Handbook of Cancer Chemotherapy (Lippincott Williams & Wilkins Handbook Series), 8th Ed.

7. Carcinomas of the Gastrointestinal Tract

Maxwell Vergo and Al B. Benson III

Cancers of the gastrointestinal (GI) tract (esophagus, stomach, small and large intestines, and anus) account for nearly 14% of all cases of cancer in the United States and for about 20% 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 radiation 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 is encouraged.

I. CARCINOMA OF THE ESOPHAGUS

A. General considerations and aims of therapy

1. Epidemiology. Cancer of the esophagus is more common in men than women and occurs more often in black patients than in white patients. The average patient is in his or her 60s at presentation. Esophageal cancers are either adenocarcinoma (EAC) or squamous cell carcinoma (ESCC). Smoking and regular alcohol use are strong risk factors for ESCC and only moderate risk fac-tors for EAC; the risk is reduced with smoking cessation in ESCC but not EAC. A unique risk factor for ESCC is other aerodigestive tract malignancies, such as head and neck or lung cancer. Risk factors associated with EAC only appear to be gastroesophageal reflux disease (GERD) and Barrett esophagitis.

EAC tends to involve the lower third of that organ, whereas the middle third is the most common site for ESCC. Although ESCC remains the most common in Asian countries, especially East Asia, the incidence of EAC has been increasing over the past two decades in Western countries. In the United States over this time, the incidence of EAC has increased three- to eightfold. The ratio of ESCC:EAC during this time has changed from 4.7:1 in 1975 to 0.43:1 in 1998. This is believed primarily to be due to increased GERD from rising rates of obesity in these regions of the world.

Optimal chemotherapy for the two histologic types of esophageal cancer is not known to be different in terms of overall survival (OS). There does appear to be an improved rate of response to neoadjuvant therapy with ESCC, but EAC patients who experience a response have an improved long-term prognosis compared to their ESCC counterparts, likely explaining the lack of OS difference.

2. 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 nerves, or fistula formation between the esophagus and the airway. The most common sites of metastasis are regional lymph nodes (which may include cervical, supraclavicular, intratho-racic, diaphragmatic, celiac axis, or periaortic lymph nodes), the liver, and the lungs.

Diagnosis is usually made by barium swallow, endoscopy, and biopsy or lavage cytology. Staging should be based on com-puted tomography (CT) scan of the abdomen and chest, careful physical examination of the cervical and supraclavicular nodes, and positron emission tomography (PET)/CT imaging to rule out distant metastatic disease. In patients without metastatic disease, endoscopic esophageal ultrasound (EUS) may be useful in assessing the depth of tumor invasion, given the difference in management of T1-T2 lesions versus T3-T4 lesions. The preoperative staging of esophageal cancer with EUS is still inadequate, owing to the inability to evaluate lymph nodes accurately; PET/CT does not seem to improve this detection for locoregional nodal status. Laparoscopy has the advantage of changing management in approximately 20% of patients who have otherwise been fully staged with CT, PET/CT, and EUS. Bronchoscopy should be done for upper- and middle-third tumors to rule out a bronchoesophageal fistula. A bone scan is useful in patients with bone pain or tenderness. Survival is related to pathologic stage, which only can be defined surgically (Table 7.1).

3. Treatment and prognosis. The primary treatment of stage I and II carcinoma of the esophagus is surgical resection. About half of esophageal cancers are operable, and half of these are resect-able. Complete surgical 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 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. For metastatic disease, 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 are helping to evaluate the optimal chemotherapy regimen and combination with radiation in the neoadjuvant setting.

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 pre-operative 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 EUS, 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 fashion.

f0123-01

f0124-01

1. Preoperative chemotherapy. The National Cancer Institute Gastrointestinal Intergroup has reported a randomized trial of 440 patients with either EAC or ESCC that compared preoperative chemotherapy (cisplatin and fluorouracil [CF] for three cycles) versus surgery alone. After a median follow-up of 55.4 months, there were no median, 1-year, or 2-year survival differences between the two groups. These results differ compared with 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 CF followed by surgery versus surgery alone. Approximately 66% of patients had adenocarcinoma. Long-term follow-up at 6 years revealed a sig-nificant difference in 5-year OS (chemotherapy versus surgery alone, 23% versus 17.1%; hazard ratio [HR] 0.84; 95% confidence interval, 0.72–0.98;p = 0.03) regardless of histological subtype. Different proportions of the two different histologies contribute to the difficulties in interpretation of these trials.

2. Radiation therapy with surgery, chemotherapy, or both. Radiation therapy, as either a preoperative or a postoperative adjunct to surgery, has not improved OS in most series, with 5-year survival rates ranging from 0% to 10%. Combined-modality treatment of radiotherapy with chemotherapy has been superior. In addition, concurrent chemotherapy and radiotherapy is superior to sequentially-administered treatment. In a randomized trial, Radiation Therapy Oncology Group (RTOG) 85–01, comparing radiotherapy alone with radiotherapy plus chemotherapy in 121 patients, 88% of whom had squamous cell cancer, the RTOG reported a 5-year survival rate of 27% for the combined-modality group and 0% for the radiation therapy alone group, with median survival times of 14.1 months and 9.3 months, re-spectively. Most patients had stage T2 disease and were node negative by CT scanning.

a. Radiation therapy plus CF

(1) Radiation therapy 180 to 200 cGy/day for 3 weeks, 5 days weekly, then 2 additional weeks to the boost field for a total of 5040 cGy, and

(2) Fluorouracil 1000 mg/m2/day by continuous infusion for 4 days on weeks 1, 5, 8, and 11, with cisplatin 75 mg/m2 intravenously (IV) at 1 mg/min on the first day of each course. Reduce fluorouracil for severe diarrhea or stomatitis and cisplatin for severe neutropenia or thrombocytopenia.

More recent phase II trials are exploring radiation with alternative chemotherapy combinations, including cisplatin with a taxane as well as the addition of a targeted agent, namely epidermal growth factor receptor (EGFR) antagonists.

Surgery, when it can be done, is probably appropriate because most patients treated with chemotherapy and radiotherapy still have residual tumor. Even though a high proportion of patients, 25% in many series, have complete pathologic responses at surgery, the preoperative identifica-tion of these patients is not accurate. A large meta-analysis of randomized controlled trials comparing neoadjuvant chemoradiation and surgery to surgery alone included nine randomized trials with 1116 patients. The meta-analysis demonstrated that neoadjuvant chemoradiation and sur-gery improved the 3-year survival (p = 0.016) and reduced distant and 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.

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 ESCC.

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 from 15% to 30% and are usually brief. Most data are for ESCC, 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 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 gastroesopha-geal junction, see Section II).

1. CF

a. Cisplatin 75 to 100 mg/m2 IV on day 1.

b. Fluorouracil 1000 mg/m2/day as a continuous IV infusion on days 1 to 5. Repeat every 28 days.

2. Paclitaxel plus cisplatin

a. Paclitaxel 175 mg/m2 IV on day 1.

b. Cisplatin 75 mg/m2 IV on day 1. Repeat every 21 days.

3. Carboplatin plus paclitaxel

a. Carboplatin area under the curve 5 IV on day 1.

b. Paclitaxel 200 mg/m2 IV on day 1. Repeat every 21 days.

4. Paclitaxel plus cisplatin plus fluorouracil

a. Paclitaxel 175 mg/m2 IV over 3 hours on day 1.

b. Cisplatin 20 mg/m2/day IV on days 1 to 5.

c. Fluorouracil 750 mg/m2/day continuous IV on days 1 to 5. Repeat every 28 days.

5. Cisplatin plus irinotecan

a. Irinotecan 65 mg/m2 IV on days 1, 8, 15, and 22.

b. Cisplatin 30 mg/m2 IV on days 1, 8, 15, and 22. The regimen is repeated every 6 weeks.

6. Irinotecan plus fluorouracil plus leucovorin

a. Irinotecan 180 mg/m2 IV over 30 minutes followed by a 30-minute break.

b. Leucovorin 125 mg/m2 IV over 15 minutes.

c. Fluorouracil 400 mg/m2 IV over 3 to 4 minutes.

d. Fluorouracil 1200 mg/m2/day continuous IV for 2 days. The regimen is repeated every 2 weeks.

7. Cetuximab. The addition of cetuximab to a chemotherapy backbone has yet to demonstrate a significant progression-free survival or OS advantage, but does appear to improve response rates. A large clinical trial (Eastern Cooperative Oncology Group [ECOG] 1206/Cancer and Leukemia Group B 80403) recently completed accrual and should further clarify the benefit of cetuximab in this disease.

8. Second-line therapy may be chosen from the list of alternative combination therapies or the single agents, including metho-trexate 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. However, these therapies are not currently included in disease treatment guidelines, such as those of the National Comprehensive Cancer Network (NCCN).

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 enteros-tomy. Peripheral alimentation is difficult with the continuous chemotherapy administration. Gastrostomy tubes are to be avoided in patients with potentially resectable lesions because of the usual requirement for a gastric pull-up after resection of the esophageal tumor.

E. Follow-up studies

For asymptomatic patients who have had potentially curative therapy, history and physical examination may be done every 3 to 6 months for years 1 to 3, every 6 months for years 3 to 5, and then annually. CT scans, endoscopy, chemistries, and complete blood count should be evaluated as clinically indicated.

II. GASTRIC CARCINOMA

A. General considerations and aims of therapy

1. 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 12th; however, worldwide it is the 4th most lethal cancer. No improvement has been seen over the last two decades though, with 5-year survival rates ranging from 45% to 71% in node-negative disease to 5% to 30% in node-positive or metastatic disease. The male-to-female ratio is nearly 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 disease. 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 junction, cardia, and proximal lesser curvature).

2. 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 as 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 supra-clavicular 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), cancer antigen (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 7.2). The revised staging method classifies patients according to the number of pathologically involved regional lymph nodes. The groupings are one to two (N1), three to six (N2), and seven or more involved lymph nodes (N3).

3. Treatment and prognosis. Most stomach cancers are adenocarci-nomas. 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, gas-trectomy are also at greater risk.

There has been controversy as to the contribution of extensive lymphadenectomy (D1 versus 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 Council trials did not show a survival benefit ofD2 over D1 lymphadenectomy. However, there was increased morbidity and mortality for those patients who underwent the D2 dissection.

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

1. Single agents with activity include epirubicin, mitomycin, doxorubicin, cisplatin, etoposide, fluorouracil, irinotecan, hydroxyurea, the taxanes, and the nitrosoureas. Single agents have low response rates (15%–30%), brief durations of response, and few complete responses, and they have little impact on survival.

2. Combinations of drugs are more widely used than single agents, largely because of higher response rates, more frequent complete responses, and the potential of longer survival. A large randomized phase III study (V325) enrolling mostly patients with metastatic gastric cancer found improved response rate (36% versus 26%), delayed time to progression (5.6 months versus 3.7 months), improved OS (18.4% versus 8.8% at 2 years), delayed decline in functionality, and delayed deterioration of quality of life with docetaxel, cisplatin, and fluorouracil (DCF) compared to CF. Significant differences in grade 3 to 4 toxicities of DCF including diarrhea (19% versus 8%), neutropenia (82% versus 57%), neutropenic fever (29% versus 12%), and neurosen-sory (8% versus 3%) as compared to CF have limited its use as a standard regimen. DCF as a treatment for advanced disease, therefore, represents an important proof of principle; however, the toxicity is of significant concern.

f0129-01

a. DCF. Dexamethasone 8 mg by mouth twice a day 1 day prior to chemotherapy, on the day of treatment, and the day after.

(1) Docetaxel 75 mg/m2 as a 1-hour infusion IV.

(2) Cisplatin 75 mg/m2 as a 2-hour infusion IV.

(3) Fluorouracil 750 mg/m2 daily as a continuous infusion IV on days 1 to 5. The regimen is repeated every 21 days.

b. CF

(1) Cisplatin 100 mg/m2 IV over 2 hours on day 1.

(2) Fluorouracil 1000mg/m2dailyasacontinuousinfusionIV on days 1 to 5. The regimen is repeated every 21 days.

A UK study randomized 274 patients to receive either epirubicin, cisplatin, and protracted infusional fluorouracil (ECF) or fluorouracil, doxorubicin, and methotrexate, which was the standard at the time. The results favored ECF with improved response rate (45% versus 20%), a 2-month improvement in median survival, and an improved 2-year OS (14% versus 5%).

c. ECF

(1) Epirubicin 50 mg/m2 IV bolus on day 1 followed by CF.

(2) Cisplatin 60 mg/m2 IV over 2 hours on day 1.

(3) Fluorouracil 200 mg/m2 daily as a continuous infusion IV on days 1 to 21 The regimen is repeated every 21 days.

The REAL 2 study enrolled 1,002 patients with mostly metastatic gastric and gastroesophageal cancer and randomized patients in a two-by-two design to receive one of four anthracycline containing regimens: epirubicin and fluorou-racil with either cisplatin (ECF) or oxaliplatin (EOF) as well as epirubicin and capecitabine with either cisplatin (ECX) or oxaliplatin (EOX). They concluded that capecitabine was noninferior to fluorouracil and that oxaliplatin was nonin-ferior to cisplatin. Of note, oxaliplatin-containing regimens appeared to be better tolerated then cisplatin-containing regimens. In a secondary subset analysis, there was suggestion of a survival benefit of EOX compared with ECF.

d. EOF

(1) Epirubicin 50 mg/m2 IV bolus on day 1 followed by oxaliplatin and fluorouracil.

(2) Oxaliplatin 130 mg/m2 IV over 2 hours on day 1.

(3) Fluorouracil 200 mg/m2 daily as a continuous infusion IV on days 1 to 21. The regimen is repeated every 21 days.

e. EOX

(1) Epirubicin 50 mg/m2 IV bolus on day 1 followed by oxali-platin and capecitabine.

(2) Oxaliplatin 130 mg/m2 IV over 2 hours on day 1.

(3) Capecitabine 625 mg/m2 twice daily on days 1 to 21. The regimen is repeated every 21 days.

f. ECX

(1) Epirubicin 50 mg/m2 IV bolus on day 1 followed by cispla-tin and capecitabine.

(2) Cisplatin 60 mg/m2 IV over 2 hours on day 1.

(3) Capecitabine 625 mg/m2 twice daily on days 1 to 21. The regimen is repeated every 21 days.

More recently, the ToGA trial enrolled 584 patients with HER2-positive (immunohistochemistry 3+ and/or fluorescence in-situ hybridization [FISH] + ) gastric cancer to receive fluorouracil or capecitabine with cisplatin and randomized to either receive trastuzumab or placebo. They found improved response rate (47.3% versus 34.5%), improved progression-free survival, and improved median OS (13.8 months versus 11.1 months). This is the first biologic agent to demonstrate a convincing survival advantage in gastric cancer.

g. CF or cisplatin and capecitabine with trastuzumab. Please note that this regimen is appropriate only in HER2-positive patients, as defined by immunohistochemistry 3+ or FISH+.

(1) Fluorouracil 800 mg/m2/day continuous infusion IV on days 1 to 5 or capecitabine 1000 mg/m2 orally twice daily on days 1 to 14.

(2) Cisplatin 80 mg/m2 IV over 2 hours on day 1.

(3) Trastuzumab 8mg/kg IV loading dose over 90 minutes on day 1. If tolerated, then the following cycle dose is 6 mg/kg IV over 30 to 90 minutes. The regimen is repeated every 21 days.

After 6 cycles, if there is stable disease, then continue only trastuzumab maintenance until progression.

Baseline echocardiogram every 3 months is recommended to assess for asymptomatic decline in ejection fraction seen with trastuzumab.

Currently, the NCCN supports the use of DCF and ECF in advanced gastric cancer with a category 1 level of evidence, but other regimens including irinotecan plus cisplatin, oxaliplatin plus a fluoropyrimidine, DCF modifications, irinotecan plus a fluoropyrimidine, and paclitaxel-based regimens are supported with a category 2B level of evidence.

h. Irinotecan and fluorouracil

(1) Irinotecan 80 mg/m2 over 30 minutes IV days 1, 8, 15, 22, 29, 36 followed by leucovorin and fluorouracil.

(2) Leucovorin 500 mg/m2 over 2 hours IV on days 1, 8, 15, 22, 29, and 36 followed immediately by fluorouracil.

(3) Fluorouracil 2000 mg/m2 continuously over 22 hours IV on days 1, 8, 15, 22, 29, and 36. The regimen is repeated every 7 weeks (6 weeks on followed by 1 week off).

i. Irinotecan plus cisplatin

(1) Irinotecan 65 mg/m2 IV over 30 minutes on days 1, 8, 15, and 22.

(2) Cisplatin 30 mg/m2 IV over 2 hours on days 1,8,15, and 22. The cycle is repeated every 6 weeks.

j. Oxaliplatin plus fluorouracil

(1) Oxaliplatin 85 mg/m2 IV over 2 hours on day 1.

(2) Leucovorin 200 mg/m2 IV over 2 hours followed by fluorouracil.

(3) Fluorouracil 2600 mg/m2 IV continuously over 24 hours. The regimen is repeated every 2 weeks.

k. Paclitaxel plus cisplatin

(1) Paclitaxel 100 mg/m2 IV over 1 hour on days 1 and 8 followed by cisplatin.

(2) Cisplatin 30 mg/m2 IV over 30 minutes (with 2L of normal saline) on days 1 and 8. This regimen is repeated every 21 days.

l. Fluorouracil, leucovorin, and oxaliplatin (FLO)

(1) Oxaliplatin 85 mg/m2 IVover 1 to 2 hours on day 1.

(2) Leucovorin 200 mg/m2 IV over 1 to 2 hours on day 1, followed by fluorouracil.

(3) Fluorouracil 2600 mg/m2 continuous IV over 24 hours. This regimen is repeated every 2 weeks.

m. FLO plus docetaxel

(1) Oxaliplatin, leucovorin, and fluorouracil as discussed previously.

(2) Docetaxel 50 mg/m2 IV over 1 to 2 hours on day 1. This regimen is repeated every 2 weeks. This “modified” DCF regimen was shown to have a more acceptable adverse event profile than the DCF regimen from V325 (complicated neutropenia, 3.8% versus 29%).

n. Capecitabine plus cisplatin

(1) Capecitabine 1000 mg/m2 orally twice daily on days 1 to 14.

(2) Cisplatin 80 mg/m2 IV on day 1. This regimen is repeated every 21 days.

C. Adjuvant chemotherapy

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).

In addition to this, in 2006 the European MAGIC trial was published accruing 503 patients with gastric cancer who were randomized to surgery alone versus three preoperative and three postoperative cycles of the ECF regimen. The patients who received chemotherapy demonstrated significant downstaging of their tumors with improved progression-free survival (19 months versus 13 months, p = 0.0001), median survival (24 months versus 20 months, p = 0.02), and 5-year survival (36% versus 23%, p = 0.009). Because 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 undergoing 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 leuco-vorin) 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 months versus 27 months, respectively; p = 0.005). Although the study did not show any significant difference in relapse-free survival or OS 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 chemora-diotherapy group were predominantly hematologic (54%) and GI (33%).

E. Recommended postoperative adjuvant combined modality regimen

1. Preradiation chemotherapy (cycle 1)

a. Leucovorin 20 mg/m2 IV bolus on days 1 to 5.

b. Fluorouracil 425 mg/m2 IV bolus on days 1 to 5.

2. Radiotherapy and chemotherapy

a. Radiation therapy 45 Gy at 180 cGy/day to the tumor (or tumor bed) and nodal chains daily for 5 days weekly for 5 weeks (begin 28 days after initial chemotherapy).

b. Chemotherapy. Started on the first day of radiotherapy and repeated during the last 3 days of radiation.

(1) Leucovorin 20 mg/m2 IV bolus followed by fluorouracil 400 mg/m2 IV bolus on the first 4 days and last 3 days of radiation therapy.

3. Postradiation chemotherapy. One month after completing chemo-radiation, repeat cycle 1 for two more cycles 1 month apart.

F. Follow-up studies

Reasonable follow-up studies for patients in remission after surgery consist of history and physical examination every 3 to 6 months for years 1 to 3, every 6 months for years 3 to 5, 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 chemotherapy may 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.

III. CANCER OF THE SMALL INTESTINE

A. Neuroendocrine tumors (NETs)

Carcinoid tumors are the most common NET of the small intestine, often found in 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. NETs tend to be less aggressive than adenocarcinomas of the small intestine. Negative prognostic findings generally include nodal metastases, high Ki67 index (>5%), high mitotic rate, presence of clinical symptoms, tumor size (>52 cm), and elevated chromogranin A or hormonally active tumor byproducts. Five-year OS approaches about 60%, which is worse than other GI NETs. Ileal NETs tend to be more invasive then appendiceal NETs. The most common sites of metastases include lymph nodes (89.8%), liver (44.1%), lung (13.6%), peritoneum (13.6%), and pancreas (6.8%), with adjacent organs being involved due to extensive fibrosis that is characteristic of this type of tumor (Table 7.3).

f0135-01

1. Carcinoid syndrome. About 10% of patients with NETs have car-cinoid syndrome, which includes diarrhea, abdominal cramps, malabsorption, flushing, bronchoconstriction, and cardiac valvu-lar disease (late sequela). Approximately 90% of patients present-ing with symptomatic NETs have metastatic disease to the liver, which may be under the level of detection of imaging. Serotonin is thought to be responsible for the abdominal symptoms. Its me-tabolite, 5-hydroxyindoleacetic acid (5-HIAA), is excreted in large quantities in the urine and is a useful marker of disease activity when measured over a 24-hour period. Other markers may be el-evated, including chromogranin A, which is the most frequently-elevated 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 kal-likrein (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 μ.g subcutaneously (SC) every 8 hours or as the long-acting formulation (octreotide LAR depot) 20 to 30 mg intramuscularly (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). A common issue with octreotide treatment is fat malabsorption and therefore the addition of pancreatic enzyme replacement may be warranted. The excretion of 5-HIAA is reduced by octreotide.

2. Treatment of advanced NETs

a. Effective agents. A recent large double-blind, randomized, phase IIIB German study (PROMID) treated patients with midgut NET either with octreotide LAR 30 mg IM every 4 weeks or pla-cebo as first-line therapy. Median time to tumor progression was improved with octreotide treatment (14.3 months versus 6 months; HR 0.34; p = 0.00007). This effect persisted whether or not the tumor was active (i.e., presence of carcinoid syndrome). Of note, 95% of these patients had Ki67 indexes of less than 2% and the majority had liver tumor burden of less than or equal to 10%, which appeared to be an important prognostic factor in subset analyses. The median OS was approximately 73.7 months in the placebo group and had not been reached in the octreotide LAR group; conclusions could not be drawn given the limited number of deaths observed during the study.

(1) Octreotide monotherapy. Octreotide LAR is dosed as 20 to 30 mg IM every 14 to 28 days. Consider run-in and overlap of approximately 2 weeks with octreotide acetate 150 ug SC three times a day to assess tolerability with a short-acting agent and then to allow the LAR to reach steady state. This can be continued despite progression with additional second-line agents.

The chemotherapy agents doxorubicin, fluorouracil, dacarbazine, and streptozocin have been shown to have limited activity in this disease. ECOG E1281 randomized 249 patients with advanced carcinoid to either fluorouracil plus doxorubicin or fluorouracil plus streptozocin and found comparable response rates (16%) and progression-free survival (approximately 5 months), but they reported a significant improvement in median OS for the streptozocin group (24.3 months versus 15.7 months; p = 0.02). Of note, crossover to dacarbazine yielded an 8% response rate and median OS of11.9 months. The following regimens were used.

(2) Streptozocin plus fluorouracil

(a) Streptozocin 500 mg/m2/day by rapid push IV on days 1 to 5.

(b) Fluorouracil 400 mg/m2/day IV on days 1 to 5 and 36 to 40. This regimen was repeated every 10 weeks.

(3) Dacarbazine. Dacarbazine 250 mg/m2/day by rapid push IV on days 1 to 5. This regimen was repeated every 4 weeks.

(4) Interferon-α 3 to 6 × 106 U/day or 10 × 106 U three times per week.

Targeted agents have shown promise in NETs. Some reports have indicated responses with interferon-α, including responses in combination with octreotide and in some patients previously treated with chemotherapy. A recent phase III study demonstrated no statistical difference in interferon-a versus the combination of streptozocin and fluorouracil.

(5) Sunitinib 50 mg orally daily for 4 weeks with a 2-week break (6-week cycles) was found to have activity in carcinoid tumors with a 10.2-month median time to progression.

(6) Other active agents, including bevacizumab 15 mg/kg IV every 3 weeks, showed improved progression-free survival over pegylated interferon-α-2b 0.5 mcg/kg SC every week in combination with depot octreotide in a phase II Southwest Oncology Group (SWOG) study. There is currently a phase III SWOG study (S0518) comparing bevaci-zumab to interferon therapy.

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 NETs or small-cell/atypical lung carcinoids are managed with a small-cell lung cancer regimen.

b. 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 7.4). 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., oxaliplatin, irinotecan, fluorouracil, and leucovorin) also are generally used to treat patients with small intestine adenocarcinoma.

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% to 50% in nonirradiated patients). About half of large-bowel cancer recurrences are in the liver.

f0138-01

1. Staging. In the past, a commonly used staging system was the Dukes staging system, including the Astler-Coller modifications. TNM staging for colorectal cancer (Table 7.5) is currently the recommended system. The seventh edition of the American Joint Committee on Cancer Staging Manual modified the stage II, stage III, and stage IV disease groups by expanding the definitions of T4, N status, and M status to more accurately reflect the wide variations in survival. For example, using the Surveillance, Epidemiology and End Results database, 5-year observed survival for T4N0 patients varies by over 10% if there is a distinctionbetween penetrating to the visceral peritoneum from invading (T4a) or adhering to adjacent structures (T4b). The same is true when N1 and N2 staging is further subclassified as one involved lymph node (N1a), one to three involved lymph nodes (N1b), four to six involved lymph nodes (N2a), and finally seven or more involved lymph nodes (N2b). In addition, tumor deposits separate but adjacent to the primary tumor without evidence of lymph node tissue is N1c staging. Metastatic disease is further classified into solitary metastasis (M1a) or more than one metastasis, given the data indicating approximately 20% of patients who undergo liver resection for their metastatic colorectal cancer are disease-free at 5 years. 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) as well as those with metastatic disease that may still derive long-term benefit from surgical or interventional procedures. 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 occur rather late in the course of the disease. PET scanning is considered to determine the presence of metastatic disease.

f0139-01

2. Serum CEA. CEA level may parallel disease activity, although it is not increased in all patients with colon cancer. It is worth measuring 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, PET, and possibly laparoscopy because some patients may have isolated, resectable, and thus potentially curable metastases, particularly involving the liver.

B. Treatment of advanced disease

1. 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 radiotherapeu-tic control. Response rates have varied widely, but a generally agreed-on figure is 10% to 15%. Fluorouracil with leucovorin and bevacizumab also has activity with a median OS of 18.3 months and progression-free survival of 8.8 months.

a. Fluorouracil plus high-dose leucovorin (weekly Roswell-Park regimen)

(1) Leucovorin 500 mg/m2 IV given over 2 hours.

(2) 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 fluorouracil plus leucovorin combination.

b. Fluorouracil bolus weekly regimen. Leucovorin 20 mg/m2 IV over 2 hours followed by fluorouracil 500 mg/m2 IV bolus injection 1 hour after leucovorin is started. Repeat weekly.

c. Fluorouracil by 24-hour continuous infusion. Fluorouracil 2600 mg/m2 is given by 24-hour continuous infusion IV weekly plus leucovorin at 500 mg/m2.

d. Simplified biweekly infusional 5-fluorouracil/leucovorin (sLV5FU2)

(1) Leucovorin 400 mg/m2 as a 2-hour IVinfusion, followed by fluorouracil.

(2) Fluorouracil 400 mg/m2 IVbolus on day 1 only, then followed by fluorouracil 2.4 g/m2 as a continuous IV infusion over 46 to 48 hours. This regimen is repeated every 2 weeks.

Chemotherapy combinations with fluorouracil, including leucovorin, irinotecan, and oxaliplatin have demonstrated equal efficacy in both first-and second-line roles. The addition of the antivascular endothelial growth factor monoclonal antibody bevacizumab to chemotherapy as well as the use of anti-EGFR monoclonal antibodies cetuximab and panitumumab in patients who are KRAS wild-type alone or with chemotherapy has further improved response rates and survival even further to beyond 2 years. Irinotecan can be used in combination with fluorouracil or alone with or without a monoclonal antibody added. Oxaliplatin does not have efficacy in colorectal cancer without fluorouracil. Capecitabine has been shown to be noninferior to fluorouracil and therefore can be used on its own or in combination, although it should be noted that folinic acid, fluorouracil, and irinotecan (FOLFIRI) has been shown to be superior to capecitabine and irinotecan in a large phase III study (BICC-C trial), so this combination is not recommended. The fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) regimen as a first-line regimen may improve response rates and survival (compared to FOLFIRI) at the cost of increased toxicity, but only one or two studies confirmed these efficacy results. The combination of bevacizumab with cetuximab or panitumumab in addition to chemotherapy in first-line therapy (CAIRO2 and PACCE studies, respectively) showed significant worsening of progression free survival as well as increased toxicity. Therefore, this combination is not currently recommended. Lastly, the BRiTE study, which was a large observational cohort design, indicated a potential improved OS with continuation of bevacizumab beyond progression of first-line therapy (19.9 months versus 31.8 months; p 0.001), but its continuation remains controversial with clinical trials currently assessing this strategy.

e. FOLFIRI

(1) Irinotecan 180 mg/m2 IV over 30 to 90 minutes on day 1.

(2) Fluorouracil 400 mg/m2 IV bolus on day 1.

(3) Leucovorin 400 mg/m2 IV over 30 to 90 minutes on day 1, followed by fluorouracil.

(4) Fluorouracil 2.4 g/m2 as a continuous infusion over 46 to 48 hours. The cycle is repeated every 2 weeks.

f. Irinotecan. Irinotecan 125 mg/m2 as a 90-minute infusion IV is given weekly for 2 weeks with a 1-week rest or 180 mg/m2 every 2 weeks or 300 to 350 mg/m2 every 3 weeks.

g. Modified FOLFOX6 (mFOLFOX6)

(1) Oxaliplatin 85 mg/m2 as a 120-minute infusion IV in 500 mL of 5% dextrose in water (D5W) on day 1.

(2) Leucovorin 400 mg/m2 as a 120-minute infusion IV, followed by fluorouracil.

(3) Fluorouracil 400 mg/m2 IVbolus on day 1.

(4) Fluorouracil 2.4 g/m2 as a continuous infusion IV over 46 to 48 hours.

The cycle is repeated every 14 days. Day 1 leucovorin may be given during the same 2-hour period as the oxali-platin, but because of the incompatibility of oxaliplatin with saline, both drugs must be in D5W.

h. FOLFOX4

(1) Oxaliplatin 85 mg/m2 as a 2-hour infusion IVin 250 to 500 mL ofD5W on day 1 only simultaneously with leucovorin.

(2) Leucovorin 200 mg/m2 as a 2-hour infusion IV on days 1 and 2, followed by fluorouracil.

(3) Fluorouracil 400 mg/m2 IVbolus on day 1 then fluorouracil 600 mg/m2 as a 22-hour infusion given on days 1 and 2 every 14 days.

mFOLFOX6 is the preferred oxaliplatin-containing regimen.

i. Capecitabine. Capecitabine is dosed at 1000 to 1250 mg/m2 administered twice daily orally on days 1 to 14 every 3 weeks (2000–2500 mg/m2/day). In areas of the world, including the United States, where food is heavily fortified with folates, the lower dose of capecitabine has been shown to be better tolerated.

j. Capecitabine plus oxaliplatin (XELOX)

(1) Oxaliplatin 130mg/m2IVday1.

(2) Capecitabine 850to 1000mg/m2bymouthtwiceadayfor 14 days every 21 days. Again, the capecitabine dose of 1000 mg/m2 is considered standard in Europe, but North American patients, likely due to higher dietary folate intake, have experienced greater toxicity with this starting dose and therefore are recommended to start with the lower 850 mg/m2 dosing.

k. FOLFOXIRI

(1) Irinotecan 165 mg/m2 IV on day 1.

(2) Oxaliplatin 85 mg/m2 IV on day 1.

(3) Leucovorin 400 mg/m2 IV on day 1.

(4) Fluorouracil 3200 mg/m2 over 48-hour continuous infusion starting on day 1. Repeat this regimen every 2 weeks.

l. Bevacizumab. Bevacizumab 5 mg/kg IV over 90 minutes (first cycle), 60 minutes (second cycle), then up to 0.5 mg/kg/minute for each subsequent cycle every other week given with FOLFOX, FOLFIRI, or sLV5FU2. Bevacizumab can be used with XELOX, but the dose of 7.5 mg/kg IV every 3 weeks is recommended. Please note that the practitioner should exercise extreme caution in patients with severe bleeding or clotting issues, active coronary artery disease, or severely uncontrolled hypertension.

m. Cetuximab 400 mg/m2 IV first infusion given over 2 hours, then 250 mg/m2 weekly or 500 mg/m2 IV every 2 weeks. This can be used alone or in combination with the listed chemotherapy regimens.

n. Panitumumab 6 mg/kg IV over 60 minutes every 2 weeks. The U.S. Food and Drug Administration has approved the use of panitumumab, another anti-EGFR monoclonal antibody, for use as a monotherapy in refractory patients with response rates of 10%, stable disease in 27%, and a 4-month improvement in progression-free survival compared to best supportive care.

Please note that only patients with KRAS wild-type mu-tational status derive benefit from these anti-EGFR monoclonal antibodies. It is also important to note that patients can get an acneiform rash that should be managed aggressively to prevent delays in therapy.

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, bevacizumab, and anti-EGFR monoclonal antibodies (KRAS wild-type only), over the course of their illness will achieve the maximum survival advantage, now estimated as a median survival of over 2 years.

C. Adjuvant chemotherapy

1. 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 survival (DFS) as well as the OS of patients. The recent update of the MOSAIC trial, which evaluated FOLFOX4 versus sLV5FU2 for Stage II/III colon cancer patients, found significant improvement in DFS and OS, but there was no significant difference in the subgroup of stage II colorectal cancer. In addition, the National Surgical Adjuvant Breast and Bowel Project (NSABP) trial evaluating a bolus regimen of oxaliplatin compared to weekly fluorouracil and leucovorin produced comparable 3-year DFS statistics as seen with MOSAIC for stage II and III patients, favoring the FLO regimen. Of note, increased GI toxicity has somewhat limited the use of this regimen. QUASAR has been the only large study to measure a difference in survival with adjuvant treatment for stage II colon cancer with an absolute improvement of 3.6%. Current NCCN and American Society of Clinical Oncology guidelines for high-risk stage II patients (based on clinical and histopathologic data) suggest a detailed discussion between the oncologist and patient as to the risk versus the benefit of receiving adjuvant chemotherapy for stage II disease. A current GI intergroup trial will define risk for stage II patients based on molecular markers including 18q allele deletion and microsat-ellite instability.

Two large 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 DFS 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 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 stage III colon cancer patients. The addition of bevacizumab has only shown transient benefit in DFS in a recent NSABP trial and did not reach its primary endpoint of DFS in the AVANT study.

Although historic 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.

a. Fluorouracil plus high-dose leucovorin (weekly Roswell Park regimen) as in Section IV.B.1.a. This is given for four cycles.

b. sLV5FU2. See Section IV.B.1.d. Twelve cycles are administered.

c. Capecitabine. See Section IV.B.1.i. Eight cycles are administered.

d. mFOLFOX6. See Section IV.B.1.g. Twelve cycles are administered.

e. FOLFOX4. See Section IV.B.1.h. Twelve cycles are administered.

f. FLO

(1) Oxaliplatin 85 mg/m2 as a 120-minute infusion IV on weeks 1, 2, and 5 of each 8-week cycle.

(2) Fluorouracil 500 mg/m2 IV bolus weekly for 6 weeks.

(3) Leucovorin 500 mg/m2 IV bolus weekly for 6 weeks. There are three 8-week cycles administered (total of 6 months).

2. Resected hepatic metastases. Past data have demonstrated that ap-proximately25% ofpatients with completely resected hepatic metastases secondary to colorectal cancer experience a long-term survival with more recent data approaching 50%. The goal of chemotherapy in patients with liver-only metastatic disease that is deemed unresectable is to convert them to a resectable status, called “conversion therapy!”; Because even a few cycles of chemotherapy can cause liver damage, the goal is to balance optimal response with that toxicity. Generally, patients receive 2 to 4 months of chemotherapy neoad-juvantly followed postoperatively with chemotherapy for a goal of approximately 6 months total if there is no evidence of residual disease. Bevacizumab can interfere with wound healing and therefore requires discontinuation 4 to 8 weeks prior to surgery.

3. Rectal cancer

a. Preoperative chemoradiation is the standard of care for patients with stage II and III rectal cancer. The NSABP R-03 showed prospectively, even though it was underpowered, that preop-erative chemoradiation improved DFS with a trend toward OS compared to postoperative chemoradiation. In addition, a German group showed improved locoregional control (without survival advantage) with preoperative compared to postoperative chemoradiation, and showed significant worse acute and long-term toxic effects with postoperative chemo-radiation. Currently, preoperative chemoradiation employing any of the following regimens is acceptable.

(1) Fluorouracil 225 mg/m2 dailyas a continuous infusion on the days of radiation. This regimen has become a standard in the United States and Europe.

(2) Capecitabine 825 mg/m2 bymouth twice daily on the days of radiation. This regimen is being compared to fluorouracil in the neoadjuvant setting in a large ECOG study, but given the noninferiority in the metastatic setting, this is acceptable.

(3) Fluorouracil 400 mg/m2 IV bolus plus leucovorin 20 mg/ m2 IV bolus for 4 days during week 1 and week 5.

b. Postoperative chemotherapy. The European Organization for Research and Treatment of Cancer 22921 trial showed nonsig-nificant trends with adjuvant chemotherapy toward improved PFS and OS (p = 0.15 and p = 0.12, respectively). In a later subset analysis of patients who were downstaged from neoadju-vant therapy (cT3-T4 to pT0-T2), adjuvant chemotherapy was shown to improve OS and DFS. New adjuvant chemotherapy trials ( for patients who receive preoperative chemoradiation) are investigating the use of FOLFOX with or without bevaci-zumab. Based on the MOSAIC trial, the addition of oxaliplatin to fluorouracil and leucovorin may be a reasonable strategy for adjuvant chemotherapy in rectal cancer.

The recommended postoperative adjuvant regimen for stage II or III rectal cancers is as follows.

(1) sLV5FU2 (see Section IV.B.1.d).

(2) Fluorouracil bolus weekly regimen (see Section IV.B.1.b).

If the patient did not receive neoadjuvant therapy, then the following regimens are recommended for adjuvant therapy:

(1) Fluorouracil plus high-dose leucovorin (weekly Roswell Park regimen), as described in Section IV.B.1.a. This regimen is given for one cycle prior to chemoradiation and then two cycles after completion of chemoradiation (see Section IV.C.3.a.1–3).

(2) mFOLFOX6, as described in Section IV.C.1.d.

(3) Capecitabine, as describedin Section IV.C.1.c.

D. Follow-up

A pooled analysis of clinical trials suggests that 85% of colorectal cancer recurrences will occur within 3 years. In the asymptomatic patient, follow-up after treatment includes history and physical examination, and CEA every 3 to 6 months for 2 years, then every 6 months for 5 years. Colonoscopy often is performed 1 year after surgery and then every 3 years if no polyps are found. CT scans of the chest, abdomen, and pelvis may be considered yearly for 3 years for patients at high risk for recurrence (i.e., lymphovascular invasion or poorly differentiated tumors).

E. Complications of therapy or disease

The complications of chemotherapy are those attributable to the in-dividual 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 is useful in treating dysuria, and loperamide or diphenoxylate 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 fluorouracil-based 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 hydration IV may be necessary. Tincture of opium or octreotide 150 jxg three times a day 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, de-hydration, neutropenia, fever, and electrolyte abnormalities. Patients receiving irinotecan should undergo weekly assessment, at least during the first cycle, to look 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 diarrhea-free or at baseline bowel function for at least 24 hours without 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 dysesthesias or paresthesias and a chronic sensory neuropathy. Potential bevacizumab toxicities include hypertension, bleeding, delayed wound healing, arterial thrombosis, proteinuria, and GI perforation. There is also a vascular syndrome, which can include myocardial infarction, pulmonary embolus, or cerebral vascular ac-cident. Cetuximab is associated with acneiform rash, hypersensi-tivity, 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 about a 50% cure rate. Major associations include a human papillomavirus infection; past receptive anal intercourse or sexually transmitted infection; past cervical, vulvar, or vaginal cancer; immunosuppression after solid organ transplantation; a human immuno-deficiency virus infection; and smoking.

A. Local disease (Table 7.6)

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

1. Radiotherapy 4500 cGy in 25 fractions (5 weeks), concurrent with fluorouracil and mitomycin.

2. Fluorouracil 1000 mg/m2 by continuous infusion IV daily for 4 days (days 1 to 4 and 29 to 32).

3.Mitomycin 10 mg/m2 IV on days 1 and 29.

f0148-01

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 1000 mg/m2 by continuous infusion IV 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 the following.

1. Cisplatin 75 mg/m2 IV on days 1, 29, 57, and 85.

2. Fluorouracil 1000 mg/m2 by continuous infusion IV on days 1 to 4, 29 to 32, 57 to 60, and 85 to 88.

3. Radiation 45 to 59 Gy, starting day 57.

Five-year DFS and OS were not statistically different (DFS, mitomycin-based 54% versus cisplatin-based 60%; p = 0.17; OS, mitomycin-based 75% versus cisplatin-based 70%; p = 0.10), but the cumulative colostomy rate was decreased with mitomycin-based therapy (10% versus 19%; p = 0.02).

B. Metastatic disease

For metastatic disease, the following regimen may be considered.

1. Fluorouracil 1000 mg/m2/day IV continuously on days 1 to 5.

2. Cisplatin 100 mg/m2 IV on day 2. Repeat this regimen every 4 weeks.

Cetuximab is currently under investigation in this disease.

Selected Readings

American Joint Committee on Cancer. AJCC cancer staging manual (7th ed.). New York: Springer; 2010.

National Comprehensive Cancer Network. NCCN guidelines and derivative information products: user guide. Retrieved from http://www.nccn.org/clinical.asp

Esophagus

Allum WH, Stenning SP, Bancewicz J. Long-term results of a randomized trial of surgery with or without preoperative chemotherapy in esophageal cancer. J Clin Oncol. 2009;27:5062–5067.

Cooper JS, Guo MD, Herskovic A, et al. Chemoradiotherapy of locally advanced esophageal cancer: long-term follow-up of a prospective randomized trial (RTOG 85-01). Radiation Therapy Oncology Group. JAMA.1999;281:1623–1627.

Urschel JD, Vasan H. A meta-analysis of randomized controlled trials that compared neo-adjuvant chemo-radiation and surgery to surgery alone for resectable esophageal cancer. Am J Surg. 2003;185:538–543.

Stomach

Cunningham D, Allum WH, Stenning SP, et al. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med. 2006;355:11–20.

Hartgrink HH, van de Velde CJ, Putter H, et al. Extended lymph node dissection for gastric cancer: who may benefit? Final results of the randomized Dutch gastric cancer group trial. J Clin Oncol.2004;22:2069–2077.

Macdonald JS, Smalley SR, Benedetti J, et al. Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. N Engl J Med. 2001;345:725–730.

Van Cutsem E, Kang Y, Chung H, et al. Efficacy results from the ToGA trial: A phase III study of trastuzumab added to standard chemotherapy (CT) in first-line human epidermal growth factor receptor 2 (HER2)-positive advanced gastric cancer (GC). J Clin Oncol. 2009;27:18s.

Van Cutsem E, Moiseyenko VM, Tjulandin S, et al. Phase III study of docetaxel and cisplatin plus fluorouracil compared with cisplatin and fluorouracil as first-line therapy for advanced gastric cancer: a report of the V325 Study Group. J Clin Oncol. 2006;24:4991–4997.

Waters JS, Norman A, Cunningham D, et al. Long-term survival after epirubicin, cis-platin and fluorouracil for gastric cancer: results of a randomized trial. 2009 ASCO Annual Meeting, abstract #LBA4509. Br J Cancer.1999;80:269–272.

Small Intestine

Panzuto F, Di Fondo M, Iannicelli E, et al. Long-term clinical outcome of somatostatin analogues for treatment of progressive, metastatic, well-differentiated entero-pancreatic endocrine carcinoma. Ann Oncol. 2006;17:461–466.

Rinke A, Muller HH, Schade-Brittinger C, et al. Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMID study group. J Clin Oncol. 2009;27:4656–4663.

Large Intestine

Andre T, Boni C, Navarro M, et al. Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial. J Clin Oncol.2009;27:3109–3116.

Collette L, Bossett JF, den Dulk M, et al. Patients with curative resection of cT3-4 rectal cancer after preoperative radiotherapy or radiochemotherapy: does anyone benefit from adjuvant fluorouracil-based therapy? A trial of the European Organisation for Research and Treatment of Cancer Radiation Oncology Group. J Clin Oncol. 2007;25:4379–4386.

Grothey A, Sugrue MM, Purdie DM, et al. Bevacizumab beyond first progression is associated with prolonged overall survival in metastatic colorectal cancer: results from a large observational cohort study (BRiTE). J Clin Oncol.2008;26: 5326–5334.

Roh MS, Colangelo LH, O'Connell MJ, et al. Preoperative multimodality therapy improves disease-free survival in patients with carcinoma of the rectum: NSABP R-03. J Clin Oncol. 2009;27:5124–5130.

Tournigand C, Andre T, Achille E, et al. FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol. 2004;22:229–237.

QUASAR Collaborative Group, Gray R, Barnwell J, et al. Adjuvant chemotherapy versus observation in patients with colorectal cancer: a randomized study. Lancet. 2007;370:2020–2029.

Van Cutsem E, Nowacki E, Lang I, et al. The CRYSTAL trial: efficacy and safety of irinotecan and 5-FU/LV with and without cetuximab in the first-line treatment of metastatic colorectal cancer. 2007 ASCO Annual Meeting Proceedings Part 1. J Clin Oncol. 2007;25(18S):4000.

Van Cutsem E, Peeters M, Siena S. Open label phase HI trial of panitumumab plus best supportive care versus best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol.2007;25:1658–1664.

Amis

Ajani JA, Winter KA Gunderson LL, et al. Fluorouracil, mitomycin, and radiotherapy vs fluorouracil, cisplatin, and radiotherapy for carcinoma of the anal canal: a ran domized controlled trial. JAMA2008;299:1914–1921.