible for only about 5% of human cancer. But they are much more common causes of cancer in animals, where their experimental study has played a key role in the identification of oncogenes. Both DNA and RNA viruses are implicated. * Hepatitis B virus (HBV) causes primary liver cancer. Vaccination of the children of susceptible populations is used for prevention.* The Epstein Barr Virus (EBV) is implicated iasopharyngeal cancer.* The Human Papilloma Virus (HPV), especially certain subtypes like 16, are associated with cervical cancer. These viruses also cause warts, which are benign tumors. Some parasitic infections are associated with cancer.* Infections with Schistosoma haematobium (schistosomiasis) may be associated with bladder cancer. This parasite enters the skin from water infected by snails. * The liver fluke, Clonorchis sinensis, is associated with cancer of the gall bladder and hepatobiliary ducts.
As a lifestyle factor diet has been shown to play a significant role in the causation of cancer worldwide. But little is known as yet about how it plays its role as a carcinogen. This is currently a very active area of cancer research. There are several studies which show that excessive fat in the diet raises the risk of colorectal and breast cancer, and possibly other cancers as well, such as prostate cancer.
Methods of food preparation and preservation can also create risks. There are studies showing that nitrites are associated with stomach cancer. Other studies are showing that certain broad classes of foods may containprotective substances against cancer. These include certain vegetables (the cruciferous group), whole grain products (fiber) and citrus fruits.
The three major classes of external carcinogens, and perhaps to some extent diet (although how it plays its role is not yet understood), exert their effect through multiple steps involving a final common pathway – the oncogenes. The final result is malignant transformation and then the development through further genomic instability the properties of invasiveness and metastasis.
Lifestyle and the conditions in which people live determine the prevalence of environmental risk factors. Five groupings of these risk factors make up the social factors in cancer etiology.
Click here for a summary of each of the key risk factors that are implicated currently in the causation of cancer.
This slide shows the relative importance of the various risks and causes of cancer. It is based on a study of cancer mortality in the
In developing countries cancer causes about 1 in 20 deaths. The incidence is increasing as living standards improve and life expectancy is prolonged leading to a decline in communicable diseases and an increase innoncommunicable diseases.
In developed countries, cancer is second only to cardiovascular diseases as a cause of mortality and accounts for about 1/4 of all deaths. Three factors contribute to the increase in cancer mortality: *in developed countries deaths from cardiovascular diseases are declining; *the “graying” of the population means that people are living longer and cancer is more frequent in older age groups; and *increasing use of tobacco, mostly as cigarette smoking, during the past few decades has resulted in a greater incidence of related cancers, especially lung cancer. Indeed the increase in smoking in young women is resulting in a rapid rise in the incidence of lung cancer, which in some developed countries is surpassing breast cancer as the commonest cancer in women.
In contrast, perinatal disorders and infections comprise less than 10% of the mortality in developed countries, and it continues to drop.
The basis for the striking contrast in the last two slides between developing and developed countries is the transition phenomenon, which is illustrated here.
The incidence of cancer at various body sites may differ in different countries. Oral cancer is common in
Temporal trends in cancer tend to show epidemics that rise to a peak and then recede over very long time periods of decades. The long time periods hide the epidemic nature of the disease. Projections of incidence, prevalence and mortality are important for planning cancer control interventions.
Cancer impacts not only the patient, but also his or her family and community. In
The economic burden of cancer to a country is shown in this example of a study done in the
Material was taken from the lecture of:
The W.H.O. Collaborating Centre for Cancer Control was founded by Dr. Jerry in 1993 at the Tom Baker Cancer Centre in
2. PRINCIPLES OF CANCER TREATMENT
SURGICAL ONCOLOGY
Surgery is the oldest treatment for cancer and, until recently, was the only treatment that could cure patients with cancer. The surgical treatment of cancer has changed dramatically over the last several decades. Advances in surgical techniques and a better understanding of the patterns of spread of individual cancers have allowed surgeons to perform successful resections for an increased number of patients. The development of alternate treatment strategies that can control microscopic disease has prompted surgeons to reassess the magnitude of surgery necessary. The surgeon who treats cancer must be familiar with the natural history of individual cancers and with the principles and potentialities of surgery, radiation therapy, chemotherapy, immunotherapy, and other new treatment modalities. The surgeon has a central role in the prevention, diagnosis, definitive treatment, palliation, and rehabilitation of the cancer patient. The principles underlying each of these roles of the surgical oncologist are discussed in this chapter.
HISTORICAL PERSPECTIVE
Although the earliest discussions of the surgical treatment of tumors are found in the Edwin Smith papyrus from the Egyptian Middle Kingdom (about 1600 BC), the modern era of elective surgery for visceral tumors began in frontier
The treatment of most tumors depended on two subsequent developments in surgery. The first of these was the introduction of general anesthesia by two dentists, Dr. William Morton and Dr. Crawford Long. The first major operation using general ether anesthesia was an excision of the submaxillary gland and part of the tongue, performed by Dr. John Collins Warren on October 16, 1846, at the Massachusetts General Hospital. The second major development stimulating the widespread application of surgery resulted from the introduction of the principles of antisepsis by Joseph Lister in 1867. Based on the concepts of Pasteur, Lister introduced carbolic acid in 1867 and described the principles of antisepsis in an article in The Lancet in that same year. These developments freed surgery from pain and sepsis and greatly increased its use for the treatment of tumors. In the decade before the introduction of ether, only 385 operations were performed at the
Lists selected milestones in the history of surgical oncology. Although this list does not include all of the important developments, it does provide the tempo of the application of surgery to cancer treatment. [ref: 4] Major figures in the evolution ofsurgical oncology included Albert Theodore Billroth who, in addition to developing meticulous surgical techniques, performed the first gastrectomy, laryngectomy, and esophagectomy. In the 1890s, William Stewart Halsted elucidated the principles of en bloc resections for cancer, as exemplified by the radical mastectomy. Examples of radical resections for cancers of individual organs include the radical prostatectomy by Hugh Young in 1904, the radical hysterectomy by Ernest Wertheim in 1906, the abdominoperineal resection for cancer of the rectum by W. Ernest Miles in 1908, and the first successful pneumonectomy performed for cancer by Evarts Graham in 1933. Modern technical innovations continue to extend the surgeon’s capabilities. Recent examples include the development of microsurgical techniques that enable the performance of free grafts for reconstruction, automatic stapling devices, sophisticated endoscopic equipment that allows for a wide variety of “incisionless” surgery, and majorimprovements in postoperative management and critical care of patients that have extended the safety of major surgical therapy.
Critics who believe that the application of surgery has reached a plateau beyond which it will not progress should remember the words of a famous British surgeon, Sir John Erichsen, who in his introductory address to the medical institutions at University College, said, There must be a final limit to the development of manipulative surgery, the knife cannot always have fresh fields for conquest and although methods of practice may be modified and varied and even improved to some extent, it must be within a certain limit. That this limit has nearly, if not quite, been reached will appear evident if we reflect on the great achievements of modern operative surgery. Very little remains for the boldest to devise or the most dextrous to perform. These comments, published in The Lancet in 1873, preceded most important developments in modern surgical oncology.
THE OPERATION
ANESTHESIA
Modern anesthetic techniques have greatly increased the safety of major oncologic surgery. Regional and general anesthesia play important roles in a wide variety of diagnostic techniques, in local therapeutic maneuvers, and in major surgery. These techniques should be understood by all oncologists. Anesthetic techniques may be divided into regional and general anesthesia. Regional anesthesia involves a reversible blockade of pain perception by the application of local anesthetic drugs. These agents generally work by preventing the activation of pain receptors or by blocking nerve conduction. Agents commonly used for local and topical anesthesia for biopsies in cancer patients, are shown in Tables 15-2 and 15-3. [ref: 5] Topical anesthesia refers to the application of local anesthetics to the skin or mucous membranes. Good surface anesthesia of the conjunctiva and cornea, oropharynx and nasopharynx, esophagus, larynx, trachea, urethra, and anus can result from the application of these agents. Local anesthesia involves injecting anesthetic agents directly into the operative field. Field block refers to injection of local anesthetic by circumscribing the operative field with a continuous wall of anesthetic agent. Lidocaine (Xylocaine) in concentrations from 0.5% to 1% is the most common anesthetic agent used for this purpose. Results from the deposition of a local anesthetic surrounding major nerve trunks. It can provide local anesthesia to entire anatomic areas.
Major surgical procedures in the lower portion of the body can be performed using epidural or spinal anesthesia. Epidural anesthesia results from the deposition of a local anesthetic agent into the extradural space within the vertebral canal. Catheters can be left in place in the epidural space, allowing the intermittent injection of local anesthetics for prolonged operations. The major advantage of epidural over spinal anesthesia is that it does not involve puncturing the dura, and the injection of foreign substances directly into the cerebrospinal fluid is avoided. Spinal anesthesia involves the direct injection of a local anesthetic into the cerebrospinal fluid. Puncture of the dural sac generally is performed between the L-2 and L-4 vertebrae. Spinal anesthesia provides excellent anesthesia for intraabdominal operations, operations on the pelvis, or procedures involving the lower extremities. Because the patient is awake during spinal anesthesia and is breathing spontaneously, it often has been thought that spinal anesthesia is safer than general anesthesia. There is no difference in the incidence of intraoperative hypotension with spinal anesthesia compared with general anesthesia, and there is no clear benefit in using spinal anesthesia for patients with ischemic heart disease. Because patients are awake during spinal anesthesia and can become agitated during the surgical procedure, spinal anesthesia actually can cause more myocardial stress than general anesthesia. The health status of patients with preoperative evidence of congestive heart failure is more likely to be worsened by general anesthesia than by spinal anesthesia. In one series, heart failure developed de novo in 4% of adults over the age of 40 years who were undergoing major surgery, and worsened in 22% of patients who had a history of heart failure. [ref: 6] Spinal anesthesia was not associated with any new or worsened heart failure. Because of local irritating effects of general anesthesia on the lung, it has been suggested that spinal anesthesia may be safer for patients with severe pulmonary disease.
General anesthesia refers to the reversible state of loss of consciousness produced by chemical agents that act directly on the brain. Most major oncologic procedures are performed using general anesthesia, which can be induced using intravenous or inhalational agents. The advantages of intravenous anesthesia are the extremely rapid onset of unconsciousness and improved patient comfort and acceptance. Ultrashort-acting barbiturates such as sodium thiopental, or tranquilizers such as the benzodiazepines or droperidol, are the most frequently used intravenous agents for general anesthesia or for sedation during regional anesthesia. A variety of inhalational anesthetic agents are in clinical use. Nitrous oxide is popular, usually in combination with narcotics and muscle relaxants. This technique provides a safe form of general anesthesia with the use of nonexplosive agents. Two other agents in widespread use are the fluorinated hydrocarbons, halothane (Fluothane) and enflurane (Ethrane). Although they are used frequently, the fluorinated hydrocarbons have a variety of side effects. Halothane depresses myocardial function, reduces cardiac output, causes significant vasodilation, and sensitizes the myocardium to endogenous and administered catecholamines which can lead to life-threatening cardiac arrhythmias. In rare instances, halothane can cause severe hepatotoxicity, which begins 2 to 5 days after surgery. Enflurane also depresses myocardial function but does not appear to sensitize the myocardium to catecholamines and has not been associated with hepatic toxicity. The newest of the halogenated hydrocarbons is isoflurane, which was introduced in 1980. Isoflurane depresses the myocardium less than halothane or enflurane, but it has more potent vasodilatoryproperties.Virtually all general anesthetics affect biochemical mechanisms, including depression of bone marrow, alteration of the phagocytic activity of macrophages, and exhibition of immunosuppressive properties. General anesthetic agents, such as cyclopropane and diethyl ether, are rarely used because of their explosive potential.
Intravenous neuromuscular blocking agents, called muscle relaxants, are commonly used during general anesthesia. These agents are nondepolarizing (e.g., curare), preventing access of acetylcholine to the receptor site of the myoneural junction, or depolarizing (e.g., succinylcholine), acting in a manner similar to that of acetylcholine by depolarizing the motor end plate. These agents induce profound muscle relaxation during surgical procedures but have the disadvantage of inhibiting spontaneous respiration because of paralysis of respiratory muscles.Succinylcholine is short acting (3 to 5 minutes) with a rapid recovery phase. Curare-induced paralysis lasts for 30 to 40 minutes after usual clinical doses of 0.3 to 0.5 mg/kg. Pancuronium has fewer side effects than curare but can induce tachycardia by means of sympathetic stimulation.
DETERMINATION OF OPERATIVE RISK
As with any treatment, the potential benefits of surgical intervention in cancer patients must be weighed against the risks of surgery. The incidence of operative mortality is of major importance in formulating therapeutic decisions and varies greatly in different patient situations. The incidence of operative mortality is a complex function of the basic disease process that involves surgery, anesthetic technique, operative complications, and, most importantly, the general health status of patients and their ability to withstand operative trauma.
In an attempt to classify the physical status of patients and their surgical risks, the American Society of Anesthesiologists has formulated a General Classification of Physical Status that appears to correlate well with operative mortality. Patients are classified into five groups depending on their general health status.
Operative mortality usually is defined as mortality that occurs within 30 days of a major operative procedure. In oncologic patients, the basic disease process is a major determinant of operative mortality.
Patients undergoing palliative surgery for widely metastatic disease have a high operative mortality rate even if the surgical procedure can alleviate the symptomatic problem. Examples of these situations include surgery for intestinal obstruction in patients with widespread ovarian cancer and surgery for gastric outlet obstruction in patients with cancer of the head of the pancreas. These simple palliative procedures are associated with mortality rates of about 20% in most series because of the debilitated state of the patient and the rapid progression of the basic disease.
Mortality caused by anesthetic administration alone is related directly to the physical status of the patient. In a review of 32,223 operations, Dripps and colleagues determined the mortality thought to be related to anesthetic administration alone. It is extremely difficult to differentiate the mortality caused by anesthesia from that resulting from other contributors to operative mortality. However, this analysis indicates that operative mortality due to anesthesia in physical status class 1 patients is extremely low, less than 1 in every 16,000 operations. The anesthetic mortality increased with worsened physical status.
There is considerable evidence that anesthesia-related mortality has decreased in the past two decades, largely because of the development of rigid practice standards and improved intraoperative monitoring techniques. A summary of the specific intraoperative monitoring methods used to achieve improved anesthetic safety is presented in Table 15-7. A study of 485,850 anesthetics administered in 1986 in the United Kingdom revealed the risk of death from anesthesia alone in patients from all ASA classes to be approximately 1 in 185,000. [ref: 9] In a retrospective review encompassing cases from 1976 through 1988, Eichorn estimated anesthetic mortality in ASA class I and II patients to be 1 in 200,200. [ref: 10] These are probably underestimates since underreporting of anesthetic related deaths is a problem in all studies. Most cancer patients undergoing elective surgery fall between physical status I and II; thus, an anesthetic mortality rate of 0.01 to 0.001% is a realistic estimate for this group.
Anesthesia-related mortality is rare, and factors related to the patient’s preexisting general health status and disease are far more important indicators of surgical outcome. A study of the factors contributing to the risk of 7-day operative mortality following 100,000 surgical procedures is shown in Table 15-8. [ref: 13] The 7-dayperioperative mortality in this study was 71.4 deaths per 10,000 cases, and the major determinants of death were the physical status of the patient, the emergent nature of the procedure, and the magnitude of the operation.
Several specific health factors can increase the risks of the operative procedure. Using discriminant analysis, Goldman and colleagues identified nine independent variables that correlated with life-threatening and fatal cardiac complications in patients undergoing noncardiac surgical procedures. By assigning a point value to each variable, a Cardiac Risk Index could be computed.
That separated patients into four categories of risk. The two risk factors most predictive of life threatening complications were the presence of a third heart sound (S(3)) or jugular vein distention (11 points) or a myocardial infarction in the previous 6 months (10 points). A recent myocardial infarction significantly increases the incidence of reinfarction and cardiac death associated with surgery. Significant improvements have occurred as new techniques of anesthetic monitoring and hemodynamic support have been developed.
The impact of general health status on operative mortality is seen when operative mortality as a function of age is analyzed. Palmberg and colleagues studied the postoperative mortality of 17,199 patients undergoing general surgical procedures. The overall mortality rate of patients under 70 years was 0.25%, compared with 9.2% for patients over 70 years. In these elderly patients, the operative mortality rate for emergency operations was 36.8%, compared with 7.8% for elective surgical procedures. The four leading causes of operative mortality that accounted for about 75% of all postoperative deaths in this age group were pulmonary embolism, pneumonia, cardiovascular collapse, and the primary illness itself.
More recently, Hoskings and colleagues reviewed the outcome of surgery performed on 795 patients 90 years of age or older. [ref: 18] Surgery was generally well tolerated. As with younger patients, the American Society of Anesthesiology classification was an important predictor of outcome.
Cancer is often a disease of the elderly, and there is sometimes a tendency to avoid even curative major surgery for cancer in patients of advanced age. In the
ROLES FOR SURGERY
PREVENTION OF CANCER
Because surgeons are often the primary providers of medical care, they are responsible for educating patients about carcinogenic hazards and about direct surgical intervention for the prevention of cancer. All surgical oncologists should be aware of the high-risk situations that require surgery to prevent subsequent malignant disease. Underlying conditions or congenital or genetic traits are associated with an extremely high incidence of subsequent cancer. When these cancers are likely to occur in nonvital organs, it is necessary to remove the offending organ to prevent subsequent malignancy. Examples of diseases associated with a high incidence of cancer that can be prevented by prophylactic surgery. An excellent example is presented by patients with the genetic trait for multiple polyposis of the colon. If colectomy is not performed in these patients, about half will develop colon cancer by the age of 40. By the age of 70, virtually all patients with multiple polyposis will develop colon cancer. It is therefore advisable for all patients containing the mutant gene for multiple polyposis to undergo prophylactic colectomy before the age of 20 to prevent these cancers.
In this situation, as for many of the other familial conditions associated with a high incidence of cancer, the surgeon has a responsibility for alerting the family to the hereditary nature of the disorder and its possible occurrence in other family members. Another disease associated with a high incidence of cancer of the colon is ulcerative colitis. About 40% of patients with total colonic involvement ultimately die of colon cancer if they survive the ulcerative colitis. Three percent of children with ulcerative colitis develop cancer of the colon by the age of 10, and 20% develop cancer during each ensuing decade. Colectomy is indicated for patients with ulcerative colitis if the chronicity of this disease is well established.
Other disorders that require early treatment to prevent subsequent cancers include cryptorchidism and multiple endocrine neoplasia. Cryptorchidism is associated with a high incidence of testicular cancer that probably can be prevented by early prophylactic surgery.
In the past, patients with multiple endocrine neoplasia type IIA (MEN IIA) were screened for the presence of C-cell hyperplasia and calcitonin secretion using pentagastrin stimulation tests to determine the possible need for prophylactic surgery to prevent the occurrence of medullary thyroid cancer. Recent studies using PCR-based direct DNA testing for mutations in the RET protooncogene have shown it to be the preferred method for screening MEN IIA kindreds to identify individuals in whom total thyroidectomy is indicated, regardless of the plasma calcitoninlevels.
A more complex example of the role of surgery in cancer prevention involves women at high risk for breast cancer. Because the risk of cancer in some women is increased substantially over the normal risk (but does not approach 100%), counseling is required. Women in this situation must carefully balance the benefits and risks of prophylactic mastectomy. A careful understanding of the factors involved in increased breast cancer incidence is essential for the surgical oncologist to provide sound advice in this area. Statistical techniques can provide approximations of the risk for patients depending on the frequency of disease in the family history, the age at the first pregnancy, and the presence of fibrocystic disease. For example, a woman with a family history of breast cancer in a sister or mother, who has fibrocystic disease, and is nulliparous or had a first pregnancy at a late age has an 18% probability of developing breast cancer over a 5-year period. [ref: 20] These estimates can be of value in advising women about prophylactic mastectomy.
DIAGNOSIS OF CANCER
The major role of surgery in the diagnosis of cancer lies in the acquisition of tissue for exact histologic diagnosis. The principles underlying the biopsy of malignant lesions vary depending on the natural history of the tumor under consideration. Various techniques exist for obtaining tissues suspected of malignancy, including aspiration biopsy, needle biopsy, incisional biopsy, and excisional biopsy.
Aspiration biopsy involves the aspiration of cells and tissue fragments through a needle that has been guided into the suspect tissue. Cytologic analysis of this material can provide a tentative diagnosis of the presence of malignant tissue. However, major surgical resections should not be undertaken solely on the basis of the evidence of aspiration biopsy. Even the most experienced cytologist can mistake inflammatory or benign reparative changes for malignant
cells. This error is inherent in the uncertainties of an individual cell analysis and, even in the best of hands, provides an error rate substantially higher than that of standard histologic diagnosis.
Needle biopsy refers to obtaining a core of tissue through a specially designed needle introduced into the suspect tissue. The core of tissue provided by needle biopsies is sufficient for the diagnosis of most tumor types. Soft tissue and bony sarcomas often present major difficulties in differentiating benign and reparative lesions from malignancies and often cannot be diagnosed accurately. If these latter lesions are considered in the diagnosis, attempts should be made to obtain larger amounts of tissue than are possible from a needle biopsy.
Incisional biopsy refers to removal of a small wedge of tissue from a larger tumor mass. Incisional biopsies often are necessary for diagnosing large masses that require major surgical procedures for even local excision. Incisionalbiopsies are the preferred method of diagnosing soft tissue and bony sarcomas because of the magnitude of the surgical procedures necessary to extirpate these lesions definitively. The treatment of many visceral cancers cannot be undertaken without an incisional biopsy, but be aware of opening new tissue planes contaminated with tumor by performing excisional biopsies for large lesions. An inappropriately performed excisional biopsy can compromise subsequent surgical excision. When this is a possibility, incisional biopsies should be performed.
In excisional biopsy, an excision of the entire suspected tumor tissue with little or no margin of surrounding normal tissue is done. Excisional biopsies are the procedure of choice for most tumors if they can be performed without contaminating new tissue planes or further compromising the ultimate surgical procedure.
The following principles guide the performance of all surgical biopsies:
1. Needle tracks or scars should be placed carefully so that they can be conveniently removed as part of the subsequent definitive surgical procedure. Placement of biopsy incisions is extremely important, and misplacement often can compromise subsequent care. Incisions on the extremity generally should be placed longitudinally so as to make the removal of underlying tissue and subsequent closure easier.
2. Care should be takeot to contaminate new tissue planes during the biopsy. Large hematomas after biopsy can lead to tumor spread and must be scrupulously avoided by securing excellent hemostasis during the biopsy. For biopsies on extremities, the use of a tourniquet may help in controlling bleeding. Instruments used in a biopsy procedure are another potential source of contamination of new tissue planes. It is not uncommon to take biopsy samples from several suspected lesions at one time. Care should be takeot to use instruments that may have come in contact with tumor when obtaining tissue from a potentially uncontaminated area.
3. Choice of biopsy technique should be selected carefully to obtain an adequate tissue sample for the needs of the pathologist. For the diagnosis of selected tumors, electron microscopy, tissue culture or other techniques may be necessary. Sufficient tissue must be obtained for these purposes if diagnostic difficulties are anticipated.
4. Handling of the biopsy tissue by the pathologist is also important. When the orientation of the biopsy specimen is important for subsequent treatment, the surgeon should mark distinctive areas of the tumor carefully to facilitate subsequent orientation of the specimen by the pathologist. Different fixatives are best for different types or sizes of tissue. If all biopsy specimens are placed in formalin immediately, the opportunity to perform valuable diagnostic tests may be lost. The handling of excised tissue is the surgeon’s responsibility. Biopsy tissue obtained from breast cancer lesions, for example, should be saved for estrogen receptor studies and placed in cold storage until ready for processing.
Surgery also has a role in diagnosing pathologic states in cancer patients that do not directly involve the diagnosis of cancer. Cancer patients often are immunosuppressed by their disease or their treatment and are subject to opportunistic infections not commonly seen in most general surgical patients. Open lung or liver biopsies are often important in diagnosing these lesions adequately and in planning suitable therapy.
Oncologists are becoming increasingly aware of the need for precise staging of patients when planning treatment. Lack of proper staging information can lead to poor treatment planning and compromise the ability to cure patients. Staging laparotomy can be important in determining the exact extent of spread of lymphomas.
In performing accurate surgical staging, the surgeon must be familiar with the natural history of the disease under consideration. The development of ovarian cancer treatment is an excellent example. The tendency of ovarian cancer to metastasize to the undersurface of the diaphragm is a good example of the need to biopsy an anatomic site that would not normally be biopsied by most surgeons. Extensive surgical staging may be required before undertaking other major surgical procedures with curative intent. For example, biopsy of the celiac and paraaortic lymph nodes in patients with cancer of the esophagus is often important so that unnecessary esophageal resections can be avoided.
Placement of radioopaque clips during biopsy and staging procedures is important to delineate areas of known tumor and as a guide to the subsequent delivery of radiation therapy to these areas.
TREATMENT OF CANCER
Surgery can be a simple, safe method to cure patients with solid tumors when the tumor is confined to the anatomic site of origin. Unfortunately, when patients with solid tumors present to the physician for the first time, about 70% already have micrometastases beyond the primary site. The extension of the surgical resection to include areas of regional spread can cure some of these patients, although regional spread often is an indication of undetectable distant micrometastases.
The emergence of effective nonsurgical therapies has had profound impact on the treatment of cancer patients and on the role and responsibilities of the surgeon treating the cancer patient. John Hunter, a brilliant 18th-century surgeon, characterized surgery as being “like an armed savage who attempts to get that by force which a civilized man would get by strategem.”
Although surgery continues to be the most important aspect of the treatment of most patients presenting with solid tumors, modern clinical research in oncology has been devoted to applying other adjuvant “strategems” to improve the cure rates of those 70% who ultimately fail surgical therapy alone.
The role of surgery in the treatment of cancer patients can be divided into six separate areas. In each area, interactions with other treatment modalities can be essential for a successful outcome. Definitive surgical treatment for primary cancer, selection of appropriate local therapy, and integration of surgery with other adjuvant modalities. Surgery to reduce the bulk of residual disease (Examples: Burkitt’s lymphoma, ovarian cancer)
Surgical resection of metastatic disease with curative intent (examples: pulmonary metastases in sarcoma patients, hepatic metastases from colorectal cancer)
Surgery for the treatment of oncologic emergencies
Surgery for palliation
Surgery for reconstruction and rehabilitation
Surgery for Primary Cancer
There are three major challenges confronting the surgical oncologist in the definitive treatment of solid tumors:
Accurate identification of patients who can be cured by local treatment alone
Development and selection of local treatments that provide the best balance between local cure and the impact of treatment morbidity on the quality of life
Development and application of adjuvant treatments that can improve the control of local and distant invasive and metastatic disease
The selection of the appropriate local therapy to be used in cancer treatment varies with the individual cancer type and the site of involvement. In many instances, definitive surgical therapy that encompasses a sufficient margin of normal tissue is sufficient local therapy. The treatment of many solid tumors falls into this category, including the wide excision of primary melanomas in the skin that can be cured locally by surgery alone in about 90% of cases. The resection of colon cancers with a 5-cm margin from the tumor results in anastomotic recurrences in less than 5% of cases.
In other instances, surgery is used to obtain histologic confirmation of diagnosis, but primary local therapy is achieved through the use of a nonsurgical modality such as radiation therapy. Examples include the treatment of
The magnitude of surgical resection is modified in the treatment of many cancers by the use of adjuvant treatment modalities. Rationally integrating surgery with other treatments requires a careful consideration of all effective treatment options. The surgical oncologist must be thoroughly familiar with adjuncts and alternatives to surgical treatment. It is a knowledge of this rapidly changing field that separates the surgical oncologist from the general surgeon most distinctly.
In some instances, effective adjuvant modalities have led to a decrease in the magnitude of surgery. The evolution of childhood rhabdomyosarcoma treatment is a striking example of the successful integration of adjuvant therapies with surgery in the treatment of cancer.
Childhood rhabdomyosarcoma is the most common soft tissue sarcoma in infants and children. Before 1970, surgery alone was used almost exclusively, and 5-year survival rates of 10% to 20% were commonly reported. Local surgery alone failed in patients with rhabdomyosarcomas of the prostate and extremities because of extensive invasion of surrounding tissues and the early development of metastatic disease. The failure of surgery alone to control local disease in patients with childhood rhabdomyosarcoma led to the introduction of adjuvant radiation therapy. This resulted in a marked improvement in local control rates that was further improved dramatically by the introduction of combination chemotherapy with vincristine, dactinomycin, and cyclophosphamide. Long-term cure rates are in the range of 80%. Many other examples of the integration of surgery with other treatment modalities appear throughout this book.
Surgery for Residual Disease
The concept of cytoreductive surgery has received much attention in recent years. In some instances, the extensive local spread of cancer precludes the removal of all gross disease by surgery. The surgical resection of bulk disease in the treatment of selected cancers may well lead to improvements in the ability to control residual gross disease that has not been resected. Studies that suggest the merit of this approach are discussed in Chapters 44 and 35 (Burkitt’s lymphoma and ovarian cancer, respectively).
Enthusiasm for cytoreductive surgery has led to the inappropriate use of surgery for reducing the bulk of tumor in some cases. Clearly, cytoreductive surgery is of benefit only when other effective treatments are available to control the residual disease that is unresectable. Except in rare palliative settings, there is no role for cytoreductive surgery in patients in whom little other effective therapy exists.
Surgery for Metastatic Disease
The value of surgery in the cure of patients with metastatic disease tends to be overlooked. As a general principle, patients with a single site of metastatic disease that can be resected without major morbidity should undergo resection of that metastatic cancer. Many patients with few metastases to lung or liver or brain can be cured by surgical resection. This approach is especially true for cancers that do not respond well to systemic chemotherapy. The resection of pulmonary metastases in patients with soft tissue and bony sarcomas can cure as many as 30% of patients. As effective systemic therapy is developed for the treatment of these diseases, cure rates may increase. Studies have shown that similar cure rates occur in patients with adenocarcinomas when resected metastatic disease to the lung is the sole clinical site of metastases. Small numbers of pulmonary metastases often are the only clinically apparent metastatic disease in patients with sarcomas. However, this is rare in the natural history of most adenocarcinomas. If solitary metastases to the lung do occur in patients with carcinoma of the colon or other adenocarcinomas, then surgical resection is indicated.
Similarly, there is increasing enthusiasm for the resection of hepatic metastases, especially from colorectal cancer, in patients in whom the liver is the only site of known metastatic disease. In patients with solitary hepatic metastases from colorectal cancer, resection can lead to long-term cure in about 25% of patients. This far exceeds the cure rates of any other available treatment.
The resection for cure of solitary brain metastases should also be considered when the brain is the only site of known metastatic disease. The exact location and functional sequelae of resection should be considered when making this treatment decision.
SURGERY FOR ONCOLOGIC EMERGENCIES
As in the treatment of all patients, emergencies arise for oncologic patients that require surgical intervention. These generally involve the treatment of exsanguinating hemorrhage, perforation, drainage of abscesses, or impending destruction of vital organs. Each category of surgical emergency is unique and requires an individual approach. The oncologic patient often is neutropenic, thrombocytopenic, and has a high risk of hemorrhage or sepsis. Perforations of an abdominal viscus can result from direct tumor invasion or from tumor lysis resulting from effective systemic treatments. Perforation of the gastrointestinal tract after effective treatment for lymphoma involving the intestine is not uncommon. The ability to identify patients at high risk for perforation may lead to the use of surgery to prevent this problem. Surgery to decompress cancer invading the central nervous system represents another surgical emergency that can lead to preservation of function.
Surgery for Palliation
Surgical resection often is required for the relief of pain or functional abnormalities. The appropriate use of surgery in these settings can improve the quality of life for cancer patients. Palliative surgery may include the relief of mechanical problems such as intestinal obstruction or the removal of masses that are causing severe pain or disfigurement.
Surgery for Reconstruction and Rehabilitation
Surgical techniques are being refined that aid in the reconstruction and rehabilitation of cancer patients after definitive therapy. The ability to reconstruct anatomic defects can substantially improve function and cosmetic appearance. The development of free flaps using microvascular anastomotic techniques is having a profound impact on the ability to bring fresh tissue to resected or heavily irradiated areas. Loss of function (especially of extremities) often can be rehabilitated by surgical approaches. This includes lysis of contractures or muscle transposition to restore muscular function that has been damaged by previous surgery or radiation therapy.
RADIATION THERAPY
To understand the practice of radiation therapy, one must seek its roots in principles derived from three separate areas. The first is practical radiation physics. This must be understood much as the surgeon understands the use of the equipment available in the operating room and as the internist understands the pharmacologic basis of therapeutics. The basic concepts of physics necessary to consider radiation therapy in the disease-related chapters are introduced in this chapter.
The second important discipline to be understood is cell, tissue, and tumor biology. This chapter describes the fundamental principles of radiation biology and cell kinetics; cell kinetics in relation to chemotherapy and radiation therapy. These two discussions provide the rudiments of cell biology necessary to understand the uses of radiation.
A large clinical experience in radiation use has resulted in certain principles of treatment. These are discussed separately and related to the physical and biologic concepts that may underlie their success.
PHYSICAL CONSIDERATIONS
Only the most important concepts of the physics of ionizing radiation can be discussed in this chapter. If more detailed information is needed, a standard textbook of radiation physics is a more appropriate source of information.
Ionizing radiation is energy that, during absorption, causes the ejection of an orbital electron. A large amount of energy is associated with ionization. Ionizing radiation can be electromagnetic or particulate, and electromagnetic radiation can be considered as a wave and as a packet of energy (a photon). It is the particulate nature of electromagnetic radiation that explains much of its biologic activity. The packet of energy is large enough to cause ionizations, and these are distributed unevenly through tissue. Examples of particulate radiation are the subatomic particles: electrons, protons, alpha particles, neutrons, negative pi mesons, and atomic nuclei. All of these have been experimentally considered or are being used in radiation therapy.
ELECTROMAGNETIC RADIATION
Electromagnetic radiation consists of roentgen and gamma radiation. They differ only in the way in which they are produced: gamma rays are produced intranuclearly, and roentgen rays are produced extranuclearly. In practice, this means that gamma rays used in radiation therapy are produced by the decay of radioactive isotopes and that almost all of the roentgen rays used in radiation therapy are made by electrical machines. Exceptions are roentgen rays produced by orbital electron rearrangements, as in the decay of iodine 125 (**125I), which is a radioactive isotope but produces photons by extranuclear processes. **125I also emits a small number of gamma rays from the nucleus.
The intensity of electromagnetic radiation dissipates as the inverse square of the distance from the source. The dose of radiation 2 cm from a point source is 25% of the dose at 1 cm. The relative prevalence of the three dominant absorption mechanisms of electromagnetic radiation depends on the energy of the radiation. The first is photoelectric absorption, which predominates at lower energies. In this circumstance, the photon interaction results in the ejection of a tightly bound orbital electron. The vacancy left in the atomic shell is then filled by another electron falling from an outer shell of the same atom or from outside the atom. All or most of the photon energy of the transition is lost in this process. Photoelectric absorption varies with the cube of the atomic number (Z**3). This has significant practical implications because it explains why materials with high atomic numbers, such as lead, are such effective shielding materials. It also means that bones absorb significantly more radiation than soft tissues at lower photon energies, the basis for conventional diagnostic radiology.
The second type of radiation absorption is the
The third type of absorption is the pair production process. This type of absorption requires an incident photon energy greater than 1.02 MeV. In this process, positive and negative electrons are produced at the same time.
The fundamental quantity necessary to describe the interaction of radiation with matter is the amount of energy absorbed per unit mass. This quantity is called absorbed dose, and the rad was the most commonly used unit. Absorbed dose is measured in joules per kilogram; another name for 1 joule/kg is the Gray (1 Gray = 100 rad), which is now the recommended unit. The roentgen (R) is a unit of roentgen rays or gamma rays based on the ability of radiation to ionize air. At the energies used in radiation therapy, 1 R of roentgen rays or gamma rays results in a dose of somewhat less than 1 rad (0.01 Gy) in soft tissue.
The different ranges of electromagnetic radiations used in clinical practice are superficial radiation or roentgen rays from about 10 to 125 KeV; orthovoltage radiation or electromagnetic radiation between 125 and 400 KeV; and supervoltage or megavoltage radiation for energies above 400 KeV. There are important differences between these classes. As energy increases, the penetration of the roentgen rays increases (Fig. 16-1), and at supervoltage energies, absorption in bone is not higher than that in surrounding soft tissues, as is the case with lower energies. This is because at supervoltage energies, Compton absorption predominates. Compared with orthovoltage, supervoltageradiation is skin sparing, meaning that the maximum dose is not reached in the skin but instead occurs below the surface. The electrons created in the interaction travel some distance and do not attain full intensity until they reach some depth, resulting in a reduced dose to the skin. With orthovoltage radiation, the skin frequently is the dose-limiting normal tissue.
RADIATION TECHNIQUES
Two general types of radiation techniques are used clinically — brachytherapy and teletherapy.
In brachytherapy, the radiation device is placed within or close to the target volume. Examples of this are interstitial and intracavitary radiation used in the treatment of many gynecologic and oral tumors. Teletherapy uses a device located at a distance from the patient, as is the case in most orthovoltage or supervoltage machines.
Because the radiation source is close to or within the target volume with brachytherapy, the dose is determined largely by inverse-square considerations. This means that the geometry of the implant is important. Spatial arrangements have been determined for different types of applications based on the particular anatomic considerations of the tumor and important normal tissues. An example of isodose distribution around anintracavitary application for carcinoma of the cervix is shown in Figure 16-2. The dose decreases rapidly as the distance from the applicator increases. This emphasizes the importance of proper placement. The applicator pictured is used to treat the cervix, uterus, and important paracervical tissues, while limiting excessive irradiation of the bladder and rectum in front of and behind the tumor.
Historically, the removable interstitial and intracavitary sources used were radium and radon, the latter primarily for permanent implants. Marie Curie, the discoverer of radium, recognized its importance early and championed the medical use of these isotopes. They were important tools in early cancer therapy but now have been largely replaced by manmade isotopes, which overcome most of the disadvantages of the naturally occurring ones.
Initially, even removable isotopes were used by directly applying the isotope, and thereby exposing the operator to significant radiation doses. This problem has largely been circumvented through the use of **137Cs, **192Ir, and **60Co. The first two have a lower energy and are much easier to shield. Afterloading techniques are used for removable implants as often as possible. Receptacles for the radioactive material are placed in the patient in the form of needles, tubes, or intracavitary applicators. When they have been satisfactorily placed they areafterloaded with the radiation sources. Permanent implants are primarily done today with **198Au and **125I. The latter is also used for removable implants. Its low energy makes shielding a simple matter.
Teletherapy isodose depends on inverse-square considerations and tissue absorption. The distribution of radiation depends on characteristics of the machine and the patient. The isodose curve depends on the energy of radiation, the distance from the source of radiation, and the density and atomic number of the absorbing material. The beam of radiation produced in typical radiation treatment may be modified to make isodose distributions conform to the specific target volume, and individually designed shields are used to protect vital normal tissues.
SURVIVAL CURVES
Survival curves plot the fraction of cells surviving radiation against the dose given. Survival is determined by the ability to form a macroscopic colony. The simplest relation can be seen for bacteria in which survival is a constant exponential function of dose. The importance of this exponential relation is that for a given dose increment, a constant proportion, rather than a constant number, of cells is killed. Because of the randomness of radiation damage, if there is on average one lethal lesion per cell, some cells have one lesion, some more than one, and some less than one. Under such circumstances, the proportion of cells that have less than one, that is, no lethal events, is e/**1, or a survival fraction of 0.37. The dose required to reduce the survival fraction to 37% on the exponential curve is known as the D(o). This term is related to the slope of the exponential survival curve. If a smaller dose is required to reduce the survival fraction to 37%, the cells are more sensitive to radiation.
Chemotherapy
Chemotherapy is the use of anticancer drugs to treat cancerous cells. Chemotherapy has been used for many years and is one of the most common treatments for cancer. In most cases, chemotherapy works by interfering with the cancer cell’s ability to grow or reproduce. Different groups of drugs work in different ways to fight cancer cells. Chemotherapy may be used alone for some types of cancer or in combination with other treatments such as radiation or surgery. Often, a combination of chemotherapy drugs is used to fight a specific cancer. Certain chemotherapy drugs may be given in a specific order depending on the type of cancer it is being used to treat. While chemotherapy can be quite effective in treating certain cancers, chemotherapy drugs reach all parts of the body, not just the cancer cells. Because of this, there may be many side effects during treatment. Being able to anticipate these side effects can help you and your caregivers prepare, and, in some cases prevent these symptoms from occurring.
How is chemotherapy administered?
Chemotherapy can be given:
- as a pill to swallow.
- as an injection into the muscle or fat tissue.
- intravenously (directly to the bloodstream; also called IV).
- topically (applied to the skin)
- directly into a body cavity
What are some of the chemotherapy drugs and their potential side effects?
There are over 50 chemotherapy drugs that are commonly used. The following table gives examples of some chemotherapy drugs and their various names. It lists some of the cancer types but not necessarily all of the cancers for which they are used, and describes various side effects. Side effects may occur just after treatment (days or weeks) or they may occur later (months or years) after the chemotherapy has been given. The side effects list provided below do not comprise an all-inclusive list. Other side effects are possible.
As each person’s individual medical profile and diagnosis is different, so is his/her reaction to treatment. Side effects may be severe, mild, or absent. Be sure to discuss with your cancer care team any/all possible side effects of treatment before the treatment begins.
|
Chemotherapy Drug |
Possible Side Effects |
|
carboplatin (Paraplatin) › usually given intravenously (IV) |
› decrease in blood cell counts |
|
cisplatin (Platinol, Platinol-AQ) › usually given intravenously (IV) |
› decrease in blood cell counts |
|
cyclophosphamide (Cytoxan, Neosar) › can be given intravenously (IV) or orally |
› decrease in blood cell counts |
|
doxorubicin (Adriamycin) › given intravenously (IV) |
› decrease in blood cell counts |
|
etoposide (VePesid) › can be given intravenously (IV) or orally |
› decrease in blood cell counts |
|
fluorouracil (5-FU) › given intravenously (IV) |
› decrease in blood cell counts |
|
gemcitabine (Gemzar) › given intravenously (IV) |
› decrease in blood cell counts |
|
irinotecan (Camptosar) › given intravenously (IV) |
› decrease in blood cell counts |
|
methotrexate › may be given intravenously (IV), intrathecally (into the spinal column), or orally |
› decrease in blood cell counts |
|
paclitaxel (Taxol) › given intravenously (IV) |
› decrease in blood cell counts |
|
topotecan (Hycamtin) › given intravenously (IV) |
› decrease in blood cell counts |
|
vincristine › usually given intravenously (IV) |
› numbness or tingling in the fingers or toes |
|
vinblastine (Velban) › given intravenously (IV) |
› decrease in blood cell counts |
Biological Therapy For Cancer Treatment
Biological therapy (also called immunotherapy, biological response modifier therapy, or biotherapy) uses the body’s immune system to fight cancer. The cells, antibodies, and organs of the immune system work to protect and defend the body against foreign invaders, such as bacteria or viruses. Physicians and researchers have found that the immune system might also be able to both determine the difference between healthy cells and cancer cells in the body, and to eliminate the cancer cells.
Biological therapies are designed to boost the immune system, either directly or indirectly, by assisting in the following:
- making cancer cells more recognizable by the immune system, and therefore more susceptible to destruction by the immune system
- boosting the killing power of immune system cells
- changing the way cancer cells grow, so that they act more like healthy cells
- stopping the process that changes a normal cell into a cancerous cell
- enhancing the body’s ability to repair or replace normal cells damaged or destroyed by other forms of cancer treatment, such as chemotherapy or radiation
- preventing cancer cells from spreading to other parts of the body
How does the immune system fight cancer? The immune system includes different types of white blood cells – each with a different way to fight against foreign or diseased cells, including cancer:
- lymphocytes – white blood cells, including B cells, T cells, and NK cells.
B cells – produce antibodies that attack other cells.
T cells – directly attack cancer cells themselves and signal other immune system cells to defend the body.
natural killer cells (NK cells) – produce chemicals that bind to and kill foreign invaders in the body.
monocytes – white blood cells that swallow and digest foreign particles.
These types of white blood cells – B cells, T cells, natural killer cells, and monocytes – are in the blood and thus circulate to every part of the body, providing protection from cancer and other diseases. Cells secrete two types of substances: antibodies and cytokines. Antibodies respond to (harmful) substances that they recognize, called antigens. Specific (helpful) antibodies match specific (foreign) antigens by locking together. Cytokines are proteins produced by some immune system cells and can directly attack cancer cells. Cytokines are “messengers” that “communicate” with other cells.
What are the different types of biological therapies?
There are many different types of biological therapies used in cancer treatment, including the following:
- nonspecific immunomodulating agents. Nonspecific immunomodulating agents are biological therapy drugs that stimulate the immune system, causing it to produce more cytokines and antibodies to help fight cancer and infections in the body. Fighting infection is important for a person with cancer.
- biological response modifiers (BRMs). Biological response modifiers (BRMs) change the way the body’s defenses interact with cancer cells. BRMs are produced in a laboratory and given to patients to:
- boost the body’s ability to fight the disease.
- direct the immune system’s disease fighting powers to disease cells.
- strengthen a weakened immune system.
BRMs include interferons, interleukins, colony-stimulating factors, monoclonal antibodies, cytokine therapy, and vaccines:
- interferons (IFN)
Interferons (IFN) are a type of biological response modifier that naturally occurs in the body. They are also produced in the laboratory and given to cancer patients in biological therapy. They have been shown to improve the way a cancer patient’s immune system acts against cancer cells. Interferons may work directly on cancer cells to slow their growth, or they may cause cancer cells to change into cells with more normal behavior. Some interferons may also stimulate natural killer cells (NK) cells, T cells, and macrophages – types of white blood cells in the bloodstream that help to fight cancer cells. - interleukins (IL)
Interleukins (IL) stimulate the growth and activity of many immune cells. They are proteins (cytokines) that occur naturally in the body, but can also be made in the laboratory. Some interleukins stimulate the growth and activity of immune cells, such as lymphocytes, which work to destroy cancer cells - colony-stimulating factors (CSFs)
Colony-stimulating factors (CSFs) are proteins given to patients to encourage stem cells within the bone marrow to produce more blood cells. The body constantly needs new white blood cells, red blood cells, and platelets, especially when cancer is present. CSFs are given, along with chemotherapy, to help boost the immune system. When cancer patients receive chemotherapy, the bone marrow’s ability to produce new blood cells is suppressed, making patients more prone to developing infections. Parts of the immune system cannot function without blood cells, thus colony-stimulating factors encourage the bone marrow stem cells to produce white blood cells, platelets, and red blood cells. With proper cell production, other cancer treatments can continue enabling patients to safely receive higher doses of chemotherapy. - monoclonal antibodies. Monoclonal antibodies are agents, produced in the laboratory, that bind to cancer cells. When cancer-destroying agents are introduced into the body, they seek out the antibodies and kill the cancer cells. Monoclonal antibody agents do not destroy healthy cells.
- cytokine therapy. Cytokine therapy uses proteins (cytokines) to help your immune system recognize and destroy those cells that are cancerous. Cytokines are produced naturally in the body by the immune system, but can also be produced in the laboratory. This therapy is used with advanced melanoma and with adjuvant therapy (therapy given after or in addition to the primary cancer treatment). Cytokine therapy reaches all parts of the body to kill cancer cells and prevent tumors from growing.
- vaccine therapy. Vaccine therapy is still an experimental biological therapy. The benefit of vaccine therapy has not yet been proven. With infectious diseases, vaccines are given before the disease develops. Cancer vaccines, however, are given after the disease develops, when the tumor is small. Scientists are testing the value of vaccines for melanoma and other cancers. Sometimes, vaccines are combined with other therapies such as cytokine therapy.
Side effects of biological therapies. As each person’s individual medical profile and diagnosis is different, so is his/her reaction to treatment. Side effects may be severe, mild, or absent. Be sure to discuss with your cancer care team any/all possible side effects of treatment before the treatment begins. Side effects of biological therapy, which often mimic flu-like symptoms, vary according to the type of therapy given and may include the following:
- fever
- chills
- nausea
- vomiting
- loss of appetite
- fatigue
Specifically, cytokine therapy often causes fever, chills, aches, and fatigue. Other side effects include a rash or swelling at the injection site. Therapy can cause fatigue and bone pain and may affect blood pressure.
Hormone Therapy For Cancer Treatment
Hormones are chemicals produced by glands, such as the ovaries and testicles. Hormones help some types of cancer cells to grow, such as breast cancer and prostate cancer. In other cases, hormones can kill cancer cells, make cancer cells grow more slowly, or stop them from growing. Hormone therapy as a cancer treatment may involve taking medications that interfere with the activity of the hormone or stop the production of the hormones. Hormone therapy may involve surgically removing a gland that is producing the the hormones.
How does hormone therapy work? Your physician may recommend a hormone receptor test to help determine treatment options and to help learn more about the tumor. This test can help to predict whether the cancer cells are sensitive to hormones. The hormone receptor test measures the amount of certain proteins (called hormone receptors) in cancer tissue. Hormones (such as estrogen and progesterone that naturally occur in the body) can attach to these proteins. If the test is positive, it is indicating that the hormone is probably helping the cancer cells to grow. In this case, hormone therapy may be given to block the way the hormone works and help keep the hormone away from the cancer cells (hormone receptors). If the test is negative, the hormone does not affect the growth of the cancer cells, and other effective cancer treatments may be given.
If the test indicates that the hormones are affecting your cancer, the cancer may be treated in one of following ways:
- treating cancer cells to keep them from receiving the hormones they need to grow
- treating the glands that produce hormones to keep them from making hormones
- surgery to remove glands that produce the hormones, such as the ovaries that produce estrogen, or the testicles that produce testosterone
The type of hormone therapy a person receives depends upon many factors, such as the type and size of the tumor, the age of the person, the presence of hormone receptors on the tumor, and other factors.
Your physician may prescribe hormone therapies before some cancer treatments or after other cancer treatments. If hormone therapy is given before the primary treatment, it is called neoadjuvant treatment. Neoadjuvant treatments help to kill cancer cells and contribute to the effectiveness of the primary therapy. If hormone therapy is given after the primary cancer treatment, it is called adjuvant treatment. Adjuvant therapy is given to improve the chance of a cure.
With some cancers, patients may be given hormone therapy as soon as cancer is diagnosed, and before any other treatment. It may shrink a tumor or it may halt the advance of the disease. And in some cancer, such as prostate cancer, it is helpful in alleviating the painful and distressing symptoms of advanced disease. The National Cancer Institute (NCI) states that although hormone therapy cannot cure prostate cancer, it will usually shrink or halt the advance of disease, often for years.
What medications are used for hormone therapy?
Hormone therapy may be used to prevent the growth, spread, and recurrence of breast cancer. The female hormone estrogen can increase the growth of breast cancer cells in some women. Tamoxifen (Nolvadex®) is a medication used in hormone therapy to treat breast cancer by blocking the effects of estrogen on the growth of malignant cells in breast tissue. However, tamoxifen does not stop the production of estrogen.
Hormone therapy may be considered for women whose breast cancers test positive for estrogen and progesterone receptors.
Drugs recently approved by the US Food and Drug Administration (FDA), called aromatase inhibitors, are used to prevent the recurrence of breast cancer in postmenopausal women. These drugs, such as anastrozole (Arimidex®) and letrozole (Femara®), prevent estrogen production. Anastrozole is effective only in women who have not had previous hormonal treatment for breast cancer. Letrozole is effective in women who have previously been treated with tamoxifen. Possible side effects of these drugs include osteoporosis or bone fractures. Another new drug for recurrent breast cancer is fulvestrant (Faslodex®). Also approved by the FDA, this drug eliminates the estrogen receptor rather than blocking it, as is the case with tamoxifen, letrozole, or anastrozole. This drug is used following previous antiestrogen therapy. Side effects for fulvestrant include hot flashes, mild nausea, and fatigue.
Men who have breast cancer may also be treated with tamoxifen. Tamoxifen is currently being studied as a hormone therapy for treatment of other types of cancer.
With prostate cancer, there may be a variety of medications used in hormone therapy. Male hormones, such as testosterone, stimulate prostate cancer to grow. Hormone therapy is given to help stop hormone production and to block the activity of the male hormones. Hormone therapy can cause a tumor to shrink and the prostate-specific antigen (PSA) levels to decrease.
What are the side effects of hormone therapy?
The following are some potential side effects that may occur with hormone therapy. However, the side effects will vary depending upon the type of hormone therapy that is given. Every person’s hormone treatment experience is different and not every person will experience the same side effects. Discuss the potential side effects of your hormone therapy with you physician.
As each person’s individual medical profile and diagnosis is different, so is his/her reaction to treatment. Side effects may be severe, mild, or absent. Be sure to discuss with your cancer care team any/all possible side effects of treatment before the treatment begins.
For prostate cancer, either the surgical removal of the testes or hormone drug therapy can improve the cancer. Both surgery and drugs may cause the following side effects:
- hot flashes
- impotence
- a loss of desire for sexual relations
- male breast enlargement
For breast cancer, some women may experience side effects from tamoxifen that are similar to the symptoms some women experience in menopause. Other women do not experience any side effects when taking tamoxifen. The following are some of the side effects that may occur when taking tamoxifen:
- hot flashes
- nausea and/or vomiting
- vaginal spotting (a blood stained discharge from the vagina that is not part of the regular menstrual cycle)
- increased fertility in younger women
- irregular menstrual periods
- fatigue
- skin rash
- loss of appetite or weight gain
- headaches
- vaginal dryness or itching and/or irritation of the skin around the vagina
Taking tamoxifen also increases the risk of endometrial cancer (involves the lining of the uterus) and uterine sarcoma (involves the muscular wall of the uterus), both cancers of the uterus. There is also a very small risk of blood clots and stroke, eye problems such as cataracts, and liver toxicities. Tamoxifen should be avoided during pregnancy.
Tamoxifen is used to treat men with breast cancer as well. As each person’s individual medical profile and diagnosis is different, so is his/her reaction to treatment. Side effects may be severe, mild, or absent. Be sure to discuss with your cancer care team any/all possible side effects of treatment before the treatment begins.
Men may experience the following side effects:
- headaches
- nausea and/or vomiting
- skin rash
- impotence
- decrease in sexual interest
Angiogenesis Inhibitors For Cancer Treatment
What is angiogenesis?
§ Angiogenesis, the formation of new blood vessels, is a process controlled by certain chemicals produced in the body. Although this may help iormal wound healing, cancer can grow when these new blood vessels are created. Angiogenesis provides cancer cells with oxygen and nutrients. This allows the cancer cells to multiply, invade nearby tissue, and spread to other areas of the body (metastasize).
§ What are angiogenesis inhibitors and how do they work?
§ A chemical that interferes with the signals to form new blood vessels is referred to as an angiogenesis inhibitor.
§ Sometimes called antiangiogenic therapy, this experimental treatment may prevent the growth of cancer by blocking the formation of new blood vessels. In some animal case studies, angiogenesis inhibitors have caused cancer to shrink and resolve completely.
§ In humans, angiogenesis inhibitors are only used in clinical trials at this time. These drugs are still considered investigational. Research studies are now underway to help scientists learn whether the approach will apply to human cancers. Patients with cancers of the breast, prostate, pancreas, lung, stomach, ovary, cervix, and others are being studied. If the research studies demonstrate that angiogenesis inhibitors are both safe and effective for cancer treatment in humans, these drugs will need approval by the US Food and Drug Administration (FDA) to become available for widespread use.
Hyperthermia For Cancer Treatment
Hyperthermia is heat therapy. Heat has been used for hundreds of years as therapy. According to the National Cancer Institute(NCI), scientists believe that heat may help shrink tumors by damaging cells or depriving them of the substances they need to live. There are research studies underway to determine the use and effectiveness of hyperthermia in cancer treatment.
How is it used? Heat can be applied to a very small area or to an organ or limb. Hyperthermia is usually used with chemotherapy, radiation therapy, and other treatment therapies. The types of hyperthermia described in the following chart:
|
Type of Hyperthermia |
Treatment Area |
Method of Application |
|
local hyperthermia |
Treatment area includes a tumor or other small area. |
or
|
|
regional hyperthermia |
An organ or a limb is treated. |
or
|
|
whole body hyperthermia |
The whole body is treated when cancer has spread. |
|
Are there any side effects? There are no known complications of hyperthermia. Side effects may include skin discomfort or local pain. Hyperthermia can also cause blisters and occasionally burns but generally these heal quickly.
Laser Therapy For Cancer Treatment
The term LASER stands for “Light Amplification by the Stimulated Emission of Radiation.” Laser light is concentrated so that it makes a very powerful and precise tool. Laser therapy uses light to treat cancer cells. Consider the following additional information regarding laser therapy:
– Lasers can cut a very tiny area, less than the width of the finest thread, to remove very small cancers without damaging surrounding tissue.
– Lasers are used to apply heat to tumors in order to shrink them.
– Lasers are sometimes used with drugs that are activated by laser light to kill cancer cells.
– Lasers can bend and go through tubes to access hard to reach places.
– Lasers are used in microscopes to enable physicians to view the site being treated.
How are lasers used during cancer surgery? Laser surgery is a type of surgery that uses special light beams instead of instruments, such as scapels, to perform surgical procedures. There are several different types of lasers, each with characteristics that perform specific functions during surgery. Laser light can be delivered either continuously or intermittently and can be used with fiber optics to treat areas of the body that are often difficult to access. The following are some of the different types of laser used for cancer treatment:
– carbon dioxide (CO2) lasers
Carbon dioxide (CO2) lasers can remove a very thin layer of tissue from the surface of the skin without removing deeper layers. The CO2 laser may be used to remove skin cancers and some precancerous cells.
– Neodymium:yttrium-aluminum-garnet (Nd:YAG) lasers
Neodymium:yttrium-aluminum-garnet (Nd:YAG) lasers can penetrate deeper into tissue and can cause blood to clot quickly. The laser light can be carried through optical fibers to reach less accessible internal parts of the body. For example, the Nd:YAG laser can be used to treat throat cancer.
– laser-induced interstitial thermotherapy (LITT). Laser-induced interstitial thermotherapy (LITT) uses lasers to heat certain areas of the body. The lasers are directed to areas between organs (interstitial areas) that are near a tumor. The heat from the laser increases the temperature of the tumor, thereby shrinking, damaging, or destroying the cancer cells.
– argon lasers. Argon lasers pass only through superficial layers of tissue such as skin. Photodynamic therapy (PDT) uses argon laser light to activate chemicals in the cancer cells.
What is photodynamic therapy? Because cancer cells can be selectively destroyed while most healthy cells are spared, photodynamic therapy (PDT) is useful for the treatment of certain cancer tumors. Photodynamic therapy uses chemicals in the cancer cells that react to the argon light. These chemicals, called photosensitizing agents, are not naturally found in the cancer cells. In PDT, the chemicals are given to the cancer patient by injection. Cells throughout the body absorb the chemicals. The chemicals collect and stay longer in the cancer cells than in the healthy cells. At the right time, when the healthy cells surrounding the tumor may already be relatively free of the chemicals, the red light of an argon laser can be focused directly on the tumor. It hits the tumor and, as the cells absorb the light, a chemical reaction destroys the cancer cells.
Argon lasers can pass through about an inch of tissue without damaging it, so PDT can be used for the treatment of cancers that are close to the surface of the skin. It can also be directed at cancers that are located in the lining of the internal organs, such as:
– in the lungs by using a bronchoscope
– in the esophagus and gastrointestinal tract by using an endoscope
– in the bladder by using a cystoscope
What cancers may be treated with laser therapy?
Lasers are used in surgery for the following types of cancer because they often have a special requirement that only lasers can meet – such as the ability to reach a hard to treat location, apply heat, or cut only a very small area:
vocal cord, cervical, skin, lung, vaginal, vulvar, penile, palliative surgery.
Laser surgery is also used for palliative surgery in cancer patients. The purpose of palliative surgery is to help the patient feel better or function better even though it may not treat the cancer. An example of this type of surgery may involve surgery to remove a growth that is making it difficult for a patient to eat comfortably.
Side effects of photodynamic therapy. The side effects of photodynamic therapy are relatively mild and may include a small amount of damage to healthy tissue. Also, a patient’s skin and eyes are sensitive to light for as long as six weeks or more after treatment is completed. Depending on the area that is treated, patients may experience other temporary side effects. As each person’s individual medical profile and diagnosis is different, so is his/her reaction to treatment. Side effects may be severe, mild, or absent. Be sure to discuss with your cancer care team any/all possible side effects of treatment before the treatment begins.
3. TNM Classification of Malignant Tumours
TNM is a cancer staging system that describes the extent of a person’s cancer.
· T describes the size of the original (primary) tumor and whether it has invaded nearby tissue,
· N describes nearby (regional) lymph nodes that are involved,
· M describes distant metastasis (spread of cancer from one part of the body to another).
The TNM staging system for all solid tumors was devised by Pierre Denoix between 1943 and 1952, using the size and extension of the primary tumor, its lymphatic involvement, and the presence of metastases to classify the progression of cancer.
TNM is developed and maintained by the Union for International Cancer Control (UICC) to achieve consensus on one globally recognised standard for classifying the extent of spread of cancer. The TNM classification is also used by the American Joint Committee on Cancer (AJCC) and the International Federation of Gynecology and Obstetrics (FIGO). In 1987, the UICC and AJCC staging systems were unified into a single staging system.
Most of the common tumors have their own TNM classification. Not all tumors have TNM classifications, e.g., there is no TNM classification for brain tumors.
The general outline for the TNM classification is below. The values in parentheses give a range of what can be used for all cancer types, but not all cancers use this full range.
Mandatory parameters:
· T: size or direct extent of the primary tumor
· Tx: tumor cannot be evaluated
· Tis: carcinoma in situ
· T0: no signs of tumor
· T1, T2, T3, T4: size and/or extension of the primary tumor
· N: degree of spread to regional lymph nodes
· Nx: lymph nodes cannot be evaluated
· N0: tumor cells absent from regional lymph nodes
· N1: regional lymph node metastasis present; (at some sites: tumor spread to closest or small number of regional lymph nodes)
· N2: tumor spread to an extent between N1 and N3 (N2 is not used at all sites)
· N3: tumor spread to more distant or numerous regional lymph nodes (N3 is not used at all sites)
· M: presence of distant metastasis
· M0: no distant metastasis
· M1: metastasis to distant organs (beyond regional lymph nodes)[2]
The Mx designation was removed from the 7th edition of the AJCC/UICC system.
Other parameters:
· G (1–4): the grade of the cancer cells (i.e. they are “low grade” if they appear similar to normal cells, and “high grade” if they appear poorly differentiated)
· S (0-3): elevation of serum tumor markers
· R (0-2): the completeness of the operation (resection-boundaries free of cancer cells or not)
· L (0-1): invasion into lymphatic vessels
· V (0-2): invasion into vein (no, microscopic, macroscopic)
· C (1–5): a modifier of the certainty (quality) of the last mentioned parameter
Prefix modifiers:
· c: stage given by clinical examination of a patient. The c-prefix is implicit in absence of the p-prefix
· p: stage given by pathologic examination of a surgical specimen
· y: stage assessed after chemotherapy and/or radiation therapy; in other words, the individual had neoadjuvant therapy.
· r: stage for a recurrent tumor in an individual that had some period of time free from the disease.
· a: stage determined at autopsy.
· u: stage determined by ultrasonography or endosonography. Clinicians often use this modifier although it is not an officially defined one
For the T, N and M parameters exist subclassifications for some cancer-types (e.g. T1a, Tis, N1i)
Examples:
· Small, low-grade cancer, no metastasis, no spread to regional lymph nodes, cancer completely removed, resection material seen by pathologist: pT1 pN0 M0 R0 G1; this grouping of T, N, and M would be considered Stage I.
· Large, high grade cancer, with spread to regional lymph nodes and other organs, not completely removed, seen by pathologist: pT4 pN2 M1 R1 G3; this grouping of T, N, and M would be considered Stage IV. Most Stage I tumors are curable; most Stage IV tumors are inoperable.
Uses and aims:
Some of the aims for adopting a global standard are to:
· Aid medical staff in staging the tumour helping to plan the treatment.
· Give an indication of prognosis.
· Assist in the evaluation of the results of treatment.
· Enable facilities around the world to collate information more productively.
Since the number of combinations of categories is high, combinations are grouped to stages for better analysis.
Versions: It is crucial to be aware that the criteria used in the TNM system have varied over time, sometimes fairly substantially, according to the different editions that AJCC and UICC have released. The dates of publication and adoption for use of AJCC editions is summarized here; past editions are available from AJCC for web download.
· Edition 1 published 1977 and went into effect 1978
· Edition 2 published 1983 and went into effect 1984
· Edition 3 published 1988 and went into effect 1989
· Edition 4 published 1992 and went into effect 1993
· Edition 5 published 1997 and went into effect 1998
· Edition 6 published 2002 and went into effect 2003
· Edition 7 published 2009 and went into effect 2010
As a result, a given stage may have quite a different prognosis depending on which staging edition is used, independent of any changes in diagnostic methods or treatments, an effect that has been termed “stage migration.” The technologies used to assign patients to particular categories have changed also, and by intuitive consideration it can be seen that increasingly sensitive methods tend to cause individual cancers to be reassigned to higher stages, making it improper to compare that cancer’s prognosis to the historical expectations for that stage. Finally, of course, a further important consideration is the effect of improving treatments over time as well.
Educational materials prepared by Prof. Igor Y. Galaychuk,
02.2014.
