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Journal of Clinical Oncology, Vol 25, No 4 (February 1), 2007: pp. 418-423 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.04.9452 Randomized Phase II Trial of Paclitaxel Plus Carboplatin or Gemcitabine Plus Cisplatin in Eastern Cooperative Oncology Group Performance Status 2 Non–Small-Cell Lung Cancer Patients: ECOG 1599
From the Fox Chase Cancer Center; Albert Einstein Cancer Center, Philadelphia, PA; Dana-Farber Cancer Institute, Boston, MA; University of Wisconsin Cancer Center, Madison, WI; Mayo Clinic, Rochester, MN; and Vanderbilt University, Nashville, TN Address reprint requests to Corey J. Langer, MD, FACP, Thoracic Oncology, Fox Chase Cancer Center, 333 Cottman Ave, Philadelphia, PA 19111; e-mail: cj_langer{at}fccc.edu
Purpose: Appropriate therapy for Eastern Cooperative Oncology Group (ECOG) performance status (PS) -2 patients with advanced non–small-cell lung cancer (NSCLC) remains challenging. PS-2 patients on ECOG 1594 had a median survival (MS) of only 4.1 months and 1-year overall survival (OS) of 19%. Three percent had grade 5 toxicity. Patients and Methods: ECOG 1599, the first PS 2–specific, US cooperative group trial for treatment-naïve advanced NSCLC, randomly assigned patients to dose-attenuated carboplatin/paclitaxel (the least toxic regimen in ECOG 1594) or gemcitabine/cisplatin (which yielded an MS of 7.9 months in PS-2 patients). Patients received either carboplatin (area under the concentration-time curve, 6) and paclitaxel 200 mg/m2 every 3 weeks (CbP) or gemcitabine 1 g/m2 days 1 and 8 and cisplatin 60 mg/m2 day 1 every 3 weeks (CG).
Results: One hundred three patients were enrolled; 100 proved eligible. Median age was 66 years; 46% had at least 5% weight loss; 88% had stage IV or recurrent disease. Median number of cycles administered was three per arm. CbP featured more grade 3 neutropathy (10% v 0%) and more grade Conclusion: Platinum-based combination chemotherapy for PS-2 patients with NSCLC is feasible with acceptable toxicity, but survival in these patients remains inferior to that of PS-0 to -1 patients.
Performance status (PS) is a critical prognostic factor in advanced non–small-cell lung cancer (NSCLC). In the 1980s and 1990s, clinical trials and retrospective analyses suggested that patients with advanced NSCLC and compromised PS experienced substantial toxicity, gaining virtually no benefit from systemic chemotherapy.1-8 A 1986 Eastern Cooperative Oncology Group (ECOG) trial was one of the first to demonstrate impaired outcome for PS-2 patients.9 Four hundred eighty-six patients were randomly assigned over 2 years among four platinum-based combinations. Nineteen percent had PS 2, defined as symptomatic from disease and spending less than 50% of waking hours in bed. Median survival (MS) for PS-0 and PS-1 patients was 36 and 26 weeks, respectively, but it was only 10 weeks for PS-2 patients.9 PS-2 patients also sustained 10% incidence of treatment-related deaths, substantially higher than the incidence in PS-0 to -1 patients. Consequently, PS-2 patients were excluded from subsequent ECOG NSCLC trials. By the mid-1990s, improved supportive therapy (antiemetics, growth factors, and antibiotic management for myelosuppression) and somewhat less toxic active agents permitted ECOG investigators to enroll PS-2 patients onto 1594, a randomized, phase III, prospective trial evaluating four separate platinum-based regimens.10 More than 1,200 patients were ultimately accrued to 1594. However, after the first 68 patients, accrual of the PS-2 cohort was halted due to a high incidence of adverse events, including five deaths. A subsequent analysis showed that only two of the five were clearly treatment related.11 Nevertheless, toxicity was perceived as worse for this group compared with patients with PS 0 to 1. Further analysis showed that toxicity was only marginally worse. The overall response rate for PS-2 patients was only 14%, with MS 4.1 months and a 1-year overall survival (OS) rate of 19.1%. The gemcitabine/cisplatin (CG) arm, despite the greatest toxicity, yielded the best MS and 1-year OS in this group: 7.9 months and 38.5%. The carboplatin/paclitaxel (CbP) arm featured the least toxicity. Based on these findings, we proceeded with a PS-2–specific trial in advanced NSCLC, evaluating dose-attenuated versions of both regimens for feasibility and activity in PS-2 patients with incurable NSCLC.
The primary objective was an assessment of overall survival for each regimen in PS-2 NSCLC; secondarily, evaluation of response rate, time to progression, and toxicities. Eligibility stipulated advanced, incurable, chemotherapy-naïve NSCLC; ECOG PS 2; age at least 18 years; adequate physiologic indices, including absolute neutrophil count of at least 2,000; platelets at least 100,000; creatinine 1.5 mg/dL or lower; bilirubin 1.5 mg/dL or lower; and signed informed consent. Patients were deemed ineligible if they had received prior radiation to assessable disease (unless disease progression was confirmed at that site by physical examination, radiography, or pathology) or had pre-existing grade 2 or higher sensory neuropathy, CNS metastases untreated or actively growing despite prior radiation or surgery, or other active concurrent malignancies. Patients were also excluded for pregnancy, allergies to polyoxyethylate castor oil and significant comorbidities precluding chemotherapy, including active congestive heart failure and recent myocardial infarction.
Protocol Treatment On arm A (CbP), patients received 200 mg/m2 paclitaxel intravenously (IV) day 1 over 3 hours. Carboplatin was administered at a dose targeting an area under the concentration-time curve (AUC) of 6, over 30 minutes immediately after paclitaxel. Before paclitaxel, all patients received routine premedication including dexamethasone, diphenhydramine (or equivalent), and cimetidine (or other H2 blockers). Treatment was cycled at 3-week intervals, including standard antiemetic prophylaxis. Patients enrolled onto arm B (CG) received gemcitabine 1,000 mg/m2 IV over 30 minutes on days 1 and 8 and cisplatin 60 mg/m2 IV day 1 over 1 hour. Cycles were repeated every 3 weeks. Routine prehydration and aggressive antiemetics preceded cisplatin. Standard ECOG response criteria were used. Patients with complete response (CR), partial response (PR), or stable disease were allowed to continue treatment for up to six cycles, or until disease progression or unacceptable toxicity. Criteria for treatment cessation included progressive disease, excessive toxicity, patient choice, or intercurrent comorbidities.
Statistical Methods Because of overriding concern about severe toxicity in this vulnerable population, a two-stage design was independently applied to each arm so that symptomatic treatment-related grade 4 or 5 toxicity, excluding transient, asymptomatic hematologic toxicity in either regimen, would result in termination of that arm. The trial was designed to halt a particular regimen if more than eight instances of such toxicities occurred among the first 20 patients enrolled. This design necessitated a mandatory interim stopping period for toxicity analysis. Descriptive statistics were used to describe patient characteristics on study. OS and progression-free survival (PFS) were estimated by the Kaplan-Meier method.4 CIs for toxicity rate were estimated using exact binomial CIs adjusted for two-stage design.5 These were calculated for overall response rate and 1-year OS rates.6 All reported P values were associated with two-sided tests, unless otherwise specified.
Patient Demographics One hundred three patients were accrued (54 in arm A, 49 in arm B) between May 31, 2000, and November 20, 2002. The study underwent mandatory suspension on May 8, 2001, and, in the absence of unacceptable toxicity, was reopened on November 27, 2001. One patient deemed ineligible had stage IIIb disease without pleural effusion. Four eligible patients also never started protocol therapy. Two experienced rapid decline in performance status; a third required emergency treatment for ventricular arrhythmia; a fourth died as a result of cardiopulmonary arrest before treatment was initiated. Baseline demographics were comparable for both arms (Table 1). Median age was 66 years. Sixty-five percent were male; 46% had at least 5% weight loss. Eighty-eight percent had stage IV or recurrent disease. A slightly higher proportion of men were enrolled on the CG arm (71% v 59%). The CbP arm had a higher proportion of stage IIIb patients (19% v 10%). These differences were not statistically significant. Twenty percent of patients had squamous histology.
Toxicity Of 51 patients receiving CbP, 27% completed all six cycles of therapy, 11% received more than six cycles, and 49% received at least four. The median number of treatment cycles for both arms was three. Of 47 treated patients receiving CG, 31% completed all six cycles, 10% received more than six cycles, and 46% received at least four. Toxicity is summarized in Table 2. One patient in arm A had lethal toxicity (grade 5 febrile neutropenia). The CbP arm featured substantially more grade 3 or higher neutropenia than did the CG arm (59% v 33%); the relative incidence of grade 4 neutropenia was 34% and 10%, respectively. CbP also featured significantly more grade 3 sensory neuropathy (10% v 0%) and grade 2 sensory neuropathy (16% v 2%). However, CG resulted in significantly more grade 3 or higher thrombocytopenia (38% v 14%). It yielded significantly more grade 3 nausea/vomiting (23% v 6%), grade 3 fatigue (22% v 12%), and grade 1 or higher creatinine elevation (43% v 6%).
Treatment Discontinuation The most common reason for treatment discontinuation was progressive disease (49% in arm A, 40% in arm B; Table 3). Excess toxicity precipitated treatment suspension for 16% in arm A and 15% in arm B, whereas other reasons were more common in the cisplatin-based arm (13% v 4%). Comorbidities that were unrelated to treatment resulted in treatment suspension for 4% in arm A and 9% in arm B.
Objective Responses The overall objective response rate for arm B was 23% (90% CI, 13.1 to 34.4), including 1 CR. For arm A, it was 14% (90% CI, 6.4 to 23.4). Median response duration for patients on arms A and B were 5.3 and 6.5 months, respectively. Grouping stable disease and response together, arm A featured disease control rates of 55% versus 53% for arm B. Objective responses are show in Table 4.
Survival Data PFS was defined as time from random assignment to tumor progression or death without documented disease progression (Fig 1). Kaplan-Meier estimate of PFS for CbP was 3.5 months (95% CI, 2.6 to 6.0), and 3.0 months for CG arm (95% CI, 1.7 to 4.8). Survival data are show in Table 4.
OS was defined as time from random assignment to death or last contact. Figure 2 displays Kaplan-Meier estimate of OS by treatment arm. MS was 6.9 months for the CG arm, with 1-year OS of 25.5% (95% CI, 13.1 to 38.0) and a 2-year survival rate of 13% (95% CI, 3.3 to 22.0). MS for CbP was 6.2 months, with 1-year OS of 19.6% (95% CI, 8.7 to 30.5) and a 2-year survival rate of 7.8% (95% CI, 0.5 to 15.2).
As of this report (May 2005), two patients (4%) in the CbP arm remained alive, whereas three patients (6%) in the CG arm survived. The study was not designed to compare 1-year OS in the two treatment groups at the usual .05 level. Given the original design of the study, we had only 20% power to detect an absolute 10% improvement in 1-year OS, assuming the 1-year OS in one arm was 20%.
Although the assignment of PS is a subjective phenomenon, open to both questions and debate, we have long recognized that impaired PS is associated with compromised survival in patients with advanced NSCLC. A retrospective recursive partitioning analysis of multiple ECOG studies through the 1980s and early 1990s showed that performance status, sex, and appetite (and, by inference, weight loss) were the three most important prognostic factors. These prognostic indices relate directly to the intrinsic biology of the tumor and the patient, both of which may be inextricably linked. Historically, PS-2 patients with advanced NSCLC have fared poorly. In a phase III trial by Alberola et al12 comparing gemcitabine/cisplatin to triplet therapy (cisplatin/gemcitabine/vinorelbine), as well as sequential nonplatinum doublets (gemcitabine/vinorelbine ifosfamide/vinorelbine), PS-2 individuals had an MS of only 4.8 months, compared with 9.1 months for PS 0 to 1. van Meerbeeck et al13 mounted a phase III trial comparing cisplatin combinations with either paclitaxel or gemcitabine compared with the nonplatinum constituents (paclitaxel/gemcitabine), with no significant long-term survival difference among the three arms. However, MS in the PS-2 cohort was only 3.3 months, compared with 8.6 months for PS 0 to 1. In a phase III trial pairing carboplatin (AUC, 6) with paclitaxel at either low dose (175 mg/m2) or high dose (225 mg/m2), Kosimidis14 showed similar striking differences based on PS: MS in the PS-2 cohort was 3.8 months compared with 11.5 months for PS 0 to 1. ECOG 1599 is the first United States PS-2–specific trial ever conducted in treatment-naïve advanced NSCLC. The results demonstrate that combination platinum-based therapy is feasible in this group. With appropriate attenuation of initial paclitaxel, gemcitabine, and platinum doses, toxicities essentially matched those observed historically in the PS-0 to -1 population. Paclitaxel/carboplatin yielded more sensory neuropathy and neutropenia, but less nausea/vomiting, thrombocytopenia, and fatigue, and fewer creatinine elevations compared with gemcitabine/cisplatin. Disease control rates were comparable. MS exceeded 6 months for each regimen, somewhat better than the historic control of 4 months or less previously observed in ECOG trials,9-11,15 and as such constitutes a reasonable benchmark for future research. Still, 1-year OS did not exceed 30% in either arm. There were no statistically significant differences in survival between the two arms. The 1% grade 5 adverse event rate, in the context of a multi-institutional cooperative group trial, was acceptable. With regard to this study, we must acknowledge several concerns. Potential imbalances exist in the baseline demographics of each arm. The GC arm had fewer women, more patients who underwent prior radiotherapy, and fewer patients with stage III disease. Hence, it is conceivable that outcome might have been considerably better in this arm had baseline demographics been completely identical. But it is still doubtful that 1-year OS would exceed 30%. In addition, we did not establish baseline quality of life (QoL) or compare QoL between arms; this sort of comparison, however, is generally the province of phase III trials, and probably has more important implications in studies where the nature of therapeutic interventions are more disparate. A number of additional issues remain outstanding. We recognize that the assignment of PS is subjective, and open to both questions and debate. In the context of ECOG trials, the assignment of PS was based on physician designation, although nursing viewpoints may have helped inform this designation. From the standpoint of study entry, PS can only be assigned at baseline. We readily recognize that QoL, both at baseline and during the course of study, may depend on supportive care interventions, not necessarily response status, and we must acknowledge the potential palliative role of radiation in PS-2 patients. We need to better understand reasons for compromised PS (ie, comorbidity v disease burden v both), and determine the extent to which each influences outcome. In addition, a standard of treatment in this population must be established. Should PS-2 patients receive combination therapy, or should single agents with improved toxicity profile be pursued sequentially? It is conceivable that chemotherapy can potentially exacerbate the clinical situation in patients who are relatively asymptomatic from the cancer itself, but highly symptomatic from the comorbidities, whereas those patients whose poor PS is due to cancer burden may actually benefit far more from treatment. Unfortunately, ECOG 1599 did not provide comprehensive data on preexisting comorbidity, compromising our capacity to distinguish outcome based on disease burden versus pre-existing illnesses. In a Southern Italian Cooperative Oncology Group trial by Frasci et al16 focusing on elderly patients, baseline Charlson score (comorbidity index) correlated with both treatment completion rates and MS. Eighty-two percent of those with Charlson scores higher than 2 stopped treatment early, compared with a 30% early treatment-discontinuation rate among those with Charlson scores of 0 to 2. Those with Charlson score 0 had an MS of 6.5 versus 4.8 months for Charlson scores 1 to 2, whereas the MS of those with Charlson scores higher than 2 was 3.7 months. Similarly, in the MILES (Multi-Center Italian Lung Elderly Study) effort comparing gemcitabine/vinorelbine with the constituent single agents, baseline instrumental activities of daily living and QoL predicted outcome.17 Had sufficient data been collected on ECOG 1599, a similar determination could have been accomplished. To date, we still lack PS-2-specific studies directly comparing platinum-based doublets to either platinum alone or to the nonplatinum partner. Lilienbaum et al18 mounted a phase III trial comparing paclitaxel 225 mg/m2 alone with combination paclitaxel at an identical dose with carboplatin (AUC, 6). Both regimens were administered at 3-week intervals. Final results revealed a significant improvement in response rate and MS for those enrolled in the combination arm, but OS was not significantly better. However, PS-2 individuals receiving combination paclitaxel/carboplatin had an MS nearly double that observed for those receiving paclitaxel alone (4.7 v 2.4 months), with nearly doubled respective 1-year OS rates (18% v 10%; log-rank P = .0123). There were no 2-year survivors among the PS-2 individuals receiving paclitaxel alone, whereas nearly 10% in the combination therapy group survived 2 years. These results suggest that combination platinum-based therapy is preferable to the single-agent nonplatinum partner. However, a randomized phase II trial reported by Kosimidis et al19 failed to demonstrate a convincing benefit for combination therapy. One hundred two PS-2 individuals were randomly assigned to either gemcitabine alone, 1,250 mg/m2 every two weeks (G), or an identical dose in combination with carboplatin (CbG; AUC, 3) on days 1 and 15. MS for the gemcitabine arm was 4.8 months, compared with 6.7 months for the combination. In addition, there was a trend toward improved response rate for the combination (14% v 4%). However, there was no difference in 1-year OS (17.8% for G v 20% for CbG), or for symptom improvement rate (71% v 67%). Although this study failed to demonstrate a convincing improvement in survival for the combination, both arms demonstrated fairly high disease-specific symptom benefit.
In other studies in advanced NSCLC, single-agent therapy has not proved favorable. On Southwest Oncology Group (SWOG) 0027, a mixed cohort of elderly ( These results strongly underscore the need for a formal phase III trial in the PS-2 cohort comparing a nonplatinum single agent with a combination single agent and platinum regimen. Clearly, the potential pool of patients eligible for such an effort is large; others have documented that at least 30% of those newly diagnosed with NSCLC are PS 2.22
Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment: N/A Leadership: N/A Consultant: Corey J. Langer, Lilly, BMS Stock: N/A Honoraria: N/A Research Funds: Corey J. Langer, Lilly, BMS, All Testimony: N/A Other: N/A
Administrative support: Corey Langer Collection and assembly of data: Corey Langer Manuscript writing: Corey Langer, Sigui Li, Joan Schiller, William Tester, Bernardo L. Rapoport, David H. Johnson Final approval of manuscript: Corey J. Langer, Sigui Li, Joan Schiller, William Tester, Bernardo L. Rapoport, David H. Johnson
Supported in part by Public Health Service Grants No. CA23318, CA66636, CA21115, CA27525, CA21076, CA13650, CA49957, and by the National Cancer Institute, National Institutes of Health, and the Department of Health and Human Services. The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Stanley KE: Prognostic factors for survival in patients with inoperable lung cancer. J Natl Cancer Inst 65:25-32, 1980[Medline] 2. Albain K, Crowley J, LeBlanc M, et al: Survival determinants in extensive-stage non-small lung cancer: The Southwest Oncology Group experience. J Clin Oncol 9:1618-1626, 1991[Abstract] 3. Paesmans M, Sculier JP, Libert P, et al: Prognostic factors for survival in advanced non-small cell lung cancer: Univariate and multivariate analyses including recursive partitioning and amalgamation algorithms in 1,052 patients. J Clin Oncol 13:1221-1230, 1995[Abstract] 4. Le Chevalier T, Brisgand D, Douillard JY, et al: Randomized study of vinorelbine and cisplatin versus vindesine and cisplatin versus vinorelbine alone in advanced non-small cell lung cancer: Results of a European multicenter trial including 612 patients. J Clin Oncol 12:360-367, 1994[Abstract] 5. Le Chevalier T, Brisgand D, Soria JC, et al: Long term analysis of survival in the European randomized trial comparing vinorelbine/cisplain to vindesine/cisplatin and vinorelbine alone in advanced non-small cell lung cancer. The Oncologist 6(suppl 1):8-11, 2001 6. Cullen MH, Billingham LJ, Woodroffe CM, et al: Mitomycin, ifosfamide, and cisplatin in unresectable non-small-cell lung cancer: Effects on survival and quality of life. J Clin Oncol 17:3188-3194, 1999 7. Billingham L, Cullen M: The benefits of chemotherapy in patient subgroups with unresectable non-small-cell lung cancer. Ann Oncol 12:1671-1675, 2001 8. Vansteenkiste J, Vandebroek J, Nackaerts K, et al: Influence of cisplatin-use, age, performance status and duration of chemotherapy on symptom control in advanced non-small cell lung cancer: Detailed symptom analysis of a randomized study comparing cisplatin-vindesine to gemcitabine. Lung Cancer 40:191-199, 2003[CrossRef][Medline] 9. Ruckdeschel J, Finkelstein D, Ettinger D, et al: A randomized trial of the four most active regimens for metastatic non-small cell lung cancer. J Clin Oncol 4:14-22, 1986[Abstract] 10. Schiller JH, Harrington D, Belani CP, et al: Comparison of four chemotherapy regimens for advanced non-small cell lung cancer. N Engl J Med 346:92-98, 2002 11. Sweeney C, Zhu J, Sandler A, et al: Outcome of patients with a performance status of 2 in Eastern Cooperative Oncology Group Study E1594: A phase III trial in metastatic non-small cell lung carcinoma. Cancer 92:2639-2647, 2001[CrossRef][Medline] 12. Alberola V, Camps C, Provencio M, et al: Cisplatin plus gemcitabine versus a cisplatin-based triplet versus non-platinum sequential doublets in advanced non–small-cell lung cancer: A Spanish Lung Cancer Group phase III randomized trial. J Clin Oncol 21:3207-3213, 2003 13. Smit EF, van Meerbeeck JP, Lianes P, et al: Three-arm randomized study of two cisplatin-based regimens and paclitaxel plus gemcitabine in advanced non-small-cell lung cancer: A phase III trial of the European Organization for Research and Treatment of Cancer Lung Cancer Group–EORTC 08975. J Clin Oncol 21:3909-3917, 2003 14. Kosmidis P, Mylonakis N, Nicolaides C, et al: Paclitaxel plus carboplatin versus gemcitabine plus paclitaxel in advanced non-small-cell lung cancer: A phase III randomized trial. J Clin Oncol 20:3578-3585, 2002 15. Jiroutek M, Johnson D, Blum R, et al: Prognostic factors in advanced non-small cell lung cancer (NSCLC): Analysis of Eastern Cooperative Oncology Group (ECOG) trials from 1981-1992. Proc Am Soc Clin Oncol 17:461, 1998 (abstr 1774) 16. Frasci G, Lorusso V, Panza N, et al: Gemcitabine plus vinorelbine versus vinorelbine alone in elderly patients with advanced non-small cell lung cancer. J Clin Oncol 18:2529-2536, 2000 17. Gridelli C, Perrone F, Gallo C, et al: Chemotherapy for elderly patients with advanced non-small-cell lung cancer: The Multicenter Italian Lung Cancer in the Elderly Study (MILES) phase III randomized trial. J Natl Cancer Inst 95:362-372, 2003 18. Lilenbaum RC, Herndon J, List M, et al: Single-agent (SA) versus combination chemotherapy (CC) in advanced non-small cell lung cancer (NSCLC): A CALGB randomized trial of efficacy, quality of life (QOL), and cost-effectiveness. Proc Am Soc Clin Oncol 21:1a, 2002 (abstr 2) 19. Kosimidis PA, Dimopoulos MA, Syrigos C, et al: Gemcitabine vs gemcitabine-carboplatin for patients with advanced non-small cell lung cancer and PS 2: A prospective randomized phase II study of the Hellenic Cooperative Oncology Group. J Clin Oncol 23:627, 2004 (suppl; abstr 7058) 20. Hesketh PJ, Chansky K, Lau DH, et al: Sequential vinorelbine (V) and docetaxel (D) in advanced non-small cell lung cancer (NSCLC) patients age > 70, or with performance status (PS) 2: A SWOG phase II trial (S0027). J Clin Oncol 23:627, 2004 (suppl; abstr 7056) 21. Lilenbaum R, Rubin M, Samuel J, et al: A phase II randomized trial of docetaxel weekly or every 3 weeks in elderly and/or poor performance status (PS) patients (pts) with advanced non-small cell lung cancer (NSCLC). J Clin Oncol 23:627, 2004 (suppl; abstr 7057) 22. Kelly K: Challenges in defining and identifying patients with non-small cell lung cancer and poor performance status. Semin Oncol 31(suppl 6):3-7, 2004[Medline] Submitted April 17, 2006; accepted November 15, 2006. This article has been cited by other articles:
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
3 neutropenia (59% v 33%), whereas CG yielded more grade 
