8 - Carcinomas of the Gastrointestinal Tract | Handbook of Cancer Chemotherapy

Editors: Skeel, Roland T.

Title: Handbook of Cancer Chemotherapy, 7th Edition

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Chapter 8

Carcinomas of the Gastrointestinal Tract

Al B. Benson III

Cancers of the gastrointestinal (GI) tract (esophagus, stomach, small and large intestines, and anus) account for approximately 14% of all cases of cancer in the United States and for approximately 15% of cancer deaths. Colon cancer is by far the most common of these malignancies, with cancer of the rectum, stomach, esophagus, small intestine, and anus occurring with decreasing frequency. Surgery continues to be the principal curative modality, but irradiation and chemotherapy have increasingly important roles and, in certain adjuvant situations, improve the cure rate produced by surgery. Select patients with isolated, resectable metastatic colorectal cancer lesions also may be cured with surgical resection. Chemotherapy alone is not curative in patients with overt metastatic disease. Recent combination drug regimens have produced objective responses in up to 60% of patients, with increasing numbers of individuals obtaining stabilization of their disease. There is little question that meaningful palliation and an increase in survival can be achieved in patients who respond to chemotherapy or achieve disease stabilization. Controlled clinical trials, often by cooperative groups, have been useful in defining the natural history and therapeutic benefit of various treatment modalities. Participation in such clinical trials should be encouraged.

I. Carcinoma of the esophagus

A. General considerations and aims of therapy

Epidemiology. Cancer of the esophagus has been predominantly of squamous cell (epidermoid) histology and represents approximately 1% of the cases of cancers in the United States. Risk factors include heavy tobacco and alcohol use. It is more common in men than in women and occurs more often in blacks than in whites. The average patient is in his or her sixties at presentation. In certain parts of China, epidermoid esophageal cancer is the most common kind of cancer, which is thought to be related to dietary habits of the region and perhaps a consequence of fungal contamination of pickled vegetables. Other predisposing factors for esophageal cancer include achalasia, a history of lye burns of the esophagus, and prior epidermoid carcinomas of the aerodigestive tract.

In recent years, the incidence of adenocarcinoma of the esophagus (along with adenocarcinoma of the proximal stomach) has increased greatly. By the mid-1980s, it accounted for approximately one third of all esophageal cancer cases among white men and in some institutions, it is approaching 60% of newly diagnosed cancers of the esophagus. Adenocarcinoma is predominantly a disease of
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middle-aged white men, is less strongly linked with alcohol and tobacco use, and is frequently associated with Barrett's esophagus (epithelial metaplasia of the lower esophagus), which is sometimes seen with reflux esophagitis. The rate of increase of adenocarcinomas of the esophagus and gastric cardia during the 1970s and 1980s exceeded that of any other cancer, including lung cancer, non Hodgkin's lymphoma, and melanoma. The cause of this impressive increase is not known, although recent epidemiologic studies have implicated obesity, which has been increasing in the U.S. population during the last few decades. This may in turn be associated with epithelial metaplasia in the esophagus (Barrett's esophagus). Adenocarcinomas of the esophagus tend to involve the lower third of that organ, whereas the middle third is the most common site for the epidermoid subtype. Optimal chemotherapy for the two histologic types of esophageal cancer is not known to be different, with little or no difference in response rate in most series. It has been suggested, however, that a lower expression of thymidylate synthase in squamous cell carcinoma than in adenocarcinoma may make the former more sensitive to fluorouracil-based chemotherapy. Other predictive molecular markers or laboratory correlates are under investigation. For example, investigators have recently genotyped patients with resectable squamous cell or adenocarcinoma of the esophagus or gastroesophageal junction that has resulted in a correlation of genetic markers with efficacy, including pathologic response and survival.

Clinical manifestations and pretreatment evaluation. Carcinoma of the esophagus is usually associated with progressive and persistent dysphagia. Pain, hoarseness, weight loss, and chronic cough are unfavorable manifestations that indicate spread to regional structures (e.g., mediastinal nodes), recurrent laryngeal nerve, or fistula formation between the esophagus and the airway. The most common sites ofmetastasis are regional lymphnodes (which may include cervical, supraclavicular, intrathoracic, diaphragmatic, celiac axis, or periaortic), the liver, and the lungs.

Diagnosis is usually made by barium swallow, endoscopy, and biopsy or lavage cytology. Staging should be based on chest radiographic appearance, computed tomography (CT) scan of the abdomen and chest, and careful physical examination of the cervical and supraclavicular nodes. Endoscopic esophageal ultrasound may be useful in assessing the depth of tumor invasion. The preoperative staging of esophageal cancer is still inadequate, owing to the inability to evaluate lymph nodes accurately. Bronchoscopy should be done for upper and middle third tumors, and a bone scan is useful in patients with bone pain or tenderness. Recent studies investigating positron emission tomography scanning suggest improved nodal evaluation as compared with endoscopic esophageal ultrasound and CT. In addition, a Cancer and Leukemia Group B (CALGB) trial

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demonstrated that thoracoscopy and laparoscopy also may refine staging accuracy. Survival is related to pathologic stage, which can be defined only surgically (Table 8.1).

Table 8.1. TNM stages for carcinoma of the esophagus

Primary tumor
Tis	Carcinoma in situ
T1	Invades lamina propria or submucosa
T2	Invades muscularis propria
T3	Invades adventitia
T4	Invades adjacent structures
Regional lymph nodes
N0	No nodal metastasis
N1	Regional node metastasis
Distant metastasis
M0	None
M1	Present
Stage grouping
0	Tis, N0, M0
I	T1, N0, M0
IIA	T2 or T3, N0, M0
IIB	T1 or T2, N1, M0
III	T3, N1, M0 T4, any N, M0
IV	Any T, any N, M1
Modified from American Joint Committee on Cancer. AJCC staging manual, 6th ed. New York: Springer-Verlag, 2002.

Treatment and prognosis. The primary treatment of stage I and II carcinoma of the esophagus is surgical resection. Approximately half of esophageal cancers are operable, and half of these are resectable. Complete surgical resection (R0 resection) results in a median survival of approximately 18 months with 15% to 20% of patients surviving 5 years. Patients with more advanced disease (stage III) are best treated, at least initially, with nonsurgical means, usually a combination of radiation therapy and chemotherapy. In patients who respond to such treatment, the carcinoma may subsequently be operable, whereas patients with metastatic disease to the liver, lung, or bone are best treated with systemic therapy. Palliative feeding procedures such as with a jejunostomy or gastrostomy tube may be useful if subsequent surgical resection is not to be done. The overall median survival time is less than 1 year, and the overall 5-year survival rate is 5% to 10%. The prognosis is related to the size of the lesion, the depth of penetration of the esophagus, and nodal involvement. Current controlled clinical trials help evaluate the relative
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roles of chemotherapy, radiation, and surgery in all stages of the two predominant histologic types. Most emphasis has been on preoperative ( neoadjuvant ) combined-modality treatment, with few supporting data available for postoperative treatment, although the concept is being evaluated as more patients survive initial combined-modality therapy. This is important because many patients who achieve good local control have disease recurrence in distant sites subsequent to surgery. Recent randomized clinical trials, however, have produced conflicting results with respect to the long-term survival benefits of neoadjuvant therapy.

B. Combined-modality treatment for potentially curable patients

The poor results with immediate surgery, due in part to inadequate staging techniques, have focused attention for some years on preoperative combined-modality treatment with radiation therapy, chemotherapy, or both, followed by surgery (or, in some instances, not followed by surgery). This approach is controversial because of uncertainty of staging and conflicting results from randomized clinical trials. When this approach is used, aggressive staging including endoscopic ultrasound, CT scanning, and laparoscopy is needed and is often combined with jejunostomy feeding tube placement for nutritional support. Despite conflicting results from randomized trials, patients with stage II and III disease are often treated in this manner.

Preoperative chemotherapy. The National Cancer Institute Gastrointestinal Intergroup has reported a randomized trial of 440 patients with either adenocarcinoma or epidermoid cancer of the esophagus, which compared preoperative chemotherapy (cisplatin and fluorouracil for three cycles) versus surgery alone. After a median followup of 55.4 months, there were no median, 1-year, or 2-year survival differences between the two groups. These results differ when compared with recent data from the Medical Research Council Clinical Trials Unit in the United Kingdom, which included 802 patients randomized to receive either two cycles of preoperative cisplatin and fluorouracil followed by surgery or surgery alone. Approximately 66% of patients had adenocarcinoma. In this study, the median survival was 16.8 months for the preoperative chemotherapy patients as compared with 13.3 months for the patients treated with surgery alone, a statistically significant difference. The 2-year survival rates were 43% and 34%, respectively. Different proportions of the two different histologies contribute to the difficulties in interpretation of these trials.
Radiation therapy with surgery, chemotherapy, or both. Radiation therapy, as either a preoperative or a postoperative adjunct to surgery, has not improved overall survival in most series. Radiation therapy alone has 5-year survival rates ranging from 0% to 10%. Combinedmodality treatment of radiotherapy with chemotherapy has been superior. In a randomized trial comparing radiotherapy alone with radiotherapy plus chemotherapy in 121 patients, 88% of whom had squamous cell cancer, the Radiation Therapy Oncology Group reported a 5-year survival
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rate of 27% for the combined-modality group and 0% for the radiation therapy alone group. Median survival times were 14.1 and 9.3 months, respectively. Most patients had stage T2 disease and were node negative by CT scanning. The Eastern Cooperative Oncology Group (ECOG) performed a similar trial of 135 patients with stage I or II squamous cell cancer of the esophagus. Patients were randomized to receive 40 Gy of radiation alone or radiation with a 96-hour continuous infusion of fluorouracil plus mitomycin. Median survival was improved for patients treated with chemoradiation (14.8 months) as compared with those receiving radiation therapy alone (9.2 months). A recent German study of 172 patients with locally advanced squamous cell carcinoma of the esophagus evaluated induction chemotherapy (fluorouracil, leucovorin, etoposide, and cisplatin) followed by chemoradiotherapy (40 Gy, cisplatin, etoposide) followed by surgery versus induction chemotherapy followed by chemoradiotherapy (at least 65 Gy) without surgery. The surgical group of patients demonstrated superior 2-year progression-free survival (64.3% vs. 40.7%, p = 0.003); however, treatment-related mortality was increased in the surgery group (12.8% vs. 3.5%, p = 0.03). There was no difference in survival. A recently reported meta-analysis of randomized controlled trials comparing neoadjuvant chemoradiation and surgery to surgery alone included nine randomized trials with 1,116 patients. The meta-analysis demonstrated that neoadjuvant chemoradiation and surgery improved the 3-year survival and reduced local-regional cancer recurrence (p = 0.038). There was also a higher rate of complete resection, although there was a nonsignificant trend toward increased treatment mortality with neoadjuvant chemoradiation. In addition, concurrent use of chemotherapy and radiotherapy was superior to sequentially administered treatment. More recent phase II trials have explored radiation with alternative chemotherapy combinations, including oxaliplatin, irinotecan, docitaxel, and paclitaxel alone and with molecular targeted agents. Combined chemotherapy and radiotherapy is therefore a reasonable approach for patients who refuse surgery or whose disease is unresectable for anatomic or physiologic reasons, particularly those with epidermoid carcinoma.
- Radiation therapy + fluorouracil + cisplatin
  - Radiation therapy of 180 to 200 cGy/day for 3 weeks, 5 days weekly, and then additional radiation for 2 weeks to the boost field for a total of 5,040 cGy, and
  - Fluorouracil 1,000 mg/m²/day by continuous infusion for 4 days on weeks 1, 5, 8, and 11, with cisplatin 75 mg/m² IV at 1 mg/minute on the first day of each course. Reduce fluorouracil for severe diarrhea or stomatitis and cisplatin for severe neutropenia or thrombocytopenia.
  - Surgery, when it can be done, is probably appropriate because most patients treatedwith chemotherapy and radiotherapy still have residual tumor. Even though a high proportion of patients, 25% in many
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    series, have complete pathologic responses at surgery, the preoperative identification of these patients is not accurate.
  A randomized trial from Ireland of 113 patients with adenocarcinoma of the esophagus has shown a 3-year survival rate of 32% for patients treated with preoperative chemotherapy with fluorouracil and cisplatin (CF) and with radiotherapy followed by surgery as compared with 6% for patients treated with surgery alone. Similarly, a study from the University of Michigan of 100 patients (68% adenocarcinoma) has shown a 3-year survival rate of 30% for combined-modality treatment as compared with 16% for surgery alone, with a reduction in local recurrence in the combined group (42% vs. 19%). At a median follow-up of 8.2 years, there was no difference in survival between the two groups (17.6 and 16.9 months, respectively). Optimal results may involve all three major treatment modalities, with at least some of the chemotherapy being given concurrently with radiation therapy. Alternative preoperative treatments are being defined in phase II trials, incorporating such agents as paclitaxel and irinotecan, and postoperative chemotherapy is also being evaluated. The following regimens have been used in potentially resectable patients:
- Cisplatin + fluorouracil + radiotherapy (Dublin regimen)
  - Fluorouracil 15 mg/kg (555 mg/m²) IV over 16 hours daily, days 1 to 5, and
  - Cisplatin 75 mg/m² IV infused over 8 hours on day 7 after 1 full day of hydration. Repeat both drugs at 6 weeks.
  - Radiotherapy of 40 Gy in 15 fractions over 3 weeks, beginning on the first day of chemotherapy.
  - Surgery is done 8 weeks after beginning treatment, blood counts permitting.
- Fluorouracil + cisplatin + vinblastine + radiotherapy (Michigan regimen)
  - Vinblastine 1 mg/m² IV on days 1 to 4 and 17 to 20 of radiotherapy, and
  - Cisplatin 20mg/m²/day by continuous IV infusion on days 1 to 5 and 17 to 21 of radiotherapy, and
  - Fluorouracil 300 mg/m²/day by continuous IV infusion on days 1 to 21 of radiotherapy, and
  - Radiotherapy 45 Gy in 15 fractions (300 cGy b.i.d.) for 3 weeks
  - Surgery done at 6 weeks.

C. Treatment of advanced (metastatic) disease

Various agents with modest activity when used alone are available. These include cisplatin, carboplatin, fluorouracil, bleomycin, paclitaxel, docetaxel, irinotecan, gemcitabine, methotrexate, mitomycin, vinorelbine, and doxorubicin. Response rates range from15% to 30% and are usually brief. Most data are for epidermoid carcinoma, the exception being paclitaxel, which appears equally effective in both histologic types. The most active drugs appear to be cisplatin, paclitaxel, and fluorouracil. Patients with no history of prior chemotherapy are more likely to

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respond than those who have had previous treatment. Single agents are less helpful than combination chemotherapy because of their lower response rates and brief duration of response. Cisplatin-based regimens have been most extensively tested. Among the most active are the following (for adenocarcinoma of the distal esophagus and gastroesophageal junction also see Section II, in this chapter):

Cisplatin + fluorouracil
- Cisplatin 75 to 100 mg/m² IV on day 1.
- Fluorouracil 1,000 mg/m²/day as a continuous IV infusion on days 1 to 5. Repeat every 28 days.
Paclitaxel + cisplatin
- Paclitaxel 175 mg/m² IV.
- Cisplatin 75 mg/m² IV. Repeat every 21 days.
Carboplatin + paclitaxel
- Carboplatin area under the curve (AUC) 5 IV.
- Paclitaxel 150 mg/m² IV. Repeat every 21 days.
Paclitaxel + cisplatin + fluorouracil
- Paclitaxel 175 mg/m² IV over 3 hours on day 1.
- Cisplatin 20 mg/m²/day IV on days 1 to 5.
- Fluorouracil (fluorouracil) 750 mg/m²/day continuous IV on days 1 to 5. Repeat every 28 days.
Cisplatin + irinotecan
- Irinotecan 65 mg/m² IV days 1, 8.
- Cisplatin 30 mg/m² IV days 1, 8. The regimen is repeated every 21 days.
Second-line therapy. May be chosen from the list of alternative combination therapies or the single agents, including methotrexate 40 mg/m² IV weekly; bleomycin 15 U/m² IV twice weekly; vinorelbine 25 mg/m² IV weekly; or mitomycin 20 mg/m² IV every 4 to 6 weeks.

D. Supportive care

Esophagitis during a combined-modality treatment program is nearly universal, and nutritional support frequently is required, preferably using alimentation by feeding tube placed by enterostomy. Peripheral alimentation is difficult with the continuous chemotherapy administration. Gastrostomy tubes are to be avoided because of the usual requirement for a gastric pull-up after resection of the esophageal tumor.

E. Follow-up studies

For asymptomatic patients with potentially curative therapy, history and physical examination may be done every 4 months for 1 year, then every 6months for 2 years. Chest radiographs, CT scans, endoscopy, chemistries, and complete blood count should be evaluated as clinically indicated.

II. Gastric carcinoma

A. General considerations and aims of therapy

Epidemiology. The incidence of stomach cancer has decreased dramatically in the United States since the beginning of the century, although it has stabilized in the last 20 years. The leading cause of cancer death in 1930, it now ranks eighth; however, worldwide it is the second most lethal cancer. No improvement has been seen, however, in 5-year survival rates, which range from 90% (T1, N0) to 30% to 50% (T3, N0) and from 30% to 40% (stage II) to less than 10% (stage IIIB). A recent large randomized
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U.S. clinical trial, however, has shown improved survival for individuals treated with surgery followed by combined radiation and chemotherapy. The man-to-woman ratio is approximately two to one. Stomach cancer is still the leading cause of cancer deaths among men in Japan and is also common in China, Finland, Poland, Peru, and Chile. A high rate of chronic gastritis and intestinal metaplasia of the stomach is associated with a high incidence of gastric cancer. Helicobacter pylori has been implicated in such changes and in gastric cancer, particularly the more distal intestinal type, as well as in peptic ulcer. Although the incidence in the United States has decreased, the location of gastric cancers has migrated proximally. Nearly half the stomach cancers occurring in white men are located proximally (gastroesophageal [GE] junction, cardia and proximal lesser curvature).
Clinical manifestations and evaluation. The most common symptoms are weight loss, abdominal pain, nausea, vomiting, changes in bowel habits, fatigue, anorexia, and dysphagia. The diagnosis generally is made by endoscopy and biopsy, although barium swallow is frequently helpful. Endoscopic ultrasonography is increasingly used; it is more accurate in gauging the depth of the cancer in the gastric wall than in determining nodal involvement. Laparoscopy is also helpful in improving clinical staging since it can more accurately identify peritoneal metastases and further evaluate the liver. Metastases are to the liver, pancreas, omentum, esophagus, and bile ducts by direct extension and to regional and distant lymph nodes such as those in the left supraclavicular area. Pulmonary and bone metastases are a late finding. Staging of suspected gastric cancer should initially include CT scans of the chest, abdomen, and pelvis. Tumor markers such as carcinoembryonic antigen (CEA), CA 19-9, and CA 72-4 may be useful for subsequent assessment of the response to therapy. Prognosis is reflected by accurate staging (Table 8.2). The revised staging method classifies patients according to the number of pathologically involved regional lymph nodes. The groupings are 1 to 6 (N1), 7 to 15 (N2), and more than 15 involved lymph nodes (N3).

Treatment and prognosis. Most stomach cancers are adenocarcinomas. Important prognostic factors include tumor grade and gross appearance. Diffusely infiltrating lesions are less likely to be cured than sharply circumscribed, nonulcerating lesions. The presence of regional lymph node involvement or involvement of contiguous organs in the surgical specimen indicates an increased likelihood of recurrence, as does the presence of dysphagia at the time of diagnosis. Patients with proximal lesions or lesions requiring total, rather than distal subtotal, gastrectomy are also at greater risk.

There has been controversy as to the contribution of extensive lymphadenectomy (D1 vs. D2 dissection) to survival benefit. Japanese surgeons have widely promoted the D2 dissection; however, randomized clinical trials including the Dutch Gastric Cancer Group and the Medical Research

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Council trials did not show a survival benefit of D2 over D1 lymphadenectomy. However, there was increased morbidity and mortality for those patients who underwent the D2 dissection.

Table 8.2. TNM stages for carcinoma of the stomach

Primary tumor
Tis	Carcinoma in situ
T1	Invades lamina propria or submucosa
T2	Invades muscularis propria or subserosa
T3	Penetrates serosa (visceral peritoneum)
T4	Invades adjacent structures
Regional lymph nodes
N0	No nodal metastasis
N1	Metastasis in 1 6 regional lymph nodes
N2	Metastasis in 7 15 regional lymph nodes
N3	Metastasis in >15 regional lymph nodes
Distant metastasis
M0	None
M1	Present
Stage grouping
0	Tis, N0, M0
IA	T1, N0, M0
IB	T1, N1, M0 T2, N0, M0
II	T1, N2, M0 T2, N1, M0 T3, N0, M0
IIIA	T2, N2, M0 T3, N1, M0 T4, N0, M0
IIIB	T3, N2, M0
IV	T4, N1, M0 T1, N3, M0 T2, N3, M0 T3, N3, M0 T4, N2, M0 T4, N3, M0 Any T, any N, M1
Modified from American Joint Committee on Cancer. AJCC staging manual, 6th ed. New York: Springer-Verlag, 2002.

B. Treatment of advanced (metastatic, locally unresectable, or recurrent) disease

Single agents with activity include epirubicin, mitomycin, doxorubicin, cisplatin, etoposide, fluorouracil,
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irinotecan, hydroxyurea, the taxanes, and the nitrosoureas. Single agents have lowresponse rates (15% 30%), brief durations of response, and few complete responses, and they have little impact on survival.
Combinations of drugs are more widely used than single agents, largely because of higher response rates, more frequent complete responses, and the theoretical potential of longer survival. A controlled trial (1985) of fluorouracil alone versus fluorouracil plus doxorubicin (Adriamycin) (FA) versus fluorouracil, doxorubicin, and mitomycin (FAM), however, failed to show a survival benefit for the combinations, which were more costly and toxic. Response rates, which were measurable in only approximately half the patients, were higher with the combinations. An European study compared methotrexate, fluorouracil, and doxorubicin (FAMTX) with etoposide, leucovorin, and fluorouracil (ELF) and with CF, showing no significant difference among the combinations. Another European trial compared epirubicin, cisplatin, and fluorouracil (ECF) to FAMTX, which favored ECF with improved response rate (45% vs. 20%) and a 2-month improvement in median survival. More recently, a large international advanced gastric cancer trial of 457 patients compared docetaxel, cisplatin, and fluorouracil (DCF) versus CF. The DCF regimen demonstrated significant toxicity including fatigue; however, it showed improved response rate (36% vs. 26%), improved time to tumor progression (5.6 vs. 3.7 months), and improved one- and 2-year survival (40.2% vs. 31.8%; 18.4% vs. 8.8%, respectively). DCF as a treatment for advanced disease, therefore, represents an important proof of principle; however, the toxicity is of significant concern. Recent clinical trials are exploring other docetaxel-containing combination regimens (e.g., oxaliplatin) in an effort to maintain efficacy but to reduce Toxicity.
- DCF (docetaxel, cisplatin, and fluorouracil). Dexamethosone 8 mg PO b.i.d. 1 day before chemotherapy, on the day of treatment, and the day after.
  - Docetaxel 75 mg/m² as a 1-hour IV infusion.
  - Cisplatin 75 mg/m² as a 2-hour IV infusion.
  - Fluorouracil 750 mg/m² daily as a continuous intravenous infusion days 1 to 5.
  The regimen is repeated every 21 days.
- ECF (epirubicin, cisplatin, and fluorouracil)
  - Epirubicin 50 mg/m² IV bolus on day one followed by
  - Cisplatin 60 mg/m² IV over 2 hours on day one
  - Fluorouracil 200 mg/m² daily as a continuous intravenous infusion days 1 to 21.
  The regimen is repeated every 21 days.
- CF (cisplatin, fluorouracil)
  - Cisplatin 100 mg/m² IV over 2 hours on day 1.
  - Fluorouracil 1,000 mg/m² daily as a continuous IV infusion on days 1 to 5.
    
    The regimen is repeated every 28 days.
- Irinotecan and cisplatin
  - Irinotecan 65 mg/m² over 30 minutes IV on days 1 and 8.
  - Cisplatin 30 mg/m² IV over 1 hour, days 1, 8.
    
    The regimen is repeated every 21 days.
- Irinotecan + cisplatin
  - Irinotecan 70 mg/m² IV over 30 minutes on days 1 and 15.
  - Cisplatin 80 mg/m² IV over 2 hours on day 1.
    
    The cycle is repeated every 28 days.
- FAMTX. Before methotrexate administration, hydrate with 1 L of isotonic sodium bicarbonate (1.4% bicarbonate; urine pH must be higher than 7.0). Infuse 2 L of an identical solution over 24 hours after methotrexate is given. The regimen is as follows:
  - Methotrexate 1.5 g/m² by IV bolus infusion after the hydration and urine alkalinization on day 1, and
  - Fluorouracil 1.5 g/m² by IV bolus infusion starting 1 hour after the end of the methotrexate infusion, and
  - Leucovorin 15 mg/m² orally starting 24 hours later on day 2, given every 6 hours for 3 days or until the methotrexate level is less than 2 x 10^-8M. If the methotrexate level is more than 2.5 x 10^-6M at 24 hours, increase leucovorin dose to 30 mg/m² every 6 hours for 96 hours.
  - Doxorubicin 30 mg/m² IV on day 15 if the white blood cell count is more than 3,000/ L or the absolute neutrophil count is more than 1,500/ L and the platelet count is more than 70,000/ L.
    
    The cycle is repeated every 4 weeks. Renal function must be normal and blood levels of methotrexate should be monitored with this regimen.
- ELF. The ELF (leucovorin, etoposide, and fluorouracil) regimen was designed to be less toxic as compared to adriamycin- and cisplatin-containing regimens. The regimen is as follows:
  - Leucovorin 300 mg/m² as a 10-minute IV infusion, followed by
  - Etoposide 120 mg/m² as a 50-minute IV infusion, followed by
  - Fluorouracil 500 mg/m² IV as a 10-minute infusion.
    
    All agents are given on days 1, 2, and 3. The course is repeated in 21 to 28 days.
- Hydroxyurea + leucovorin + fluorouracil + cisplatin. A large phase II study of this regimen in France has reported a response rate of 62%andmedian survival time of 11 months. The regimen is as follows:
  - Hydroxyurea 1.5 to 2 g PO on days 0, 1, and 2, and
  - Leucovorin 200 mg/m² IV as a 2-hour infusion on days 1 and 2, before
  - Fluorouracil 400 mg/m² IV bolus and 600 mg/m² by 22-hour infusion on days 1 and 2, then
  - Cisplatin 80 mg/m² IV on day 3 every other cycle.
    
    The cycle is repeated every 14 days.

C. Adjuvant chemotherapy

Although no single randomized phase III adjuvant gastric chemotherapy trial has demonstrated a survival benefit, a meta-analysis published in 2001 of over 3,658 clinical trial patients (21 comparisons) who were randomized to receive adjuvant chemotherapy versus surgery alone showed a small survival benefit for those who received adjuvant therapy (18% reduced risk of death, HR = 0.82, p < 0.001).

Most recently, the European MAGIC Medical Research Council Adjuvant Gastric Infusional Chemotherapy trial included 503 patients with gastric cancer to receive surgery alone versus three preoperative and three postoperative cycles of the DCF regimen. The patients who received chemotherapy demonstrated significant downstaging of their tumors with improved progression-free survival (19 vs. 13 months, p = 0.0001), median survival (24 vs. 20 months, p = 0.02), and 5-year survival (36% vs. 23%, p = 0.009). Since only 55% of patients were able to begin postoperative therapy, it is postulated that the preoperative chemotherapy provided the most significant benefit. Other neoadjuvant regimens, including combinations with radiation, are under study.

D. Combined-modality therapy

The U.S. Gastrointestinal Intergroup has reported the results of a 556-patient randomized trial comparing surgery with or without postoperative chemotherapy (fluorouracil and leucovorin) and combined chemotherapy and radiation followed by two additional cycles of chemotherapy. Patients had resected stages IB through stage IV M0 adenocarcinoma of the stomach or gastroesophageal junction. Postoperative combined therapy produced a statistically significant median survival benefit (36 vs. 27 months, respectively; p = 0.005). Although the study did not show any significant difference in relapse-free or overall survival according to the extent of lymph node dissection, 54% of patients had a D0 lymphadenectomy (surgery that did not remove all of the N1 nodes), 36% had a D1 dissection, and only 10% underwent a D2 dissection (includes perigastric, celiac, splenic, hepatic artery, and cardial lymph nodes). Major toxic effects (grade 3 or higher) in the chemoradiotherapy group were predominantly hematologic (54%) and gastrointestinal (GI) (33%).

E. Recommended postoperative adjuvant combinedmodality regimen

Preradiation chemotherapy (cycle 1)
- Leucovorin 20 mg/m² IV bolus on days 1 to 5
- Fluorouracil 425 mg/m² IV bolus on days 1 to 5
Radiotherapy and Chemotherapy
- Radiation therapy. 45 Gy at 180 cGy/day to the tumor (or tumor bed) and nodal chains daily for 5 days weekly x 5 weeks (begin 28 days after initial chemotherapy).
- Chemotherapy. Started on the first day of radiotherapy and repeated during the last 3 days of radiation.
  
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  - Leucovorin 20 mg/m² IV bolus on days 1 to 4
  - Fluorouracil 400 mg/m² IV bolus on days 1 to 4, each dose given after the leucovorin
Postradiation chemotherapy. Onemonth after completing chemoradiation, begin two 5-day cycles of leucovorin and fluorouracil as given during cycle 1.

F. Follow-up studies

Reasonable follow-up studies for patients in remission after surgery consist of history and physical examination every 4 to 6 months for 3 years, and then annually. Complete blood cell count, chemistries, endoscopy, and radiologic imaging should be evaluated as clinically indicated. Vitamin B₁₂ supplementation is recommended for patients who have had proximal resections or total gastrectomy.

G. Complications

Hematologic and GI toxicities from the chemotherapymay be accentuated by concurrent radiotherapy. If the complications are sufficiently severe, chemotherapy, radiotherapy, or both should be withheld until improvement. Consideration is given to treating at reduced doses. Hematopoietic growth factors may be of benefit in preventing severe infections secondary to neutropenia, but their use has not yet resulted in improved survival.

H. Treatment of refractory disease

If the patient's disease recurs or progresses with the recommended regimens, it is reasonable to consider combinations containing drugs not previously administered or any of the single agents mentioned in Section II.B.1.

III. Cancer of the small intestine

A. Carcinoid tumors

Carcinoid tumors are the most common tumors of the appendix and ileum. They may develop in other parts of the GI tract but much less frequently. The usual histologic criteria of malignancy are not always applicable. Invasion and evidence of distant spread are more useful prognostic features. In one series, the 60% of patients with intestinal carcinoids that were still confined to the wall of the gut had a 5-year survival rate of 85%, whereas those with tumors invading the serosa or beyond had a 5% survival rate at 5 years. Patients in the latter group were nearly always symptomatic, whereas patients in the former group were not. (Their tumors were discovered at surgery for appendicitis or other causes.) Tumors of the appendix are usually benign by these criteria, whereas those of the ileum are more often invasive. Surgical resection is the definitive therapy. Currently, with approximately 2,500 new cases of malignant carcinoid per year, it is expected that at least 50% of patients will survive 5 years.

Carcinoid syndrome. Approximately 10% of patients with carcinoid tumors have the carcinoid syndrome, which includes diarrhea, abdominal cramps, malabsorption, flushing, bronchoconstriction, and cardiac valvular disease (late sequela). With tumors of intestinal origin, liver metastases are nearly always present. Serotonin is thought to be responsible for the abdominal symptoms. Its metabolite, 5-hydroxyindoleacetic acid (5-HIAA), is excreted in large quantities in the urine and is a useful marker of disease activity. Other markers may be elevated, including chromogranin A, which is the most frequently elevated
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carcinoid marker. The symptoms may respond to simple antidiarrheal therapy. The flushing caused by the syndrome has been attributed to bradykinin, formed by the interaction of kallikrein (produced by the tumor) with a plasma protein. If simple symptomatic measures do not suffice, the best treatment is the synthetic long-acting somatostatin analog octreotide acetate (Sandostatin). This agent, injected at a usual initial dose of 150 g SC every 8 hours or as the long-acting formulation (octreotide LAR depot) 20 to 30 mg IM every month, effectively decreases the secretion of serotonin and other gastroenteropancreatic peptides such as insulin or gastrin. It has been helpful in ameliorating the symptoms of carcinoid tumors (e.g., flushing and diarrhea). There are even modest objective antitumor effects, and improvement in survival is suggested in limited reports. The excretion of 5-HIAA is reduced by octreotide.
Treatment of advanced carcinoid tumors
- Effective agents. The chemotherapy agents doxorubicin, fluorouracil, dacarbazine, and streptozocin have been shown to have limited activity in this disease. Response rates for combinations including fluorouracil and streptozocin, for example, are 25% to 35%, with response durations usually less than 9 months; the overall response rate for patients with tumors of intestinal origin is 41%. A median duration of response of 7 months may be expected, and patients with a good performance status have the greatest likelihood of response. Tumor response correlates well with reduction of 5-HIAA excretion. Some reports have indicated responses with interferon- , including responses in combination with octreotide and in some patients previously treated with chemotherapy. When the disease is confined to the liver, it is sometimes possible to achieve good palliation with hepatic artery embolization, chemoembolization, or most recently, yttrium 90 microspheres. Of note, poorly differentiated neuroendocrine tumors or small cell/atypical lung carcinoids are managed with a small cell lung cancer regimen.
- Recommended regimens
  - Octreotide LAR 20 to 30 mg IM q14 to 28 days.
  - Interferon- 3 to 6x 10⁶ U/day or 10 x 10⁶ U three times per week.
- Precautions. Treatment of carcinoid tumors may precipitate or exacerbate the carcinoid syndrome during the first days of treatment, and the serotonin antagonists cyproheptadine and methysergide as well as octreotide should be available.

B. Adenocarcinomas

Adenocarcinomas of the small intestine are so uncommon that there is no large chemotherapy experience to report. Survival of patients with small intestinal cancer is a function of stage (Table 8.3). Radiation and infusional fluorouracil may be considered for patients with local recurrence or unresectable disease. The chemotherapy regimens employed for advanced colorectal cancer (e.g.,

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oxaliplatin, irinotecan, fluorouracil, and leucovorin) also are generally used to treat patients with small intestine adenocarcinoma.

Table 8.3. TNM stages for carcinoma of the small intestine

Primary tumor
Tis	Carcinoma in situ
T1	Invades lamina propria or submucosa
T2	Invades muscularis propria
T3	Invades through the muscularis propria into subserosa or into nonperitonealized perimuscular tissue with extension of 2 cm
T4	Perforates visceral peritoneum or directly invades other organs or structures
Regional lymph nodes
N0	No nodal metastasis
N1	Regional node metastasis
Distant metastasis
M0	None
M1	Present
Stage grouping
0	Tis, N0, M0
I	T1 or T2, N0, M0
II	T3 or T4, N0, M0
III	Any T, N1, M0
IV	Any T, any N, M1
Modified from American Joint Committee on Cancer. AJCC staging manual, 6th ed. New York: Springer-Verlag, 2002.

IV. Cancer of the large intestine

A. General considerations and aims of therapy

Taken together, cancers of the colon and rectum are by far the most frequent malignancies of the GI tract, and account for the most deaths. Approximately half of patients found to have large bowel cancers are cured by surgery, which remains the only curative modality. Local recurrence is much more common for rectal cancer (40% 50% in nonirradiated patients). Approximately half of large bowel cancer recurrences are in the liver.

Staging. In the past, a commonly used staging system was the Dukes' staging system, including the Astler Coller modifications. TNMstaging for colorectal cancer (Table 8.4) is currently the recommended system. The sixth edition of the American Joint Committee on Cancer (AJCC) Staging Manual has expanded the subsets of patients with stage II (IIA T3, N0; IIB T4, N0) and stage III (IIIA T1 2, N1; IIIB T3 4, N1; IIIC any T, N2) disease, which more accurately reflects the wide variations in survival. Recent models utilizing the staging subsets have incorporated T stage, lymph node status and grade of tumor.

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For example, a stage IIA patient with a low-grade tumor, has a predicted 5-year disease-free survival after surgery of approximately 74%; however, the survivorship of a IIB patient declines to 63%. Stage IIIA patients actually have a better chance of survival as compared to stage IIB patients even without adjuvant therapy (approximately 71% with a low-grade tumor). The worse prognosis is for a stage IIIC patient who has a projected 5-year disease-free survival of less than 25%, even with fluorouracil chemotherapy. This pathologic staging method is helpful for selecting patients who are at sufficiently high risk to justify adjuvant therapy such as chemotherapy or irradiation (rectal cancer). Staging is most accurately performed at the time of surgery. Abdominal, chest, and pelvic CT are helpful for preoperative assessment of extrabowel involvement, but the findings may be falsely negative when small peritoneal implants are present. Bone scans are seldom needed, except for assessment of bone pain, because bone metastases

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occur rather late in the course of the disease. Positron emission tomography scanning is considered to determine the presence of metastatic disease.

Table 8.4. TNM stages for carcinoma of the colon and rectum

Primary tumor
Tis	Carcinoma in situ and intramucosal (within lamina propria)
T1	Invades through muscularis mucosa into submucosa
T2	Invades muscularis propria
T3	Invades through muscularis propria into subserosa or nonperitonealized pericolic or perirectal tissues
T4	Invades adjacent organs or structures or perforates visceral peritoneum
Regional lymph nodes
N0	No nodal metastasis
N1	Metastasis in 1 3 regional nodes
N2	Metastasis in >4 regional nodes
Distant metastasis
M0	None
M1	Present
Stage grouping
0	Tis, N0, M0
I	T1 or T2, N0, M0
IIA	T3, N0, M0
IIB	T4, N0, M0
IIIA	T1 2, N1, M0
IIIB	T3 4, N1, M0
IIIC	Any T, N2, M0
IV	Any T, any N, M1
Modified from American Joint Committee on Cancer. AJCC staging manual, 6th ed. New York: Springer-Verlag, 2002.

Serum CEA. CEA level may parallel disease activity, although it is not increased in all patients with colon cancer. It is worth measuring it preoperatively and, if elevated, postoperatively because failure of an elevated value to return to normal may signify incomplete removal of the tumor. Likewise, a serial rise in CEA values after an initial fall to normal indicates recurrence. CEA values may also be an indicator of response during chemotherapy treatment. Patients who have a normal serum CEA level preoperatively may still demonstrate an elevated CEA value at the time of recurrence. A rising CEA level is an indication for careful re-evaluation with CT, positron emission tomography, and possibly laparoscopy because some patients may have isolated, resectable, and thus potentially curable metastases, particularly involving the liver.

B. Treatment of advanced disease

Effective agents and combinations. For more than 40 years, fluorouracil has been the standard agent in the treatment of advanced colorectal disease not amenable to surgical or radiotherapeutic control. Response rates have varied widely, but a generally agreed-on figure is 10% to 15%. Recent chemotherapy combinations with fluorouracil, including leucovorin, irinotecan and oxaliplatin, have demonstrated improved response rates and survival. The addition of the antivascular endothelial growth factor (anti-VEGF) monoclonal antibody bevacizumab to chemotherapy has further improved response rates and survival.

Second-line treatment for metastatic colorectal cancer is of particular interest because of the benefits of singleagent irinotecan in this setting. Trials have demonstrated response rates of greater than 20%, with greater than 50% of patients achieving stable disease and with median survivals of approximately 12months. In addition, an European study, which randomized metastatic colorectal cancer patients who had progressed within 6 months of treatment with fluorouracil to receive irinotecan versus supportive care, demonstrated a significant 1-year survival advantage (36.2% vs. 13.8%; p = 0.0001) for those patients receiving irinotecan, including an improved pain-free survival.

More recent second-line clinical trials have demonstrated the superiority of FOLFOX4 (See the regimens associated with the acronyms in Section IV.B.3.) as compared to the LV5FU2 regimen for patients who received previous IFL chemotherapy (time to tumor progression 5.6 vs. 2.6 months, p < 0.0001). Oxaliplatin as a single agent has been shown to be inactive. ECOG demonstrated that FOLFOX plus bevacizumab was superior to FOLFOX for previously treated patients (response rate 21.08% vs. 9.2%; progression-free survival 7.2 vs. 4.8 months, p < 0.0001; overall survival 12.9 vs. 10.8 months, p = 0.0018). Cetuximab given as a second- or third-line agent produces a response rate of approximately 10%, while cetuximab and
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irinotecan have a response rate of approximately 23% for patients who have progressed on a previous irinotecan regimen.

First-line irinotecan trials for previously untreated patients with advanced colorectal cancer also have demonstrated response and survival benefits as compared with fluorouracil and leucovorin. For example, a U.S. trial comparing weekly IFL (bolus fluorouracil) with fluorouracil and leucovorin and with irinotecan alone revealed an overall response rate favoring the three-drug combination (39% vs. 21% vs. 18%, respectively) and a median survival advantage (14.8 vs. 12.6 vs. 12 months, respectively; p = 0.04). An European trial evaluating infusional fluorouracil regimens with or without irinotecan also confirmed a response advantage for the three drugs (49% vs. 31%) and improved median survival (17.5% vs. 14.1%; p = 0.03).

More recent first-line clinical trials have demonstrated the superiority of FOLFOX versus IFL (response rate 45% vs. 31%, p = 0.002; time to progression 8.7 months vs. 6.9 months, p = 0.0014; and overall survival 19.5 months vs. 14.8 months, p = 0.0001). In addition, IFL plus bevacizumab has enhanced efficacy as compared to IFL (median survival 20.3 vs. 15.6 months, p < 0.001; progression-free survival 10.6 vs. 6.4 months, p < 0.001; overall response 45% vs. 35%, p < 0.01). Fluorouracil/leucovorin and bevacizumab also has activity with a median overall survival of 18.3 months and progression-free survival of 8.8 months.

Capecitabine is the only oral fluoropyrimidine available for use in colorectal cancer in the United States. Two trials have demonstrated a better response with capecitabine than with fluorouracil and leucovorin with similar median time to disease progression, median time to treatment failure, and median overall survival (approximately 13.3 months for fluorouracil/leucovorin and 12.5 months for fluorouracil/leucovorin in a U.S. study). Capecitabine is therefore available for first-line colorectal cancer patients, particularly those who may not be optimal candidates for an irinotecan or oxaliplatin combination.

The current principle of treatment strategy for patients with advanced colorectal cancer encompasses a new paradigm. Treatment now represents a continuum whereby patients who are exposed to all active agents, including fluorouracil, irinotecan, oxaliplatin, and bevacizumab, over the course of their illness, will achieve the maximum survival advantage, now estimated as a median survival of more than 2 years.
Liver metastasis. A 2-week continuous infusion with floxuridine with or without leucovorin plus dexamethasone given every 28 days and administered by an implantable or portable infusion pump produces one of the highest responses for metastatic colorectal cancer to the liver. The impact on survival, however, remains controversial, with no definitive survival benefit shown by the hepatic artery infusion. More recently, investigators have included systemic therapy alternating with the hepatic artery infusion.

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Recommended regimens
- mFOLFOX6
  - Oxaliplatin 85 mg/m² as a 2-hour IV infusion in 500 mL of D5W on day 1 only, and
  - Leucovorin 400mg/m² as a 2-hour IV infusion followed by
  - Fluorouracil 400 mg/m² IV bolus on day 1 only, then followed by
  - Fluorouracil 2.4 to 3.0 g/m² as a continuous IV infusion over 46 hours, repeated every 2 weeks.
  The cycle is repeated every 14 days. Day 1 leucovorin may be given during the same 2-hour period as the oxaliplatin, but because of the incompatibility of oxaliplatin with saline, both drugs must be given in D5W.
- FOLFOX4
  - Oxaliplatin 85 mg/m² as a 2-hour IV infusion in 250 to 500 mL of D5W on day 1 only simultaneously with leucovorin,
  - Leucovorin 200 mg/m² as a 2-hour IV infusion, days 1 and 2, followed by
  - Fluorouracil 400 mg/m² IV bolus on day 1 then fluorouracil 600 mg/m² as a 22-hour infusion given on days 1 and 2 every 14 days.
- FOLFIRI
  - Irinotecan 180 mg/m²
  - Fluorouracil 400 mg/m² IV bolus, and
  - Leucovorin 400 mg/m², all on day 1 followed by fluorouracil
  - 2.4 to 3.0 g/m² as a continuous infusion over 24 hours
    
    Repeat every 2 weeks.
- Irinotecan + infusional fluorouracil + leucovorin
  - Irinotecan 80 mg/m² plus
  - Leucovorin 500 mg/m² with
  - Fluorouracil 2,300 mg/m² by 24-hour infusion are administered weekly for 6 weeks with a 1-week break.
- Irinotecan + fluorouracil + leucovorin
  - Irinotecan 180 mg/m² on day 1
  - Leucovorin 200 mg/m² days 1 and 2,
  - Fluorouracil 400 mg/m² IV bolus days 1 and 2, and
  - Fluorouracil 600 mg/m² as a continuous infusion over 24 hours on days 1 and 2, repeated every 2 weeks.
- Irinotecan + fluorouracil + leucovorin (IFL)
  - Irinotecan 125 mg/m² as a 90-minute IV infusion with
  - Fluorouracil 500 mg/m² and
  - Leucovorin 20 mg/m²
  administered weekly for 4 weeks with a 2-week rest. Recent toxicity data are such that many oncologists have begun using irinotecan 100 mg/m² and fluorouracil 400 mg/m² with leucovorin 20 mg/m². Dose escalation to full dose is an option for patients with minimal toxicity. Note: This is an inferior regimen when given
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  alone, and is only to be given with bevacizumab. Toxicity concerns limit the usefulness of this combination, however, and recent data suggest that FOLFIRI and bevicizumab is a superior regimen.
- Irinotecan. Irinotecan 125 mg/m² as a 90-minute IV infusion is given weekly for 4 weeks with a 2-week rest or 180 mg/m² every 2 weeks or 300 to 350 mg/m² every 3 weeks.
- Fluorouracil + high-dose leucovorin (weekly)
  - Leucovorin 500 mg/m² IV is given over 2 hour
  - Fluorouracil 500 mg/m² IV bolus injected 1 hour after beginning the leucovorin infusion.
  The combination is administered weekly for 6 weeks followed by a 2-week rest. This regimen is now widely favored as the preferred bolus fluorouracil + leucovorin combination.
- Fluorouracil + leucovorin (5-day)
  - Leucovorin 20 mg/m² IV is followed by
  - Fluorouracil 425 mg/m² IV. The combination is given daily for 5 days. Courses are repeated every 4 weeks.
  Significant numbers of patients require dose reductions, and therefore, the weekly regimen is now favored (Section IV.B.3.h) over this 5-day regimen.
- Fluorouracil by 24-hour continuous infusion. Fluorouracil 2,600mg/m² is given by 24-hour continuous IV infusion weekly.
- Fluorouracil by protracted venous infusion. Fluorouracil 250 to 300 mg/m² over 24 hours is given continuously until toxicity (e.g., erythrodysesthesia, mucositis, or diarrhea) or for 4 weeks continuously followed by a 1-week break.
- LV5FU2
  - Leucovorin 400 mg/m² as a 120-minute IV infusion, followed by
  - Fluorouracil 400 mg/m² IV bolus on day 1 only, then followed by
  - Fluorouracil 2.4 to 3.0 g/m² as a continuous IV infusion over 46 hours
    
    Repeated every 2 weeks.
- Bevacizumab. Bevacizumab 5 mg/kg IV over 90 minutes (first cycle), 60 minutes (second cycle), and then over 30 minutes for each subsequent cycle every other week given with FOLFOX, FOLFIRI, IFL (not recommended) or LV5FU2.
- Cetuximab. 400 mg/m² IV first infusion given over 2 hours, then 250 mg/m² weekly with or without irinotecan.
- Capecitabine. Capecitabine 1,250 mg/m² administered twice daily orally on days 1 to 14 every 3 weeks (2,500 mg/m²/day). Many oncologists have begun patients on a lower dose of 1,000 mg/m² PO b.i.d. on days 1 to 14 every 3 weeks because of toxicity including erythrodysesthesia and mucositis in particular.
  
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  The following regimens are used less commonly:
- Capox
  - Oxaliplatin 130 mg/m² IV day one with
  - Capecitabine 850 mg/m² PO b.i.d. for 14 days every 21 days.
- Fluorouracil + methotrexate + leucovorin
  - Methotrexate 200 mg/m² IV is given over 30 minutes after hydration with 1,500 mL of 5% dextrose in 0.5N saline, followed at 24 hours by
  - Fluorouracil 600 mg/m² IV bolus, followed by
  - Leucovorin 10 mg/m² (to the nearest 5 mg) PO every 6 hours x six doses. The regimen is repeated every 2 weeks.
- Hepatic artery infusion. Most patients are managed by an implantable pump. A preferred regimen includes floxuridine 0.25 mg/kg/day in heparinized saline (50,000 U of heparin) plus 20 mg of dexamethasone administered for 2 weeks, alternating with 2 weeks of heparinized saline without floxuridine. Some patients will need a dose reduction of floxuridine to 0.15 to 0.2 mg/kg. The dexamethasone has helped prevent biliary sclerosis that sometimes accompanies such treatment. If leucovorin is added, the recommended dose of floxuridine is 0.18 mg/kg.

C. Adjuvant chemotherapy

Colon cancer. For patients with node-positive (stage III) resectable colon cancer, the combination of fluorouracil plus leucovorin given either by the 5-day or the weekly schedule for 6 months improves the disease-free as well as the overall survival of patients. The recent MOSAIC (Multicenter International Study of Oxaliplatin/5-fluorouracil/ Leucovorin in the Adjuvant Treatment of Colon Cancer) trial, which evaluated FOLFOX4 versus LV5FU2 in patients with stage II/III colon cancer, has confirmed a 4-year disease-free survival advantage favoring FOLFOX, with a difference between the two arms of 6.6% (p < 0.001). The greatest percent difference between both arms was seen for stage III patients with N2 disease (11.5%). Overall survival data are not yet available. In addition, the NSABP (National Surgical Adjuvant Breast and Bowel Project) trial evaluating a bolus regimen of fluorouracil and oxaliplatin (FLOX) compared to weekly fluorouracil and leucovorin produced comparable 3-year disease-free survival statistics as seen with MOSAIC for stage II and III patients, favoring the FLOX regimen. Three recent adjuvant trials for patients with stage III colon cancer comparing irinotecan with either infusional fluorouracil or bolus fluorouracil versus fluorouracil and leucovorin failed to show a disease-free survival advantage for the combination; therefore, irinotecan cannot be recommended as an adjuvant therapy strategy at this time. Additional trials comparing capecitabine versus fluorouracil/leucovorin and infusional fluorouracil versus bolus fluorouracil and leucovorin have
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demonstrated that each of these approaches produce comparable results. For patients who are candidates for combination therapy, the FOLFOX regimen has become a standard for patients with stage III colon cancer.

Most randomized clinical trials have not demonstrated a survival advantage for stage II patients who have been treated with adjuvant chemotherapy, and the current standard is observation. Current guidelines from The American Society of Clinical Oncology (ASCO) suggest detailed discussion between the oncologist and patient as to the risk versus benefit of receiving adjuvant chemotherapy for stage II disease. There are high-risk stage II patients (e.g., stage IIB) where adjuvant therapy is a consideration based upon risk. A current Gastrointestinal Intergroup trial will define risk for stage II patients on the basis of molecular markers including 18q allele deletion and microsatellite instability.

Although historical data support the use of postoperative radiotherapy for locally advanced colon cancer (Dukes B3 or C3 or any T4 lesion), a small intergroup trial did not confirm its efficacy. Combination chemotherapy should probably be incorporated into the regimen and used for a total of 6 months after radiation therapy.

The recommended colon cancer adjuvant regimens for node-positive patients (stage III) are as follows:
- Fluorouracil + high-dose leucovorin (weekly) as in Section IVB.3.h. Many physicians now favor this weekly regimen because of the toxicity noted with the 5-day schedule in Section IV.C.1.B.
- Fluorouracil + leucovorin (5-day).
  - Leucovorin 20 mg/m² IV daily x5 and
  - Fluorouracil 425 mg/m² IV daily x 5 on weeks 1, 5, 9, 14, 19, and 24.
- LV5FU2. (See Section IV.B.3.l.)
- Capecitabine. (See Section IV.B.3.o.) Eight cycles are administered.
- mFOLFOX6. (See Section IV.B.3.a.)
- FOLFOX4. (See Section IV.B.3.b.)
- FLOX
  - Oxaliplatin 85 mg/m² as a 120-minute IV infusion on weeks 1, 3, and 5 of each 8-week cycle.
  - Fluorouracil 500 mg/m² IV bolus weekly for 6 weeks.
  - Leucovorin 500 mg/m² IV bolus weekly for 6 weeks.
  There are three 8-week cycles administered.
Resected hepatic metastases. Past data have demonstrated that patients with resected hepatic metastases secondary to colorectal cancer have a survival of at least 25%. Two recent clinical trials evaluating hepatic artery infusion with floxuridine compared to surgery have demonstrated significant reduction in recurrence of hepatic metastases with a trend toward improved survival for the patients receiving the hepatic artery infusion. Recent retrospective clinical trial analyses suggest that neoadjuvant chemotherapy (FOLFOX or FOLFIRI with or without bevacizumab) may improve the hepatic resection rate. Ongoing clinical trials should provide confirmatory data.

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Rectal cancer
- Preoperative irradiation. Several studies have shown that preoperative irradiation benefits patients with rectal cancer, although there are disadvantages in terms of accuracy of staging, delay before surgery, incomplete knowledge of the extent of tumor for treatment planning, and inappropriate administration of radiation to patients with early (stage I) disease or most patients with advanced (stage IV) disease. Possible advantages include downstaging of tumor, improved sphincter preservation, improved resectability, and earlier initiation of systemic therapy. Better preoperative staging includes the use of magnetic resonance imaging and endorectal ultrasound. Ongoing clinical trials are exploring combinations of neoadjuvant therapy incorporating capecitabine, bevacizumab, and oxaliplatin as attempts to improve the pathologic complete response rate for patients with clinical stage II and III rectal cancer. Currently, preoperative chemoradiation employing fluorouracil 225 mg/m² daily as a continuous infusion during the course of the radiation therapy has become a U.S. and European standard. Capecitabine 825 mg/m² PO twice daily on the days of radiation is an alternative to the continuous infusion of fluorouracil that is used by some oncologists, but has not been compared for efficacy.
- Postoperative irradiation, with and without chemotherapy. Several controlled clinical trials have shown convincingly that radiation therapy alone reduces local recurrence but has little or no effect on overall survival. Fluorouracil-based chemotherapy added to radiation therapy is superior to either modality alone in terms of both local control and distant disease, thus improving overall survival. The optimal administration of fluorouracil during radiation therapy appears to be by protracted venous infusion, requiring a port and ambulatory pump, or by bolus with leucovorin. New adjuvant chemotherapy trials (for patients who receive preoperative chemoradiation) are investigating the use of FOLFOX with or without bevacizumab.
  
  The recommended postoperative adjuvant regimen for stage II or III rectal cancers is as follows:
  - Fluorouracil 500 mg/m² IV bolus daily on days 1 to 5 and days 36 to 40.
  - Radiation therapy 4,500 cGy in 180-cGy fractions over 5 weeks, with tumor boost of 540 to 900 cGy, beginning on day 64.
  - Fluorouracil 225mg/m²/day by protracted venous infusion throughout the period of radiation therapy, days 64 to 105.
  - Fluorouracil 500 mg/m² IV bolus daily, on days 134 to 138 and days 169 to 173.
  If leucovorin is added to the fluorouracil schedule (without radiation), the dose of leucovorin is 20mg/m² and the dose of fluorouracil is 425 mg/m²/day for 5 days before radiation. After radiation, fluorouracil
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  should be reduced to 380 mg/m²/day with the leucovorin.
  
  As with the preoperative chemoradiation, capecitabine 825 mg/m² PO twice daily on the days of radiation is an alternative to the continuous infusion of fluorouracil that is used by some oncologists, but has not been compared for efficacy. If capecitabine is used before and after radiation, the starting dose should be 1,000 to 1,250 mg/m² PO twice daily for 14 days of each 21-day cycle.

D. Follow-up

A recent pooled analysis of clinical trials suggests that 80% of colorectal cancer recurrences will occur within 3 years. In the asymptomatic patient, follow-up after treatment includes history, physical examination, and CEA every 3 months for 2 years, then every 6 months for 3 years. Colonoscopy is often performed 1 year after surgery and then every 3 years if no polyps are found. CT scans may be considered yearly for 3 years for patients at high risk for recurrence.

E. Complications of therapy or disease

The complications of chemotherapy are those attributable to the individual drugs. Myelosuppression, nausea, vomiting, and diarrhea are common and may require dose modification and symptomatic treatment. Radiation complications are similar and also include dysuria, tenesmus, and rectal discharge of blood or mucus. Phenazopyridine (Pyridium) is useful in treating dysuria, and loperamide (Imodium) or diphenoxylate (Lomotil) is recommended for diarrhea. If toxicity is substantial (grade 3 or 4) during radiotherapy, a treatment delay of at least 1 week is warranted. During chemotherapy with fluorouracilbased regimens, mild diarrhea (grade 1) may be treated symptomatically. Moderate diarrhea (grade 2 or 3) is an indication for dose reduction by 50%, and severe diarrhea (grade 3 or 4) is an indication for stopping chemotherapy for 1 week or longer. Dehydration is a real risk with grade 3 or 4 diarrhea, and IV hydration may be necessary. Tincture of opium or octreotide 150 g t.i.d. may help to alleviate severe diarrhea.

Recent recommendations for management of irinotecan toxicity include evaluation for a GI syndrome, which can encompass diarrhea, nausea, vomiting, anorexia, abdominal cramping, dehydration, neutropenia, fever, and electrolyte abnormalities. There is also a vascular syndrome, which can include myocardial infarction, pulmonary embolus, or cerebral vascular accident. Patients receiving irinotecan should undergo weekly assessment, at least during the first cycle, looking for concurrent toxicities. In addition to treating the diarrhea with loperamide, tincture of opium, or octreotide, oral fluoroquinolone should be initiated in any patient experiencing neutropenia even in the absence of fever or diarrhea or in any patient experiencing fever and diarrhea even in the absence of neutropenia. Antibiotics should be initiated in any hospitalized patient with prolonged diarrhea regardless of granulocyte count and should be continued until resolution of diarrhea. Any patient who experiences significant treatment-related diarrhea should not receive irinotecan until he or she is diarrhea-free or at baseline bowel function for at least 24 hours without

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the use of antidiarrheal agents or antibiotics. In addition, abdominal cramping should be considered equivalent to diarrhea.

Oral mucositis can often be prevented on subsequent courses without dose reduction by holding ice in the mouth for 20 minutes before, during, and after the IV bolus of fluorouracil. Nausea is usually not severe with fluorouracil regimens and usually responds to prochlorperazine or dexamethasone. Hematopoietic growth factors are seldom warranted for the mild neutropenia that is observed with bolus fluorouracil therapy.

Oxaliplatin causes an acute cold sensitivity associated with distal dysesthesia/paresthesias and a chronic sensory neuropathy. Potential bevacizumab toxicities include hypertension, bleeding, delayed wound healing, arterial thrombosis, proteinuria, and GI perforation. Cetuximab is associated with acneiform rash, hypersensitivity, interstitial lung disease, and infusion reactions.

V. Cancer of the anal canal

These cancers, constituting only 1% to 3% of all cases of large bowel cancer, were historically treated by abdominoperineal resection with approximately a 50% cure rate. They have been seen more commonly in women. However, in recent years, there is an increase of these cancers in men, particularly homosexuals. The human papillomavirus has been implicated in some patients, and anal warts are sometimes seen as well. Patients infected with the human immunodeficiency virus also have an increased incidence of anal cancer.

A. Local disease

It has been found that combined-modality treatment with chemotherapy and irradiation is curative in 75% to 80% of patients and therefore allows avoidance of abdominoperineal resection with retention of anal function. The following regimen is recommended:

Radiotherapy 4,500 cGy in 25 fractions (5 weeks), and concurrently
Fluorouracil 1,000 mg/m² by continuous IV infusion daily x 4 days (days 1 to 4 and 29 to 32), and
Mitomycin 10 mg/m² IV on days 1 and 29.

A biopsy should be done 8 weeks after radiation therapy only for a suspicious residual area of abnormality. If negative, no further treatment is needed. If positive, consider an additional 900 cGy (five fractions) and a 4-day course of fluorouracil 1,000 mg/m² by continuous IV infusion on days 1 to 4 and cisplatin 100 mg/m² IV on day 2. If the biopsy is persistently positive, an abdominoperineal resection is appropriate.

A large U.S. Gastrointestinal Intergroup trial compared the standard regimen of mitomycin and fluorouracil versus preradiation chemotherapy followed by chemoradiotherapy using
- Cisplatin 75 mg/m² IV on days 1, 29, 57, and 85 and
- Fluorouracil 1,000 mg/m² by continuous IV infusion on days 1 to 4, 29 to 32, 57 to 60, and 85 to 88 plus
- Radiation 45 to 59 Gy, starting day 57.
Overall survival was not statistically different (5-year: 69%) nor was time to local-regional/distal relapse. The colostomy
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rate, however, favored the standard regimen of mitomycin and fluorouracil (5-year: 10% vs. 20%, p = 0.12).

B. Metastatic disease

For metastatic disease, the following regimen may be considered:

Mitomycin 10 mg/m² IV every 4 weeks x 2, then every 10 weeks, and
Doxorubicin 30 mg/m² IV every 4 weeks x 2, then every 5 weeks, and
Cisplatin 60 mg/m² IV, every 4 weeks x 2, then every 5 weeks.