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Impact of Complete Response to Chemotherapy on Overall Survival in Advanced Colorectal Cancer: Results From Intergroup N9741

Grace K. Dy, James E. Krook, Erin M. Green, Daniel J. Sargent, Thierry Delaunoit, Roscoe F. Morton, Charles S. Fuchs, Ramesh K. Ramanathan, Stephen K. Williamson, Brian P. Findlay, Barbara A. Pockaj, Robert P. Sticca, Steven R. Alberts, Henry C. Pitot, IV, Richard M. Goldberg

From the Mayo Clinic and Mayo Foundation, Rochester; Duluth CCOP, Duluth, MN; Jolimont Hospital, La Louvière, Belgium; Iowa Oncology Research Association CCOP, Des Moines, IA; Dana Farber Cancer Center Institute, Boston, MA; University of Pittsburgh Medical Center and Cancer Center, Pittsburgh, PA; University of Kansas Medical Center, Kansas City, KS; National Cancer Institute of Canada, St Catharines, Ontario, Canada; University of North Dakota School of Medicine and Health Sciences, Grand Forks, ND; and the University of North Carolina at Chapel Hill, Chapel Hill, NC

Address reprint requests to: Grace K. Dy, MD, Mayo Clinic, 200 First St SW, Rochester, MN 55905; e-mail: dy.grace{at}mayo.edu

	ABSTRACT

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Purpose: To evaluate clinical characteristics and survival outcomes among patients with locally advanced or metastatic colorectal cancer who achieve a complete response (CR) to systemic treatment either alone or with multimodality approach.

Patients and Methods: Data were collected retrospectively from CRC patients enrolled onto the phase III trial N9741, a National Cancer Institute–funded and Gastrointestinal Cancer Intergroup–sponsored study coordinated by the North Central Cancer Treatment Group. Patients were randomly assigned to combinations of oxaliplatin, fluorouracil (FU)/leucovorin (LV) and irinotecan. The three treatment arms consist of IFL (irinotecan + FU/LV), FOLFOX4 (oxaliplatin + FU/LV), and IROX (irinotecan + oxaliplatin). Median follow-up was 42.6 months.

Results: Sixty-two (4%) of 1,508 patients had a CR to chemotherapy alone, and an additional 32 (2%) had a CR after multimodality treatment. Factors associated with achieving CR with systemic chemotherapy alone included FOLFOX4 treatment, patients with assessable disease, or a single site of metastasis. Continuing protocol treatment beyond two cycles after documentation of CR was not associated with improved survival. The rate of curative intent resection was significantly higher for patients treated with oxaliplatin-containing regimens (P = .02). Median survival was similar between patients with CR after chemotherapy alone (44.3 months) or after multimodality approach (47.4 months; P = .81).

Conclusion: FOLFOX4 was more likely to produce a CR than were IFL or IROX. Oxaliplatin regimens were more likely to result in successful surgical resections. Patients who have CR to systemic chemotherapy alone can achieve impressive survival outcomes similar to those seen among patients who attained a CR status after multimodality treatment.

	INTRODUCTION

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Colorectal cancer (CRC) accounts for 10% to 15% of all cancers and is the second leading cause of cancer deaths in Western countries. Approximately half of all patients develop metastatic disease. It is estimated that 153,760 new cases of CRC will be diagnosed in the United States in 2007.¹ It is known that palliative chemotherapy is more effective than the best supportive care at prolonging survival and improving quality of life.² During the last decade, new cytotoxic drugs, oxaliplatin,^3-6 irinotecan,^7-10 and agents with novel mechanisms of action, cetuximab¹¹ and bevacizumab,¹² have become a part of the armamentarium in the treatment of advanced CRC. Recent randomized trials have reported impressive results in terms of response rates and the prolongation of overall survival (OS) and/or time to disease progression (TTP) in comparison to outcomes observed with standard fluorouracil (FU)/leucovorin (LV) therapy.¹³

Despite these improvements, a complete response (CR) to systemic chemotherapy in patients with advanced CRC remains uncommon. Data from past reports indicate that the CR rate to first-line FU/LV (or capecitabine) alone is 1% or lower; to irinotecan-FU combinations 2% to 3%; and oxaliplatin-FU combinations 1.5% to 4.5%. CRs are generally not observed with second-line therapies in various large randomized trials.^4-8,11

There appears to be an association between the tumor response rate to systemic chemotherapy and improved survival in metastatic colorectal cancer.¹⁴ The favorable survival outcomes established during the last decade with the new agents are consistent with such a correlation. Whether achievement of a CR independently provides a survival advantage or is a surrogate for less advanced disease is not established. The utility of maintenance chemotherapy after the achievement of CR is also a topic of some controversy. The present study was thus initiated to characterize the clinical features and to evaluate survival and disease progression outcomes among patients who had a CR to systemic treatment as part of the large multicenter phase III trial N9741, the primary results of which were reported previously.⁵ We also update previously reported data on patients who underwent surgery or other ablative techniques with curative intent after neoadjuvant chemotherapy and were subsequently deemed clinical complete responders to multimodality therapy.¹⁵

	PATIENTS AND METHODS

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Study Design
We conducted a retrospective review of the database established for the intergroup N9741 phase III trial. Five National Cancer Institute cooperative oncology groups collaborated in this randomized multicenter trial to compare combinations of FU/LV, irinotecan, and oxaliplatin in patients with locally advanced, recurrent or metastatic colorectal cancer: North Central Cancer Treatment Group (lead group), Cancer and Acute Leukemia Group B, Eastern Cooperative Oncology Group, Southwestern Oncology Group, and the National Cancer Institute of Canada Clinical Trials Group. Patients were randomly assigned between November 1998 and July 2002.

In addition to the primary inclusion and exclusion criteria enumerated previously,⁵ only patients who completed at least one cycle of assigned treatment and who had a CR documented on two or more consecutive evaluations (using computed tomography [CT] scan, magnetic resonance imaging [MRI] scan, or physical examination for measurable disease; additional imaging modalities acceptable for assessable disease included ultrasound) at least 4 weeks apart were classified as complete responders in this review. The data pertaining to the group of patients with CR from multimodality treatment consist of the results seen in patients with partial response (PR) or stable disease to systemic therapy who were subsequently rendered disease free by surgery or other nonchemotherapeutic intervention, inclusive of the initial results reported in a separate publication.¹⁵

Treatment Regimen
The regimens were as follows: arm A was IFL (irinotecan [full dose 125 mg/m^2; reduced dose 100 mg/m²] intravenous (IV) infusion and bolus FU [original dose 500 mg/m^2; reduced dose 400 mg/m²] plus LV 20 mg/m² on days 1, 8, 15, and 22 every 6 weeks); arm F was FOLFOX4 (oxaliplatin 85 mg/m² IV infusion on day 1 and bolus FU 400 mg/m² plus LV 200 mg/m² followed by FU 600 mg/m² in 22-hour infusions on days 1 and 2 every 2 weeks); and arm G was IROX (oxaliplatin 85 mg/m² and irinotecan 200 mg/m² every 3 weeks). Treatment continued until progression, unmanageable toxic effects, or withdrawal of consent. The protocol stipulated that patients who had a confirmed CR to chemotherapy were to receive two additional treatment cycles, and then have the option of continuing with their current regimen until progression, or were allowed to cease treatment and restart the same regimen at the time of tumor progression. Toxic effects (except paresthesia) were graded using the National Cancer Institute Common Toxicity Criteria version 2.0. Functional sensory neurological impairments that interfered with daily activities or caused disability were classified as grade 3 or 4 paresthesia, respectively.

Statistical Analysis
Kaplan-Meier analyses and log-rank P values were used in the analyses of TTP, OS, and time to CR. In the comparison of patients with and without CR, the Kruskal-Wallis test was used for continuous variables and a ² test was used for categoric variables. For the comparison of time-to-event end points comparing patients with and without a CR, a landmark analysis was used, including only those patients who were alive (for OS) or progression free (for TTP) after 6 months on study. This conservative analysis is used to account for the bias present due to the fact that patients must be alive and progression free for at least 2 months to be potentially classified as a CR. All P values reported are two sided, with P < .05 used to denote statistical significance.

	RESULTS

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Patient Characteristics
Median follow-up at the time of this analysis was 42.6 months. Of 1,508 patients treated on arms A, F, or G, 62 patients (4%) had a confirmed CR to systemic chemotherapy alone. The CR rate of patients receiving FOLFOX4 was higher (6.2%, 43 of 696; P < .001) than that of patients from either arm A (1.9%, eight of 429) or arm G (2.9%, 11 of 383). Median time to CR from initiation of treatment was 6.3 months (range, 1.6 to 25.3 months).

Demographic characteristics of patients with and without CR to chemotherapy alone are presented in Table 1. Patients with low tumor burden (assessable disease or single site of metastasis) or who received FOLFOX were more likely to experience CR. Assessable disease refers to a tumor mass without clearly defined bidimensional measurements or whose maximal dimension was less than 2 cm by CT or MRI, or smaller than 1 cm by physical examination or chest x-ray.

Procedures employed with the multimodality approach included partial hepatectomy alone in 20 patients, additional RFA of liver lesion(s) at open laparotomy in seven, percutaneous RFA alone in three, and lobectomy for lung involvement in two. Four patients had their primary tumor simultaneously removed with the metastases. The rate of curative resection was significantly higher for patients treated with oxaliplatin-containing regimens (P = .02). Specifically, the number and rates of resection/RFA by arm were as follows: IFL, n = 4 (0.9%); FOLFOX4, n = 17 (2.4%); and IROX, n = 11 (2.9%).

Disease Progression
Among the 62 patients with CR to chemotherapy alone, 52 (84%) had disease progression after a median follow-up duration of 49.7 months. In a nonlandmark analysis, patients who achieved CR had a superior TTP (median, 15.4 months) to that of those who did not achieve CR (median, 7.3 months; P < .001; hazard ratio, 0.41; 95% CI, 0.32 to 0.55; Fig 1). The median TTP for CR patients was also superior to that of patients who achieved a PR, with a median TTP in the nonlandmark analysis for partial responders of 10.7 months (P < .001). Among patients with CR to systemic chemotherapy, there was no correlation between treatment arm and TTP (P = .72). Thirty seven (60%) of the complete responders received subsequent-line chemotherapy (26% same regimen, 74% alternative regimen) on disease progression, in contrast to 42% of patients who had PR only (20% same regimen, 80% alternative regimen).

View larger version (13K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Comparison of time to disease progression between patients with or without complete response to systemic chemotherapy.

OS
Among the 62 patients with CR to systemic chemotherapy alone, 28 (45%) were alive at last follow-up. In these patients, there was no correlation between treatment arm and survival (P = .25). Patients who achieved a CR had improved OS (median, 44.3 months) compared with patients who did not achieve CR (median, 17.1 months in the non–landmark analysis; P < .001; hazard ratio, 0.27; 95% CI, 0.19 to 0.38; Fig 2), or even among those who achieved a PR (median survival, 22.5 v 44.3 months; P < .0001). These results did not change when the models were univariately and multivariately adjusted for number of sites of disease, Eastern Cooperative Oncology Group performance status, and treatment arm. The median OS of these patients is similar to that of patients who underwent curative intent multimodality treatment after systemic chemotherapy (47.4 months; P = .81). Among the 32 patients rendered disease free from the multimodality approach, those treated with hepatectomy alone have yet to reach median survival. Those treated with additional RFA had a median survival of 37.7 months.

View larger version (10K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Comparison of overall survival according to best response to systemic chemotherapy (non–landmark analysis).

Landmark Analysis
To minimize survivor treatment selection bias resulting from inherent disease biology from the preceding TTP and OS analyses, we performed a landmark analysis wherein we consider only patients who are alive and progression free at 6 months after study enrollment. In this subset, achieving a CR remained significantly associated with superior TTP (9.9 months) and OS (38.3 months) compared with non-CR patients (4.8 and 13.1 months, respectively; both P < .001) in this analysis. This OS for patients with a CR to systemic chemotherapy alone does not differ significantly from the outcomes of patients who underwent multimodality treatment (TTP, 16.6 months; OS, 41.4 months).

Adverse Events
There were no differences between patients with and without a CR in the rates of grade 3 or higher adverse events (CR, 84%; others, 78%; P = .25). There were more patients with grade 3 or higher peripheral neuropathy among complete responders, although this difference was not statistically significant (23% v 15%; P = .14). However, the groups did differ in terms of numbers of patients with dose reductions (CR, 69%; others, 57%; P = .05) and treatment delays (CR, 89%; others, 61%; P < .001), all likely consequences of the fact that patients who achieved a CR continued to receive treatment for significantly longer than did patients who did not (median, 7.7 v 5.4 months; P < .001).

	DISCUSSION

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Intergroup N9741 was the largest North American trial to date to address the activity of new agents in combination with FU for first-line treatment in advanced CRC. This trial demonstrated improved response rates, TTP, and OS in patients receiving oxaliplatin and infusional FU/LV.⁵

Our study is a retrospective analysis of a select patient group, and was not prespecified in the trial design. Nevertheless, our findings remain relevant in hypothesis generation. Despite possible methodologic biases (subset analysis, nonrandomized comparisons), our results provide the largest and likely most reliable data set available to address several practical clinical questions. Analysis of our data clearly indicate a survival advantage associated with achievement of a CR. The potential benefits in terms of disease progression and survival outcomes associated with a CR were independent of the treatment regimen employed once a CR was achieved. Given that achieving a CR is independently associated with improved survival, and that second-line treatment rarely achieves CR, use of the most active (in terms of inducing a CR) and well tolerated first-line regimen(s) should clearly be preferred. Indeed, recent reports of the triple combination FOLFOXIRI showed a promising overall response rate of 72% (CR, 13%), rendering a secondary curative resection possible in 26% of the patients.^16,17 These studies support the use of combination therapy as initial treatment for unresectable metastatic CRC, particularly in patients who are potential candidates for curative resections. Whether the addition of so-called targeted therapies such as bevacizumab¹² and cetuximab¹¹ will increase the likelihood of a CR to initial therapy and prolongation of survival remains unknown.

Our data demonstrate that the introduction of more effective therapies has resulted in a concomitant improvement, albeit small, in the CR rates to systemic chemotherapy in advanced CRC. Moreover, no difference was observed in survival between patients who receive maintenance treatment beyond two cycles after documentation of CR and those who did not, although this is not a randomized comparison. This is similar to the observations from randomized studies in other tumor types, such as non–small-cell lung cancer and ovarian cancer, which do not support maintenance therapy once maximal response is obtained. Our findings are also congruent with the recently reported OPTIMOX-2 results, conducted to assess whether maintenance therapy is useful or whether treatment can be suspended until renewed tumor growth. OPTIMOX-2 was a successor study to the OPTIMOX-1 trial, where patients were randomly assigned to the FOLFOX7 regimen interrupted by an oxaliplatin-free interval (FOLFOX7 regimen given for six cycles, followed by 12 cycles of biweekly FU and LV alone, with planned reintroduction of FOLFOX7 after the 12 cycle oxaliplatin-free interval) or FOLFOX4. In OPTIMOX-1, patients randomly assigned to omit the oxaliplatin after cycle 6 maintained comparable outcomes and reduced toxicity compared with those of patients randomly assigned to receive continuous FOLFOX4 until disease progression.¹⁸ The OPTIMOX-2 trial further investigated the role of maintenance therapy (FU/LV alone without oxaliplatin) utilized in the OPTIMOX-1 trial compared with a chemotherapy-free interval, with FOLFOX7 reintroduced on disease progression. Although there is an advantage with maintenance FU/LV in terms of progression-free survival (8.7 v 6.9 months; P = .009), the primary end point of total duration of disease control was virtually the same (12.9 v 11.7 months; P = .41).¹⁹ Of note, the median time to CR in our trial was 6 months, which is nearly twice as long as the initial treatment phase utilized with the OPTIMOX-2 approach. Whether sustained treatment to CR provides an advantage to patients over treatment for a prescribed interval of time is yet to be definitely confirmed, but it is an issue of practical relevance.

The OS in patients with CR to systemic therapy was almost identical to that of those who underwent multimodality therapy. This suggests that there is benefit derived from rendering patients disease free by any method. Interestingly, criteria that predict improved survival after surgical resection (single site of metastasis, low volume of disease) predict for improved survival from systemic therapy alone when CR is achieved. With effective and well-tolerated systemic therapies, optimal timing of resection and length of neoadjuvant therapy are unresolved issues. The benefit of continuing systemic treatment to achieve CR is counterbalanced by the development of hepatic steatohepatitis and sinusoidal changes with which increased postoperative morbidity and mortality has been associated in some studies.^20-23 Moreover, there is the possible discrepancy between clinical CR (based on imaging studies, on surgical exploration) and actual complete clearance of cancer.^24,25 Whether there is a biologic difference between the patient population that can benefit from early surgery versus chemotherapy alone remains to be elucidated, and genome-wide gene expression analysis may potentially help to discriminate between the most suitable treatment alternatives. These issues prompt the question regarding the role of neoadjuvant therapy, but nevertheless do not diminish the value of our observations.

In conclusion, this study demonstrates that achievement of a CR with first-line chemotherapy in advanced CRC is associated with improved OS. Therapeutic trials in the future for metastatic CRC should consider exploring the use of CR status as a potential surrogate end point for future therapeutic trials for metastatic CRC, particularly in the neoadjuvant setting because this can shorten the observation period in determining the traditional survival end points. Continued systemic chemotherapy beyond two cycles after confirmation of CR was not associated with better survival than watchful observation in this subgroup of patients, which is consistent with the data thus far from the OPTIMOX trials. Although FOLFOX4 is more likely to produce a CR than IFL or IROX, the improvement in OS once a CR is achieved was not related to the treatment arm. Our findings do not detract from the now well-established importance of surgical resection of metastatic disease with curative intent; such therapy allows these patients, who may have achieved only a PR, to achieve outcomes similar to those with a chemotherapy-induced CR. Rather, our study supports development of better systemic treatment options and further investigations to delineate its complementary role with surgery to optimize the treatment of patients with advanced CRC.

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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Although all authors completed the disclosure declaration, the following authors or their immediate family members 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.

Employment: N/A Leadership: N/A Consultant: Daniel J. Sargent, Sanofi-Aventis, Genentech, Pfizer; Ramesh K. Ramanathan, Sanofi-Aventis; Richard M. Goldberg, Pfizer, Sanofi-Aventis Stock: Roscoe F. Morton, Genentech; Brian P. Findlay, Sanofi-Aventis Honoraria: Daniel J. Sargent, Sanofi-Aventis; Charles S. Fuchs, Genentech, Pfizer, Sanofi-Aventis; Ramesh K. Ramanathan, Discovery Group; Brian P. Findlay, Sanofi-Aventis, Roche; Richard M. Goldberg, Pfizer, Sanofi-Aventis Research Funds: Stephen K. Williamson, Funds, Pfizer Testimony: N/A Other: N/A

	AUTHOR CONTRIBUTIONS

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Conception and design: Grace K. Dy, James E. Krook, Erin M. Green, Daniel J. Sargent, Richard M. Goldberg

Provision of study materials or patients: Grace K. Dy, James E. Krook, Daniel J. Sargent, Roscoe F. Morton, Charles S. Fuchs, Ramesh K. Ramanathan, Stephen K. Williamson, Brian P. Findlay, Barbara A. Pockaj, Robert P. Sticca, Steven R. Alberts, Henry C. Pitot, Richard M. Goldberg

Collection and assembly of data: Grace K. Dy, Erin M. Green, Daniel J. Sargent, Thierry Delaunoit

Data analysis and interpretation: Grace K. Dy, James E. Krook, Erin M. Green, Daniel J. Sargent, Charles S. Fuchs, Ramesh K. Ramanathan

Manuscript writing: Grace K. Dy, James E. Krook, Erin M. Green, Daniel J. Sargent, Roscoe F. Morton, Barbara A. Pockaj, Robert P. Sticca, Richard M. Goldberg

Final approval of manuscript: Grace K. Dy, James E. Krook, Erin M. Green, Daniel J. Sargent, Roscoe F. Morton, Charles S. Fuchs, Ramesh K. Ramanathan, Stephen K. Williamson, Brian P. Findlay, Barbara A. Pockaj, Robert P. Sticca, Steven R. Alberts, Henry C. Pitot, Richard M. Goldberg

	ACKNOWLEDGMENTS

 
This study was conducted as a collaborative trial of the North Central Cancer Treatment Group and Mayo Clinic.

	NOTES

 
Supported in part by Public Health Service Grant Nos. CA-25224, CA-32102, CA-38926, CA-21115, CA-37404, CA-35195, CA-35101.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

	REFERENCES

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Submitted January 9, 2007; accepted May 14, 2007.

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This Article Abstract Full Text (PDF) Publisher's Note Erratum (v25,p5339) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Dy, G. K. Articles by Goldberg, R. M. Search for Related Content PubMed PubMed Citation Articles by Dy, G. K. Articles by Goldberg, R. M.