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Journal of Clinical Oncology, Vol 24, No 24 (August 20), 2006: pp. 3912-3918 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.06.1812 Lack of Benefit of Maintenance Paclitaxel in First-Line Chemotherapy in Metastatic Breast Cancer
From the National Cancer Research Institute, Genoa; Morgagni-Pierantoni Hospital, Forli; Oncology Institute, Bari; Oncology Institute of Romagna; S. Carlo Hospital, Potenza; and the University of Modena and Reggio Emilia, Modena, Italy Address reprint requests to Alessandra Gennari, MD, PhD, National Cancer Research Institute, Largo Rosanna Benzi, 10, 16132 Genoa, Italy; e-mail: alessandra.gennari{at}istge.it
PURPOSE: This randomized study compared maintenance paclitaxel with control in metastatic breast cancer patients not experiencing progression after first-line anthracycline/paclitaxel combination chemotherapy. METHODS: Between April 1998 and October 2003, 459 metastatic breast cancer patients received first-line combination chemotherapy with epirubicin or doxorubicin plus paclitaxel. Of these, 255 who had a response or stable disease were then randomly assigned onto the Maintenance Paclitaxel 1 (MANTA1) study, comparing eight courses of maintenance paclitaxel versus control (ie, no additional chemotherapy administration). The primary end point was progression-free survival. RESULTS: The study was prematurely concluded after a futility analysis, which was performed on 215 of the 238 patients randomly assigned within December 2002. Of these, 109 patients were assigned to maintenance paclitaxel and 106 were assigned to stopping chemotherapy. No significant difference in median progression-free survival was observed (8.0 months for maintenance paclitaxel and 9.0 months for control). There was no significant difference in median survival time (28.0 v 29.0 months). When the Bayesian method for monitoring clinical trials was applied to these data, even under an enthusiastic prior distribution, in the posterior distribution there was only an 8.6% chance of observing a 3-month improvement in median progression-free survival in the group receiving maintenance paclitaxel. After these results study accrual was closed. CONCLUSION: Compared with control, the administration of additional courses of paclitaxel in patients who achieve disease control after six to eight courses of first-line anthracycline plus paclitaxel combination chemotherapy does not improve progression-free survival.
The management of metastatic breast cancer is a major clinical challenge for medical oncologists. Despite all available endocrine and chemotherapeutic agents, it rarely can be cured. Therefore, therapeutic goals are palliative; the primary objective is prolongation of survival with good quality of life and control of the disease and its symptoms. For patients with hormone receptor–negative disease, or for those whose disease has become resistant to endocrine therapy or is rapidly progressive and life threatening, cytotoxic chemotherapy is indicated.1 Although the selection of chemotherapy generally is affected by patient and disease-related factors, as well as patient/physician preferences, controversy remains about how long chemotherapy should be continued after the achievement of disease control. During the last two decades, some clinical trials have addressed the issue of optimal chemotherapy duration. These studies indicated that prolonged chemotherapy results in a longer time to progression,2-7 a longer survival,4 and an improved quality of life,2 compared with standard therapy duration. Since these studies, new agents have been introduced in the management of breast cancer: among these, taxanes showed great promise against advanced breast cancer and dominated the therapeutic scene during the last 10 years. In 1996, the breast cancer practice guidelines of the National Comprehensive Cancer Network recommended the use of chemotherapy with paclitaxel or other drugs untilprogression8 in metastatic breast cancer, even though evidence on the role of taxanes as maintenance therapy was lacking. Concurrently, results from early phase II studies indicated that, despite the impressive level of activity, the duration of response after anthracycline-taxane combination chemotherapy was similar to that observed with older regimens.9-12 With these premises, in 1997 we designed the Maintenance Paclitaxel 1 (MANTA1) study, the primary objective of which was to define the role of maintenance therapy with paclitaxel in metastatic breast cancer patients not experiencing progression after first-line combination chemotherapy with an anthracycline plus paclitaxel.
Patient Selection Patients were eligible if they had metastatic measurable and/or assessable disease, and no evidence of progression after six to eight courses of first-line chemotherapy (induction treatment) with one of the following regimens: epirubicin 90 mg/m2 day 1 plus paclitaxel 200 mg/m2 (3-hour infusion) day 1, or doxorubicin 50 mg/m2 day 1 plus paclitaxel 200 mg/m2 (3-hour infusion) day 2, administered once every 3 weeks. Written informed consent was obtained from all patients.
Other criteria included age between 18 and 70 years; Eastern Cooperative Oncology Group performance status
Treatments
Doses were adjusted on the basis of the toxicity observed in the previous cycle. With the occurrence of neurotoxicity (National Cancer Institute Common Toxicity Criteria, version 2 scale), criteria for dose modification were as follows: if grade 1 neurotoxicity occurred, paclitaxel was administered at the dose of 135 mg/m2; if grade
Efficacy
Toxicity
Statistical Methods Sample size. The expected median progression-free survival of metastatic breast cancer patients who achieve disease control after first-line chemotherapy was estimated to be 10 months. The minimal improvement, justifying the adoption of maintenance paclitaxel, was estimated to be at least 3 months. With 262 eligible patients in each arm (456 total events), the trial had a power of 80% to detect a 30% improvement in median progression-free survival, testing at the two-sided .05 significance level. No interim analysis was planned a priori. Efficacy analyses. All analyses were primarily on an intent-to-treat basis, including all randomly assigned patients. Progression-free survival was defined as the time from random assignment until objective disease progression or death, whichever occurred first. Survival was calculated from the date of random assignment to the date of death as a result of any reason. Progression-free survival and overall survival were estimated using the Kaplan-Meier life-table method and compared by a two-sided log-rank test.
The Cox proportional hazards model was used in progression-free survival to adjust the treatment effect for potential confounding factors. The covariates included in this model were age (
All analyses were performed using SAS statistical package (release 8.00; SAS Institute, Cary, NC). All P values were two sided. Differences at P Although not prespecified in the study protocol, in the context of data monitoring board activities, an interim analysis for futility, according to the Bayesian approach proposed by Fayers et al,15 was prompted by the slow accrual rate and by the availability of new evidence on paclitaxel schedule optimization, which showed an improved activity and efficacy of weekly paclitaxel, compared with the conventional schedule of administration once every 3 weeks in metastatic breast cancer.16 Bayesian analysis. Three types of prior distributions on log(h1/h2), where h1 is the progression rate for maintenance paclitaxel and h2 is the progression rate for the control arm, were used: a noninformative prior distribution, a skeptical prior distribution, and an enthusiastic prior distribution. The noninformative prior distribution represents a lack of clinical opinion as to the likely treatment difference (classical frequentist approach). The skeptical prior distribution represents the position that the null hypothesis (no difference) is likely to be true. The enthusiastic prior distribution is based on the results of published trials of longer versus shorter chemotherapy duration in metastatic breast cancer, consistently showing a significant progression-free survival improvement with longer treatment duration (mean, 0.262; standard deviation, 0.16). The distributions of the observed data from the interim analyses were used to modify the prior distributions, resulting in a posterior distribution that reflected the revised beliefs in the light of the new data.
Enrollment of Patients Between April 1998 and October 2003, a total of 459 patients received induction treatment with doxorubicin or epirubicin plus paclitaxel as first-line chemotherapy for metastatic disease. Of these, 255 were randomly assigned in the MANTA1 study, with an accrual rate of 45 patients per year. The remaining 204 patients did not undergo random assignment. Main reasons were disease progression in 76 patients, ineligibility in 60 patients (due to residual toxicity in 45 patients), and consent withdrawal in four patients. Forty-three patients did not undergo random assignment for unknown or other reasons. The MANTA1 study flowchart is represented in Figure 1.
Patient Characteristics The study database was frozen as of December 2002. This analysis was performed as of September 2003 on 238 patients randomly assigned within 2002 (of the original 255 patients). Twenty-three patients were excluded due to outcome data unavailability: of them, 10 received maintenance paclitaxel and 13 received no chemotherapy. Of the 215 analyzed, 109 had been assigned to maintenance paclitaxel and 106 had been assigned to stopping chemotherapy. All of the demographic, biologic, and clinical characteristics were well balanced in the two arms (Table 1).
Efficacy Maintenance paclitaxel was not shown in this study to be associated with an improved outcome. Eighty-four occurrences of disease progression were observed among the 109 patients randomly assigned to maintenance paclitaxel, compared with 80 occurrences of disease progression among the 106 patients in the control arm. The median time to disease progression in the group assigned to maintenance paclitaxel was 8 months (95% CI, 7 to 12 months) versus 9 months (95% CI, 7 to 13 months) in the group randomly assigned to stopping chemotherapy (P = .817; Fig 2). The results of the multivariate proportional hazards Cox’s regression analysis and the subgroup analyses are shown in Figure 3. The adjusted relative risk of progression (maintenance v control) was 1.01 (95% CI, 0.72 to 1.43; P = .94). The lack of efficacy of maintenance paclitaxel was consistent among the analyzed subgroups.
Maintenance paclitaxel was not shown in this study to be associated with a lower rate of death at 2 years (57% in both groups). Fifty-two deaths occurred among the 109 patients randomly assigned to maintenance paclitaxel, compared with 46 deaths among the 106 patients in the control arm. The median survival was 28 months (95% CI, 23 to 40 months) in the group administered maintenance paclitaxel and 29 months (95% CI, 24 to 47 months) in the group assigned to stopping chemotherapy (P = .547; Fig 4). The adjusted relative risk of death was 1.12 (95% CI, 0.72 to 1.73; P = .62).
Bayesian Analysis Using the noninformative/neutral prior distribution of the benefit associated with maintenance therapy, the probability that the improvement in median progression-free survival could be as large as planned (3 months) in patients who received maintenance paclitaxel compared with those stopping chemotherapy was 2.8%. Under the enthusiastic prior distribution (ie, a high confidence that the alternative hypothesis or better is true), there was only an 8.6% chance in the posterior distribution that the improvement in median progression-free survival could be as long as planned (3 months). A sceptical stance, of course, produced a smaller chance of a clinically worthwhile benefit (0.6%). As a result of this analysis, the study protocol committee (P.C., D.A., M.D.L., A.G.) recommended that the trial be closed.
Toxicity and Treatment Compliance
Patient compliance with maintenance paclitaxel was good, with a median number of courses/patient of six (range, one to eight); 40% of the patients completed the eight planned courses of treatment, 22% received six to seven courses of treatment, and 33% received fewer than six courses of treatment. In 5% of the patients the planned treatment was never started.
Reasons for stopping paclitaxel were progressive disease or death in 27% of the patients, refusal in 9% of the patients, and grade
Our findings suggest that women with metastatic breast cancer who do not experience progression after six to eight courses of doxorubicin or epirubicin plus paclitaxel, do not receive any benefit, in terms of time to disease progression, from the administration of additional courses of single-agent paclitaxel. The issue of chemotherapy duration in metastatic breast cancer has been evaluated in several studies2-7 in the last 20 years; however, this is the first trial to report results of treatment duration with modern cytotoxic regimens. In our study, maintenance chemotherapy consisted of paclitaxel, administered on a conventional schedule once every 3 weeks. We recognize that this may be no longer regarded as the optimal administration schedule of paclitaxel; weekly regimens are more appropriate.16 However, at the time this study was designed, the decision was based on available evidence. Despite the fact that the study was stopped prematurely when follow-up data were available on fewer than 50% of the planned number of patients, the results provide strong evidence against the hypothesis that maintenance paclitaxel is associated with a clinically worthwhile effect on progression-free survival. This evidence is based on the results of an unplanned interim analysis using the Bayesian approach. It is well known that conventional interim analyses (conditional power) aimed at stopping studies for futility need not to be planned in advance, and this applies to Bayesian analyses as well. This analysis indicates that, even under the most enthusiastic prior distribution scenario, the probability of a 3-month improvement in progression-free survival associated with maintenance paclitaxel was less than 9%. This enthusiastic prior distribution was derived from the results of previous randomized trials of shorter versus longer chemotherapy duration in metastatic breast cancer, showing a consistent benefit in progression-free survival with prolonged treatments. A meta-analysis of abstracted data from some of these studies also revealed a significant reduction in the hazard of death with longer chemotherapy duration, supporting a policy of prolonging treatment in the absence of progressive disease or unacceptable toxicity.17,18 Under this hypothesis, it is unlikely that our results (hazard ratio for overall survival, 1.12; 95% CI, 0.72 to 1.73) are due to chance. It is possible that the type of induction chemotherapy adopted (ie, the combination of an anthracycline plus paclitaxel) selected for randomization onto the MANTA1 study a subgroup patients less sensitive to the benefits of maintenance. It is well known that patients undergoing aggressive chemotherapy for metastatic breast cancer are generally younger and healthier, and have better responses than those who are treated with conventional therapies.19,20 Indeed, the median progression-free survival of 9 months observed in the control arm of this study compares favorably with those reported by other trials with a similar design (ie, randomization after completion of induction chemotherapy),3,5-7 and median overall survival is far superior than in all other trials, with the exception of the Eastern Cooperative Oncology Group study, which was limited to complete responders6 (Table 3). Thus, one may speculate that in the subset of metastatic breast cancer patients achieving disease control after six to eight courses of anthracycline/paclitaxel combination chemotherapy, no additional benefit is associated with the administration of additional cycles of single-agent paclitaxel.
The observation of a better outcome in our patients, independently of maintenance therapy, is coherent with recent evidence indicating that the prognosis of advanced breast cancer has significantly improved over time, possibly due to the availability of newer active agents and to the amelioration of supportive care.21-24 The results of this study lead us to conclude that the policy of prolonging treatment in chemotherapy sensitive patients after aggressive modern combination chemotherapy cannot be recommended for women with metastatic breast cancer. The issue of chemotherapy duration is still an open question in the treatment of metastatic breast cancer, and has a key impact on clinical practice as well as on the design of future clinical trials. A number of randomized clinical trials on maintenance chemotherapy are currently ongoing in advanced breast cancer; moreover, a systematic overview of the completed studies, aimed at comparing the effects on survival and quality of life of shorter versus longer durations of chemotherapy, currently is being conducted.25 Alternative and innovative strategies to prolong the benefit of first-line chemotherapy and to maintain a good quality of life in metastatic breast cancer patients may include the sequential administration of novel target-directed agents to responding patients. However, this issue needs to be addressed in the context of prospective randomized clinical trials.
The following members of the MANTA1 collaborative group also participated to the study: National Cancer Research Institute, Genoa, Italy: Del Mastro L.; Morgagni-Pierantoni Hospital, Forli, Italy: Scarpi E., Ibrahim T., Massa I.; Oncology Institute, Bari, Italy: Latorre A., Sambiasi D.; University of Modena and Reggio Emilia, Modena, Italy: D’Amico R.; S. Carlo Hospital, Potenza, Italy: Bilancia D., Di Nota A.; Santa Maria Nuova Hospital, Reggio Emilia, Italy: Boni C., Moretti G.; University of Rome, Rome, Italy: Cortesi E.; San Salvatore Hospital, Pesaro, Italy: Catalano G.; S. Carlo Borromeo Hospital, Milan: Tabiadon D.; Ramazzini Hospital, Carpi (MO), Italy: Artioli F.; Hospital degli Infermi, Rimini, Italy: Ravaioli A.; Avezzano Hospital, Avezzano, Italy: Recchia F.; University of L’Aquila, L’Aquila, Italy: Marchetti P.; Second University of Naples School of Medicine, Naples, Italy: Catalano G.; S.M. Annunziata Hospital, Florence, Italy: Fioretto L.; Regina Elena Cancer Institute, Rome, Italy: Lopez M.; San Giacomo Hospital, Rome, Italy: Zampa G.
Although all authors completed the disclosure declaration, the following author or 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 discription 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) $10,000–99,000 (C)
We thank the patients, physicians, and nurses who have participated in the Maintenance Paclitaxel 1 (MANTA1) trial; the members of the data monitoring board, especially Carla Dani (data manager); and the dedicated teams from Bristol-Myers Squibb, Italy, in particular Cosimo Paga, for their support.
Supported in part by Associazione Italiana Ricerca sul Cancro (AIRC) and Bristol-Myers Squibb Italy. Presented at the 41st Annual Meeting of the American Society of Clinical Oncology, Orlando, FL, May 13-17, 2005. Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Conte PF, Baldini E, Gennari A, et al: Dose-finding study and pharmacokinetics of epirubicin and paclitaxel over 3 hours: A regimen with high activity and low cardiotoxicity in advanced breast cancer. J Clin Oncol 15: 2510-2517, 1997 11. Conte PF, Gennari A: Anthracyclines-paclitaxel combinations in the treatment of breast cancer. Ann Oncol 8: 939-943, 1997 12. Venturini M, Bruzzi P, Del Mastro L, et al: Effect of adjuvant chemotherapy with or without anthracyclines on the activity and efficacy of first-line cyclophosphamide, epidoxorubicin, and fluorouracil in patients with metastatic breast cancer. J Clin Oncol 14: 764-773, 1996 13. Miller AB, Hoogstraten B, Staquet M, et al: Reporting results of cancer treatment. Cancer 47: 207-214, 1981[CrossRef][Medline] 14. Criteria Committee of the New York Heart Association.Nomenclature and Criteria for Diagnosis of Diseases of the Heart and Great Vessels (ed 8). Boston, MA, Little Brown, 1979 15. Fayers PM, Ashby D, Parmar MKB: Bayesian data monitoring in clinical trials. Stat Med 16: 1413-1430, 1997[CrossRef][Medline] 16. Seidman AD, Berry D, Cirrincione C, et al: Phase III study of weekly paclitaxel via 1-hour infusion vs. standard 3-hour infusion every third week in the treatment of metastatic breast cancer, with trastuzumab for HER2+ metastatic breast cancer (MBC), and randomized for trastuzumab for HER2 normal MBC. J Clin Oncol 22: 6s, 2004 (suppl; abstr 512) 17. Stockler MR, Wilcken NRC, Coates AS: Chemotherapy for metastatic breast cancer: When is enough enough? Eur J Cancer 33: 2147-2148, 1997[CrossRef][Medline] 18. Coates AS, Stockler MR, Wilcken NRC: Controversies in metastatic breast cancer: Optimal duration of chemotherapy. Am Soc Clin Oncol Ed Book, 2003 19. Falkson G, Holcroft C, Gelman RS, et al: Ten-year follow up study of premenopausal women with metastatic breast cancer: An eastern cooperative oncology group study. 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Stockler M, Wilcken N, Coates A, Ghersi D: Duration of chemotherapy for metastatic breast cancer (protocol). Oxford, United Kingdom, Cochrane Library 3, 2004 Submitted February 14, 2006; accepted June 12, 2006. This article has been cited by other articles:
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2, and a life expectancy of at least 12 weeks; and adequate renal, hepatic, and cardiac function. Exclusion criteria included presence of peripheral neuropathy grade 
2 by National Cancer Institute Common Toxicity Criteria, version 2.0, after induction chemotherapy; adjuvant taxane-based therapy was not allowed. The study was conducted under the approval of the appropriate ethical review boards. Recommendations of the Declaration of Helsinki for biomedical research involving human subjects were also followed. 
