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Journal of Clinical Oncology, Vol 26, No 14 (May 10), 2008: pp. 2336-2341 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.15.8261 Survival Following Recurrence in Stage II and III Colon Cancer: Findings From the ACCENT Data Set
From the National Surgical Adjuvant Breast and Bowel Project Operations Office, Pittsburgh; Eastern Cooperative Oncology Group, Philadelphia, PA; Mayo Clinic, Rochester, MN; Cancer and Leukemia Group B, Chicago, IL; Federation Francophone de Cancerologie Digestive, University of the Mediterranean, Marseilles; Groupe Cooperateur Multidisciplinaire en Oncologie, Paris, France; and Southwest Oncology Group Statistical Center, Seattle, WA Corresponding author: Michael J O'Connell, MD, NSABP Foundation, Inc, Four Allegheny Center, 5th Floor, Pittsburgh, PA 15212-5234; e-mail: michael.oconnell{at}nsabp.org
Purpose This study was undertaken to examine five possible prognostic factors in patients with recurrent stage II and III colon cancer: time from randomization on an adjuvant therapy clinical trial to tumor recurrence (< 1 year, 1 to 2 years, 2 to 3 years, 3 to 4 years, > 4 years), initial stage (II v III), initial adjuvant treatment (fluorouracil [FU]-based v surgery alone), the era in which the patient entered an adjuvant therapy clinical trial (1978 to 1985, 1986 to 1992, 1993 to 1999), and patient age at recurrence. Methods The Adjuvant Colon Cancer End Points (ACCENT) data set was analyzed using univariate and multivariate Cox proportional hazards models, stratified by study. Results 5,722 (32.9%) of 17,381 patients experienced recurrence. Median survival following recurrence was 13.3 months. Time from randomization to recurrence was highly prognostic of survival following recurrence (P < .0001). Longer survival following recurrence was seen in patients with initial stage II versus III disease (P < .0001; 14.3% 6-year overall survival after recurrence in initial stage II patients), patients entered more recently onto trials (P < .0001), and patients initially treated with surgery alone versus FU adjuvant treatment (P = .0005). All relationships were maintained in multivariate models. Conclusion Time from initial treatment to recurrence and initial stage are important prognostic factors in patients with recurrent colon cancer. Survival following recurrence increased modestly from 1978 to 1999. Patients who had a recurrence following adjuvant therapy had poorer prognosis than those who progressed after surgery alone. These prognostic factors may be useful for clinical trial design and treatment decisions in patients with recurrent colon cancer.
The assessment of prognosis for patients with recurrent colon cancer is typically based on observations made when advanced disease is identified. Factors such as tumor grade, performance status, weight loss, and anatomic sites of metastatic disease provide useful information regarding the aggressiveness of the malignant disease and anticipated survival time. Based on data from clinical trials in patients with metastatic disease, prognostic models have been developed, with some external validation.1,2 These prognostic factors help guide clinical management decisions regarding the selection, intensity, and duration of palliative systemic therapy. We wished to determine, in patients who had previously undergone a complete resection of stage II or III disease, whether characteristics of a primary colon cancer, such as initial stage or duration of disease-free interval from diagnosis to tumor recurrence, could provide additional valuable information regarding the subsequent clinical behavior of the malignant disease once tumor recurrence was diagnosed. We also sought to examine if prognosis after tumor recurrence was influenced by prior receipt of adjuvant chemotherapy following surgical resection of the primary tumor. In addition, we investigated whether there was improvement in prognosis for patients with recurrent colon cancer over the past several decades. Finally, we explored whether patient age at recurrence influenced subsequent survival. The ACCENT data set described below afforded a unique opportunity to address these questions in a large group of patients with stage II or III colon cancer who had participated in prospective randomized clinical trials of postoperative adjuvant FU-based chemotherapy.
The data set assembled by the Adjuvant Colon Cancer End Points (ACCENT) Group, a collection of individual patient data from 18 trials testing FU-based adjuvant therapy for patients with stage II and III colon cancer, was used for all analyses. These trials were conducted from 1978 to 1999, involved 20,898 patients, and included 43 distinct treatment arms (34 active treatment arms, nine surgery-only arms). Human investigations in these trials were performed after approval by local human investigations committees and in accordance with assurances filed with and approved by the Department of Health and Human Services. Further details regarding the data set are presented in Sargent et al.3 The QUASAR (Quick, Safe, and Reliable) trial4 was excluded from this analysis, as in this trial follow-up for recurrence was based on local practice as opposed to a protocol-specified schedule of imaging studies (Appendix Table A1, online only, provides details about the clinical trials included in this report). We restricted our analysis to the subset of patients who experienced tumor recurrence after initial therapy and focused on five specific factors that were consistently collected. These factors, using prespecified cutoff values, were: time from randomization to recurrence (< 1 year, 1 to 2 years, 2 to 3 years, 3 to 4 years, > 4 years), initial stage (II v III), initial adjuvant treatment (FU-based v surgery-only control), the era in which the patient entered onto study (1978 to 1985, 1986 to 1992, 1993 to 1999) and age at recurrence (< 50, 51 to 60, 61 to 70, > 70 years). Analyses of the impact of initial adjuvant treatment on survival following recurrence were limited to patients enrolled on trials that randomized patients between surgery alone control and surgery plus chemotherapy. Univariate analyses were performed using Kaplan-Meier methods and log-rank testing, stratified by study (except for era of study). Cox proportional hazards models were used for multivariate analyses. Tests for interaction among each of the five factors and the baseline variables of age at initial diagnosis, gender, and initial stage were performed using a likelihood ratio test. Due to the confounding effect that stratification by study has on the era in which a patient entered the initial adjuvant trial, we fit all models with and without stratification to see if there was any differential effect. We found that stratification by study did not meaningfully alter any results for the models (data not shown); thus, the multivariate models reported are without stratification. The appropriateness of the proportional hazards assumption was examined using graphical methods and tested by the method of Grambsch and Therneau.5 Departure from proportionality was present for several covariates, likely due to the large sample size. Visual examination for time-varying coefficients indicated these were minor variations in the late years of follow-up (> 3 years). We therefore continued to use the Cox model. All P values reported are two-sided, with P < .05 denoting statistical significance.
The median follow-up in living patients was 8 years from randomization and 3.7 years following recurrence. 5,722 (32.9%) of 17,381 patients experienced a disease recurrence. The median time from recurrence to death was 13.3 months. Characteristics of the 5,722 patients with tumor recurrence are summarized in Appendix Table A2 (online only). In particular, 80% of patients had stage III primary colon cancer, and 20% had stage II disease. Eighty-four percent of patients received surgery plus chemotherapy for their primary colon cancer, and 16% were treated with surgery alone. In univariate analyses, all five factors studied were highly prognostic for patient survival (Table 1). Time from randomization to recurrence was strongly related to survival following recurrence (P < .0001). There was a consistent trend, with median survival following recurrence ranging from 9.9 months for early recurrences in year 0 to 1, to 19.1 months for late recurrences at year 4+ (Fig 1A). Patients with initial stage II disease had longer survival following recurrence compared to stage III patients (median 18.2 v 12.5 months, P < .0001, hazard ratio (HR) = 0.70; Fig 2A). A surprisingly high 14.3% 6-year overall survival following recurrence was observed in patients with initial stage II disease. In addition, a significant interaction was found for survival between the patient's initial stage and time from randomization to recurrence (P = .00011). Specifically, time from randomization was significantly associated with survival following recurrence in patients with initial stage III disease (P < .0001, Fig 1B), but not in patients with initial stage II disease (P = .1875, Fig 1C).
The era in which a patient was entered onto a clinical trial also significantly impacted survival following recurrence. Patients entering more recent trials had superior survival after recurrence (median 11.5 v 13.2 v 15.2 months for patients entered onto trials in 1978 to 1985, 1986 to 1992 and 1993 to 1999, respectively, P < .0001; Fig 2B). Patients initially randomized to surgery alone had superior survival following recurrence compared to those initially treated with FU adjuvant chemotherapy (median 14.2 v 11.5 months, P = .0005, HR = 0.83; Fig 3). Patients who were age  70 years at time of disease recurrence had poorer survival following recurrence, with a median survival of 14.3 months in patients younger than age 50 years versus 12.3 months in patients age 70 years (P < .0001).
In multivariate models, adjusted for age at initial diagnosis, gender, and each of the five factors considered, each factor except age at recurrence (P = .52) remained significantly associated with survival (Table 2; Fig 4A). When the multivariate HRs were examined by stage, each of the factors remained significantly associated with survival for patients with initial stage III tumors. However, time from randomization to recurrence was not significantly associated with survival in stage II patients (Fig 4B).
Two characteristics related to the primary colon tumor were found to be highly prognostic of survival following recurrence in the analyses of the ACCENT data set presented in this report: initial stage and interval to recurrence. Stage II patients without evidence of regional lymph node metastases at the time of diagnosis had longer survival following tumor recurrence compared to stage III patients. One possible explanation for this observation is that patients with nodal involvement at the time of initial diagnosis may be more likely to have subclinical metastases at other sites compared to those without nodal spread. Alternatively, initial regional lymph node involvement may signal a biologically different, more aggressive tumor that runs its course more quickly once recurrence is identified. A final alternative explanation is that nodal involvement at the time of initial diagnosis may reflect that the patient is later in the natural history of disease, and the resulting poorer prognosis is carried forward into prognosis following a recurrence. Similarly to tumors that initially present as stage II disease, tumors that do not recur for long periods of time following initial treatment of the primary disease tend to behave in a more indolent fashion following tumor recurrence. The observation that stage III patients who have tumor recurrence in a short period of time have much shorter survival following recurrence suggests that optimal strategies for advanced disease management may differ due to the disparate clinical behavior of these two subgroups. This is an issue that could be resolved by prospective clinical trials. These factors should also be taken into account in the design and analysis of clinical trials of new therapies for recurrent colon cancer, since the median survival difference of 5.7 months found between patients with initial stage II and stage III disease is larger than any difference between regimens studied in phase III first-line trials in advanced colorectal cancer.6-8 Our findings also emphasize the importance of adequate determination of the lymph node status for patients with early-stage colon cancers. Patients who were assigned to receive adjuvant FU-based chemotherapy following surgical resection of the stage II or III colon cancer had poorer survival rates following tumor recurrence than did chemotherapy-naïve patients. This may be due to a selection effect (more aggressive tumors may be destined to recur after adjuvant therapy), a sensitivity effect (tumors relapsing after adjuvant therapy may be less likely to respond to further treatment at the time of recurrence), or an imbalance in the use of chemotherapy after relapse in patients who previously received adjuvant therapy due to physician reluctance to reuse the same chemotherapy after which the patient had relapsed. Several caveats must be kept in mind when considering the impact of prior adjuvant therapy on subsequent clinical course, however. First, our observations relate only to FU-based adjuvant therapy. None of the patients in this analysis received adjuvant regimens with newer cytotoxic agents such as oxaliplatin or irinotecan, or targeted therapy with agents such as bevacizumab or cetuximab. Only a minority of patients in our study had access to the newer cytotoxic and targeted agents now available for the treatment of recurrent disease, as reflected in the short survival time following recurrence in this study as compared to expectations in more contemporary treatment settings. Thus, it is possible that non–cross-resistant therapy at the time of recurrence might mitigate the adverse effects of prior adjuvant therapy we observed in our study. In the future, investigators may wish to subdivide patients enrolled into advanced disease clinical trials with metachronous metastatic disease into separate strata depending on prior receipt of adjuvant chemotherapy, with a third stratum for those patients who present with advanced disease at the time of initial diagnosis. Survival following recurrence steadily improved from 1978 to 1999, perhaps related to improvement in surgical technique, supportive care, the availability of irinotecan and oxaliplatin for treatment of recurrent disease in the most recent era, or other factors such as improved diagnostic techniques resulting in some lead-time bias. This emphasizes the importance of concurrently randomized clinical trials to assess the benefit of new therapies for recurrent disease. With the current availability of several new agents (irinotecan, oxaliplatin, bevacizumab, cetuximab and panitumumab) effective for the treatment of metastatic colon cancer6-10 which have been introduced into clinical practice following the time period of the ACCENT clinical trials, and an increasing emphasis on surgical resection of limited metastatic disease which can prolong survival,11,12 we anticipate that survival following tumor recurrence will improve from the 13.1 month median survival observed in this analysis. In fact, the recently published final results of the GERCOR C96.1 adjuvant therapy clinical trial,13 which is included in the ACCENT database, reported a median survival of 24 months from tumor relapse, likely reflecting the impact of both newer agents and surgical resection for the treatment of metastatic disease. The analyses presented in this report demonstrate the value of the ACCENT data set to evaluate clinical prognostic factors in patients with colon cancer. It will be useful to add newer adjuvant studies to the database that include agents such as capecitabine, oxaliplatin, irinotecan, bevacizumab, and cetuximab to assure that future ACCENT studies will remain relevant to contemporary clinical practice.
Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. 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 or Leadership Position: None Consultant or Advisory Role: Richard M. Goldberg, Sanofi-aventis (C); Axel Grothey, Sanofi-aventis (C); Jean-François Seitz, Bayer (C), Sanofi-aventis (C); Thierry André, Roche (C), Amgen (C); Daniel J. Sargent, Sanofi-aventis (C), Genentech (C), Roche (C) Stock Ownership: None Honoraria: Thierry André, Roche, Amgen, Sanofi-aventis; Daniel J. Sargent, Genentech, Sanofi-aventis, Roche Research Funding: Axel Grothey, Sanofi-aventis Expert Testimony: None Other Remuneration: None
Conception and design: Michael J. O'Connell, Richard M. Goldberg, Daniel G. Haller, Daniel J. Sargent Financial support: Daniel J. Sargent Administrative support: Daniel J. Sargent Provision of study materials or patients: Richard M. Goldberg, Jean-François Seitz, Jacqueline K. Benedetti, Thierry André, Daniel G. Haller, Daniel J. Sargent Collection and assembly of data: Richard M. Goldberg, Axel Grothey, Daniel J. Sargent Data analysis and interpretation: Michael J. O'Connell, Megan E. Campbell, Richard M. Goldberg, Axel Grothey, Jacqueline K. Benedetti, Daniel G. Haller, Daniel J. Sargent Manuscript writing: Michael J. O'Connell, Megan E. Campbell, Richard M. Goldberg, Axel Grothey, Thierry André, Daniel G. Haller, Daniel J. Sargent Final approval of manuscript: Michael J. O'Connell, Megan E. Campbell, Richard M. Goldberg, Axel Grothey, Jean-François Seitz, Jacqueline K. Benedetti, Thierry André, Daniel G. Haller, Daniel J. Sargent
We thank NSABP: Greg Yothers, H.S. Wieand, Norman Wolmark; SWOG: Charles Blanke; Ospedali Riuniti, Bergamo: Roberto Labianca; ECOG: Robert Catalano, Al Benson; NCIC: C. O'Callaghan; Univ Siena: G. Francini; GERCOR: Aimery de Gramont; IDDI: Marc Buyse; NCCTG: Erin Green, Steven Alberts; QUASAR: Richard Gray; and NSABP Scientific Publications: Barbara C. Good, Wendy L. Rea.
Supported in part by Public Health Service Grants No. U10CA-12027, U10CA-69974, U10CA-37377 and U10CA-69651 from the National Cancer Institute, Department of Health and Human Services. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Köhne CH, Cunningham D, Di CF, et al: Clinical determinants of survival in patients with 5-fluorouracil-based treatment for metastatic colorectal cancer: Results of a multivariate analysis of 3825 patients. Ann Oncol 13:308-317, 2002 2. Díaz R, Aparicio J, Girones R, et al: Analysis of prognostic factors and applicability of Kohne's prognostic groups in patients with metastatic colorectal cancer treated with first-line irinotecan or oxaliplatin-based chemotherapy. Clin Colorectal Cancer 5:197-202, 2005[Medline] 3. Sargent DJ, Wieand HS, Haller DG, et al: Disease-free survival versus overall survival as a primary end point for adjuvant colon cancer studies: Individual patient data from 20,898 patients on 18 randomized trials. J Clin Oncol 23:8664-8670, 2005 4. QUASAR Collaborative Group: Comparison of fluorouracil with additional levamisole, higher-dose folinic acid, or both, as adjuvant chemotherapy for colorectal cancer: A randomized trial. Lancet 355:1588-1596, 2000[CrossRef][Medline] 5. Grambsch PM, Therneau TM: Proportional hazards tests and diagnostics based on weighted residuals (Corr: 95V82 p668). Biometrika 81:515-526, 1994 6. 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 7. Goldberg RM, Sargent DJ, Morton RF, et al: A randomized controlled trial of fluorouracil plus leuco-vorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol 22:22-30, 2004 8. 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 9. Cunningham D, Humblet Y, Siena S, et al: Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 22; 351:337-345, 2004 10. Van Cutsem E, Peeters M, Siena S, et al: Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory met-astatic colorectal cancer. J Clin Oncol 25:1658-1664, 2007 11. Delaunoit T, Alberts SR, Sargent DJ, et al: Chemotherapy permits resection of metastatic colorectal cancer: Experience from Intergroup N9741. Ann Oncol 16:425-429, 2005 12. Fong Y, Cohen AM, Fortner JG, et al: Liver resection for colorectal metastases. J Clin Oncol 15:938-946, 1997 13. André T, Quinaux E, Louvet C, et al: Phase III study comparing a semimonthly with a monthly regimen of fluorouracil and leucovorin as adjuvant treatment for stage II and III colon cancer patients: Final results of GERCOR C96.1 J Clin Oncol 25:3732-3738, 2007 Submitted December 14, 2007; accepted January 25, 2008.
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
