Improved Outcomes in Colon and Rectal Surgery part 32 pot

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J Clin Oncol 2008; 26(29): 4828–33. 150. Blalock A. Recent Advances in Surgery. N Engl J Med 1944; 231: 261–7. 151. Girard P, Ducreux M, Baldeyrou P, et al. Surgery for lung metastases from colorectal cancer: analysis of prognostic factors. J Clin Oncol 1996; 14(7): 2047–53. 152. Headrick JR, Miller DL, Nagorney DM, et al. Surgical treatment of hepatic and pulmonary metastases from colon cancer. Ann Thorac Surg 2001; 71(3): 975–9. 153. Labow DM, Buell JE, Yoshida A, et al. Isolated pulmonary recurrence after resection of colorectal hepatic metastases– is resection indicated? Cancer J 2002; 8(4): 342–7. 154. McAfee MK, Allen MS, Trastek VF, et al. Colorectal lung metastases: results of surgical excision. Ann Thorac Surg 1992; 53(5): 780–5. 155. Colice GL, Shafazand S, Griffin JP, et al. Physiologic evaluation of the patient with lung cancer being considered for resectional surgery: ACCP evidenced-based clinical practice guidelines (2nd edition). Chest 2007; 132(3 Suppl): 161S–77S. 156. Ginsberg RJ, Rubinstein LV. Randomized trial of lobec- tomy versus limited resection for T1 N0 non-small cell lung cancer. Lung Cancer Study Group. Ann Thorac Surg 1995; 60(3): 615–22. 157. Saito Y, Omiya H, Kohno K, et al. Pulmonary metastasectomy for 165 patients with colorectal carcinoma: A prognostic assess- ment. J Thorac Cardiovasc Surg 2002; 124(5): 1007–13. 158. Irshad K, Ahmad F, Morin JE, et al. Pulmonary metastases from colorectal cancer: 25 years of experience. Can J Surg 2001; 44(3): 217–21. 159. Hendriks JM, van Putte B, Romjin S, et al. Pneumonectomy for lung metastases: report of ten cases. Thorac Cardiovasc Surg 2003; 51(1): 38–41. 160. Koong HN, Pastorino U, Ginsberg RJ. Is there a role for pneumonectomy in pulmonary metastases? International Registry of Lung Metastases. Ann Thorac Surg 1999; 68(6): 2039–43.  29 Chemotherapy for colon and rectal cancer Liliana Bordeianou and Judith L Trudel CHALLENGING CASE A 56-year-old man presented with a 5 cm rectal cancer. It was located posteriorally at 8 cm from the anal verge. The preop ultrasound suggested a T3N1 tumor. The patient received preoperative chemoradiotherapy. He had a superb clinical response with tumor shrinkage. Six weeks after completing the therapy, the patient underwent a low anterior resection with a diverting loop ileostomy. The final pathology was a T1N0 with five negative lymph nodes identified. All margins were negative. Should the patient receive postoperative chemotherapy? CASE MANAGEMENT There is little data on which to base this clinical decision. Most practioneers lean toward recommendations for postoptherapy based on the pretreatment clinical stage if the patient receives neoadjuvant therapy. In a good risk patient, most would recom- mend 6 months of postoperative adjuvant chemotherapy. INTRODUCTION Colorectal cancer (CRC) is the third most common cancer diag- nosed in men and women in the United States. Approximately 148,810 new cases of colon and rectal cancer were reported in 2007, with an estimated 49,960 deaths attributed to it.(1) This is higher than the number of deaths attributed to pancreatic cancer, liver and intrahepatic bile duct cancer or esophageal cancer. While surgery remains the mainstay of treatment for this common disease, it is the recent noteworthy changes in the indications for chemotherapy, the timing strategy as far as chemotherapy administration and the actual therapeutic regimens used to treat advanced colon and rectum cancers that may provide the next step toward the improvement in the survival rates of these patients. CHEMOTHERAPY AGENTS OR COMBINATIONS MOST COMMONLY USED AGAINST COLORECTAL CANCER 5-FU with Either Leucovorin or Levamisole Since its original use in the 1950s, 5-FU remains one the oldest chemotherapeutic agents used today to target colorectal cancer. 5-FU inhibits DNA synthesis via blockage of thymidylate synthase. At first used alone, and then in combination with levamisole, 5-FU/levamisole combination was noted to significantly decrease recurrence rates and improve overall survival, particularly in Dukes’C patients.(2) This observation was subsequently confirmed in a large study of 971 patients with stage III and IV disease (intergroup 0035) which in 1990 showed that this drug combination reduced the risk of cancer recurrence by 41% and the overall death by 33 % in this group of patients.(3) Given these results, this drug combination was regarded as gold standard therapy for CRC till 1996, when an even more effective regimen using 5-FU in combination with leucovorin (folinic acid) was described. Leucovorin is a 5-FU biomodulator. Leucovorin and 5-FU form a stable ternary complex with thymydylate synthetase, per- mitting prolonged inhibition of the enzyme by 5-FU. Its appli- cability to stage II and stage II disease was confirmed by the IMPACT (International Multicenter Pooled Analyses of Colon Cancer Trials) study of 1,526 patients in 1995, which showed that 5-FU/leucovorin increased the 3-year disease free survival from 62% to 71% while overall survival increased from 78% to 83%.(4) The NSAPB C-03 randomized trial of 1,081 stage II and stage III patients comparing MOF (semustine, vincristine and 5-FU) to 5-FU/leucovorin had documented a similar advantage of 5-FU/leucovorin, with a 3 year disease-free survival increase from 64% to 73% and an overall survival increase from 77% to 84%.(5) The relative merits of levamisole and leucovorin as modulators of 5-FU-based adjuvant chemotherapy, and the optimal duration of treatment were documented in several studies between 1998 and 2000. The NCCTG/NCIC (National Cancer Institute of Canada) study of 915 patients compared 6 months 5-FU/leucovorin; 6 months 5-FU/ leucovorin/levamisole; 1 year 5-FU/levamisole; and 1 year 5-FU/leucovorin/levamisole.(6) Triple therapy for 6 months was as effective as 12 months; and 6-month triple therapy provided superior 5-year overall survival and disease-free survival compared to 5-FU/levamisole.(6) The Intergroup trial 0089 of 3,759 patients compared 1 year 5-FU/levamisole; 5-FU/high-dose leucovorin for 32 weeks; 5-FU/ low-dose leucovorin for 6 cycles; and 5-FU/low-dose leucovorin/ levamisole for 6 cycles.(7) There were no differences between the four treatment arms with regards to 5-year disease-free and overall survival. The NSABP CO-4 study essentially confirmed these results. (8) The QUASAR Collaborative Group study confirmed the survival advantage provided by leucovorin modulation over levamisole.(9) Based on the results of these studies, the new standard for treatment was changed to 6 months of adjuvant chemotherapy with 5-FU/ leucovorin for stage III, node-positive disease. Until recently, this course of therapy was the standard of care for patients with advanced colorectal cancer. However, with increas- ing understanding of the molecular basis of cancer and the development of biologic-based therapy, chemotherapy for CRC has evolved once more and a variety of new agents are now available to treat this disease. Oxaliplatin-Containing Regimens (FOLFOX, XELOX) Oxaliplatin inhibits DNA replication through creation of bulky DNA adducts. It was first introduced to treat patients with recurrent or metastatic colorectal cancer that was otherwise unresectable. A study of 795 patients enrolled by Intergroup N9741 compared FOLFOX (oxaliplatin and infused fluorouracil plus leucovorin) to either IFL (irinotecan and bolus fluorouracil plus leucovorin) or IROX (irinotecan and oxaliplatin) to show that patients treated with FOLFOX had an increased median survival of 19.5 months (compared to 15 and 17.4 months in  chemotherapy for colon and rectal cancer the control arms) and an increased time to progression: 8.7 months as compared to 6.9 and 6.5 months in the two control arms.(10) Given the improved response rates with FOLFOX in metastatic disease, the MOSAIC trial of 2,246 patients compared this regimen to the standard 5-FU leucovorin regimen in the adjuvant setting of resected colon cancer. After a median follow-up of 56.2 months, the 3 year disease- free survival in the FOLFOX group was 76.4% (compared to 69.8% observed in 5-FU/leucovorin group).(11) On the strength of these results, FOLFOX is now the most popular first-line therapy for the adjuvant treatment of resected CRC and for metastatic CRC. In patients interested in avoiding IV infusions, the combination of capecitabine and oxaliplatin (XELOX) may be used. Capecitabine is the prodrug to 5-FU, and is administered orally. Irinotecan-Containing Regimens (FOLFIRI, IFL, IROX) Irinotecan inhibits DNA replication and transcription via topoisomeraze blockade. Irinotecan has been shown to have activity against CRC, though its effects are less pronounced than those of oxaliplatin. IFL therapy (5-FU, leucovorin and irinotecan) has been shown to be superior to 5FU/leucovorin therapy alone in patients with metastatic colorectal cancer.(12) However, the N9741 Intergroup trial described above showed that patients treated with FOLFOX had superior results to those treated with FOLFIRI (5-FU and irinotecan), or IROX(irinotecan and oxaliplatin).(10) Based on the results of this and other studies irinotecan containing combinations are now mostly used as second line therapy.(13) Bevacizumab (AVASTIN®) Bevacizumab (a monoclonal antibody that binds to the vascular endothelial growth factor (VEGF) ligand) is one of the first biologic therapy agents shown to be effective against CRC. Bevacizumab, which blocks angiogenesis, was first found to improve efficacy of FOLFOX alone in patients with metastatic disease: the median duration of survival for the group treated with FOLFOX and bevacizumab was 12.9 months compared with 10.8 months for the group treated with FOLFOX alone.(14, 15) Additional information on the feasibility and efficacy of bevacizumab in combination with FOLFOX or other oxaliplatin combinations was gleaned in the TREE-2 trial, where the percentages of patients with progressive disease decreased substantially in all arms when bevacizumab was added.(16) Cetuximab (ERBITUX®) Cetuximab (a monoclonal antibody blocking epidermal growth factor (EGFR) is currently approved only as therapy as a single agent or in combination with irinotecan for patients with previously treated advanced colorectal cancer. A number of recently published trials suggested that patients treated with cetuximab have a longer time to disease progression, and this effect is aug- mented with addition of bevacizumab.(17) INDICATIONS AND TIMING OF CHEMOTHERAPY FOR COLORECTAL CANCER Adjuvant Chemotherapy for Stage III and Stage IV Colon Cancer While surgical resection is the only curative treatment for local- ized colon cancer, the 5-year survival rates vary from 93% in the patients with Stage I disease to 44% in patients with Stage III disease (Table 29.1). For the patients who have undergone potentially curative resection, disease recurrence is thought to derive from clinically occult micrometastases. The goal of Table 29.1 American Joint Committee on Cancer (AJCC) colon cancer staging versus survival (37). Stage T Stage N Stage M Stage 5-year Survival I T1 (tumor invades submucosa) T2 (tumor invades muscularis propria) N0 (no regional lymph nodes metastasis) M0 (no evidence of distant metastasis) 93% IIA T3 (tumor invades through muscularis propria into subserosa or nonperitonealized pericolic tissues) N0 M0 85% IIB T4 (tumor directly invades into other organs and/or perforates visceral peritoneum) N0 M0 72% IIIA T1 T2 N1 (metastasis to 1–3 regional lymph nodes) M0 83% IIIB T3 T4 N1 M0 64% IIIC Any T N2 (metastasis to four or more regional lymph nodes) M0 44% IV Any T Any N M1 (distant metastasis) 8% 2 improved outcomes in colon and rectal surgery postoperative (adjuvant) chemotherapy is to eradicate these micrometastases. Adjuvant chemotherapy for colon cancer has been studied for at least 40 years. Interestingly, 5-FU monotherapy did not improve 5-year survival following curative resection.(18) However, the discovery of modulators of 5-FU activity and of the effects of combination regimens on survival reignited the interest in adjuvant chemotherapy. The first large-scale trial to demonstrate a survival benefit for adjuvant chemotherapy in colon cancer, National Surgical Adjuvant Breast and Bowel project (NSABP) C-01 included 1,166 patients with Dukes’ B or C colon cancer.(19) The patients randomized to adjuvant MOF chemotherapy instead of surgery alone had significant improvement in their 5-year overall survival. These improvements became even more pronounced as advances in chemotherapy described earlier and postoperative (adjuvant) systemic therapy has become routine and standard for node positive or metastatic disease. Clinical data indicates that access to a multidrug regimen consisting of two or more of the agents discussed earlier (in addition to 5-FU therapy) has almost doubled median survival in the patients with advanced colorectal cancer from 10–12 months to more than 20 months. Adjuvant Chemotherapy for Stage II Colon Cancer In contrast to the clear benefit of adjuvant chemotherapy for patients with node-positive disease, its role in resected stage II colon cancer remains controversial. While a number of clinical trials have included stage II patients and have suggested a benefit from adjuvant therapy, none of these have reached statistical significance. Several meta- analyses have been performed to evaluate this question further. An NSABP analysis of the data pooled from the adjuvant C-01, C-02, C-03 and C-04 trials of 3,820 patients (1,556 with T3N0 disease) suggested that the relative reduction in recurrence and mortality from adjuvant therapy for patients with resected T3N0 colon cancer was comparable to that seen in patients with node-positive disease. (20) In contrast, a 2004 systematic review by the Ontario Cancer Care Program did not find a statistically significant improvement in survival in the T3N0 patients treated with at least one 5-FU chemotherapy regimen after surgery.(21) In hopes of settling this debate, a panel of the American Society of Clinical Oncology reviewed all the pertinent information in regards to this issue.(22) This panel con- cluded that routine use of adjuvant chemotherapy for medically fit patients with stage II colon cancer is not recommended. Parenthetically, the panel also felt that selected patients with stage II disease—such as patients with inadequately sampled nodes, T4 lesions, perforation, or poorly differentiated histology—could still be considered for adjuvant therapy.(22, 23) The identification of patients with stage II colon cancer who might benefit from adjuvant chemotherapy is an area of ongoing research. The prognostic value of additional molecular markers, such as microsatellite instability and loss of 18Q allele is being investigated. (http://cancer.gov). Neoadjuvant Chemoradiotherapy for T3 or Node-Positive Rectal Cancer The management of rectal cancer is radically different from the management of colon cancer. While recommendations for adjuvant postoperative therapy for advanced colon cancer are based on the pathological stage revealed by the surgical specimen, rectal cancer staging determines initial management. This, after much debate, is based on conclusive evidence that has clearly shown neoadjuvant preoperative therapy to improve local control, disease- free survival, and overall survival compared to surgery alone or to postoperative adjuvant therapy. The Swedish Rectal Cancer Trial examined whether neoadjuvant preoperative radiation therapy was of benefit to patients with advanced rectal cancer. The study randomly assigned 1,168 patients to receive or not receive radiation therapy prior to surgery. After 5 years, preoperative radiation therapy was associated with significant improvements in both local control (89% vs. 73%) and overall survival (58% vs. 48%).(24) The German Rectal Cancer Trial examined whether radiation is more beneficial before or after surgery. The study randomly assigned 823 patients with clinically staged T3/T4 or node-positive rectal cancer to either neoadjuvant or adjuvant chemoradiotherapy. With a 46 month median follow-up, preoperative chemoradiotherapy was associated with a significantly lower local recurrence rate (6% vs. 13%), though the 5-year disease-free and overall survival rates were similar.(25) These two studies made preoperative radiotherapy for advanced rectal cancer the standard of care. At least two randomized trials have directly assessed the potential benefits of concurrent chemotherapy with neoadjuvant radiotherapy. A European trial randomly assigned 762 patients with T3/4 rectal cancer within reach of the digital rectal exam to either preoperative radiotherapy alone or preoperative chemoradiotherapy. At a median 69 month follow-up, the combined modality group had lower local recurrence rates (8.1% vs. 16.5 %), but the rate of sphincter preservation surgery and 5-year overall survival rates were similar.(26) Another study, EORTC 22921 showed a similar benefit with chemoradiotherapy enhancing local control in comparison to radiotherapy alone.(27) Based on these studies, neoadjuvant chemoradiotherapy is generally considered in all patients with T3 N0 and node positive tumors of any T stage. Stage of the disease determines the need for neoadjuvant therapy. Because of this, the importance of pretreatment staging of rectal tumors becomes paramount and can- not be overemphasized. The standard of care now dictates that all patients with rectal cancer should undergo a staging endorec- tal ultrasound or pelvic MRI to determine initial management. Tumors penetrating into perirectal fat and/or lymph nodes should undergo neoadjuvant chemoradiotherapy. Tumors that do not penetrate through muscularis propria (T1-2, N0) are candidates for initial surgical resection. If the final pathological stage con- firms the stage suspected on imaging, no further chemotherapy (and/or radiation) is indicated. However, if the final pathology reveals penetration into perirectal fat or into the lymph nodes, postoperative chemoradiotherapy is indicated. Adjuvant Chemotherapy Alone for T3 or Node-Positive Rectal Cancer The benefit of 5-FU based postoperative chemotherapy in patients undergoing chemoradiotherapy has not been studied in prospective randomized trials. However, in EORTC trial 22921, patients who had received preoperative radiotherapy with or without chemotherapy were then further randomized to postoperative  chemotherapy for colon and rectal cancer chemotherapy versus no further therapy.(27) In the entire group, there were trends favoring adjuvant chemotherapy in both 5-year progression free survival (58% vs. 52%), and overall survival (67% vs. 63%), but the trends were not statistically significant, Nevertheless, these results are frequently quoted as justification of adjuvant chemotherapy for patients treated with or without preoperative chemoradiotherapy. Further information of the benefits of postoperative chemotherapy are expected from the multicentre British CHRONICLE trial.(28) SIDE EFFECTS OF CHEMOTHERAPY The benefits of modern chemotherapy with regards to its abil- ity to delay disease progression and improve survival in patients with advanced colon and rectal cancer are unquestionable. Nonetheless, these benefits should be balanced against individual patient tolerance to the side effects of chemotherapy (Table 29.2), as this may impact therapeutic effectiveness. The elderly and the medically compromised patients represent a group at particular risk. Very few elderly patients or patients with renal/hepatic failure or other major comorbidities have been enrolled in clinical trials; the choices of therapeutic regimens in these subgroups should be tailored to individual patients. 5-FU/leucovorin alone is fairly well tolerated, and the most commonly described side effects are those of diarrhea, stomatitis, vomiting and nasea. These side effects become much more pronounced when mutidrug chemotherapy regimens are used. For example, addition of oxaliplatin to 5-FU, which is the most common first line chemotherapy regimen currently used in the US to treat colorectal cancer (FOLFOX), leads to an increased rate of diarrhea, nausea and vomiting, as well as alopecia. In addition, the rates of significant neutropenia become relatively high. One of the clinically relevant side effect of oxaliplatin-based chemotherapy is a late-onset predominantly sensory neuropathy with may require drug discontinuation despite ongoing tumor response. Ultimately, more than 50 percent of patients receiving FOLFOX discontinue treatment for reasons other than disease progression.(29) Multidrug combinations adding irinotecan, or bevacizumab to the standard 5-FU can cause serious toxic events, mainly severe hematological toxicity, diarrhea, thrombotic events, and neu- rosensory disorders.(30) The 5-FU, leucovorin, irinotecan, plus bevacuzimab regimen especially, while having the highest proba- bility of improving survival, might also lead to significant adverse effects to as many as 84.9% of patients, including a 1.5% chance of gastrointestinal perforation.(30) While these side effects are temporary in patients undergoing adjuvant treatment for nonmetastatic disease, their effect on quality of life becomes quite important when the treatments are continuous and indefinite, as is the current practice in the patients with metastatic disease. One potential way of reducing treatment- related side effects in this cohort is via a “chemotherapy holiday”, but the impact of a completely chemo-free interval on long term survival is of significant concern. Two European phase II trials, OPTIMOX1 (which compared continuous FOLFOX versus maintenance chemotherapy with 5-FU/leucovorin) and OPTIMOX2 (which compared maintenance chemotherapy using a nonoxali- platin regimen versus a totally chemotherapy free interval) were designed to address some of these concerns.(31, 32) Their results unfortunately suggested that a full break in therapy resulted in a decrease in overall survival and that some form of maintenance treatment is preferable to chemotherapy-free intervals. FUTURE DIRECTIONS One of the major drawbacks of the current chemotherapy regimens for colorectal cancer is our inability to identify before treatment which patient will respond to a particular combination of chemotherapy drugs. Knowledge of tumor gene expression and other biomarkers will hopefully provide clues and inroads in this direction. Microarray proﬁling of gene expression in colorectal cancer patients has already been shown to stratify risk and predict lymph node involvement.(33) Just like in patients with breast cancer, patients with CRC might soon be screened in a prospective fashion to determine those with stage III disease that are unlikely to recur or those who may be resistant to a particular drug regimen. A promising area for colorectal cancer treatment is immunotherapy. The goal of cancer immmunotherapy is to stimulate the body’s immune system in order to improve host defense mecha- nisms against growing tumors, through either cell mediated or humoral immunity pathways. Over 25 different vaccines, virus- modified tumor cells, gene-modified tumor cells, tumor-antigen derived peptides, tumor lysates, proteins or carbohydrates have Table 29.2 Side Effects and Mechanism of Action of Commonly Used Chemotherapeutic Agents Chemotherapy Agent Mechanism of Action Common Side-Effects 5-FU Inhibits DNA synthesis via blockage of thymidylate synthase Heartburn, nausea, vomiting, anorexia, stomatitis, esophagitis, diarrhea, myelosuppression, cardiac toxicity Oxaliplatin Inhibits DNA replication through creation of bulky DNA adducts Peripheral neuropathy, anemia, thrombocytopenia, neutropenia, nausea, diarrhea, vomiting, abdominal pain, fatigue Irinotecan Inhibits DNA replication and transcription via topoisomeraze blockade Alopecia, diarrhea, nausea, emesis, severe myelosupression, colitis, gastrointestinal ulceration, gastrointestinal bleeding, ileus Bevacizumab (Avastin®) A monoclonal antibody that binds to the vascular endothelial growth factor (VEGF) ligand and inhibits tumor blood supply growth Alopecia, thrombosis, bleeding, hyperkalemia, hypertension, abdominal pain, anorexia, vomiting, diarrhea, neutropenia, delayed wound healing and wound dehiscence, bowel perforation Cetuximab (Erbitux®) A monoclonal antibody that blocks epidermal growth factor (EGFR) and decreases tumor growth Fatigue, confusion, pruritis, insomnia, abdominal pain, nausea, vomiting, diarrhea,weakness, lung disease, dyspepsia  improved outcomes in colon and rectal surgery been studied in Phase I and II studies. Three large studies look- ing at the immune stimulation with autologous irradiated tumor vaccine plus BCG in colorectal cancer patients suggest that this approach may have merits. For example, one study randomized 98 patients with colon or rectal cancer treated surgically to vaccination with autologous irradiated tumor plus BCG versus placebo. While the study did not find a significant difference in the outcomes between the two arms, a subset analysis of the colon cancer patients did show an improvement in disease-free survival.(34) Similarly, Eastern Cooperative Oncology Group (ECOG) randomized stage II and II colon cancer patients to surgery alone versus surgery and vaccine and found that patients with a marked delayed cutaneous hypersensitivity response had a trend toward better disease-free and overall survival.(35) Finally a study of 244 patients with colon cancer randomized to receive a postoperative vaccine showed that the overall risk for recurrence was decreased by 44% in all vacci- nated patients, with a 61% reduction in stage II patients.(36) CONCLUSION In the past 20 years, advances in the adjuvant treatment of colon and rectal cancer have significantly increased the rates of disease- free and overall survival, increased survival rates in metastatic disease, and decreased the rates of recurrence. Ongoing research focuses on developing more potent chemotherapeutic agents and on identifying patients who may best benefit from those advances. REFERENCES 1. Jemal A, Siegel R, Ward E et al. Cancer statistics, 2008. CA Cancer J Clin 2008; 58(2): 71–96. 2. Laurie JA, Moertel CG, Fleming TR et al. Surgical adjuvant therapy of large-bowel carcinoma: an evaluation of levamisole and the combination of levamisole and fluorouracil. The North Central Cancer Treatment Group and the Mayo Clinic. J Clin Oncol 1989; 7(10): 1447–56. 3. Moertel CG, Fleming TR, Macdonald JS et al. Levamisole and fluorouracil for adjuvant therapy of resected colon carcinoma. N Engl J Med 1990; 322(6): 352–8. 4. Efficacy of adjuvant fluorouracil and folinic acid in colon cancer. International Multicentre Pooled Analysis of Colon Cancer Trials (IMPACT) investigators. Lancet 1995; 345(8955): 939–44. 5. Wolmark N, Rockette H, Fisher B et al. 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J Am Coll Surg 2007; 205(3): 468–478. 14. Giantonio BJ, Levy DE, O’Dwyer PJ et al. A phase II study of high-dose bevacizumab in combination with irinotecan, 5-fluorouracil, leucovorin, as initial therapy for advanced colorectal cancer: results from the Eastern Cooperative Oncology Group study E2200. Ann Oncol 2006; 17(9): 1399–403. 15. Giantonio BJ, Catalano PJ, Meropol NJ et al. Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200. J Clin Oncol 2007; 25(12): 1539–44. 16. Hochster HS. Bevacizumab in combination with chemotherapy: first-line treatment of patients with metastatic colorectal cancer. Semin Oncol 2006; 33(5 Suppl 10): S8–14. 17. Saltz LB, Lenz HJ, Kindler HL et al. Randomized phase II trial of cetuximab, bevacizumab, and irinotecan compared with cetuximab and bevacizumab alone in irinotecan-refractory colorectal cancer: the BOND-2 study. J Clin Oncol 2007; 25(29): 4557–61. 18. Buyse M, Zeleniuch-Jacquotte A, Chalmers TC. Adjuvant therapy of colorectal cancer. Why we still don’t know. JAMA 1988; 259(24): 3571–78. 19. Smith RE, Colangelo L, Wieand HS, Begovic M, Wolmark N. Randomized trial of adjuvant therapy in colon carcinoma: 10-year results of NSABP protocol C-01. J Natl Cancer Inst 2004; 96(15): 1128–32. 20. Mamounas E, Wieand S, Wolmark N et al. Comparative efficacy of adjuvant chemotherapy in patients with Dukes’ B versus Dukes’ C colon cancer: results from four National Surgical Adjuvant Breast and Bowel Project adjuvant studies (C-01, C-02, C-03, and C-04). J Clin Oncol 1999; 17(5): 1349–55. 21. Figueredo A, Charette ML, Maroun J, Brouwers MC, Zuraw L. 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Preoperative radiotherapy with or without concurrent fluorouracil and leucovorin in T3-4 rectal cancers: results of FFCD 9203. J Clin Oncol 2006; 24(28): 4620–5. 27. Bosset JF, Calais G, Mineur L et al. Enhanced tumorocidal effect of chemotherapy with preoperative radiotherapy for rectal cancer: preliminary results–EORTC 22921. J Clin Oncol 2005; 23(24): 5620–7. 28. Glynne-Jones R, Meadows H, Wood W. Chemotherapy or no chemotherapy in clear margins after neoadjuvant chemo- radiation in locally advanced rectal cancer: CHRONICLE. A randomised phase III trial of control vs. capecitabine plus oxaliplatin. Clin Oncol (R Coll Radiol) 2007; 19(5): 327–9. 29. Seymour MT, Maughan TS, Ledermann JA et al. Different strategies of sequential and combination chemotherapy for patients with poor prognosis advanced colorectal cancer (MRC FOCUS): a randomised controlled trial. Lancet 2007; 370(9582): 143–52. 30. Hurwitz H, Fehrenbacher L, Novotny W et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004; 350(23): 2335–42. 31. Tournigand C, Cervantes A, Figer A et al. OPTIMOX1: a ran-OPTIMOX1: a randomized study of FOLFOX4 or FOLFOX7 with oxaliplatin in a stop-and-Go fashion in advanced colorectal cancer–a GERCOR study. J Clin Oncol 2006; 24(3): 394–400. 32. Andre T, Tournigand C, Mineur L et al. Phase II study of an optimized 5-fluorouracil-oxaliplatin strategy (OPTIMOX2) with celecoxib in metastatic colorectal cancer: a GERCOR study. Ann Oncol 2007; 18(1): 77–81. 33. Croner RS, Peters A, Brueckl WM et al. Microarray versus conventional prediction of lymph node metastasis in colorectal carcinoma. Cancer 2005; 104(2): 395–404. 34. Hoover HC Jr, Brandhorst JS, Peters LC et al. Adjuvant active specific immunotherapy for human colorectal cancer: 6.5- year median follow-up of a phase III prospectively randomized trial. J Clin Oncol 1993; 11(3): 390–9. 35. Harris JE, Ryan L, Hoover HC Jr. et al. Adjuvant active spe-Adjuvant active specific immunotherapy for stage II and III colon cancer with an autologous tumor cell vaccine: Eastern Cooperative Oncology Group Study E5283. J Clin Oncol 2000; 18(1): 148–57. 36. Vermorken JB, Claessen AM, van Tinteren H et al. Active spe-Active specific immunotherapy for stage II and stage III human colon cancer: a randomised trial. Lancet 1999; 353(9150): 345–50. 37. O’Connell JB, Maggard MA, Ko CY. Colon cancer survival rates with the new American Joint Committee on Cancer sixth edition staging. J Natl Cancer Inst 2004; 96(19): 1420–5.   Radiation therapy: Acute and late toxicity Roland Hawkins CHALLENGING CASE A 62-year-old man presents with blood per rectum. He has mild rectal discomfort with bowel movements and a feeling of incom- plete evacuation. Two years previously he received external beam radiotherapy for prostate cancer. His rectal examination is normal except for some blood on the gloved finger. A flexible sigmoidos- copy demonstrates friable mucosa with neovascularity of the distal 4 cm of rectum. The mucosa is friable with telangectasia. CHALLENGING CASE MANAGEMENT The history and endoscopic exam is suggestive of radiation proctitis. Management includes fiber and topical therapy. The friable areas of the rectum can be treated with topical application of a large swab soaked with 10% formalin passed through an anoscope or proctos- cope. Argon plasma coagulation is also effective treatment. INTRODUCTION Apart from a few exceptional circumstances, radiation treatment is used as an adjunct to surgical resection in the potentially curative treatment of adenocarcinoma of the rectum. As such, it is employed to reduce the tumor burden and eradicate deposits of cancer in pelvic lymph nodes and soft tissue not removed, or not expected to be removed, by the surgeon. In this setting, radiation treatment is administered either before or following en bloc resection of the involved length of large bowel by low anterior (LAR) or abdominal perineal resection (APR) that is intended to remove all evident disease, i.e., to be an R0 resection. Preoperative treatment is referred to as neoadjuvant or adjuvant, and postoperative treatment as adjuvant. These are usually administered to patients with locally advanced but resectable stage II or III disease (Table 30.1). Less often adjuvant radiation treatment is administered following local excision of less advanced disease. Local excision is elected in patients with small distal rectal tumors to avoid APR or LAR. Recurrence after apparently curative surgery for rectal cancer may develop in structures adjacent to the margin of resection or regional nodes in the pelvis (local recurrence), or as metastasis to the peritoneal surface or distant organs (distant recurrence). Treatment with radiation and/or chemotherapy added to surgery is judged as beneficial in so far as it increases overall patient survival and reduces the incidence of local and distant recurrence. Overall survival is the most important outcome in judging benefit. It is unambiguously evaluable and reflects the balance of benefit and potentially lethal adverse effects of treatment. Local recurrence is not often salvagable. Its prevention is important, if not a requirement, for achieving cure of the disease. It may itself be life threatening and may act as a source of distant metastasis. Further, uncontrolled recurrence in the pelvis is particularly det- rimental to the quality of life of patients who are not cured by the treatment by causing pain, bleeding, infection, obstruction and incontinence affecting bowel and urogenital organs. Distant recurrence is important because it is the most unsalvageable life threatening form of treatment failure. Evolution of the method of radiation treatment over the past 30 years has produced what are now two more or less standard regimens, referred to here as the short and long treatment courses. The short course has been used only for preoperative treatment. It typically consists of a dose of 25 Gy in fractions of 5 Gy each over a period of 5 to 7 days with surgery following within a week. The long course has been used for both pre and postoperative treatment. It typically consists of 45 to 54 Gy in fractions of 1.8 to 2 Gy over a period of 5 to 6 weeks. When used preoperatively the long course is usually followed by about 6 weeks rest before surgery and may include concurrent chemotherapy. There are several ways to compare the intensity of radiation treatment courses that differ in fractionation of dose and are given over different time intervals. One in current use consists of calculating a biologically equivalent dose (BED) for each treatment course using the relation: (1) BED = nd  1 + d a/b  - g a (T - T k ) Wherein n is the number of fractions, d is the dose per fraction, a/b is a ratio characteristic of cell type or tissue and ranging from about 2 to 20 or more. For meta-analysis overview of the effect of radiation in the treatment of rectal cancer a/b has been assumed to be about 10.(2, 3) The value of the g/a ratio corrects for the repopulation of cells during the length of the treatment course and has been assumed to be 0.6 Gy per day. The value of T is the time from first to last radiation fraction in days and T k is a lag time taken to be 7 days. With these parameters the BED of the short course of 5 fractions of 5 Gy each is 37.5 Gy and that of a long course consisting of 50.4 Gy in 28 fractions of 1.8 Gy each is 40.9 Gy, implying they are roughly equivalent. The validity of equation 1 in establishing equivalency with respect to the chance Table 30.1 Staging of rectal carcinoma. Dukes TNM Group TNM (AJCC and UICC) Description A I T1N0M0 T2N0M0 Tumor limited to submucosa, Tumor into, not through, muscularis propria B II T3N0M0 T4N0M0 Tumor through muscularis propria Tumor invades other organs or through peritoneal serosa. C III N1 or N2, any T N1 (1 to 3 nodes +), N2 (>3 nodes +) D IV M1, any T or N Distant metastasis  radiation therapy: acute and late toxicity of eliminating pelvic cancer or causing any specific organ injury is dependent on the appropriateness to the specific endpoint in question and of the values chosen for a/b , g/a and T k . The physiologic death, disintegration, and disappearance of nearly all cells lethally injured by radiation takes place only after they and/or their descendents go through one or more, often aberrant, mitotic cell divisions. An exception to this is some lym- phocyte subsets that die within hours of irradiation. As a result there is a time lag between irradiation and response of a cancer that is variable and dependent on the mitotic activity of the cancer cells. This lag ranges from a few days up to a year or more for the various carcinomas. A typical time to manifest the maxi- mal response of a carcinoma to radiation is the order of a month or two. The same phenomenon is in part responsible for delay of up to a year or more in the development of some forms of radiation injury. With short course preoperative radiation there is little time for tumor response before surgery. There is evidence that at surgery after short course irradiation the average tumor size and average number of nodes with metastatic carcinoma has decreased slightly but this is not sufficient to produce a change in the distribution of tumor or nodal stage in a study population.(4) With long course preoperative irradiation more time is allowed for response of the disease and down staging to occur. This is evident in some of the trials listed in tables 30.3 and 30.4 and was demonstrated in a trial in which all patients were treated with 13 daily fractions of 3 Gy each and randomly assigned to surgery within 2 weeks after the end of radiation or surgery 6 to 8 weeks after radiation.(5) With both the long and short course, radiation treatment is directed at the pelvis with the superior border placed at about the L5S1 interspace. The inferior border is placed at least 3 to 5 cm below the most distal extent of tumor or below the obdura- tor foramen. For distal tumors it may include all or part of the anal canal. In earlier studies treatment was restricted to anterior- posterior directed beams.(6) More recently, laterally directed beams that exclude bowel in the anterior part of the pelvis are a standard part of treatment plans. Only the volume in which the beams overlap is exposed to the full prescribed dose. This usually includes, in addition to the rectum, small and large bowel in the posterior pelvis, the posterior part of bladder and prostate, the soft tissue in the ischiorectal fossa and presacral areas, the sac- rum and the lymph nodes of the internal iliac and most distal part of the common iliac chains. If there is extension of tumor to invade urogenital organs the external iliac nodes are sometimes included. After APR, the perineal incision, which tends to be a site of recurrence, is included in the treatment volume.(7, 8) Tables 30.2, 30.3 and 30.4 summarize several trials in which ran- domization was between arms composed of various combinations of pre and postoperative radiation and chemotherapy.(9–26) The radiation treatment plans in each are similar to either the short or long course described above and can be gleaned from the table by noting the dose shown. When the dose is about 25 Gy it is a short course and when 40 to 60 Gy it is similar to the long course. The benefits and adverse effects of preoperative and postoperative radiation treatment reported in these studies will be examined and compared. Adjuvant treatment after local excision is also discussed. BENEFIT OF ADJUVANT AND NEOADJUVANT RADIATION TREATMENT Several randomized trials of postoperative adjuvant therapy in the late 1970s and 1980s listed in Table 30.2 indicate that postoperative radiation and chemotherapy can lead to statistically Table 30.2 Postoperative adjuvant radiation studies. Study Open/Closed Number of Pts. Therapy Arms Local (Pelvic) Recurrence % at 5 years Overall Survival % at 5 years Comments GITSG (9) 202 S S–C S–44Gy S–44Gy-C 24 27 20 11 46 56 52 59 (p = 0.07) T3,T4 or N+ Semustine and 5Fu NCCTG (10) 794751 204 S–50.4Gy S–50.4Gy+C 25 13 (p = 0.036) 47 57 (p = 0.02) Semustine and 5Fu. NSABP (11) R-01 11/77 to 10/86 555 S S–46Gy S–C 25 16 (p = 0.06) 21.4 43 41 53 (p = 0.01) Semustine, 5Fu, vincristine Norway (12, 13) 144 S S–46Gy+C 30 12 (p = 0.01) 50 64 (p = 0.05) Bolus 5Fu on 6 days during radiation NSABP (14) R-02 694 S–C S–50.4Gy+C 14 8 (p = 0.02) 58 58 Semustine, 5Fu, vincristine in 10 week cycles or 5Fu and leukovorin in 8 week cycles. Retrospective Study of Trans anal excision (15) MGH/Emory 99 LE (T1) LE–xrt (T1) LE–(T2) LE–xrt (T2) 11 0.0 67 15 (p = 0.004) Concurrent chemotherapy for some patients RTOG 8902 (16) 65 LE (T1, fav) LE-xrt (T1,2,3) 14.3 17.6 86 72 fav = favorable features, see text. S indicates LAR or APR, LE is local excision, C is chemotherapy. A dose in Gy indicates irradiation. The dash line shows time sequence. . interested in avoiding IV infusions, the combination of capecitabine and oxaliplatin (XELOX) may be used. Capecitabine is the prodrug to 5-FU, and is administered orally. Irinotecan-Containing. FOLFIRI (5-FU and irinotecan), or IROX(irinotecan and oxaliplatin).(10) Based on the results of this and other studies irinotecan containing combinations are now mostly used as second line therapy.(13) Bevacizumab. (EGFR) and decreases tumor growth Fatigue, confusion, pruritis, insomnia, abdominal pain, nausea, vomiting, diarrhea,weakness, lung disease, dyspepsia  improved outcomes in colon and rectal

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