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Originally published as JCO Early Release 10.1200/JCO.2005.01.914 on June 6 2005 © 2005 American Society of Clinical Oncology.
Whither Irinotecan?OHSU Cancer Institute, Portland, OR For four decades, oncologists had a limited choice of drug options to use in treatment of advanced colorectal cancer: fluorouracil (FU), FU, or FU. Researchers were (not) kept busy investigating the unexciting question of whether to administer the FU by bolus, by continuous infusion, or with leucovorin (LV). Now, we have a number of active drugs, making life difficult for the practitioner and paradoxically slowing meaningful cooperative group research, particularly in the face of studies rapidly conducted by pharmaceutical companies. Five new chemotherapeutic and targeted biologic agents have been approved for treatment of metastatic colorectal cancer over the last 9 years, and it is quite difficult to choose a single optimal treatment among the individual drugs and their many possible combinations. One of the five, irinotecan, was first approved by the US Food and Drug Administration in 1995, and it has itself already become an old-timer. Just 5 years ago, irinotecan was considered a standard part of first-line therapy in the United States, but with the introduction of oxaliplatin, irinotecan is now used in a minority of front-line advanced colorectal cancer patients. However, two trials in this issue by Köhne et al1 and Colucci et al2 remind us that irinotecan is an active drug that can still play a role both in research trials and in standard-of-care treatment regimens. Köhne et al1 randomly assigned patients with untreated metastatic colorectal cancer to the Arbeitsgemeinschaft fur Internistische Onkologie regimen (a schedule that uses weekly high-dose infusional FU and LV)3 with or without irinotecan. The infusional FU dose on the experimental arm was lowered to 2.3 g/m2 over 24 hours compared with a dose of 2.6 g/m2 for the control arm. After observing higher rates of serious gastrointestinal adverse events and toxic deaths, investigators further reduced the FU dose to 2.0 g/m2. The trial was designed with relatively low power (80%) to detect a relatively large difference (2.5 months) in the primary outcome of progression-free survival. Patients in the experimental group did achieve a median progression-free survival improvement of 2.1 months compared with the control group (8.5 v 6.4 months, respectively; hazard ratio = 0.65; 95% CI, 0.53 to 0.79). The response rate was also higher in patients administered irinotecan compared with patients who did not receive irinotecan (62.2% v 34.4%, respectively, with no overlap in CIs), but there was no improvement in overall survival. Even with the lower dose of FU, the combination arm was substantially more toxic. Almost 34% of patients administered irinotecan with amended-dose FU plus LV required a first-cycle dose reduction compared with 18% of patients not administered irinotecan. Several paragraphs could be devoted to critiquing methods, finding patient imbalances, and complaining about the lack of survival benefit. Some of these factors may have favored the controls and, thereby, abrogated potential differences between arms. For example, the control arm had a much higher percentage of patients with rectal primary tumors, which is a prognostic factor associated with superior survival in metastatic disease. Controls also received more FU, although it is hard to argue for a fluoropyrimidine dose-intensity effect in colorectal cancer. However, the experimental arm had a larger fraction of patients who received prior irradiation, which could at least partly explain its higher toxicity rates. Regardless, these are minor issues, and the Köhne et al1 trial is the third in a series of large-scale phase III studies comparing FU/LV to FU/LV plus irinotecan, all of which reach essentially the same conclusions that irinotecan is an effective drug and that adding it to FU/LV improves on that combination but at the cost of higher toxicity.1,4,5 The Köhne et al1 results are reasonable, believable, and clinically meaningful. Colucci et al2 and the Gruppo Oncologico Dell'Italia Meridionale randomly assigned chemotherapy-naïve advanced colorectal cancer patients either to the Douillard regimen of irinotecan, infusional FU, and LV or to oxaliplatin, infusional FU, and LV (FOLFOX4).2,5,6 This trial was powered primarily to evaluate objective response rates, which proved to be similar on both arms (31% for the Douillard regimen compared with 34% for FOLFOX4). Time to progression and median survival were virtually identical for the irinotecan-containing and oxaliplatin-based arms (7 v 7 months and 14 v 15 months, respectively). The overall incidence rates for any grade 3 and 4 toxicities were not compared between arms, and individual events varied only slightly; there was more nausea, diarrhea, and alopecia associated with the Douillard regimen and more thrombocytopenia and neurotoxicity associated with FOLFOX4. There were two toxic deaths with the Douillard regimen, but no chemotherapy-related mortality was observed with FOLFOX4. Dose modification was not quantified. The Colucci et al2 trial is also subject to some criticism. The investigators stratified patients using an admittedly wholly arbitrary definition of "extensive" tumor burden, with patient imbalances in potential prognostic factors (such as percentage of patients with synchronous v metachronous metastases), and they had a large number of inassessable patients. Response rates were lower than expected, and using objective response rates to derive sample size once again resulted in a study that was not well powered to determine potential survival differences. Overall survival itself was poor on both arms, possibly because patients received relatively little primary chemotherapy (median, eight cycles) or salvage chemotherapy (61% of patients receiving the Douillard regimen and 58% of patients receiving FOLFOX4 were treated with second-line therapy). Overall, however, the two arms suffered equally from these problems. The study by Colucci et al2 is the second modestly sized phase III study comparing infusional FU/LV plus irinotecan to FU/LV plus oxaliplatin,7 and both studies concluded that combination therapies including either agent are roughly equally effective in front-line therapy of advanced colorectal cancer patients. Where does this leave us in terms of selecting the best drugs for use in the clinic and in designing new trials? What individual agents or combinations should be tested? The North American Intergroup Colon Task Force began to discuss a successor trial to N9741, the last completed Intergroup phase III study, in April 2001. For a variety of reasons, a new, clinically relevant, and sustainable phase III trial has yet to begin accrual in previously untreated metastatic colorectal cancer. The original proposal for the N9741 replacement planned to test irinotecan, FU, and LV with or without the selective cyclo-oxygenase-2 (COX-2) inhibitor celecoxib. Delay arose because of debate over which of the following irinotecan-based regimens to use as the control: the standard 42-day irinotecan, bolus FU, and LV (IFL) regimen, modified IFL (a shortened 2 weeks on, 1 week off schedule), or an infusional regimen. This question prompted vigorous additional arguments over using the US Food and Drug Administration–approved Douillard regimen compared with the more convenient irinotecan, LV, and FU (FOLFIRI) regimen, which uses a prolonged 46-hour infusion of the fluoropyrimidine and does not require repeat bolus injections of FU and LV. Meanwhile, COX-2 inhibitors fell out of favor as a result of concerns over lack of efficacy in advanced disease and major worries about potential cardiovascular toxicity. Ironically, these concerns proved well founded; other COX-2 studies in cancer or cancer prevention proceeded but were suspended or terminated in 2004 because of high rates of myocardial infarctions and strokes. The results of N9741 complicated the development of a successor trial even further.8,9 N9741 demonstrated that FOLFOX4 enhanced survival compared with bolus IFL. Given this new information, the Intergroup protocol design group abandoned irinotecan in favor of oxaliplatin, while it jettisoned celecoxib for one of the newer oral epidermal growth factor receptor (EGFR) inhibitors (possibly erlotinib or gefitinib), which were available biologic agents of interest. When these agents seemed to be ineffective by demonstrating a lack of single-agent objective responses in advanced colorectal cancer, the Intergroup turned to bevacizumab because it seemed to improve the activity of both irinotecan- and oxaliplatin-based regimens.10-13 At the same time, a parallel Intergroup idea of directly comparing FOLFOX to FOLFIRI, with or without cetuximab (an EGFR antibody that had shown significant activity against refractory colorectal cancer), moved forward, as did the other Intergroup trial that compared FOLFOX to capecitabine plus oxaliplatin, with or without bevacizumab. Two large, parallel, phase III trials that were coordinated by separate cooperative groups eventually opened for a few months, accrued poorly, and then closed prematurely, which was an absolute catastrophe in terms of wasted time, money, and patient and physician good will. To be fair, impetus for modification or closure of these trials included US Food and Drug Administration approval for bevacizumab in first-line treatment of colorectal cancer and the desire to confirm the Tournigand et al7 findings in a larger scale setting. After much discussion within the Intergroup, in early January 2005, a replacement trial concept was proposed and approved by the National Cancer Institute. The proposed study will allow investigators and patients to select either FOLFOX or FOLFIRI chemotherapy, with stratification for choice. Patients will then be randomly assigned to the chosen chemotherapy plus bevacizumab alone, cetuximab alone, or the combination of both biologic agents. The new protocol, which primarily only asks which is the best first-line biologic regimen, should be activated within the next several months. Additional issues addressed within the protocol will be duration of therapy and potential curative surgery for patients with limited metastatic disease. The primary objective, mandated by the National Cancer Insitute, will be overall survival. What has the Intergroup learned, and how do these lessons and the lessons derived from the Köhne et al1 and Colucci et al2 studies apply to the practitioner trying to select the optimal chemotherapy for the individual patient with metastatic colorectal cancer? First, it is time to stop worrying about whether there is a best overall front-line chemotherapy regimen. More specifically, an equivalency study comparing oxaliplatin with irinotecan would almost certainly be fruitless. N9741 suggested that FOLFOX4 was better than IFL, but the infusional FU used in FOLFOX4 compared with the bolus FU in IFL likely contributed to some of the efficacy differences. Both Colucci et al2 and Tournigand et al,7 in admittedly underpowered studies using only infusional regimens, demonstrated no major efficacy differences in response rates, progression-free survival, or overall survival for upfront patients administered FOLFOX4 or the Douillard/FOLFIRI regimens, reinforcing the fact that both oxaliplatin and irinotecan are effective when combined with infusional FU. Despite previous toxicity concerns regarding the use of irinotecan with bolus FU-based regimens, the Colucci et al2 trial had similar rates of most grade 3 and 4 events on both arms (although more toxic deaths and a higher 60-day mortality rate were observed with irinotecan). The Tournigand et al7 study showed that FOLFIRI had a lower rate of serious or life-threatening events than FOLFOX. Additionally, a variety of phase II and phase III trials, including the trial by Köhne et al1, demonstrate broadly similar response rates and median survival for oxaliplatin- and irinotecan-containing FU-based regimens.1,4-6 Finally, Grothey et al,14 in a review of seven large randomized trials in colorectal cancer, concluded that overall survival can be excellent if patients receive all active drugs, even as part of second- or third-line treatment. The Köhne et al1 study indirectly reached a similar conclusion. Survival curves converged after the time of first-line failure, reflecting the benefit of current salvage treatment. With regard to the current Intergroup trial design, it does remain remotely possible that there would be some previously undescribed interaction between specific chemotherapeutic and biologic agents, leading to efficacy variations among oxaliplatin- and irinotecan-containing combination regimens. However, trials designed to detect potential survival differences arising from these putative interactions would need to be quite large and would not represent a good use of limited Intergroup resources. The second issue is that initial treatment must include a biologic agent. The two colorectal cancer phase III trials that briefly opened both included potential randomization to chemotherapy alone, and both trials were soundly rejected by community physicians and by patients alike when bevacizumab and cetuximab were approved by the US Food and Drug Administration. Interestingly, this occurred when the only data we had for these biologic agents compared irinotecan-based chemotherapy to the same chemotherapy plus bevacizumab or cetuximab.12,15 FOLFOX plus bevacizumab became a community standard long before we had any efficacy data assessing the use of oxaliplatin with the angiogenesis inhibitor. The third and most difficult issue lies in deciding the quality and quantity of data required (phase II v phase III studies, cooperative group v pharmaceutical sponsored, number of trials testing the new regimen, and so on) before adopting a new agent for general use or even for further testing. COX-2 inhibitors and various EGFR antagonists all looked promising early in the testing process, suggesting they would be beneficial in advanced colorectal cancer. The COX-2 agents fell out of favor when they seemed both ineffective and toxic, with or without chemotherapy.16,17 The EGFR inhibitors are a mixed story. Antibodies to EGFR seem effective, whereas the small-molecule tyrosine kinase inhibitors of EGFR seem ineffective, at least as single agents.10,11,15 In contrast, bevacizumab was promising in early studies, and it remained a keeper through testing in randomized, large-scale, phase III trials.12,13,18 In designing new studies and in adopting new regimens for therapeutic use, it pays to be both a good guesser and to have a good drug. The Intergroup's problems in designing the new colorectal cancer trial were, at least, partly the result of having too many choices. This is actually an enviable position, and we should not lose sight of what well-designed studies have allowed us to achieve in the treatment of advanced disease. With supportive care or FU-based chemotherapy alone, median survival time in metastatic colorectal cancer remained between 6 months and 1 year.19,20 The study by Colucci et al2 suggests a potential median survival improvement to 14 or 15 months with the addition of irinotecan or oxaliplatin to the fluoropyrimidine. The Köhne et al1 trial, which showed a median survival time of 20.1 months with irinotecan (more in line with most recently reported combination regimens), also confirms that we have new and highly active nonfluoropyrimidine agents.1,2 Although targeted therapy holds the promise that someday we can custom, select, effective regimens for the individual, for now, we are forced to proceed empirically. We can continue to improve our treatment of patients with advanced colorectal cancer but only by designing interesting and innovative cooperative group trials that will rapidly open, speedily accrue, and move on to the next important questions in a timely fashion. Author's Disclosures of Potential Conflicts of Interest The following author or their immediate family members has indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C)
REFERENCES
1. Köhne C-H, van Cutsem E, Wils J, et al: Phase III study of weekly high-dose infusional fluorouracil plus folinic acid with or without irinotecan in patients with metastatic colorectal cancer. J Clin Oncol 23: 4856-4865, 2005
2. Colucci G, Gebbia V, Paoletti G, et al: 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 23: 4866-4875, 2005 3. Köhne CH, Schoffski P, Wilke H, et al: Effective biomodulation by leucovorin of high-dose infusion fluorouracil given as a weekly 24-hour infusion: Results of a randomized trial in patients with advanced colorectal cancer. J Clin Oncol 16: 418-426, 1998[Abstract]
4. Saltz LB, Cox JV, Blanke C, et al: Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer: Irinotecan Study Group. N Engl J Med 343: 905-914, 2000 5. Douillard JY, Cunningham D, Roth AD, et al: Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: A multicentre randomised trial. Lancet 355: 1041-1047, 2000[CrossRef][Medline]
6. de Gramont A, Figer A, Seymour M, et al: Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 18: 2938-2947, 2000
7. 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 22: 229-237, 2004
8. 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 22: 23-30, 2004 9. Goldberg RM, Morton RF, Sargent DJ, et al: N9741: Oxaliplatin + CPT-11 or 5-fluorouracil/leucovorin in advanced colorectal cancer—Final efficacy data from an intergroup study. Prog Proc 2004 GI Cancers Symp 1: 148, 2004 (abstr 215)
10. Baselga J, Rischin D, Ranson M, et al: Phase I safety, pharmacokinetic, and pharmacodynamic trial of ZD1839, a selective oral epidermal growth factor receptor tyrosine kinase inhibitor, in patients with five selected solid tumor types. J Clin Oncol 20: 4292-4302, 2002 11. Oza AM, Townsley CA, Siu LL, et al: Phase II study of erlotinib (OSI-774) in patients with metastatic colorectal cancer. Proc Am Soc Clin Oncol 22: 196, 2003 (abstr 785)
12. Hurwitz H, Fehrenbacher L, Novotny W, et al: Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350: 2335-2342, 2004 13. National Cancer Institute: Bevacizumab combined with oxaliplatin-based chemotherapy prolongs survival for previously treated patients with advanced colorectal cancer. http://www.cancer.gov/newscenter/pressreleases/BevacizumabOxaliplatin
14. Grothey A, Sargent D, Goldberg RM, et al: Survival of patients with advanced colorectal cancer improves with the availability of fluorouracil-leucovorin, irinotecan, and oxaliplatin in the course of treatment. J Clin Oncol 22: 1209-1214, 2004
15. Cunningham D, Humblet Y, Siena S, et al: Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 351: 337-345, 2004 16. Becerra CR, Frenkel EP, Ashfaq R, et al: Increased toxicity and lack of efficacy of rofecoxib in combination with chemotherapy for treatment of metastatic colorectal cancer: A phase II study. Int J Cancer 105: 868-872, 2003[CrossRef][Medline] 17. Blanke CD, Benson AB, Dragovich T, et al: A phase II trial of celecoxib, irinotecan, 5-fluorouracil, and leucovorin in patients with unresectable or metastatic colorectal cancer. Proc Am Soc Clin Oncol 21: 127a, 2002 (abstr 505)
18. Kabbinavar F, Hurwitz H, Fehrenbacher L, et al: Phase II, randomized trial comparing bevacizumab plus fluorouracil/leucovorin with FU/LV alone in patients with metastatic colorectal cancer. J Clin Oncol 21: 60-65, 2003 19. Scheithauer W, Rosen H, Kornek GV, et al: Randomised comparison of combination chemotherapy plus supportive care with supportive care alone in patients with metastatic colorectal cancer. BMJ 306: 752-755, 1993 20. Piedbois P, Michiels S: Survival benefit of 5-FU/LV over 5-FU bolus in patients with advanced colorectal cancer: An updated meta-analysis based on 2,751 patients. Proc Am Soc Clin Oncol 22: 294, 2003 (abstr 1180)
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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