Colorectal Cancer

SYMPOSIUM ON SOLID TUMORS COLORECTAL CANCER

Colorectal Cancer SHARLENE GILL, MD; A. WILLIAM BLACKSTOCK, MD; AND RICHARD M. GOLDBERG, MD

Cancers of the colon and rectum will affect 1 in 17 North Americans during their lifetime. The progress witnessed in the treatment of these cancers in recent years has been remarkable. Improvements have been realized in surgical technique, radiation therapy, and systemic therapies, particularly with the addition of oxaliplatin and irinotecan to the previously limited armamentarium of fluorouracil alone. Targeted therapies directed at the vascular endothelial growth factor pathway and the epidermal growth factor pathway are now key players in the treatment of colorectal cancer. With current-day therapies, more than 75% of patients with localized disease are recurrence free at 3 years, and up to 50% of patients with advanced unresectable disease are alive at 2 years. This review focuses on the evidence supporting the current role of chemotherapy and radiation therapy in the adjuvant management of colorectal cancers and the strategy of combining chemotherapy and biological therapy in the treatment of metastatic disease.

Mayo Clin Proc. 2007;82(1):114-129 CALGB = Cancer and Leukemia Group B; CRC = colorectal cancer; DFS = disease-free survival; ECOG = Eastern Cooperative Oncology Group; EGFR = epithelial growth factor receptor; FLOX = fluorouracil bolus, leucovorin with oxaliplatin; FOLFIRI = folinic acid with infusion fluorouracil and irinotecan; FOLFOX = folinic acid with infusion fluorouracil and oxaliplatin; FOLFOXIRI = folinic acid with infusion fluorouracil, oxaliplatin, and irinotecan; IFL = irinotecan plus bolus fluorouracil and leucovorin; MOSAIC = Multicenter International Study of Oxaliplatin/5-Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer; MTD = maximum tolerated dose; NCCTG = North Central Cancer Treatment Group; NSABP = National Surgical Adjuvant Breast and Bowel Project; OPTIMOX = optimized fluorouracil-oxaliplatin; OS = overall survival; RR = response rate; TME = total mesorectal exci-sion; TTP = time to progression; VEGF = vascular endothelial growth factor; X-ACT = Xeloda Adjuvant Chemotherapy Trial

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ach year in the United States and Canada, colorectal cancer (CRC) will be diagnosed in an estimated more than 160,000 people with approximately 65,000 related deaths, accounting for at least 10% of all cancer deaths.1,2 The lifetime risk of developing CRC is 1 in 17, affecting men and women alike, with 90% of cases occurring after the age of 50 years. Although the societal burden of CRC remains significant, advances have been achieved both in our understanding of colorectal tumorigenesis and in patient outcomes. Overall 5-year survival rates have increased during the past 2 decades from 50% to 63%.3 These survival increases may largely be attributed to improvements in surgical management, adjuvant therapy for localized high-risk disease, and the multimodality management of advanced metastatic disease. This review concentrates on the current state of the art for colorectal surgery, combined modality chemotherapy and radiation in rectal cancer, chemotherapy after resection of localized disease, and chemotherapy in the setting of advanced disease. 114

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ADJUVANT THERAPY FOR COLON CANCER SURGICAL ADVANCES Recently, several important surgical questions relevant to the management of CRC were resolved. Of probably most importance is the widespread acceptance of the technique called total mesorectal excision (TME) that was popularized by Cecil et al4 for resection of rectal cancers. The sharp dissection of the entire intact vascular, lymphatic, and fatty tissues surrounding the rectum rather than the former technique of blunt dissection has decreased the local recurrence rate from as high as 50% in some cases to less than 10%. Laparoscopic colectomy has been convincingly shown in a randomized study of more than 800 patients to be an equivalent cancer operation to open colectomy and is associated with modest decreases in hospital stay, use of pain medications, and quality of life.5 The use of methylene blue injection at the tumor site just before resection to identify sentinel nodes has been evaluated as a technique to improve staging by pointing the pathologist to the nodes most likely to harbor metastatic disease. However, this technique appears to miss an important number of metastatic foci and has not been widely adopted in colon cancer surgery in contrast to its widespread use in breast and melanoma resections.6 ADJUVANT TREATMENT During the past 20 years, adjuvant chemotherapy for CRC has evolved from experimental status to become the standard of care. Patients with stage III colon cancer diagnosed From the Department of Medical Oncology, British Columbia Cancer Agency, Vancouver, British Columbia (S.G.); Department of Radiation Oncology, Comprehensive Cancer Center of Wake Forest University, Winston-Salem, NC (A.W.B.); and Division of Hematology/Oncology, University of North Carolina at Chapel Hill (R.M.G.). Dr Gill has received financial support through grants or contracts from Hoffman-La Roche, Ltd. Dr Blackstock has served as a consultant to and received honoraria from AstraZeneca, sanofi-aventis, Eli Lilly and Co, Merck & Co, Inc, and Millenium Pharmaceuticals, Inc. Dr Goldberg has served as a consultant and received honoraria from sanofi-aventis, Pfizer Inc, BristolMyers Squibb Co, AstraZeneca, Boehringer Ingelheim, and Genentech, Inc, and has testified to the Food and Drug Administration on behalf of BristolMyers Squibb. Address correspondence to Richard M. Goldberg, MD, Division of Hematology/Oncology, University of North Carolina at Chapel Hill, CB# 7305, 3009 Old Clinic Building, Chapel Hill, NC 27599-7305 (e-mail: [email protected] .edu). Individual reprints of this article and a bound reprint of the entire Symposium on Solid Tumors will be available for purchase from our Web site www.mayoclinicproceedings.com. © 2007 Mayo Foundation for Medical Education and Research

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in 2006 who receive folinic acid with infusion fluorouracil and oxaliplatin (FOLFOX) chemotherapy after optimal surgery have a 75% likelihood that they will be disease free at 3 years, and most will be cured of their disease.7 In the prechemotherapy era, when surgery alone was the standard of care, 50% of patients with stage III colon cancer remained recurrence free 3 years later.8 Optimism prevails that the median survival advantages realized by the addition of targeted therapies to chemotherapy in the treatment of patients with advanced CRC will culminate in higher cure rates as phase 3 adjuvant trials currently in progress mature. The first definitive data of adjuvant chemotherapy efficacy came from parallel trials performed by the North Central Cancer Treatment Group (NCCTG) and the National Surgical Adjuvant Breast and Bowel Project (NSABP) initiated in the late 1980s. The NSABP investigators showed that treatment with the combination of semustine, vincristine, and fluorouracil led to a clinically and statistically significant disease-free survival (DFS) and 5-year overall survival (OS) advantage (59%) for patients with stage III disease over surgery alone (50%).9 Concurrently, NCCTG investigators, in data confirmed by later trials, found a similar improvement with 1 year of treatment using fluorouracil modulated by either levamisole or leucovorin.10 Because regimens that combine fluorouracil and leucovorin were found to be more active and had toxicity advantages over either fluorouracil plus levamisole or the semustine, vincristine, and fluorouracil regimen in the next generation of studies, they became the next standard of care.11,12 The largest American study to date, Intergroup 0089, randomized 3759 patients with stage II and III disease to fluorouracil plus levamisole for 12 months, fluorouracil plus high-dose leucovorin administered weekly for 6 of 8 weeks for 4 cycles (the Roswell Park regimen), fluorouracil plus low-dose leucovorin administered daily for 5 days every 4 to 5 weeks for 6 cycles (the Mayo Clinic regimen), and fluorouracil plus low-dose leucovorin plus levamisole.13 The only significant difference in OS or DFS was observed in the comparison between the fluorouracil, low-dose leucovorin, and levamisole arm and the fluorouracil and levamisole arm, favoring the addition of leucovorin. The 5-year OS for the stage III subgroup was 60% compared with 65% (P=.0054). The study showed that either fluorouracil plus high-dose leucovorin or fluorouracil plus low-dose leucovorin led to a survival advantage for patients with stage III colon cancer and that levamisole added toxicity without incremental benefit (Table 1). Perhaps most importantly, this study demonstrated 6 months to be as effective as 12 months of adjuvant therapy. Because the Mayo Clinic regimen led to more stomatitis and neutropenia, the weekly Roswell Park regimen, despite its Mayo Clin Proc.

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TABLE 1. Results of Intergroup Adjuvant Colon Study 0089*

Treatment arm Fluorouracil-leucovorin (Mayo Clinic schedule, 6 mo) Fluorouracil-leucovorin (Roswell Park schedule, 6 mo) Fluorouracil-levamisole (12 mo) Fluorouracil-leucovorinlevamisole (6 mo)

DFS (%)

OS (%)

5 y 10 y

5 y 10 y

953

60

49

66

52

946 835

58 55

47 45

66 64

52 50

827

49

68

54

59

No. of patients

*DFS = disease-free survival; OS = overall survival.

association with a higher rate of severe diarrhea, became the preference for many oncologists. An important determinant in this choice was the fact that, with weekly therapy, individual tailoring to toxicity during a treatment course was possible, whereas the toxicity related to the 5 daily doses of the Mayo Clinic regimen generally manifests itself during the week after the drugs had been delivered. The circumstance in which thousands of patients have been treated in different studies with similar treatment regimens lends itself to meta-analyses in an attempt to obtain a better understanding of the meaning of data from the combined sample. Modern technology permits the pooling of individual patient data for reanalysis rather than averaging data across studies. The relative benefit of adjuvant fluorouracil-based chemotherapy, both for all patients with stage II and III colon cancer and for patients with substages of disease based on T and N characteristics, was estimated by creating just such a model that pooled individual patient data from 7 pivotal adjuvant trials, all of which included surgery alone control arms.14 In this model, adjuvant therapy with modulated fluorouracil for patients with stage II and III colon cancer decreased the risk of death by 26% at 5 years, leading to a 5-year survival rate of 71% with treatment and 64% with surgery alone. For all patients with stage III disease, there was a 40% reduction in risk of death. Moreover, OS statistics differed by substage, from 58% to 71% after treatment for N1 disease and from 29% to 44% after treatment for N2 disease. These and other data led the American Joint Commission on Cancer to revise the staging manual such that both stages II and III were subdivided to delineate intramural vs transmural disease and for stage III up to or more than 3 positive nodes.15 Because most adjuvant studies have enrolled relatively few patients with stage II disease, pooled analyses have been the best way to judge the benefits of therapy in this group. In our pooled analysis, the reduction in odds of death for patients with stage II disease was 17%, reflecting the fact that the surgical cure rate is higher in this subgroup of patients. Only one adequately powered randomized trial has shown a significant benefit for chemotherapy for pa-

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tients with stage II disease. The British QUASAR (Quick and Simple and Reliable) investigators enrolled 3238 patients, 91% of whom had Dukes B disease and 71% of whom had colon cancer (the remaining patients had rectal cancer) to 1 of 3 fluorouracil treatment arms or to observation.16 The study demonstrated significant improvement in DFS and an 18% reduction in the risk of recurrence associated with fluorouracil-based therapy. The authors estimate a survival benefit of 1% to 5%. One difficulty in interpreting this study arises because 30% of patients had rectal cancer, a disease with a higher rate of recurrence than identically staged colon cancer. Inclusion of these higherrisk patients in an observation arm could have resulted in an overestimation of adjuvant benefit. The American Society of Clinical Oncology recently convened an expert panel that provided recommendations for adjuvant therapy for stage II colon cancer, concluding that treatment might be considered for patients with higher than average risk, including those with inadequately sampled nodes (<13), T4 primary lesions, perforation, obstruction, lymphovascular invasion, or poorly differentiated tumors, but should not be administered as a matter of routine.17 The concept of infusing fluorouracil during several days or continuously was pioneered in the United States, although its utility was primarily investigated by European medical oncologists. Intergroup 0153 randomized patients to continuous infusion or bolus fluorouracil-leucovorin.18 In this study of 1135 patients, continuous fluorouracil administered at 250 mg/m2 daily for 27 weeks was compared with the Mayo Clinic fluorouracil-leucovorin schedule for 6 cycles (approximately 32 weeks). No difference in DFS or OS was noted in the study, but continuous intravenous fluorouracil had a significantly improved toxicity profile. However, more patients chose to stop before completing the 6 months of prescribed therapy in the infusion arm of the study. Chau et al19 randomized 400 patients to 12 weeks of continuous fluorouracil or to a standard 6-month course of bolus fluorouracil-leucovorin (Mayo Clinic regimen) and demonstrated a trend toward superiority of the continuous regimen (hazard ratio for OS, 0.79; 95% confidence interval, 0.61-1.03; P=.083). However, the trial was inadequately powered to demonstrate either superiority of infusion therapy or equivalence to the bolus regimen. The optimal duration of therapy remains an open question, and the potential to reduce the course of treatment to 3 months clearly deserves further study to minimize cost, maximize convenience, and protect patients from cumulative toxicity, especially the neurotoxicity associated with oxaliplatinbased chemotherapy. The combination of both a bolus loading dose of fluorouracil followed by fluorouracil infusion was investigated 116

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in part because fluorouracil is cell cycle specific in its action and appears to have dual mechanisms of action related to inhibition of thymidylate synthetase and incorporation of the abnormal pyrimidine into RNA.20 Groups of European investigators created regimens based on this approach. The leucovorin–fluorouracil 2 regimen initiated by de Gramont et al administers leucovorin, 200 mg/m2, and fluorouracil, 400-mg/m2 bolus followed by 600 mg/m2 infused continuously for 22 hours, with treatment repeated on days 1 and 2 every 2 weeks.21 They randomized 905 patients to either leucovorin–fluorouracil 2 or the Mayo Clinic regimen and demonstrated no clinically or statistically significant outcome differences between the arms. Although this study was not sufficiently powered to establish true equivalence of the 2 arms, this regimen is considered standard by many European oncologists. Convenience would make an oral fluoropyrimidine an attractive alternative to either bolus and/or infusion fluorouracil if equivalent efficacy could be established. Because fluorouracil is erratically absorbed from the gastrointestinal tract, prodrugs with reliable absorption characteristics have been formulated, and 2 have been compared with fluorouracil-leucovorin in the adjuvant setting. Tegafur-uracil is a combination of the fluorouracil prodrug tegafur and an inhibitor of dihydropyrimidine dehydrogenase that blocks degradation of fluorouracil in the gastrointestinal tract. Capecitabine is a distinctive oral formulation that undergoes a series of enzymatic conversions to fluorouracil.22 The NSABP compared tegafur-uracil to bolus fluorouracil-leucovorin delivered according to the Roswell Park regimen in resected stage II and III colon cancer. The study discerned no difference in outcomes or toxicity between the 2 regimens.20 Tegafur-uracil has never been approved in the United States and is not likely to become available because of Food and Drug Administration rules regarding the components of combination drugs. The Xeloda Adjuvant Chemotherapy Trial (X-ACT) compared capecitabine at a dose of 1250 mg/m2 twice daily to the Mayo Clinic regimen in resected stage III colon cancer (Table 2).23 This study was powered for a primary end point of equivalence to fluorouracil-leucovorin. The hazard ratio for DFS of 0.87 (95% confidence interval, 0.75-1.00) met the criteria for borderline superiority, indicating that treatment with capecitabine has potential activity and toxicity advantages over the Mayo Clinic regimen. The toxicity profiles differed, with more neutropenia and stomatitis in patients in the fluorouracil-leucovorin arm and more hand-foot syndrome and asymptomatic elevation of serum bilirubin levels observed in patients receiving capecitabine. The first trial to compare the combination of folinic acid with infusion fluorouracil and oxaliplatin (FOLFOX4) to

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TABLE 2. Outcomes of and Grade 3 to 4 Toxic Effects in Recent Trials of Adjuvant Chemotherapy* X-ACT† (N=1987)

MOSAIC (N=2246)

NSABP C-07‡ (N=2492)

Mayo Clinic regimen

Capecitabine

Leucovorinfluorouracil 2

FOLFOX4

RPMI

FLOX

61 26 ... 13 3 14 … <1 6

64 2 … 11 3 2 … 17 20

73 5 <1 7 1 2 <1 … …

78 41 2 11 6 3 12 … …

72 … … … … … 1 … …

77 4 … 38 … … 8 … …

3-y DFS Neutropenia Febrile neutropenia Diarrhea Vomiting Stomatitis Paresthesias Hand-foot syndrome Hyperbilirubinemia

*Data are percentages. Ellipsies denote unreported data. DFS = disease-free survival; FLOX = fluorouracil bolus, leucovorin with oxaliplatin; FOLFOX = folinic acid with infusion fluorouracil and oxaliplatin; MOSAIC = Multicenter International Study of Oxaliplatin/5-Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer; NSABP = National Surgical Adjuvant Breast and Bowel Project; RPMI = Roswell Park Memorial Institute; X-ACT = Xeloda Adjuvant Chemotherapy Trial. †X-ACT included patients with stage III disease only, and MOSAIC and NSABP C-07 included a mixture of patients with stage II and III disease. ‡Data from the NSABP C-07 have been presented in abstract form only; full toxicity data are not available. Data from N Engl J Med.23

the leucovorin–fluorouracil 2 program enrolled 2246 patients with stages II and III colon cancer.7 FOLFOX4 adds biweekly oxaliplatin at a dose of 85 mg/m2 daily to the leucovorin–fluorouracil 2 backbone described previously. Interim results showed that 78% of FOLFOX4-treated patients and 73% of leucovorin–fluorouracil 2–treated patients were recurrence free at 3 years. At 4 years, 76% of FOLFOX-treated patients compared with 69% of patients treated with leucovorin–fluorouracil 2 remained disease free (hazard ratio, 0.77; 95% confidence interval, 0.650.90).24 No difference has been observed in survival to date. However, because of improvements in the management of metastatic disease, prolonged follow-up may be needed beyond the traditional 5 years to discern if such a difference exists. Oxaliplatin caused significantly more grade 3 and 4 neutropenia, febrile neutropenia, thrombocytopenia, nausea and vomiting, diarrhea, neuropathy, and allergic reactions (Table 2). Of the 12% of patients who developed sensory neuropathy interfering with function, only 1% continued to have residual severe neuropathy 1 year later. The NSABP C-07, which randomized 2492 patients with stages II and III colon cancer to receive the Roswell Park Memorial Institute regimen of fluorouracil-leucovorin with (FLOX) or without oxaliplatin confirmed these findings.25 Three-year DFS increased from 72% to 77% (hazard ratio for DFS, 0.79). Grade 3 or greater adverse effects were observed in 51% of patients receiving fluorouracil-leucovorin compared with 61% receiving FLOX. Of note, the FLOX regimen prescribes approximately two thirds of the cumulative oxaliplatin dose specified by the FOLFOX4 regimen, suggesting that less exposure to oxaliplatin than the cumulative dose of 1020 mg/m2 deMayo Clin Proc.

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livered through the administration of 12 fortnightly doses of FOLFOX4 may be sufficient to achieve the advantages that accrue to patients treated with oxaliplatin-based combinations. In circumstances in which 2 regimens appear to have similar activity, the toxicity comparison across regimens becomes highly relevant. Predictably, grade 3 or higher diarrhea in the bolus fluorouracil-based FLOX arm of NSABP C-07 was 38% but was only 11% in the infusion fluorouracil-based Multicenter International Study of Oxaliplatin/5-Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer (MOSAIC) trial. Furthermore, in the NSABP C-07 trial, 56 patients (4.5%) treated with FLOX and 34 patients (2.7%) treated with fluorouracilleucovorin were hospitalized for treatment of gastrointestinal toxic effects characterized by diarrhea, dehydration, and bowel wall thickening or grade 3 or 4 diarrhea in conjunction with neutropenia and sepsis. The incidence of neutropenia in FLOX-treated patients was less than that reported with FOLFOX: 4% vs 41% (although the incidence of febrile neutropenia with FOLFOX was only 2%). The incidence of peripheral neuropathy was lower with FLOX: 85% and 92% had any grade of neuropathy and 8% and 12% had grade 3 neuropathy on FLOX and FOLFOX, respectively. The MOSAIC and NSABP C-07 trials, with their comparable improvements in the relative risk of relapse of 24% and 21%, respectively, have solidly shifted the standard of care to oxaliplatin plus fluorouracil-leucovorin. Preliminary data indicate that capecitabine can be safely combined with oxaliplatin.26 The most relevant comparison, that of FOLFOX vs capecitabine-oxaliplatin, will need to be ad-

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dressed in future trials. Such an equivalence trial would by necessity be large, has yet to open, and may in fact never occur. The 3 trials to date that have added irinotecan to fluorouracil-leucovorin in the adjuvant setting led to unanticipated disappointment. The Cancer and Leukemia Group B (CALGB) chaired the first trial, a US Intergroup study that compared the irinotecan plus bolus fluorouracil and leucovorin (IFL) regimen to bolus fluorouracil-leucovorin.27 This trial was amended to accrue additional patients beyond the original goal to provide greater statistical power. During this extension phase, the CALGB Data Safety Monitoring Committee stopped accrual because of toxicity concerns, including a high early toxic death rate of 2.1%. Outcomes were reported earlier than planned after a protocol-specified interim analysis indicated that IFL could not be proved superior to fluorouracil-leucovorin. In the second trial, the Pan European Trial in Adjuvant Colon Cancer 3, the addition of irinotecan to infusion fluorouracil-leucovorin favored but did not significantly improve 3-year DFS (P=.091).28 The third study that examined the potential benefits of adjuvant irinotecan was the French ACCORD2 (Action concertée dans les Cancers Colorectaux et Digestifs in the Adjuvant Treatment of Colon Cancer) trial.29 By design, this study limited its enrollment to 400 patients with stage III disease with high risk of recurrence because of N2 disease or N1 disease with concomitant perforation or obstruction. Again the irinotecan plus fluorouracil arm failed to show a benefit over fluorouracil-leucovorin. This outcome contrasts with the experience in the MOSAIC trial in which the subset of patients treated with FOLFOX accrued the greatest relative benefit with respect to DFS of all subsets enrolled. These trials indicate that currently irinotecan-based regimens should not be administered to patients in the adjuvant setting. Since the mid-1990s, the duration of adjuvant therapy chosen for clinical trials and in clinical practice approximated 6 months based on the results of the Intergroup 0089 trial and others. The 2 oxaliplatin-based studies, those evaluating irinotecan regimens and the X-ACT trial evaluating capecitabine, were designed to deliver 6 months of therapy. The single relevant study comparing 6 months of bolus fluorouracil-leucovorin to 3 months of protractedinfusion fluorouracil trended in favor of shorter-duration therapy but was underpowered and therefore not considered definitive.19 It is plausible that shorter treatment courses are adequate, and this should be considered when toxicity concerns lead patients and physicians to abbreviate the planned 6-month course of treatment. Two meta-analyses consider the relative benefits of adjuvant fluorouracil-leucovorin in patients 70 years and older. Both conclude that the benefits of fluorouracil-based 118

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chemotherapy extend to older people who were deemed fit enough and chose to enroll in the studies that were subject to combined analyses. Their survival benefit equals that of younger patients, and there is little, if any, evidence that this population has increased toxic effects, with the possible exception of the incidence of leukopenia.30,31 When older patients treated with oxaliplatin-fluorouracil combinations were compared with younger patients enrolled in the MOSAIC trial, the relative benefits and toxic effects were comparable regardless of age.32 It appears that comorbidities and patient preference rather than age should be the major determinants when older patients are confronted with potential adjuvant therapy decisions. Many potential molecular markers of prognosis and markers for prediction of response to therapy have been explored in series of patients with CRC, including thymidylate synthase, dipyrimidine dehydrogenase, ploidy, vascular and lymphatic density, and the presence or absence of microsatellite instability and of specific chromosomal rearrangements.33-35 Currently, the most important prognostic data remain those obtained from the gross and microscopic disease. A review of these markers is beyond the scope of this article. Two current trials are investigating 2 monoclonal antibodies, bevacizumab and cetuximab, comparing FOLFOX chemotherapy to FOLFOX plus one or the other antibody (NSABP C-08 and Intergroup N0147). Bevacizumab targets vascular endothelial growth factor (VEGF), inhibiting the ingrowth of new blood vessels and restoring a more normal pattern of vascular permeability. Cetuximab targets the epithelial growth factor receptor (EGFR), a stimulatory receptor found on at least 80% of colon cancer cells. When present, EGFR is associated with a pattern of aggressive growth and metastases. Several models with which to calculate the potential risk for patients based on important prognostic factors are available on the Internet. The Mayo Clinic adjuvant colorectal calculator is based on the combined analysis trial published by Gill et al and can be found at www.mayoclinic.com /calcs.14 Another evidence-based risk calculator can be found at www.adjuvantonline.com. These calculators can provide visual guidelines for physicians to present to patients during discussions of adjuvant therapy and can be particularly useful in discussing therapy for patients with stage II disease. ADJUVANT THERAPY FOR RECTAL CANCER Surgery remains the primary treatment in the management of localized cancers of the colon and rectum. For most curable colonic lesions, surgery alone or surgery in conjunction with systemic chemotherapy represents the standard of care in the United States.10,36 Radiotherapy has

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been more extensively incorporated into the treatment of cancers of the rectum than of the colon.37-39 A recently reported Intergroup trial (Intergroup 0130) demonstrated no benefit with the addition of adjuvant radiation therapy after resection for cancers of the colon.40 This article reviews current adjuvant chemoradiation approaches for the treatment of locally advanced rectal cancer, addresses areas of controversy, and provides an introduction to novel strategies currently under investigation. POSTOPERATIVE ADJUVANT CHEMORADIATION The use of adjuvant pelvic chemoradiation in resected, locally advanced rectal cancer has been shown to improve outcome vs surgery alone (Table 3).41-45 The impact of this treatment has been limited to improvements in local tumor control, whereas an OS benefit remains unclear. The Gastrointestinal Study Group 7175 trial randomized patients to surgery alone, surgery and adjuvant radiation, surgery and adjuvant fluorouracil-semustine chemotherapy, and surgery with adjuvant radiation and concurrent fluorouracilsemustine chemotherapy.41 A pairwise comparison demonstrated a statistically significant advantage in DFS and OS for patients receiving chemoradiation compared with patients treated with surgery alone. An NCCTG–Mayo Clinic trial randomized patients to either adjuvant radiation therapy or chemoradiation using fluorouracil-semustine chemotherapy.42 Local failure, DFS, and OS were all superior in the chemoradiation treatment arm. The study was criticized because it did not contain a surgery alone or chemotherapy alone treatment arm. In early 1990, the Consensus Development Conference on adjuvant therapy for patients with colon and rectal cancers was held at the National Institutes of Health.43 Based on updated data from the Gastrointestinal Study Group, NCCTG-Mayo, and NSABP44 experiences, combined modality treatment with fluorouracil-based chemotherapy and pelvic irradiation was recommended as standard therapy for patients with locally advanced rectal cancer. A more recent report from the NSABP R-02 has confirmed improved local control for patients receiving postoperative chemoradiation; the cumulative incidence of locoregional recurrences was reduced from 13% to 8% at 5 years. However, no concomitant prolongation occurred in DFS or OS.45 The subsequent Intergroup 0114 trial randomized 1695 patients with locally advanced rectal cancer to 2 cycles of postoperative chemotherapy followed by chemoradiation therapy and then 2 additional cycles of chemotherapy. The chemotherapy regimens evaluated were bolus fluorouracil alone, fluorouracil and leucovorin, fluorouracil and levamisole, and fluorouracil with leucovorin and levamisole. Toxicity, relapse-free survival, and OS were similar between all treatment arms. The authors concluded that the Mayo Clin Proc.

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TABLE 3. Selected Randomized Adjuvant Postoperative Chemoradiation Trials* Clinical trial

Local failure rate (%)

Survival rate (%)

24 20 21

32 43 46

11

56

25

48

14

58

25 21 16

43 53 NS

13 8

58 58

GITSG 198541 (N=202) Observation Radiation Fluorouracil-semustine Radiation and fluorouracilsemustine Mayo/NCCTG42 (N=204) Radiation Radiation and fluorouracilsemustine NSABP R-0144 (N=555) Observation MOF chemotherapy Radiation NSABP R-0245 (N=694) Fluorouracil chemotherapy Radiation and fluorouracil

*GITSG = Gastrointestinal Tumor Study Group; MOF = semustine, vincristine, and fluorouracil; NCCTG = North Central Cancer Treatment Group; NSABP = National Surgical Adjuvant Breast and Bowel Project.

results of the 0114 trial did not support the use of postoperative chemotherapy regimens other than those using fluorouracil alone. One of the most commonly used postoperative regimens in the United States comes from the experience reported by O’Connell et al.46 In this trial of 660 patients, patients were randomized to postoperative bolus fluorouracil or protracted venous infusion fluorouracil during radiation therapy. Patients receiving the protracted infusion fluorouracil had an increased time to relapse (P=.01) and improved survival (P=.005). NEOADJUVANT RADIATION European groups have successfully moved forward with evaluating the use of preoperative radiation (alone) in patients with rectal cancer. The Swedish Rectal Cancer Trial randomized 1110 patients with T1-3 rectal cancer to surgery alone vs preoperative hypofractionated radiation (25 Gy in 5 fractions) followed by surgery.47 The investigators observed that patients randomized to the preoperative radiation arm experienced not only improved local tumor control, 89% vs 73%, but also improvement in OS, 58% vs 48% at 5 years (P=.004). A recent meta-analysis of preoperative radiation trials confirmed an improvement in local control, DFS, and OS for patients receiving preoperative radiation therapy compared with surgery alone.48 To try to discern the impact of improved surgical techniques on locoregional tumor control and survival, the Dutch Colorectal Cancer Group recently completed a trial randomizing patients to TME with or without preoperative radiation therapy.49 The mesorectum refers to the lymphcontaining fatty tissue that surrounds the rectum encased in

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the endopelvic fascia. Because the mesorectum contains most of the lymphatic drainage from the rectal bowel wall, adequate lymphadenectomy depends on adequate mesorectal excision. The TME reflects a surgical technique that mandates a sharp surgical dissection along the entire rectum and mesorectum en bloc.50 This method was developed to minimize the risk of residual nodal tissue and maximize the circumferential surgical margin. Heald et al51 reported a local failure rate of 8% at 10 years in a study of 519 patients undergoing TME surgery alone. In the Dutch trial, patients with rectal cancer were randomized to either a TME alone or TME after a preoperative course of radiation (5 Gy in 5 fractions for a total dose of 25 Gy). The authors observed that a short-term course of preoperative radiation before optimal TME surgery reduced the risk of local recurrence at 2 years from 8.2% to 2.4% (P<.001) in the entire cohort of patients. Thus, even in patients who undergo optimal surgery from physicians specifically trained in TME, preoperative radiation therapy reduces the incidence of local failure. As one might expect, the magnitude of the benefit of radiation was greater in patients with more advanced disease; patients with stage III disease after TME alone had a local failure rate of 15% vs 4.3% in patients receiving preoperative radiation therapy. The importance of delivering chemotherapy concurrent with conventional preoperative radiation was recently evaluated by Gerard et al.52 In this randomized trial, 733 patients with locally advanced rectal cancer were randomized to radiation alone (45 Gy for 25 fractions) vs radiation delivered with concurrent bolus fluorouracil (350 mg/m2) and folinic acid (20 mg/m2) on days 1 to 5 during weeks 1 and 5 of the radiation. Although survival between the arms was not different, 12% of patients randomized to the chemoradiation treatment arm experienced a pathologic complete response vs 4% for those patients receiving radiation alone (P<.0001). Local failure was observed in 17% of patients receiving radiation alone vs 8% of patients receiving chemoradiation. In a similar trial, the European Organisation for Research and Treatment of Cancer 22921 study randomized 1011 patients to conventional preoperative radiation alone vs concurrent fluorouracil-based chemoradiation.53 The study also included a second postsurgery randomization to either observation or 4 cycles of additional fluorouracil chemotherapy. Although survival results were not reported, local control was improved for patients randomized to preoperative chemoradiation: 17% of patients in the preoperative radiation alone arm experienced local failure vs 9% of patients receiving chemoradiation. In summary, neoadjuvant hypofractionated radiation improves locoregional disease control after TME, and preoperative conventional radiation delivered in combination with fluorouracil-based chemotherapy is superior to radiation alone. 120

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PREOPERATIVE VS POSTOPERATIVE CHEMORADIATION Attempts in the United States to answer the important question of whether adjuvant preoperative chemoradiation therapy is comparable or superior to postoperative chemoradiation have been unsuccessful. The NSABP R-03 trial randomized 267 patients to preoperative vs postoperative fluorouracil-based chemoradiation (using conventional radiation doses and techniques). This trial was closed before completion because of poor accrual; however, the available results suggested an advantage for undergoing a sphincter-preserving surgery for patients randomized to the preoperative treatment arm, whereas surgical complications and DFS were similar between the 2 groups.54,55 In the recently completed German Rectal Cancer Study Group, patients were randomized to conventional radiation therapy and concurrent fluorouracil-based chemotherapy delivered either preoperatively or postoperatively.56 Although the OS between the 2 arms was similar, the 5-year cumulative incidence of local relapse was 6% for patients receiving preoperative chemoradiotherapy vs 13% for patients treated in the postoperative group (P=.006). Toxicity was also improved with preoperative therapy; grade III/IV acute toxicity was reported in 27% of the preoperatively treated patients vs 40% in the postoperative treatment group (P=.001). These data confirm that preoperative chemoradiation results in comparable survival compared with postoperative therapy for patients with locally advanced rectal cancer and may provide a local control advantage. CONTROVERSIES The Role of Local Excision. The traditional surgical approach to rectal cancers has been low anterior resection of the rectum or abdominoperineal resection, both of which have attendant risks of morbidity.57 Some patients are willing to trade the potential survival benefits offered by radical resection and resultant colostomy in favor of a less invasive surgical resection.58 In response to these concerns, more aggressive sphincter-sparing approaches, such as local excision, have been more frequently used for highly selected patients with localized rectal cancer. The 3 operative approaches for local excision of a distal rectal lesion are transanal, posterior transsphincteric (York-Mason procedure), and posterior proctotomy (Kraske procedure). Patient selection for local excision (vs conventional resections) is paramount for optimizing the opportunity for complete surgical resection. In general, the best candidates for local excision include patients with small, low-lying tumors confined to the muscularis propria. Positive margins or unfavorable pathologic criteria are associated with higher rates of locoregional failure.59 The results of 2 major prospective trials that evaluated the role of local excision in the treatment of early-stage

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rectal cancer have been reported. The long-term results of the Radiation Therapy Oncology Group trial 89-02 were recently published.60 In this prospective study, 65 patients were assigned to 3 treatment arms based on pathologic data, including tumor size, T stage, histologic grade, and margin status. The 3 arms included observation or adjuvant treatment with fluorouracil and 1 of 2 different dose levels of local-regional radiation therapy. With a median followup of 6.1 years, the 5-year local failure rate was 12%. In the CALGB 8984 study, patients with early stage cancers treated with either local excision alone (T1) or excision and adjuvant pelvic chemoradiation (T2) demonstrated a 78% DFS at 6 years and an 85% OS.61 Of the 9 patients who experienced isolated local recurrence, 5 underwent salvage abdominoperineal resection and were without evidence of disease at 2 to 7 years after surgery. These results suggest that adequate salvage can be achieved in selected patients. In summary, local excision for patients with curative rectal cancer remains investigational. Long-term follow-up from the CALGB 8984 study will be important in understanding the risk of late recurrences after local excision with or without chemoradiation in this setting. Adjuvant Chemoradiation for Stage IIa/IIIa Disease. As suggested by Wolmark, the lead investigator of the adjuvant NSABP R-02 trial, it is not clear that a “5% absolute decrease in the cumulative incidence of locoregional relapse is sufficient to justify the routine use of postoperative radiotherapy.”45 In a retrospective review of 117 patients with T3 N0 rectal disease, Willett et al62 defined a subset of patients (well to moderately differentiated tumors extending ≤2 mm into the perirectal fat without lymphatic or vascular invasion) who experienced a 10-year local control and recurrence-free survival rate of 95% and 87%, respectively, after surgical resection alone. Tepper et al,63 using data from the Intergroup 0114 trial, defined tumors as either low risk (T1-2 N+ or T3 N0) or high risk (T3 N+ and T4). Patients in the low-risk group had a local failure rate of 9% at 5 years compared with 18% for patients in the high-risk group (P<.0001). Overall, the 7-year survival rates were 70% and 45% for the low-risk and high-risk groups, respectively. In a pooled analysis reported by Gunderson et al,64 patients with T1-2 N1 and T3 N0 lesions had a 5-year survival of 85% and 84%, respectively, when treated with surgery followed by chemotherapy. These results were similar to those achieved with surgery and chemoradiation, respectively: a 5-year survival of 78% to 83% for patients with T1-2 N1 lesions and 74% to 80% for patients with T3 N0 tumors. Surgery and chemotherapy for patients with T1-2 N1 lesions resulted in a local failure rate of 5%, which is not different from the local failure observed in patients undergoing surgery and chemoradiation (5%-7%). For patients with T3 N0 tumors undergoing surgery and chemotherapy, the Mayo Clin Proc.

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local failure rate increased to 11%, which again was not substantially different from patients receiving adjuvant chemoradiation (local failure ranged from 5% to 10%). As suggested by Tepper et al,63 the role of adjuvant chemoradiation is unclear for patients with T1-2 N+ or T3 N0 disease, tumors for which the surgeon has been formally trained to perform a TME and for which there is pathologic confirmation that a TME resection has been performed. The CALGB is currently considering a surgical trial to discern the need for adjuvant therapy for patients with stage IIa/IIIa disease. NOVEL CHEMORADIATION STRATEGIES IN RECTAL CANCER Irinotecan. Irinotecan, a plant alkaloid isolated from Camptotheca acuminata, is a topoisomerase I inhibitor with established activity in colon cancer.65,66 Available clinical data for the concurrent administration of radiation and irinotecan for patients with locally advanced rectal cancer are limited but expanding. Minsky et al67 reported the results of a preoperative strategy incorporating daily low-dose irinotecan and pelvic radiation. In this phase 1 trial, patients received bolus irinotecan daily during weeks 1, 2, 4, and 5 of the pelvic radiation, for a total dose of 50.4 Gy. A daily dose of 10 mg/m2 was declared the maximum tolerated dose (MTD), with diarrhea and neutropenia as the dose-limiting toxic effects. The investigators have subsequently abandoned the phase 2 study because of excessive gastrointestinal-related toxic effects. Mitchell et al,68 using weekly administration of irinotecan, reported the results of their phase 1/2 study of irinotecan, fluorouracil, and concurrent pelvic radiation at the annual American Society of Clinical Oncology meeting in 2001. Patients with primary or recurrent clinical stage T3-4 adenocarcinoma of the rectum received escalating doses of irinotecan, 30 to 50 mg/m2, throughout 90 minutes on days 1, 8, 15, and 22 of the radiation. The fluorouracil was administered as a protracted venous infusion at a daily dose of 300 mg/m2 initially and subsequently reduced to 225 mg/m2 on days 1 to 5 weekly (also during pelvic radiation). The total dose of radiation was 54 Gy given in 1.8-Gy daily fractions. Surgery was performed 8 to 10 weeks after the completion of therapy. Of the 46 patients who were able to undergo surgery, an encouraging 11 patients (24%) demonstrated a complete pathologic response. As concluded by the investigators, treatment with preoperative irinotecan, fluorouracil, and radiation for locally advanced rectal cancer is feasible. The MTD for weekly irinotecan in this trial was 50 mg/m2. In an expanded evaluation of the phase 1 results reported by Mohiuddin et al,69 the Radiation Therapy Oncology Group completed a randomized phase 2 trial of 106 patients with locally advanced rectal cancer. Patients received either preoperative infusion fluorouracil and pelvic radiation or preoperative infusion fluorouracil plus irinotecan and pelvic

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Surgically resectable adenocarcinoma of the rectum

Stratification Sex Clinical stage Intent of type of surgery (sphincter saving; non–sphincter saving)

Randomization

Group 1 Fluorouracil, 225 mg/m2, and 50.4 Gy of radiation

Group 2 Fluorouracil, 225 mg/m2, oxaliplatin, 50 mg/m2, and 50.4 Gy of radiation

Group 3 Capecitabine, 825 mg/m2, and 50.4 Gy of radiation

Group 4 Capecitabine, 825 mg/m2, oxaliplatin, 50 mg/m2, and 50.4 Gy of radiation

FIGURE 1. National Surgical Adjuvant Breast and Bowel Project R-04 treatment schema.

radiation. Of the 106 patients, 96 were evaluable for response. The toxicity and pathologic complete response rates (RRs) were identical: 26% for patients receiving radiation and fluorouracil vs 26% for patients in the experimental arm. Although the results have been presented only in abstract form, it is unclear that the addition of irinotecan to standard fluorouracil-based preoperative chemoradiation provides an advantage in this clinical setting. Capecitabine. As discussed previously, fluorouracil as continuous infusion remains a common schedule when used in the setting of preoperative chemoradiation. However, this dosing schedule of fluorouracil requires specialized pumps and long-term venous access. Capecitabine is a fluoropyrimidine carbamate that is converted to the active fluorouracil by the action of 3 enzymes: an esterase, a deaminase, and a phosphorylase. The latter enzyme, thymidine phosphorylase, has higher concentrations in many tumor types compared with matched normal tissue and is particularly higher in excised human colon cancer. This finding suggests that higher tumor concentrations of fluorouracil might be expected because of a higher production of active drug in the tumor tissue, providing a favorable target-to-nontarget ratio for radiosensitization. In one of the initial reports to evaluate radiation and capecitabine, Kim et al70 treated 45 patients with locally advanced rectal cancer with preoperative chemoradiation. Conventional radiation of 45 Gy for 25 fractions was delivered concur122

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rently with 2 cycles of 14-day oral capecitabine (1650 mg/ m2 daily) and leucovorin, each of which was followed by a 7-day rest period. Toxicity was modest and consistent with fluorouracil therapy, and a pathologic complete response was achieved in 31% of patients. A similar experience has been reported by De Paoli et al.71 In this phase 2 trial of 53 patients, preoperative capecitabine (1650 mg/m2 daily) was given concurrent with conventional radiation (50.4 Gy for 28 fractions). Eighty-nine percent of patients completed therapy with modest toxic effects. A pathologic complete response was observed in 24% of patients, whereas 59% of patients with low-lying tumors (≤5 cm from anal verge) were able to undergo a sphincter-preserving surgery. The combination of capecitabine, oxaliplatin, and radiation has also been reported. In a phase 1 study reported by Glynne-Jones et al,72 capecitabine was dose escalated and delivered with concurrent oxaliplatin (130 mg/m2 on days 1 and 29) and conventional pelvic radiation therapy. The MTD of capecitabine was 1650 mg/m2 daily. Although significant diarrhea was observed in 2 patients at the MTD dose, 5 patients at the time of surgery had no residual disease. Rodel et al,73 in a trial with 32 patients, elected to proceed with standard dose capecitabine (1650 mg/m2) and radiation but to dose escalate the oxaliplatin. The MTD for weekly oxaliplatin was 50 mg/m2, with unacceptable gastrointestinal toxic effects observed at the 60-mg/m2 dose level. As depicted in Figure 1 and discussed later, a phase 3

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trial is currently under way to further evaluate the combination of conventional radiation and concurrent capecitabineoxaliplatin chemotherapy. Oxaliplatin. The antitumor activity of oxaliplatin in patients with CRC has been clearly established.74 Given these encouraging clinical data and the preclinical data suggesting that oxaliplatin has radiation-sensitizing properties, several phase 1/2 studies evaluating the combination have been reported.38 Freyer et al75 reported phase 1 data on 17 patients with locally advanced rectal cancer. Patients received dose-escalated oxaliplatin (80 mg/m2, 100 mg/m2, or 130 mg/m2) followed by bolus L-folinic acid (100 mg/m2 daily) and continuous infusion fluorouracil (350 mg/m2 daily) with concurrent pelvic radiation (45 Gy given through 5 weeks in 1.8-Gy fractions). The chemotherapy was given during the first and last weeks of radiation. The dose-limiting toxic effects of asthenia, severe diarrhea, and vomiting were observed in 1 patient at the 130-mg/m2 dose level. Two of the 8 patients who underwent surgery had complete pathologic responses. The authors recommend 130 mg/m2 as the safe dose for phase 2 evaluation. The Eastern Cooperative Oncology Group (ECOG) and the CALGB have conducted trials evaluating preoperative concurrent radiation and oxaliplatin. In the ECOG trial, oxaliplatin was given 3 times at 14-day intervals in 3 dose cohorts, 55, 70, and 85 mg/m2, concurrent with 5 weeks of conventional pelvic radiation and infusion fluorouracil chemotherapy.76 Sixteen patients were enrolled with no unanticipated toxic effects at any dose level. Seven of 12 patients had either a pathologic complete response or microscopic residual disease. The recommended phase 2 dose was 85 mg/m2. In the CALGB trial, oxaliplatin was delivered on a weekly schedule concurrent with standard radiation and infusion fluorouracil chemotherapy.77 The recommended phase 2 dose was 60 mg/m2. The investigators also observed an encouraging pathologic complete RR of 25%. The results of this trial were subsequently incorporated into the ongoing NSABP trial discussed subsequently. Current US Cooperative Group Chemoradiation Trial. At present, the Intergroup is comparing preoperative radiation and concurrent capecitabine with or without oxaliplatin with preoperative radiation and continuous intravenous infusion fluorouracil with or without oxaliplatin for patients with locally advanced rectal cancer (Figure 1). The primary aims of the study are to compare the rate of local-regional relapse in patients receiving preoperative oral capecitabine and radiation to that of patients receiving continuous infusion fluorouracil and radiation. The trial will also compare the local-regional relapse in patients receiving preoperative oxaliplatin with those not receiving oxaliplatin. It is anticipated that this trial will accrue apMayo Clin Proc.

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proximately 1600 patients and require 3 to 4 years to complete. In a concept currently under review at the National Cancer Institute, ECOG proposes to randomize 2100 patients with locally advanced rectal cancer to one of the following adjuvant regimens: fluorouracil-based chemoradiation followed by multiple cycles of oxaliplatin-fluorouracil-leucovorin chemotherapy vs the same radiation followed by oxaliplatin-fluorouracil-leucovorin-bevacizumab. This study will provide important information on the role of anti-VEGF agents in the adjuvant treatment of rectal cancer. In summary, standard therapy for patients with locally advanced rectal cancer involves delivering conventional radiation in combination with fluorouracil-containing chemotherapy. A preoperative approach yields comparable survival and perhaps improved local tumor control compared with postoperative chemoradiation therapy. Clinical trials evaluating fluorouracil-oxaliplatin and radiation in this clinical setting have confirmed the feasibility of this combination, and an ongoing phase 3 trial is under way to establish the potential improved efficacy of this approach. THERAPY FOR ADVANCED CRC Among patients with newly diagnosed CRC, 25% will present with metastatic disease. An additional 30% of those with localized resectable disease will subsequently develop a metastatic recurrence. Although a proportion of selected patients with liver and/or lung limited oligometastases may be amenable to curative-intent resection, systemic therapy remains the main treatment strategy. Recent improvements in median survival have been significant, with survival approaching up to 2 years with treatment78 compared with an estimated survival of 6 months with best supportive care alone. Treatment regimens discussed in this section are summarized in Table 4. FIRST-LINE SYSTEMIC THERAPY N9741 was an Intergroup trial that compared 3 randomassignment allocations: FOLFOX4 and irinotecan plus oxaliplatin to IFL, the standard first-line regimen for metastatic CRC at the time of this study.79 FOLFOX4 was associated with superior time to progression (TTP) (8.7 vs 6.9 months; P=.0014), RR (45% vs 31%; P=.002), and median survival (19.5 vs 14.8 months; P=.0001) compared with IFL. The IFL regimen also resulted in more diarrhea, vomiting, nausea, and febrile neutropenia, whereas patients following the FOLFOX4 regimen experienced higher rates of paresthesias. Although IFL is no longer recommended for first-line therapy, the combination of folinic acid with infusion fluo-

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TABLE 4. Description of Chemotherapy Regimens Discussed in This Review* Leucovorinfluorouracil 2 IFL IROX FOLFOX4 FOLFOX6 FOLFOX7 FOLFIRI FUFOX FOLFOXIRI CAPIRI CAPOX XELIRI XELOX

Leucovorin, 400 mg/m2, on day 1 with bolus fluorouracil, 400 mg/m2, followed by a 46-h infusion of fluorouracil, 2400-3000 mg/m2, every 2 wk Irinotecan, 125 mg/m2, with bolus fluorouracil, 500 mg/m2, and leucovorin, 20 mg/m2, on days 1, 8, 15, and 22 every 6 wk Oxaliplatin, 85 mg/m2, on day 1 with bolus fluorouracil, 400 mg/m2, and leucovorin, 200 mg/m2, followed by a 22-h infusion of fluorouracil, 600 mg/m2, on days 1 and 2 every 2 wk Oxaliplatin, 85 mg/m2, on day 1 with bolus fluorouracil, 400 mg/m2, and leucovorin, 200 mg/m2, followed by a 22-h infusion of fluorouracil, 600 mg/m2, on days 1 and 2 every 2 wk Oxaliplatin, 100 mg/m2, with bolus fluorouracil, 400 mg/m2, and leucovorin, 400 mg/m2, followed by a 46-h infusion of fluorouracil, 2400 mg/m2, every 2 wk Oxaliplatin, 130 mg/m2, leucovorin, 400 mg/m2, and a 46-h infusion of fluorouracil, 2400 mg/m2, every 2 wk Irinotecan, 180 mg/m2, with bolus fluorouracil, 400 mg/m2, and leucovorin, 400 mg/m2, followed by a 46-h infusion of fluorouracil, 2400 mg/m2, every 2 wk Oxaliplatin, 50 mg/m2, with leucovorin, 500 mg/m2, and a 24-h infusion of fluorouracil, 2000 mg/m2, on days 1, 8, 15, and 22 every 5 wk Irinotecan, 165 mg/m2, on day 1, oxaliplatin, 85 mg/m2, on day 1, leucovorin, 200 mg/m2, followed by a 48-h infusion of fluorouracil, 3200 mg/m2, every 2 wk Capecitabine, 1000 mg/m2, orally twice daily on days 1 to 14 plus irinotecan, 80 mg/m2, on days 1 and 8 Capecitabine, 1000 mg/m2, orally twice daily on days 1 to 14 and oxaliplatin, 70 mg/m2, on days 1 and 8 every 21 d Capecitabine, 1000 mg/m2, orally twice daily on days 1 to 14 plus irinotecan, 250 mg/m2, on day 1 every 21 d Capecitabine, 1000 mg/m2, orally twice daily on days 1 to 14 plus oxaliplatin, 130 mg/m2, on day 1 every 21 d

*CAPIRI = capecitabine plus irinotecan; CAPOX = capecitabine plus oxaliplatin; FOLFIRI = folinic acid with infusion fluorouracil and irinotecan; FOLFOX = folinic acid with infusion fluorouracil and oxaliplatin; FOLFOXIRI = folinic acid with infusion fluorouracil, oxaliplatin, and irinotecan; IFL = irinotecan plus bolus fluorouracil and leucovorin; IROX = irinotecan plus oxaliplatin; XELIRI = capecitabine and irinotecan; XELOX = capecitabine plus oxaliplatin.

rouracil and irinotecan (FOLFIRI) is a reasonable doublet choice for first-line chemotherapy. In a French study (Groupe Coopérateur Multidisciplinaire en Oncologie), 220 patients with metastatic CRC were randomly assigned to a sequence of FOLFIRI followed by FOLFOX6 or the reverse.80 Both strategies (FOLFOX6-FOLFIRI or FOLFIRI-FOLFOX6) achieved impressive equivalent first-line RRs (54% and 56%, respectively) and median survivals (20.6 and 21.5 months, respectively). Equivalent RR efficacy was also demonstrated in the randomized trial of first-line FOLFOX4 (36%) vs FOLFIRI (34%) reported by Colucci et al.81 In both these trials, toxic effects varied, with nausea, mucositis, and alopecia more frequent with FOLFIRI and neutropenia and paresthesias more frequent with FOLFOX. Strategies to best optimize the use of available chemotherapies are being evaluated. To address whether an approach of first-line doublet therapy is superior to a single staged approach (drug A until it fails, then drug B until it fails) or a staged combination approach (drug A until it fails, then add drug B until both fail), the United Kingdom Medical Research Council completed the FOCUS (Fluorouracil, Oxaliplatin, and CPT-11 [irinotecan] Use and Sequencing) randomized trial.82 Although the staged combi124

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nation approach was equivalent to first-line combination therapy, a trend toward inferiority was observed for the single staged approach. The amelioration of treatmentrelated toxic effects is also a priority. The major doselimiting toxicity of oxaliplatin is cumulative neuropathy. The optimized fluorouracil-oxaliplatin 1 (OPTIMOX1) trial83 randomly assigned patients to FOLFOX4 until progression or to OPTIMOX1, a strategy of 6 cycles of modified FOLFOX7 followed by maintenance leucovorin–fluorouracil 2 for 12 cycles. For patients with nonprogressive disease, FOLFOX7 was then reintroduced. Overall RR, progression-free survival, and survival were similar despite the decreased use of oxaliplatin in the OPTIMOX1 arm. The next generation of OPTIMOX trials are evaluating a stop-and-go strategy (no maintenance leucovorin–fluorouracil 2 [OPTIMOX2]) and integration of molecular targeted therapies (OPTIMOX3). Biweekly infusion fluorouracil therapy is inconvenient, and the use of the oral fluorouracil prodrug capecitabine appears promising. In a randomized phase 2 trial of capecitabine plus irinotecan or oxaliplatin, substantial first-line RRs (42.6% and 51.3%, respectively) and TTP (7.9 and 7.9 months, respectively) were seen.84 A phase 2 trial of the capecitabine plus oxaliplatin regimen also reported a simi-

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lar tolerability and efficacy with a first-line RR of 55%, a TTP of 7.7 months, and median survival of 19.5 months.85 Phase 3 trials are ongoing, particularly comparing infusion fluorouracil-leucovorin plus oxaliplatin with capecitabine plus oxaliplatin as first-line therapy. In one such trial, when compared with the weekly Arbeitgeneinschaft Internische Onkologie regimen plus oxaliplatin, capecitabine plus oxaliplatin achieved comparable RRs (45% vs 41%) and progression-free survival (35 vs 30 weeks).86 Recognizing that exposure to all 3 active chemotherapy agents extends survival78 and that a proportion of patients may not be suitable for second-line therapy, the strategy of combining oxaliplatin, irinotecan, and fluorouracil in a single first-line regimen may be of interest.87 In a randomized trial of folinic acid with infusion fluorouracil, oxaliplatin, and irinotecan (FOLFOXIRI) vs FOLFIRI, conducted by the Gruppo Oncologico Nord Ovest, FOLFOXIRI yielded a superior RR (60% vs 34%; P<.0001), progression-free survival (9.8 vs 6.9 months; P=.0006), and OS (22.6 vs 16.7 months; P=.03).88 Diarrhea, vomiting, and neutropenia were also more common in the triplet arm. Bevacizumab (Avastin, Genentech, South San Francisco, Calif) is a humanized monoclonal antibody to VEGF-A, thus halting the VEGF signaling pathway. Emerging evidence suggests that the observed additive efficacy of cytotoxic fluorouracil-based chemotherapy when combined with bevacizumab is mediated by anti-VEGF–induced vascular normalization, which may alleviate hypoxia and improve drug delivery.89 The pivotal trial was a randomized comparison of first-line IFL plus placebo with IFL plus bevacizumab, 5 mg/kg every 2 weeks.90 In this trial, median survival was increased from 15.6 to 20.3 months (P<.001) with the addition of bevacizumab, as were TTP (10.6 vs 6.2 months; P<.001) and RR (45% vs 35%; P=.004). Notable toxic effects with bevacizumab were limited to grade 3 hypertension (10.3% vs 2.3%), increased risk of arterial thromboembolic events, and rare reports of gastrointestinal perforation and wound dehiscence. Bevacizumab in combination with first-line fluorouracil-leucovorin monotherapy has been evaluated in 2 phase 2 trials91,92 and as a third treatment arm of the trial by Hurwitz et al,93 which was discontinued after a planned interim analysis established acceptable safety for the IFL plus bevacizumab arm. In a combined efficacy analysis of these 3 cohorts, the addition of bevacizumab to fluorouracil-leucovorin resulted in an improvement in survival (17.9 vs 14.6 months; P=.008), TTP (8.8 vs 5.6 months; P<.0001), and RR (34% vs 24%; P=.019).94 A randomized, phase 2, 2 × 2 factorial Intergroup trial of first-line FOLFOX vs capecitabine plus oxaliplatin with or without bevacizumab (Southwest Oncology Group trial 0303) was initiated in April 2004 but has since been closed because of poor accrual. Mayo Clin Proc.

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The VEGF signaling pathway can also be targeted by inhibition of the receptor tyrosine kinase. Valatanib (PTK787, Novartis International AG, Basel, Switzerland) is an oral small molecule tyrosine kinase inhibitor with pan-VEGF receptor activity. CONFIRM1 (colorectal oral novel therapy for the inhibition of angiogenesis and retarding of metastases in first line) was a randomized trial of first-line FOLFOX with or without valatanib.95 Reported last year, this study failed to meet its primary end point of improved TTP (7.7 vs 7.6 months; P=.118). At present, combination therapy with infusion fluorouracil and oxaliplatin or irinotecan is an appropriate choice for the first-line management of patients with reasonable performance status and unresectable metastatic CRC. For less fit patients with a poorer performance status, first-line monotherapy with fluorouracil-leucovorin or capecitabine remains a viable treatment option. It is further reasonable to combine either doublet or fluorouracil-leucovorin with bevacizumab in the first-line setting. SECOND-LINE CHEMOTHERAPY Selecting an appropriate second-line regimen depends on several factors, including the first-line regimen, the degree of response to first-line therapy, toxicity concerns, and the performance status of the patient. Rothenberg et al96 randomized 463 patients who progressed after IFL to leucovorin–fluorouracil 2, oxaliplatin alone, or FOLFOX4. The RRs (1%, 1%, and 10%, respectively) and TTP (8.1, 8.7, and 9.8 months, respectively) were superior for FOLFOX4. The role of sequential therapy was further highlighted in the previously described study by Tournigand et al.80 Eighty-two percent of patients receiving FOLFIRI received second-line FOLFOX with an RR of 15%, whereas 74% of patients receiving FOLFOX received second-line FOLFIRI with a modest RR of 4%. Giantonio et al97 recently reported the results of ECOG 3200, a randomized second-line trial of FOLFOX plus placebo vs FOLFOX plus bevacizumab vs bevacizumab alone in patients with IFL-refractory metastatic CRC. Survival, TTP, and RR with FOLFOX plus bevacizumab (10 mg/kg every 2 weeks) was superior to FOLFOX alone (12.9 vs 10.8 months, P=.0018; 7.2 vs 4.8 months, P<.001; and 22% vs 9%, P<.001, respectively). No meaningful activity was seen with single-agent bevacizumab (RR, 3%). The addition of bevacizumab to second-line chemotherapy is therefore an appropriate option in bevacizumabnaive patients. THIRD-LINE CHEMOTHERAPY AND BEYOND Standard therapeutic options are limited once a patient has exhausted fluorouracil, irinotecan, oxaliplatin, and bevacizumab treatment. Cetuximab (Erbitux, ImClone Systems,

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New York, NY) is a chimeric monoclonal antibody against the extracellular domain of EGFR. Earlier studies suggested efficacy in patients with irinotecan-refractory metastatic CRC.98,99 The BOND trial was a United Kingdom Medical Research Council randomized (2:1 assignment) phase 2 trial of irinotecan plus cetuximab (400-mg/mg2 loading dose then 250 mg/m2 weekly) or cetuximab alone in irinotecanrefractory metastatic CRC.100 More than 60% of enrolled patients had also previously progressed with oxaliplatin. The RRs (primary end point), TTP, and survival were 23%, 4.1 months, and 8.6 months, respectively, for irinotecan plus cetuximab and 11%, 1.5 months, and 6.9 months, respectively, for cetuximab alone. Cetuximab use was associated with an acneiform rash. Overexpression of EGFR as measured by immunohistochemical analysis does not appear to correlate with response but may be correlated with the severity of rash.100,101 Despite the lack of phase 3 survival data, cetuximab was approved in the United States, Canada, and the European Union for second- or subsequent-line therapy in patients with EGFR-positive, irinotecan-refractory metastatic CRC, recognizing that this was an area of an unmet medical need. A trial of interest is the recently completed National Cancer Institute of Canada Clinical Trials Group Study CO-17, which randomized patients with chemotherapyrefractory disease between cetuximab and best supportive care. Results are expected in 2006. EPIC (Erbitux Plus Irinotecan in Colon Cancer) (CA225-006) is a randomized trial of irinotecan plus cetuximab vs irinotecan alone in oxaliplatin-refractory advanced disease, whereas the EXPLORE (Erbitux Plus FOLFOX for Colorectal Cancer) trial (CA225-014) randomly assigns patients with irinotecan-refractory disease to second-line FOLFOX or FOLFOX plus cetuximab. A provocative randomized phase 2 study (BOND2) of cetuximab plus bevacizumab with or without irinotecan in 74 previously treated patients with advanced CRC was reported last year.102 The 3-drug combination was associated with a RR of 37% and a TTP of 7.9 months, which is remarkable for this otherwise chemotherapy-refractory population. BOND3 will examine a similar treatment assignment in bevacizumab-refractory patients. NEOADJUVANT CHEMOTHERAPY The liver is typically the initial and most common site of CRC metastases. Resection of liver-limited metastases can be curative in approximately 35% of selected patients.103 The likelihood of complete resection depends on the extent of hepatic involvement, tumor location, and hepatic reserve.104 Despite advances in surgery and the use of ablative techniques, including radiofrequency ablation and cryosurgery, most patients will still not be candidates for 126

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resection. With the availability of better systemic therapies, a neoadjuvant approach in patients with unresectable metastatic CRC has the potential to downstage disease to resectability and improve disease control and, potentially, curability. Emerging evidence supports a greater likelihood of resectability with an oxaliplatin-based regimen. In N9741, 26 (3.3%) of 795 randomized patients subsequently underwent curative metastasectomy; 92% of these patients had received an oxaliplatin-based regimen.105 Similarly, the rate of metastasectomy was higher with firstline FOLFOX vs FOLFIRI (13% vs 7%) in the trial by Tournigand et al.80 A trial of neoadjuvant chemotherapy can also be used as an in vivo test of chemosensitivity to guide postresection therapy and may identify those patients for whom surgery would not be appropriate. In a review of clinical trial patients with liver-limited unresectable metastases, the efficacy of neoadjuvant chemotherapy was a strong predictor for resectability of liver metastases.106 Consideration for neoadjuvant therapy may also be extended to patients with resectable disease, in whom it may facilitate more complete resections and limited hepatectomies. Recognizing that multiple treatment options may need to be considered in this setting, a computer-based decision model (OncoSurge) has been developed based on expert panel appropriateness ratings and best available evidence.107 We hope that the availability of such a tool will facilitate decisions regarding the appropriate local and systemic management of patients with primarily liver-limited metastatic disease. IS THERE A STANDARD SYSTEMIC STRATEGY FOR METASTATIC CRC? New effective chemotherapies and biologic therapies have introduced several potential treatment combinations for the management of metastatic CRC. The most advantageous strategy for using all available therapies and achieving maximal clinical benefit continues to be defined. At present, it is difficult to prescribe a single standard regimen for first- and subsequent-line therapy. The selection of therapy needs to be judicious and deliberate, based on an appraisal of the best available clinical evidence. Many questions remain, and patient enrollment in clinical trials should continue to be encouraged. The current Intergroup trial (CALGB/Southwest Oncology Group C80405) will randomize patients treated with either first-line FOLFOX or FOLFIRI to the addition of bevacizumab alone, cetuximab alone, or bevacizumab plus cetuximab. The statistical assumptions for this trial project an estimated survival of 27.5 months in the superior arms; this previously unimaginable magnitude of survival sets the tone for much of the excitement in this arena. However, with increasing choice comes increas-

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ing responsibility. One must reflect on the consequent potential clinical and financial toxic effects of such therapies. Ongoing and planned correlative studies investigating prognostic and predictive molecular and pharmacogenomic profiles will ultimately be invaluable to better individualize and rationalize treatment selections and prospectively identify patients most likely to benefit from a given therapy. SUMMARY The optimal management of CRC requires an evidencebased, multidisciplinary approach. Encouragingly, significant advances have been achieved on all fronts: surgical therapy, radiation therapy, and systemic therapy. This progress has been the consequence of efforts by multinational investigators and patients who have conducted and participated in well-designed clinical studies from around the world. The changes in practice resulting from past, present, and future research efforts have and will continue to translate into improved outcomes for our patients with both localized and advanced CRC. REFERENCES 1. Jemal A, Murray T, Ward E, et al. Cancer statistics, 2005 [published correction appears in CA Cancer J Clin. 2005;55:259]. CA Cancer J Clin. 2005;55:10-30. 2. Canadian Cancer Statistics. Toronto: Canadian Cancer Society; 2005. 3. Greenlee RT, Hill-Harmon MB, Murray T, Thun M. Cancer statistics, 2001 [published correction appears in CA Cancer J Clin. 2001;51:144]. CA Cancer J Clin. 2001;51:15-36. 4. Cecil TD, Sexton R, Moran BJ, Heald RJ. Total mesorectal excision results in low local recurrence rates in lymph node-positive rectal cancer. Dis Colon Rectum. 2004 Jul;47:1145-1149. Epub 2004 Jun 3. 5. Clinical Outcomes of Surgical Therapy Study Group. A comparison of laparoscopically assisted and open colectomy for colon cancer. N Engl J Med. 2004;350:2050-2059. 6. Bertagnolli MM, Redston M, Miedema B, et al. Sentinel node staging of resectable colon cancer: results of CALGB 80001 [abstract]. J Clin Oncol. 2004;22(suppl 14):246s. Abstract 3506. 7. Andre T, Boni C, Mounedji-Boudiaf L, et al, Multicenter International Study of Oxaliplatin/5-Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer (MOSAIC) Investigators. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med. 2004;350:2343-2351. 8. Moertel CG, Fleming TR, Macdonald JS, et al. Levamisole and fluorouracil for adjuvant therapy of resected colon carcinoma. N Engl J Med. 1990;322: 352-358. 9. Wolmark N, Fisher B, Rockette H, et al. Postoperative adjuvant chemotherapy or BCG for colon cancer: results from NSABP protocol C-01. J Natl Cancer Inst. 1988;80:30-36. 10. Moertel CG, Fleming TR, Macdonald JS, et al. Fluorouracil plus levamisole as effective adjuvant therapy after resection of stage III colon carcinoma: a final report. Ann Intern Med. 1995;122:321-326. 11. O’Connell MJ, Mailliard JA, Kahn MJ, et al. Controlled trial of fluorouracil and low-dose leucovorin given for 6 months as postoperative adjuvant therapy for colon cancer. J Clin Oncol. 1997;15:246-250. 12. Wolmark N, Rockette H, Fisher B, et al. The benefit of leucovorinmodulated fluorouracil as postoperative adjuvant therapy for primary colon cancer: results from National Surgical Adjuvant Breast and Bowel Project protocol C-03. J Clin Oncol. 1993;11:1879-1887. 13. Haller DG, Catalano PJ, Macdonald JS, et al. Phase III study of fluorouracil, leucovorin, and levamisole in high-risk stage II and III colon cancer: final report of Intergroup 0089. J Clin Oncol. 2005;23:8671-8678.

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79. Goldberg RM, Sargent DJ, Morton RF, et al. A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol. 2004 Jan 1;22:23-30. Epub 2003 Dec 9. 80. Tournigand C, Andre T, Achille E, et al. FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol. 2004 Jan 15;22:229-237. Epub 2003 Dec 2. 81. Colucci G, Gebbia V, Paoletti G, et al, Gruppo Oncologico Dell’Italia Meridionale. Phase III randomized trial of FOLFIRI versus FOLFOX4 in the treatment of advanced colorectal cancer: a multicenter study of the Gruppo Oncologico Dell’Italia Meridionale. J Clin Oncol. 2005 Aug 1;23:4866-4875. Epub 2005 Jun 6. 82. Seymour MT, for the UK NCRI Colorectal Studies Group. Fluorouracil, oxaliplatin and CPT-11 (irinotecan), use and sequencing (MRC FOCUS): a 2135-patient randomized trial in advanced colorectal cancer (ACRC) [abstract]. J Clin Oncol. 2005;23(suppl):250s. Abstract 3518. 83. Tournigand C, Cervantes A, Figer A, et al. 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;24:394-400. 84. Grothey A, Jordan K, Kellner O, et al. Randomized phase II trial of capecitabine plus irinotecan (Caplri) vs capecitabine plus oxaliplatin (CapOx) as first-line therapy of advanced colorectal cancer (ACRC) [abstract]. Proc Am Soc Clin Oncol. 2003;22:1022. Abstract 1022. 85. Cassidy J, Tabernero J, Twelves C, et al. XELOX (capecitabine plus oxaliplatin): active first-line therapy for patients with metastatic colorectal cancer. J Clin Oncol. 2004;22:2084-2091. 86. Arkenau H, Schmoll H, Kubicka S, et al. Infusional 5-fluorouracil/ folinic acid plus oxaliplatin (FUFOX) versus capecitabine plus oxaliplatin (CAPOX) as first line treatment of metastatic colorectal cancer (MCRC): results of the safety and efficacy analysis [abstract]. J Clin Oncol. 2005;23(suppl):247s. Abstract 3507. 87. Goetz MP, Erlichman C, Windebank AJ, et al. Phase I and pharmacokinetic study of two different schedules of oxaliplatin, irinotecan, fluorouracil, and leucovorin in patients with solid tumors. J Clin Oncol. 2003 Oct 15;21:3761-3769. Epub 2003 Sep 8. 88. Falcone A, Masi G, Murr R, et al. Biweekly irinotecan, oxaliplatin, and infusional 5FU/LV (FOLFOXIRI) versus FOLFIRI as first-line treatment of metastatic colorectal cancer (MCRC): results of a randomized, phase III trial by the Gruppo Oncologico Nord Ovest (GONO) [abstract]. In: Proceedings of the 2006 Gastrointestinal Cancers Symposium; San Francisco, Calif; January 26-28, 2006. Abstract 227. 89. Jain RK. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science. 2005;307:58-62. 90. Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004;350:2335-2342. 91. Kabbinavar F, Hurwitz HI, Fehrenbacher L, et al. Phase II, randomized trial comparing bevacizumab plus fluorouracil (FU)/leucovorin (LV) with FU/ LV alone in patients with metastatic colorectal cancer. J Clin Oncol. 2003; 21:60-65. 92. Kabbinavar FF, Schulz J, McCleod M, et al. Addition of bevacizumab to bolus fluorouracil and leucovorin in first-line metastatic colorectal cancer: results of a randomized phase II trial. J Clin Oncol. 2005 Jun 1;23:3697-3705. Epub 2005 Feb 28.

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