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© 1999 American Society for Clinical Oncology Efficacy of Adjuvant Fluorouracil and Folinic Acid in B2 Colon CancerFrom the Mayo Clinic, Rochester, MN; Gruppo Italiano di Valutazione Interventi in Oncologia; Fondation Française de Cancerologie Digestive; National Cancer Institute of Canada Clinical Trials Group; and University of Siena. Address reprint requests to Charles Erlichman, MD, Department of Oncology, Mayo Clinic, 200 First St, SW, Rochester, MN 55905; email erlichman.charles{at}mayo.edu
PURPOSE: The goal of this analysis was to determine whether fluorouracil (FU) and folinic acid (leucovorin, LV) is an effective adjuvant therapy for patients after potentially curative resection of colon cancer in patients with B2 tumors. PATIENTS AND METHODS: One thousand sixteen patients with B2 colon cancer entered onto five separate trials were randomized to FU + LV or observation. A pooled analysis for event-free (EFS) and overall survival (OS) using a stratified log-rank and Cox model was performed. RESULTS: The median follow-up duration was 5.75 years. Patients receiving FU + LV did not experience a significant increase in EFS or OS. The hazards ratio at 5 years was 0.83 (90% confidence interval, 0.72 to 1.07) for EFS and 0.86 (90% confidence interval, 0.68 to 1.07) for OS. The 5-year EFS was 73% for controls and 76% for FU + LV. The 5-year OS was 80% for controls and 82% for FU + LV. Increasing age and poorly differentiated tumors were significant indicators of poor prognosis (P < .02). CONCLUSION: This data set does not support the routine use of FU + LV in all patients with B2 colon cancer. Longer follow-up may identify a small benefit. At present, studies in B2 colon cancer designed with a no-treatment control arm should be considered appropriate.
THE USE OF fluorouracil (FU) combined with folinic acid (leucovorin, LV) in the treatment of metastatic colorectal cancer is a rationally developed combination based on an understanding of the mechanism of action of FU, delineated in preclinical systems with demonstrable in vivo efficacy.1-3 The clear effect on response rate that FU + LV has had in metastatic colorectal cancer has not been translated conclusively into a survival advantage in the advanced-disease setting.4-9 Nevertheless, these promising results encouraged investigators to evaluate the treatment as adjuvant therapy for early-stage colon cancer. In this regard, patients with Dukes' stage B2 (T3 and T4, N0 M0) and Dukes' stage C (T1-4 N1-3 M0) were enrolled onto studies comparing FU + LV to no adjuvant therapy. These studies have reported a significant benefit for the combination treatment of FU + LV when given over a period of 6 months.10-13 An additional trial compared semustine, vincristine, and fluorouracil (MOF) to FU + LV and similarly showed a benefit of FU + LV over MOF.14 Each of these studies was designed to address the question of whether FU + LV is active in B2 and C colon cancer patients. None of the studies was designed to address a priori the question of whether FU + LV was effective in the individual subsets of B2 and C. Whereas there are sufficient data from these studies to conclude that FU + LV is effective adjuvant therapy in patients with stage C colon cancer, the effectiveness of therapy in the B2 subset lacks clarity. In an attempt to address this issue, we have undertaken a pooled analysis of the subset of patients with B2 colon cancer who were entered onto five randomized trials. Initial reports of these trials have been published previously.10-12 This analysis was undertaken to determine whether FU + LV increases event-free survival (EFS) and overall survival (OS) in patients with B2 colon cancer, compared with the standard of care (ie, no treatment). A preliminary result of this study was reported at the American Society of Clinical Oncology meeting in 1997.13 This report presents the final results of this pooled analysis.
Analysis Protocol The approach to the analysis has been published previously.10,15,16 The studies included in this analysis were performed by the Gruppo Italiano di Valutazione Interventi in Oncologia (GIVIO), the National Cancer Institute of Canada Clinical Trials Group (NCIC-CTG), the Fondation Française de Cancerologie Digestive (FFCD), the North Central Cancer Treatment Group (NCCTG) Intergroup,12 and the University of Siena group.11 The protocol established the criteria for pooling of the study patients into one common data set, standard definitions and coding for events and patient characteristics, the minimum clinical difference to be tested in the main hypothesis and the required statistical power, duration of follow-up, and appropriate timing for the main comparison, and the analytic approach. In the last quarter of 1996, a common database was set up and verified. The analysis was carried out during the first half of 1997.
Trial Designs
Information on toxicity was obtained differently in the five trials. In the NCIC-CTG trial, patients were evaluated for toxicity weekly during treatment and usually by oncology nurses or trial data managers. Full blood cell counts were also obtained weekly, and biochemistry evaluations were performed monthly before each cycle. In the FFCD, GIVIO, and Siena studies, patients were assessed mainly by physicians, monthly before each cycle. Full blood cell counts and biochemistry evaluations were also performed monthly. In the NCIC-CTG and NCCTG coordinated trials, the National Cancer Institute's common toxicity criteria were used. In the FFCD, GIVIO, and Siena trials, the World Health Organization's toxicity scoring system was used. In all five trials, systems of quality assurance were similar; consistency was checked, and discrepancies with patient notes were investigated.
Statistical Methods
Patient Characteristics There were 1,025 patients in the data set. Nine were deemed ineligible because of inadequate data to determine stage or incorrect stage, leaving 1,016 patients (99.1%) for this analysis. The median follow-up time for the population was 5.75 years. The individual follow-up times for each of the studies were 5.17, 5.29, 5.89, 6.41, and 8.54 years (Table 1). Patient characteristics for the control and treatment arms are listed in Table 2. The arms were well balanced for each of the characteristics examined. In some cases, performance status and T stage are missing because T3 and T4 separation was not available in the data set from Francini et al11 and performance status was unavailable for either the FFCD or Francini data set. There were only 1% and 2% T4 tumors in the control and FU + LV arms, respectively. Tumor differentiation, although distributed equally between the two treatment arms, was predominantly identified as well or moderately differentiated, with more than 83% of tumors occurring in these categories. The median dose of FU administered in each of the studies was 9.5, 10.5, 11.1, 12, and 24 g/m2 (Table 1). The median dose for the total population was 11.1 g/m2. As patients in the study published by Francini et al received 12 months of chemotherapy, approximately twice the dose of FU was administered in this study when compared with the other trials. The median relative dose-intensity (dose received divided by dose planned) was 97%, 85%, 98%, 90%, and 98% in the GIVIO, NCIC-CTG, FFCD, NCCTG intergroup, and Siena trials, respectively.
Outcome
Toxicity Analysis
The use of FU and LV in the adjuvant treatment of stage C colon cancer, in comparison to a control arm of no therapy, is supported by a series of previously published studies.10-14 However, the role of adjuvant chemotherapy in patients with B2 carcinoma of the colon is still unclear and controversial. Individual studies have not demonstrated clearly that a statistically significant benefit arises from adjuvant chemotherapy in patients with B2 colon cancer. A recent analysis of INT-0035, a randomized clinical trial to determine the role of FU and levamisole in B2 colon cancer, did not demonstrate any benefit of this therapy.21 In an attempt to delineate this issue more clearly, we undertook a pooled analysis of over 1,000 patients with B2 colon cancer randomized in five separate trials in which there was a no-treatment control arm and the treatment with FU + LV was administered on a daily x 5 schedule every 28 to 35 days for either 6 or 12 months. The combination was generally well tolerated, and a good dose-intensity with a low frequency of severe toxic effects was observed. Unfortunately, this analysis did not reveal a statistically significant benefit to FU + LV in patients with B2 carcinoma of the colon. Despite the greater than expected 5-year control EFS (73% observed v 63% expected), the improvement in EFS for patients receiving treatment was minimal. It should be noted that the two arms in this data set were equally balanced for relapse rate, second malignancy, and deaths from any cause. Hence, it is not likely that a lack of effect of FU + LV in this analysis is due to an imbalance of events other than colon cancer favoring the control arm. The differences in hazards rate for EFS and OS in the NCCTG and NCIC-CTG studies raises the possibility that there are differences in the study populations. It is possible that there is a difference in the proportion of patients with poor prognostic indicators such as bowel obstruction, perforation, or adhesion to adjacent organs in these studies, compared with the overall group. Such an imbalance could make the hazards rate worse in the NCIC-CTG trial and improve it in the NCCTG trial. Although we cannot rule this out completely, T4 tumors, which reflect adhesions to adjacent organs, make up less than 1.5% of the total population. The higher hazards rate for the NCIC-CTG trial may also relate to this study having the lowest median dose of FU administered and patients starting therapy up to 56 days after surgery. Such speculative explanations may contribute to the lack of observed effects of therapy but cannot be addressed further in this data set. The National Surgical Adjuvant Breast and Bowel Project (NSABP) has reported in each of their trials14,22-25 (C-01, C-02, C-03, C-04) that the relative reduction of recurrence and mortality in patients with B2 disease was comparable to that in patients with Dukes' C disease. It should be noted that these trials were not designed to evaluate treatment effect in the B2 subset prospectively. The results of the NSABP analyses cannot be directly compared with those in our analysis because, in two of the NSABP studies, C-03 and C-04, the experimental arm was compared with an arm containing treatment. In C-01 and C-02, the comparison was not of FU + LV to no treatment but of MOF and portal vein infusion, respectively, to no treatment. Although the cumulative odds ratio shows a benefit in stage B2 patients, when the absolute differences in 5-year survival are examined, the difference (3% in C-01, 12% in C-02, 8% in C-03, and 4% in C-04) is greatest for patients receiving portal vein infusion. In C-03, which has a FU + LV arm, the difference may be explained by the increased incidence of second primary tumors in MOF-treated patients (25 patients in the MOF arm and 11 in the FU + LV arm). In C-04, the difference of 4% is comparable to that which we observed, ie, 2% (Table 4). Another factor that may explain the difference in the results of this analysis and the apparent benefit of therapy in NSABP trials is the difference in the proportion of patients with poorly differentiated tumors or of patients who are elderly. Differences in other prognostic factors, such as bowel obstruction, may also exist between this data set and the patients enrolled on NSABP studies. It is conceivable that if we had had sufficient numbers of patients with poorly differentiated tumors and they had experienced more events, a statistically significant difference for this subset might be defined. It is intriguing that tumor grade had a significant impact on EFS and OS. Despite the fact that central pathology review was not undertaken and pathology reports were derived from four different countries and many individual centers, the poorly differentiated category had an EFS and an OS comparable to that of patients with stage C colon cancer. Such a result strongly suggests that, in B2 colon cancer, the biology of the disease has a greater impact on patient outcome than the therapeutic intervention. Hence, we believe that these data support the need for more pertinent biologic markers26-31 of the malignant process to better identify patients at high risk of tumor relapse. Such markers may include proliferation markers such as MIB-1, tumor ploidy, microsatellite instability, p53, K-ras mutations, MMP-2 and MMP-9, and DCC. Ongoing analysis of large tumor banks for such markers in the multivariate manner will identify those markers that have independent prognostic significance. Our data indicate that, at best, 50 patients would have to receive FU + LV and be exposed to its attendant side effects to cure one individual, assuming the absolute risk reductions at 5 years indicated in Table 4. This would suggest a very minimal effect at best of this therapeutic intervention in the total B2 population. However, based on the decrease in point estimates of hazards ratios for EFS and OS, a 12% and 14% benefit, respectively, can be hypothesized. This study does not have sufficient power to detect such an effect at this time, although it may be relevant in high-risk patients with Dukes' B2 colon cancer. If such reasoning were extrapolated to patients with poorly differentiated tumors, a 14% decrease in hazards ratio would translate into a 5% absolute difference in 5 years from 55% to 60%, decreasing the number of patients treated for each one cured to 20. In conclusion, this analysis does not support the routine use of FU + LV in all patients with B2 colon cancer. Studies in B2 colon cancer designed with a no-treatment control arm should still be considered appropriate.
The members of the IMPACT B2 Writing Committee were: C. Erlichman, M. O'Connell, and M. Kahn (Mayo Clinic, Rochester, MN); S. Marsoni, V. Torri, B. Tardio, A. Zaniboni, G. Pancera, G. Martignoni, R. Labianca, and A. Barni (Gruppo Italiano di Valutazione Interventi in Oncologia); J.F. Seitz, C. Milan, L. Bedenne, M. Giovannini, and Y.P. Letreut (Fondation Française de Cancerologie Digestive); J. Skillings, L. Shepard, and B. Zee (National Cancer Institute of Canada Clinical Trials Group); and R. Petrioli and G. Francini (University of Siena). Other participants were as follows: from the Gruppo Italiano di Valutazione Interventi in Oncologia (GIVIO): E. Aitini, G. Apolone, A. Auzzani, S. Banducci, G.D. Beretta, O. Biffi, F. Bucci, G. Cardi, D. Cifatte, G. Colucci, A. Comandone, G. Comella, C. Confalonieri, A. Contu, M. Costanzo, C. Crespi, E. Damiani, D. De Giorgi, V. Dongiovanni, G. Fabris, G. Fabrizio, G. Facendola, P.A. Fantoni, A. Ferragni, B. Fiori, F. Florianello, L. Frontini, E. Galli, P. Garattini, G. Gherardi, A. Giovanelli, F. Giuliani, P. Gosso, P. Ianniello, B. Kildani, S. Leo, A. Liberati, G. Maffione, E. Maiello, L. Maiorino, P. Manente, M. Marzola, M. Mastrodonato, F. Meriggi, B. Molinari, G.F. Molinari, N. Monferroni, O. Nascimben, C. Natale, S. Negretti, S. Palazzo, D. Panvivi, V. Parisi, T. Pedicini, F. Peradotto, S. Pessa, E. Piatto, G. Pizzi, A. Prosperi, F. Prusciano, C. Rabbi, A. Raina, A. Ruggiero, C. Sava, F. Scanzi, P. Setti Carraro, F. Smerieri, B. Stivala, A. Taiana, F. Testore, A. Tinazzi, G. Turcato, S. Zonato. From the National Cancer Institute of Canada Clinical Trials Group (NCIC-CTG): J. Ayoub, K. Belanger, G. Biron, A.J. Bodurtha, G. Boos, M. Burnell, P. Cano, D. Charpentier, W.S.W. Chow, J. Chritchley, C. Cripps, S.P. Dang, M.L. Davis, M. Davidson, B. Dingle, D. Dryer, E. Ferland, A. Fields, S. Fine, J. Jolivet, L. Kaiser, I. Kerr, W.I. Kocha, C. Kotwall, H. Drieger, M. Lepine-Martin, C. Little, W.S. Lofters, M. Maheu, M. Moore, J. Pater, B. Pressnail, J. Rayner, R. Reznick, T. Ross, L. Rotstein, L. Rudinskas, B. Schacter, A. Shah, J. Skillings, H. Stern, M. Tweedale, T. Vandenberg, D. Walde, H.J. Watt, K. Wilson, A. Wong, S. Yoshida. From the Fondation Française de Cancerologie Digestive (FFCD): C. Baldit, J.L. Baroni, J.P. Bazin, L. Bedenne, A. Blanchi, J.C. Bognel, J.F. Bosset, O. Bouche, J.M. Brandone, R. Bricot, P. Burtin, L. Cador, M. Charbit, A. Charlier, Y. Courouble, P. Couzigou, J. Cuilleret, J.R. Delpero, M. Ducreux, F. Dumas, E. Echinard, P.L. Etienne, J.L. Friguet, M. Gignoux, M. Giovannini, J.P. Herr, J. Lafon, P. Letreut, J.P. Latrive, C. Lauvaux, C. Louvet, R. Mackiewicz, C. Maurel, C. Messerschmitt, L. Morand, J. Moreau, T. Morin, B. Nordlinger, P.M. Noterdaeme, J.C. Ollier, R. Picaud, P. Pienkowski, J.P. Plachot, R. Portet, H. Rallier du Baty, P. Rougier, G. Rozental, B. Sastre, J.F. Seitz, A. Votte-Lambert, B. Watrin, P. Zeitoun. From the North Central Cancer Treatment Group (NCCTG) Intergroup: J.A. Mailliard, J.S. Macdonald, D.G. Haller, R.J. Mayer, H.S. Wieand. From the University of Siena: G. Francini, R. Petrioli, L. Lorenzini, S. Mancini, S. Armenio, G. Tanzini, S. Marsili, A. Aquino, G. Marzocca, S. Civitelli, L. Mariani, D. De Sando, S. Bovenga, M. Lorenzi.
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ABSTRACT
INTRODUCTION
2 test. 
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