CARCINOMA of CERVIX and UTERUS.

OVARIAN CANCER.

Molecular Biology of Gynecologic Cancers

ENDOMETRIAL CANCER

Although this most common gynecologic cancer carries the best prognosis, it is important to differentiate between the classic endometrioid tumors that tend to be estrogen dependent and well differentiated, from other less common high-risk uterine malignancies, such as uterine papillary serous carcinomas (UPSCs), clear cell carcinomas, mixed mullerian tumors (MMTs), or sarcomas, which appear to have a different biology.

MICROSATELLITE INSTABILITY

The replication error (RER+) phenotype is characteristic of cancers arising in HNPCC kindreds (a familial cancer syndrome with a high incidence of colon, endometrial, gastric, and a lower incidence of ovarian and pancreatic cancers), and is also found in approximately 20% of sporadic endometrial cancers. The RER+ phenotype per se does not appear to correlate with clinicopathologic features of the tumors or clinical outcome; thus the hereditary form of endometrial cancer alone does not appear to portend a worse prognosis than the sporadic form. Mutation of the transforming growth factor (TGF) beta receptor type II gene is common in RER+ colon and gastric cancers, but uncommon in RER+ endometrial cancers even those arising in HNPCC kindreds, suggesting that the genesis of RER+ tumors even within the same familial cancer syndrome is not the same. Among sporadic endometrial cancers, when present, the microsatellite instability is confined to the malignant cells, and is not seen in the adjacent normal epithelium. Although inactivation of both alleles of either hMSH2 or MLH1 (DNA mismatch repair genes) appears to underlie microsatellite instability in tumors of HNPCC kindreds, similar to the findings in sporadic colon cancers, sporadic endometrial cancers were not associated with mutations of any of the four known human mismatch repair genes. In contrast, 25% of uterine sarcomas, an entity not recognized to be part of a familial cancer syndrome, exhibits microsatellite instability that may be related to a mutation in the hMSH2 gene. Again, clinical outcome was not correlated with RER+ status in those tumors; thus this finding does not underlie the more aggressive biology of the sarcomas.

ONCOGENES

Kirsten (Ki)-ras activating point mutations in codons 12 and 13 have been implicated in the development of atypical endometrial hyperplasias and endometrioid carcinomas in Japanese women, as well as in colon cancers. Recent studies of endometrial cancers arising in US women, however, show the prevalence of such mutations to be significantly lower (11% versus 31%) than in Japan. Endometrioid cancers arising in Japanese women tend to be high grade and deeply invasive, are less common than in the United States, and are not generally associated with hormonal exposure. These data suggest that genetic or environmental factors may influence endometrial carcinogenesis. Notable was the almost complete absence of Ki-ras mutations in an aggressive form of endometrial cancer, UPSC, when compared to the usual endometrioid tumors.

Overexpression of HER-2/neu has been associated with advanced stage, deep myometrial invasion, and poor survival in endometrial cancers in several studies. Gene amplification did not underlie all cases of HER-2/neu overexpression, although both gene amplification and overexpression were each associated with poor outcomes. When multivariate analysis was used to determine if HER-2/neu was an independent prognostic factor in endometrial cancers taking into account other molecular features such as DNA ploidy, epidermal growth factor receptor, or p53 status, HER-2/neu status failed to achieve significance. Both c-myc gene amplification and c-fms overexpression have also been associated with advanced stage and high grade endometrial cancers.

HORMONE-RELATED MOLECULAR ABNORMALITIES

This is a logical direction for endometrial cancer research, because estrogen acts as a tumor promoter for the classic endometrioid cancers. Aromatase cytochrome p450 is part of the complex responsible for conversion of C19 steroids to estrogen; its increased expression in endometrial cancers, but not in normal endometria, suggests a role in promotion of neoplastic proliferation.

The findings of both gonadotropin-releasing hormone (GnRH) (the ligand) and its receptor, as well as the luteinizing hormone (LH) receptor in endometrial cancers may serve as a rationale for the therapeutic use of GnRH analogues in the treatment of endometrial cancer (although this approach has not been shown to be clinically relevant to date). GnRH analogues may act directly on GnRH-sensitive cancers, as well as indirectly by decreasing systemic LH levels. A clue to the signal transduction pathway of GnRH comes from data in ovarian cancers, where GnRH has an antimitogenic effect by stimulating protein tyrosine phosphatase activity.

Tamoxifen has been associated with an increased risk of development of endometrial cancers, with a possible preferential risk for the high grade nonendometrioid subtypes, such as UPSC or MMTs, although this is controversial. Molecular abnormalities associated with UPSC include overexpression of p53 and c-myc gene amplification; p53 overexpression correlated with a poor prognosis. Two functional different isoforms of progesterone receptor have been described, which may account for some of the tissue-specific differences in the effects of progestins and antiprogestins on the breast as compared with the endometrium.

OVARIAN CANCER

Most of the recent breakthroughs in understanding the molecular basis for this disease has been in the area of hereditary epithelial ovarian cancer syndromes, which affect up to 5% of ovarian cancer cases. Much work is still needed to understand the biology underlying sporadic ovarian cancers, which invariably present as advanced stage disease and have a poor long-term outcome.

CERVICAL AND VULVAR CANCER

The study of the role of viruses in the carcinogenesis of lower genital tract malignancies (thought to be a field effect) has focused on cervical cancer, the third most common gynecologic cancer in the United States. Extension of those studies to vulvar cancer has led to support for two separate etiologies of vulvar cancer: one related to human papillomavirus (HPV), with epidemiologic risk factors similar to that for cervical cancer, and the other that does not appear to be HPV related.

HUMAN PAPILLOMAVIRUS. That HPV is a critical factor for cervical carcinogenesis, and that the HPV E6 and E7 genes are oncogenic are clearly established. Infection of human keratinocytes by the oncogenic HPV subtypes leads to abnormalities in differentiation and growth; however, only after long-term culture of immortalized cells does an occasional clone become tumorigenic in nude mice, suggesting that HPV infection alone is not sufficient for cervical carcinogenesis. This is supported by data from transgenic mice studies, where E6/E7 genes can give rise to hyperplastic and neoplastic lesions of epithelial cell types after a latent period, however, epidermoid cervical cancers have not been noted. Cervical cancers of mesenchymal origin were noted to arise after a long latent period in some of the female progeny of transgenic mice into whom HPV-18 LCR/E6/E7 was introduced. While the majority of invasive cancers contain integrated forms of HPV, usually at fragile sites that result in cis activation of protooncogenes such as c-myc, and the large majority of dysplasias contain episomal forms of HPV, this is not always the case. In invasive cancers, HPV-18 is always found to be integrated in the host genome, while HPV-16 can be found in an episomal location one third of the time. When DNA integration occurs, it does so by preferentially disrupting the E2 open reading frame, thus, the negative effect of the E2 protein on E6/E7 transcriptional activity; or in such a way that transcriptional initiation from host sequences gives rise to overexpression of E6/E7. High level transcription of E6/E7 is seen in CIN 3 and invasive cancers when compared to CIN 1 and 2. Such overexpression has been shown in vitro to lead to radioresistance of cervical cancer cells. Among both low grade and high grade dysplasias, the presence of oncogenic HPV subtypes has been reported to be closely associated with monoclonality.

Cervical Cancer

Cervical cancer forms in the interior lining of the cervix, the junction of the vagina and uterus. The development of cervical cancer is typically slow, and occurs over a period of years. The progression to cervical cancer begins with the development of precancerous changes in normal cells. Most of these changes, even if left untreated, will not progress to cancer. However, in 2013 the American Cancer Society estimates 12,340 women will be diagnosed with invasive cervical cancer and 4,030 will die of the disease in the United States.

Cervical cancer is most often diagnosed in middle-aged women, with half of those diagnosed between the ages of 35 and 55. Cervical cancer is very rarely seen in women less than 20 years of age, but approximately 20% of cases occur in women over 65, demonstrating the necessity of continued screening procedures. The five year survival rate of invasive cervical cancer is currently 71% and improvements in screening and the development of prophylactic vaccines have decreased the incidence of late-stage cancer.

Anatomy of the Female Reproductive System

The cervix is part of the female reproductive tract that makes up the lower part of the uterus, also known as the womb. The upper endocervix connects to the uterus and the lower ectocervical region opens to the vagina. This connection allows for the passage of a fetus during delivery. ⁽¹⁾

The graphic above depicts the major components of the female reproductive tract.

1. Vagina - female sex organ, passageway for menstrual blood and fetus during childbirth

2. Cervix - region connecting the uterus to the vagina; the muscles of the cervix support the weight of the fetus during pregnancy

3. Uterus (womb) - location where fertilized egg develops into a fetus and is nourished until birth. Note that the walls of the uterus are thick and lined with muscles

4. Fallopian (uterine) Tube - location of fertilization of an egg by a sperm cell

5. Ovary - produce and store gametes (eggs) and produce the female sex hormones, estrogen and progesterone.

Types of Cervical Cancer

The two types of cervical cancer are squamous cell carcinoma and adenocarcinoma, which are distinguished based on their appearance under a microscope. Both squamous cell and adenocarcinoma begin in the cells that line hollow organs, but squamous cells have a thin, flat appearance while adenocarcinomas involve cells with secretory functions. Squamous cell carcinoma is far more common and makes up approximately 90% of cervical carcinoma cases. Both types have similar risk factors, prognoses and treatments.⁽¹⁾

Risk Factors

There are several risk factors for the development of cervical cancer, both genetic and environmental. These include:

Human Papillomavirus (HPV) Infection
Family History of Cervical Cancer
Age
Sexual and Reproductive History
Socioeconomic Status
Smoking
HIV Infection
In Utero DES Exposure
Long-term use of oral contraceptives

Human Papillomavirus (HPV) Infection:

HPV infection is associated with virtually all cases of cervical cancer. HPV is among the most common sexually transmitted diseases and most women clear the infection within two years without complications. Long term infection with high-risk strains of HPV can lead to the development of cervical dysplasia and cancer.⁽¹⁾

Because of the very high correlation between HPV infection and cervical cancer, the following paragraphs describe HPV in more detail.

The Human papillomaviruses are a family of sexually transmitted viruses consisting of over 100 different viral strains, 40 of which are known to infect the human genital tract and 15 of which have been associated with cervical cancer. Most infections are asymptomatic, but some strains of HPV lead to the development of genital warts.

HPV contains a small, circular, double stranded DNA genome. The virus infects epithelial cells, one of the rapidly dividing cells that form the skin and mucous membranes. The virus reproduces within the host cell and when the cell dies, as part of natural cell turnover, the new virus particles (virions) are released and can infect other cells. The DNA of low-risk types of HPV remains separate from the host DNA, while high-risk forms are able to combine with (insert into) the host DNA. Insertion into the host genome is problematic because it interrupts the transcriptional regulation of the viral genes. Without this control, the viral genome is transcribed at a much higher rate. The HPV genome contains at least two genes whoseprotein products function as oncogenes. These genes are called E6 and E7. The E6 and E7 proteins inhibit the human tumor suppressorproteins p53 and pRb, respectively. Inactivation of p53 leads to cell immortalization and inactivation of pRb leads to increased cell division. While either one of these mutations has the potential to lead to the development of cancer, the ability of HPV to inactivate both tumor suppressors further increases the efficiency of the transformation from normal to cancerous cells.⁽²⁾

Infection with low-risk HPV strains generally produces benign lesions with a minimal chance of progression to dysplasia or cancer. However, high risk HPV strains (16, 18, 31, 33 and 35) are implicated in 99% of those diagnosed with cervical cancer. It is important to note that most women infected with high-risk strains of HPV infection will not develop cancer. The risk of developing dysplasia or cancer after HPV infection is, in part, dependent on the amount of virus present during infection and the length of time it takes to clear the infection.⁽²⁾

There is no cure or treatment for HPV infection. Even without treatment, most infections are cleared by the immune system within two years. If the infection persists there is an increased chance of viral DNA integration and progression to cancer. ⁽¹⁾Women can be tested to learn if they are infected with HPV. Even though there is currently no cure for HPV infection, the knowledge can help women make responsible choices regarding their sexual practices.

· Pathology Report and Staging

· Cervical Intraepithelial Neoplasia: Cervical intraepithelial neoplasia (CIN) is an abnormal condition that is detectable by Pap smears and other cervical exams. CIN is the growth of abnormal cells in the lining of the cervix. Though CIN it is not cancerous, it has the potential to progress to cancer if left untreated. There are three stages (or grades) of CIN: CIN 1, CIN 2 and CIN 3. The stages are define by how abnormal the cells appear, slight, moderate and high. The risk of cancer development increases with increasing CIN grade. CIN is relatively common, with 1.4 million low grade and 330,000 high grade cases diagnosed in the United States in 2006. Cervical lesions are treated depending on the degree of severity. CIN 1 lesions may be removed or closely monitored; CIN 2/3 lesions are usually surgically removed. In either case, careful follow-up screening is performed to ensure that there is no recurrence. Despite the high incidence of CIN, if these irregularities are treated, progression to cancer is very rare. ⁽¹⁾ The image below shows microscopic images of normal cervical tissue, CIN 1, CIN 2 and CIN 3

Cervical Cancer Staging: If a lesion is determined to be cancerous, the disease is staged. Staging is typically based on guidelines produced by the Federation Internationale de Gynecologie et d' Obstetrique (FIGO). In this system tumors are classified by their size and location. An alternative system is used by the American Joint Committee on Cancer (AJCC). ⁽²⁾ Staging of the cancer helps the clinicians to design an appropriate plan of treatment.

· View the FIGO guide to cervical cancer staging.

Treatment

Depending on the stage and location of the cancer, several different treatments are used for cervical cancer. Common treatment methods are listed below. ^(1)(2)(3)

Surgery:

Cryosurgery - used for pre-invasive cancer; kills cancer cells by freezing them with a metal probe that has been cooled by liquid nitrogen.

Laser Surgery - used for pre-invasive cancer; laser beams are used to burn off abnormal cells or remove tissue for further study.

Cone Biopsy - used to preserve fertility in women with early stage cancer or to obtain a sample for further study; a cone-shaped section of tissue is taken from the cervix.

Simple Hysterectomy - the uterus and cervix are removed either through the vagina or the abdominal wall; results in infertility.

Radical Hysterectomy and Pelvic Lymph Node Dissection - the uterus, upper vagina and lymph nodes are removed through the vagina or the abdominal wall; results in infertility.

Photo of woman holding abdomen in pain.

Pelvic Externation - for recurrent cancer; radical hysterectomy is accompanied by removal of the bladder, vagina, rectum and part of the colon; results in infertility.For details on surgical treatment view the section on Surgery.

Radiation: Either internal (also called brachytherapy) or external radiation may be used to treat cervical cancer. For details on these treatments view the section on Radiotherapy.

Chemotherapy: Several different drugs may also be used to treat primary or recurrent cervical cancer. For details on specific chemotherapy treatments view the section on Chemotherapy.

NOTE: Sometimes radiation and chemotherapy are given at the same time. The rationale is that the low levels of chemotherapy given make the cancer cells more sensitive to the radiation. The technique is called chemoradiotherapy or radiosensitization.⁽⁴⁾

If a woman is pregnant at the time of diagnosis, a decision must be made, based on the stage of the cancer, whether to continue the pregnancy to term. Treatment for cervical cancer cannot be administered during pregnancy, and aggressive cancers often require immediate treatment.

Learn more about cervical cancer treatment at the Winship Cancer Institute of Emory University.

Information about clinical trials:

The Society of Gynecologic Oncology has produced a series of educational publications on cervical cancer, ovarian cancer, endometrial cancer and vulvar cancer. Their materials include planning guides and survivorship care plans.

Ovarian cancer

The term "ovarian cancer" includes several different types of cancer that all arise from cells of the ovary. Most commonly, tumors arise from the epithelium, or lining cells, of the ovary. These include epithelial ovarian (from the cells on the surface of the ovary), fallopian tube, and primary peritoneal (the lining inside the abdomen that coats many abdominal structures) cancer. These are all considered to be one disease process. There is also an entity called borderline ovarian tumors that have the microscopic appearance of a cancer, but tend not to spread much. However, there are also less common forms of ovarian cancer that come from within the ovary itself, including germ cell tumors and sex cord-stromal tumors. All of these diseases will be discussed, as well as their treatment.

Epithelial ovarian cancer

Epithelial ovarian cancer (EOC) accounts for about 70% of all ovarian cancers. It is generally thought of as one of three types of cancer that include ovarian, fallopian tube, and primary peritoneal cancer that all behave, and are treated the same way, depending on the type of cell that causes the cancer. The four most common cell types of epithelial ovarian cancer are serous, mucinous, clear cell, and endometrioid. These cancers arise due to DNA changes in cells that lead to the development of cancer. Serous cell type is the most common variety. It is now thought that many of these cancers actually come from the lining in the fallopian tube, and fewer of them from the lining on the surface of the ovary, or the peritoneum. However, it is often hard to identify the sources of these cancers when they present at advanced stages, which is very common.

Borderline ovarian tumors

Borderline ovarian tumors account for a small percentage (approximately 10%) of epithelial ovarian cancers. They are most often serous or mucinous cell types. They often have presentations of large masses, but uncommonly metastasize. Often, thorough surgical staging is curative, even at more advanced stages.

Germ cell ovarian cancers

Germ cells tumors arise from the reproductive cells of the ovary. These account for less than 2% of all ovarian tumors. They include dysgerminomas, yolk sac tumors, embryonal carcinomas, polyembryomas, non-gestational choriocarcinomas, immature teratomas, and mixed germ cell tumors. They are relatively uncommon and also generally present in younger-aged women than does EOC.

Stromal ovarian cancers

Another category of ovarian tumor is the sex cord-stromal tumors. These arise from supporting tissues within the ovary itself. As with germ cell tumors, these are uncommon, accounting for only 5% to 8% of ovarian tumors. These cancers come from various types of cells within the ovary. They are much less common than the epithelial tumors. These include granulosa-stromal tumors and Sertoli-Leydig cell tumors.

The statistics for ovarian cancer

According to the National Cancer Institute (NCI), in 2013 there will be an estimated 22,240 new cases of ovarian cancer and 14,030 deaths from the disease. The vast majority of the cases are EOC and are found at stage 3 or later, meaning the cancer has spread beyond the pelvis or to the lymph nodes. This is mostly due to the lack of definite symptoms at the early stages of development of the disease process. An individual woman has a lifetime risk of 1.37%, thus it is an uncommon disease. The median age of diagnosis is 63. However, approximately 25% of cases are diagnosed between ages 35 and 54. Caucasian women have the highest rate at 13.3 cases per 100,000.

Like many other cancers, when ovarian cancer is found at an early stage (for example, localized to the ovary or fallopian tube) the survival at 5 years is very good. Approximately 92% of women at stage 1 will still be alive at 5 years. However, the 5-year survival for all women diagnosed with ovarian cancer is only 45%. This is because it is often found at an advanced stage in which the disease has already spread within the abdomen.

Survival is also dependent on the type of care the patient receives. Unfortunately, approximately half of all women with the disease are never referred to a gynecologic oncologist. These are physicians with special training in gynecologic (ovarian, uterine, cervical, vulvar, and vaginal) cancers. If a woman does not involve a doctor with this specialized training in her care, then studies show very clearly that her survival is significantly worse, often by many years. For this reason, every woman with this disease ideally will obtain a referral to a gynecologic oncologist before she starts any treatment or has any surgery.

What are the risk factors for ovarian cancer?

Risk factors are related to two major categories: menstrual cycles (ovulation) and family history. The more a woman ovulates (cycles) over her lifetime, the higher her risk of ovarian cancer. Thus starting her period (menarche) at a younger age, ending her period (menopause) at a late age, and not getting pregnant (nulliparity) are all risk factors. It was once thought that infertilitypatients who underwent preparation for IVF (ovarian stimulation for in vitro fertilization) were at increased risk, but this has since been shown not to be the case in a large comprehensive review of the subject.

Approximately 10% of ovarian cancers are genetically related. Because of this, current guidelines suggest that all women with ovarian cancer should undergo testing for BRCA1 and BRCA2 gene changes (mutations). Lynch syndrome (typically colon and uterine cancer), Li-Fraumeni syndrome, and Cowden's syndrome are also associated with ovarian cancer but are less common. All patients with ovarian cancer will ideally discuss this topic with their doctor. These gene mutations can affect males as well as females. If a patient is positive for one of these, then her siblings and her children can be tested as well. Testing involves a simple blood test that can be drawn at many offices and laboratories. The results of this test can greatly affect how family members are monitored for various cancers, and family members of both sexes are encouraged to be tested.

The less common varieties of ovarian cancer (borderline, germ cell, and stromal tumors) have few definable risk factors. The germ cell tumors are often seen in younger age groups, and are treated very differently both surgically and chemotherapeutically.

Ovarian cancer symptoms and signs

Screening tests are used to test a healthy population in an attempt to diagnose a disease at an early stage. Unfortunately, there are no good screening tests for ovarian cancer, despite extensive ongoing research. Imaging (ultrasound, X-rays, and CT scans), and blood tests should not be used as a screen, as they are inaccurate and lead many women to surgery who do not need it. Diagnosis is often suspected based on symptoms and physical exam, and these are followed by imaging. The signs and symptoms, when present, are very vague. These can include fatigue, getting full quickly (early satiety), abdominal swelling, clothes suddenly not fitting, leg swelling, changes in bowel habits, changes in bladder habits, abdominal pain, andshortness of breath.

As mentioned above, these symptoms can be very subtle and vague, as well as very common. This only makes diagnosing the disease that much more difficult. Some studies suggest that the average patient with ovarian cancer sees up to three different doctors prior to obtaining a definitive diagnosis. Often, it is the persistence of the patient that leads to a diagnosis. Borderline tumors can present with similar symptoms. In addition, they are often seen with very large masses in the ovary. Often these masses are large enough to cause bloating, abdominal distension, constipation, and changes in bladder habits.

In the more uncommon ovarian types (stromal and germ cell tumors), symptoms are similar. Sometimes, granulosa cell tumors can present with severe pain and blood in the belly from a ruptured tumor. These can often be confused with a ruptured ectopic pregnancy, as they tend to be found in women of reproductive age.

How is ovarian cancer diagnosed?

Often vague symptoms eventually lead to a clinical diagnosis, or one based on suspicion generated by exams, laboratory tests, and imaging. However, an accurate diagnosis requires some of the tumor to be removed, either by biopsy (less often), or preferably, surgery to verify the diagnosis. Often a high clinical suspicion can trigger a referral to a gynecologic oncologist.

Various types of imaging studies can be used to diagnose this disease. Ultrasound and CT (CAT) scans are the most common. These can often give pictures that show masses in the abdomen and pelvis, fluid in the belly (ascites), obstructions of the bowels or kidneys, or disease in the chest or liver. Many times this is all that is necessary to trigger a referral to a specialist, as the suspicion for ovarian cancer can be quite high. PET scans can be used, but often are not necessary if a CT scan is able to be performed.

Blood work can be helpful as well. The CA-125 is a blood test that is often, but not always, elevated with ovarian cancer. If a postmenopausal woman has a mass and an elevated CA-125, she has an extremely high risk of having a cancer. However, in younger women, CA-125 is extraordinarily inaccurate. It is elevated by a large number of disease processes, including but not limited to, diverticulitis, pregnancy, irritable bowel syndrome, appendicitis, liver disease, stomach disease, and more. No one should get this test done unless they actually have a mass, or their doctor has some reason to get it. It should not be drawn just to see the level since it is not a reliable screening test for ovarian cancer.

That being said, there is some new research that is developing that looks at following CA-125 over the life of a patient. In some very early work, there is a suggestion that by watching this trend closely we might be able to detect more cancers at an earlier stage. This has not yet been proven. As stated above, this can be a difficult decision process. Often it can lead women to have other unnecessary tests that can even lead them to unnecessary surgery. Until more work is done, it is currently recommended that CA-125 be drawn only in the setting of the discovery of a pelvic mass.

HE4 is another, newer blood test that is starting to be used while women undergo workup for a mass that has been found. It is commonly used to try to help decide if a referral to a gynecologic oncologist is warranted. When abnormal, in conjunction with a CA-125, it can assist in the decision process as to the risk of the mass being cancerous.

OVA-1 is a test that is performed by a private company. This test uses a series of blood tests, and then plugs the results into an equation that then gives the doctor a result about the likelihood that a mass is cancerous. A high level of the test has been shown in some studies to increase the suspicion of a cancer being present. This study is often not covered by insurance, and has not yet been adapted as a standard of care.

Ovarian cancer staging

Staging is the process of classifying a tumor according to the extent to which it has spread in the body at the time of diagnosis.Ovarian cancer staging:

Stage 1: Limited to one or both ovaries

Stage 2: Limited to disease in the pelvis

Stage 3: Disease outside of the pelvis, but limited to the abdomen, or lymph node involvement, but not including the inside of the liver

Stage 4: Disease spread to the liver or outside of the abdomen

Complete staging of an ovarian cancer includes hysterectomy, removal of the ovaries, tubes, pelvic and aortic lymph node biopsies or dissection, the omentum (a large fatty structure that provides support for abdominal organs), and peritoneal (lining tissue of the abdomen) biopsies.

Ovarian cancer staging is determined surgically, unless it is stage 4 (metastasis outside of the abdomen, or metastasis to the liver -- not on the surface of the liver). If it is stage 4, or very advanced stage 3, then often this is proven with biopsy, andchemotherapy is begun neoadjuvantly (before surgery). If the disease does not present with obvious stage 4 disease, then aggressive surgical staging and debulking (see next section) is often considered. This decision is based on the health of the patient, as well as the judgment of the surgeon as to the chance of achieving an optimal debulking (see treatment below).

If medically feasible, apparent early stage cancers should be staged thoroughly. This is due to the fact that of clinical stage 1 tumors, greater than 30% will have metastatic disease on formal staging. This knowledge can lead to treatment recommendations that might not otherwise be made.

Treatment for ovarian cancer

Epithelial ovarian cancer treatment most often consists of surgery and chemotherapy. The order is best determined by a gynecologic oncologist. Surgery consists of an effort to remove all visible disease in the abdomen, commonly called surgical debulking. If one imagines a handful of wet sand thrown on the ground, you will see small piles and bigger piles. This is often how the abdomen looks when in surgery. It is the job of the surgeon to remove, (also known as debulking) as much of these masses as possible. This surgery usually results in removal of both tubes and ovaries, the uterus (hysterectomy), removal of the omentum (omentectomy -- a large fat pad that hangs off of the colon), lymph node biopsies and any other organ involved in the disease. This can mean a portion of the small bowel, large bowel, liver, the spleen, the gallbladder, a portion of the stomach, a portion of the diaphragm, and removal of a portion of the peritoneum (a thin lining in the abdomen that covers many of the organs and the inside of the abdominal wall). Done properly, this can be a very extensive surgery. The patients who live the longest have all of the visible nodules taken out at time of surgery. To be an “optimal debulking,” at minimum, no individual nodule greater than 1 cm should be left behind. If this cannot be done, then the patient should be closed, chemotherapy started, and the patient brought back to the operating room for a second surgery after a few rounds of chemotherapy (neoadjuvant chemotherapy and interval debulking surgery).

It should be noted that now many gynecologic oncologists believe that “optimal debulking” should mean that there is no visible disease left at the time of surgery. This has been a shift over the last years. Historically the goal was to leave no individual nodule greater than 2 cm behind. This has steadily progressed to the point where the term “optimal debulking” is now accepted by many to mean that there is no disease left to remove. As we have progressed to this point, surgery has become more involved, on a more routine basis. This has led to a concern about undertreatment of elderly patients due to a fear that they cannot survive the surgical risks.

There has recently been new research indicating that if all visible disease cannot be removed at the time of surgery, that giving chemotherapy for three cycles before surgery may be just as beneficial as up front surgery. When this is done, the amount of surgery needed to optimally debulk a patient is significantly less. This is a concept that has been used historically, but it was always felt to be substandard. With recent research as well as ongoing research, more information is coming out that supports the use of this strategy in certain circumstances.

Any patient healthy enough to tolerate chemotherapy will often benefit greatly from its use. The drugs used in ovarian cancer tend to have fewer side effects, and thus are easier to tolerate than many other chemotherapy drugs. Currently, there are two ways to give chemotherapy in ovarian cancer. Traditionally, it is given into the vein intravenously (IV). When initially diagnosed, the two most common drugs are carboplatin and paclitaxel. Most commonly, the carboplatin is given every 21 days and the paclitaxel is given every 21 days, or every 7 days. Another way of giving the chemotherapy is to place it directly into the abdomen (intraperitoneal or IP). In many studies, intraperitoneal administration has been shown to significantly increase survival. This is most often used after optimal surgical debulking. Currently the drugs used are cisplatin and paclitaxel. In a 21 day cycle, the paclitaxel is given IV on day 1, followed by cisplatin IP on day 2, and paclitaxel IP on day 8. This regimen is the current standard in IP ovarian cancer chemotherapy. There are studies that are looking at substituting carboplatin for the cisplatin, because the side effects are less. We do not have an answer for this yet.

The drug bevacizumab has also been used experimentally in the initial treatment of ovarian cancer. When used in the initial rounds of chemotherapy and then used for 12 months after the initial six cycles of chemotherapy, there is research indicating that the cancer, if not cured, will come back at a later date than would be expected with traditional chemotherapy regimens (increased progression-free survival). This has not yet been shown to increase survival however. Bevacizumab is a very good drug to use in ovarian cancer; however, the timing of its use is still being determined.

Some centers are starting to experiment with heated intraperitoneal chemotherapy (HIPEC). However, at this time, HIPEC is very experimental. There are significant risks and complications from surgery with HIPEC, and it has not yet been shown to extend survival over standard chemotherapy. Until a trial is done proving its usefulness, HIPEC should be used with caution.

Maintenance chemotherapy is a concept that gives long-term chemotherapy, often for a year, of a single drug. The idea is that, if the patient is not cured, then this may prevent the recurrence from occurring for an extended amount of time. Drugs that have been studied with this approach include paclitaxel and bevacizumab. We have yet to show an increased survival using this method of treatment. This creates controversy, because if the patient will not live longer, then why subject them to 12 months of chemotherapy? As of now, there is no definitive answer on whether or not this should be done. Each patient can discuss this with her treating physician to get information.

When epithelial ovarian cancer recurs, the timing of the recurrence dictates how it is treated. Sometimes, a patient may be a good candidate for surgery again. If not, then chemotherapy is used. The type of drugs used are determined by how long it has been since the last time a patient has taken a drug containing platinum. If it has been less than 6 months, then the patient is termed platinum resistant. If it has been more than 6 months since the last day of platinum-based chemotherapy, then often a platinum-containing drug will be used again.

If the patient is still platinum sensitive, then often she will receive a platinum drug with another drug. This can be paclitaxel again, or another taxane type drug, such as docetaxel. Also, another class of drugs, such as gemcitabine or pegylated liposomal doxorubicin, may be used. Often the combination is chosen based on how a patient tolerated her previous chemotherapy, as well as the side effect profile that will best suit the patient. If the patient is platinum resistant, then often a single drug is used. These can include drugs that have previously been used. Agents used include pegylated liposomal doxorubicin, docetaxel, paclitaxel, topotecan, gemcitabine, etoposide, and bevacizumab. The order, schedule and dosing are quite variable, depending on many factors.

The Gynecologic Oncology Group is a national organization that sponsorsclinical trials in gynecologic cancers. Patients can ask their physician if they are eligible for a trial that may help them, as this is how new drugs are discovered. If a doctor or hospital does not participate in the GOG trials, a doctor can often contact a regional center that does.

Stromal and germ cell ovarian tumors are most often treated with a combination of bleomycin, etoposide, and cisplatin. There is much less research on these as they are more curable and much less common than epithelial tumors. Because of their rarity, it will be very difficult to find effective new treatments.

Prognosis of ovarian cancer

Epithelial ovarian cancer is the most deadly of the gynecologic cancers. Approximately 80% of patients will eventually die of the disease. However, survival in the short term is quite good, meaning many years. With the addition of IP chemotherapy, the survival of ovarian cancer has been significantly extended. According to recent studies, if a patient undergoes optimal debulking, followed by IP chemotherapy, then they have a greater than 50% chance to still be alive in 6 years. This is quite good compared to other advanced stage cancers. Even in the recurrent setting, epithelial ovarian cancer is often very sensitive to chemotherapy. The disease can often go in to complete remission (no detectable disease) many times. However, once it recurs, it is not curable and will continue to come back.

Germ cell and stromal tumors have a much better prognosis. They are often cured because they are more often detected at early stages.

Can ovarian cancer be prevented?

There is no known way to truly prevent ovarian cancer. One would think that removal of the fallopian tubes and ovaries would prevent the disease but this is not always the case (primary peritoneal cancer can arise in the pelvis even after the ovaries have been removed). However, there are ways to significantly reduce your risk. If a woman takes birth control pills for more than 10 years, then her risk of ovarian cancer drops significantly. Tubal ligation has long been known to decrease the risk of ovarian cancer. Recently, removal of the entire tube has been shown to further decrease the risk. This procedure, called a salpingectomy, can be considered by any woman considering a tubal ligation. Removal of the ovaries does decrease the risk of cancer, but at the cost of increasing death due to heart disease and other causes. Currently this procedure is often saved for specific situations (genetic risk, family history) in patients under 60 to 65 years of age and is not used in the general population. Until recently, if a woman was close to menopause and was undergoing surgery, then the ovaries and tubes would be removed. The recent studies indicating that many of these cancers actually come from the fallopian tube, and the studies indicating that removal of even postmenopausal ovaries causes other problems has caused a significant shift in this philosophy. Certainly, the tubes should be removed at the time of hysterectomy for any woman. The need for removal of the ovaries is much more uncertain.

Genetic abnormalities are an exception to this recommendation. If a patient is positive for a BRCA or Lynch syndrome genetic defect (mutation), then the patient should strongly consider removal of her tubes and ovaries to decrease the chance of her getting a cancer. Women with these mutations are at a very high risk of ovarian cancer, and in this situation the risk of heart disease is not as significant as dying of one of these cancers. This can be planned at the end of child bearing, or at age 35. Each patient is recommended to discuss this with her doctor, or a genetic counselor.

Endometrial cancer

Cancer of the womb (the uterus ). Endometrial cancer occurs most often in women between the ages of 55 and 70 years. It accounts for about 6% of cancer in women. Women at elevated risk for endometrial cancer include those who are obese, who have few or no children, who began menstruating at a young age, who had a latemenopause, and women of high socioeconomic status. It is thought that most of these risk factors are related to hormones, especially excess estrogen.

Abnormal bleeding after menopause is the most common symptom of endometrial cancer. The diagnosis is based on the results of the pelvic examination, ultrasound, biopsy of the uterus, and D & C (dilatation and curettage).

Treatment may involve surgery, radiation therapy, hormone therapy, orchemotherapy . In its early stage, endometrial cancer is usually treated by surgery. The uterus and cervix are removed by hysterectomy. Radiation therapy may be done before surgery to shrink the cancer or after surgery to prevent recurrence of the cancer. A combination of external and internal radiation therapy is often used. If the cancer has spread extensively or has recurred after treatment, a female hormone (progesterone) or chemotherapy may be recommended.

· The uterus is a hollow organ in females located in the pelvis that functions to support fetal development until birth; the top is the fundus, the middle is the corpus, and bottom is the cervix.

· Uterine cancer is the abnormal (malignant) growth of any cells that comprise uterine tissue.

· Although the exact causes of uterine cancers are not known, risk factors include women with endometrial overgrowth (hyperplasia), obesity, never had children, menses before age 12, menopause after age 55, estrogen therapy, taking tamoxifen, radiation to the pelvis, family history of uterine cancer, and Lynch syndrome (inherited colorectal cancer).

· Common signs and symptoms of uterine cancer are abnormal vaginal bleeding or discharge, pain with urination and sex, and pelvic pains.

· Uterine cancer is diagnosed usually with a pelvic exam, ultrasound, and biopsy.

· Uterine cancer stages (0 to IV) are determined by biopsy, chest X-ray, and/or CT or MRI scans.

· Treatment options may include one or more of the following: surgery, radiation, hormone therapy, and chemotherapy. Treatment depends on the cancer stage with stage IV as the most aggressive.

· Surgical therapy usually involves removal of the uterus, ovaries, fallopian tubes, adjacent lymph nodes, and part of the vagina.

· Radiation therapy may be by external radiation or by internal radiation (brachytherapy).

· Chemotherapy usually requires IV administration of drugs designed to kill cancer cells.

· Hormone therapy (usually progesterone) is used on cancer cells that require another hormone (estrogen) for growth.

· Second opinions can be obtained by referrals made by your doctor, local medical society, and many others.

· Follow-up care is important. Complications can be treated early and possible cancer resurgence can be diagnosed early.

· Support groups are varied and many are local. The National Cancer Institute (NCI) can help locate support groups and possible clinical trials.

What is the uterus?

The uterus is part of a woman's reproductive system. It's a hollow organ in the pelvis.

The uterus has three parts:

· Top: The top (fundus) of your uterus is shaped like a dome. From the top of your uterus, the fallopian tubes extend to the ovaries.

· Middle: The middle part of your uterus is the body (corpus). This is where a baby grows.

· Bottom: The narrow, lower part of your uterus is the cervix. The cervix is a passageway to the vagina.

The wall of the uterus has two layers of tissue:

· Inner layer: The inner layer (lining) of the uterus is the endometrium. In women of childbearing age, the lining grows and thickens each month to prepare for pregnancy. If a woman does not become pregnant, the thick, bloody lining flows out of the body. This flow is a menstrual period.

· Outer layer: The outer layer of muscle tissue is the myometrium.

What is uterine cancer (endometrial cancer)?

Cancer begins in cells, the building blocks that make up tissues. Tissues make up the uterus and the other organs of the body.

Normal cells grow and divide to form new cells as the body needs them. When normal cells grow old or get damaged, they die, and new cells take their place.

Sometimes, this process goes wrong. New cells form when the body doesn't need them, and old or damaged cells don't die as they should. The buildup of extra cells often forms a mass of tissue called a growth or tumor.

Tumors in the uterus can be benign (not cancer) or malignant (cancer). Benign tumors are not as harmful as malignant tumors:

· Benign tumors (such as a fibroid, a polyp, or endometriosis):

o are usually not a threat to life

o can be treated or removed and usually don't grow back

o don't invade the tissues around them

o don't spread to other parts of the body

· Malignant growths:

o may be a threat to life

o usually can be removed but can grow back

o can invade and damage nearby tissues and organs (such as the vagina)

o can spread to other parts of the body

Cancer cells can spread by breaking away from the uterine tumor. They can travel through lymph vessels to nearby lymph nodes. Also, cancer cells can spread through the blood vessels to the lung, liver, bone, or brain. After spreading, cancer cells may attach to other tissues and grow to form new tumors that may damage those tissues. See the Staging section for information about uterine cancer that has spread.

What causes uterine cancer? Who is at risk for uterine cancer?

When you get a diagnosis of uterine cancer, it's natural to wonder what may have caused the disease. Doctors usually can't explain why one woman gets uterine cancer and another doesn't.

However, we do know that women with certain risk factors may be more likely than others to develop uterine cancer. A risk factor is something that may increase the chance of getting a disease.

Studies have found the following risk factors for uterine cancer:

· Abnormal overgrowth of the endometrium (endometrial hyperplasia): An abnormal increase in the number of cells in the lining of the uterus is a risk factor for uterine cancer. Hyperplasia is not cancer, but sometimes it develops into cancer. Common symptoms of this condition are heavy menstrual periods, bleeding between periods, and bleeding after menopause. Hyperplasia is most common after age 40. To prevent endometrial hyperplasia from developing into cancer, the doctor may recommend surgery to remove the uterus (hysterectomy) or hormone therapy with progesterone and regular follow-up exams.

· Obesity: Women who are obese have a greater chance of developing uterine cancer.

· Reproductive and menstrual history: Women are at increased risk of uterine cancer if at least one of the following apply:

o Have never had children

o Had their first menstrual period before age 12

o Went through menopause after age 55

· History of taking estrogen alone: The risk of uterine cancer is higher among women who used estrogen alone (without progesterone) for menopausal hormone therapy for many years.

· History of taking tamoxifen: Women who took the drug tamoxifen to prevent or treat breast cancer are at increased risk of uterine cancer.

· History of having radiation therapy to the pelvis: Women who had radiation therapy to the pelvis are at increased risk of uterine cancer.

· Family health history: Women with a mother, sister, or daughter with uterine cancer are at increased risk of developing the disease. Also, women in families that have an inherited form of colorectal cancer(known as Lynch syndrome) are at increased risk of uterine cancer.

Many women who get uterine cancer have none of these risk factors, and many women who have known risk factors don't develop the disease.

What are uterine cancer symptoms and signs?

The most common symptom of uterine cancer is abnormal vaginal bleeding. It may start as a watery, blood-streaked flow that gradually contains more blood. After menopause, any vaginal bleeding is abnormal.

These are common symptoms of uterine cancer:

· Abnormal vaginal bleeding, spotting, ordischarge

· Pain or difficulty when emptying the bladder

· Pain during sex

· Pain in the pelvic area

These symptoms may be caused by uterine cancer or by other health problems. Women with these symptoms should tell their doctor so that any problem can be diagnosed and treated as early as possible.

How is a diagnosis of uterine cancer determined?

If you have symptoms that suggest uterine cancer, your doctor will try to find out what's causing the problems.

You may have a physical exam and blood tests. Also, you may have one or more of the following tests:

· Pelvic exam: Your doctor can check your uterus, vagina, and nearby tissues for any lumps or changes in shape or size.

· Ultrasound: An ultrasound device uses sound waves that can't be heard by humans. The sound waves make a pattern of echoes as they bounce off organs inside the pelvis. The echoes create a picture of your uterus and nearby tissues. The picture can show a uterine tumor. For a better view of the uterus, the device may be inserted into the vagina (transvaginal ultrasound).

· Biopsy: The removal of tissue to look for cancer cells is a biopsy. A thin tube is inserted through the vagina into your uterus. Your doctor uses gentle scraping and suction to remove samples of tissue. A pathologist examines the tissue under a microscope to check for cancer cells. In most cases, a biopsy is the only sure way to tell whether cancer is present.

You may want to ask the doctor these questions before having a biopsy:

· Why do I need a biopsy?

· How long will it take? Will I be awake? Will it hurt?

· What is the chance of infection or bleeding after the biopsy? Are there any other risks?

· How soon will I know the results? How do I get a copy of the pathology report?

· If I do have cancer, who will talk with me about treatment? When?

Grade

If cancer is found, the pathologist studies tissue samples from the uterus under a microscope to learn the grade of the tumor. The grade tells how much the tumor tissue differs from normal uterine tissue. It may suggest how fast the tumor is likely to grow.

Tumors with higher grades tend to grow faster than those with lower grades. Tumors with higher grades are also more likely to spread. Doctors use tumor grade along with other factors to suggest treatment options.

How is the stage determined for uterine cancer?

If uterine cancer is diagnosed, your doctor needs to learn the extent (stage) of the disease to help you choose the best treatment. The stage is based on whether the cancer has invaded nearby tissues or spread to other parts of the body.

When cancer spreads from its original place to another part of the body, the new tumor has the same kind of abnormal cells and the same name as the primary (original) tumor. For example, if uterine cancer spreads to the lung, the cancer cells in the lung are actually uterine cancer cells. The disease is metastatic uterine cancer, not lung cancer. It's treated as uterine cancer, not as lung cancer. Doctors sometimes call the new tumor "distant" disease.

To learn whether uterine cancer has spread, your doctor may order one or more tests:

· Lab tests: A Pap test can show whether cancer cells have spread to the cervix, and blood tests can show how well the liver and kidneys are working. Also, your doctor may order a blood test for a substance known as CA-125. Cancer may cause a high level of CA-125.

· Chest x-ray: An x-ray of the chest can show a tumor in the lung.

· CT scan: An x-ray machine linked to a computer takes a series of detailed pictures of your pelvis, abdomen, or chest. You may receive an injection of contrast material so your lymph nodes and other tissues show up clearly in the pictures. A CT scan can show cancer in the uterus, lymph nodes, lungs, or elsewhere.

· MRI: A large machine with a strong magnet linked to a computer is used to make detailed pictures of your uterus and lymph nodes. You may receive an injection of contrast material. MRI can show cancer in the uterus, lymph nodes, or other tissues in the abdomen.

In most cases, surgery is needed to learn the stage of uterine cancer. The surgeon removes the uterus and may take tissue samples from the pelvis and abdomen. After the uterus is removed, it is checked to see how deeply the tumor has grown. Also, the other tissue samples are checked for cancer cells. These are the stages of uterine cancer:

· Stage 0: The abnormal cells are found only on the surface of the inner lining of the uterus. The doctor may call this carcinoma in situ.

· Stage I: The tumor has grown through the inner lining of the uterus to the endometrium. It may have invaded the myometrium.

· Stage II: The tumor has invaded the cervix.

· Stage III: The tumor has grown through the uterus to reach nearby tissues, such as the vagina or a lymph node.

· Stage IV: The tumor has invaded the bladder or intestine. Or, cancer cells have spread to parts of the body far away from the uterus, such as the liver, lungs, or bones.

What are treatment options for uterine cancer?

Treatment options for people with uterine cancer are surgery, radiation therapy,chemotherapy, and hormone therapy. You may receive more than one type of treatment.

The treatment that's right for you depends mainly on the following:

· Whether the tumor has invaded the muscle layer of the uterus

· Whether the tumor has invaded tissues outside the uterus

· Whether the tumor has spread to other parts of the body

· The grade of the tumor

· Your age and general health

You may have a team of specialists to help plan your treatment. Your doctor may refer you to a specialist, or you may ask for a referral. Specialists who treat uterine cancer include gynecologists, gynecologic oncologists (doctors who specialize in treating female cancers), medical oncologists, and radiation oncologists. Your health care team may also include an oncology nurse and a registered dietitian.

Your health care team can describe your treatment choices, the expected results of each, and the possible side effects. Because cancer therapy often damages healthy cells and tissues, side effects are common. Before treatment starts, ask your health care team about possible side effects and how treatment may change your normal activities. You and your health care team can work together to develop a treatment plan that meets your needs.

At any stage of disease, supportive care is available to control pain and other symptoms, to relieve the side effects of treatment, and to ease emotional concerns. Information about such care is available on NCI's Web site at http://www.cancer.gov/cancertopics/coping.

Also, NCI's Cancer Information Service can answer your questions about supportive care. Call 1-800-4-CANCER (1-800-422-6237). Or chat using LiveHelp, NCI's instant messaging service, at http://www.cancer.gov/livehelp.

You may want to talk with your doctor about taking part in a clinical trial. Clinical trials are research studies testing new treatments. They are an important option for people with all stages of uterine cancer. See the Taking Part in Cancer Research section.

You may want to ask your doctor these questions before you begin treatment:

· What is the grade of the tumor? What is the stage of the disease? Has the tumor invaded the muscle layer of the uterus or spread to other organs?

· What are my treatment choices? Which do you suggest for me? Why?

· What are the expected benefits of each kind of treatment?

· What can I do to prepare for treatment?

· Will I need to stay in the hospital? If so, for how long?

· What are the risks and possible side effects of each treatment? How can side effects be managed?

· What is the treatment likely to cost? Will my insurance cover it?

· How will treatment affect my normal activities?

· Would a research study (clinical trial) be a good choice for me?

· Can you recommend other doctors who could give me a second opinion about my treatment options?

· How often should I have checkups?

Surgery for the treatment of endometrial cancer

Surgery is the most common treatment for women with uterine cancer. You and your surgeon can talk about the types of surgery (hysterectomy) and which may be right for you.

The surgeon usually removes the uterus, cervix, and nearby tissues. The nearby tissues may include:

· Ovaries

· Fallopian tubes

· Nearby lymph nodes

· Part of the vagina

The time it takes to heal after surgery is different for each woman. After a hysterectomy, most women go home in a couple days, but some women leave the hospital the same day. You'll probably return to your normal activities within 4 to 8 weeks after surgery.

You may have pain or discomfort for the first few days. Medicine can help control your pain. Before surgery, you should discuss the plan for pain relief with your doctor or nurse. After surgery, your doctor can adjust the plan if you need more pain control.

It's common to feel tired or weak for a while. You may have nausea and vomiting. Some women are constipated after surgery or lose control of their bladder. These effects are usually temporary.

If you haven't gone through menopause yet, you'll stop having menstrual periods after surgery, and you won't be able to become pregnant. Also, you may have hot flashes,vaginal dryness, and night sweats. These symptoms are caused by the sudden loss of female hormones. Talk with your doctor or nurse about your symptoms so that you can develop a treatment plan together. There are drugs and lifestyle changes that can help, and most symptoms go away or lessen with time.

Surgery to remove lymph nodes may cause lymphedema (swelling) in one or both legs. Your health care team can tell you how to prevent or relieve lymphedema.

For some women, a hysterectomy can affect sexual intimacy. You may have feelings of loss that make intimacy difficult. Sharing these feelings with your partner may be helpful. Sometimes couples talk with a counselor to help them express their concerns.

You may want to ask your doctor these questions before having surgery:

· What type of surgery do you recommend for me? Why?

· Will lymph nodes and other tissues be removed? Why?

· How will I feel after surgery? If I have pain, how can it be controlled?

· How long will I be in the hospital?

· When will I be able to return to normal activities?

· What are the long-term effects of the surgery?

· How will the surgery affect my sex life?

Radiation therapy.

Radiation therapy is an option for women with all stages of uterine cancer. It may be used before or after surgery. For women who can't have surgery for other medical reasons, radiation therapy may be used instead to destroy cancer cells in the uterus. Women with cancer that invades tissue beyond the uterus may have radiation therapy and chemotherapy.

Radiation therapy uses high-energy rays to kill cancer cells. It affects cells in the treated area only.

Doctors use two types of radiation therapy to treat uterine cancer. Some women receive both types:

· External radiation therapy: A large machine directs radiation at your pelvis or other areas with cancer. The treatment is usually given in a hospital or clinic. You may receive external radiation 5 days a week for several weeks. Each session takes only a few minutes.

· Internal radiation therapy (also called brachytherapy): A narrow cylinder is placed inside your vagina, and a radioactive substance is loaded into the cylinder. Usually, a treatment session lasts only a few minutes and you can go home afterward. This common method of brachytherapy may be repeated two or more times over several weeks. Once the radioactive substance is removed, no radioactivity is left in the body.

Side effects depend mainly on which type of radiation therapy is used, how much radiation is given, and which part of your body is treated. External radiation to the abdomen and pelvis may cause nausea, vomiting, diarrhea, or urinary problems. You may lose hair in your genital area. Also, your skin in the treated area may become red, dry, and tender.

You are likely to become tired during external radiation therapy, especially in the later weeks of treatment. Resting is important, but doctors usually advise patients to try to stay as active as they can.

For women who have not had surgery to remove the ovaries, external radiation aimed at the pelvic area can harm the ovaries. Menstrual periods usually stop, and women may have hot flashes and other symptoms of menopause. Menstrual periods are more likely to return for younger women.

After either type of radiation therapy, you may have dryness, itching, or burning in your vagina. Your doctor may advise you to wait to have sex until a few weeks after radiation therapy ends.

Also, radiation therapy may make the vagina narrower. A narrow vagina can make sex or follow-up exams difficult. There are ways to prevent this problem. If it does occur, however, your health care team can tell you about ways to expand the vagina.

Although the side effects of radiation therapy can be upsetting, they can usually be treated or controlled. Talk with your doctor or nurse about ways to relieve discomfort.

You may want to ask your doctor these questions about radiation therapy:

· Why do I need this treatment?

· Which type of radiation therapy do you suggest for me?

· When will the treatments begin? When will they end?

· Will I need to stay in the hospital?

· How will I feel during treatment?

· How will radiation therapy affect my sex life?

· How will we know if the radiation treatment is working?

· Will I have any long-term side effects?

What about chemotherapy for the treatment of endometrial cancer?

Chemotherapy uses drugs to kill cancer cells. It may be used after surgery to treat uterine cancer that has an increased risk of returning after treatment. For example, uterine cancer that is a high grade or is Stage II, III, or IV may be more likely to return. Also, chemotherapy may be given to women whose uterine cancer can't be completely removed by surgery. For advanced cancer, it may be used alone or with radiation therapy.

Chemotherapy for uterine cancer is usually given by vein (intravenous). It's usually given in cycles. Each cycle has a treatment period followed by a rest period.

You may have your treatment in an outpatient part of the hospital, at the doctor's office, or at home. Some women may need to stay in the hospital during treatment.

The side effects depend mainly on which drugs are given and how much. Chemotherapy kills fast-growing cancer cells, but the drugs can also harm normal cells that divide rapidly:

· Blood cells: When drugs lower the levels of healthy blood cells, you're more likely to get infections, bruise or bleed easily, and feel very weak and tired. Your health care team will check for low levels of blood cells. If your levels are low, your health care team may stop the chemotherapy for a while or reduce the dose of the drug. There are also medicines that can help your body make new blood cells.

· Cells in hair roots: Chemotherapy may cause hair loss. If you lose your hair, it will grow back after treatment, but the color and texture may be changed.

· Cells that line the digestive system: Chemotherapy can cause a poor appetite, nausea and vomiting, diarrhea, or mouth and lip sores. Your health care team can give you medicines and suggest other ways to help with these problems. They usually go away when treatment ends.

Other possible side effects include skin rash, tingling or numbness in your hands and feet, hearing problems, loss of balance, joint pain, or swollen legs and feet. Your health care team can suggest ways to control many of these problems. Most go away when treatment ends.

Hormone therapy.

Some uterine tumors need hormones to grow. These tumors have hormone receptors for the hormones estrogen, progesterone, or both. If lab tests show that the tumor in your uterus has these receptors, then hormone therapy may be an option. Hormone therapy may be used for women with advanced uterine cancer. Also, some women with Stage I uterine cancer who want to get pregnant and have children choose hormone therapy instead of surgery. The most common drug used for hormone therapy is progesterone tablets. Possible side effects include weight gain, swelling, and breast tenderness.

How does a person go about getting a second opinion after a uterine cancer diagnosis?

Before starting treatment, you may want a second opinion about your diagnosis, stage of cancer, and treatment plan. Some people worry that the doctor will be offended if they ask for a second opinion. Usually the opposite is true. Most doctors welcome a second opinion. And many health insurance companies will pay for a second opinion if you or your doctor requests it. Some companies require a second opinion.

If you get a second opinion, the second doctor may agree with your first doctor's diagnosis and treatment plan. Or the second doctor may suggest another approach. Either way, you have more information and perhaps a greater sense of control. You can feel more confident about the decisions you make, knowing that you've looked at all of your options.

It may take some time and effort to gather your medical records and see another doctor. In most cases, it's not a problem to take several weeks to get a second opinion. The delay in starting treatment usually will not make treatment less effective. To make sure, you should discuss this delay with your doctor.

There are many ways to find a doctor for a second opinion. You can ask your doctor, a local or state medical society, a nearby hospital, or a medical school for names of specialists.

Also, you can get information about treatment centers near you from NCI's Cancer Information Service. Call 1-800-4-CANCER (1-800-422-6237). Or chat using LiveHelp, NCI's instant messaging service, at http://www.cancer.gov/livehelp.

What sort of follow-up treatment is needed during and after uterine cancer treatment?

It's important for you to take very good care of yourself before, during, and after cancer treatment. Taking care of yourself includes eating well so that you get the right amount of calories to maintain a good weight. You also need enough protein to keep up your strength. Eating well may help you feel better and have more energy.

Sometimes, especially during or soon after treatment, you may not feel like eating. You may be uncomfortable or tired. You may find that foods don't taste as good as they used to. In addition, the side effects of treatment (such as poor appetite, nausea, vomiting, or mouth blisters) can make it hard to eat well.

Your doctor, a registered dietitian, or another health care provider can suggest ways to help you meet your nutrition needs.

Follow-up Care

You'll need regular checkups (such as every 3 to 6 months) after treatment for uterine cancer. Checkups help ensure that any changes in your health are noted and treated if needed. You should contact your doctor if you have any of the following health problems between checkups:

· Bleeding from your vagina, bladder, orrectum

· Bloated abdomen or swollen legs

· Pain in the abdomen or pelvis

· Shortness of breath or cough

· Loss of appetite or weight for no known reason

Uterine cancer may come back after treatment. Your doctor will check for return of cancer. Checkups may include a pelvic exam, lab tests (such as for CA-125), a chest x-ray, a CT scan, or an MRI.

What support is available for patients with uterine cancer?

Learning that you have uterine cancer can change your life and the lives of those close to you. These changes can be hard to handle. It's normal for you, your family, and your friends to need help coping with the feelings that a diagnosis of cancer can bring.

Concerns about treatments and managing side effects, hospital stays, and medical bills are common. You may also worry about caring for your family, keeping your job, or continuing daily activities.

Here's where you can go for support:

· Doctors, nurses, and other members of your health care team can answer questions about treatment, working, or other activities.

· Social workers, counselors, or members of the clergy can be helpful if you want to talk about your feelings or concerns. Often, social workers can suggest resources for financial aid, transportation, home care, or emotional support.

· Support groups also can help. In these groups, patients or their family members meet with other patients or their families to share what they have learned about coping with cancer and the effects of treatment. Groups may offer support in person, over the telephone, or on the Internet. You may want to talk with a member of your health care team about finding a support group.

· NCI's Cancer Information Service can help you locate programs and services for people with cancer. Call 1-800-4-CANCER (1-800-422-6237). Or chat using LiveHelp, NCI's instant messaging service, at http://www.cancer.gov/livehelp.

· Your doctor or a sex counselor may be helpful if you and your partner are concerned about the effects of uterine cancer on your sex life. Ask your doctor about possible treatment of side effects and whether these effects are likely to last. Whatever the outlook, you and your partner may find it helps to discuss your concerns.

What research is being done on uterine cancer?

Doctors all over the world are conducting many types of clinical trials (research studies in which people volunteer to take part). Clinical trials are designed to find out whether new treatments are safe and effective.

Even if the people in a trial do not benefit directly from a treatment, they may still make an important contribution by helping doctors learn more about uterine cancer and how to control it. Although clinical trials may pose some risks, doctors do all they can to protect their patients.

Doctors are studying new ways to use surgery, chemotherapy, radiation therapy, and hormone therapy for treatment of uterine cancer.

NCI is sponsoring many studies with women who have uterine cancer:

· Surgery: Doctors are studying whether lymphedema develops after a woman has one of three types of surgery to remove the uterus and nearby lymph nodes:

o The surgeon makes a large incision to remove the uterus and lymph nodes.

o The surgeon makes small incisions for a laparoscope. A laparoscope is a thin, lighted tube with a lens for viewing. The surgeon uses a tool on the laparoscope to remove the uterus and lymph nodes (laparoscopic surgery).

o The surgeon removes the uterus through the vagina and makes small incisions so that a laparoscope may be used to remove the lymph nodes.

· Radiation therapy and chemotherapy:

o For women who have had surgery, doctors are comparing the effectiveness of external beam radiation therapy with that of brachytherapy followed by chemotherapy.

o Doctors are comparing chemotherapy alone with the combination of chemotherapy, external beam radiation therapy, and brachytherapy.

If you're interested in being part of a clinical trial, talk with your doctor.

NCI's Web site includes a section on clinical trials at http://www.cancer.gov/clinicaltrials. It has general information about clinical trials as well as detailed information about specific ongoing studies of uterine cancer.

Also, NCI's Cancer Information Service can provide information about clinical trials. Call 1-800-4-CANCER (1-800-422-6237). Or chat using LiveHelp, NCI's instant messaging service, at http://www.cancer.gov/livehelp .

CARCINOMA OF THE CERVIX

NATURAL HISTORY AND PATTERN OF SPREAD

The junction between the primarily columnar epithelium of the endocervix and squamous epithelium of the ectocervix is a site of continuous metaplastic change; this change is most active in utero, at puberty, and during first pregnancy, and declines after menopause.

Viral-induced atypical squamous metaplasia developing in this region can progress to higher-grade squamous intraepithelial lesions. The greatest risk of neoplastic transformation coincides with periods of greatest metaplastic activity, and most carcinomas arise from this zone of metaplastic transformation in the squamocolumnar junction.

The mean age of women with CIN is 15.6 years younger than that of women with invasive cancer, suggesting a slow progression of CIN to invasive carcinoma. In a 13-year observational study of women with CIN 3, Miller found that disease progressed in only 14%, whereas it persisted in 61% and disappeared in the remainder. Syrjanen and colleagues reported spontaneous regression in 38% of high-grade HPV-associated squamous intraepithelial lesions. However, in a large prospective study, Richart and Barron reported mean times to development of carcinoma in situ of 58, 38, and 12 months for patients with mild, moderate, or severe dysplasia, respectively, and predicted that 66% of all dysplasias would progress to carcinoma in situ within 10 years. Once tumor has broken through the basement membrane, it may penetrate the cervical stroma directly or via vascular channels. Invasive tumors may develop as exophytic growths protruding from the cervix into the vagina or as endocervical lesions that can cause massive expansion of the cervix despite a relatively normal appearing cervical portio. From the cervix, tumor may extend superiorly to the lower uterine segment, inferiorly to the vagina, or into the paracervical spaces via the broad or uterosacral ligaments. Tumor may become fixed to the pelvic wall by direct extension or by coalescence of central tumor with regional adenopathy. Tumor may also extend anteriorly to involve the bladder or posteriorly to the rectum, although rectal mucosal involvement is a rare finding at initial presentation. The cervix has a rich supply of lymphatics organized in three anastomosing plexuses that drain the mucosal, muscularis, and serosal layers. The lymphatics of the cervix also anastomose extensively with those of the lower uterine segment, possibly explaining the frequency of uterine extension from endocervical primary tumors. The most important lymphatic collecting trunks exit laterally from the uterine isthmus in three groups. Upper branches originating in the anterior and lateral cervix follow the uterine artery, are sometimes interrupted by a node as they cross the ureter, and terminate in the uppermost hypogastric nodes. Middle branches drain to deeper hypogastric (obturator) nodes, and the lowest branches follow a posterior course to the inferior and superior gluteal, common iliac, presacral, and subaortic nodes. Additional posterior lymphatic channels arising from the posterior cervical wall may drain to superior rectal nodes or may continue upward in the retrorectal space to the subaortic nodes overlying the sacral promontory. Anterior collecting trunks pass between the cervix and bladder with the superior vesical artery to terminate in the internal iliac nodes. Summarizes the reported incidences of pelvic and paraaortic node involvement for patients who underwent lymphadenectomy as part of primary surgical treatment or before radiation therapy for cervical carcinomas. The incidences reported for radical hysterectomy series vary widely, probably reflecting surgeons' different criteria for selecting patients for radical surgery rather than for primary radiation treatment. Many series exclude patients with extrapelvic disease. Variations in the completeness of lymphadenectomies and histologic processing may also lead to underestimates of the true incidence of regional spread from carcinomas of the cervix. Cervical cancer usually follows a relatively orderly pattern of metastatic progression initially to primary echelon nodes in the pelvis, then to paraaortic nodes and distant sites. Even patients with locoregionally advanced disease rarely have detectable hematogenous metastases at initial diagnosis of their cervical cancer. The most frequent sites of distant recurrence are lung, extrapelvic nodes, liver, and bone. Although the lumbar spine is said to be a relatively frequent site of skeletal metastases, more recent studies using abdominal imaging demonstrate that most patients with isolated lumbar spine involvement actually have direct extension of disease from paraaortic nodes.

PATHOLOGY

Cervical Intraepithelial Neoplasia

Several systems have been developed to classify cervical cytology. Although criteria for the diagnosis of CIN vary somewhat between pathologists, the important characteristics of this lesion are cellular immaturity, cellular disorganization, nuclear abnormalities, and increased mitotic activity. The degree of neoplasia is determined from the extent of the mitotic activity, immature cell proliferation, and nuclear atypia. If mitoses and immature cells are present only in the lower one third of the epithelium, the lesion usually is designated CIN 1. Involvement of the middle or upper third is diagnosed as CIN 2 or CIN 3, respectively.

The term cervical intraepithelial neoplasia, as proposed by Richart, refers only to a lesion that may progress to invasive carcinoma. Although CIN 1-2 is sometimes referred to as mild to moderate dysplasia, CIN is now preferred over the term dysplasia. Because the word dysplasia means abnormal maturation, proliferating metaplasia without mitotic activity has sometimes been erroneously called dysplasia.

The Bethesda system of classification, designed to further standardize reporting of cervical cytology, was developed following a National Cancer Institute consensus conference in 1988 and was refined in 1991. This system, which separates condylomata and CIN 1, classified as low-grade squamous intraepithelial lesions (LSIL), from high-grade squamous intraepithelial lesions (HSIL), is meant to replace the Papanicolaou system and is now widely used in the United States.

ADENOCARCINOMA IN SITU. The diagnosis of adenocarcinoma in situ (AIS) is made when normal endocervical gland cells are replaced by tall, irregular columnar cells with stratified, hyperchromatic nuclei and increased mitotic activity, but the normal branching pattern of the endocervical glands is maintained and there is no obvious stromal invasion. About 50% of women with cervical AIS also have squamous CIN, and AIS is often an incidental finding in patients operated on for squamous carcinoma.

Microinvasive Carcinoma

Because the definition of microinvasive carcinoma is based on the maximum depth and linear extent of involvement, it can be diagnosed only from a specimen that includes the entire neoplastic lesion and cervical transformation zone. This requires a cervical cone biopsy.

The earliest invasion appears as a protrusion of cells from the stromoepithelial junction; these cells are better differentiated than the adjacent noninvasive cells and have abundant pink-staining cytoplasm, hyperchromatic nuclei, and small to medium nucleoli. As the tumor progresses, invasion occurs at multiple sites, and its depth and linear extent become measurable. The depth of invasion should be measured with a micrometer from the base of the epithelium to the deepest point of invasion. Although lesions that have invaded less than 3 mm (FIGO stage IA1) rarely metastasize, about 5% of tumors that invade 3 to 5 mm (FIGO stage IA2) have positive pelvic lymph nodes.

Although investigators occasionally label very small adenocarcinomas as microinvasive, the term probably should not be used for these tumors. No definable, consistent method has been found to measure the depth of an invasive adenocarcinoma because it may have originated from the mucosal surface or the periphery of underlying glands. For this reason, adenocarcinomas are generally classified as either AIS or invasive carcinoma (FIGO stage IB).

Invasive Squamous Cell Carcinoma

Between 80% and 90% of cervical carcinomas are squamous. A number of systems have been used to grade and classify squamous carcinomas, but none have been consistently demonstrated to predict prognosis. One of the most commonly used systems categorizes squamous neoplasms as either large cell keratinizing, large cell nonkeratinizing, or small cell carcinoma. The latter should not be (but often is) confused with anaplastic small cell carcinoma, which resembles oat cell carcinoma of the lung because it contains small tumor cells that have scanty cytoplasm, small round to oval nuclei, small or absent nucleoli, coarsely granular chromatin, and high mitotic activity. In contrast, small cell squamous carcinomas have small to medium nuclei, open chromatin, small or large nucleoli, and more abundant cytoplasm. About 30% to 50% of anaplastic small cell carcinomas display neuroendocrine features. Most authorities believe that patients with large cell squamous carcinoma, with or without keratinization, have a better prognosis than those with small cell neoplasms and that small cell anaplastic carcinomas behave more aggressively than poorly differentiated small cell squamous carcinomas.

Invasive Adenocarcinoma

Invasive adenocarcinoma may be pure or mixed with squamous cell carcinoma (adenosquamous carcinoma). A wide variety of cell types, growth patterns, and differentiation have been observed. About 80% of cervical adenocarcinomas are made up predominantly of cells whose differentiated features resemble endocervical glandular epithelium with intracytoplasmic mucin production. The remaining tumors are populated by endometrioid cells, clear cells, intestinal cells, or a mixture of more than one cell type. By histologic examination alone, some of these tumors are indistinguishable from those arising elsewhere in the endometrium or ovary. Minimal deviation adenocarcinoma (adenoma malignum) is an extremely well-differentiated adenocarcinoma in which the branching glandular pattern strongly resembles normal endocervical glands. Because of this, the tumor may not be recognized as malignant in small biopsy specimens and the correct diagnosis may be delayed. Earlier studies reported a dismal outcome for women with this tumor, but more recently, patients have been reported to have a favorable prognosis if the disease is detected early.

Young and Scully have described a villoglandular papillary subtype of adenocarcinoma that primarily affects young women, appears to metastasize infrequently, and has a favorable prognosis. Glucksmann and Cherry first described glassy cell carcinoma, a form of poorly differentiated adenosquamous carcinoma with cells that have abundant eosinophilic, granular, ground-glass cytoplasm, large round to oval nuclei, and prominent nucleoli. Other rare variants of adenosquamous carcinoma include adenoid basal carcinoma and adenoid cystic carcinoma. The former is a well-differentiated tumor that histologically resembles basal cell carcinoma of the skin and tends to have a favorable prognosis. Adenoid cystic carcinomas consist of basaloid cells in a cribriform or cylindromatous pattern and tend to have an aggressive behavior with frequent metastases, although the natural history of these tumors may be long. Whether the prognoses of these rare subtypes are different from other adenocarcinomas of similar grade is uncertain. A variety of neoplasms may infiltrate the cervix from adjacent sites, presenting differential diagnostic problems. In particular, it may be difficult or impossible to determine the origin of adenocarcinomas involving the endocervix and uterine isthmus. Although endometrioid histology suggests endometrial origin and mucinous tumors in young patients are most often of endocervical origin, both histologic types can arise in either site. Metastatic tumors from the colon, breast, or other sites may involve the cervix secondarily. Malignant mixed mullerian tumors, adenosarcomas, and leiomyosarcomas arise occasionally in the cervix, but more often involve it secondarily. Primary lymphomas and melanomas of the cervix are extremely rare.

CLINICAL MANIFESTATIONS

Preinvasive disease is usually detected during routine screening from cervical cytology. Patients with early invasive disease may also be asymptomatic. The first symptom of invasive cervical cancer is usually abnormal vaginal bleeding, often following coitus or vaginal douching. This may be associated with a clear or foul-smelling vaginal discharge. Pelvic pain may result from locoregionally invasive disease or from coexistent pelvic inflammatory disease. Flank pain may be a symptom of hydronephrosis, often complicated by pyelonephritis. The triad of sciatic pain, leg edema, and hydronephrosis is almost always associated with extensive pelvic wall involvement by tumor. Patients with very advanced tumors may have hematuria or incontinence from a vesicovaginal fistula caused by direct extension of tumor to the bladder. External compression of the rectum by a massive primary tumor may cause constipation, but the rectal mucosa is rarely involved at initial diagnosis.

DIAGNOSIS, CLINICAL EVALUATION, AND STAGING

Diagnosis. The long preinvasive stage of cervical cancer, relatively high prevalence of the disease in unscreened populations, and the sensitivity of cytologic screening have made cervical carcinoma an ideal target for cancer screening. In the United States, screening with cervical cytology and pelvic examination has led to a decrease in the mortality rate from cervical cancer of more than 70% since 1940. Only nations with comprehensive screening programs have experienced substantial decreases in cervical cancer death rates during this period. Authorities disagree about the optimal frequency of cervical cancer screening. In a 1988 consensus statement, the American Cancer Society and other medical groups recommended annual Pap smears beginning at age 18 years or with the onset of sexual activity and added that, after three or more consecutive normal annual examinations, the cytologic evaluation could be performed less frequently at the discretion of the physician. For patients who have had repeated negative tests, the marginal gain from screening more often than every 3 years decreases sharply. The US Preventive Services Task Force has recommended that screening be discontinued after age 65 years if results have been consistently normal, and the Canadian Task Force suggests that the interval be extended to 5 years after age 35 if previous studies have been normal. Although these groups have suggested tailoring the frequency of Pap smears to patient risk, practical definitions of low and high risk remain controversial. As a result, most clinicians continue to recommend that their patients be screened more frequently than recommended by the national guidelines. The false-negative rate of the Pap smear is about 10% to 15% in women with invasive cancer. The sensitivity of the test may be improved by ensuring adequate sampling of the squamocolumnar junction and the endocervical canal; smears without endocervical or metaplastic cells are inadequate and must be repeated. Because AIS originates near or above the transformation zone, it may not be sampled with conventional cervical smears. Detection of high endocervical lesions may be improved when specimens are obtained with a cytobrush. Also, because hemorrhage, necrosis, and intense inflammation may obscure the results, the Pap smear is a poor way to diagnose gross lesions; these should always be biopsied. Patients with abnormal cytology who do not have a gross cervical lesion must be evaluated by colposcopy and directed biopsies. Following application of a 3% acetic acid solution, the cervix is examined under 10- to 15-fold magnification with a bright, filtered light that enhances the acetowhitening and vascular patterns characteristic of dysplasia or carcinoma. The skilled colposcopist can accurately distinguish between low- and high-grade dysplasia, but microinvasive disease cannot consistently be distinguished from intraepithelial lesions. If no abnormalities are found on colposcopic examination or if the entire squamocolumnar junction cannot be visualized in a patient with an atypical Pap smear, endocervical curettage should be performed. Some authorities advocate the routine addition of endocervical curettage to colposcopic examination to minimize the risk of missing occult cancer within the endocervical canal. However, it is probably reasonable to omit this step in previously untreated women if the entire squamocolumnar junction is visible with a complete ring of unaltered columnar epithelium in the lower canal. Cervical cone biopsy is used to diagnose occult endocervical lesions and is an essential step in the diagnosis and management of microinvasive carcinoma of the cervix. The geometry of the cone is individualized and tailored to the geometry of the cervix, the location of the squamocolumnar junction, and the site and size of the lesion. Cervical cone biopsy yields an accurate diagnosis and decreases the incidence of inappropriate therapy when (1) the squamocolumnar junction is poorly visualized on colposcopy and a high-grade lesion is suspected; (2) a high-grade dysplastic epithelium extends into the endocervical canal; (3) the cytology suggests a high-grade dysplasia or carcinoma in situ; (4) a microinvasive carcinoma is found on directed biopsy; (5) the endocervical curettings show high-grade CIN; or (6) the cytology is suspicious for AIS.

Clinical Evaluation of Patients with Invasive Carcinoma

All patients with invasive cervical cancer should be evaluated with a detailed history and physical examination, paying particular attention to inspection and palpation of the pelvic organs with bimanual and rectovaginal examinations. Standard laboratory studies should include complete blood count and renal function and liver function tests. All patients should have a chest radiograph to rule out lung metastases and an intravenous pyelogram to determine the kidneys' location and to rule out ureteral obstruction by tumor. Cystoscopy and proctoscopy or barium enema should be obtained in patients with bulky tumors. Many clinicians obtain computed tomography (CT) or magnetic resonance imaging (MRI) scans to evaluate regional nodes, but the accuracy of these studies is compromised by their failure to detect small metastases and because patients with bulky necrotic tumors often have enlarged reactive lymph nodes.

In a large Gynecologic Oncology Group study that compared the results of radiographic studies with subsequent histologic findings, Heller and colleagues found that 79% of the cases with paraaortic lymph node involvement were detected by lymphangiography whereas only 34% were detected by CT. MRI can provide useful information about the location and depth of invasion of tumors in the cervix, [ref: 100-102] but gives less accurate assessments of parametrial involvement. [ref: 103] Clinical Staging The International Federation of Gynecology and Obstetrics (FIGO) has defined the most widely accepted staging system for carcinomas of the cervix. The latest (1994) update of this system is summarized in Table 35.2-4. Since the earliest versions of the cervical cancer staging system, [ref: 106] there have been numerous changes, particularly in the definition of stage I disease. [ref: 107] Preinvasive disease was not placed in a separate category until 1950, and the stage IA category for "cases with early stromal invasion" was first described in 1962. Cases of early stromal invasion and occult invasion were redistributed between stages IA(i), IA(ii), and IB(occult) several times until 1985, when FIGO eliminated stage IB(occult and provided the first specific definitions of microinvasive disease (stages IA1 and IA2). In 1994, these definitions were changed again and, for the first time, stage IB tumors were subdivided according to tumor diameter (Table 35.2-4). Although these changes have gradually improved the discriminatory value of the staging system, the many fluctuations in the definitions of stage IA and IB have complicated our ability to compare the outcomes of patients whose tumors were staged and treated during these periods. [ref: 107] In addition, gynecologic oncologists in the United States have for many years stag disease using the Society of Gynecologic Oncologists' definition of a microinvasive carcinoma, that is, tumor that "invades the stroma in one or more places to a depth of 3 mm or less below the base of the epithelium and in which lymphatic or vascular involvement is not demonstrated," a definition that still differs from the current FIGO classification. FIGO stage is based on careful clinical examination and the results of specific radiologic studies and procedures. These should be performed and the stage should be assigned before any definitive therapy is administered. The clinical stage should never be changed on the basis of subsequent findings. When it is doubtful to which stage a particular case should be allotted, the case should be assigned to the earlier stage. FIGO warns that, because it is impossible to tell from clinical examination whether a smooth and indurated parametrium is truly cancerous or only inflammatory, a case should be classified as stage III only if the parametrium is nodular out on the pelvic wall or if the growth itself extends out on the pelvic wall. In the rules for clinical staging, FIGO states that palpation, inspection, colposcopy, endocervical curettage, hysteroscopy, cystoscopy, proctoscopy, intravenous urography, and radiologic examination of the lungs and skeleton may be used for clinical staging. Suspected bladder or rectal involvement should be confirmed by biopsy. Findings of bullous edema or malignant cells in cytologic washings from the urinary bladder are not sufficient to diagnose bladder involvement. FIGO clearly states that findings by examinations such as lymphangiography, arteriography, venography, and laparoscopy are of value of planning therapy but, because these are not yet generally available and the interpretation of results is variable, the findings of such studies should not be the basis for changing the clinical stage. Examination under anesthesia is desirable but not required. The rules and notes to the FIGO staging system are integral parts of the clinical staging system and should be strictly observed to minimize inconsistencies in staging between institutions. Although most clinicians use the FIGO classification system, a number of European groups use a staging system that divides stage IIB tumors according to the extent of parametrial involvement and divides stage III tumors according to whether there is unilateral or bilateral pelvic wall fixation. Until the mid-1980s, most reports from the University of Texas M.D. Anderson Cancer Center used a similar staging system that also categorized patients with bulky endocervical tumors in a special category. [ref: 107] Although surgically treated patients are sometimes classified according to a TNM pathologic staging system, this has not been widely accepted because it cannot be applied to patients who are treated with primary radiotherapy. [ref: 109] Surgical Evaluation of Regional Spread In the 1970s, studies of diagnostic preradiation lymph node dissection used a transperitoneal approach that led to unacceptable morbidity and mortality rates from radiation-related bowel complications, particularly after treatment with high radiation doses and extended fields. More recently, extraperitoneal dissection, which induces fewer bowel adhesions, has been recommended. With this approach, postradiotherapy small bowel complications occur in fewer than 5% of patients. Laparoscopic node dissection is advocated by some surgeons but remains investigational. The late complication rate of radiotherapy following such procedures has not yet been defined. Although the indications for surgical staging are controversial, advocates argue that the procedure identifies patients with microscopic paraaortic or common iliac node involvement who can benefit from extended-field irradiation. Some investigators have also suggested, on the basis of first principles and encouraging pelvic control rates, that debulking of large pelvic nodes before radiotherapy may improve outcome. Because patients with radiographically positive pelvic nodes are at greatest risk for occult metastasis to paraaortic nodes, they may have the greatest chance of benefiting from surgical staging. Some have advocated pretreatment blind biopsy of the scalene node in patients with positive paraaortic nodes and in patients with a central recurrence who are being considered for exenteration. The reported incidence of supraclavicular metastasis varies widely (5% to 20% or more) for patients with positive paraaortic lymph nodes.

PROGNOSTIC FACTORS

Although the survival and pelvic disease control rates of cervical cancer patients are correlated with FIGO stage, prognosis is also influenced by a number of tumor characteristics that are not included in the staging system. Clinical tumor diameter is strongly correlated with prognosis for patients treated with radiation or surgery. For this reason, FIGO recently modified the stage I category to subdivide tumors according to clinical tumor diameter (i.e., 4 cm or less or more than 4 cm). [ref: 105] For patients with more advanced disease, other estimates of tumor bulk, such as the presence of medial versus lateral parametrial involvement in FIGO stage IIB tumors or of unilateral versus bilateral parametrial or pelvic wall involvement, have also been correlated with outcome. The predictive value of the staging system itself may, in part, reflect an association between the stage categories and the primary tumor volume. Operative findings often do not agree with clinical estimates of parametrial or pelvic wall involvement, and some authors have found that the predictive power of stage diminishes or is lost when comparisons are corrected for differences in clinical tumor diameter. Lymph node metastasis is also an important predictor of prognosis. For patients treated with radical hysterectomy for stage IB disease, survival rates are usually reported as 85% to 95% for patients with negative nodes and 45% to 55% for those with lymph node metastases. Inoue and Morita [ref: 128] reported that survival was correlated with the size of the largest node, and several authors have reported correlations between the number of involved pelvic lymph nodes and survival. Survival rates for patients with positive paraaortic nodes treated with extended-field radiation therapy vary between 10% and 50% depending on the extent of pelvic disease and paraaortic lymph node involvement. For patients treated with radical hysterectomy, several histologic parameters have been associated with a poor prognosis. Lymph-vascular space invasion, deep stromal invasion (10 mm or more or more than 70% invasion), and microscopic evidence of parametrial extension are strongly correlated with lymph node involvement and recurrence, whereas the presence of a strong inflammatory response in the cervical stroma predicts a good outcome. [ref: 141] Uterine body involvement is associated with an increased rate of distant metastases in patients treated with radiation or surgery. [ref: 142-146]. Although several investigators have reported similar survival rates for patients with squamous carcinomas or adenocarcinomas, [ref: 147-152] others have drawn the opposite conclusion, noting unusually high pelvic relapse rates in patients treated surgically for adenocarcinomas and poorer survival rates in patients who undergo surgery or irradiation. [ref: 153-159] In a multivariate analysis of 1767 patients treated with radiation for FIGO stage IB disease, Eifel and colleagues [ref: 156] reported a highly significant independent correlation between histology and survival. Using Cox regression analysis, the relative risk of death from cancer for 106 patients with adenocarcinomas 4 cm or more in diameter was 1.9 times that for patients with squamous tumors (P < .01) (Fig. 35.2-3). Pelvic disease control rates were similar for patients with squamous or adenocarcinomas, but there was a significantly higher incidence of distant metastases in patients with adenocarcinomas. Although the prognostic significance of histologic grade has been disputed for squamous carcinomas, there is a clear correlation between the degree of differentiation and the clinical behavior of adenocarcinomas. Several studies have demonstrated a relationship between hemoglobin level and prognosis of patients with locally advanced cervical cancer. [ref: 117,163-165] The strongest evidence that anemia plays a causative role in pelvic recurrence comes from a small 1978 randomized study conducted at the Princess Margaret Hospital. [ref: 163] All patients were maintained at a hemoglobin level of at least 10 gm%, but those in the treatment arm were maintained through transfusions at hemoglobin levels of 12.5 gm% or more. The 25 anemic patients in the control arm had a significantly higher locoregional recurrence rate than patients in the study who received transfusions. Unfortunately, the results of this small study have never been confirmed, and subsequent studies aimed at overcoming the theoretical radiobiologic consequences of intratumoral hypoxia (hypoxic cell sensitizers, hyperbaric oxygen breathing, neutron therapy) have not been successful. [ref: 166-171] Hockel and colleagues reported a relationship between intratumoral pO(2) measurements and the outcome of patients with cervical cancer, but larger studies will be needed to confirm the prognostic value of intratumoral pO(2).

In a study of sera obtained before treatment from 587 patients with cervical cancers, Duk and colleagues [ref: 173] reported a strong correlation between the concentration of squamous cell carcinoma antigen and the stage and size of the tumor as well as the presence of lymph node metastases; multivariate analysis also showed that serum squamous cell carcinoma antigen was an independent predictor of prognosis in their study.

Other clinical and biologic features that have been investigated for their predictive power with variable results include patient age, platelet count, [ref: 178,179] tumor vascularity, DNA ploidy or S phase, [ref: 182,183] and HPV infection. In a preliminary study of archival material from 21 patients with histologically negative lymph node dissections, Ikenberg and colleagues [ref: 187] recently reported a higher rate of disease recurrence when a polymerase chain reaction assay of the lymph nodes was strongly positive for HPV-16 DNA.

TREATMENT

A number of factors may influence the choice of treatment, including tumor size, stage, and histology; evidence of lymph node involvement; risk factors for surgery or radiation; and patient preference. However, as a rule, intraepithelial lesions are treated with superficial ablative techniques, microinvasive cervical cancers invading less than 3 mm (stage IA1) are managed with conservative surgery (excisional conization or extrafascial hysterectomy), early invasive cancers (stages IA2 and IB1 and some small stage IIA tumors) are managed with either radical surgery or irradiation, and locally advanced cancers (stages IB2 through IVA) are managed with radiation therapy. Selected patients with centrally recurrent disease after maximum radiation therapy may be treated with radical exenterative surgery; pelvic recurrence after hysterectomy is treated with irradiation.

Preinvasive Disease (Stage 0)

Patients with noninvasive squamous lesions can be treated with superficial ablative therapy (cryosurgery or laser therapy) or with loop excision if (1) the entire transformation zone has been visualized colposcopically, (2) directed biopsies are consistent with Pap smear results, (3) endocervical curettage findings are negative, and (4) there is no cytologic or colposcopic suspicion of occult invasion. If patients do not meet these criteria, a conization should be performed.

With cryotherapy, abnormal tissue is frozen with a supercooled metal probe until an ice ball forms that extends 5 mm beyond the lesion. Because cryonecrosis tends to be patchy and may be inadequate after a single freeze, the tissue should be frozen a second time after it has visibly thawed. [ref: 188,189] Another common and equally effective technique ablates tissue with a carbon dioxide laser beam. After laser ablation, there is less distortion and more rapid healing of the cervix, but the procedure requires more training and more expensive equipment than cryosurgery.

Many practitioners now consider loop diathermy excision to be the preferred treatment. With this technique, a charged electrode is used to excise the entire transformation zone and distal canal. Loop diathermy is easily learned, less expensive than laser excision, and preserves the excised lesion and transformation zone for histologic evaluation. [ref: 190-194] However, some authorities think that low-grade lesions may be overtreated with this method. [ref: 195] Loop excision should not be considered an alternative to formal excisional conization when microinvasive or invasive cancer is suspected or for patients with AIS, because it may inadequately treat disease within the cervical canal and complicate further treatment. Cryotherapy, laser excision, and loop excision are all outpatient office procedures that maintain fertility. Although recurrence rates are low (10% to 15%) and progression to invasion rare (less than 2% in most series), lifelong surveillance of these patients must be maintained. Vaginal or type I abdominal hysterectomy currently is reserved for women who have other gynecologic conditions that justify the procedure; invasive cancer still must be excluded before surgery to rule out the need for a more extensive operative procedure.

Microinvasive Carcinoma (Stage IA)

The standard treatment for patients with stage IA1 disease is total (type I) or vaginal hysterectomy. Because the risk of pelvic lymph node metastases from these minimally invasive tumors is less than 1%, pelvic lymph node dissection is not usually recommended. Selected patients with tumors that meet the Society of Gynecologic Oncologists' definition of microinvasion (FIGO stage IA1 disease without lymph-vascular space invasion) and who wish to maintain fertility may be adequately treated with a therapeutic cervical conization if the margins of the cone are negative. In 1991, Burghardt and colleagues [ref: 198] reported one recurrence (which was fatal) in 93 women followed for more than 5 years after therapeutic conization for minimal (less than 1 mm) microinvasion. Morris and colleagues [ref: 199] reported no invasive recurrences in 14 patients followed for a mean of 26 months after conization for tumors invading 0.5 to 2.8 mm. However, patients who have this conservative treatment must be followed closely with periodic cytology, colposcopy, and endocervical curettage.

Diagnostic or therapeutic conization for microinvasive disease is usually performed with a cold knife or carbon dioxide laser on a patient under general or spinal anesthesia. Because an accurate assessment of the maximum depth of invasion is critical, the entire specimen must be sectioned and carefully handled to maintain its original orientation for microscopic assessment. Complications occur in 2% to 12% of patients, are related to the depth of the cone, and include hemorrhage, sepsis, infertility, stenosis, and cervical incompetence. [ref: 200] The width and depth of the cone should be tailored to produce the least amount of injury while providing clear surgical margins.

For patients with 3 to 5 mm of stromal invasion (FIGO stage IA2), the risk of nodal metastases is approximately 5%. Therefore, a bilateral pelvic lymphadenectomy should be performed in conjunction with a modified radical (type II) hysterectomy. Modified radical hysterectomy is a less extensive procedure than a classic radical hysterectomy. The cervix, upper vagina, and paracervical tissues are removed after careful dissection of the ureters to the point of their entry to the bladder. The medial one half of the cardinal ligaments and the uterosacral ligaments are also removed. With this treatment, significant urinary tract complications are rare and cure rates exceed 95%. Although surgical treatment is standard for in situ and microinvasive cancer, patients with severe medical problems or other contraindications to surgical treatment can be successfully treated with radiation therapy. Grigsby and Perez [ref: 205] reported a 10-year progression-free survival rate of 100% in 21 patients with carcinoma in situ and in 34 patients with microinvasive carcinoma treated with radiation alone. Hamberger and colleagues [ref: 206] reported that all patients with stage IA disease and 89 (96%) of 93 patients with small stage IB disease (less than one cervical quadrant involved) were disease free 5 years after treatment with intracavitary irradiation alone.

Stages IB and IIA

Early stage IB cervical carcinomas can be treated effectively with combined external-beam irradiation and brachytherapy or with radical hysterectomy and bilateral pelvic lymphadenectomy. The goal of both treatments is to destroy malignant cells in the cervix, paracervical tissues, and regional lymph nodes.

Overall survival rates for patients with stage IB cervical cancer treated with surgery or radiation usually range between 80% and 90%, suggesting that the two treatments are equally effective. However, biases introduced by patient selection, inconsistencies in the definition of FIGO stage IB disease, and variable indications for postoperative radiotherapy or adjuvant hysterectomy confound comparisons about the efficacy of radiotherapy versus surgery.

In a 1976 review of 321 patients, Morley and Seski [ref: 216] reported similar 5-year survival rates of 91.3% and 87.3% for patients treated with surgery or radiotherapy, respectively. Though treatment was assigned alternately for most patients in this series, the study was not truly randomized; exclusion of some patients found to have unfavorable findings at surgery and deviations from the alternating scheme could have led to biased results. In another review of their experience, Hopkins and Morley [ref: 217] noted that a significant difference in survival favoring surgical treatment disappeared when the authors excluded from the radiation group patients who were selected for radiation treatment only after radical hysterectomy was aborted because of intraoperative findings of extrauterine disease. Because young women with small, clinically node-negative tumors tend to be favored candidates for surgery and because tumor diameter and nodal status are inconsistently described in published series, it is difficult to compare the results reported for patients treated with the two modalities.

Preliminary results of the first prospective trial randomizing patients with stage IB or IIA cervical cancer to radical surgery or radical radiotherapy were recently reported. [ref: 218] In the surgical arm, findings of parametrial involvement, positive margins, deep stromal invasion, or positive nodes led to the use of postoperative pelvic irradiation in 62 (54%) of 114 patients with tumors 4 cm or smaller in diameter and in 46 (84%) of 55 patients with tumors greater than 4 cm in diameter. Patients in the radiotherapy arm received a relatively low dose of radiation to the cervix with a median dose to point A of 72 Gy. The authors reported similar survival rates for the two treatments, but the frequent use of combined modality treatment led to a significantly higher rate of complications in patients treated with initial surgery.

For patients with stage IB1 squamous carcinomas, the choice of treatment is based primarily on patient preference, anesthetic and surgical risks, physician preference, and an understanding of the nature and incidence of complications with the two treatment approaches (described in detail later). The overall rate of major complications is similar for patients with comparable tumors treated with surgery or radiotherapy, although urinary tract complications tend to be more frequent after surgical treatment, and bowel complications are more common after radiation therapy. Surgical treatment tends to be preferred for young women with small tumors because it permits preservation of ovarian function and may cause less vaginal shortening. Radiation therapy is often selected for older, postmenopausal women to avoid the morbidity of a major surgical procedure.

Some surgeons have also advocated the use of radical hysterectomy as initial treatment for patients with larger (stage IB2) tumors. [ref: 219-221] However, patients who have tumors measuring more than 4 cm in diameter usually have deep stromal invasion and are at high risk for lymph node involvement and parametrial extension. Because patients with these risk factors have an increased rate of pelvic disease recurrence, surgical treatment is usually followed by postoperative irradiation, exposing the patient to the risks of both treatments. Consequently, many gynecologic and radiation oncologists believe that patients with bulky (stage IB2) carcinomas are better treated with radical radiotherapy.

RADICAL HYSTERECTOMY. The standard surgical treatment for stages IB and IIA cervical carcinomas is radical (type III) hysterectomy and bilateral pelvic lymph node dissection. This procedure involves en bloc removal of the uterus, cervix, and paracervical, parametrial, and paravaginal tissues to the pelvic sidewalls bilaterally, taking as much of the uterosacral ligaments as possible.

The uterine vessels are ligated at their origin, and the proximal one third of the vagina and paracolpos are resected. For women younger than 40 to 45 years, the ovaries usually are not removed. If intraoperative findings suggest a need for postoperative pelvic irradiation, the ovaries may be transposed out of the pelvis. Intraoperative and immediate postoperative complications of radical hysterectomy include blood loss (average 0.8 L), ureterovaginal fistula (1% to 2%), vesicovaginal fistula (less than 1%), pulmonary embolus (1% to 2%), small bowel obstruction (1% to 2%), and postoperative fever secondary to deep vein thrombosis, pulmonary infection, pelvic cellulitis, urinary tract infection, or wound infection (25% to 50%). [ref: 222] Subacute complications include lymphocyst formation and lower extremity edema, which occurs with a risk related to the extent of the node dissection. Lymphocysts may obstruct a ureter, but hydronephrosis usually improves with drainage of the lymphocyst. [ref: 223] Complications risks may be increased in patients who receive preoperative or postoperative irradiation.

Although most patients have transient decreased bladder sensation after radical hysterectomy, with appropriate management severe long-term bladder complications are infrequent. However, chronic bladder hypotonia or atony occur in approximately 3% to 5% of patients, despite careful postoperative bladder drainage. Bladder atonia probably results from damage to the bladder's innervation and may be related to the extent of the parametrial and paravaginal dissection. Radical hysterectomy may be complicated by stress incontinence, but reported incidences vary widely. Patients may also experience constipation and, rarely, chronic obstipation after radical hysterectomy.

RADIATION THERAPY AFTER RADICAL HYSTERECTOMY.

The role of postoperative irradiation in patients with cervical carcinoma has not yet been clearly established. Most investigators have reported that postoperative irradiation decreases the risk of pelvic recurrence in patients whose tumors have high-risk features (lymph node metastasis, deep stromal invasion, insecure operative margins, or parametrial involvement). However, because the patients who received postoperative radiotherapy in these studies were selected for the high-risk features of their tumors, it is difficult to determine the impact of adjuvant irradiation on survival.

Stages IB and IIA (Continued). In 1989, Kinney and colleagues retrospectively compared the outcome of 60 patients who had postoperative irradiation with 60 unirradiated patients who were matched for stage (stage IB versus IIA), tumor size, and number and site of positive nodes. There were fewer isolated pelvic failures in the irradiated group, but there was no significant difference in survival. However, even this study did not characterize patients in terms of all the risk factors that can influence the choice of treatment. Some authors have hypothesized that the dose of radiation that can be given safely postoperatively may be inadequate to control microscopic disease in a surgically disturbed, hypovascular site. [ref: 234] If this is true, it would be an argument for primary radiotherapeutic management of tumors with known high-risk features.

The overall risk of major complications (particularly small bowel obstructions) is probably increased in patients who receive postoperative pelvic irradiation, but inconsistencies in the methods of analysis and the relatively small number of patients in most series make studies of this subject difficult to interpret. Montz and colleagues reported a 20% risk of small bowel obstruction requiring surgery in 20 patients treated with postoperative irradiation compared with 3 (5%) of 60 patients treated with hysterectomy alone. Bandy and colleagues [ref: 240] reported that patients who were irradiated after hysterectomy also had more long-term problems with bladder contraction and instability than those treated with surgery alone.

RADICAL RADIATION THERAPY. Radiation therapy also achieves excellent survival and pelvic control rates in patients with stage IB cervical cancers. Eifel and colleagues [ref: 116] reported a 5-year disease-specific survival rate of 90% for 701 patients treated with radiation alone for stage IB1 squamous tumors less than 4 cm in diameter. The central and pelvic tumor control rates were 99% and 98%, respectively. Disease-specific survival rates were 86% and 67% for patients with tumors measuring 4 to 4.9 cm or 5 cm or more in diameter, respectively. Pelvic tumor control was achieved in 82% of patients with tumors 5 cm or more in diameter. Perez and colleagues [ref: 118] and Lowrey and colleagues reported similar excellent disease control rates for patients with stage IB tumors. Survival rates for patients with FIGO stage IIA disease treated with irradiation range between 70% and 85% and are also strongly correlated with tumor size.

As with radical surgery, the goal of radiation treatment is to sterilize disease in the cervix, paracervical tissues, and regional lymph nodes in the pelvis. Patients are usually treated with a combination of external-beam irradiation to the pelvis and brachytherapy. Clinicians balance external and intracavitary treatment in different ways for these patients, weighting one or the other component more heavily. However, brachytherapy is a critical element in the curative radiation treatment of all carcinomas of the cervix. Even relatively small tumors that involve multiple quadrants of the cervix are usually treated with total doses of 80 to 85 Gy to point A. This dose may be reduced by 5% to 10% for very small superficial tumors. Although patients with small tumors may be treated with somewhat smaller fields than patients with more advanced locoregional disease, care must still be taken to cover adequately the obturator, external iliac, low common iliac, and presacral nodes. Radiation technique and potential complications are discussed in more detail later.

Stages IIB, III, and IVA

Radiation therapy is the primary treatment for most patients with locoregionally advanced cervical carcinoma. The success of treatment depends on a careful balance between external-beam radiation therapy and brachytherapy, optimizing the dose to tumor and normal tissues, and the overall duration of treatment. Five-year survival rates of 65% to 75%, 35% to 50%, and 15% to 20% are reported for patients treated with radiotherapy alone for stages IIB, IIIB, and IVA tumors, respectively. In a French Cooperative Group study of 1383 patients treated with radiotherapy according to Fletcher guidelines, Horiot and colleagues [ref: 120] reported 5-year survival rates of 76%, 50%, and 20.5% for patients with stages IIB, IIIB, and IVA tumors, respectively. With appropriate radiotherapy, even patients with massive locoregional disease have a significant chance for cure.

External-beam irradiation is used to deliver a homogeneous dose to the primary cervical tumor and to potential sites of regional spread. An initial course of external irradiation may also improve the efficacy of subsequent intracavitary treatment by shrinking bulky endocervical tumor (bringing it within the range of the high-dose portion of the brachytherapy dose distribution) and by shrinking exophytic tumor that might prevent satisfactory placement of vaginal applicators. For this reason, patients with locally advanced disease usually begin with a course of external-beam treatment. Subsequent brachytherapy exploits the inverse square law to deliver a high dose to the cervix and paracervical tissues while minimizing the dose to adjacent normal tissues. Although many clinicians delay intracavitary treatment until pelvic irradiation has caused some initial tumor regression, breaks between external-beam and intracavitary therapy should be discouraged, and every effort should be made to complete the entire treatment in less than 7 to 8 weeks. The favorable results documented in reports from large single institutions have been based on policies that dictate relatively short overall treatment durations (less than 8 weeks), [ref: 256] and several studies in patients with locally advanced cervical cancer have suggested that longer treatment courses are associated with decreased pelvic control and survival rates.

EXTERNAL-BEAM TECHNIQUE. High-energy photons (15 to 18 MV) are usually preferred for pelvic treatment because they spare superficial tissues that are unlikely to be involved with tumor. At these energies, the pelvis can be treated either with four fields (anterior, posterior, and lateral fields) or with anterior and posterior fields alone (Fig. 35.2-6). When high-energy beams are not available, four fields are usually used because less penetrating 4 to 6 MV photons often deliver an unacceptably high dose to superficial tissues when only two fields are treated. However, lateral fields must be designed with great care because clinicians' estimates of the location of potential sites of disease on a lateral radiograph may be inaccurate. In particular, "standard" anterior and posterior borders that have been described in the past may shield regions at risk for microscopic regional disease in the presacral and external iliac nodes and in the presacral and cardinal ligaments; care must also be taken not to underestimate the posterior extent of central cervical disease in patients with bulky tumors. [ref: 262,263] The caudad extent of disease can be determined by placing radiopaque seeds in the cervix or at the lowest extent of vaginal disease. Information gained from radiologic studies can also improve estimates of disease extent. Lymphangiograms are helpful in tailoring blocks, particularly at the anterior border of lateral fields. MRI and CT scans can also help clinicians to design lateral field borders with an improved understanding of uterine position. In fact, some investigators have argued that these studies should be obtained routinely for patients with bulky disease to avoid errors in lateral field design. [ref: 264] However, when all these factors are considered, differences in the volume treated with a four-field or a high-energy two-field technique may be small. For this reason, some clinicians prefer to use the simpler technique for patients with bulky tumors.

Tumor response should be evaluated with periodic pelvic examinations to determine the best time to deliver brachytherapy treatment. Some practitioners prefer to maximize the brachytherapy component of treatment and begin as soon as the tumor has responded enough to permit a good placement (with very bulky tumors this may still require 40 Gy or more). Subsequent pelvic irradiation is delivered with a central block. A somewhat higher total paracentral dose can be delivered with this approach, but greater reliance is placed on the complex match between the brachytherapy dose distribution and the border of the central shield. Other clinicians prefer to give an initial dose of 40 to 45 Gy to the whole pelvis, believing that the ability to deliver a homogeneous distribution to the entire region at risk for microscopic disease and the additional tumor shrinkage achieved before brachytherapy outweigh other considerations. In fact, both approaches have been in use for several decades and, when optimally used, appear to give excellent tumor control rates with acceptable complication rates.

BRACHYTHERAPY TECHNIQUE. Fletcher described the following three conditions for successful cervical brachytherapy: (1) the geometry of the radioactive sources must prevent underdosed regions on and around the cervix, (2) an adequate dose must be delivered to the paracervical areas, and (3) mucosal tolerance must be respected. These factors dictate the character, intensity, and timing of brachytherapy.

Brachytherapy is usually delivered using afterloading applicators that are placed in the uterine cavity and vagina. A number of different intracavitary systems have been used; in the United States, variations of the Fletcher-Suit-Delclos system are used most commonly. The intrauterine tandem and vaginal applicators are carefully positioned, usually with the patient under anesthesia, to provide an optimal relationship between the system and adjacent tumor and normal tissues. Vaginal packing is used to hold the tandem and colpostats in place and to maximize the distance between the sources and adjacent bladder and rectum. Radiographs should be taken at the time of insertion to verify accurate placement, and the system should be repositioned if it can be improved. Encapsulated radioactive sources are inserted in the applicators after the patient has returned to her hospital bed, reducing exposure to personnel during applicator placement. Remote afterloading devices that further reduce personnel exposure are often used in departments that treat many gynecologic patients. Although **226Ra was used to treat most patients before the 1980s, it has gradually been replaced by **137Cs, which produces a similar dose distribution and avoids the radiation protection problems caused by the radon gas byproduct of radium decay.

BRACHYTHERAPY DOSE. Optimal placement of the uterine tandem and vaginal ovoids produces a pear-shaped distribution, delivering a high dose to the cervix and paracervical tissues and a reduced dose to the rectum and bladder.

Treatment dose has been specified in a number of ways, making it very difficult to compare experiences. Paracentral doses are most frequently expressed at a single point, usually designated point A. This reference point has been calculated in a number of different ways, but it is usually placed 2 cm lateral and 2 cm superior to the external cervical os, in the central plane of the intracavitary system. Point A lies approximately at the crossing of the ureter and the uterine artery, but it bears no consistent relationship to the tumor or target volume. Point A was originally developed as part of the Manchester treatment system (a modification of the earlier Paris system). It was meant to be used in the context of a detailed set of rules governing the placement and loading of the intracavitary system. Today this context is often lost.

In 1985 the International Commission on Radiation Units and Measurements recommended that reference points like point A not be used because "such points are located in a region where the dose gradient is high and any inaccuracy in the determination of distance results in large uncertainties in the absorbed doses evaluated at these points." Instead, they recommended that doses be specified in terms of the following: (1) total reference air Kerma -- expressed in muGy at 1 meter -- is an alternative to milligram-hours that allows for the use of various radionuclides; it is proportional to the dose at points distant from the system, providing an estimate of the integral dose to the pelvis; (2) description of the reference volume, that is, the volume of tissue receiving 60 Gy or more, and (3) doses to specific normal tissue reference points (bladder, rectum, vagina). Although normal tissue reference points provide useful information about the dose to a portion of normal tissue, several studies have demonstrated that they consistently underestimate the maximum dose to those tissues. Whatever system of dose specification is used, emphasis should always be placed on achieving an optimized relationship between the intracavitary applicators and the cervical tumor and other pelvic tissues. Source strengths and positions should be carefully chosen to provide optimal tumor coverage without exceeding normal tissue tolerance. However, optimized source placement can rarely correct for a poorly positioned applicator.

A detailed description of the characteristics of an ideal intracavitary system and of the considerations that influence source strength and position are beyond the scope of this chapter. However, an effort should always be made to deliver 85 Gy or more to point A for patients with bulky central disease. If the intracavitary placement has been optimized, this can usually be accomplished without exceeding a dose of 75 Gy to the bladder reference point or 70 Gy to the rectal reference point, doses that are usually associated with an acceptably low risk of major complications. The dose to the surface of the lateral wall of the apical vagina should not usually exceed 130 to 140 Gy. Suboptimal placements occasionally force compromises in the dose to tumor or normal tissues. To choose a treatment that optimizes the therapeutic ratio in these circumstances requires experience and a detailed understanding of factors that influence tumor control and normal tissue complications.

A total dose (external beam and intracavitary) of 50 to 55 Gy appears to be sufficient to sterilize microscopic disease in the pelvic nodes in most patients. It is customary to boost the dose to a total of 60 to 65 Gy in lymph nodes known to contain gross disease and in heavily involved parametria.

BRACHYTHERAPY DOSE RATE. Traditionally, cervical brachytherapy has been performed with sources that yield a dose rate (at point A) of approximately 40 to 50 cGy/hr. These low dose rates permit repair of sublethal cellular injury, normal tissues are preferentially spared, and the therapeutic ratio is optimized. To reduce the 3 to 4 days of hospitalization needed to deliver an appropriate dose of low-dose-rate irradiation, some investigators have explored the use of intermediate-dose-rate brachytherapy (80 to 100 cGy/hr). However, in a randomized trial, Haie-Meder and colleagues reported a significant increase in complications when the dose rate was doubled from 40 to 80 cGy/hr, indicating that the total dose must be reduced and the therapeutic ratio of treatment may be compromised with higher dose rates.

INTERSTITIAL BRACHYTHERAPY. Several groups have advocated the use of interstitial brachytherapy to treat patients whose anatomy or tumor distribution make it difficult to obtain an ideal intracavitary placement. Interstitial implants are usually placed transperineally, guided by a Lucite template that encourages parallel placement of hollow needles that penetrate the cervix and paracervical spaces; needles are usually loaded with **192Ir. Advocates of the procedure describe the relatively homogeneous dose distribution achieved with this method, the ease of inserting implants in patients whose uteri are difficult to probe, and the ability to place sources directly into the parametrium. Initial reports were enthusiastic, describing these theoretical advantages and high initial local control rates.

Recently several groups have been exploring the use of MRI-guided needle placement, interstitial hyperthermia, and high-dose-rate interstitial therapy to improve local control and complication rates. However, outside of an investigational setting, interstitial treatment of primary cervical cancers should probably be limited to patients who cannot accommodate intrauterine brachytherapy and to those with distal vaginal disease that requires a boost with interstitial brachytherapy.

COMPLICATIONS OF RADICAL RADIOTHERAPY. During radiotherapy of the pelvis, most patients have mild fatigue and mild to moderate diarrhea that usually is controllable with antidiarrheal medications; some patients have mild bladder irritation. When extended fields are treated, patients may have nausea, gastric irritation, and mild depression of peripheral blood counts. Acute symptoms may be increased in patients receiving concurrent chemotherapy. Unless the ovaries have been transposed, all premenopausal patients who receive pelvic radiotherapy experience ovarian failure by the completion of treatment.

Complications of intracavitary therapy include uterine perforation, fever, and the usual risks of anesthesia. Thromboembolic complications are rare. In a review of 327 patients who had gynecologic brachytherapy for a variety of indications, Dusenberry and colleagues reported four (1.2%) thromboembolic complications. In a recent unpublished review of 1784 patients treated with radiotherapy for Stage IB cervical cancer at M. D. Anderson, there were 3 (0.17%) suspected cases of pulmonary embolus, none of which were fatal. Patients with bulky disease on the pelvic wall may have a somewhat greater risk of thromboembolic events.

Estimates of the risk of late complications of radical radiotherapy vary according to the grading system, duration of follow-up, method of calculation, treatment method, and prevalence of risk factors in the study population. However, most reports quote an overall risk of major complications (requiring transfusion, hospitalization, or surgical intervention) of 5% to 15%. Perez and colleagues reported a crude risk of major complications of 14.8% with a median follow-up of 12 years. In a report from the Patterns of Care Study, Lanciano and colleagues reported an actuarial risk of 8% at 3 years. In a study of 1784 patients with stage IB disease, Eifel and colleagues reported an overall actuarial risk of major complications of 7.7% at 5 years. Although the actuarial risk was greatest during the first 3 years of follow-up, there was a continuing risk to surviving patients of approximately 0.34% per year, resulting in an overall actuarial risk of 14.4% at 20 years.

During the first 3 years after treatment, rectal complications are most common and include bleeding, stricture, ulceration, and fistula. In the study by Eifel and colleagues, the risk of major rectosigmoid complications was 2.3% at 5 years. Urinary tract complications, including hematuria, fistula, and ureteral stricture, occurred less frequently during the first 3 years, but had a continuing risk with added follow-up. The actuarial risk of developing a fistula of any type was 1.7% at 5 years.

Small bowel obstruction is an infrequent complication of standard radiotherapy for patients without special risk factors. The risk is increased dramatically in patients who have undergone transperitoneal lymph node dissections. However, there appears to be little added risk if the operation is performed with a retroperitoneal approach. Other factors that can increase the risk of small bowel complications in patients treated for cervical cancer include pelvic inflammatory disease, thin body habitus, and the use of high doses or large volumes of external-beam irradiation, particularly with low-energy treatment beams and large daily fraction sizes.

Most patients treated with radical radiotherapy have some agglutination and telangiectasia of the apical vagina. More significant vaginal shortening can occur, particularly in elderly, postmenopausal women and those with extensive tumors treated with a high dose of irradiation. Vaginal function can be optimized with appropriate estrogen support and vaginal dilatation.

Stages IIB, III, and IVA (Continued). Investigators were encouraged to explore neoadjuvant treatment because of the high response rates reported for a variety of cisplatin-containing combinations evaluated in phase II studies of previously untreated patients with cervical cancer. However, it was not possible to determine from these uncontrolled trials whether high response rates to chemotherapy would lead to improved survival rates. Five randomized trials comparing neoadjuvant chemotherapy followed by irradiation and irradiation alone have been reported. Chauvergne and colleagues randomized 151 patients with stages IIB or III disease to receive radical radiotherapy alone or preceded by chemotherapy (cisplatin, methotrexate, chlorambucil, and vincristine). Although objective responses to chemotherapy were observed in 31 (43%) of 73 patients, there was no difference in the survival or pelvic disease control rates of patients in the two treatment arms. In a randomized study of 184 patients with stages IIB to IVA squamous carcinomas, Kumar and colleagues found no significant difference in disease-free or overall survival between patients treated with bleomycin, cisplatin, and ifosfamide followed by irradiation or with irradiation alone. Tattersall and colleagues reported no difference in survival when they compared chemotherapy (cisplatin, bleomycin, and Velban) followed by pelvic irradiation with radiotherapy alone in 71 patients who had positive pelvic lymph nodes discovered at radical hysterectomy. Souhami and colleagues reported a significantly poorer survival rate (23% versus 39%; P =. 02) for patients who received neoadjuvant chemotherapy (cisplatin, bleomycin, vincristine, and mitomycin-C) in a study of 107 patients with stage IIIB cervical cancers. In another large prospective trial reported by Tattersall and colleagues, 129 patients who received neoadjuvant chemotherapy (cisplatin and epirubicin) had a significantly poorer pelvic disease control rate (P = .003) and survival rate (P = .02) than 131 patients treated with radiation therapy alone, despite a high initial response rate to chemotherapy (63%).

In summary, despite high response rates of locally advanced cervical cancers to initial chemotherapy, none of the randomized studies reported to date has demonstrated an improvement in outcome when neoadjuvant chemotherapy was added to radical radiotherapy. In many ways, this recapitulates the experience with treatment of locally advanced head and neck cancers for which it has been hypothesized that the failure to influence outcome with neoadjuvant chemotherapy may reflect cross-resistance of clonagens to drugs and radiation or accelerated repopulation of tumor clonogens induced by neoadjuvant chemotherapy. CONCURRENT CHEMORADIATION. A number of investigators have reported high response rates and encouraging survival rates in uncontrolled phase I/II studies of patients with locally advanced cervical carcinomas treated with concurrent chemotherapy and irradiation. Drugs that are most commonly given concurrently with radiation therapy include hydroxyurea, 5-fluorouracil, mitomycin-C, and cisplatin.

Hydroxyurea, a drug that has been demonstrated in vitro to sensitize cells to radiation by arresting them in a sensitive portion of the cell cycle, was identified as an attractive subject for clinical study in the early 1970s. After a small randomized study suggested encouraging results, the Gynecologic Oncology Group conducted a larger study randomizing patients with stage IIIB or IVA disease either to receive oral hydroxyurea (80 mg/kg, up to 6 g per dose, every 3 days for 12 weeks) or placebo during radiotherapy. [ref: 333] The authors of this study reported that patients who received hydroxyurea had a higher complete response rate (68% versus 48%), a longer median progression-free interval (13.6 versus 7.6 months), and a longer median survival (19.5 versus 10.7 months). However, this trial has been criticized because 100 (53%) of the 190 patients entered in the study were considered to be either ineligible or inevaluable and were excluded from the analysis. The minimum recommended dose of radiotherapy was also conservative for patients with theses advanced tumors (70 Gy if a combination of external-beam and intracavitary irradiation was used or 60 Gy if only external-beam irradiation was used), possibly contributing to the poor overall survival rates in both arms. A second Gynecologic Oncology Group study compared hydroxyurea (80 mg/kg, given twice per week during external-beam irradiation) with misonidazole, a nitroimidazole hypoxic cell sensitizer that has since been demonstrated to be of no benefit in several trials that compared misonidazole with a placebo. Patients with stages IIB to IIIB squamous carcinomas were eligible for this study if they had negative paraaortic lymph nodes confirmed by staging laparotomy. Of 294 evaluable patients, 178 (61%) had stage IIB disease. An updated analysis of this study in 1993 showed a marginal advantage in progression-free survival (P = .05) and survival (P = .07), which appeared to be most marked for patients with stages IIIB and IVA disease. This has been interpreted as confirmatory evidence of the value of hydroxyurea as a radiosensitizer in this setting. However, the suggestion from several studies that nitroimidazole sensitizers may actually decrease pelvic control rates in patients with cervical cancer may invalidate this conclusion.

A third Gynecologic Oncology Group study using similar entry criteria randomized patients to receive either hydroxyurea (80 mg/kg orally twice weekly during external-beam irradiation) or cisplatin (50 mg/m**2 intravenously on days 1 and 29) and 5-fluorouracil (1000 mg/m**2 as a continuous intravenous infusion on days 2 through 5 and days 30 through 33 of radiation). This study closed to patient accrual in 1990, and the results should be analyzed and reported soon. Ongoing studies that address the value of chemosensitization in patients with locally advanced cervical cancer include (1) a Gynecology Oncology Group study randomizing patients to receive either hydroxyurea, weekly cisplatin, or a combination of hydroxyurea, 5-fluorouracil, and cisplatin during external-beam irradiation and (2) a Radiation Therapy Oncology Group study comparing cisplatin plus 5-fluorouracil (administered in three cycles during external-beam and intracavitary irradiation) with extended field irradiation plus brachytherapy.

In summary, concurrent treatment of locally advanced cervical cancers with chemotherapy and radiotherapy is an approach that holds considerable promise, although additional studies are needed to confirm the benefit of this treatment. To confirm that concurrent chemotherapy improves the therapeutic ratio achievable with radical radiotherapy, future studies also need to provide careful documentation of the late complications of treatment. The morbidity of radiotherapy with and without chemotherapy has not yet been compared in a randomized study, but one uncontrolled study suggests that late gastrointestinal toxicity may be increased with concurrent administration of some drugs.

INTRAARTERIAL CHEMOTHERAPY. Intraarterial infusion of chemotherapeutic agents delivered neoadjuvantly, concurrent with radiotherapy, or as salvage treatment for recurrent disease has generated interest for some years because of the distinct arterial supply to the central pelvis. A number of drugs have been used in small pilot studies, but 5-fluorouracil and cisplatin have been the most popular in this setting. Unfortunately, this technique is difficult and invasive, the toxicity reported in some series has been substantial, and the results have been variable in several small series of patients. However, occasional optimistic reports have maintained a low level of interest in this approach, particularly for concurrent intraarterial chemotherapy and irradiation.

Stage IVB

Patients who present with disseminated disease are almost always incurable. Management of these patients must emphasize palliation of symptoms with appropriate pain medications, and localized radiotherapy. Tumors may respond to chemotherapy, but the duration of responses is usually short.

SINGLE-AGENT CHEMOTHERAPY. Fifty-two drugs have been studied in sufficient numbers of patients with carcinoma of the cervix to assess their activity. Nineteen of these have yielded response rates (partial and complete) of at least 15% and may be of therapeutic value.

Several of the platinum compounds have been evaluated in greater detail. Cisplatin has been studied in a variety of doses and schedules. [ref: 360,362,363] These studies have demonstrated activity of the drug at a dose of 50 mg/m**2 given intravenously at a rate of 1 mg/min every 3 weeks. Although there appears to be a small but statistically significant increase in the response rate with a doubling of the dose to 100 mg/m**2, this has not resulted in a detectable improvement in the rates of progression-free or overall survival. More prolonged infusion of the same dose over 24 hours yields a similar response rate with less nausea and vomiting, although the recent development of more effective antiemetic agents reduces the clinical importance of this observation. The response rates of other platinum compounds (i.e., carboplatin and iproplatin) are lower than those observed with cisplatin, which remains the platinum compound of choice for patients with cervical carcinomas.

Ifosfamide has been studied as a single agent in patients with recurrent cervical cancer in at least five phase II trials. Response rates ranged between 33% and 50% in three studies that were conducted in patients who had received no previous chemotherapy. [ref: 350,354-356] However, the response rates were much lower in two phase II trials that included patients who had received prior systemic chemotherapy, with only three partial responses (8%) in 36 patients. COMBINATION CHEMOTHERAPY. Most reports of combination chemotherapy for carcinoma of the cervix have described uncontrolled phase II trials of drug combinations that have included at least some agents with known activity. Most studies have been small, with reported response rates ranging from 0% to 100%. In general, data from these phase II studies provide no firm evidence that any of the studied combinations are superior to single-agent therapy for patients with disseminated or recurrent cervical cancer. However, combinations based on ifosfamide and cisplatin and those based on 5-fluorouracil and cisplatin have attracted significant interest and deserve further discussion.

Several small phase II studies have evaluated treatment with combinations of ifosfamide and either cisplatin or carboplatinum in patients who had not received prior radiotherapy. Response rates for these combinations ranged between 50% and 63%. A number of investigators have combined bleomycin with ifosfamide and a platinum compound. Three studies included patients who had not had prior radiotherapy, and reported response rates were 65% to 100%. Reports of treatment with these drugs in previously irradiated patients have yielded mixed, but generally lower, response rates of between 13% and 72%.

Combinations of cisplatin and continuous infusion 5-fluorouracil also produce high response rates in previously untreated patients. [ref: 310,311] Again, response rates decrease significantly if patients have had previous irradiation.

The Gynecologic Oncology Group recently completed a large prospective randomized trial comparing cisplatin alone with cisplatin plus ifosfamide and cisplatin plus dibromodulcitol in patients with advanced or recurrent cervical cancers. The addition of ifosfamide to cisplatin improved the response rate (33% versus 19%, P = .02) and progression-free survival rate (4.6 versus 3.2 months, P < .05), but caused significantly greater toxicity (leukopenia, peripheral neuropathy, renal toxicity, and encephalopathy) and did not significantly improve the overall median survival. The addition of dibromodulcitol did not improve the response rate or survival duration.

PALLIATIVE RADIOTHERAPY. Localized radiotherapy can provide effective pain relief for symptomatic metastases in bone, brain, lymph nodes, or other sites. A rapid course of pelvic radiotherapy can also provide excellent relief of pain and bleeding for patients who present with incurable disseminated disease.

Notice:

These study materials were prepared from the book

CANCER: Principles & Practice of Oncology. 5^th Ed., USA.

Prepared by Prof. Igor Galaychuk, MD,

2014