An Overview of Approaches to Adjuvant Therapy for Colorectal Cancer in the United States

An Overview of Approaches to Adjuvant Therapy for Colorectal Cancer in the United States Timothy J. Hobday Abstract Adjuvant chemotherapy for colon cancer and combined chemotherapy and radiation therapy (RT) for rectal cancer increases the proportion of patients cured of their disease. Adjuvant chemotherapy is indicated for stage III colon cancer, and although controversial for stage II disease, there is evidence to suggest that these patients may benefit as well.Adjuvant chemotherapy and RT is recommended for patients with stage II/III rectal cancer. Studies incorporating oral fluoropyrimidines as well as combination chemotherapy have been completed, with results demonstrating the value of these approaches.A new generation of studies will evaluate the biologic agents bevacizumab and cetuximab in the adjuvant therapy of colorectal cancer. For rectal cancer, optimal outcomes are dependent not only on the systemic therapy, but also on the expertise of the surgeon and the timing of RT, with improved local control and toxicity seen with preoperative therapy. Clinical Colorectal Cancer, Vol. 5, Suppl. 1, S11-S18, 2005 Key words: Bevacizumab, Cetuximab, Irinotecan, Oxaliplatin, Radiation therapy

Introduction Colorectal cancer (CRC) is the second leading cause of cancer death in the United States, with an estimated 145,000 new cases diagnosed in 2005 and > 56,000 deaths.1 The natural history of CRC resected for cure is well known and is predominantly predicted by tumor and nodal pathologic staging. The degree of primary tumor penetration and the number of regional lymph nodes involved by the cancer are independent prognostic factors for cure as reflected in the most recent American Joint Committee on Cancer tumornode–metastasis (TNM) staging system. Stage II (node-negative) disease was subdivided into stage IIA (T3N0) and stage IIB (T4N0), and stage III disease was subdivided into stages IIIA (T1/2N1), IIIB (T3/4N1), and IIIC (TXN2).2 Large datasets of patients treated with surgery alone support the clinically relevant differences in outcome based on this staging classification.3,4 The current TNM classification and estimates of 5-year overall survival (OS) are outlined in Table 1.2 As survival correlates with pathologic stage at diagnosis, continued research into the development and implementation of colorectal screening and prevention are of paramount importance in reducing the public health burden of CRC. Division of Medical Oncology, Department of Oncology, Mayo Clinic, Rochester, MN Submitted: Mar 1, 2005; Revised: Mar 22, 2005; Accepted: Mar 22, 2005 Address for correspondence: Timothy J. Hobday, MD, Mayo Clinic, 200 First St SW, Rochester, MN 55905 E-mail: [email protected]

Table 1 Stage

Tumor-Node–Metastais Stage and Approximate Survival with Resection Alone2 TNM Classification

Estimated 5-Year Survival (%)

T1/2N0M0

> 90

A

T3N0M0

65-75

B

T4N0M0

50-60

A

T1/2N1M0

50-55

B

T3/4N1M0

35-40

C

TXN2M0

20

TXNXM1

£5

I II

III

IV

Of those with resected CRC, approximately half will have disease relapse. With the exception of a small percentage of patients with disease relapse that is resectable for cure, recurrent disease will lead to death. The goal of adjuvant therapy is to significantly improve the natural history of resected CRC through eradication of micrometastatic disease in those at significant risk of recurrence, with close attention paid to longterm toxicity, because many patients considered for adjuvant therapy will be cured of their disease. Over the past few decades, a series of large prospective, randomized trials have clearly established a benefit for adjuvant 5-fluorouracil (5-FU)–based chemotherapy for stage III disease, with an improvement in 5-year OS associated

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Adjuvant Therapy of Colorectal Cancer with a reduction in mortality of 30%-35% compared with surgery alone across several studies.5-7 A beneficial role for adjuvant therapy in patients with stage II disease has yet to be proven in a prospective, randomized clinical trial; however, the existing evidence suggests that this population may also benefit. As the therapeutic options for CRC have rapidly expanded in the past decade, the outcomes for patients with metastatic disease has dramatically improved compared with the era of treatment with 5-FU alone, with almost a doubling of median survival for patients treated with 5-FU, irinotecan, and oxaliplatin.8 Bevacizumab, a monoclonal antibody against vascular endothelial growth factor (VEGF), has been shown to improve survival when added to combination chemotherapy (5-FU with irinotecan or oxaliplatin) compared with the same chemotherapy alone.9,10 Cetuximab, a monoclonal antibody against the epidermal growth factor receptor (EGFR), has also shown single-agent activity and synergy with chemotherapy in refractory advanced disease.11 These advances have already been incorporated into completed and ongoing trials in the adjuvant setting, with a benefit in terms of disease-free survival (DFS) demonstrated with FOLFOX4 (5-FU/leucovorin [LV]/oxaliplatin) versus 5-FU/LV alone.12 More data from this and the next generation of trials are eagerly anticipated. The anatomic features that distinguish colon from rectal cancer raise important issues regarding the treatment of this disease, particularly with regard to local control. Rectal cancer (generally defined as tumor located below the peritoneal reflection) is associated with an increased risk of local failure and generally requires expert surgery and radiation therapy (RT) integrated with chemotherapy for optimal results. This review will focus on the recent and ongoing results of clinical trials in the adjuvant therapy of CRC, with current recommendations and reflections from the perspective of a US oncologist.

Single Agent Fluoropyrimidines Modulated 5-Fluorouracil Monotherapy Regimens The value of modulated 5-FU regimens as adjuvant therapy for stage III colon cancer was firmly established by the North American Intergroup trial, INT-0035.5 This study confirmed and solidified the findings of an earlier North Central Cancer Treatment Group (NCCTG) trial6 and demonstrated a 40% reduction in the relative risk of recurrence and a 33% reduction in the risk of death with 1 year of 5-FU/levamisole compared with observation.5 Several refinements in the modulation of 5-FU (incorporating LV and shortening the length of treatment to 6-7 months) ensued, leading to the Intergroup study, INT-0089.13 This study established that 6-7 months of bolus 5-FU/LV administered daily for 5 days every 4-5 weeks (Mayo Clinic regimen) or weekly for 6 weeks of an 8-week cycle (Roswell Park regimen) was as effective as 1 year of 5-FU/levamisole and that levamisole did not add benefit to LV-containing regimens. Therefore, for the past decade, these 2 bolus 5-

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FU/LV regimens have been the standard approaches to adjuvant therapy for stage III disease in the United States.

Oral Fluoropyrimidines Two trials presented at the 40th Annual Meeting of the American Society of Clinical Oncology (ASCO) in 2004 suggested a role for oral pyrimidines in the adjuvant therapy of colon cancer. The National Surgical Adjuvant Breast and Bowel Project (NSABP) C-06 trial randomized patients with stage II/III disease to receive intravenous 5-FU/LV (Roswell Park schedule) versus oral uracil/tegafur and LV. With a mean duration of follow-up of 64 months; there was no difference in efficacy or toxicity between the treatment arms.14 Uracil/tegafur is not available in the United States, limiting the applicability of this trial. The Xeloda® in Adjuvant Colon Cancer Therapy (X-ACT) study compared oral capecitabine with the Mayo Clinic regimen of bolus 5-FU/LV in 1987 patients with stage III disease. The primary endpoint of the study was DFS; the study was powered to show noninferiority of capecitabine compared with 5-FU/LV. With a mean follow-up of almost 4 years, the primary endpoint of noninferiority of DFS was met. Interestingly, a trend toward improvement in 3-year DFS (hazard ratio [HR], 0.87; 95% CI, 0.751.00) and OS (HR, 0.84; 95% CI, 0.69-1.01) was seen with an absolute difference of 4% for each endpoint.15 These studies suggest that oral fluoropyrimidines may be substituted for intravenous 5-FU monotherapy regimens but does not let us draw conclusions regarding this substitution in combination chemotherapy regimens. Several ongoing or recently completed trials should be reported in the near future. A trial comparing capecitabine monotherapy versus capecitabine/oxaliplatin has completed accrual. The Quick and Simple and Reliable (QUASAR) 2 study compares capecitabine alone with capecitabine in combination with irinotecan. Another trial compares capecitabine/oxaliplatin with FOLFOX. The integration of bevacizumab is also being investigated in these ongoing capecitabine-based trials.

Integration of Newer Agents with 5-Fluorouracil At least 4 large randomized phase III trials have completed accrual comparing 5-FU monotherapy regimens with combination regimens including irinotecan (2 trials) or oxaliplatin (2 trials). We now have efficacy data for 2 of these trials.

5-Fluorouracil/Leucovorin and Oxaliplatin The MOSAIC trial enrolled 2246 patients with stage II (40%) or stage III (60%) colon cancer12 (Table 212,16). Patients were randomized to receive 12 cycles of bolus 5-FU/LV followed by a 22-hour infusion of 5-FU on days 1 and 2 every 14 days (LV5FU2) or FOLFOX4, which is the identical 5-FU/LV schedule with oxaliplatin at 85 mg/m2 given on day 1.12 The primary endpoint of the trial was 3-year DFS. With a median follow-up of 38 months, there was a statistically significant advantage in this endpoint for FOLFOX4 over 5-FU/LV alone, with 3-year DFS rates of 78.2% and 72.9%, respec-

Timothy J. Hobday tively (P = 0.002). All-cause mortality in Table 2 MOSAIC Trial: FOLFOX4 Versus LV5FU2 as Adjuvant Therapy this trial was acceptable at 0.5% in both of Stage II/III Colon Cancer12,16 arms. Modest increases in hematologic 3-Year Disease-Free 4-Year Disease-Free 4-Year Overall Group (N) Regimen and gastrointestinal side effects were Survival Survival Survival seen with the combination that included All Patients 84% FOLFOX4 78.2% 76% P = 0.002 P = 0.0008 P = NS oxaliplatin. The main toxicity concern (N = 2246) 82.4% LV5FU2 72.9% 69% with the FOLFOX4 regimen is peripherExploratory al neuropathy. Grade 3 neuropathy interSubset fering with function was seen in 12.4% Analyses of patients, and grade 2 neuropathy was Stage III FOLFOX4 72.2% 69.7% NA seen in an additional 31.6%. After 18 (n = 1347) LV5FU2 65.3% 61.0% months’ follow-up, persistent grade 3 Stage II FOLFOX4 87.0% 85.1% NA neuropathy remained in only 0.5% of pa(n = 899) LV5FU2 84.3% 81.3% tients, with 3.4% experiencing persisting High-Risk FOLFOX4 84.9% grade 2 neuropathy. The observed early Stage II NA NA LV5FU2 79.8% (n = 576)* and late resolution of serious neuropathy is encouraging even though 25% of paAbbreviations: NA = not available; NS = not significant *One of the following: T4 tumor, < 10 nodes examined, high grade, obstruction, perforation, or venous invasion. tients had some persistent symptoms at 18 months. Based on these data, the US Food and Drug administration (FDA) has approved FOLFOX4 as adjuvant therapy in stage III CRC. Ongoing Clinical Trial Strategies Updated efficacy data for this trial have recently been presentand Endpoints in Stage III ed, with a median follow-up of 48 months.16 For the entire Colon Cancer study population, 4-year DFS was 76% for FOLFOX4 versus Traditionally, the gold standard for evaluation of efficacy 69% for 5-FU/LV (HR, 0.76; 95% CI, 0.65-0.90; P = 0.0008). for adjuvant therapy trials has been 5-year OS. Recently, the There was no significant difference in OS (84% vs. 82.4%). In FDA approved FOLFOX4 as adjuvant therapy for stage III a subgroup analysis, patients with stage III disease had 4-year colon cancer based on the MOSAIC trial reporting an advanDFS rates of 69.7% with FOLFOX4 and 61.0% with 5tage in 3-year DFS. If, indeed, this is a valid surrogate for 5FU/LV; the corresponding results for patients with stage II disyear OS, it would shorten the time to reporting of results of ease were 85.1% and 81.3%. ongoing trials by several years and facilitate the rapid inteThe NSABP C-07 trial has completed accrual. This trial gration of new therapies into the design of adjuvant trials. At compared the weekly bolus 5-FU/LV schedule with the same the 2004 Annual Meeting of ASCO, Sargent et al reported an regimen plus oxaliplatin every 2 weeks. No efficacy results analysis of individual patient data from 12,915 patients are available for this trial. pooled from 15 randomized phase III colon cancer adjuvant trials.20 The hypothesis was that 3-year DFS was an appro5-Fluorouracil and Irinotecan priate endpoint to replace 5-year OS. In the first 3 years, 31% The North American Intergroup trial CALGB 89803 comof patients had recurrence of disease, with only 7% of cases recurring in years 4 and 5. Of patients disease-free at 3 years, pared bolus weekly 5FU/LV with IFL (the same regimen of 95% were alive at 5 years, and 86% who had disease recur5-FU/LV with the addition of irinotecan) in 1264 patients rence at 3 years were dead at 5 years. The correlation between with stage III disease. Results have been reported with a me3-year DFS and 5-year OS for all patients across trials was dian follow-up of 3 years. The HRs for OS and failure-free 0.94. Based on this information, the Oncology Drug Advisosurvival (FFS) for 5-FU/LV versus IFL were 0.88 and 0.81, ry Committee to the FDA recommended 3-year DFS as an aprespectively, in disfavor of IFL. Statistical futility boundaries propriate endpoint for evaluation of adjuvant therapy trials in were met such that further follow-up will not result in a bencolon cancer. efit for IFL. Treatment-related mortality rates were 2.8% for IFL and 1.0% for 5-FU/LV (P = 0.008). Therefore, IFL Integration of Biologic Agents should not be used in the adjuvant therapy of CRC.17 Cetuximab Data from the European PETACC-3 study are anxiously In refractory metastatic CRC, cetuximab has shown reproawaited based on data in the metastatic setting demonstrating ducible single-agent activity with a response rate of approxithe superiority of FOLFOX4 compared with IFL in terms of mately 10%. In addition, a response rate of 20%-23% is seen efficacy and toxicity18 but similar activity and toxicity comin combination with irinotecan when disease is refractory to pared with FOLFIRI (infusional 5-FU and irinotecan).19 This irinotecan alone. Toxicity with cetuximab has been generally trial has completed accrual of > 2000 patients with stage III mild, with development of an acneiform rash most common, disease randomized to receive FOLFIRI versus an infusional although there is a 3% incidence of anaphylactic infusion re5-FU/LV regimen. action with rare deaths resulting.11,21 No prospective random-

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Adjuvant Therapy of Colorectal Cancer ized data have been reported for the combination of cetuximab and FOLFOX regimens. The NCCTG is leading the ongoing North American Intergroup adjuvant trial N0147 that addresses important issues of optimal chemotherapy as well as the integration of cetuximab in the adjuvant setting. Patients with stage III colon cancer are randomized to receive 1 of 3 chemotherapy strategies: 6 months of modified FOLFOX6, 6 months of FOLFIRI, or a sequential arm of 3 months of FOLFOX followed by 3 months of FOLFIRI. A second randomization will assign patients to receive cetuximab or no cetuximab. The trial will enroll 4800 patients. There is no requirement for EGFR positivity of patient tissue, because recent evidence suggests that efficacy does not correlate with immunohistochemically determined EGFR expression.22

Bevacizumab The survival benefit gained by the addition of bevacizumab to chemotherapy in metastatic CRC has been demonstrated by 2 large randomized phase III trials. In patients with previously untreated disease, the addition of bevacizumab to IFL chemotherapy resulted in a statistically significant improvement in response rate as well as a prolongation of median survival of 4.7 months (20.3 months vs. 15.6 months; P < 0.001).9 For patients previously treated with irinotecan, a second trial randomized patients to FOLFOX4 with or without bevacizumab as second-line treatment of metastatic disease. Median survival was 10.7 months with FOLFOX4 alone and 12.5 months with the addition of bevacizumab (P = 0.0024).10 Bevacizumab has been associated with proteinuria, clinically significant hypertension, an increase in arterial thrombotic events, as well as rare intestinal perforation. The NSABP C-08 trial will investigate bevacizumab in the adjuvant setting. More than 2700 patients with stage II/III disease will receive modified FOLFOX6 chemotherapy for 6 months with or without 12 months of bevacizumab.

Conclusions Regarding Stage III Colon Cancer The use of any 5-FU/LV–based adjuvant chemotherapy regimen for ≥ 6 months results in a clear and meaningful improvement in survival for patients with stage III disease. All such patients should be offered adjuvant therapy unless significant comorbid illness precludes safe administration of therapy. Age alone should not be used as a contraindication for therapy; elderly patients derive as much benefit from chemotherapy as younger patients.23 A discussion of FOLFOX chemotherapy should be held with all patients with stage III disease based on the MOSAIC trial. The absolute improvement in 4-year DFS of 7% (9% in the stage III patient subset) should be balanced against the modest increased toxicity of the combination regimen. Based on the results of the X-ACT trial, capecitabine is a reasonable option in those patients considered for single-agent adjuvant chemotherapy; although this has not been approved by the FDA. Most patients with stage III disease in the US will

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have access to one of the ongoing large national multicenter trials, and enrollment into these trials should be a priority.

Stage II Colon Cancer Adjuvant chemotherapy for stage II colon cancer remains controversial. The rate of cure for stage II disease with surgery alone is 75%-80% and a prospective trial to detect a small (< 5%) improvement in survival would need to enroll several thousand patients. No prospective trial to date has demonstrated a survival benefit in this patient group. The International Multicenter Pooled Analysis of Colon Cancer Trials (IMPACT) investigators and the NSABP attempted to answer this question with pooled data from multiple trials. The IMPACT analysis reviewed individual patient data from 1016 patients treated on 5 different trials and found a 2% improvement in OS with 5-FU–based therapy, which approached statistical significance.24 The NSABP compared the inferior arms of 4 adjuvant trials (treatment 1) with the superior arms of these trials (treatment 2) and reported an HR for death of 0.70 for treatment 2. They concluded that patients with stage II disease derive a similar relative reduction in risk as those with stage III disease and should receive chemotherapy.25 A recent ASCO practice guideline based on an extensive review of the literature and an accompanying updated metaanalysis of adjuvant trials published since 1997 by the Cancer Care Ontario Program in Evidence Based Medicine26 did not support the routine administration of chemotherapy to all patients with stage II disease.27 However, it is acknowledged that indirect evidence may allow for the option of adjuvant systemic therapy for individuals who may be at increased risk of recurrence. Although criteria for defining high-risk stage II disease have yet to be prospectively validated, the presence of stage IIB disease (T4NO), perforation, obstruction, or inadequate lymph node sampling/evaluation may place patients at higher risk for recurrence. The QUASAR investigators from the United Kingdom reported updated results at the 2004 Annual Meeting of ASCO of a study that randomized > 3200 patients with resected CRC and “uncertain indications” for adjuvant chemotherapy as judged by the oncologist and patient to adjuvant 5-FU–based chemotherapy or observation. Of the entire group, 92% had stage II disease. With a median follow-up of 4.6 years, a statistically significant improvement in the rate of recurrence (22.2% vs. 26.2%; P = 0.001) and survival (80.3% vs. 77.4%; P = 0.02) was associated with adjuvant therapy. When only patients with stage II disease were evaluated, the improvement in survival remained statistically significant.28 The MOSAIC investigators reported a subgroup analysis of this trial in patients with stage II disease deemed to be at high risk for recurrence based on ≥ 1 of the following: T4 disease, perforation, obstruction, < 10 nodes examined, poorly differentiated histology, or venous invasion. This group consisted of almost 600 patients. The 3-year DFS rates were 84.9% with FOLFOX4 and 79.8% with 5-FU/LV, with an HR of 0.72 (95% CI, 0.48-1.08).29

Timothy J. Hobday The North American Intergroup, led by the Eastern Cooperative Oncology Group, is developing a randomized phase III trial for patients with stage II disease. The approach will include prospective risk stratification based on microsatellite instability (MSI) status and assessment for loss of heterozygosity at chromosome 18q. Those patients with MSI and no loss of heterozygosity at 18q will be assigned to observation alone. Those with the presence of either molecular marker associated with increased risk of relapse will be assigned to receive chemotherapy with a modified FOLFOX6 regimen with or without bevacizumab.

Conclusions Regarding Stage II Colon Cancer There continues to be a lack of prospective randomized clinical trials that prove a survival benefit of chemotherapy for unselected patients with stage II disease. The QUASAR trial suggests a 3% improvement in survival with 5-FU–based chemotherapy, and this would be consistent with the magnitude of benefit suggested by earlier analyses of multiple older trials. In addition, the MOSAIC trial also suggests an overall improvement in 3-year DFS for patients with stage II disease beyond that achieved with 5-FU/LV, especially in those at high risk. Although these data are from retrospective subset analyses and therefore are not definitive, the weight of the accumulated evidence suggests a small (< 5%) survival benefit for 5-FU/LV chemotherapy. This should be discussed with all patients with stage II disease and balanced against the toxicity of chemotherapy. An attempt at risk stratification for each patient is important in this discussion. In patients at high risk, the data of the MOSAIC trial should also be discussed but with a clear emphasis on the uncertainty any survival benefit of this approach. When clinical trials for stage II disease are available, enrollment of patients will be of paramount importance so that we can better evaluate the benefits of treatment for these patients and hopefully improve patient selection in this heterogeneous group.

Rectal Cancer Until recently, as endorsed by a National Institutes of Health consensus panel in 1990, postoperative combined-modality therapy with RT and 5-FU–based chemotherapy has long been the standard of care in the United States for patients with stage II/III disease. Improved local control and survival were demonstrated in early randomized trials of combined-modality adjuvant therapy compared with surgery alone or surgery with RT alone.30,31 A subsequent Intergroup trial demonstrated improved local control and survival when 5-FU was administered as a continuous infusion throughout RT compared with bolus 5-FU alone as a radiation sensitizer.32 Most recently, the Intergroup INT-0144 trial reported no advantage of infusional 5-FU chemotherapy versus bolus 5-FU/LV during the chemotherapy-only phase of adjuvant treatment and found infusional 5-FU to be the equivalent of bolus 5-FU/LV as a radiation sensitizer in terms of 3-year DFS and OS.33 These trials generally enrolled patients with stage T3/4N0 and TXN+

disease. A pooled analysis of data from multiple trials of this era with varying treatment strategies demonstrates the independent prognostic importance of tumor and nodal stages. Patients with T1/2N1 disease had similar outcomes as those with T3N0 disease, raising questions regarding the necessity of RT for these patients. However, even with combinedmodality therapy, these intermediate-risk cases had approximately a 10% local recurrence rate.34 These trials were performed before optimal surgical therapy for rectal cancer with total mesorectal excision (TME) was widespread in the United States. It is still unclear how many patients in the United States have expert and optimal surgery performed for rectal cancer. Total mesorectal excision entails sharp dissection of the entire mesorectum, resulting in an en bloc specimen containing the primary tumor and regional vasculature and lymphatic structures, thereby optimizing resection margins and limiting local recurrence.35 In the era before TME, 5-year local recurrence rates with resection alone ranged from 25% to 35%, whereas TME series reports local recurrence rates of < 15%.36 It is clear that the surgeon and pathologist are important variables in the outcome of therapy for rectal cancer, because local recurrence rates differ among surgeons,37 and inadequate staging through evaluation of an inadequate number of resected regional lymph nodes affects prognosis and treatment options. Therefore, it may be that subsets of patients with rectal cancer at low risk for local recurrence who undergo TME may not need RT as a component of their adjuvant therapy. The Dutch TME trial randomized patients with resectable rectal cancer to receive TME alone or a short course (5 treatments of 5 Gy) of preoperative RT followed by TME, with excellent surgical and pathology quality control. At 2 years, the rate of local recurrence was significantly improved in patients who received RT followed by TME versus those who received TME alone (8.2% vs. 2.4%; P < 0.001), suggesting that RT remains an important of optimal adjuvant therapy.35 Additional studies are needed to determine whether patients at lower risk, such as those with T3N0 or T1/2N+ disease, low-grade tumors, proximal location, or optimal surgical resection truly benefit from adjuvant RT. Ideally, individual tumor molecular characteristics will help further refine patient selection in the future by defining those at the lowest risk of local and systemic recurrence. Preoperative RT and chemotherapy has become more accepted in the United States over the past several years. This approach is attractive for distal cancers based on the potential ability to downstage the tumor and allow for a low anterior resection to be performed, obviating a permanent colostomy. In addition, preoperative therapy can improve local control and long-term morbidity perhaps by radiating tissue with better oxygenation, having less small intestine in the radiation field, and avoiding the radiation of the surgical anastomosis. Two large North American trials were launched in the 1990s to compare preoperative versus postoperative RT and chemotherapy but closed as a result of poor accrual. The German Rectal Cancer Study Group published a land-

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Adjuvant Therapy of Colorectal Cancer Table 3

dated and patients were stratified by the operating surgeon. Results from this study of approximately 800 patients revealed no difference in 5-year OS or DFS. Preoperative therapy resulted in a lower rate of local recurrence (6% vs. 13%; P = 0.006). In patients judged to need an abdominoperineal resection (APR) before randomization, 39% of patients were able to have a sphincter-preserving operation in the preoperative therapy arm, compared with 19% in the postoperative therapy arm (P = 0.004). There was no difference in the incidence of delayed wound healing, anastomotic leak, or overall operative morbidity. There was less grade 3/4 acute and chronic toxicity associated with preoperative therapy. The main cautionary note to emerge from this study was the inaccuracy of preoperative staging. Of patients who went directly to surgery, pathologic stage I disease was seen in 18% of patients, and evidence of stage IV disease was seen in 10% of patients. Therefore, 28% of these patients would have been exposed to the toxicity and cost of RT with no benefit. Until preoperative staging is improved, those patients who do not definitively have stage II/III disease need to be considered carefully before therapeutic intervention preoperatively. This may be especially true in those who have endorectal ultrasound–staged T3N0 cancers in the proximal rectum or tumors of uncertain stage in a location where APR will be mandatory even with tumor regression.

Results of German Rectal Cancer Study Group Trial38

Outcome

Preoperative CRT

Postoperative CRT

P Value

5-Year Overall Survival

76%

74%

0.80

5-Year DFS

68%

65%

0.32

5-Year Local Recurrence Rate

6%

13%

0.006

?

18%

NA

116

78

NA

45 (39%)

15 (19%)

0.004

Pathologic Stage I Disease Without Previous Therapy APR Deemed Necessary at Randomization Sphincter-Preserving Surgery Subsequently Performed

Median follow-up was 46 months. Abbreviations: CRT = chemotherapy and radiation therapy; NA = not applicable

mark article in 2004 demonstrating the benefits of preoperative combined-modality therapy (Table 3).38 Eligible patients with preoperatively staged II/III disease as shown by computed tomography and endorectal ultrasound were randomly assigned to preoperative or postoperative chemotherapy and RT. The RT treatment consisted of 5040 cGy in 28 fractions along with a 120-hour infusion of 5-FU during the first and fifth weeks of RT. An additional boost of 540 cGy was delivered to the tumor bed in the postoperative treatment group only. Four additional cycles of bolus 5-FU chemotherapy were delivered to all patients. Randomization was balanced by preoperative prognostic factors. Treatment with TME was man-

Figure 1 Trial

N0147

United States Rectal Cancer Trials in Development The development and conduct of NSABP R-04 and the Intergroup rectal adjuvant trial have been confounded by the rapidly changing landscape of adjuvant therapy for colon cancer, therapy for metastatic CRC, and the development of combination

Selected Phase III Adjuvant Trials Ongoing or in Development in the United States Site

Stage

Colon

III

NSABP C-08

Colon

II/III

E5202

Colon

II

NSABP R-04

Rectal

II/III

E3201

Rectal

Treatment

R

R

FOLFOX for 6 months FOLFIRI for 6 months FOLFOX for 3 months

Cetuximab FOLFIRI for 3 months

FOLFOX for 6 months plus Bevacizumab for 12 months FOLFOX for 6 months

Low Risk*

Observation

High Risk

FOLFOX for 6 months FOLFOX for 6 months plus Bevacizumab

R

5-FU Infusion plus RT R

Oxaliplatin R

Capecitabine plus RT

II/III

no Cetuximab

Preoperative Chemotherapy or RT

*As

Resection

determined by loss of heterozygosity at chromosome 18q and microsattelite instability status. Abbreviation: R = Randomize

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Resection no Oxaliplatin

R

FOLFOX for 6 months FOLFOX for 6 months plus Bevacizumab

Timothy J. Hobday therapies in conjunction with RT in phase I/II studies. At the current time, the NSABP R-04 trial consists of preoperative chemotherapy and RT with a 2-×-2 factorial design. Patients with stage II/III disease will receive continuous-infusion 5-FU or capecitabine, with a second randomization to oxaliplatin or no oxaliplatin. The trial endpoint will be local control. Patients on this study will also be eligible to enter Intergroup study E3201, which will assess different systemic therapies after resection in patients who have received preoperative RT and chemotherapy. The current version in development will randomize patients to receive FOLFOX alone or with bevacizumab.

Conclusions Regarding Adjuvant Therapy for Rectal Cancer The combination of chemotherapy and RT remains a standard approach to patients with stage II/III rectal cancer. Preoperative combined-modality therapy is preferred in these patients to improve local control and decrease acute and chronic toxicity. Careful evaluation of preoperative staging studies is imperative to limit the inevitable overtreatment of patients with true stage I disease. All patients should undergo a TME resection by a surgeon with experience in this technique. Postoperative chemotherapy should be based on the preoperative stage, because we do not have clear evidence that pathologic complete response to neoadjuvant therapy precludes the need for systemic therapy. At this time, there is no clear subset of patients that has been prospectively proven to be at low enough risk to preclude RT; although, multidisciplinary discussions regarding treatment of patients at lower risk are important.

Conclusion Adjuvant therapy of resected CRC is rapidly evolving. New trials have replaced 5-FU monotherapy arms as control regimens because of the advantage in DFS seen in the MOSAIC trial, despite the fact that no trial has yet demonstrated a survival benefit with combination chemotherapy (Figure 1). Preoperative therapy for rectal cancer has become standard even though the limitations of staging need to be kept in mind. Hopefully, the integration of new biologic therapies into adjuvant trials will advance the field further. There may be more evidence recently of a benefit for patients with stage II colon cancer, but this remains controversial. As our therapeutic options expand, we need to explore ways to better define and select not the one best regimen for all patients but the best regimen for individual patients based on predictors of efficacy and tolerability. This will only come through large correlative studies incorporating pharmacogenomics and individual tumor characteristics to ongoing adjuvant and metastatic trials. Investigators should make the contribution of blood and tissue specimens to ongoing clinical trials a priority to assist in advancing the science that will help our future patients.

Acknowledgment The author acknowledges the efforts of Hannah Koble in preparing the manuscript.

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