Comparison of Outcomes of Phase II Studies and Subsequent Randomized Control Studies Using Identical Chemotherapeutic Regimens
http://www.100md.com
▲還散笫雖悝◎
the Department of Medical Oncology and Hematology, Princess Margaret Hospital and University of Toronto, Toronto, Ontario, Canada
ABSTRACT
PURPOSE: To determine whether promising results from phase II studies could be reproduced in phase III studies, and to examine which characteristics of phase II studies might be of predictive value for subsequent phase III studies.
METHODS: We searched for all phase III studies of chemotherapy in advanced solid malignancies, published in the English language literature from July 1998 to June 2003. Each phase III study was reviewed to identify preceding phase II studies. Phase II and phase III studies included in this analysis must have used identical regimens. Data were extracted from both phase II and phase III studies.
RESULTS: Of 181 phase III studies identified, 43 used therapeutic regimens identical to those in 49 preceding phase II studies. Twelve phase III studies (28%) were "positive." The vast majority (81%) of phase III studies have lower response rates than preceding phase II studies, with a mean difference of 12.9% among all studies analyzed. None of the phase II study characteristics evaluated significantly predicted for "positive" phase III studies, but the sample size of phase II studies demonstrated a trend toward being predictive (P = .083).
CONCLUSION: Promising results from phase II studies frequently do not translate into "positive" phase III studies. Response rates in most phase III studies are lower than those in preceding phase II studies.
INTRODUCTION
There is a well-established paradigm of developing new antitumor agents or chemotherapy regimens in cancer therapeutics. This development progresses from phase I to phase II to phase III studies. Phase I studies generally enroll patients with advanced or refractory diseases for which no standard options exist. The primary objectives of phase I studies are to evaluate the safety and tolerability of new antitumor agents and combination chemotherapy regimens, and to recommend doses and schedules to be further evaluated in phase II studies. The main objective of phase II studies is to demonstrate antitumor activity in patients with specific types of malignancies. The most common end point of phase II studies is the response rate.1
However, approval of new agents and adoption of new therapeutic regimens are usually based on results from phase III studies. These randomized controlled trials compare one or more therapeutic regimens to the standard regimen or the best supportive care, and they are the cornerstone of evidence-based clinical oncology. Primary outcomes of phase III studies are usually overall survival and quality of life. Other outcomes such as disease- or progression-free survival and response rate are also commonly reported. Phase III studies enroll hundreds to thousands of patients, and could take many years to complete. It was estimated that the average cost of a pharmaceutical industry-sponsored phase III study was more than US $10 million, while that of a public-funded phase III study was over US $1 million.2 The average length of phase III studies in oncology was estimated to be 4.5 years, and the mean time spent by clinical trial personnel was 200 hours per patient.2,3 Therefore, phase III studies are not only expensive but also labor intensive and time consuming. However, the majority of phase III studies are "negative," (ie, the experimental therapeutic regimen does not show statistically significant improvements in the overall survival or quality of life over existing standard regimens). In a recent review of phase III studies of extensive-stage small-cell lung cancer conducted in North America from 1972 to 1990, five (24%) of 21 studies showed statistically significant survival advantages in favor of experimental regimens.4 The proportions of "positive" studies are similarly low among published studies in advanced non每small-cell lung cancer and advanced breast cancer at 15% and 2%, respectively.5,6
Despite the low a priori probability of "positive" phase III studies, there are no proven strategies to prioritize different agents and regimens and to optimize the chance of successful phase III studies. The decision to proceed to phase III studies is often based on results from phase II studies. In addition, promising results from phase II studies are sometimes used as justifications for applying antitumor agents in unproven clinical situations. Recently, results from phase II studies have formed the basis of some accelerated approvals by the US Food and Drug Administration.7,8 These accelerated approvals are provisionally granted on the basis of a surrogate end point, such as response rate, from a single phase II study in situations in which the phase II study results are compelling and capable of fulfilling an unmet clinical need for a serious or life-threatening illness.8 The majority of anticancer agents continue to require data from phase III randomized clinical trials for their approval.
The objectives of our study are to determine whether promising results from phase II studies could be reproduced in phase III studies, and to examine which characteristics of phase II studies might be of predictive value for "positive" subsequent phase III studies.
METHODS
We searched MEDLINE and CancerLit for all phase III studies published throughout a 5-year period from July 1998 to June 2003. Search terms included combinations of phase III/randomized study and cancer or carcinoma. In addition, 15 general medicine and specialized oncology journals were manually searched for any possible omission. These journals were: American Journal of Clinical Oncology, Annals of Oncology, British Journal of Cancer, British Medical Journal, Cancer, Clinical Cancer Research, European Journal of Cancer, International Journal of Clinical Oncology, Journal of American Medical Association, Journal of Clinical Oncology, Journal of the National Cancer Institute, Lancet, Lancet Oncology, Lung Cancer, and New England Journal of Medicine. We included studies comparing one or more experimental chemotherapeutic regimens with the standard regimen or best supportive care in patients with advanced solid malignancies. Phase III studies involving combined chemotherapy and radiation therapy, adjuvant or neoadjuvant therapy, surgery, or hematologic malignancies were excluded from our study.
Each phase III study identified was retrieved and reviewed by one investigator (M.I.Z.). If a phase III study was based on preceding phase II studies, those phase II studies were also retrieved. Chemotherapy regimens from both phase II and phase III studies were reviewed, and only those pairs of studies using identical chemotherapy regimens were included. Identical chemotherapy regimens were defined as those utilizing the same chemotherapeutic agents, the same administration schedule, and the same intended patient population. In addition, doses of chemotherapeutic agents used in phase III studies must be at least 85% those used in phase II studies.
Results of each phase III study were reviewed and determined to be either "positive" or "negative." A study was considered to be "positive" if the stated primary end points of the study were met. If the primary end points of a study were not explicitly stated, then the study was considered to be "positive" if the experimental regimen was statistically superior to the standard regimen or best supportive care in terms of overall survival or quality of life.
each phase II study, the following data were extracted: number of patients enrolled, number of assessable patients, the reported response rate and whether the study was multicentered and/or randomized. If the reported response rate was based on the number of assessable patients, then the response rate was recalculated based on numbers of patients responded and accrued, as would be the case if this had been an arm on a randomized trial analyzed using the intent-to-treat principle. For example, a total of 97 patients were enrolled onto a phase II study of vinorelbine and doxorubicin as first-line therapy in patients with advanced breast cancer.9 Eighty-nine patients received at least two cycles of therapy and were eligible for response evaluation. Objective responses were observed in 66 of 89 assessable patients for a reported response rate of 74%. Therefore, the response rate based on the number of patients accrued was calculated to be 69%. The impact factor of the journal in which a phase II study was published was taken from the 2002 ISI Journal Citation Reports (Thomson Scientific, Philadelphia, PA). Impact factors for discontinued journals, journals not included in ISI Journal Citation Reports, or studies presented in abstract form only were classified as missing data. Data extraction was carried out by one investigator (M.I.Z.) initially and reviewed by a second investigator (E.X.C.) for consistency. Differences in extraction were resolved by consensus.
Since there were instances in which a phase III study was based on multiple phase II studies, or a single phase II study was the basis for several phase III studies, response rates from each pair of phase II and subsequent phase III studies were compared using generalized estimating equations (GEEs) with an empirically estimated correlation matrix. The GEE analysis assumed that multiple phase II studies preceding a particular phase III study were correlated with one another and adjusted for this correlation. This method of analysis was chosen over other statistical methods for correlated data because of the known efficiency of GEE methods, especially for samples of small sizes, and the ease of model specification. Characteristics of phase II studies were also analyzed using GEE to see whether one or more were predictive of "positive" phase III studies. A logit link function and a binomial distribution were assumed, with an independent correlation structure estimated for each characteristic of phase II studies. The underlying assumption of this method is that studies were conducted independently of one another. In addition, this method assumes that same characteristics from related studies are likely correlated, and allows for adjustment of the SE of each parameter. Other correlation structures were investigated, with similar results. Both univariate and multivariate analysis were performed. In the multivariate analysis model, all characteristics of phase II studies were included, except whether it was a randomized study or not. In our sample, there were only two randomized phase II studies; therefore, inclusion of this characteristic in the multivariate analysis model would have resulted in an overspecified model. Logistic regression analyses were also performed, treating each pair of phase II/phase III studies independently as a simple check of the GEE results. All reported P values are from the GEE analysis. Statistical analyses were performed using the SAS software (Version 8.02; SAS Institute, Cary, NC).
RESULTS
A total of 181 phase III studies were identified during the specified 5-year period. Among them, 43 phase III studies used identical chemotherapeutic regimens from 49 preceding phase II studies (refer to the Appendix for a complete list of studies). These 49 phase II studies were performed from 1982 to 1997. There were instances in which single phase II studies led to multiple phase III studies, or conversely, multiple phase II studies led to single phase III studies. For example, six phase II studies formed the basis of 11 subsequent phase III studies, and there were nine phase III studies, each of which was based on two or more preceding phase II studies. The most common type of cancer studied was lung cancer, followed by breast cancer, colorectal cancer, and melanoma. The mean number of patients enrolled in phase III studies was 363 (range, 154 to 1,155), and the mean number of assessable patients in a phase II study was 52 (range, 12 to 137). Most phase II studies (71%) were multicentered studies, but there were only two randomized phase II studies. Twelve (28%) phase III studies were considered to be positive. These studies included six studies in lung cancer, four in colorectal cancer, and two in breast cancer. The characteristics of phase III and phase II studies included in this report are summarized in Table 1.
The mean reported response rate was 34.2% (range, 10.8% to 85.7%) in phase III studies and 43.2% (range, 16.0% to 87.0%) in phase II studies. Eight phase III studies (18.6%) reported response rates greater than or equal to those in phase II studies, while the response rate was not reported in one phase III study. Response rates from phase III studies were plotted against reported response rates from corresponding phase II studies in Figure 1. Most data points fell below the line of unity, as the vast majority (81%) of phase III studies had lower response rates than their preceding phase II studies. The mean difference in response rates between phase III studies and their preceding phase II studies was 每12.9% (range, 每36.5% to 18%; 95% CI, 每9.8% to 16.0%; P < .001). This value meant that, on average, the response rate of phase III studies was 12.9% less than that of phase II studies. Response rates were recalculated in 20 phase II studies (41%) based on the intent-to-treat principle. This recalculation resulted in an additional three phase III studies having higher response rates. However, the effects of these changes were small. After recalculation, the mean difference in response rates between phase III studies and their preceding phase II studies was slightly reduced to 每10.4%, but still remains statistically significant (range, 每36.5% to 21.1%; 95% CI, 每7.1% to 每13.7%; P < .001).
Several characteristics extracted from all phase II studies were further analyzed with univariate analysis. They included number of assessable patients, reported response rate, whether the study was multicenter or randomized, and the journal impact factor. None of these characteristics were significantly predictive for positive phase III studies univariately (Table 2). However, the number of assessable patients seems to be most predictive among all the factors examined. For every 10-patient increase in the number of assessable patients in a phase II study, the odds of observing a "positive" phase III study increased 1.18 times (95% CI, 0.98 to 1.42; P = .083; Table 2). There was no statistical improvement (P = .28) in predicting positive phase III studies for the multivariate model. Results obtained from GEE and logistic regression analyses were similar.
DISCUSSION
Although results from phase II studies were often used as justification for phase III studies, our results showed that the majority of phase III studies based on preceding phase II studies were "negative," and promising results from phase II studies were infrequently reproduced in phase III studies. There are several explanations for our findings, with the first potential explanation being the "regression-to-the-truth" phenomenon. This phenomenon is analogous to the regression-to-the-mean concept.10 Random fluctuations occur in the measurement of a biologic variable over time. For any particular type of cancer, many phase II studies were conducted, evaluating different combinations, doses, and schedules of chemotherapeutic agents. By chance alone, one or more of these phase II studies would produce a response rate far removed from the "true" response rate. Chemotherapeutic regimens used in such studies might then be deemed promising, and be tested in phase III studies. On further testing, the "true" response rate was approached, thus response rates in phase III studies were lower than those in phase II studies. This phenomenon is intensified in phase II studies with small numbers of patients, where randomly occurring tumor responses have large influences on response rates. As a corollary, the influence of this phenomenon can be reduced by increasing the number of patients in phase II studies. Our study seems to support the existence of this phenomenon in cancer clinical trials in that there is a trend toward significance for the number of assessable patients in a phase II study. Therefore, clinical investigators should be aware of this phenomenon in their decision making.
Outcomes of nonrandomized studies, such as phase II studies, depend on specific characteristics of the patient population studied.7,11 Selection bias can result not only from known prognostic variables such as age, income, performance status, and number of metastatic sites, but also from previously unknown or unstudied variables. For example, Lamont et al recently reported that patients with head and neck cancer enrolled in phase II studies had better survival the further they lived from the treatment center.12 It is possible that promising results from phase II studies were a result of enrollment of high proportions of patients with good prognostic factors. However, the effect of this selection bias is eliminated in subsequent phase III studies because of random assignment.7
Response rates in phase II studies are usually calculated by including only assessable patients, the number of whom could be substantially fewer than the total number of patients actually enrolled in a phase II study. On the other hand, phase III studies are generally analyzed according to the intention-to-treat principle, such that all patients enrolled in a study are included in the data analysis regardless of whether they received any treatment or not.13 Therefore, response rates in phase II studies could be potentially inflated by including only assessable patients. We attempted to account for this difference in data analysis by recalculating response rates in phase II studies using the number of patients enrolled. Although this recalculation resulted in an additional three phase III studies with higher response rates, the overall impact of this recalculation was minimal (mean difference, 每12.9% v 每10.4%), indicating that methods of calculating response rates were not significant contributors to our findings.
The final explanation is the influence of newer and more sensitive imaging techniques, resulting in a "response migration" phenomenon similar to the "stage migration" phenomenon.14 Imaging techniques used in phase III studies might have improved compared with those employed in earlier phase II studies.15,16 Thus, patients who would have been deemed to have a partial response with older imaging techniques in phase II studies may only have stable disease or even progressive disease with newer imaging techniques in phase III studies. In addition, investigator-reported response rates in phase II studies were often lower than those obtained after independent reviews.17-19 However, independent reviews of response were infrequent in phase II studies, while they were often mandated in phase III studies.
Other strategies of selecting chemotherapy regimens from phase II studies for phase III studies have been proposed. One approach is to consider only chemotherapeutic regimens from multi-institutional phase II studies, since these studies are more likely to include a broader spectrum of patients.20 Several statistical models have also been proposed based on expected powers of phase II studies or using the 75% upper confidence limit of survival of historical patients as the lower limit of acceptable clinical activity of phase II studies.21-23 Others have advocated randomized phase II study designs.24,25 Inoue et al proposed a Bayesian phase II/III design in which patients were randomized between experimental and standard treatments.26 The decision of whether to proceed to a phase III study was made repeatedly during a time interval rather than at one single time point, and it was based on predictive probabilities that the experimental therapy was superior given the observed data. None of these models and proposals has been prospectively evaluated or validated; therefore, it is not known whether these strategies will lead to improved selection of candidate regimens for phase III studies.
The failure to reproduce promising phase II studies in subsequent randomized phase III studies is not unique to the field of cancer therapy. Investigators in other specialities of medicine have also been confronted by this problem. For example, several recent large randomized phase III studies failed to demonstrate benefits of new strategies in treating chronic heart failure despite promising results from phase II studies.10 Similar to the dilemma for clinical oncologists, there were no clear strategies for cardiologists to optimize the chance of success in phase III studies.27
Our study is limited in that we only reviewed phase III studies published in the English language literature during a 5-year period. Furthermore, only fully published studies were reviewed. However, unpublished studies are more likely to be "negative" studies.28 Inclusion of those studies will likely strengthen rather than weaken our results. In addition, response rates in phase II studies were not adjusted in our analysis. Response rates depend on tumor types, chemotherapeutic regimens studied, patient characteristics, and prior therapies. Therefore, it is not practical to adjust the reported response rate since each phase II study was conducted under a unique combination of conditions. The lack of predictive value of the reported response rate may partially reflect this phenomenon. Finally, only 43 phase III and 49 phase II studies were included in our analysis. Conclusions from our study are limited by the small sample size.
Our study shows that promising results from phase II studies are seldom reproduced in randomized phase III studies. Furthermore, the likelihood of a "positive" randomized phase III study is low even if the chemotherapeutic regimen is identical to that in preceding phase II studies. Therefore, investigators should be aware of these limitations in their decision making to initiate phase III studies.
Appendix: List of Studies
Van Cutsem E, Twelves C, Cassidy J, et al: Oral capecitabine compared with intravenous fluorouracil plus leucovorin in patients with metastatic colorectal cancer: Results of a large phase III study. J Clin Oncol 19:4097-4106, 2001
Van Cutsem E, Findlay M, Osterwalder B, et al: Capecitabine, an oral fluoropyrimidine carbamate with substantial activity in advanced colorectal cancer: results of a randomized phase II study. J Clin Oncol 18:1337-1345, 2000
Hoff PM, Ansari R, Batist G, et al: Comparison of oral capecitabine versus intravenous fluorouracil plus leucovorin as first-line treatment in 605 patients with metastatic colorectal cancer: results of a randomized phase III study. J Clin Oncol 19:2282-2292, 2001
Roszkowski K, Pluzanska A, Krzakowski M, et al: A multicenter, randomized, phase III study of docetaxel plus best supportive care versus best supportive care in chemotherapy-naive patients with metastatic or nonresectable localized non每small-cell lung cancer (NSCLC). Lung Cancer 27:145-157, 2000
Mattson K, Bosquee L, Dabouis G, et al: phase II study of docetaxel in the treatment of patients with advanced non每small-cell lung cancer in routine daily practice. Lung Cancer 29:205-216, 2000
Fossella FV, Lee JS, Murphy WK, et al: phase II study of docetaxel for recurrent or metastatic non每small-cell lung cancer. J Clin Oncol 12:1238-1244, 1994
Cerny T, Kaplan S, Pavlidis N, et al: Docetaxel (Taxotere) is active in non每small-cell lung cancer: a phase II trial of the EORTC Early Clinical Trials Group (ECTG). Br J Cancer 70:384-387, 1994
Francis PA, Rigas JR, Kris MG, et al: phase II trial of docetaxel in patients with stage III and IV non每small-cell lung cancer. J Clin Oncol 12:1232-1237, 1994
Fossella FV, DeVore R, Kerr RN, et al: Randomized phase III trial of docetaxel versus vinorelbine or ifosfamide in patients with advanced non每small-cell lung cancer previously treated with platinum-containing chemotherapy regimens: The TAX 320 Non-Small Cell Lung Cancer Study Group. J Clin Oncol 18:2354-2362, 2000
Fossella FV, Lee JS, Shin DM, et al: phase II study of docetaxel for advanced or metastatic platinum-refractory non每small-cell lung cancer. J Clin Oncol 13:645-651, 1995
Gandara DR, Vokes E, Green M, et al: Activity of docetaxel in platinum-treated non每small-cell lung cancer: results of a phase II multicenter trial. J Clin Oncol 18:131-135, 2000
Robinet G, Kleisbauer JP, Thomas P: phase II study of docetaxel (Taxotere) in first- and second-line NSCLC. Proc Am Soc Clin Oncol 16:480, 1997 (abstr 1726)
Jungnelius U, Ringborg U, Aamdal S, et al: Dacarbazine-vindesine versus dacarbazine-vindesine-cisplatin in disseminated malignant melanoma: A randomized phase III trial. Eur J Cancer 34:1368-1374, 1998
Ringborg U, Jungnelius U, Hansson J, et al: Dacarbazine-vindesine-cisplatin in disseminated malignant melanoma: A phase I-II trial. Am J Clin Oncol 13:214-217, 1990
Gundersen S: Dacarbazine, vindesine, and cisplatin combination chemotherapy in advanced malignant melanoma: a phase II study. Cancer Treat Rep. 71:997-999, 1987
Ranson M, Davidson N, Nicolson M, et al: Randomized trial of paclitaxel plus supportive care versus supportive care for patients with advanced non每small-cell lung cancer. J Natl Cancer Inst 92:1074-1080, 2000
Gatzemeier U, Heckmayr M, Neuhauss R, et al: phase II study with paclitaxel for the treatment of advanced inoperable non每small-cell lung cancer. Lung Cancer 12:S101-S106, 1995 (suppl 2)
Ranson MR, Jayson G, Perkins S, et al: Single-agent paclitaxel in advanced non每small-cell lung cancer: single-center phase II study using a 3-hour administration schedule. Semin Oncol 24:S12, 1997 (suppl 12)
von der Maase H, Hansen SW, Roberts JT, et al: Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, phase III study. J Clin Oncol 18:3068-3077, 2000
Moore MJ, Winquist EW, Murray N, et al: Gemcitabine plus cisplatin, an active regimen in advanced urothelial cancer: a phase II trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 17:2876-2881, 1999
Ohtsu A, Shimada Y, Shirao K, et al: Randomized phase III trial of fluorouracil alone versus fluorouracil plus cisplatin versus uracil and tegafur plus mitomycin in patients with unresectable, advanced gastric cancer: The Japan Clinical Oncology Group Study (JCOG9205). J Clin Oncol 21:54-59, 2003
Ohtsu A, Shimada Y, Yoshida S, et al: phase II study of protracted infusional 5-fluorouracil combined with cisplatinum for advanced gastric cancer: Report from the Japan Clinical Oncology Group (JCOG). Eur J Cancer 30A:2091-2093, 1994
Kosmidis P, Mylonakis N, Nicolaides C, et al: Paclitaxel plus carboplatin versus gemcitabine plus paclitaxel in advanced non每small-cell lung cancer: A phase III randomized trial. J Clin Oncol 20:3578-3585, 2002
Douillard JY, Lerouge D, Monnier A, et al: Combined paclitaxel and gemcitabine as first-line treatment in metastatic non每small-cell lung cancer: A multicenter phase II study. Br J Cancer 84:1179-1184, 2001
Giaccone G, Smit EF, van Meerbeeck JP, et al: A phase I-II study of gemcitabine and paclitaxel in advanced non每small-cell lung cancer patients. Ann Oncol 11:109-112, 2000
Auerback M, Chaudhry M, Richards P, et al: phase II study of gemcitabine and paclitaxel in metastatic non每small-cell lung cancer. Proc Am Soc Clin Oncol 19:522, 2000 (abstr 2052)
Schilsky RL, Levin J, West WH, et al: Randomized, open-label, phase III study of a 28-day oral regimen of eniluracil plus fluorouracil versus intravenous fluorouracil plus leucovorin as first-line therapy in patients with metastatic/advanced colorectal cancer. J Clin Oncol 20:1519-1526, 2002
Mani S, Hochster H, Beck T, et al: Multicenter phase II study to evaluate a 28-day regimen of oral fluorouracil plus eniluracil in the treatment of patients with previously untreated metastatic colorectal cancer. J Clin Oncol 18:2894-2901, 2000
Comella P, Frasci G, Panza N, et al: Randomized trial comparing cisplatin, gemcitabine, and vinorelbine with either cisplatin and gemcitabine or cisplatin and vinorelbine in advanced non每small-cell lung cancer: interim analysis of a phase III trial of the Southern Italy Cooperative Oncology Group. J Clin Oncol 18:1451-1457, 2000
Comella P, Frasci G, Panza N, et al: Cisplatin, gemcitabine, and vinorelbine combination therapy in advanced non每small-cell lung cancer: a phase II randomized study of the Southern Italy Cooperative Oncology Group. J Clin Oncol 17:1526-1534, 1999
Noda K, Nishiwaki Y, Kawahara M, et al: Irinotecan plus cisplatin compared with etoposide plus cisplatin for extensive small-cell lung cancer. N. Engl. J. Med. 346:85-91, 2002
Kudoh S, Fujiwara Y, Takada Y, et al: phase II study of irinotecan combined with cisplatin in patients with previously untreated small-cell lung cancer. West Japan Lung Cancer Group. J Clin Oncol 16:1068-1074, 1998
Crino L, Scagliotti GV, Ricci S, et al: Gemcitabine and cisplatin versus mitomycin, ifosfamide, and cisplatin in advanced non每small-cell lung cancer: A randomized phase III study of the Italian Lung Cancer Project. J Clin Oncol 17:3522-3530, 1999
Crino L, Scagliotti G, Marangolo M, et al: Cisplatin-gemcitabine combination in advanced non每small-cell lung cancer: a phase II study. J Clin Oncol 15:297-303, 1997
Jassem J, Pienkowski T, Pluzanska A, et al: Doxorubicin and paclitaxel versus fluorouracil, doxorubicin, and cyclophosphamide as first-line therapy for women with metastatic breast cancer: final results of a randomized phase III multicenter trial. J Clin Oncol 19:1707-1715, 2001
Amadori D, Frassineti GL, Zoli W, et al: Doxorubicin and paclitaxel (sequential combination) in the treatment of advanced breast cancer. Oncology (Huntingt) 11:30-33, 1997
Middleton MR, Grob JJ, Aaronson N, et al: Randomized phase III study of temozolomide versus dacarbazine in the treatment of patients with advanced metastatic malignant melanoma. J Clin Oncol 18:158-166, 2000
Bleehen NM, Newlands ES, Lee SM, et al: Cancer Research Campaign phase II trial of temozolomide in metastatic melanoma. J Clin Oncol 13:910-913, 1995
Blanke CD, Shultz J, Cox J, et al: A double-blind placebo-controlled randomized phase III trial of 5-fluorouracil and leucovorin, plus or minus trimetrexate, in previously untreated patients with advanced colorectal cancer. Ann. Oncol. 13:87-91, 2002
Blanke CD, Kasimis B, Schein P, et al: phase II study of trimetrexate, fluorouracil, and leucovorin for advanced colorectal cancer. J Clin Oncol 15:915-920, 1997
Namer M, Soler-Michel P, Turpin F, et al: Results of a phase III prospective, randomized trial, comparing mitoxantrone and vinorelbine (MV) in combination with standard FAC/FEC in front-line therapy of metastatic breast cancer. Eur J Cancer 37:1132-1140, 2001
Llombart-Cussac A, Pivot X, Rhor-Alvarado A, et al: First-line vinorelbine-mitoxantrone combination in metastatic breast cancer patients relapsing after an adjuvant anthracycline regimen: results of a phase II study. Oncology 55:384-390, 1998
Pacini P, Rinaldini M, Algeri R, et al: FEC (5-fluorouracil, epidoxorubicin and cyclophosphamide) versus EM (epidoxorubicin and mitomycin-C) with or without lonidamine as first-line treatment for advanced breast cancer. A multicentric randomized study. Final results. Eur J Cancer 36:966-975, 2000
Pacini P, Tucci E, Algeri R, et al: Combination chemotherapy with epirubicin and mitomycin C as first-line treatment in advanced breast cancer. Eur J Cancer 30A:460-463, 1994
Georgoulias V, Papadakis E, Alexopoulos A, et al: Platinum-based and nonplatinum-based chemotherapy in advanced non每small-cell lung cancer: a randomized multicenter trial. Lancet 357:1478-1484, 2001
Georgoulias V, Kouroussis C, Androulakis N, et al: Front-line treatment of advanced non每small-cell lung cancer with docetaxel and gemcitabine: a multicenter phase II trial. J Clin Oncol 17:914-920, 1999
Eton O, Legha SS, Bedikian AY, et al: Sequential biochemotherapy versus chemotherapy for metastatic melanoma: results from a phase III randomized trial. J Clin Oncol 20:2045-2052, 2002
Legha SS, Ring S, Eton O, et al: Development and results of biochemotherapy in metastatic melanoma: the University of Texas M.D. Anderson Cancer Center experience. Cancer J. Sci. Am 3:S9-S15, 1997 (suppl 1)
Blajman C, Balbiani L, Block J, et al: A prospective, randomized phase III trial comparing combination chemotherapy with cyclophosphamide, doxorubicin, and 5-fluorouracil with vinorelbine plus doxorubicin in the treatment of advanced breast carcinoma. Cancer 85:1091-1097, 1999
Spielmann M, Dorval T, Turpin F, et al: phase II trial of vinorelbine/doxorubicin as first-line therapy of advanced breast cancer. J Clin Oncol 12:1764-1770, 1994
Motzer RJ, Murphy BA, Bacik J, et al: phase III trial of interferon alfa-2a with or without 13-cis-retinoic acid for patients with advanced renal cell carcinoma. J Clin Oncol 18:2972-2980, 2000
Motzer RJ, Schwartz L, Law TM, et al: Interferon alfa-2a and 13-cis-retinoic acid in renal cell carcinoma: antitumor activity in a phase II trial and interactions in vitro. J Clin Oncol 13:1950-1957, 1995
Creagan ET, Suman VJ, Dalton RJ, et al: phase III clinical trial of the combination of cisplatin, dacarbazine, and carmustine with or without tamoxifen in patients with advanced malignant melanoma. J Clin Oncol 17:1884-1890, 1999
Del Prete SA, Maurer LH, O'Donnell J, et al: Combination chemotherapy with cisplatin, carmustine, dacarbazine, and tamoxifen in metastatic melanoma. Cancer Treat Rep. 68:1403-1405, 1984
McClay EF, Mastrangelo MJ, Bellet RE, et al: Combination chemotherapy and hormonal therapy in the treatment of malignant melanoma. Cancer Treat Rep. 71:465-469, 1987
Chapman PB, Einhorn LH, Meyers ML, et al: phase III multicenter randomized trial of the Dartmouth regimen versus dacarbazine in patients with metastatic melanoma. J Clin Oncol 17:2745-2751, 1999
Therasse P, Mauriac L, Welnicka-Jaskiewicz M, et al: Final results of a randomized phase III trial comparing cyclophosphamide, epirubicin, and fluorouracil with a dose-intensified epirubicin and cyclophosphamide + filgrastim as neoadjuvant treatment in locally advanced breast cancer: an EORTC-NCIC-SAKK multicenter study. J Clin Oncol 21:843-850, 2003
Piccart MJ, Bruning P, Wildiers J, et al: An EORTC pilot study of filgrastim (recombinant human granulocyte colony-stimulating factor) as support to a high-dose-intensive epiadriamycin-cyclophosphamide regimen in chemotherapy-naive patients with locally advanced or metastatic breast cancer. Ann. Oncol. 6:673-677, 1995
von Pawel J, von Roemeling R, Gatzemeier U, et al: Tirapazamine plus cisplatin versus cisplatin in advanced non每small-cell lung cancer: A report of the international CATAPULT I study group. Cisplatin and Tirapazamine in Subjects with Advanced Previously Untreated Non-Small-Cell Lung Tumors. J Clin Oncol 18:1351-1359, 2000
Miller VA, Ng KK, Grant SC, et al: phase II study of the combination of the novel bioreductive agent, tirapazamine, with cisplatin in patients with advanced non每small-cell lung cancer. Ann. Oncol. 8:1269-1271, 1997
Souquet PJ, Tan EH, Rodrigues PJ, et al: GLOB-1: a prospective randomized clinical phase III trial comparing vinorelbine-cisplatin with vinorelbine-ifosfamide-cisplatin in metastatic non每small-cell lung cancer patients. Ann. Oncol. 13:1853-1861, 2002
Tan EH, Ang PT, Wee J, et al: Vinorelbine, ifosfamide and cisplatin in advanced non每small-cell lung cancer. Acta Oncol. 38:619-622, 1999
Sculier JP, Lafitte JJ, Lecomte J, et al: A three-arm phase III randomized trial comparing combinations of platinum derivatives, ifosfamide and/or gemcitabine in stage IV non每small-cell lung cancer. Ann. Oncol. 13:874-882, 2002
Berghmans T, Klastersky J, Markiewicz E, et al: Cisplatin-carboplatin-gemcitabine or ifosfamide-gemcitabine in advanced nonsmall cell lung carcinoma: two pilot studies. Anticancer Res 19:5651-5655, 1999
Gordon AN, Fleagle JT, Guthrie D, et al: Recurrent epithelial ovarian carcinoma: a randomized phase III study of pegylated liposomal doxorubicin versus topotecan. J Clin Oncol 19:3312-3322, 2001
Gordon AN, Granai CO, Rose PG, et al: phase II study of liposomal doxorubicin in platinum- and paclitaxel-refractory epithelial ovarian cancer. J Clin Oncol 18:3093-3100, 2000
Negoro S, Masuda N, Takada Y, et al: Randomized phase III trial of irinotecan combined with cisplatin for advanced non每small-cell lung cancer. Br. J. Cancer 88:335-341, 2003
Masuda N, Fukuoka M, Fujita A, et al: A phase II trial of combination of CPT-11 and cisplatin for advanced non每small-cell lung cancer. CPT-11 Lung Cancer Study Group. Br. J. Cancer 78:251-256, 1998
Norris B, Pritchard KI, James K, et al: phase III comparative study of vinorelbine combined with doxorubicin versus doxorubicin alone in disseminated metastatic/recurrent breast cancer: National Cancer Institute of Canada Clinical Trials Group Study MA8. J Clin Oncol 18:2385-2394, 2000
Sandler AB, Nemunaitis J, Denham C, et al: phase III trial of gemcitabine plus cisplatin versus cisplatin alone in patients with locally advanced or metastatic non每small-cell lung cancer. J Clin Oncol 18:122-130, 2000
Schiller JH, Harrington D, Belani CP, et al: Comparison of four chemotherapy regimens for advanced non每small-cell lung cancer. N. Engl. J. Med. 346:92-98, 2002
Di Costanzo F, Gasperoni S, Malacarne P, et al: High-dose folinic acid and 5-fluorouracil alone or combined with hydroxyurea in advanced colorectal cancer: a randomized trial of the Italian Oncology Group for Clinical Research. Am J Clin Oncol 21:369-375, 1998
Di Costanzo F, el Taani H, Parriani D, et al: Hydroxyurea may increase the activity of fluorouracil plus folinic acid in advanced gastrointestinal cancer: phase II study. Cancer Invest 14:234-238, 1996
Hudes G, Einhorn L, Ross E, et al: Vinblastine versus vinblastine plus oral estramustine phosphate for patients with hormone-refractory prostate cancer: A Hoosier Oncology Group and Fox Chase Network phase III trial. J Clin Oncol 17:3160-3166, 1999
Hudes GR, Greenberg R, Krigel RL, et al: phase II study of estramustine and vinblastine, two microtubule inhibitors, in hormone-refractory prostate cancer. J Clin Oncol 10:1754-1761, 1992
Kelly K, Crowley J, Bunn PA Jr, et al: Randomized phase III trial of paclitaxel plus carboplatin versus vinorelbine plus cisplatin in the treatment of patients with advanced non每small-cell lung cancer: a Southwest Oncology Group trial. J Clin Oncol 19:3210-3218, 2001
Laohavinij S, Maoleekoonpairoj S, Cheirsilpa A, et al: phase II study of paclitaxel and carboplatin for advanced non每small-cell lung cancer. Lung Cancer 26:175-185, 1999
Dittrich C, Sevelda P, Salzer H, et al: Lack of impact of platinum dose-intensity on the outcome of ovarian cancer patients. 10-year results of a prospective randomized phase III study comparing carboplatin-cisplatin with cyclophosphamide-cisplatin. Eur J Cancer 39:1129-1140, 2003
Dittrich C, Sevelda P, Baur M, et al: In vitro and in vivo evaluation of the combination of cisplatin and its analog carboplatin for platinum dose intensification in ovarian carcinoma. Cancer 71:3082-3090, 1993
Bonneterre J, Roche H, Monnier A, et al: Docetaxel versus 5-fluorouracil plus vinorelbine in metastatic breast cancer after anthracycline therapy failure. Br. J. Cancer 87:1210-1215, 2002
Ravdin PM, Burris HA, III, Cook G, et al: phase II trial of docetaxel in advanced anthracycline-resistant or anthracenedione-resistant breast cancer. J Clin Oncol 13:2879-2885, 1995
Valero V, Holmes FA, Walters RS, et al: phase II trial of docetaxel: a new, highly effective antineoplastic agent in the management of patients with anthracycline-resistant metastatic breast cancer. J Clin Oncol 13:2886-2894, 1995
Kaufmann M, Bajetta E, Dirix LY, et al: Exemestane is superior to megestrol acetate after tamoxifen failure in post menopausal women with advanced breast cancer: results of a phase III randomized double-blind trial. The Exemestane Study Group. J Clin Oncol 18:1399-1411, 2000
Kvinnsland S, Anker G, Dirix LY, et al: High activity and tolerability demonstrated for exemestane in post menopausal women with metastatic breast cancer who had previously failed on tamoxifen treatment. Eur J Cancer 36:976-982, 2000
Jones S, Belt R, Cooper B, et al: A phase II study of antitumor efficacy and safety of exemestane (EXE) as second-line hormonal treatment of post menopausal patients with metstatic breast cancer (MBC) refractory to tamoxifen (TAM). Breast Cancer Res Treat 50:1998 (abstr 436)
Vanhoefer U, Rougier P, Wilke H, et al: Final results of a randomized phase III trial of sequential high-dose methotrexate, fluorouracil, and doxorubicin versus etoposide, leucovorin, and fluorouracil versus infusional fluorouracil and cisplatin in advanced gastric cancer: A trial of the European Organization for Research and Treatment of Cancer Gastrointestinal Tract Cancer Cooperative Group. J Clin Oncol 18:2648-2657, 2000
Lacave AJ, Baron FJ, Anton LM, et al: Combination chemotherapy with cisplatin and 5-fluorouracil 5-day infusion in the therapy of advanced gastric cancer: a phase II trial. Ann. Oncol. 2:751-754, 1991
Cunningham D, Pyrhonen S, James RD, et al: Randomized trial of irinotecan plus supportive care versus supportive care alone after fluorouracil failure for patients with metastatic colorectal cancer. Lancet 352:1413-1418, 1998
Rougier P, Bugat R, Douillard JY, et al: phase II study of irinotecan in the treatment of advanced colorectal cancer in chemotherapy-naive patients and patients pretreated with fluorouracil-based chemotherapy. J Clin Oncol 15:251-260, 1997
Rougier P, Van Cutsem E, Bajetta E, et al: Randomized trial of irinotecan versus fluorouracil by continuous infusion after fluorouracil failure in patients with metastatic colorectal cancer. Lancet 352:1407-1412, 1998
Nabholtz JM, Falkson C, Campos D, et al: Docetaxel and doxorubicin compared with doxorubicin and cyclophosphamide as first-line chemotherapy for metastatic breast cancer: results of a randomized, multicenter, phase III trial. J Clin Oncol 21:968-975, 2003
Dieras V, Barthier S, Beuzeboc P, et al: phase II study of Taxotere in combination with doxorubicin as first line chemotherapy of metastatic breast cancer. Breast Cancer Res Treat 50:262, 1998 (abstr 266)(Mohammad I. Zia, Lillian )
ABSTRACT
PURPOSE: To determine whether promising results from phase II studies could be reproduced in phase III studies, and to examine which characteristics of phase II studies might be of predictive value for subsequent phase III studies.
METHODS: We searched for all phase III studies of chemotherapy in advanced solid malignancies, published in the English language literature from July 1998 to June 2003. Each phase III study was reviewed to identify preceding phase II studies. Phase II and phase III studies included in this analysis must have used identical regimens. Data were extracted from both phase II and phase III studies.
RESULTS: Of 181 phase III studies identified, 43 used therapeutic regimens identical to those in 49 preceding phase II studies. Twelve phase III studies (28%) were "positive." The vast majority (81%) of phase III studies have lower response rates than preceding phase II studies, with a mean difference of 12.9% among all studies analyzed. None of the phase II study characteristics evaluated significantly predicted for "positive" phase III studies, but the sample size of phase II studies demonstrated a trend toward being predictive (P = .083).
CONCLUSION: Promising results from phase II studies frequently do not translate into "positive" phase III studies. Response rates in most phase III studies are lower than those in preceding phase II studies.
INTRODUCTION
There is a well-established paradigm of developing new antitumor agents or chemotherapy regimens in cancer therapeutics. This development progresses from phase I to phase II to phase III studies. Phase I studies generally enroll patients with advanced or refractory diseases for which no standard options exist. The primary objectives of phase I studies are to evaluate the safety and tolerability of new antitumor agents and combination chemotherapy regimens, and to recommend doses and schedules to be further evaluated in phase II studies. The main objective of phase II studies is to demonstrate antitumor activity in patients with specific types of malignancies. The most common end point of phase II studies is the response rate.1
However, approval of new agents and adoption of new therapeutic regimens are usually based on results from phase III studies. These randomized controlled trials compare one or more therapeutic regimens to the standard regimen or the best supportive care, and they are the cornerstone of evidence-based clinical oncology. Primary outcomes of phase III studies are usually overall survival and quality of life. Other outcomes such as disease- or progression-free survival and response rate are also commonly reported. Phase III studies enroll hundreds to thousands of patients, and could take many years to complete. It was estimated that the average cost of a pharmaceutical industry-sponsored phase III study was more than US $10 million, while that of a public-funded phase III study was over US $1 million.2 The average length of phase III studies in oncology was estimated to be 4.5 years, and the mean time spent by clinical trial personnel was 200 hours per patient.2,3 Therefore, phase III studies are not only expensive but also labor intensive and time consuming. However, the majority of phase III studies are "negative," (ie, the experimental therapeutic regimen does not show statistically significant improvements in the overall survival or quality of life over existing standard regimens). In a recent review of phase III studies of extensive-stage small-cell lung cancer conducted in North America from 1972 to 1990, five (24%) of 21 studies showed statistically significant survival advantages in favor of experimental regimens.4 The proportions of "positive" studies are similarly low among published studies in advanced non每small-cell lung cancer and advanced breast cancer at 15% and 2%, respectively.5,6
Despite the low a priori probability of "positive" phase III studies, there are no proven strategies to prioritize different agents and regimens and to optimize the chance of successful phase III studies. The decision to proceed to phase III studies is often based on results from phase II studies. In addition, promising results from phase II studies are sometimes used as justifications for applying antitumor agents in unproven clinical situations. Recently, results from phase II studies have formed the basis of some accelerated approvals by the US Food and Drug Administration.7,8 These accelerated approvals are provisionally granted on the basis of a surrogate end point, such as response rate, from a single phase II study in situations in which the phase II study results are compelling and capable of fulfilling an unmet clinical need for a serious or life-threatening illness.8 The majority of anticancer agents continue to require data from phase III randomized clinical trials for their approval.
The objectives of our study are to determine whether promising results from phase II studies could be reproduced in phase III studies, and to examine which characteristics of phase II studies might be of predictive value for "positive" subsequent phase III studies.
METHODS
We searched MEDLINE and CancerLit for all phase III studies published throughout a 5-year period from July 1998 to June 2003. Search terms included combinations of phase III/randomized study and cancer or carcinoma. In addition, 15 general medicine and specialized oncology journals were manually searched for any possible omission. These journals were: American Journal of Clinical Oncology, Annals of Oncology, British Journal of Cancer, British Medical Journal, Cancer, Clinical Cancer Research, European Journal of Cancer, International Journal of Clinical Oncology, Journal of American Medical Association, Journal of Clinical Oncology, Journal of the National Cancer Institute, Lancet, Lancet Oncology, Lung Cancer, and New England Journal of Medicine. We included studies comparing one or more experimental chemotherapeutic regimens with the standard regimen or best supportive care in patients with advanced solid malignancies. Phase III studies involving combined chemotherapy and radiation therapy, adjuvant or neoadjuvant therapy, surgery, or hematologic malignancies were excluded from our study.
Each phase III study identified was retrieved and reviewed by one investigator (M.I.Z.). If a phase III study was based on preceding phase II studies, those phase II studies were also retrieved. Chemotherapy regimens from both phase II and phase III studies were reviewed, and only those pairs of studies using identical chemotherapy regimens were included. Identical chemotherapy regimens were defined as those utilizing the same chemotherapeutic agents, the same administration schedule, and the same intended patient population. In addition, doses of chemotherapeutic agents used in phase III studies must be at least 85% those used in phase II studies.
Results of each phase III study were reviewed and determined to be either "positive" or "negative." A study was considered to be "positive" if the stated primary end points of the study were met. If the primary end points of a study were not explicitly stated, then the study was considered to be "positive" if the experimental regimen was statistically superior to the standard regimen or best supportive care in terms of overall survival or quality of life.
each phase II study, the following data were extracted: number of patients enrolled, number of assessable patients, the reported response rate and whether the study was multicentered and/or randomized. If the reported response rate was based on the number of assessable patients, then the response rate was recalculated based on numbers of patients responded and accrued, as would be the case if this had been an arm on a randomized trial analyzed using the intent-to-treat principle. For example, a total of 97 patients were enrolled onto a phase II study of vinorelbine and doxorubicin as first-line therapy in patients with advanced breast cancer.9 Eighty-nine patients received at least two cycles of therapy and were eligible for response evaluation. Objective responses were observed in 66 of 89 assessable patients for a reported response rate of 74%. Therefore, the response rate based on the number of patients accrued was calculated to be 69%. The impact factor of the journal in which a phase II study was published was taken from the 2002 ISI Journal Citation Reports (Thomson Scientific, Philadelphia, PA). Impact factors for discontinued journals, journals not included in ISI Journal Citation Reports, or studies presented in abstract form only were classified as missing data. Data extraction was carried out by one investigator (M.I.Z.) initially and reviewed by a second investigator (E.X.C.) for consistency. Differences in extraction were resolved by consensus.
Since there were instances in which a phase III study was based on multiple phase II studies, or a single phase II study was the basis for several phase III studies, response rates from each pair of phase II and subsequent phase III studies were compared using generalized estimating equations (GEEs) with an empirically estimated correlation matrix. The GEE analysis assumed that multiple phase II studies preceding a particular phase III study were correlated with one another and adjusted for this correlation. This method of analysis was chosen over other statistical methods for correlated data because of the known efficiency of GEE methods, especially for samples of small sizes, and the ease of model specification. Characteristics of phase II studies were also analyzed using GEE to see whether one or more were predictive of "positive" phase III studies. A logit link function and a binomial distribution were assumed, with an independent correlation structure estimated for each characteristic of phase II studies. The underlying assumption of this method is that studies were conducted independently of one another. In addition, this method assumes that same characteristics from related studies are likely correlated, and allows for adjustment of the SE of each parameter. Other correlation structures were investigated, with similar results. Both univariate and multivariate analysis were performed. In the multivariate analysis model, all characteristics of phase II studies were included, except whether it was a randomized study or not. In our sample, there were only two randomized phase II studies; therefore, inclusion of this characteristic in the multivariate analysis model would have resulted in an overspecified model. Logistic regression analyses were also performed, treating each pair of phase II/phase III studies independently as a simple check of the GEE results. All reported P values are from the GEE analysis. Statistical analyses were performed using the SAS software (Version 8.02; SAS Institute, Cary, NC).
RESULTS
A total of 181 phase III studies were identified during the specified 5-year period. Among them, 43 phase III studies used identical chemotherapeutic regimens from 49 preceding phase II studies (refer to the Appendix for a complete list of studies). These 49 phase II studies were performed from 1982 to 1997. There were instances in which single phase II studies led to multiple phase III studies, or conversely, multiple phase II studies led to single phase III studies. For example, six phase II studies formed the basis of 11 subsequent phase III studies, and there were nine phase III studies, each of which was based on two or more preceding phase II studies. The most common type of cancer studied was lung cancer, followed by breast cancer, colorectal cancer, and melanoma. The mean number of patients enrolled in phase III studies was 363 (range, 154 to 1,155), and the mean number of assessable patients in a phase II study was 52 (range, 12 to 137). Most phase II studies (71%) were multicentered studies, but there were only two randomized phase II studies. Twelve (28%) phase III studies were considered to be positive. These studies included six studies in lung cancer, four in colorectal cancer, and two in breast cancer. The characteristics of phase III and phase II studies included in this report are summarized in Table 1.
The mean reported response rate was 34.2% (range, 10.8% to 85.7%) in phase III studies and 43.2% (range, 16.0% to 87.0%) in phase II studies. Eight phase III studies (18.6%) reported response rates greater than or equal to those in phase II studies, while the response rate was not reported in one phase III study. Response rates from phase III studies were plotted against reported response rates from corresponding phase II studies in Figure 1. Most data points fell below the line of unity, as the vast majority (81%) of phase III studies had lower response rates than their preceding phase II studies. The mean difference in response rates between phase III studies and their preceding phase II studies was 每12.9% (range, 每36.5% to 18%; 95% CI, 每9.8% to 16.0%; P < .001). This value meant that, on average, the response rate of phase III studies was 12.9% less than that of phase II studies. Response rates were recalculated in 20 phase II studies (41%) based on the intent-to-treat principle. This recalculation resulted in an additional three phase III studies having higher response rates. However, the effects of these changes were small. After recalculation, the mean difference in response rates between phase III studies and their preceding phase II studies was slightly reduced to 每10.4%, but still remains statistically significant (range, 每36.5% to 21.1%; 95% CI, 每7.1% to 每13.7%; P < .001).
Several characteristics extracted from all phase II studies were further analyzed with univariate analysis. They included number of assessable patients, reported response rate, whether the study was multicenter or randomized, and the journal impact factor. None of these characteristics were significantly predictive for positive phase III studies univariately (Table 2). However, the number of assessable patients seems to be most predictive among all the factors examined. For every 10-patient increase in the number of assessable patients in a phase II study, the odds of observing a "positive" phase III study increased 1.18 times (95% CI, 0.98 to 1.42; P = .083; Table 2). There was no statistical improvement (P = .28) in predicting positive phase III studies for the multivariate model. Results obtained from GEE and logistic regression analyses were similar.
DISCUSSION
Although results from phase II studies were often used as justification for phase III studies, our results showed that the majority of phase III studies based on preceding phase II studies were "negative," and promising results from phase II studies were infrequently reproduced in phase III studies. There are several explanations for our findings, with the first potential explanation being the "regression-to-the-truth" phenomenon. This phenomenon is analogous to the regression-to-the-mean concept.10 Random fluctuations occur in the measurement of a biologic variable over time. For any particular type of cancer, many phase II studies were conducted, evaluating different combinations, doses, and schedules of chemotherapeutic agents. By chance alone, one or more of these phase II studies would produce a response rate far removed from the "true" response rate. Chemotherapeutic regimens used in such studies might then be deemed promising, and be tested in phase III studies. On further testing, the "true" response rate was approached, thus response rates in phase III studies were lower than those in phase II studies. This phenomenon is intensified in phase II studies with small numbers of patients, where randomly occurring tumor responses have large influences on response rates. As a corollary, the influence of this phenomenon can be reduced by increasing the number of patients in phase II studies. Our study seems to support the existence of this phenomenon in cancer clinical trials in that there is a trend toward significance for the number of assessable patients in a phase II study. Therefore, clinical investigators should be aware of this phenomenon in their decision making.
Outcomes of nonrandomized studies, such as phase II studies, depend on specific characteristics of the patient population studied.7,11 Selection bias can result not only from known prognostic variables such as age, income, performance status, and number of metastatic sites, but also from previously unknown or unstudied variables. For example, Lamont et al recently reported that patients with head and neck cancer enrolled in phase II studies had better survival the further they lived from the treatment center.12 It is possible that promising results from phase II studies were a result of enrollment of high proportions of patients with good prognostic factors. However, the effect of this selection bias is eliminated in subsequent phase III studies because of random assignment.7
Response rates in phase II studies are usually calculated by including only assessable patients, the number of whom could be substantially fewer than the total number of patients actually enrolled in a phase II study. On the other hand, phase III studies are generally analyzed according to the intention-to-treat principle, such that all patients enrolled in a study are included in the data analysis regardless of whether they received any treatment or not.13 Therefore, response rates in phase II studies could be potentially inflated by including only assessable patients. We attempted to account for this difference in data analysis by recalculating response rates in phase II studies using the number of patients enrolled. Although this recalculation resulted in an additional three phase III studies with higher response rates, the overall impact of this recalculation was minimal (mean difference, 每12.9% v 每10.4%), indicating that methods of calculating response rates were not significant contributors to our findings.
The final explanation is the influence of newer and more sensitive imaging techniques, resulting in a "response migration" phenomenon similar to the "stage migration" phenomenon.14 Imaging techniques used in phase III studies might have improved compared with those employed in earlier phase II studies.15,16 Thus, patients who would have been deemed to have a partial response with older imaging techniques in phase II studies may only have stable disease or even progressive disease with newer imaging techniques in phase III studies. In addition, investigator-reported response rates in phase II studies were often lower than those obtained after independent reviews.17-19 However, independent reviews of response were infrequent in phase II studies, while they were often mandated in phase III studies.
Other strategies of selecting chemotherapy regimens from phase II studies for phase III studies have been proposed. One approach is to consider only chemotherapeutic regimens from multi-institutional phase II studies, since these studies are more likely to include a broader spectrum of patients.20 Several statistical models have also been proposed based on expected powers of phase II studies or using the 75% upper confidence limit of survival of historical patients as the lower limit of acceptable clinical activity of phase II studies.21-23 Others have advocated randomized phase II study designs.24,25 Inoue et al proposed a Bayesian phase II/III design in which patients were randomized between experimental and standard treatments.26 The decision of whether to proceed to a phase III study was made repeatedly during a time interval rather than at one single time point, and it was based on predictive probabilities that the experimental therapy was superior given the observed data. None of these models and proposals has been prospectively evaluated or validated; therefore, it is not known whether these strategies will lead to improved selection of candidate regimens for phase III studies.
The failure to reproduce promising phase II studies in subsequent randomized phase III studies is not unique to the field of cancer therapy. Investigators in other specialities of medicine have also been confronted by this problem. For example, several recent large randomized phase III studies failed to demonstrate benefits of new strategies in treating chronic heart failure despite promising results from phase II studies.10 Similar to the dilemma for clinical oncologists, there were no clear strategies for cardiologists to optimize the chance of success in phase III studies.27
Our study is limited in that we only reviewed phase III studies published in the English language literature during a 5-year period. Furthermore, only fully published studies were reviewed. However, unpublished studies are more likely to be "negative" studies.28 Inclusion of those studies will likely strengthen rather than weaken our results. In addition, response rates in phase II studies were not adjusted in our analysis. Response rates depend on tumor types, chemotherapeutic regimens studied, patient characteristics, and prior therapies. Therefore, it is not practical to adjust the reported response rate since each phase II study was conducted under a unique combination of conditions. The lack of predictive value of the reported response rate may partially reflect this phenomenon. Finally, only 43 phase III and 49 phase II studies were included in our analysis. Conclusions from our study are limited by the small sample size.
Our study shows that promising results from phase II studies are seldom reproduced in randomized phase III studies. Furthermore, the likelihood of a "positive" randomized phase III study is low even if the chemotherapeutic regimen is identical to that in preceding phase II studies. Therefore, investigators should be aware of these limitations in their decision making to initiate phase III studies.
Appendix: List of Studies
Van Cutsem E, Twelves C, Cassidy J, et al: Oral capecitabine compared with intravenous fluorouracil plus leucovorin in patients with metastatic colorectal cancer: Results of a large phase III study. J Clin Oncol 19:4097-4106, 2001
Van Cutsem E, Findlay M, Osterwalder B, et al: Capecitabine, an oral fluoropyrimidine carbamate with substantial activity in advanced colorectal cancer: results of a randomized phase II study. J Clin Oncol 18:1337-1345, 2000
Hoff PM, Ansari R, Batist G, et al: Comparison of oral capecitabine versus intravenous fluorouracil plus leucovorin as first-line treatment in 605 patients with metastatic colorectal cancer: results of a randomized phase III study. J Clin Oncol 19:2282-2292, 2001
Roszkowski K, Pluzanska A, Krzakowski M, et al: A multicenter, randomized, phase III study of docetaxel plus best supportive care versus best supportive care in chemotherapy-naive patients with metastatic or nonresectable localized non每small-cell lung cancer (NSCLC). Lung Cancer 27:145-157, 2000
Mattson K, Bosquee L, Dabouis G, et al: phase II study of docetaxel in the treatment of patients with advanced non每small-cell lung cancer in routine daily practice. Lung Cancer 29:205-216, 2000
Fossella FV, Lee JS, Murphy WK, et al: phase II study of docetaxel for recurrent or metastatic non每small-cell lung cancer. J Clin Oncol 12:1238-1244, 1994
Cerny T, Kaplan S, Pavlidis N, et al: Docetaxel (Taxotere) is active in non每small-cell lung cancer: a phase II trial of the EORTC Early Clinical Trials Group (ECTG). Br J Cancer 70:384-387, 1994
Francis PA, Rigas JR, Kris MG, et al: phase II trial of docetaxel in patients with stage III and IV non每small-cell lung cancer. J Clin Oncol 12:1232-1237, 1994
Fossella FV, DeVore R, Kerr RN, et al: Randomized phase III trial of docetaxel versus vinorelbine or ifosfamide in patients with advanced non每small-cell lung cancer previously treated with platinum-containing chemotherapy regimens: The TAX 320 Non-Small Cell Lung Cancer Study Group. J Clin Oncol 18:2354-2362, 2000
Fossella FV, Lee JS, Shin DM, et al: phase II study of docetaxel for advanced or metastatic platinum-refractory non每small-cell lung cancer. J Clin Oncol 13:645-651, 1995
Gandara DR, Vokes E, Green M, et al: Activity of docetaxel in platinum-treated non每small-cell lung cancer: results of a phase II multicenter trial. J Clin Oncol 18:131-135, 2000
Robinet G, Kleisbauer JP, Thomas P: phase II study of docetaxel (Taxotere) in first- and second-line NSCLC. Proc Am Soc Clin Oncol 16:480, 1997 (abstr 1726)
Jungnelius U, Ringborg U, Aamdal S, et al: Dacarbazine-vindesine versus dacarbazine-vindesine-cisplatin in disseminated malignant melanoma: A randomized phase III trial. Eur J Cancer 34:1368-1374, 1998
Ringborg U, Jungnelius U, Hansson J, et al: Dacarbazine-vindesine-cisplatin in disseminated malignant melanoma: A phase I-II trial. Am J Clin Oncol 13:214-217, 1990
Gundersen S: Dacarbazine, vindesine, and cisplatin combination chemotherapy in advanced malignant melanoma: a phase II study. Cancer Treat Rep. 71:997-999, 1987
Ranson M, Davidson N, Nicolson M, et al: Randomized trial of paclitaxel plus supportive care versus supportive care for patients with advanced non每small-cell lung cancer. J Natl Cancer Inst 92:1074-1080, 2000
Gatzemeier U, Heckmayr M, Neuhauss R, et al: phase II study with paclitaxel for the treatment of advanced inoperable non每small-cell lung cancer. Lung Cancer 12:S101-S106, 1995 (suppl 2)
Ranson MR, Jayson G, Perkins S, et al: Single-agent paclitaxel in advanced non每small-cell lung cancer: single-center phase II study using a 3-hour administration schedule. Semin Oncol 24:S12, 1997 (suppl 12)
von der Maase H, Hansen SW, Roberts JT, et al: Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, phase III study. J Clin Oncol 18:3068-3077, 2000
Moore MJ, Winquist EW, Murray N, et al: Gemcitabine plus cisplatin, an active regimen in advanced urothelial cancer: a phase II trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 17:2876-2881, 1999
Ohtsu A, Shimada Y, Shirao K, et al: Randomized phase III trial of fluorouracil alone versus fluorouracil plus cisplatin versus uracil and tegafur plus mitomycin in patients with unresectable, advanced gastric cancer: The Japan Clinical Oncology Group Study (JCOG9205). J Clin Oncol 21:54-59, 2003
Ohtsu A, Shimada Y, Yoshida S, et al: phase II study of protracted infusional 5-fluorouracil combined with cisplatinum for advanced gastric cancer: Report from the Japan Clinical Oncology Group (JCOG). Eur J Cancer 30A:2091-2093, 1994
Kosmidis P, Mylonakis N, Nicolaides C, et al: Paclitaxel plus carboplatin versus gemcitabine plus paclitaxel in advanced non每small-cell lung cancer: A phase III randomized trial. J Clin Oncol 20:3578-3585, 2002
Douillard JY, Lerouge D, Monnier A, et al: Combined paclitaxel and gemcitabine as first-line treatment in metastatic non每small-cell lung cancer: A multicenter phase II study. Br J Cancer 84:1179-1184, 2001
Giaccone G, Smit EF, van Meerbeeck JP, et al: A phase I-II study of gemcitabine and paclitaxel in advanced non每small-cell lung cancer patients. Ann Oncol 11:109-112, 2000
Auerback M, Chaudhry M, Richards P, et al: phase II study of gemcitabine and paclitaxel in metastatic non每small-cell lung cancer. Proc Am Soc Clin Oncol 19:522, 2000 (abstr 2052)
Schilsky RL, Levin J, West WH, et al: Randomized, open-label, phase III study of a 28-day oral regimen of eniluracil plus fluorouracil versus intravenous fluorouracil plus leucovorin as first-line therapy in patients with metastatic/advanced colorectal cancer. J Clin Oncol 20:1519-1526, 2002
Mani S, Hochster H, Beck T, et al: Multicenter phase II study to evaluate a 28-day regimen of oral fluorouracil plus eniluracil in the treatment of patients with previously untreated metastatic colorectal cancer. J Clin Oncol 18:2894-2901, 2000
Comella P, Frasci G, Panza N, et al: Randomized trial comparing cisplatin, gemcitabine, and vinorelbine with either cisplatin and gemcitabine or cisplatin and vinorelbine in advanced non每small-cell lung cancer: interim analysis of a phase III trial of the Southern Italy Cooperative Oncology Group. J Clin Oncol 18:1451-1457, 2000
Comella P, Frasci G, Panza N, et al: Cisplatin, gemcitabine, and vinorelbine combination therapy in advanced non每small-cell lung cancer: a phase II randomized study of the Southern Italy Cooperative Oncology Group. J Clin Oncol 17:1526-1534, 1999
Noda K, Nishiwaki Y, Kawahara M, et al: Irinotecan plus cisplatin compared with etoposide plus cisplatin for extensive small-cell lung cancer. N. Engl. J. Med. 346:85-91, 2002
Kudoh S, Fujiwara Y, Takada Y, et al: phase II study of irinotecan combined with cisplatin in patients with previously untreated small-cell lung cancer. West Japan Lung Cancer Group. J Clin Oncol 16:1068-1074, 1998
Crino L, Scagliotti GV, Ricci S, et al: Gemcitabine and cisplatin versus mitomycin, ifosfamide, and cisplatin in advanced non每small-cell lung cancer: A randomized phase III study of the Italian Lung Cancer Project. J Clin Oncol 17:3522-3530, 1999
Crino L, Scagliotti G, Marangolo M, et al: Cisplatin-gemcitabine combination in advanced non每small-cell lung cancer: a phase II study. J Clin Oncol 15:297-303, 1997
Jassem J, Pienkowski T, Pluzanska A, et al: Doxorubicin and paclitaxel versus fluorouracil, doxorubicin, and cyclophosphamide as first-line therapy for women with metastatic breast cancer: final results of a randomized phase III multicenter trial. J Clin Oncol 19:1707-1715, 2001
Amadori D, Frassineti GL, Zoli W, et al: Doxorubicin and paclitaxel (sequential combination) in the treatment of advanced breast cancer. Oncology (Huntingt) 11:30-33, 1997
Middleton MR, Grob JJ, Aaronson N, et al: Randomized phase III study of temozolomide versus dacarbazine in the treatment of patients with advanced metastatic malignant melanoma. J Clin Oncol 18:158-166, 2000
Bleehen NM, Newlands ES, Lee SM, et al: Cancer Research Campaign phase II trial of temozolomide in metastatic melanoma. J Clin Oncol 13:910-913, 1995
Blanke CD, Shultz J, Cox J, et al: A double-blind placebo-controlled randomized phase III trial of 5-fluorouracil and leucovorin, plus or minus trimetrexate, in previously untreated patients with advanced colorectal cancer. Ann. Oncol. 13:87-91, 2002
Blanke CD, Kasimis B, Schein P, et al: phase II study of trimetrexate, fluorouracil, and leucovorin for advanced colorectal cancer. J Clin Oncol 15:915-920, 1997
Namer M, Soler-Michel P, Turpin F, et al: Results of a phase III prospective, randomized trial, comparing mitoxantrone and vinorelbine (MV) in combination with standard FAC/FEC in front-line therapy of metastatic breast cancer. Eur J Cancer 37:1132-1140, 2001
Llombart-Cussac A, Pivot X, Rhor-Alvarado A, et al: First-line vinorelbine-mitoxantrone combination in metastatic breast cancer patients relapsing after an adjuvant anthracycline regimen: results of a phase II study. Oncology 55:384-390, 1998
Pacini P, Rinaldini M, Algeri R, et al: FEC (5-fluorouracil, epidoxorubicin and cyclophosphamide) versus EM (epidoxorubicin and mitomycin-C) with or without lonidamine as first-line treatment for advanced breast cancer. A multicentric randomized study. Final results. Eur J Cancer 36:966-975, 2000
Pacini P, Tucci E, Algeri R, et al: Combination chemotherapy with epirubicin and mitomycin C as first-line treatment in advanced breast cancer. Eur J Cancer 30A:460-463, 1994
Georgoulias V, Papadakis E, Alexopoulos A, et al: Platinum-based and nonplatinum-based chemotherapy in advanced non每small-cell lung cancer: a randomized multicenter trial. Lancet 357:1478-1484, 2001
Georgoulias V, Kouroussis C, Androulakis N, et al: Front-line treatment of advanced non每small-cell lung cancer with docetaxel and gemcitabine: a multicenter phase II trial. J Clin Oncol 17:914-920, 1999
Eton O, Legha SS, Bedikian AY, et al: Sequential biochemotherapy versus chemotherapy for metastatic melanoma: results from a phase III randomized trial. J Clin Oncol 20:2045-2052, 2002
Legha SS, Ring S, Eton O, et al: Development and results of biochemotherapy in metastatic melanoma: the University of Texas M.D. Anderson Cancer Center experience. Cancer J. Sci. Am 3:S9-S15, 1997 (suppl 1)
Blajman C, Balbiani L, Block J, et al: A prospective, randomized phase III trial comparing combination chemotherapy with cyclophosphamide, doxorubicin, and 5-fluorouracil with vinorelbine plus doxorubicin in the treatment of advanced breast carcinoma. Cancer 85:1091-1097, 1999
Spielmann M, Dorval T, Turpin F, et al: phase II trial of vinorelbine/doxorubicin as first-line therapy of advanced breast cancer. J Clin Oncol 12:1764-1770, 1994
Motzer RJ, Murphy BA, Bacik J, et al: phase III trial of interferon alfa-2a with or without 13-cis-retinoic acid for patients with advanced renal cell carcinoma. J Clin Oncol 18:2972-2980, 2000
Motzer RJ, Schwartz L, Law TM, et al: Interferon alfa-2a and 13-cis-retinoic acid in renal cell carcinoma: antitumor activity in a phase II trial and interactions in vitro. J Clin Oncol 13:1950-1957, 1995
Creagan ET, Suman VJ, Dalton RJ, et al: phase III clinical trial of the combination of cisplatin, dacarbazine, and carmustine with or without tamoxifen in patients with advanced malignant melanoma. J Clin Oncol 17:1884-1890, 1999
Del Prete SA, Maurer LH, O'Donnell J, et al: Combination chemotherapy with cisplatin, carmustine, dacarbazine, and tamoxifen in metastatic melanoma. Cancer Treat Rep. 68:1403-1405, 1984
McClay EF, Mastrangelo MJ, Bellet RE, et al: Combination chemotherapy and hormonal therapy in the treatment of malignant melanoma. Cancer Treat Rep. 71:465-469, 1987
Chapman PB, Einhorn LH, Meyers ML, et al: phase III multicenter randomized trial of the Dartmouth regimen versus dacarbazine in patients with metastatic melanoma. J Clin Oncol 17:2745-2751, 1999
Therasse P, Mauriac L, Welnicka-Jaskiewicz M, et al: Final results of a randomized phase III trial comparing cyclophosphamide, epirubicin, and fluorouracil with a dose-intensified epirubicin and cyclophosphamide + filgrastim as neoadjuvant treatment in locally advanced breast cancer: an EORTC-NCIC-SAKK multicenter study. J Clin Oncol 21:843-850, 2003
Piccart MJ, Bruning P, Wildiers J, et al: An EORTC pilot study of filgrastim (recombinant human granulocyte colony-stimulating factor) as support to a high-dose-intensive epiadriamycin-cyclophosphamide regimen in chemotherapy-naive patients with locally advanced or metastatic breast cancer. Ann. Oncol. 6:673-677, 1995
von Pawel J, von Roemeling R, Gatzemeier U, et al: Tirapazamine plus cisplatin versus cisplatin in advanced non每small-cell lung cancer: A report of the international CATAPULT I study group. Cisplatin and Tirapazamine in Subjects with Advanced Previously Untreated Non-Small-Cell Lung Tumors. J Clin Oncol 18:1351-1359, 2000
Miller VA, Ng KK, Grant SC, et al: phase II study of the combination of the novel bioreductive agent, tirapazamine, with cisplatin in patients with advanced non每small-cell lung cancer. Ann. Oncol. 8:1269-1271, 1997
Souquet PJ, Tan EH, Rodrigues PJ, et al: GLOB-1: a prospective randomized clinical phase III trial comparing vinorelbine-cisplatin with vinorelbine-ifosfamide-cisplatin in metastatic non每small-cell lung cancer patients. Ann. Oncol. 13:1853-1861, 2002
Tan EH, Ang PT, Wee J, et al: Vinorelbine, ifosfamide and cisplatin in advanced non每small-cell lung cancer. Acta Oncol. 38:619-622, 1999
Sculier JP, Lafitte JJ, Lecomte J, et al: A three-arm phase III randomized trial comparing combinations of platinum derivatives, ifosfamide and/or gemcitabine in stage IV non每small-cell lung cancer. Ann. Oncol. 13:874-882, 2002
Berghmans T, Klastersky J, Markiewicz E, et al: Cisplatin-carboplatin-gemcitabine or ifosfamide-gemcitabine in advanced nonsmall cell lung carcinoma: two pilot studies. Anticancer Res 19:5651-5655, 1999
Gordon AN, Fleagle JT, Guthrie D, et al: Recurrent epithelial ovarian carcinoma: a randomized phase III study of pegylated liposomal doxorubicin versus topotecan. J Clin Oncol 19:3312-3322, 2001
Gordon AN, Granai CO, Rose PG, et al: phase II study of liposomal doxorubicin in platinum- and paclitaxel-refractory epithelial ovarian cancer. J Clin Oncol 18:3093-3100, 2000
Negoro S, Masuda N, Takada Y, et al: Randomized phase III trial of irinotecan combined with cisplatin for advanced non每small-cell lung cancer. Br. J. Cancer 88:335-341, 2003
Masuda N, Fukuoka M, Fujita A, et al: A phase II trial of combination of CPT-11 and cisplatin for advanced non每small-cell lung cancer. CPT-11 Lung Cancer Study Group. Br. J. Cancer 78:251-256, 1998
Norris B, Pritchard KI, James K, et al: phase III comparative study of vinorelbine combined with doxorubicin versus doxorubicin alone in disseminated metastatic/recurrent breast cancer: National Cancer Institute of Canada Clinical Trials Group Study MA8. J Clin Oncol 18:2385-2394, 2000
Sandler AB, Nemunaitis J, Denham C, et al: phase III trial of gemcitabine plus cisplatin versus cisplatin alone in patients with locally advanced or metastatic non每small-cell lung cancer. J Clin Oncol 18:122-130, 2000
Schiller JH, Harrington D, Belani CP, et al: Comparison of four chemotherapy regimens for advanced non每small-cell lung cancer. N. Engl. J. Med. 346:92-98, 2002
Di Costanzo F, Gasperoni S, Malacarne P, et al: High-dose folinic acid and 5-fluorouracil alone or combined with hydroxyurea in advanced colorectal cancer: a randomized trial of the Italian Oncology Group for Clinical Research. Am J Clin Oncol 21:369-375, 1998
Di Costanzo F, el Taani H, Parriani D, et al: Hydroxyurea may increase the activity of fluorouracil plus folinic acid in advanced gastrointestinal cancer: phase II study. Cancer Invest 14:234-238, 1996
Hudes G, Einhorn L, Ross E, et al: Vinblastine versus vinblastine plus oral estramustine phosphate for patients with hormone-refractory prostate cancer: A Hoosier Oncology Group and Fox Chase Network phase III trial. J Clin Oncol 17:3160-3166, 1999
Hudes GR, Greenberg R, Krigel RL, et al: phase II study of estramustine and vinblastine, two microtubule inhibitors, in hormone-refractory prostate cancer. J Clin Oncol 10:1754-1761, 1992
Kelly K, Crowley J, Bunn PA Jr, et al: Randomized phase III trial of paclitaxel plus carboplatin versus vinorelbine plus cisplatin in the treatment of patients with advanced non每small-cell lung cancer: a Southwest Oncology Group trial. J Clin Oncol 19:3210-3218, 2001
Laohavinij S, Maoleekoonpairoj S, Cheirsilpa A, et al: phase II study of paclitaxel and carboplatin for advanced non每small-cell lung cancer. Lung Cancer 26:175-185, 1999
Dittrich C, Sevelda P, Salzer H, et al: Lack of impact of platinum dose-intensity on the outcome of ovarian cancer patients. 10-year results of a prospective randomized phase III study comparing carboplatin-cisplatin with cyclophosphamide-cisplatin. Eur J Cancer 39:1129-1140, 2003
Dittrich C, Sevelda P, Baur M, et al: In vitro and in vivo evaluation of the combination of cisplatin and its analog carboplatin for platinum dose intensification in ovarian carcinoma. Cancer 71:3082-3090, 1993
Bonneterre J, Roche H, Monnier A, et al: Docetaxel versus 5-fluorouracil plus vinorelbine in metastatic breast cancer after anthracycline therapy failure. Br. J. Cancer 87:1210-1215, 2002
Ravdin PM, Burris HA, III, Cook G, et al: phase II trial of docetaxel in advanced anthracycline-resistant or anthracenedione-resistant breast cancer. J Clin Oncol 13:2879-2885, 1995
Valero V, Holmes FA, Walters RS, et al: phase II trial of docetaxel: a new, highly effective antineoplastic agent in the management of patients with anthracycline-resistant metastatic breast cancer. J Clin Oncol 13:2886-2894, 1995
Kaufmann M, Bajetta E, Dirix LY, et al: Exemestane is superior to megestrol acetate after tamoxifen failure in post menopausal women with advanced breast cancer: results of a phase III randomized double-blind trial. The Exemestane Study Group. J Clin Oncol 18:1399-1411, 2000
Kvinnsland S, Anker G, Dirix LY, et al: High activity and tolerability demonstrated for exemestane in post menopausal women with metastatic breast cancer who had previously failed on tamoxifen treatment. Eur J Cancer 36:976-982, 2000
Jones S, Belt R, Cooper B, et al: A phase II study of antitumor efficacy and safety of exemestane (EXE) as second-line hormonal treatment of post menopausal patients with metstatic breast cancer (MBC) refractory to tamoxifen (TAM). Breast Cancer Res Treat 50:1998 (abstr 436)
Vanhoefer U, Rougier P, Wilke H, et al: Final results of a randomized phase III trial of sequential high-dose methotrexate, fluorouracil, and doxorubicin versus etoposide, leucovorin, and fluorouracil versus infusional fluorouracil and cisplatin in advanced gastric cancer: A trial of the European Organization for Research and Treatment of Cancer Gastrointestinal Tract Cancer Cooperative Group. J Clin Oncol 18:2648-2657, 2000
Lacave AJ, Baron FJ, Anton LM, et al: Combination chemotherapy with cisplatin and 5-fluorouracil 5-day infusion in the therapy of advanced gastric cancer: a phase II trial. Ann. Oncol. 2:751-754, 1991
Cunningham D, Pyrhonen S, James RD, et al: Randomized trial of irinotecan plus supportive care versus supportive care alone after fluorouracil failure for patients with metastatic colorectal cancer. Lancet 352:1413-1418, 1998
Rougier P, Bugat R, Douillard JY, et al: phase II study of irinotecan in the treatment of advanced colorectal cancer in chemotherapy-naive patients and patients pretreated with fluorouracil-based chemotherapy. J Clin Oncol 15:251-260, 1997
Rougier P, Van Cutsem E, Bajetta E, et al: Randomized trial of irinotecan versus fluorouracil by continuous infusion after fluorouracil failure in patients with metastatic colorectal cancer. Lancet 352:1407-1412, 1998
Nabholtz JM, Falkson C, Campos D, et al: Docetaxel and doxorubicin compared with doxorubicin and cyclophosphamide as first-line chemotherapy for metastatic breast cancer: results of a randomized, multicenter, phase III trial. J Clin Oncol 21:968-975, 2003
Dieras V, Barthier S, Beuzeboc P, et al: phase II study of Taxotere in combination with doxorubicin as first line chemotherapy of metastatic breast cancer. Breast Cancer Res Treat 50:262, 1998 (abstr 266)(Mohammad I. Zia, Lillian )