Colorectal cancer (CRC) is the fourth most common REVIEW. Advances in Chemotherapy for Colorectal Cancer. Staging and Prognostic Factors

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1 CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2006;4: REVIEW Advances in Chemotherapy for Colorectal Cancer DIRK M. BERNOLD* and FRANK A. SINICROPE*, *Division of Oncology, Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, Minnesota Gastroenterologists have a primary role in the management of colorectal cancer patients in that they frequently establish the diagnosis, direct or perform tumor staging evaluations, and initiate referrals for oncologic treatment. Several important advances have been made in the adjuvant treatment of colon and rectal cancers and in therapy of metastatic disease. These advances include the development of more effective combination chemotherapy regimens and molecularly targeted antibodies. These antibodies are directed against regulators of angiogenesis (vascular endothelial growth factor) and tumor cell growth (epidermal growth factor receptor) and have been shown to enhance the efficacy of cytotoxic chemotherapy. In the treatment of localized rectal cancer, the integration of chemotherapy and radiation with surgery has resulted in neoadjuvant approaches that achieve improved tumor control, sphincter preservation, and reduce treatment-related toxicities. This review presents an update of the current approach to colon and rectal cancer treatment, highlighting recent chemotherapeutic advances in the management of these highly prevalent malignancies. Colorectal cancer (CRC) is the fourth most common cancer and is second only to lung cancer as a cause of cancer-related mortality in the United States (US). 1 In 2004, approximately 105,000 new cases of colon cancer and 41,000 cases of rectal cancer were diagnosed in the US. 1 The survival of patients with CRC has improved steadily over the past several decades, in part owing to earlier diagnosis, improved surgical techniques, and the development of effective adjuvant therapy. Surgery remains the primary treatment modality in patients with localized CRC. Pathologically determined tumor stage is the most important prognostic factor and determines the need for postoperative adjuvant therapy. 2 Adjuvant therapy is given in an attempt to eradicate micrometastases and to thereby increase the cure rate after surgical resection. For colon cancer, adjuvant therapy is the standard of care when metastasis to regional lymph nodes occurs and consists of postoperative systemic chemotherapy. In patients with rectal cancer, adjuvant therapy is given for transmural disease and/or regional lymph node involvement and uses radiation therapy combined with chemotherapy in the preoperative or postoperative setting. Before 1995, 5-fluorouracil (5-FU) was the only effective chemotherapeutic agent in the treatment of CRC. However, significant progress since has been made with the development of newer agents and their use in combination chemotherapy regimens. Recent advances in treatment include the development of antibodies targeting vascular endothelial growth factor (VEGF), a known regulator of tumor cell angiogenesis, and the epidermal growth factor receptor (EGFR). 3,4 EGFR is a receptor tyrosine kinase that is an important regulator of growth and survival pathways in colorectal cancer cells. 3 Both anti-vegf 5 and anti-egfr 6 monoclonal antibodies have been shown to enhance the efficacy of chemotherapy in patients with advanced CRC resulting in their approval by the US Food and Drug Administration. The objective of this review is to provide an update regarding newer chemotherapy regimens for treatment of localized and metastatic disease, including the incorporation of biologic agents into the metastatic setting. Staging and Prognostic Factors Pathologic tumor stage at the time of surgical resection remains the most important prognostic variable in patients with colon and rectal cancer. 2 In addition to the original Dukes staging system, the TNM system of the American Joint Committee on Cancer (AJCC) is now the most commonly used staging system for CRC. 2 Abbreviations used in this paper: APR, abdominoperineal resection; CALGB, Cancer and Leukemia Group B; CAPIRI, capecitabine and irinotecan; CAPOX, capecitabine and oxilaplatin; CRC, colorectal cancer; DFS, disease-free survival; EGFR, epidermal growth factor receptor; 5-FU, 5-fluorouracil; FOLFIRI, infusional 5-FU with irinotecan; FOLFOX, infusional 5-FU/LV with oxaliplatin; IFL, irinotecan, 5-FU, and leucovorin; IROX, irinotecan with oxaliplatin; LV, leucovorin; MSI, microsatellite instability; NSABP, National Surgical Adjuvant Breast and Bowel Project; OS, overall survival; VEGF, vascular endothelial growth factor by the American Gastroenterological Association Institute /06/$32.00 doi: /j.cgh

2 July 2006 COLORECTAL CANCER CHEMOTHERAPY 809 Important components of this system include the depth of bowel wall invasion by the primary tumor (T) and the extent of regional lymph node involvement (N). The TNM groupings for stage III colon cancer were recently modified based upon an analysis utilizing the National Cancer Data Base including more than 50,000 patients diagnosed with stage III disease from 1987 through Based on the local extent of disease, 3 distinct subcategories within a traditional stage III cohort of colon cancer were identified as follows: stage IIIA (T1/2, N1), stage IIIB (T3/4, N1), and stage IIIC (any T, N2). 7 The 5-year observed survival rates for these 3 subcategories were 59.8%, 42.0%, and 27.3%, respectively, and differences among subgroups were highly significant (P.0001). Thus, this subgrouping provides additional prognostic information within the category of stage III disease and are included in the latest iteration of the TNM system. 2 Studies have shown that the accuracy of the staging improves with the number of nodes removed and evaluated. 7 9 The AJCC and the College of American Pathologists have recommended examination of at least 12 lymph nodes for identification of stage III patients. 2 A variety of clinical and pathologic features in CRCs have been studied to determine their prognostic value. These include bowel obstruction or perforation, tumor adherence to adjacent organs, lymphovascular or perineural invasion, histologic grade, and chromosomal abnormalities Prior studies also have shown that DNA ploidy and proliferative activity may be prognostic, yet lack of standardized methodology for ploidy analysis by flow cytometry has led to inconsistent results and prospective studies are lacking None of these potential prognostic markers yet has been deemed by consensus opinion to impact clinical outcome consistently to warrant their inclusion in the TNM system. 16 Although the majority of sporadic CRCs show chromosomal instability owing to allelic imbalance and DNA aneuploidy, 25,26 another pathway that accounts for 15% 20% of sporadic colon cancers is characterized by microsatellite instability (MSI). MSI is caused by frame-shift mutations and basepair substitutions in short, tandem repeat nucleotide sequences known as microsatellites This form of genetic instability is caused by loss of DNA mismatchrepair function that in sporadic cases is caused almost universally by hypermethylation of the CpG island of the hmlh1 gene. 30 Loss of mismatch repair as a result of germline mutation in 1 of the mismatch-repair genes is the hallmark of hereditary nonpolyposis CRC, which accounts for 4% of all CRC cases. 31 Tumors with the phenotype of high-frequency MSI are characterized by proximal location, frequent diploidy, and pathologic features that commonly include poor differentiation, mucinous histology, and peritumoral lymphocytic infiltration. 29,32,33 CRCs with high-frequency MSI have been shown to present at an earlier tumor stage and show better overall survival rates than do stage-matched patients with microsatellite stable and low-frequency MSI cancers. 15,29,32,34,35 At this time, however, the use of MSI testing for the determination of prognosis or in therapeutic decision making awaits further study. Chemotherapeutic Agents Current treatment of CRC continues to be based on fluorouracil, a fluorinated pyrimidine that inhibits thymidylate synthase, the rate-limiting enzyme in nucleotide biosynthesis FU generally is administered with leucovorin (LV), a reduced folate, that stabilizes the binding of fluorouracil to thymidylate synthase, thereby enhancing its inhibition of DNA synthesis. 37 When given in bolus form, the major toxicities are neutropenia, stomatitis, and diarrhea. Infusional 5-FU is associated with less hematologic toxicity in comparison with bolus administration, however, palmar plantar erythrodysesthesia (hand foot syndrome) is more common. 38 Capecitabine (Xeloda; Hoffman La Roche Inc, Nutley, NJ) is an oral prodrug of 5-FU and, once absorbed, it undergoes enzymatic conversion to 5-FU. The toxicity profile of capecitabine is similar to infusional 5-FU. 39,40 Irinotecan (CPT-11; Camptosar; Pfizer Pharmaceuticals, New York, NY) inhibits cell growth via inhibition of the topoisomerase I enzyme. 41 Topoisomerase I is responsible for the uncoiling of DNA during replication by inducing reversible single-strand breaks. If these breaks are not repaired, then cell death ensues. Irinotecan is hydrolyzed to an active metabolite known as SN-38 by hepatic carboxylesterase. In turn, SN-38 then is converted to an inactive form by uridine diphosphate glucuronosyltransferase isoform 1A1. 42 In patients with polymorphisms of uridine diphosphate glucuronosyltransferase isoform 1A1, the toxicities of irinotecan are more severe. 43,44 Uridine diphosphate glucuronosyltransferase isoform 1A1 testing has been approved recently by the Food and Drug Administration to identify patients with this polymorphism that can guide dose reductions of irinotecan. Toxicities of irinotecan include diarrhea, nausea, vomiting, myelosuppression, and alopecia. Oxaliplatin causes inter- and intra-dna cross-linking which inhibits DNA replication and transcription, leading to cell-cycle nonspecific death. 45 A synergistic combination is seen with 5-FU in in vitro and in clinical studies. 46 Oxaliplatin causes the down-regulation of thy-

3 810 BERNOLD AND SINICROPE CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 4, No. 7 midylate synthase, which may potentiate 5-FU and account for the synergy. Toxicities of oxaliplatin differ from those of other platinum agents. The most common side effect is cumulative neurotoxicity, characterized by numbness or tingling of the hands, feet, and perioral regions, which often is exaggerated by cold temperatures, and can be dose limiting. 47,48 The neuropathies often diminish after the cessation of therapy, but can take months to resolve, and in some cases may be permanent. Molecularly Targeted Therapy Although the traditional toxic effects of chemotherapy generally are not associated with targeted therapy, these agents tend to have their own specific adverse effects that are related to blockade of their biological targets. Cetuximab (Erbitux; Imclone Systems Inc, New York, NY) is a human/mouse chimeric antibody that binds to the EGFR, which frequently is overexpressed in human CRCs. 49,50 The binding competitively inhibits other ligands from attaching to the receptor, causing inhibition of cell growth and apoptosis. Toxicities include an acneiform rash, drying of the skin, and hypersensitivity infusion reactions in 3% of patients. The severity of the rash often corresponds with efficacy of therapy. 51 Cetuximab has activity as monotherapy and has been found to be synergistic with chemotherapy such as irinotecan. 6,52 Panitumumab is a fully humanized antibody to EGFR that has shown single-agent activity in advanced CRC patients. Response rates for single-agent panitumumab are similar to cetuximab, and clinical trials are ongoing to establish its efficacy in combination with cytotoxic chemotherapy. 53,54 This antibody may alleviate the issue of hypersensitivity reactions seen with cetuximab. Bevacizumab (Avastin; Genentech, San Francisco, CA) is a humanized antibody directed against VEGF. 55 Angiogenesis (ie, new blood vessel formation) has been shown to be important in tumor growth and metastasis, and bevacizumab may inhibit new vessel formation through binding VEGF, thereby limiting tumor growth. In addition, bevacizumab also may exert direct effects on the tumor and its vasculature, thereby inhibiting the tumor more directly. Bevacizumab has been shown to decrease interstitial pressure and to increase oxygenation in tumors, thereby potentially improving the ability of chemotherapy to reach and act within the tumor. 56 Bevacizumab can cause hypertension, bleeding, thrombosis, gastrointestinal perforation, and can delay wound healing. 57 In clinical studies, toxicities included grade 3 or 4 hypertension in 12% of patients, venous thrombosis in 12%, arterial thrombosis in 4%, gastrointestinal perforation in 2% 4%, and hemorrhage in 3%. Bevacizumab lacks single-agent activity in advanced CRC patients. However, this antibody has been shown to enhance the efficacy of front-line treatment with 5-FU, leucovorin, and irinotecan, and second-line infusional 5-FU/LV with oxaliplatin (FOLFOX) in patients with advanced CRC. 5,58,59 Adjuvant Therapy of Colon Cancer Postoperative adjuvant chemotherapy for colon cancer after surgical resection with curative intent first was shown to be advantageous in the mid-1980s. In patients with Dukes stage B and C cancers, the combination of semustine, vincristine, and 5-FU (MOF) 60,61 was associated with an initial survival benefit at 5 years that disappeared with re-analysis of the data at 10 years. In a subsequent study conducted by the North Central Cancer Treatment Group and the Mayo Clinic, the combination of 5-FU and the antihelminthic agent levamisole showed a reduction in colon cancer recurrence with the use of chemotherapy versus observation or levamisole alone. 62 A United States Intergroup study used an identically designed schema and also found a 40% reduction in recurrence, and a reduction in overall mortality from 57% to 41%. 63 Given that 5-FU and leucovorin were standard treatment for advanced disease, this regimen was evaluated in the adjuvant setting (Table 1) and was found to be effective. A National Surgical Adjuvant Breast and Bowel Project (NSABP) study (C-03) found 5-FU and leucovorin to be superior to MOF chemotherapy, with an improvement in 5-year overall survival (OS) rate from 66% to 75%. 64 Two further studies revealed a 5% improvement in 3 year OS for adjuvant 5-FU and leucovorin when compared with observation alone Subsequent studies then were conducted to determine the optimal adjuvant regimen containing 5-FU. Studies revealed that the combination of 5-FU and leucovorin was superior to 5-FU and levamisole, and equivalent to a combination of all 3 drugs. 68,69 The maximum benefit was found to occur with 6 months of therapy. The schedule followed either that developed at the Mayo Clinic (5-FU and low-dose leucovorin daily for 5 days repeated every 4 weeks for 6 cycles) or at Roswell Park (5-FU and high-dose leucovorin weekly for 6 weeks every 8 weeks for 4 cycles). The efficacy of the 2 schedules was similar; however, the toxicity profiles were different in that the Mayo schedule caused more leukopenia and stomatitis, whereas the Roswell Park schedule was associated with an increase in diarrhea. The regimen of bolus

4 July 2006 COLORECTAL CANCER CHEMOTHERAPY 811 Table 1. Completed and Ongoing Phase III Trials of Adjuvant Therapy for Colon Cancer Regimen Stage of disease Length of follow-up period Disease-free survival, % Overall survival None 66 II and III 5 y % 5-FU/LV (P.001) 74.0% (P.01) 5-FU/LV 72 III 3 y 61.0 a Capecitabine (P NS) 5-FU/LV 76 II and III 4 y 69.8 a FOLFOX (P.001) 5-FU/LV 79 III 3 y 60.0 a FOLFIRI (P NS) LV, leucovorin; FOLFOX, infusional 5-FU with oxaliplatin; FOLFIRI, infusional 5-FU with irinotecan. a Not yet reached. 5-FU and leucovorin represented standard adjuvant chemotherapy for stage III colon cancer in the United States; however, recent data outlined later are moving toward a new standard. Current regimens in advanced CRC use protracted venous infusion of 5-FU, given a modest benefit seen compared to intravenous bolus treatment. 70,71 Protracted infusional 5-FU for 8 12 weeks was compared with the bolus 5-FU and leucovorin (Mayo schedule) in the adjuvant setting, but no statistical difference was seen in disease-free survival (DFS) or OS. Toxicities including mucositis, diarrhea, nausea, vomiting, and neutropenia occurred less often with infusional therapy. However, the need for a central venous catheter for continuous infusion limited its widespread adoption in the United States until recently. An important advance was the development of an oral fluoropyrimidine, capecitabine, that has been shown to be an effective treatment for metastatic colon cancer with results similar to 5-FU and leucovorin. 39,40 Accordingly, it was compared with 5-FU and leucovorin (Mayo schedule) in the adjuvant treatment of stage III colon cancer in the X-ACT trial (Table 1). 72 After a median follow-up period of 51 months, capecitabine was shown to be at least as beneficial as bolus 5-FU therapy, with a 3-year DFS of 64.6% vs 61% for the Mayo regimen (P NS). In general, toxicities favored the use of capecitabine except for hand foot syndrome. Therefore, capecitabine is at least as effective as 5-FU and leucovorin as adjuvant therapy. When used in combination with 5-FU and leucovorin, oxaliplatin or irinotecan (CPT-11) have been shown to increase the efficacy of 5-FU and leucovorin in patients with metastatic CRC In recent years, oxaliplatin has been combined with infusional 5-FU and leucovorin (ie, the FOLFOX regimen) in the setting of metastatic disease and has shown superior results to 5-FU and leucovorin alone. 75 Therefore, this regimen, known as FOLFOX4, has been investigated in the adjuvant setting. The MOSAIC trial, a multi-institution trial performed in Europe, compared infusional 5-FU and leucovorin with and without the addition of oxaliplatin in stage II and III disease. 76 The overall 4-year DFS was 76.4% vs 69.8%, with and without oxaliplatin, respectively, for stage II and III disease combined (Table 1). In stage III disease, the DFS benefit was 8.6%, which was statistically significant. Peripheral neuropathy, a recognized side effect of oxaliplatin, generally was reversible. The NSABP C-07 trial has confirmed the MOSAIC data, revealing a 5% benefit in 3-year DFS for the oxaliplatincontaining regimen in stage II and III disease. 77 A similar 21% reduction in recurrence was seen in both stages. These data have resulted in the decision by the US Food and Drug Administration to approve oxaliplatin for use in adjuvant therapy, and FOLFOX has become the new standard of care at this time for stage III disease. Consideration also should be given to treatment for high-risk stage II disease in otherwise healthy patients, which subsequently will be discussed further. Studies are ongoing to evaluate capecitabine in combination with oxaliplatin vs 5-FU and leucovorin and, if positive, will allow an alternative to infusional 5-FU therapy. Irinotecan in combination with bolus 5-FU and leucovorin (IFL) has shown efficacy as a front-line treatment for metastatic CRC. Accordingly, this combination was evaluated in the adjuvant setting (Cancer and Leukemia Group B [CALGB] 8803) compared with bolus 5-FU and leucovorin. 78 Analysis of the data after 2 and 6 years of follow-up evaluation failed to show benefit with the addition of irinotecan. Therefore, the IFL regimen cannot be recommended as adjuvant treatment. The explanation as to why irinotecan lacks efficacy as adjuvant treatment remains elusive. Currently, irinotecan is used commonly in first-line treatment of metastatic disease in combination with infusional 5-FU and leucovorin (infusional

5 812 BERNOLD AND SINICROPE CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 4, No. 7 5-FU/LV with irinotecan [FOLFIRI]), similar to how oxaliplatin is used in the FOLFOX regimen. The PETACC-3 trial currently is using this regimen in the adjuvant setting, and 3-year DFS data for FOLFIRI vs infusional 5-FU plus leucovorin alone are 63% and 60%, respectively, which is not statistically different (Table 1). 79 The ACCORD trial also failed to find a benefit for irinotecan in the adjuvant setting. 80 Therefore, irinotecan currently has no role in the adjuvant therapy of lymph node positive colon cancer. At this time, adjuvant chemotherapy for resected stage II colon cancer remains controversial. Many of the trials investigating adjuvant therapy for stage III disease also included stage II patients. Although these trials clearly showed a benefit for stage III disease with 5-FU based therapy, they were able only to show trends toward improvement in OS for stage II disease. 60,62,65 67 Three studies that looked specifically at stage II or Dukes stage B disease also only showed a trend toward an OS benefit Several meta-analyses then were performed to evaluate this question further and an improvement in OS was found of 2% 5% that did not achieve statistical significance More recently, the MOSAIC data investigating FOLFOX adjuvant chemotherapy revealed a statistically insignificant benefit of 3% in DFS for all stage II patients over 5-FU and leucovorin alone. When a subset analysis was performed for high-risk stage II patients (defined by bowel perforation, obstruction, T4 tumors, poorly differentiated tumors, 10 lymph nodes examined), a benefit of 5.4% was shown for FOLFOX over 5-FU and leucovorin. 76 These data were confirmed by NSABP C-07, which found a 21% reduction in recurrence at 3 years of resected stage II disease for FOLFOX over 5-FU and leucovorin alone. 77 One should note that these studies did not compare chemotherapy vs observation, but rather the benefit of the addition of oxaliplatin. The liver is the initial site of recurrence in approximately one half of CRC patients failing potentially curative surgery. Therefore, efforts have been made to determine if local therapy could prevent hepatic metastases. Numerous studies were performed evaluating portal vein or hepatic arterial infusion of 5-FU In a metaanalysis of more than 4000 patients, no statistically significant benefit was found with the addition of portal venous infusion of fluoropyrimidines. 88 Other studies have confirmed these findings, or have had significant design flaws such that prophylactic hepatic therapy cannot be recommended. Surgery is performed to resect hepatic metastases in selected patients, and up to 25% of such patients can obtain prolonged DFS after resection. To improve postsurgical outcome, adjuvant chemotherapy has been evaluated in these patients. Studies of systemic 5-FU and leucovorin have been shown to be of little benefit in improving survival. 90,91 Trials also have used hepatic arterial infusion with floxuridine in combination with systemic 5-FU and leucovorin Although there has been moderate benefit with this treatment approach, this therapy often is complicated by drug-induced hepatoxicity, cholangitis, or catheter complications, and most patients who failed treatment showed disease outside of the liver. Given newer systemic therapies, most oncologists are opting for the use of systemic treatment including FOLFOX. Bevacizumab and cetuximab have been shown to enhance the efficacy of standard chemotherapy agents in the metastatic setting (discussed later). Both agents currently are being evaluated with FOLFOX chemotherapy in the adjuvant setting through studies conducted by the North Central Cancer Treatment Group and NSABP. Rectal Cancer After the resection of stage I rectal cancer, cure rates can be as high as 90%. However, cure rates decrease to less then 70% for stage II and III disease. Unlike colon cancer in which most recurrences are distant, local recurrences can exceed 50% of all recurrences in lymph node positive rectal cancer. 11 Salvage surgery for local recurrence is difficult technically and is associated with significant morbidity, which further emphasizes the need for local control. Given the physiologically fixed nature of the rectum in comparison with the colon, radiation therapy is used as a treatment modality for rectal cancer. In North America there are 2 conventional treatments for clinically resectable rectal cancer. The traditional approach is surgery followed by chemoradiation for T3 or node-positive disease. For patients who are found to have T3 or T4 disease via endoscopic ultrasound before surgery, neoadjuvant chemoradiation is now the most common strategy used in addition to postoperative systemic chemotherapy. Adjuvant Therapy Initial investigations into adjuvant treatment for stage II and III disease involved postoperative radiation therapy alone These studies showed improved local control with radiation, but no improvement in overall survival. Several trials then compared patients with resected Dukes stage B2 and C rectal cancers receiving radiation, radiation plus 5-FU based chemotherapy, or simply observation. Given these and other study results, a National Cancer Institute Consensus Conference con-

6 July 2006 COLORECTAL CANCER CHEMOTHERAPY 813 cluded in 1990 that combined modality chemoradiotherapy was the standard postoperative treatment for patients with pathologic T 3 and/or N 1 2 disease. Numerous studies then attempted to optimize the schedules and agents used for chemotherapy. In a Mayo/North Central Cancer Treatment Group randomized trial, postoperative singleagent 5-FU by continuous infusion given during radiation was found to give a 10% benefit in overall survival when compared with bolus 5-FU during radiation. 100 Subsequent studies found no benefit for the addition of leucovorin or levamisole to 5-FU during radiation in the adjuvant treatment of rectal cancer Given the earlier-described studies, current adjuvant therapy for resected stage II and III rectal cancer would include infusional or bolus 5-FU during radiation therapy either sandwiched (ie, systemic chemotherapy before and after concurrent chemoradiation) and followed by 4 cycles of bolus 5-FU chemotherapy. Most investigators prefer continuous infusion 5-FU during radiation because of better patient tolerance, followed by systemic 5-FU based chemotherapy. Earlier studies reported substantial rates of acute and long-term toxicity from pelvic radiation therapy, attributed in part to large radiation fields and/or high doses per fraction. Long-term toxicities of chemoradiotherapy include bowel and bladder dysfunction such as chronic diarrhea, small-bowel obstruction, and anastomotic stricture. Careful treatment planning can lessen, although not eliminate, the complication rate Preoperative radiation therapy may produce a lower complication rate because much of the irradiated rectum will be removed in the surgical specimen, and there is less likely to be small bowel fixed in the pelvis. Preoperative or neoadjuvant therapy is a standard approach and is delivered commonly in North America. Potential advantages include increased radiosensitivity in the unoperated pelvis, less acute toxicity, and enhanced sphincter preservation. The primary disadvantage is the potential for overtreating patients with early stage disease. However, diagnostic modalities such as endorectal ultrasound and magnetic resonance imaging have enabled more accurate staging of locally advanced disease, thus impacting choice of therapy. 111,112 Neoadjuvant therapy initially gained popularity in the setting of distal rectal cancers in which downstaging may achieve sphincter preservation and may enable a low anterior resection with colocolonic or colo-anal anastomosis, as opposed to an abdominoperineal resection (APR) APR requires placement of a permanent colostomy and entails an increased risk for urinary and sexual dysfunction. At least 9 studies have evaluated 5-FU based chemotherapy in combination with pelvic radiation in the preoperative setting for distal rectal cancers. The majority of patients had T3 disease, although some of the studies included T2 tumors. In the 7 smaller studies, sphincter-sparing surgeries were performed more than 70% of the time, whereas the 2 largest studies were able to spare the sphincter in only 40% of cases. On average, the studies revealed a 67% sphincter-preservation rate. Although these were not controlled studies, local control rates were encouraging, with recurrence rates of 7% and 12% for the largest studies. Neoadjuvant therapy also has been investigated vs postoperative chemoradiation in an attempt to reduce toxicities of therapy and also to improve survival rates of patients with rectal cancer. The German Rectal Cancer Study randomized 823 patients with stage II and III rectal cancer to chemoradiotherapy either before or after surgery. 121 At a median follow-up period of 46 months there has been no significant difference in DFS or OS between the preoperative and postoperative approaches. However, local control is improved significantly with pelvic relapse decreased from 13% to 6% with neoadjuvant therapy, and pathologic downstaging was achieved with neoadjuvant therapy. For those patients who had been deemed to require an APR before surgery, neoadjuvant therapy doubled the chances of a sphincter-sparing surgery from 19% to 39%. Grade 3 or 4 toxicities generally were equivalent between the 2 groups. However, anastomotic stenosis was significantly lower for neoadjuvant therapy compared with postoperative therapy (2.7% vs 8.5%). Importantly, there was better compliance with neoadjuvant therapy with approximately 90% of patients receiving the full course of therapy in the neoadjuvant setting vs 50% in the postoperative setting. Pathologic tumor stage in the resected specimen after neoadjuvant therapy was found to be of greater prognostic value than was the initial tumor staging at the time of diagnosis because pathologic complete response correlated with an improved local tumor control and DFS and OS rates. 122,123 The NSABP R-03 trial also compared neoadjuvant vs adjuvant chemoradiotherapy. 122,124 However, the accrual goal was not met and the study was closed early. Analysis revealed a trend toward an improvement in DFS (70% vs 65%) and OS (85% vs 78%) for patients receiving neoadjuvant therapy, but the difference was not statistically significant. Except for an increased rate of grade 4 diarrhea in the neoadjuvant group, toxicities were similar between the 2 therapies. Although the standard of care in terms of the timing of adjuvant therapy (ie, preoperative or postoperative) continues to evolve, recent data showed a benefit to neoadjuvant therapy over postoperative therapy and

7 814 BERNOLD AND SINICROPE CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 4, No. 7 Table 2. First-Line Therapy for Metastatic CRC Regimen No. of patients Response rate, % Median time to progression, mo Median OS, mo 5-FU, LV IFL (P.001) 7.0 (P.004) 14.8 (P.04) IFL FOLFOX (P.001) 9.3 (P.002) 19.5 (P.001) IROX (P.3) 6.5 (P.5) 17.4 (P.04) FOLFOX FOLFIRI (P.05) 8.5 (P.3) 21.5 (P.99) NOTE. Phase III trials included. IFL, bolus 5-FU/LV with irinotecan; FOLFOX, infusional 5-FU with oxaliplatin; IROX, irinotecan with oxaliplatin; FOLFIRI, infusional 5-FU with irinotecan. has become the preferred approach for locally advanced rectal cancers. In patients with small distal adenocarcinomas of the rectum, it often is attractive to consider local resection via a transanal excision as opposed to an APR in an effort to avoid a permanent colostomy and potential surgical morbidities. For carefully selected T1 tumors, as shown by endosonography and with good prognostic features ( 3 cm in size, within 8 cm of the anal verge, well to moderately differentiated pathology, lacking lymphovascular and perineural invasion, mobile, and negative lymph nodes), local excision alone results in cure in up to 90% of patients, and further adjuvant therapy is not recommended Patients with T2 tumors with equivalent prognostic factors unfortunately have recurrence rates in excess of 25%. 128 Therefore, adjuvant chemotherapy and radiation are recommended for these patients in a manner as described earlier if transanal resection is performed. Alternatively, these patients can be treated with an APR and then do not require adjuvant therapy. At the time of surgery, if it is found that any of these selected patients tumors fail to meet the criterion for local resection, they then should undergo an APR. Future Strategies for Systemic Therapy Capecitabine, an oral fluoropyrimidine, has known activity in metastatic CRC. Given its oral administration, it is an attractive substitute for infusional 5-FU during radiotherapy secondary to increased patient convenience and the ability to avoid central venous catheter related complications. Several small studies have investigated the use of capecitabine in conjunction with radiation therapy in both the neoadjuvant and adjuvant settings These were primarily phase I and II studies to determine toxicity and dosing. Preliminary results show capecitabine and concurrent radiation therapy to be beneficial and tolerable. A prospective randomized trial comparing either capecitabine or infusional 5-FU with radiation therapy for the treatment of rectal cancer is being conducted by the NSABP. In an effort to reduce distant relapse of disease, the systemic component of therapy clearly must be improved. The recent demonstration of the superiority of FOLFOX compared with conventional 5-FU and leucovorin in the adjuvant treatment of node-positive colon cancer suggests that such a combination also may be a more effective adjuvant treatment of rectal cancer. Oxaliplatin and irinotecan are known to be active against metastatic rectal cancer. Numerous phase I and II studies have been performed to evaluate the possibility of adding either of these drugs in conjunction with radiation and infusional 5-FU as neoadjuvant therapy. Combination therapy with either drug has been tolerable and studies have shown high rates of pathological complete response at the time of surgery. 132,133 Targeted therapy using anti-vegf or anti-egfr antibodies is being evaluated in conjunction with radiation in rectal cancer patients. EGFR inhibitors have been found to behave as radiosensitizers in other forms of malignancy such as in head and neck cancers. 134 Results of ongoing studies are awaited eagerly. Metastatic Colorectal Cancer Before the year 2000, 5-FU and leucovorin were the accepted standard treatment for metastatic CRC. This treatment was shown to extend patient survival by approximately 5 months compared with supportive care. 135,136 Subsequently, the addition of irinotecan to bolus 5-FU and leucovorin (coined the IFL regimen) was studied in a pivotal trial whereby this combination improved median survival rates from 11 to 15 months compared with 5-FU and leucovorin (Table 2). 73,74 Based on these results, IFL became the new standard first-line treatment for advanced CRC. In an effort to improve patient outcome further, a randomized trial was

8 July 2006 COLORECTAL CANCER CHEMOTHERAPY 815 Table 3. Targeted Therapy in Metastatic CRC No. of patients Study type Response rate, % Median time to progression, mo Median overall survival, mo First-line therapy 5-FU, LV Phase FU, LV, bevacizumab (P.06) 9.2 (P.001) 16.6 (P.16) IFL Phase IFL, bevacizumab (P.004) 10.6 (P.001) 20.3 (P.001) FOLFOX Phase NR NR FOLFOX, bevacizumab (P.01) NR NR Second-line therapy Cetuximab 6, Phase Cetuximab, irinotecan 6, Cetuximab, bevacizumab NR Cetuximab, bevacizumab, irinotecan NR FOLFOX Phase FOLFOX, bevacizumab (P.001) 7.2 (P.001) 12.9 (P.02) NR, not yet reached. conducted that compared IFL with infusional 5-FU and leucovorin plus oxaliplatin (termed FOLFOX), and a combination of irinotecan and oxaliplatin (IROX). 75 Analysis of these data indicated that patients treated with FOLFOX had a statistically significant increase in median survival of 19.5 months compared with 15 months for IFL, and 17.4 months for the combination of irinotecan and oxaliplatin (Table 2). Although these data suggested the superiority of oxaliplatin over irinotecan, important caveats include the fact that the bolus 5-FU in the IFL regimen was not equivalent to the infusional 5-FU used in the FOLFOX regimen. Furthermore, second-line therapy differed between the study arms because patients whose disease progressed on oxaliplatin commonly received irinotecan-based regimens, whereas those who received irinotecan during the study were unable to receive oxaliplatin as second-line treatment because it was not yet commercially available. More recently, irinotecan has been administered with infusional 5-FU and leucovorin (coined the FOLFIRI regimen), and appears to have significantly less toxicity than IFL, including a decrease in frequency and severity of diarrhea and neutropenia. 73,74,137,138 Accordingly, FOLFIRI is the preferred method for administering irinotecan in the frontline setting. Moreover, FOLFIRI has been shown to produce an equivalent survival benefit in patients with metastatic CRC as is seen with FOLFOX (Table 2). 139,140 It is important to note that both FOLFIRI and FOLFOX are considered standard initial therapeutic regimens for patients with metastatic CRC. When FOL- FOX and FOLFIRI are used in succession, median patient survival was slightly more than 20 months and the order of regimen administration did not produce a significant survival difference. 139 However, initial FOLFOX produced a higher tumor response rate and there was a trend toward an increase in surgical resection, yet the number of patients studied was relatively small. Given the simplicity of oral capecitabine over infusional 5-FU, capecitabine has been compared with 5-FU and leucovorin in advanced disease. Capecitabine produced a slightly higher objective tumor response rate, but overall survival was equivalent. 39,40 Capecitabine currently is being investigated in combination with irinotecan (CAPIRI) or oxaliplatin (CAPOX). 141 These studies are ongoing and the results are awaited eagerly for both efficacy and toxicity given the potential for capecitabine to be used as an alternative to infusional 5-FU. The most important recent advance in CRC treatment is the use of molecularly targeted therapy. An anti-egfr antibody, known as cetuximab (Erbitux), has been shown to have antitumor activity as monotherapy and enhances the efficacy of chemotherapy in metastatic CRC. 6,50,52,142 In patients whose tumors had progressed on irinotecan, cetuximab monotherapy was associated with an approximately 10% response rate that was doubled when administered in combination with irinotecan (Table 3). 6,52 Predicting response to cetuximab has proven difficult because neither overexpression of EGFR proteins nor EGFR gene amplification was found to correlate with response to therapy. 143 Cetuximab has been studied in combination with bevacizumab, a fully humanized monoclonal antibody directed at VEGF, in irinotecan-refractory patients. A 23% re-

9 816 BERNOLD AND SINICROPE CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 4, No. 7 sponse rate was achieved with this combination and when irinotecan was added, a 37% response rate was observed (Table 3). 144 These interesting and important results show that cetuximab plus bevacizumab achieves an equivalent response rate, as does cetuximab plus irinotecan. These data suggest that a combination of targeted antibodies have the potential to replace cytotoxic drugs in certain situations. Studies evaluating panitumumab, a fully humanized antibody to EGFR, have shown similar efficacy as cetuximab when given as a single agent or in combination with chemotherapy in refractory CRC. 53,54 The most common toxicity was skin rash in 95% of patients (7% grade 3), and infusion reactions were not seen in contrast to a 3% rate for cetuximab. Panitumumab has not yet been approved by the Food and Drug Administration for treatment of CRC. Bevacizumab (Avastin) was evaluated in combination with bolus 5-FU, leucovorin, and irinotecan (the IFL regimen). The median duration of survival was 20.3 months in the group given IFL plus bevacizumab, as compared with 15.6 months in the group given IFL plus placebo (hazard ratio for death,.66; P.001) (Table 3). 5 Bevacizumab also has been evaluated in combination with bolus 5-FU and leucovorin. Although an increase in response rate was seen with the addition of bevacizumab, no significant increase in survival was found although the study was underpowered for this end point. 58 A recent randomized trial evaluated bevacizumab plus FOLFOX, FOLFOX alone, or bevacizumab alone. 59 Patients in this trial had failed prior treatment with irinotecan and a fluoropyrimidine. The bevacizumab-alone arm was closed early because of an inferiority trend. Median overall and progression-free survival both were improved significantly in patients treated with bevacizumab and FOLFOX compared with FOLFOX alone (OS, 12.9 vs 10.8 mo; P.0018) (Table 3). Grades 3 4 hypertension occurred in 6% of patients treated with bevacizumab plus FOLFOX, compared with 3% of patients treated with FOLFOX alone. Grades 3 4 sensory neuropathy occurred in nearly 17% of patients treated with bevacizumab plus FOLFOX compared with only approximately 10% of patients treated with FOLFOX alone. Bowel perforation occurred in only approximately 1% of patients, but its occurrence was seen only in the bevacizumab plus chemotherapy group. There were no differences in rates of thrombosis or all-cause mortality rates at 60 days. Separately, bevacizumab has been shown to increase tumor response rates by 12% 18% when added to FOLFOX or capecitabine plus oxaliplatin (CAPOX), respectively. 145 Taken together, these data indicate that bevacizumab can increase the efficacy of currently used chemotherapy regimens against metastatic CRC. Summary Within the past few years, newer chemotherapy regimens and targeted agents have led to the establishment of new standards of care and improvements in survival of CRC patients. Recommended adjuvant therapy for lymph node positive patients (ie, stage III colon cancer) at this time consists of infusional 5-FU, leucovorin, and oxaliplatin (FOLFOX). Based on favorable results in advanced disease, the potential benefit of the addition of bevacizumab or cetuximab in the adjuvant setting currently is being evaluated in cooperative group studies. Treatment of stage II disease is not the standard of care. Consideration can be given to chemotherapy in patients with high-risk features for recurrence including tumor obstruction, perforation, or T4 or poorly differentiated tumors and favorable performance status. 146 In patients with locally advanced rectal cancer, combined modality therapy consisting of 5-FU and radiation therapy is the standard of care. Specifically, tumor penetration of the wall into perirectal fat (T3), or tumor invasion of adjacent structures (T4), warrants adjuvant treatment, as do tumors with any T stage but with lymph-node positivity. Neoadjuvant chemoradiation therapy increases the probability of sphincter preservation during surgical resection of distal rectal cancers and should be strongly considered in such patients. Recent data support the preferential use of neoadjuvant therapy after accurate staging of locally advanced rectal cancers and appears to be associated with less acute and longterm toxicity; however, the optimal timing of adjuvant therapy and the combination of agents continues to evolve. Ongoing studies are evaluating agents used in the setting of metastatic disease, that is, oxaliplatin and biological agents, for adjuvant treatment of rectal cancer, including their potential to act as radiosensitizers, with the ultimate goal of reducing recurrence and improve survival rates while attempting to minimize treatmentrelated toxicities. Newer regimens for the treatment of metastatic CRC have led to an improvement in median patient survival to longer than 20 months. Standard front-line treatment options include the FOLFOX or FOLFIRI regimens. Randomized trials indicate that bevacizumab can enhance the efficacy of combination chemotherapy, and many oncologists are administering bevacizumab in combination with FOLFOX or FOLFIRI as front-line therapy. Second-line therapy often entails administration

10 July 2006 COLORECTAL CANCER CHEMOTHERAPY 817 of the first-line regimen not initially chosen, that is, FOLFIRI if FOLFOX was used initially, and vice versa. Cetuximab is an effective agent as monotherapy and also has been shown to enhance tumor response in patients with irinotecan-refractory disease. Therefore, second- or third-line therapy may include cetuximab in combination with an irinotecan- containing regimen. Capecitabine is being investigated actively as a substitute for infusional 5-FU in multidrug regimens. Questions remain regarding the treatment of metastatic disease, such as the optimal sequencing of drugs. Because treatment for the great majority of patients strictly is palliative, the patient s quality of life remains of utmost importance throughout therapy. Given the availability of new regimens and biological agents, we have reached a welcome situation whereby effective therapeutic options abound but further study is needed to guide the optimal use and sequencing of such therapies. 147,148,149 References 1. Jemal A, Tiwari RC, Murray T, et al. Cancer statistics, CA Cancer J Clin 2004;54: American Joint Committee on Cancer AHCC Cancer Staging Manual. 6th ed. New York: Springer, 2002: Mendelsohn J, Baselga J. Status of epidermal growth factor receptor antagonists in the biology and treatment of cancer. J Clin Oncol 2003;21: Gerber HP, Ferrara N. Pharmacology and pharmacodynamics of bevacizumab as monotherapy or in combination with cytotoxic therapy in preclinical studies. Cancer Res 2005;65: Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004;350: Cunningham D, Humblet Y, Siena S, et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 2004;351: Greene FL, Stewart AK, Norton HJ. A new TNM staging strategy for node-positive (stage III) colon cancer: an analysis of 50,042 patients. Ann Surg 2002;236: Goldstein NS, Weldon S, Coffey M. Lymph node recovery from colorectal resection specimens removed for adenocarcinoma: trends over time and a recommendation for a minimum number of lymph nodes to be removed. Am J Clin Pathol 1996;106: Le Voyer TE, Sigurdson ER, Hanlon AL. Colon cancer survival is associated with increasing number of lymph nodes analyzed: a secondary survey of intergroup trial INT J Clin Oncol 2003;21: Griffin MR, Bergstralh EJ, Coffey RJ. Predictors of survival after curative resection of carcinoma of the colon and rectum. Cancer 1987;60: Minsky BD, Mies C, Recht A, et al. Resectable adenocarcinoma of the rectosigmoid and rectum. I. Patterns of failure and survival. Cancer 1988;61: Wiggers T, Arends JW, Schutte B. A multivariate analysis of pathologic prognostic indicators in large bowel cancer. Cancer 1988;61: Krasna MJ, Flancbaum L, Cody RP. Vascular and neural invasion in colorectal carcinoma. Incidence and prognostic significance. Cancer 1988;61: Jen J, Kim H, Piantadosi S, et al. Allelic loss of chromosome 18q and prognosis in colorectal cancer. N Engl J Med 1994;331: Halling KC, French AJ, McDonnell SK, et al. Microsatellite instability and 8p allelic imbalance in stage B2 and C colorectal cancers. J Natl Cancer Inst 1999;91: Compton C, Fenoglio-Preiser CM, Pettigrew N, et al. American Joint Committee on Cancer Prognostic Factors Consensus Conference: Colorectal Working Group. Cancer 2000;88: Watanabe T, Wu TT, Catalano PJ, et al. Molecular predictors of survival after adjuvant chemotherapy for colon cancer. N Engl J Med 2001;344: Popat S, Matakidou A, Houlston RS. Thymidilate synthase expression and prognosis in colorectal cancer: a systemic review and meta-analysis. J Clin Oncol 2004;22: Bauer KD, Lincoln ST, Vera-Roman JM, et al. Prognostic implications of proliferative activity and DNA aneuploidy in colonic adenocarcinomas. Lab Invest 1987;57: Schutte B, Reynders MM, Wiggers T, et al. Retrospective analysis of the prognostic significance of DNA content and proliferative activity in large bowel carcinoma. Cancer Res 1987;47: Scott NA, Wieand HS, Moertel CG, et al. Colorectal cancer. Dukes stage, tumor site, preoperative plasma CEA level, and patient prognosis related to tumor DNA ploidy pattern. Arch Surg 1987;122: Armitage NC, Ballantyne KC, Evans DF, et al. The influence of tumour cell DNA content on survival in colorectal cancer: a detailed analysis. Br J Cancer 1990;62: Witzig TE, Loprinzi CL, Gonchoroff NJ, et al. DNA ploidy and cell kinetic measurements as predictors of recurrence and survival in stages B2 and C colorectal adenocarcinoma. Cancer 1991; 68: Lanza G, Gafa R, Santini A, et al. Prognostic significance of DNA ploidy in patients with stage II and stage III colon carcinoma: a prospective flow cytometric study. Cancer 1998;82: Lengauer C, Kinzler KW, Vogelstein B. Genetic instability in colorectal cancers. Nature 1997;386: Vogelstein B, Fearon ER, Hamilton SR, et al. Genetic alterations during colorectal-tumor development. N Engl J Med 1988;319: Aaltonen LA, Peltomaki P, Leach FS, et al. Clues to the pathogenesis of familial colorectal cancer. Science 1993;260: Ionov Y, Peinado MA, Malkhosyan S, et al. Ubiquitous somatic mutations in simple repeated sequences reveal a new mechanism for colonic carcinogenesis. Nature 1993;363: Thibodeau SH, Bren G, Schaid D. Microsatellite instability in cancer of the proximal colon. Science 1993;260: Cunningham JM, Christensen ER, Tester DJ, et al. Hypermethylation of the hmlh1 promoter in colon cancer with microsatellite instability. Cancer Res 1998;58: Boland CR, Thibodeau SN, Hamilton SR, et al. A National Cancer Institute Workshop on Microsatellite Instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer. Cancer Res 1998;58: Lothe RA, Peltomaki P, Meling GI, et al. Genomic instability in colorectal cancer: relationship to clinicopathological variables and family history. Cancer Res 1993;53: Thibodeau SN, French AJ, Cunningham JM, et al. Microsatellite instability in colorectal cancer: different mutator phenotypes and the principal involvement of hmlh1. Cancer Res 1998;58: Gryfe R, Kim H, Hsieh ET, et al. Tumor microsatellite instability