Practice nursing care for Clients with Cancer I
One in every 4 deaths in the United States is caused by cancer and more than 1500 people die of cancer each day. Cancer can affect people of any age, gender, ethnicity, or geographic region.
Cancer is the second leading cause of death in people over age 65. The incidence of cancer increases with advancing age. The most commonly seen cancers in older women are colorectal, breast, lung, pancreatic, and ovarian. In older men, lung, colorectal, prostate, pancreatic, and gastric cancers occur most frequently.
Oncogenes are genes that promote cell proliferation and are capable of triggering cancerous characteristics. Several oncogenes, such as BRCA-1 and BRCA-2, are associated with breast cancer.
Tumor suppressor genes, which normally suppress oncogenes, can become inactive by deletion or mutation. Inherited cancers have been associated with tumor suppressor genes, such as p53, a suppressor gene that has been associated with sarcoma and cancer of the breast and brain.
The diagnosis and treatment of cancer is a pivotal life-changing event that prompts individuals to make immediate and ongoing adjustment to this life-threatening illness.
Effective physical and psychosocial adjustment to cancer diagnosis and treatment has been shown to lead to successful completion of treatment, enhancement of cancer patients’ ability to cope with disease, improvement of patients’ quality of life, and ultimately, improvement of survival.
The goals of cancer treatment are aimed at cure and control of cancer as well as management of cancer-related and treatment-related symptoms.
Chemotherapy uses cytotoxic medications to cure or control cancer by interrupting cell metabolism and replication and by interfering with the ability of the malignant cell to synthesize vital enzymes and chemicals.
Pain management is an important component of care for cancer patients. It is estimated that 20% to 50% of clients with early-stage cancer and up to 95% of clients with advanced cancer experience pain.
Complementary therapies are therapies that clients choose as a complement to medical treatment. Common complementary therapies for cancer include botanical agents, nutritional supplements, dietary regimens, mind-body modalities, spiritual approaches, and miscellaneous therapies. To provide sensitive care, nurses should be knowledgeable about common complementary therapies.
Tumor lysis syndrome (TLS), a combination of two or more metabolic abnormalities, is a life-threatening emergency for clients with cancer. Patients at risk for TLS include those with bulky chemosensitive cancer such as high-degrade lymphomas and acute leukemia, elevated serum uric acid, potassium, and phosphorus, and renal deficiency.
Cancer of the Esophagus
Epidemiology
Cancer of the esophagus has the greatest variation in geographic distribution of any malignancy. A 17-fold difference in age-adjusted mortality for men exists for countries with the highest and lowest incidence. Data from the World Health Organization show that the mortality is highest in
The age-adjusted overall mortality of 3.4 persons per 100,000 is similar to the incidence, indicating the high mortality rate for this cancer. The major histologic types of esophageal cancer are squamous (epidermoid) carcinoma and adenocarcinoma. Although in the past, squamous carcinoma predominated, today the incidence of adenocarcinoma of the esophagus is rapidly increasing.
Adenocarcinoma of the esophagus has been frequently classified as a gastric carcinoma. However, esophageal adenocarcinomas arising in Barrett’s epithelium are clearly esophageal in origin. Adenocarcinomas arising in the gastric cardia frequently metastasize to nodal groups in the drainage bed of the esophagus and spread submucosally along the esophagus. The treatment and prognosis of these tumors are similar to those of squamous cancer. The incidence of adenocarcinoma of the esophagus has been increasing rapidly over the past decade in the
The incidence of adenocarcinoma of the esophagus in whites is higher than in blacks.
Recently, an increase in the incidence of adenocarcinomas of the esophagus and gastric cardia was noted in white men. This increase could not be explained by a change in the incidence of gastric cancer or squamous cancer. Excessive alcohol consumption and smoking increase the risk for developing esophageal cancer, and together they act synergistically.
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PREDISPOSING CONDITIONS
TYLOSIS
Tylosis is a disease characterized by hyperkeratosis of the skin of the palms and soles and papillomata of the esophagus. The syndrome is inherited in an autosomal dominant fashion. Squamous cell carcinomas of the esophagus develop with a high frequency in affected families.
ACHALASIA
In patients with achalasia, the risk for developing esophageal carcinoma may be 14% to 16% greater than the normal population risk. Cancers can occur in the middle and lower third of the esophagus but are more common in the middle third, which frequently corresponds to the air-fluid interface of retained food and liquids. Cancers generally occur an average of 17 years after the diagnosis of achalasia: and may persist after surgical correction. Patients may benefit from annual or biannual endoscopy.
BARRETT’S ESOPHAGUS
Barrett’s esophagus is a premalignant condition that may proceed to development of adenocarcinoma of the esophagus (see later).
CAUSTIC INJURY Squamous carcinomas arising in lye strictures are responsible for 1% to 4% of esophageal carcinomas. Caustic burns to the esophagus are increasingly rare; however, squamous cell carcinoma may develop in such patients 40 to 50 years after injury.
Three quarters of all these tumors are located in the middle third of the esophagus.
Because of the increased risk, patients with prior history of caustic ingestion should be routinely screened, particularly when the time from injury exceeds 20 years.
The low incidence of carcinoma and the potentially high operative morbidity associated with resection of a chronically scarred esophagus argue against resection of these strictures. If repeated dilations fail, a bypass may relieve dysphagia in the absence of cancer.
ESOPHAGEAL DIVERTICULA
Infrequently, squamous cancers develop in esophageal diverticula. The incidence in 1249 patients was 0.4% in one series.
In this series, diverticulectomy alone was curative in the absence of full-thickness penetration, lymph node metastasis, or extension to the margin of resection.
There are reports of cancer of the upper esophagus associated with upper esophageal webs.
In 1919 Paterson and Kelley described a syndrome consisting of dysphagia from an esophageal web, iron-deficiency anemia, and glossitis. The association of esophageal webs with iron-deficiency anemia, glossitis, cheilosis, koilonychia, brittle fingernails, and splenomegaly is referred to as the Plummer-Vinson or Paterson-Kelly syndrome. The condition is premalignant: approximately 10% of individuals will develop neoplasms of the esophagus or hypopharynx.
Treatment of the webs consists of endoscopic disruption. Dilations may be necessary if endoscopic disruption is not successful. Myotomy and resection of the web may be required.
SECOND PRIMARY TUMORS
Esophageal cancers may develop as second primary tumors in patients with other primary tumors of the upper aerodigestive tract. Patients with upper aerodigestive tract cancers develop second primary tumors at the rate of 4% of patients per year.
In patients with head and neck cancers, one third of the second primary tumors arise in the esophagus. Cancers of the tonsil and palate most frequently were associated with esophageal second primaries. The appearance of a second primary tumor adversely affects survival from the first cancer. Cancers developing in this region are associated with tobacco consumption. Most second primary tumors arise in upper aerodigestive epithelium that is exposed to a carcinogen such as cigarette smoke; this phenomenon is called field cancerization.
INFECTIOUS AGENTS
Infection by certain microorganisms has been associated with the development of esophageal neoplasms. These microorganisms may act indirectly on the esophageal epithelium either by forming carcinogens or other products to enhance or attenuate carcinogenesis or by directly affecting the esophagus itself. Human papilloma virus DNA is associated with squamous cell carcinoma in
Patients at high risk for gastric carcinoma may have a high incidence of Helicobacter pylori infection, although neoplasms involving the cardia may be less likely to have a strong association with H pylori infection. Although most patients with H pylori infection will not develop gastric carcinoma, associated factors in combination with H pylori infection may predispose to carcinogenesis. In one study, over 15% of patients with Barrett’s esophagus were noted to be infected with H pylori and all 9 patients who were infected also had a chronic inflammatory reaction.
ANATOMY
The esophagus spans the interval between the hypopharynx and the stomach. The esophagus originates at the cricoid cartilage at the level of the cricopharyngeus muscle and topographically at the level of the sixth cervical vertebrae. The cervical esophagus is about
The American Joint Committee for Cancer Staging and End Results Reporting divides the esophagus into four principal regions: the cervical esophagus, extending from the cricopharyngeus to the thoracic inlet; the upper thoracic esophagus extending from the thoracic inlet to the level of the tracheal bifurcation (
The American Joint Committee for Cancer standards are based on strict anatomic and length criteria. Most radiologists and surgeons divide the esophagus into “thirds” to correspond to the following: the upper third, from the cricopharyngeus to the superior portion of the aortic arch; the middle third, from the superior portion of the aortic arch to the inferior pulmonary vein; and the distal third, from the inferior pulmonary vein to the gastroesophageal junction. This simple anatomic classification is commonly used. About 15% of all esophageal cancers occur in the upper third of the esophagus, 50% in the middle, and 35% in the lower third. The numbers vary from series to series, and some report that lesions in the lower third are the most common because these are the tumors most amenable to therapy.
BLOOD SUPPLY
The blood supply to the esophagus is segmental and has three main arterial sources: inferior thyroid artery, the bronchial arteries at the level of the carina, and the left gastric and inferior artery.
Autopsy studies have revealed that all major vascular trees that supply the esophagus divide into minute branches some distance from the esophagus. This capillary network extends into the esophagus and supplies the submucosal area with the richest vascular supply. Because of this rich vascular plexus within the submucosa, the esophagus can be mobilized and remain viable. The transhiatal esophagectomy, therefore, can be performed without significant hemorrhage as long as the dissection is performed within this 1-cm capillary zone around the esophagus. The blood supply of the cervical esophagus is the superior and inferior thyroid arteries. There may be small branches supplied from the subclavian artery. The thoracic esophagus is supplied by branches from the aorta to the esophagus just below the level of the carina. The lower esophagus and cardia are supplied by branches from the left gastric artery. The veins from the thoracic esophagus drain into the azygous and hemizygous system and the intercostal veins, which are tributaries of the azygous system.
LYMPHATIC DRAINAGE
The lymphatic supply of the esophagus is extensive. A dense network of lymphatic vessels within the mucosa and the submucosa communicate freely with lymphatic channels in the muscular layers of the esophagus and with those that extend through the esophagus into the thoracic nodes. Lymphatic fluids from any portion of the esophagus may travel to any other portion of the esophagus and may spread to any region of the thorax or draining nodal bed. Tumors and lymph from tumors from any portion of the esophagus may spread to any other portion of the esophagus because of the rich lymphatic supply and drainage system. Tumors of any portion of the esophagus may drain into the supraclavicular lymph nodes or into the cervical nodes. A careful physical examination for enlarged lymph nodes must be performed to evaluate the patient for metastases to these nodes. A thorough palpation of both supraclavicular fossae, including the areas behind the sternocleidomastoid muscles and the clavicular heads, may yield significant results to the careful examiner.
A histologic diagnosis may be obtained by needle aspiration and cytologic examination or by node excision.
A positive result demonstrates systemic spread of the disease and modifies subsequent treatment. Local control of esophageal cancers with surgery or radiation therapy must consider the potential for lymphatic involvement with tumor at the time of treatment. Although lymphatic flow is unpredictable, the pattern of the lymphatic drainage favors a longitudinal spread rather than a circumferential spread. The lymph drains to several regional beds. For the upper third of the esophagus, the lymph drains to the internal jugular, cervical, and supraclavicular areas. For the upper and middle thirds, lymph drains to the peritracheal, hilar, subcarinal, and paraesophageal, periaortic, and pericardial regions. For the distal third, lymph drains to the lesser curvature, left gastric, and celiac axis. Involvement of celiac nodes may occur in 10% of the esophageal cancers located in the cervical and upper thoracic esophagus. Up to 44% of patients with middle third esophageal tumors may have celiac nodal involvement. Commonly, the distal esophagus carcinomas drain to these beds. The rich lymphatic drainage of the esophagus is responsible for metastatic spread throughout the entire esophagus, and this must be considered when resection is performed. Ten centimeters of esophagus beyond the tumor must be resected. Because the esophagus is only 20 to
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The main objectives of clinical staging of esophageal carcinoma are
(1) to identify patients who may benefit from definitive treatment of their primary carcinoma;
(2) to exclude patients with metastases from surgery, because their survival time is short (about 6 months); and
(3) to assess responses to radiation therapy, chemotherapy, and surgical interventions. Because many esophageal cancers are being treated with preoperative radiation or chemotherapy, postsurgical evaluation may not accurately define the stage of the initial diagnosed cancer.
Patients with metastases should not be subjected to surgical resection as their primary treatment modality. Patients with lymph node involvement have a shortened life expectancy because nodal metastases, even adjacent but separate nodal metastases, often represent systemic spread of tumor beyond the limits of the resection. Excellent palliation (but not cure) may be obtained with surgery in these patients, but improvement in survival rests with better adjuvant therapy. The recommendations for preoperative clinical staging are a chest x-ray film, a barium swallow, and computed tomographic (CT) scans of the chest and upper abdomen (to include the liver and adrenals). CT scans of the chest may identify accurately patients whose tumors involve the airways or aorta. CT is a poor way to detect abdominal lymph node metastases or small liver metastases. A bone scan should be obtained in patients who complain of bone pain, along with plain films of the abnormal areas. A bronchoscopy is mandatory for patients with a middle or upper third tumor. Bone scans and bronchoscopy may identify metastases not evident by CT scan. Pulmonary function studies are helpful in assessing the patient’s physiologic reserves and ability to tolerate thoracotomy.
NATURAL HISTORY AND PATTERNS OF SPREAD
Like other cancers within the gastrointestinal system, esophageal cancers are rarely found early when they are small and more easily treated. More frequently, the patient presents late because the distensible esophagus compensates readily for partial obstruction of the lumen by a tumor. Patients with carcinoma of the esophagus commonly are not aware of their problem until the tumor is large and obstructive symptoms occur or it extends into adjacent structures.
Esophageal cancers are characterized by extensive local growth, lymph node metastases, and invasion of adjacent structures before becoming more widely disseminated. In patients with squamous cell carcinoma of the esophagus, early asymptomatic patients with in situ carcinoma have demonstrated that 3 to 4 years may pass before advanced cancer develops. The unique lymphatic drainage of the esophagus and the long interval during which the tumor is asymptomatic account for the extensive involvement of lymph nodes and structures adjacent to the esophagus at the time of diagnosis. The poor prognosis of these patients is influenced by the proximity of the aorta and trachea and the absence of a serosal covering. In one series of 117 patients with esophagectomy and extensive lymph node dissection, mortality was less than 3%. Lymphatic metastases were identified in the neck of 32% of these patients, and in about half of the lymph nodes in the chest and abdomen. The length of the esophagus involved by the neoplasm correlates with the extent of involvement of adjacent structures and inversely related to curability. Tumors
THERAPY
The two primary local control modalities for clinically localized cancer of the esophagus are surgery and radiation therapy. Surgical resection is the treatment of choice for early lesions (stages I and II). For patients with more advanced localized cancers, neither treatment has been shown definitively to be superior. A comparison of the merits of these two primary treatment modalities is presented here. The low survival rates with single modality therapy have prompted numerous investigations into multimodality therapy, including preoperative radiation therapy, preoperative chemotherapy, and combined preoperative radiation therapy and chemotherapy. Cooperative group trials in progress will resolve some of these issues. Palliation is the primary goal for patients with advanced local cancers or metastases. The primary goals of palliation are restoration of swallowing and relief of pain. Radiation therapy, chemotherapy, and endoscopic treatment all contribute to palliation and are discussed later in this chapter.
SURGICAL THERAPY FOR CARCINOMA OF THE ESOPHAGUS.
With rare exceptions, carcinoma of the esophagus is, at diagnosis, a systemic disease. In most patients, surgery represents the best chance for cure and the best palliation for dysphagia and local control of their disease. Various methods of esophagectomy have been proposed, but the individual surgeon must evaluate the benefits of a particular approach in treating the patient with esophageal carcinoma. Patients with carcinoma in situ or stage I esophageal cancer may have prolonged survival regardless of the extent of the resection.
Orringer has proposed four goals of esophagectomy:
1. To relieve dysphagia.
2. To achieve an operative mortality of less than 10%.
3. To require hospitalization of 14 or fewer days.
4. To minimize late complications and morbidity (e.g., infection, stricture, reflux, and aspiration).
Today, operative mortality of less than 5% is commonly achieved although complications are still significant. Patients with local or locoregional carcinoma of the esophagus usually are considered suitable candidates for resection of the esophagus and reestablishment of gastrointestinal continuity. Because of the surgery’s extent, adequate cardiac and pulmonary reserves are needed. Patients for resection involving thoracotomy should have adequate pulmonary reserve and cessation of smoking for a minimum of 2 weeks before surgery. Advanced age alone is not a contraindication for resection. Patients with alcoholic cirrhosis or portal hypertension may have abdominal venous varicosities that preclude resection. Surgery alone provides good palliation. It rarely results in cure, except in carcinomas in situ or in stage I carcinomas found serendipitously. Long-term survival is uncommon and numerous studies have evaluated combined modality therapy to improve palliation and survival in patients with carcinoma of the esophagus.
Preoperative Evaluation of the Patient with Esophageal Carcinoma.
Any patient who presents with dysphagia and weight loss must be considered as having esophageal carcinoma until this diagnosis is excluded by history, physical examination, and diagnostic radiographic and staging studies. Symptoms produced by advanced esophageal cancers may indicate unresectable disease. Patients without evidence of extra regional spread of the disease may be excellent candidates for surgical resection or for various multimodality treatments for carcinoma of the esophagus. Noninvasive studies can evaluate the patient for potential treatment options. Surgical resection and radiation therapy provide good local control of the tumor. Radiation therapy may result in stricture more often than surgery, particularly if the original tumor was long and changes following this treatment persist. Metastases require systemic chemotherapy or local palliation. In patients with locally resectable tumor, without metastatic disease, surgery provides excellent palliation. A number of studies are required to evaluate the patient thoroughly for resectability, including a history and physical examination. Bronchoscopy is mandatory for patients with tumors involving the middle or upper third of the esophagus, because tumor invading the posterior membranous trachea or a tracheoesophageal fistula renders the patient surgically unresectable. The barium swallow and the esophagoscopy provide information about the length of the tumor, circumferential extent of the tumor, and character of the tumor (bleeding, fungating, polypoid, etc.). Patients should have a CT scan of the chest and upper abdomen and a bone scan, although skeletal surveys in the absence of bony pain are not cost-effective. Patients with metastases from esophageal carcinoma have a shortened life expectancy, and surgical resection in these patients usually is not justified.
Endoscopic ultrasonography of the esophagus has been used to assess the extent of the circumferential involvement of the esophageal carcinoma with the surrounding structures, particularly for tumors of the upper and middle third of the esophagus, and may assist in clinical staging. The length of the esophagus involved by the cancer, infiltration of the cancer into adjacent organs, and involvement of lymph nodes may be assessed by this technique.
The results of several studies involving CT in esophageal cancer have been reviewed recently. Those using preoperative CT followed by surgical confirmation of stage have shown that CT is best at assessing local extensions of disease and at delineating liver or adrenal metastases. CT is less accurate in assessing the degree of periesophageal lymph node involvement or adjacent tissue invasion. CT underestimates the length of the esophageal lesion. CT scans are helpful in planning radiation therapy and may be useful in assessing the tumor response to radiation therapy and chemotherapy.
Lefor and colleagues examined 32 patients with CT scans of the chest to correlate preoperative staging with postoperative survival. Lesion width of more than
Patients with clinically enlarged or apparently resectable histologically positive celiac nodes are suitable for surgery. Patients with histologic evidence of extraregional metastases usually do not benefit from surgery. Resection (separately or en bloc) or biopsy of the celiac and lesser curvature lymph nodes is valuable in planning therapy and providing prognostic data. Celiac node involvement occurs in 10% of patients with upper esophageal malignancies, and with lower esophageal cancers, the incidence increases at least fivefold.
The presence of metastases (bone, liver, brain, or extensive and unresectable regional nodal metastases) precludes any attempt at resection for cure. Surgeons who attempt palliative esophageal resection or a bypass of the unresectable esophageal tumor should be experienced, and the risk of the procedure should be less than the anticipated 5-year survival rate (e.g., if the 5-year survival rate is 5%, the mortality from the operation should be less than 5%). If the patient has metastases, then palliation should include methods other than resection or bypass. The patient usually has projected survival of less than 1 year and the advantages of an esophagectomy or bypass are rarely apparent.
Preparation of the Patient for Surgery
Proper evaluation and preparation of the patient and planning of the operation often make the postoperative course of the esophagectomy patient stable and predictable. Patients are not permitted to smoke for a minimum of 2 weeks before surgery. Incentive spirometry is begun before surgery and continued throughout the postoperative course to minimize atelectasis. Active patients with a normal electrocardiogram may not require further evaluation of cardiac function before surgery. Patients older than 60 years, those with a history of heart disease or abnormal electrocardiograms, or those with atherosclerosis benefit from further evaluation before surgery.
Presurgical weight loss greater than 10% impacts negatively on subsequent survival. Roth and colleagues noted that patients with a weight loss of less than 10% responded better to chemotherapy and overall did better than patients with a weight loss greater than 10%, implying that those patients who lost less had less advanced disease.
In one study, patients who received at least 5 days of preoperative nutritional support had fewer complications. Fewer complications have been found in patients who receive preoperative total parenteral nutrition; however, the benefit was found only in those patients who were severely malnourished before surgery. Still, there is no evidence that correction of this weight loss before surgery improves prognosis. Dental hygiene should be optimized because anaerobic bacteria within the mouth can cause synergistic and perhaps fatal mediastinal infection; dental work or extraction should precede esophageal resection.
Perioperative antibiotics (such as gentamycin and clindamycin) for wound infection prophylaxis and some type of deep venous thrombosis or pulmonary embolism prophylaxis (such as subcutaneous heparin, 5000 units every 8 to 12 hours) are routinely used. In the operating room, a radial artery catheter and at least two large-bore intravenous lines are placed to provide fluids and blood products. A central line may be used in older patients or those with underlying cardiac dysfunction. An esophagoscopy is performed by the surgeon before definitive resection. Flexible or rigid bronchoscopy is performed in the operating room by the surgeon in patients with esophageal carcinoma of the middle or upper third of the esophagus.
APPROACHES TO ESOPHAGEAL RESECTION
Esophagectomy for carcinoma of the esophagus poses considerable physiologic and technical challenges. Various techniques are used to resect the esophagus. Stomach is used most commonly to reestablish alimentary tract continuity. The total thoracic esophagectomy and the transthoracic or Lewis procedure (named after Mr. Ivor Lewis, a British surgeon) require thoracotomy and celiotomy. Transhiatal esophagectomy bluntly resects the entire esophagus through the esophageal hiatus and the thoracic inlet; a thoracotomy is avoided and a cervical anastomosis is used. The value of a more radical operation (sometimes called an en bloc esophagectomy) in terms of survival, palliation of symptoms, and reduction in morbidity and mortality, is no greater than that of the transhiatal esophagectomy, which is considered a more palliative procedure. Patients with previous gastric resection may require colon or jejunum to reestablish gastrointestinal continuity.
Blood supply to the colon can be defined by preoperative angiography. Rarely used, but of historical interest, are external skin tubes or external appliances (tubes) that may be interposed for gastrointestinal continuity. Free jejunal graft interposition (15 to
Functional results after colon interposition were good to excellent in more than two thirds of all patients. Cervical anastomotic leakage was encountered on occasion (13.5%) and accounted for all the poor functional results. In another study, 21 of 26 patients had left colon interposition, and 3 patients required reoperation for empyema, ischemia, and subphrenic abscess. No patient had a leak, and the 30-day operative mortality was 4.5%. Functional results were rated as good.
The right colon may be mobilized by dividing the ileocolic and right colic arteries and basing the blood supply on the middle colic artery.
If the length is not sufficient because of a short ascending colon, the left colon may be preferable. The left colon may have a more consistent blood supply than the right colon. The left colon may be mobilized after dividing the left colic artery and placed in an isoperistaltic position. Branches from the inferior mesenteric artery may be divided to further mobilize the colon. At least
RADIATION THERAPY IN THE MANAGEMENT OF CANCER OF THE ESOPHAGUS
In the treatment of advanced or unresectable cancer, radiation therapy alone is now being used less because there is strong evidence that combined modality therapy consisting of irradiation plus concurrent chemotherapy is superior to irradiation alone. Radiotherapy alone, however, is still useful for rapid palliation of obstructive symptoms permitting a return of swallowing and eating. This palliation is achieved usually without serious morbidity and virtually no risk of treatment-related mortality. Palliative irradiation alone is given for advanced cases, but the addition of an endoluminal boost, with either low- or high-dose rate irradiation, can achieve a higher dose locally and may achieve more complete or longer duration of tumor regression. On the other hand, for the patient with relatively early staged disease that is usually deemed resectable, adjuvant irradiation has been used to decrease the risk of local recurrence and is usually given to patients who have good performance status either before or after surgery. This practice continues because the surgeon selects those with small tumors, minimal symptoms, and good performance status for “definitive” surgery; comparisons with results obtained with radiotherapy alone or with chemoradiation are impossible because selection biases favor the outcome in surgical series. Another difference between surgical and radiotherapeutic practice has been the lack of adequate staging for patients treated with the latter approach. However, preoperative staging with CT scanning, endoluminal ultrasound, or both is commonly done now and this may lead eventually to a nonoperative approach using irradiation and chemotherapy requiring a randomized study in the future.
ENDOLUMINAL IRRADIATION WITH OR WITHOUT EXTERNAL BEAM IRRADIATION
The implantation of radioactive sources endoluminally is an excellent method to palliate a patient with malignant esophageal obstruction. New endoluminal irradiation techniques include afterloading low- or high-dose rate techniques, which may produce rapid palliation of obstruction when used as the only form of irradiation, when combined with external irradiation as a “boost,” or when combined with laser tumor ablation.
Obstructive lesions suitable for this approach must be small to allow passage of the access guide into which the endoluminal treatment is given. The patient is treated as an outpatient as long as the passage of the guide tube can be tolerated. The dose distribution may be inhomogeneous over the tumor in this approach because only a short distance beyond the esophagus can be covered; doses are prescribed to 0.5 to
One study with endoluminal brachytherapy claimed an equivalent result was obtained with a low dose rate treatment schedule of 20 Gy in three fractions to 12.5 Gy in a single fraction given with a high dose rate device.
Most patients treated with a single high dose rate, however, have very poor prognosis, as demonstrated in a series of 36 patients in which one third of the treated patients were dead within 6 weeks and the median survival of the entire group was only 4 months.
Most of the survivors had temporary palliation and about a third of those who developed a reobstruction had relief with retreatment by the endoluminal approach. The addition of chemotherapy to endoluminal therapy shows little benefit compared with historical controls.
In another trial of laser ablation, those randomized to the combination of laser therapy and high dose rate fared better than those treated with only laser, but this was found only in the patients with squamous cell cancers and not in those with adenocarcinomas.
In a large series of patients with cancers arising at all sites within the esophagus, there was little morbidity from external doses of 47.5 to 70 Gy in combination with 4 to 10 Gy of endoluminal irradiation given in one to three fractions; these authors described only five patients with radiation-induced stricture. The local control rate was 32% with irradiation alone and was consistent with other reports that local control is difficult to obtain even with the use of ultra-high doses. Higher survival rates were found in those with early staged disease T1 or T2 compared with those with higher stages and with small tumors smaller than
The cause of postradiation stricture should therefore be evaluated because it can have several causes and many patients can be managed successfully by conservative means.
The benign strictures and nonmalignant ulcerations usually caused by a high-dose-rate intraluminal boost or concurrent chemotherapy can be managed successfully with conservative therapy including dilatation.
Other late complications occurring after irradiation are fistula formation, with or without hemorrhage, seen as a result of rapid resolution of tumor that invades from the esophagus into neighboring trachea, bronchus, or aorta. Other serious late complications that have been reported with irradiation are pneumonitis, pericarditis, myocarditis, and spinal cord damage.
PREOPERATIVE RADIATION
The use of irradiation before surgery is based on the observation that tumor shrinkage and sterilization occur in response to treatment and this may translate into an increased tumor resectability rate. Areas of microscopic disease not usually resected are treated, resulting in a wide treatment surrounding the esophageal tumor. Another advantage is that at the time of operation there may be less cancer cell dissemination by intraoperative manipulation if there has been prior tumor cell killing. A specific advantage for preoperative radiotherapy is also that relatively low numbers of hypoxic cells exist in a tumor before surgery compared with postoperative conditions, in which cancer cells may reside in scarred regions.
Esophagectomy is used to treat the primary tumor, including the length of the esophagus, which contributes to local control, palliation, and long-term cure. In 15% to 30% of cases, tumor is sterilized by the preoperative radiation in doses of 30 to 45 Gy; survival after preoperative radiation correlates with the extent of tumor destruction seen in the operative specimen.
Estimation of the amount of tumor sterilization is uncertain because not all patients who are irradiated are taken to surgery and not all are resectable. In one study the 2- and 5-year survival rates were doubled in patients with extensive tumor destruction compared with the survival rates in those without the effect.
The use of AF in the preoperative management of resectable esophageal cancer was tested in a series of nonrandomized patients treated at the University of Texas M.D. Anderson Cancer Center, Houston, where 42 patients were treated with either a twice-a-day or three-times-a-day fractionation schedule using doses of 1 to 1.5 Gy per treatment session.
There was a 15% pathologic downstaging found in the resected specimen. The median survival was only 11 months but there was an approximate 25% 5-year survival rate in the entire group. The treatment was tolerated well but there was a small increase in the operative morbidity associated with delayed wound healing and sepsis. These results were equal to that found in the literature but the true value of this approach compared with more conventional fractionation is uncertain because this study was not randomized and the influence of patient selection is uncertain.
The results from randomized preoperative radiation series are controversial largely because of the total doses of irradiation used and the use of a short interval between the end of irradiation and surgery, which doesn’t allow much tumor regression. For example, an intensive course of 39 to 45 Gy in 8 to 12 days was followed in less than 8 days by resection and the long-term survival in this study was identical to the surgery-alone arm.
In other preoperative randomized trials using hypofractioned regimens, the 5-year survival rates are unchanged from the surgical controls but some have shown higher postoperative mortality in the irradiated patients, which may be related to the large doses of irradiation.
POSTOPERATIVE IRRADIATION
Postoperative radiation therapy has been used in pathologically staged patients after esophagectomy, but this approach can be associated with relatively high late morbidity because large volumes of normal tissue are irradiated, particularly in patients who undergo gastric pull-up or intestinal interposition. There are also fewer data from randomized studies on the effectiveness of postoperative radiation. In the nonrandomized study by
There was a trend toward a reduction in local-regional failure from 30% for patients treated with surgery alone to 15% for patients treated with surgery and postoperative radiation. In the subgroup of patients who had no evidence of nodal involvement, a significant reduction in local-regional failure was seen (35% versus 10%, P < .02).
COMBINATIONS OF RADIATION AND CHEMOTHERAPY
Treatment of carcinoma of the esophagus with combinations of radiation therapy and chemotherapy began about 15 to 20 years ago.
The rationale for this combined modality therapy is relatively straightforward. The problem with carcinoma of the esophagus is locoregional and systemic. A combination of a local modality such as radiation therapy and a systemic modality such as chemotherapy could address these problems simultaneously. By giving the drugs and radiation together, one immediately addresses both treatment problems from the outset of therapy. Finally, some chemotherapeutic agents such as 5-fluorouracil (5-FU) and cisplatin are known to enhance the effectiveness of radiation, and their administration might add to the local cell kill produced by radiation. Some of the earliest experience with combined modality therapy in esophageal carcinoma came from
The results from the first esophageal study showed that complete responses could be obtained; the suggestion of a prolonged median survival of 18 months and a 2-year survival rate of 35% in those whose tumors were resected after chemotherapy was encouraging.
COMBINED CHEMOTHERAPY AND RADIATION THERAPY FOLLOWED BY SURGERY
Despite the encouraging results with combinations of chemotherapy plus radiation, and the knowledge that randomized trials are now showing that this combination is superior to radiation therapy alone in the curative treatment of esophageal carcinoma, local persistence and progression of disease still remain problems. In Coia’s study, 14 of 29 failures (48%) were at least partly local. In the combined modality arm of the randomized trial, 27% of patients never cleared their disease, and an additional 16% progressed in the primary area after clearance of all recognizable tumor for a 43% local failure rate. Other studies report similar results despite improvements in combined modality therapy. It can be hypothesized that the addition of a surgical esophagectomy after maximal tumor clearance by chemotherapy plus radiation therapy could contribute to the local control of disease, improve the quality of life, and possibly improve survival. A number of studies have been carried out to test this hypothesis, and they are summarized in Table 32.2-8. The only randomized trial of this treatment strategy reported is by Anderson and colleagues.
Bleomycin as a single agent was chosen for the chemotherapy, and the dose of radiation administered to these patients was low. Results in both arms were equally poor. The largest study was reported by Poplin and colleagues for the Southwest Oncology Group (SWOG) and the RTOG.
Of 113 patients enrolled on the study, only 63% made it to the operating room and only 49% actually had tumor resections. The 1-year and 2-year survival rates and median survivals were not much different than those of effective surgical protocols or combination chemotherapy plus radiation therapy protocols without surgery. At the
One problem in previous experiences with combined preoperative chemotherapy and radiation therapy has been a high postoperative mortality rate. In the SWOG/RTOG study cited above, operative mortality was 11%, and in the Leichman study, a full 30% of patients did not leave the hospital after their surgery.
In contrast, of the 41 patients in this series who had transhiatal (nonthoracotomy) esophagectomy, there was only one postoperative death (2.4%). In Forastiere’s trial, surgery appeared safe and beneficial. In most other reported combined modality series using surgery, all the long-term survivors have been patients whose surgical specimens were pathologically disease-free. In this trial, 26 of the 41 patients who had resections had positive specimens. The median survival for these patients was 26 months, and one third remained alive and disease-free at 5 years. It appears that surgery can convert some patients’ response from partial to complete. Of the 36 completely resected patients, only one has had a solitary local failure, and 4 others have had local failures concomitant with distant disease.
Therefore, 75% of completely resected patients have remained free of local disease, a figure that appears better than that from combined modality studies from which surgery has been eliminated. This group of investigators initiated a randomized trial comparing their aggressive combined modality therapy with transhiatal esophagectomy alone. Undoubtedly, additional research into preoperative chemotherapy and radiation therapy is warranted. As surgical techniques improve, postoperative mortality will decrease, further enhancing the usefulness of the technique. As chemotherapeutic regimens become more successful, the importance of local disease control will increase. Combinations of radiation plus surgery may offer the best chance for local tumor sterilization, and this mode of therapy will continue to be pursued.
Combinations of all three modalities — chemotherapy plus radiation plus surgery — must be considered investigational and are best pursued in the context of a clinical trial.
CHEMOTHERAPY
The high mortality rate for patients with cancer of the esophagus, even when clinically localized, suggests that occult dissemination of disease is present in most patients at diagnosis. Studies of patterns of recurrence and data from autopsy series confirm the potential for tumor spread to all organs. Five-year survival rates for patients who undergo total removal of all gross disease with negative margins of resection approach 20%.
However, when all operative candidates are considered, these figures fall to 5% to 10%. This provides a rationale for adding a systemic therapy to local treatments of surgery and radiation or as the primary treatment of patients with overt metastases at diagnosis. Thus, chemotherapy has been used for palliation of patients with recurrence or metastases, as an adjuvant to surgery, either preoperatively or postoperatively in potentially curable patients, and concomitantly with radiation therapy.
Clinical trials to determine the efficacy of chemotherapy employ the standard criteria of a 50% or greater decrease in tumor size. This requires a bidimensional lesion that can be serially measured. For the esophageal cancer patient with metastatic disease, this can be accomplished with reliability using pulmonary, soft tissue, and liver nodules as indicators. However, for patients with disease limited to the primary, response to chemotherapy can only be determined qualitatively. CT, MRI, and double-contrast barium esophagogram are the various techniques available.
For the most part, these studies provide unidimensional measurements of the primary. Endoscopy with brushings and biopsy should be performed to confirm a clinical complete response. However, a negative biopsy is subject to sampling error and is not a reliable indicator of complete histologic resolution of disease. Examination of the resected esophagus for those patients receiving preoperative chemotherapy is the only method to document a pathologic complete response.
Single agents have been tested in patients with recurrent or metastatic carcinoma of the esophagus. These patients often have a high tumor burden and poor performance status. Although this makes them a difficult group to study, with little prospect for prolonging survival, the results of clinical trials in this population have identified drugs with activity.
Combination regimens have also been tested in this patient group yielding higher response rates.
Duration of response to either single agent or combination chemotherapy is brief, lasting less than 3 months, and palliation of symptoms is minimal. A more promising approach is the use of chemotherapy in newly diagnosed patients before surgery or radiation, or concomitant with radiation therapy where improvement in cure rate is the goal. The accumulated experience with chemotherapy to date is almost entirely in patients with squamous cell histology. It is unclear whether the natural history and sensitivity to chemotherapy differ between the two histologies. With the rising incidence of adenocarcinoma of the esophagus, gastro-esophageal junction and cardia observed in the United States, [ref: 289 patients with this histology now comprise approximately 60% of referrals for chemotherapy. Only recently have trials with new agents and combined modality regimens included both histologies.
PREOPERATIVE CHEMOTHERAPY
The rationale for preoperative chemotherapy is based on the poor survival rates achieved with surgery even when disease appears clinically localized and the knowledge that distant dissemination occurs early. Data from several series suggest that surgery is beneficial only if all macroscopic and microscopic tumor is removed.
Approximately 75% of patients present with locally advanced disease, T3 or T4, and therefore complete resection is possible in only a minority. Moreover, even in patients with primary tumors confined to the mucosa and submucosa (T1), 30% have lymph node metastases.
The potential benefits from adding preoperative chemotherapy include downstaging the disease to facilitate surgical resection, improving local control, and eradicating micrometastatic disease. This also provides an opportunity for direct assessment of response to chemotherapy which is important in selecting patients for additional postoperative adjuvant therapy
The disadvantages of preoperative chemotherapy include the potential for drug-resistant clones to emerge, and the delay in definitive treatment with the risk of further spread of disease. This is an important concern because approximately 50% of patients will not respond to current drug regimens (i.e., cisplatin and 5-FU). This raises the complex issue of how to most accurately stage patients before preoperative treatment is initiated and which patients to select for combined therapies. Neoadjuvant trials to date have included all patients with disease localized to the primary and regional nodes, excluding only patients with metastases to distant sites. Definitive staging can only be obtained postoperatively. The routine staging studies; CT or MRI of chest, abdomen, and pelvis; and the barium esophagram cannot accurately determine depth of invasion of the primary, and extent of lymph node involvement.
Esophageal endoscopic ultrasound can accurately predict T stage, but this is highly dependent on the expertise of the endoscopist and this ultrasound is not yet widely available. Esophageal endoscopic ultrasound is less useful for determining nodal involvement. Staging laparoscopy with lymph node biopsy can complement the ultrasound to better assess regional nodes. This type of careful staging together with prospective phase III trials is needed to determine exactly which patients (stage and histology) obtain survival benefit from single and combined modality therapies. Until accurate staging methods are widely available, all patients with “local-regional” disease that can be approached surgically for total resection should be enrolled in investigational protocols. In the absence of such protocols, surgery alone is recommended as the standard of care. This will provide staging information that can be used to guide further treatment. Currently, the role of postoperative adjuvant chemotherapy or chemoradiation is undefined. There are no data to suggest that administering postoperative adjuvant chemotherapy will either prolong the disease-free interval or survival particularly for patients who have undergone a curative resection and have negative nodes. Patients who have positive margins of resection, however, should be considered for postoperative radiation.
The status of combined modality chemotherapy is also summarized in several excellent reviews. The first of a series of cisplatin-based trials from
One course of cisplatin and infusional bleomycin given preoperatively to 43 patients produced a 14% response rate with no histologic complete responses. In two subsequent trials, Kelsen tested 2 cycles of preoperative cisplatin, vindesine, and bleomycin. [ref:
Because of the high response rate and prolonged survival compared with historic controls, this regimen was pursued in a randomized comparison with preoperative radiation therapy. [ref: 298 Fifty-five percent of chemotherapy-treated patients responded, including 3 histologic complete responders. Although a cross-over design resulted in most patients receiving all three modalities, the median survival of those randomized to initial chemotherapy was only 10.4 months. Similar response rates (40% to 60% range) and median survival ranging from 9 to 14 months were reported by others evaluating cisplatin combined with vindesine or vinblastine and bleomycin or mitoguazone (MGBG). All but one trial were limited to patients with squamous histology. Forastiere and colleagues at the
Responses were observed in 31% of adenocarcinoma patients and 64% of squamous cell cancers. Curative resections were carried out in 80% but the median survival time of all patients was only 14 months, which did not differ from historic controls. Initial sites of failure correlated with histology: local-regional in 66% of squamous cell patients and distant in 78% of adenocarcinoma patients. Although postoperative chemotherapy was planned for responders to preoperative treatment, it was not feasible in 50% of candidates. These negative results led to subsequent trials by these investigators evaluating the concept of brief, intensive preoperative chemotherapy, and simultaneous radiation using cisplatin and 5-FU-based chemotherapy.
Preoperative Chemotherapy (Continued) (1 of 1) More recently, the regimen of cisplatin, 100 mg/m**2 on day 1 and 5-FU, 1000 mg/m**2/d for 96 or 120 hours every 3 weeks has been used.
For squamous histology, response rates range between 42% and 66%, with 0% to 10% pathologic complete response; curative resection rates range from 40% to 80%, and median survival rates range between 18 and 28 months. Carey treated 68 patients with squamous cell histology. Sixty-six percent had regression of tumor, including
Kies treated 26 patients with squamous cell cancer of the esophagus with 3 cycles of cisplatin and 5-FU before surgery or definitive radiation. Eleven patients (42%) had reduction in tumor size by CT, endoscopy, or barium esophagogram and improvement in dysphagia. Three of these had no visible tumor and negative biopsies. Although only 14 patients had esophagectomy as their definitive treatment, the median survival time of all 26 patients was 17.8 months, suggesting possible benefit from a third cycle of chemotherapy. Ajani gave up to 6 cycles of cisplatin and 5-FU to 34 patients with squamous cancers and observed a 66% response rate and a median survival of 28 months. Using a more intensive dosing schedule, Vignoud recycled cisplatin and 5-FU every 14 days for a total of 3 courses in 60 patients. A 60% response rate was reported, including a 10% pathologic complete response. The curative resection rate was 80% and the median survival for this group was 24 months. There is one report of preoperative cisplatin and 5-FU for adenocarcinoma of the esophagus and gastroesophageal junction. A 37% response rate was observed in 16 patients and an actuarial 4-year survival rate of 42%. The addition of leucovorin to cisplatin and 5-FU in one study of 32 patients (14 squamous, 18 adenocarcinoma) given for 2 cycles before esophagectomy and then 5-FU/hydroxyurea and radiation resulted in a 71% preoperative response rate, but only a 3% pathologic complete response. The median survival time was 20 months. Severe hematologic toxicity occurred in 20 patients necessitating dose reduction. These results and other preliminary reports do not indicate an advantage for leucovorin modulation over cisplatin and 5-FU alone and toxicity is clearly increased. Trials designed specifically for patients with adenocarcinoma of the distal esophageal or gastroesophageal junction have evaluated etoposide, 5-FU, and cisplatin; and etoposide, doxorubicin, and cisplatin.
Response rates were similar, ranging from 49% to 55% after 2 or 3 cycles. Curative resection rates varied from 65% to 90% and survival from 12.5 to 23 months. Regimens that include doxorubicin and etoposide are commonly used to treat gastric cancer. The activity of these single agents in patients with adenocarcinoma of the esophagus is unknown. These combinations appear to have antitumor activity that is comparable with cisplatin and 5-FU but toxicity is greater.
Roth and colleagues evaluated 2 cycles of neoadjuvant cisplatin, vindesine, and bleomycin followed by surgery versus surgery alone. [ref: 95 Forty-seven percent of patients responded to chemotherapy, including 1 histologic complete response. The actuarial survival curves for the two groups were not significantly different and the median survival for both groups was 9 months. However, patients responding to preoperative chemotherapy had a significantly longer survival (median greater than 20 months) when compared with nonresponders (median 6.2 months) and patients in the surgery-alone treatment group. Survival at 2 years was 27% for the neoadjuvant chemotherapy group versus 14% for the surgery-alone group. In a prognostic factor analysis, weight loss of less than 10% before randomization was the only factor predictive of longer survival. The trial conducted by Schlag testing neoadjuvant cisplatin and 5-FU was terminated early because of increased postoperative morbidity and mortality in the chemotherapy-treated group.
No survival differences were observed. The third study by Nygaard randomized 187 patients to one of four treatments: surgery alone, preoperative chemotherapy with cisplatin and bleomycin, preoperative radiotherapy, or preoperative chemotherapy followed by radiation and then surgery. There was no significant difference in survival comparing preoperative chemotherapy to surgery alone (3-year survival 3% versus 9%). The best outcome was for preoperative radiation, 3-year survival 19%.
The United States Intergroup is completing a large two-arm randomized trial comparing: 3 cycles of preoperative cisplatin and 5-FU followed by surgery and then 2 additional cycles of cisplatin and 5-FU to treatment with surgery alone. More than 400 patients were randomized, of whom approximately 55% have adenocarcinoma of the esophagus or gastroesophageal junction. Consequently, this study will have adequate statistical power to analyze outcome differences separately for squamous and adenocarcinoma histologies. Until the mature results of this trial are known, the use of preoperative chemotherapy must be considered investigational.
PALLIATION
Patients with esophageal carcinoma may be surgically unresectable because of the extent of the tumor locally or metastases distally. These patients require relief from dysphagia and pain. Numerous modalities are available for palliation of symptoms of esophageal obstruction, including external-beam irradiation, intraluminal brachytherapy, intubation through the tumor with various prostheses, placement of stents, laser opening of the occluded esophagus, and simple dilation.
The application of a given method of palliation depends to a great extent on the patient’s physical condition and the expertise of the surgeon, oncologist, and radiation therapist.
Intraluminal Brachytherapy
Patients with symptomatic esophageal carcinoma not amenable to surgical resection and previously treated with external-beam irradiation may be candidates for intraluminal brachytherapy. In this procedure, a radioactive head is placed through a catheter prepositioned through the area to be irradiated. This radioactive source passes through the area in a given amount of time to provide a finite and controlled radiation dose to the local tissues. The depth of penetration of the radiation rarely exceeds 2 or
Even without previous external-beam irradiation, intraluminal brachytherapy may be effective. Fleischman and colleagues showed that 9 of 10 patients with advanced esophageal cancer treated with intraluminal brachytherapy achieved palliation equivalent to that of external-beam irradiation.
Most patients had already experienced failures of other palliative modalities. Holting and colleagues successfully used laser and intraluminal brachytherapy in 16 of 45 patients (previously treated with laser) to prolong palliation.
SURGERY
All surgery for symptomatic carcinoma of the esophagus is palliative in the strictest sense because tumors often have spread through the lymphatics. Because of the high attendant mortality and morbidity, resection or bypass of unresectable esophageal carcinoma should be carefully considered before being undertaken as a means of palliation.
Occasionally, patients undergo mobilization of the stomach or conduit and resection of the esophagus only to have remaining gross disease found. In these patients, surgery serves as excellent palliation, and this residual disease may be further controlled by radiation therapy or a combination of radiation therapy and chemotherapy. These patients have tumors that are considered resectable on preoperative studies. The survival rate of patients with metastatic esophageal carcinoma is poor.
Such patients, already debilitated from malnutrition and tumor burden, poorly tolerate a lengthy operation and resection. Despite some advocates of this approach, most surgeons do not support bypass procedures for palliation of esophageal carcinoma because of the high attendant morbidity and mortality.
DILATION
Simple dilation is less consistently effective in the treatment of esophageal carcinoma. The neoplasm continues to grow and narrow the lumen despite frequent dilations. Lundell examined the palliative effect of repeated endoscopic dilation in 41 patients. Dysphagia recurred in all patients, and most dilations had to be repeated at 4-week intervals. Most patients required three or fewer dilations during their remaining life span. The complication rate (perforation) was low (5%), and only a short hospital stay was required.
ESOPHAGEAL INTUBATION
For many years, tubes of various sorts have been forced through the esophageal lumen partially obstructed with neoplasm in an attempt to relieve dysphagia. Complications from placement of tubes are high (10% or more), as is hospital mortality (10% or more). Pattison and colleagues examined 71 patients treated with pulsion intubation (111 patients, 15.5% mortality) and traction intubation (6 patients, 15.4% mortality). Mortality is similar in other studies. Esophageal intubation may be helpful in patients with tracheoesophageal fistula to prevent or limit soilage of the tracheobronchial tree.
Kratz and colleagues compared three tubes: Celestin tubes, implanted by laparotomy and traction; Proctor-Livingston tubes, implanted by pulsion with laparotomy for staging; and Atkinson tubes, placed by pulsion. [ref: 338 Patients with the Atkinson tube had few complications and a low mortality rate (6% mortality) compared with the others (42% mortality). Patients undergoing laparotomy had an associated 41% hospital death rate.
LASER
Laser ablation of obstructive lesions is effective in palliating more than 80% of patients with obstructing esophageal carcinoma in most series and has been shown to have a lower mortality rate and fewer complications than tube insertion. Hahl and colleagues treated 69 patients with laser therapy and 27 patients with esophageal tube insertion. Patients with laser treatment had no fatal complications, an overall complication risk of 8.7%, and a 1-year survival rate of 2%. Patients with tube insertion had a mortality rate of 11%, a complication rate of 48%, and no 1-year survivors. Laser therapy and intubation was not significantly better than laser therapy alone.
CLINICAL PRESENTATION SIGNS AND SYMPTOMS OF GASTRIC CANCER
Most patients with gastric cancer are diagnosed with advanced-stage disease and this is reflected in the vague, nonspecific symptoms that characterize the disease. Patients may have a combination of signs and symptoms such as weight loss, anorexia, fatigue, or epigastric discomfort, none of which unequivocally indicates gastric cancer.
The clinical significance of weight loss in gastric cancer should not be underestimated. De Wys has shown that in 179 patients with advanced, nonmeasurable gastric cancer, more than 80% of patients had a greater than 10% decrease in body weight. Patients with weight loss had a significantly shorter survival than those without weight loss. In some patients, symptoms may suggest the presence of a lesion in specific locations. A history of dysphagia may indicate the presence of a tumor in the cardia with extension through the gastroesophageal junction. A complaint of early satiety is actually a very infrequent symptom of gastric cancer, but is indicative of a diffusely infiltrative tumor that has resulted in loss of distensibility of the gastric wall. Persistent vomiting is consistent with an antral carcinoma obstructing the pylorus. Significant gastrointestinal bleeding is uncommon with gastric cancer; however, hematemesis does occur in about 10% to 15% of patients.
Unfortunately, many patients are diagnosed after the development of ascites, jaundice, or a palpable mass indicating extensive and incurable disease. Because the transverse colon is held in close proximity to the stomach by the gastrocolic ligament, it is a potential site of malignant fistula and large-bowel obstruction from a gastric primary. Diffuse peritoneal spread of disease frequently produces other sites of intestinal obstruction.
A large ovarian mass (Krukenburg tumor) or a large peritoneal implant in the pelvis (Blumer’s shelf), which can produce symptoms of rectal obstruction, may be felt on pelvic or rectal examination. A firm, smooth, enlarged liver or a distinct hepatic mass may indicate metastases. An epigastric mass may represent a large gastric cancer that has directly invaded or anteriorly displaced the left lateral segment of the liver. Gastric cancer may metastasize to superficial lymph nodes, so a careful examination of the supraclavicular and axillary (particularly left) lymph nodes should be performed. Nodular metastases in the subcutaneous tissue around the umbilicus or in peripheral lymph nodes represent areas in which tissue diagnosis can be established with minimal morbidity.
EVALUATION
Once gastric cancer is suspected, a barium study or flexible upper endoscopy with biopsy is performed. After the diagnosis is established, staging procedures involve careful physical examination, routine blood screening tests, and abdominal and chest computed tomography (CT) scanning. Barium contrast studies have limited accuracy for determining resectability, but by using double contrast techniques, a positive diagnosis of lesions between 5 and
Gastric outlet obstruction. A carcinoma is causing narrowing of the antrum (arrow). The speckled appearance in the fundus of the enlarged stomach is due to food residues.
CT of the chest, abdomen, and pelvis is useful for assessing the lateral extension of the tumor and presence of systemic metastases . However, up to 50% of patients will have more extensive disease at laparotomy than was predicted by preoperative CT.
Upper endoscopy is used routinely for the initial diagnosis and staging of gastric adenocarcinoma and should be performed in any patient with localized disease for which surgical treatment is anticipated. Numerous reports have demonstrated that its accuracy of diagnosis is greater than 95%. The size, location, and morphology of the tumor, including the proximal and distal extent of spread, as well as other mucosal abnormalities should be carefully evaluated. Decreased distensibility of the stomach, abnormal peristaltic activity, or abnormal pyloric function may indicate extensive submucosal infiltration or extramural extension of tumor into the vagi. The likelihood of a positive yield on biopsy is greater than 95% when 6 to 10 tissue samples are obtained.
Carcinoma.
There are a number of large filling defects in the antrum and body of the stomach.
Endoscopic ultrasonography (EUS) has been used extensively to evaluate potentially operable gastric cancer.
Barium x-ray showing gastric cancer.
CT image showing gastric cancer.
EUS uses a high-frequency (7.5 or 12 MHz) transducer at the end of an endoscope and allows highly accurate staging of the depth of invasion of the primary tumor (T stage) and is more accurate than CT scan for staging depth of penetration and assessing lymph node status.
However, although it also appears more useful than a CT scan for detecting lymph node metastases, the overall accuracy of EUS for this key determinant is less satisfactory. Because CT may identify metastases to distant sites (liver [especially right lobe], adrenal, ovaries) CT and EUS are complimentary tests. More recently, there has been a resurgence of interest in laparoscopy, particularly with the development of laparoscopic ultrasonography (LUS) probes.
Laparoscopy with LUS, although more invasive than EUS, shows promise both in identifying unsuspected metastases to liver or peritoneum, and, with LUS, in more accurately identifying lymph node metastasis and T stage. Because CT may identify metastases to distant sites (liver, adrenal, ovaries) CT, EUS, and laparoscopy are complimentary tests.
SCREENING
Mass screening programs for gastric cancer have been most successful in high-risk areas, especially in
STAGING AND PROGNOSIS
As with other neoplasms, the uniform and accurate staging of gastric cancer is essential to meaningfully predict prognosis and assess response to treatment.
Modifications from the older staging system include a simplification of T stage, such that T4 defines any tumor invading adjacent structures and elimination of the N3 disease category. Under the current staging system, tumor involvement of the periaortic, hepatoduodenal, retropancreatic, and mesenteric lymph nodes is now classified as metastatic disease. Although not a formal component of stage grouping, the histopathologic grade and type should be recorded. There is considerable disparity between the survival of patients with stomach cancer in Japanese and Western series. Although early diagnosis, a higher incidence of intestinal-type tumors, and the use of radical surgery in Japan may explain these differences in part, a major contributing factor may be the extensive and meticulous surgical and pathologic staging of gastric cancer in Japan. Several reports from the United States, Japan, and Europe have all demonstrated the significant prognostic impact of advancing T stage.
The General Rules for Gastric Cancer Study in Surgery and Pathology as published by the Japanese Research Society for Gastric Cancer (JRSGC) define the primary tumor stage based upon the depth of invasion and the presence and extent of serosal invasion.
S0 is further divided into m, mucosa; sm, submucosa; and pm, muscularis propria. The ss, subserosa,
and S1 tumors have been reclassified to further stratify the degree and type of serosal invasion. Ssalpha is a subserosal tumor with expansive growth, ssbeta is a subserosal tumor with intermediate type growth, and ssgamma is a subserosal tumor with infiltrating growth.
S2 and S3 are now defined as either se, cancer cells exposed to the peritoneal cavity; si, cancer cells infiltrating neighboring tissue; or sei, the coexistence of se and si.
The Japanese staging system extensively classifies 18 lymph node regions into four N categories depending on their relationship to the primary tumor as well as anatomic location. The careful and complete prosection of the operative specimen may often be performed by the attending surgeon. Involvement with N1 and N2 lymph node groups represent regional disease, which is encompassed by D-2 resection, whereas N3 and N4 lymph nodes are considered distant metastases. In addition, the presence and extent of intraabdominal metastases to the peritoneum and liver are categorized.
The presence of lymph node metastases including the N stage and number of positive lymph nodes are strong predictors of outcome in gastric cancer [Several studies have assessed quantitative involvement of lymph nodes and survival after resection for gastric cancer and found that survival with up to 3 to 4 metastatic lymph nodes is better than with more extensive lymph node involvementThere are several possible explanations for this observation. These include a potential difference in the biology of the tumor between the two patient populations, stage migration, or potentially that the D-2 resection does have a therapeutic advantage. Once nodal metastases are found, Japanese survival statistics are better than those seen in American patients.
TREATMENT OF LOCALIZED DISEASE SURGERY
The only potentially curative modality of localized gastric cancer is surgery. However, there are areas of disagreement among surgeons with respect to the appropriate extent of resection because improved outcome has not been conclusively linked with more radical surgery. Current areas of discussion include the potential therapeutic benefit from extended lymphadenectomy, the routine use of total versus subtotal gastrectomy for tumors of the body or antrum, and prophylactic splenectomy.
EXTENDED LYMPHADENECTOMY
There is considerable debate as to whether the routine use of an extensive en-bloc resection of second echelon lymph nodes (D-2 resection) is superior to a more limited lymphadenectomy of the perigastric lymph nodes (D-1 resection). Many retrospective studies demonstrated superior survival in patients undergoing resection with curative intent when an extended lymphadenectomy was performed. However, two small prospective random assignment trials comparing D-1 versus D-2 lymphadenectomy did not show a survival advantage, and the two large multiinstitutional prospective random assignment trials in
Approximately 30 years ago the JRSCG proposed a standardized D-2 resection for patients undergoing curative gastrectomy. As radical surgery for gastric cancer has become uniformly accepted in Japan, the operative mortality rate for D-2 resection has declined and 5-year survival after curative resection has improved. There are many large retrospective reports from Japan and other Asian countries that advocate a D-2 lymphadenectomy for patients with resectable gastric cancer. Maruyama and colleagues have reported results from more than 20,000 cases from a nationwide registry in Japan for three periods: 1963 to 1966, 1969 to 1973, and 1971 to 1985. The 30-day operative mortality declined from 3.8% in the first period to 1.0% in the latest. When patients were compared with respect to stage, depth of tumor invasion, presence of serosal invasion, and N1 or N2 nodal metastases, there was improved survival in the most recent period compared to the first. However, radical (D-2) resection did not improve survival for patients with extranodal disease such as peritoneal metastases, distant lymph node metastases (N3-4), or diffusely infiltrating carcinomas (linitus plastica). Takeda and coworkers have also reported that 5-year survival improved from 21% to 46% in 166 patients undergoing total gastrectomy with curative intent for tumors with positive serosal invasion when a D-2 lymphadenectomy was performed compared with 62 patients in whom no systematic lymphadenectomy was performed. Kodama and colleagues have compared survival in 254 patients undergoing either simple resection or 454 patients undergoing extensive regional lymph node dissection (ELD) for gastric carcinoma.
The therapeutic effect of ELD was greatest in patients with serosal invasion (T3) or with positive lymph node metastases, patients with T1-2, 4 or N0 disease did not show a benefit from ELD. In all of these studies, outcomes of patients operated on in different time periods were compared and it is possible that other factors could have influenced survival. In a series of 486 patients who underwent curative (D-2) resection for gastric cancer, Sowa and coworkers demonstrated that tumor size and depth of penetration were directly related to the incidence of lymph node metastases in gastric cancer and that the rate of skip metastases was less than 1%. In this study, as well as others, T1-2 lesions had metastases limited to perigastric lymph nodes in 15% to 40% of patients, suggesting that in cases of early gastric cancer a systematic lymphadenectomy may extirpate all nodal disease. There are also reports from the United States and Europe that are mostly retrospective series that advocate D-2 lymphadectomy for gastric cancer. Keller and colleagues, reporting for the German Stomach Cancer TNM Study Group, recommended systematic lymphadenectomy for resectable gastric cancer because occult lymph nodes metastases were pathologically identified two to three times more frequently than wheo systematic lymphadenectomy was performed. However, in more than 200 patients with tumors in the body or antrum, there was no improvement in survival stage for stage when lymphadenectomy was performed. In a series of 101 patients treated between 1975 and 1990 at Roswell Park Cancer Institute, the estimated 5-year survival was significantly better in 46 patients undergoing extended lymphadenectomy according to the guidelines of the JRSGC. However, it is not clear how patients were selected for lymphadectomy versus a more limited resection. On multivariate analysis, extent of lymphadenectomy was an independent predictor of survival; however, the data are somewhat confounding in that T and N stage were not statistically significant independent predicators of survival.
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, but gives less accurate assessments of parametrial involvement.
Clinical Staging The International Federation of Gynecology and Obstetrics (FIGO) has defined the most widely accepted staging system for carcinomas of the cervix. Since the earliest versions of the cervical cancer staging system, there have beeumerous changes, particularly in the definition of stage I disease.
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.
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.
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
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.
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.
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.,
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 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 (
Uterine body involvement is associated with an increased rate of distant metastases in patients treated with radiation or surgery.
Although several investigators have reported similar survival rates for patients with squamous carcinomas or adenocarcinomas, 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.
Other clinical and biologic features that have been investigated for their predictive power with variable results include patient age, platelet count, tumor vascularity, DNA ploidy or S phase, and HPV infection. In a preliminary study of archival material from 21 patients with histologically negative lymph node dissections, Ikenberg and colleagues 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
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
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.
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 reported one recurrence (which was fatal) in 93 women followed for more than 5 years after therapeutic conization for minimal (less than
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. 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
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 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 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.
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
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. However, patients who have tumors measuring more than
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
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. 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. 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. [ref: 220,235-239] 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.
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.
IRRADIATION FOLLOWED BY HYSTERECTOMY.
In a 1969 report from M. D. Anderson Cancer Center, Durrance and colleagues reported a lower pelvic recurrence rate for patients with bulky endocervical tumors (6 cm or larger) treated with external-beam and intracavitary irradiation followed by extrafascial hysterectomy than for those treated with radiation alone. Combined treatment was subsequently adopted by many groups as a standard approach to bulky stage IB or IIA disease. However, in a 1992 update of the M. D. Anderson experience, Thoms and colleagues suggested that the differences observed in earlier reports may have resulted from a tendency to select patients with very massive tumors (
In 1991, Mendenhall and colleagues reported no difference in pelvic disease control or survival rates for patients treated before or after the University of Florida adopted a policy (in the mid-1970s) of using combined treatment for patients with bulky (
There is, therefore, no clear evidence that adjuvant hysterectomy improves the outcome of patients with a bulky stage IB or IIA tumor, though many clinicians continue to advocate combined treatment. When combined treatment is planned, the dose of intracavitary irradiation is usually reduced by about 25%. A type I extrafascial hysterectomy is usually performed removing the cervix, adjacent tissues, and a small cuff of the upper vagina in a plane outside the pubocervical fascia. This procedure involves minimal disturbance of the bladder and ureters. Intrafascial hysterectomy is not used for cervical cancer because it does not remove all cervical tissue, and radical hysterectomy is avoided after high-dose irradiation because of an increased risk of urinary tract complications.
The Gynecologic Oncology Group recently completed a prospective randomized trial of irradiation with or without extrafascial hysterectomy in patients with stage IB tumors of
CHEMOTHERAPY FOLLOWED BY RADICAL SURGERY.
Since the late 1980s, a number of investigators have reported the results of treating patients with bulky stages IB and II cervical carcinomas with a combination of neoadjuvant chemotherapy followed by radical surgery. Neoadjuvant chemotherapy has usually included cisplatin and bleomycin plus one or two other drugs. The results of these uncontrolled studies cannot be easily compared with more traditional treatments because the series are small, often have short follow-up, and the criteria for patient selection are not always clear. Some or all of the patients in each of these series received postoperative pelvic irradiation, but detailed descriptions of this additional treatment are not always given. There has been one report of a prospective randomized trial comparing radical hysterectomy followed by postoperative radiotherapy with chemotherapy followed by surgery and irradiation. In this study, Sardi and colleagues observed similar outcomes with the two treatments for patients who had tumors smaller than 60 cm**3 (measured ultrasonographically), but they reported a significantly better projected 4-year disease-free survival with neoadjuvant chemotherapy for patients who had larger tumors.
However, most patients had been followed for less than 3 years at the time of the report. Ultimately, the cost and morbidity of this triple-modality treatment may be justified only if it proves to be more effective than treatment with radiotherapy alone.
