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© 1999 American Society for Clinical Oncology Topotecan Versus Cyclophosphamide, Doxorubicin, and Vincristine for the Treatment of Recurrent Small-Cell Lung CancerFrom the Zentralkrankenhaus Gauting, Abteilung Onkologie, Gauting bei Muenchen, Germany; University of Wisconsin Comprehensive Cancer Center, Madison, WI; The Toronto Hospital, Toronto, Canada; SmithKline Beecham Pharmaceuticals, Collegeville, PA; Groupe Français de Pneumo Cancerologie, Hopital Sainte Marguerite, Marseille, France; Salem Research, Winston-Salem, NC; Ottawa Regional Cancer Centre, Ottawa, Ontario, Canada; Clatterbridge Centre for Oncology, Wirral, Merseyside, United Kingdom; Cross-Cancer Institute, Edmonton, Alberta, Canada; Hopital Saint Jacques, Besancon, France; Nottingham City Hospital, Nottingham, United Kingdom; SmithKline Beecham Pharmaceuticals, Harlow, United Kingdom; and Alton Ochsner Medical Foundation, New Orleans, LA. Address reprint requests to Joachim von Pawel, MD, Zentralkrankenhaus Gauting, Abteilung Onkologie, Unterbrunner Str 85, Gauting bei Muenchen, Germany, 82131.
PURPOSE: Topotecan and cyclophosphamide, doxorubicin, and vincristine (CAV) were evaluated in a randomized, multicenter study of patients with small-cell lung cancer (SCLC) who had relapsed at least 60 days after completion of first-line therapy. PATIENTS AND METHODS: Patients received either topotecan (1.5 mg/m2) as a 30-minute infusion daily for 5 days every 21 days (n = 107) or CAV (cyclophosphamide 1,000 mg/m2, doxorubicin 45 mg/m2, and vincristine 2 mg) infused on day 1 every 21 days (n = 104). Eligibility included the following: bidimensionally measurable disease, Eastern Cooperative Oncology Group performance status of less than or equal to 2, and adequate marrow, liver, and renal function. Response was confirmed by blinded independent radiologic review.
RESULTS: Response rate was 26 of 107 patients (24.3%) treated with topotecan and 19 of 104 patients (18.3%) treated with CAV (P = .285). Median times to progression were 13.3 weeks (topotecan) and 12.3 weeks (CAV) (P = .552). Median survival was 25.0 weeks for topotecan and 24.7 weeks for CAV (P = .795). The proportion of patients who experienced symptom improvement was greater in the topotecan group than in the CAV group for four of eight symptoms evaluated, including dyspnea, anorexia, hoarseness, and fatigue, as well as interference with daily activity (P CONCLUSION: Topotecan was at least as effective as CAV in the treatment of patients with recurrent SCLC and resulted in improved control of several symptoms.
SMALL-CELL LUNG CANCER (SCLC) is highly sensitive to initial chemotherapy and radiation treatment. Standard first-line chemotherapy regimens—such as etoposide and cisplatin (EP)1,2; cyclophosphamide, doxorubicin, and vincristine (CAV)3,4; and alternating EP-CAV1,2—yield response rates of 65% to 90%, with 45% to 75% complete remission reported in limited disease and 20% to 30% complete remission reported in extensive disease. However, response durations are short, with a median survival of 10 to 16 months and a 5-year survival of 18% for limited disease, and a median survival of 6 to 12 months and a 5-year survival of 1% to 2% for extensive disease.5-9 The prognosis for patients who receive second-line therapy after relapse is poor.10 Response is influenced by the time to progression after cessation of first-line therapy. Patients who relapse less than 3 months after first-line therapy are commonly termed "refractory" and have response rates that are lower than those of patients who relapse more than 3 months after therapy, who are usually termed "sensitive."11 There is no standard second-line therapy for SCLC. CAV is often used after first-line treatment with EP. In two studies that included sensitive and refractory patients, CAV produced second-line response rates of 13% and 28%.3,4 The toxicity profile for this regimen is well established and acceptable, with myelosuppression being the major toxicity. For these reasons, CAV was chosen as the comparator for this study. Camptothecin analogs offer a promising new treatment option for SCLC. Topotecan HCl (Hycamtin, SK&F 104864-A; SmithKline Beecham Pharmaceuticals, Philadelphia, PA) is a water-soluble, semisynthetic analog of the alkaloid camptothecin, which, like camptothecin, is a specific inhibitor of topoisomerase I. Inhibition of this enzyme results in lethal DNA damage during the course of DNA replication. In preclinical models, topotecan was shown to be effective in a number of solid tumors (eg, Lewis lung carcinoma, colon adenocarcinomas 38 and 51, and subcutaneously implanted B16 melanoma) that were refractory to most of the established anticancer drugs (F. McCabe, personal communication, 1988). Topotecan, as a single agent, has been studied in several phase II trials as second-line therapy for SCLC. A study conducted by the European Organization for Research and Treatment of Cancer reported a 21.7% overall response rate (38% among sensitive patients, 6.4% among refractory patients) and a 33-week median duration of response.11 Two other phase II topotecan studies had response rates in sensitive patients of 14% (median survival, 25.7 weeks) and 19% (median survival, 26.6 weeks) and response rates in refractory patients of 2% (median survival, 16.3 weeks) and 3% (median survival, 20.4 weeks).12,13 A meta-analysis of these three SCLC studies in sensitive patients reported an 18% response rate and median survival of 30 weeks.14 Based on these results, a randomized trial of topotecan versus CAV was performed in the sensitive population.
Eligibility Criteria Patients were required to have documented progressive, limited, or extensive SCLC with the date of progression being at least 60 days after completion of first-line chemotherapy. At least one lesion had to be bidimensionally measurable by computed tomography, magnetic resonance imaging, ultrasound, radiograph, photograph, or physical examination. A minimum of 4 weeks was required between prior surgery or immunotherapy and study entry, and at least 24 hours was required between radiotherapy and initiation of study drugs. Other eligibility criteria included an Eastern Cooperative Oncology Group (ECOG) performance status of less than or equal to 2, hemoglobin more than or equal to 9.0 g/dL, WBC count more than or equal to 3.5 x 109/L, neutrophils more than or equal to 1.5 x 109/L, platelets more than or equal to 100 x 109/L, bilirubin less than or equal to 2.0 mg/dL, transaminase and alkaline phosphatase values less than or equal to 2 times the upper limit of normal (or, if liver metastases were present, less than or equal to 3 times the upper limit of normal), and creatinine less than or equal to 1.5 mg/dL or creatinine clearance more than or equal to 60 mL/min. Patients were ineligible if they had symptomatic brain metastases requiring corticosteroids or pre-existing cardiac disease (including clinical congestive heart failure, arrhythmias requiring treatment, or a myocardial infarction within the preceding 3 months). Also ineligible were patients for whom CAV was contraindicated (including patients with a history of demyelinating polyneuropathy or poliomyelitis), patients whose lifetime cumulative dose of doxorubicin exceeded 270 mg/m2 or cumulative dose of epirubicin exceeded 540 mg/m,2 and patients with prior topotecan therapy or more than one previous chemotherapy regimen. Written informed consent was obtained from each patient before study entry. The study was conducted in accordance with Good Clinical Practices and the Declaration of Helsinki as amended in Hong Kong (1989).
Randomization
Treatment Schedule
Dose Modification
Treatment Duration
Criteria for Efficacy The secondary efficacy variables included time to progression, time to response, survival, and improvement of disease-related symptoms. Time to progression was measured from the time of first study drug administration to documented progressive disease (or initiation of subsequent chemotherapy). Time to response and survival were measured from the time of first study drug administration to initial response and death, respectively. Symptom scores were evaluated for dyspnea, cough, chest pain, hemoptysis, anorexia, insomnia, hoarseness, fatigue, and interference with daily activity; improvement had to be sustained for two consecutive courses. Symptom evaluation also included the time to symptom worsening as defined by the interval from the first dose of study medication until the first evidence of worsening in the postbaseline assessment.
Safety Assessment
Statistical Analysis Response rates and the estimated percentage difference in response rates between treatment groups were determined along with 95% confidence intervals (CI). Traditional Kaplan-Meier survival estimates were used to summarize the time-to-event variables. These included time to response, response duration, time to progression, and survival. Time-to-event outcomes were also compared between treatments using the Cox regression model. In addition, multivariate statistical methodologies were applied to survival and response to determine other possible prognostic factors, namely sex, performance status, extent of disease, age, presence of baseline brain and/or liver metastases, response to first-line therapy (complete or partial response), response duration, and time to progression from first-line therapy. However, because the treatment groups were not balanced with respect to these additional covariates, the main conclusions of this study were based on the results adjusted for the stratification variables only.
"Symptoms of Disease" questionnaires were administered to patients at screening and immediately before each subsequent course of chemotherapy. The questionnaire was not a validated quality-of-life instrument, but rather a symptom-specific questionnaire for SCLC. Patient symptom assessments were scored on a four-point ordinal scale: 1, "Not at All," 2, "A Little Bit," 3, "Quite a Bit," and 4, "Very Much." For each of the symptoms of disease, Pearson's uncorrected
Patient Characteristics A total of 211 patients (107 treated with topotecan and 104 treated with CAV) were treated in the study. Demographic and baseline disease characteristics for all patients are presented in Table 1. The majority of patients (77% of topotecan patients and 79% of CAV patients) had received a first-line regimen containing both etoposide and platinum (cisplatin or carboplatin), and 97% of both topotecan and CAV patients had received a regimen containing etoposide. Forty-one topotecan patients (38.3%) and 45 CAV patients (43.3%) had a prior treatment regimen that included cyclophosphamide and an anthracycline. Overall, baseline characteristics were comparable between treatment groups, with the exception of sex (43% of topotecan patients were women v 32% of CAV patients; P = .091) and documented brain metastases, which were present in 11.2% of topotecan patients and 24.0% of CAV patients (P = .044).
Dose-Intensity
Efficacy
All patients who received a dose of study medication were included in the efficacy calculations (Table 3). Of all patients treated, 11 topotecan and 18 CAV patients had an overall response of "not assessable" and were classified as nonresponders. Of these, five patients (two topotecan and three CAV) were ineligible, and five patients (one topotecan and four CAV) could not be evaluated for response for the following reasons: one topotecan patient relocated to a nursing home, two CAV patients were lost to follow-up, a third died suddenly as a result of an unrelated cause, and a fourth patient was without lesion assessment after course 2. Sixteen patients (seven topotecan and nine CAV) were withdrawn from the study because of toxicity, either by the investigator or at the patient's request. One topotecan patient requesting withdrawal had tumor lysis syndrome with a 75% reduction in a jugulodigastric node. Additionally, three patients (one topotecan and two CAV) were removed for lack of clinical benefit, but did not have radiologic evidence of disease progression. Response rates were 30.4% for women compared with 19.7% for men (topotecan) and 30.3% for women compared with 12.7% for men (CAV). Of 41 patients on the topotecan arm and 45 on the CAV arm who had received a first-line regimen that included cyclophosphamide and an anthracycline, the response rates were 26.8% and 20.0%, respectively. No responding CAV patient had to be removed from study as a result of reaching the maximum allowed doxorubicin dose, and only two patients, one with stable disease and one nonassessable patient (not all lesions were assessed after course 2), were reported as discontinuing from the study after five courses of treatment. In patients experiencing relapse 60 to 90 days after completion of first-line chemotherapy, response rates were 3 of 22 patients (13.6%) for topotecan and 1 of 21 patients (4.8%) for CAV. Median duration of response to first-line chemotherapy was 33.5 weeks for topotecan responders compared with 22 weeks in topotecan nonresponders, and 28 weeks in CAV responders compared with 23 weeks in CAV nonresponders. A logistic regression model was applied to evaluate the possible effect of the aforementioned set of baseline characteristics on response rates. The logistic regression model identified presence of baseline liver metastases and sex as the only significant factors of response (P = .043 and P = .008, respectively); after adjusting for the covariates, patients in the topotecan group still had shown a greater propensity to respond than did patients in the CAV group, although the result was not statistically significant (odds ratio of 1.24; P = .557). Duration of response, time to response, time to progression, and survival. The medians and ranges of these parameters are presented in Table 4. At the time of analysis, 11.2% of topotecan patients and 12.5% of CAV patients were censored for survival. Overall median survival was 25.0 weeks for topotecan patients and 24.7 weeks for CAV patients (P = .795). Six- and 12-month survival times for topotecan patients were 46.7% and 14.2%, respectively, and 45.2% and 14.4% for CAV patients, respectively. (Survival curves are displayed in Fig 1).
The Cox regression model for survival did not exhibit a statistically significant result (P = .795) between treatments, with a risk ratio of topotecan to CAV of 1.039. As expected, baseline performance status and extent of disease were statistically significant prognostic factors for survival (P < .001). An additional Cox model was created to investigate the effect of the aforementioned set of baseline characteristics on survival. In addition to the stratification factors, the model identified sex, baseline liver metastases, and baseline brain metastases as significant factors for survival (P < .05); after adjusting for the covariates, the effect of treatment was still not statistically significant (risk ratio of 1.17; P = .322). Improvement in symptoms of disease. Greater symptomatic improvement was seen in patients who received topotecan for symptoms of dyspnea (P = .002), anorexia (P = .042), hoarseness (P = .043), and fatigue (P = .032), as well as for interference with daily activity, (P = .023). No symptom improvement was statistically superior for CAV (Table 5). Significant differences in the length of time to worsening of dyspnea (P = .046) and anorexia (P = .003) were noted, with symptoms progressing more slowly in the topotecan group.
Safety
The incidence of grade 4 thrombocytopenia (P < .001) and grade 3/4 anemia (P < .001) was significantly higher in patients who received topotecan. Grade 4 thrombocytopenia was observed in 28.8% of topotecan patients (30 of 104) in 9.8% of courses and required platelet transfusions in 19.6% of patients in 5.8% of courses. Grade 4 thrombocytopenia occurred in 5.0% of patients (five of 101) in 1.4% of CAV courses, requiring platelet transfusions in 1.9% of patients in 0.6% of courses. Grade 3/4 anemia occurred in 42.3% of topotecan patients in 17.3% of treatment courses compared with 19.8% of CAV patients in 7.2% of courses. RBC transfusions were administered to 52.3% of topotecan patients in 24.7% of courses versus 26.9% of CAV patients in 11.7% of courses (P < .001, patients and courses). Analyses of neutrophil and platelet nadirs for each course of therapy showed no evidence of cumulative toxicity for patients in the topotecan group. Because of the small number of patients in later courses, no conclusions could be reached for patients in the CAV group. Infectious complications. Suspected or documented infection occurred within 2 days of grade 4 neutropenia in 28% of patients (30 of 107) and 8.7% of courses (39 of 446) in the topotecan group, and in 26% of patients (27 of 104) and 12.8% of courses (46 of 359) in the CAV group. In addition, 4.7% of patients and 1.1% of topotecan courses and 4.8% of patients and 1.4% of CAV courses were associated with sepsis. Seven deaths (four topotecan, three CAV) were associated with therapy-induced myelosuppression with sepsis/infection. Nonhematologic toxicities. The most frequently reported related or possibly related adverse experiences for both groups were alopecia, fatigue, and gastrointestinal disturbances, including nausea, vomiting, and anorexia (Table 7). Dose reductions for nonhematologic toxicity occurred in one topotecan patient (0.9%) due to grade 3 fatigue and in 11 CAV patients (10.6%) (P = .003). Nine of the 11 CAV reductions were due to neurotoxicity. Baseline left ventricular ejection fraction (LVEF) was obtained for 100 topotecan and 97 CAV patients, but only 26 topotecan and 35 CAV patients had LVEF evaluation at the end of study. The incidence of worsening of LVEF, as judged by investigators based on echocardiogram or multiple gated acquisition results, was higher in the CAV population (six of 35 patients or 17.1%) compared with patients who received topotecan (two of 26 patients or 7.7%).
Deaths. The majority of patients in both treatment groups died as a result of progressive disease. In addition to the deaths secondary to treatment-related hematologic toxicity and sepsis previously described, two topotecan deaths were reported as possibly related or related to therapy. One death that was caused by acute respiratory insufficiency occurred 26 days after cycle 1. This occurred in a patient with significant pulmonary involvement, pleural and pericardial effusions, and progressive disease. Although unlikely, the investigator felt that topotecan could not be ruled out as a cause. A second patient died 33 days after cycle 1 as a result of an intracerebral hemorrhage into brain metastases, reported as secondary to topotecan-induced thrombocytopenia. A platelet count of 25 x 109/L was documented 3 weeks before the patient's death, and no further laboratory evaluations were performed, as the patient was declared "do not resuscitate." One patient on CAV died as a result of progressive disease coincident with reported CAV-related renal failure and pancytopenia 8 days after cycle 1. Reasons for withdrawal from study. Ten topotecan patients (9.3%) and 10 CAV patients (9.6%) were withdrawn from the study because of treatment-related toxicity. The primary reasons for withdrawal in both treatment groups were hematologic toxicity and associated sequelae. Treatment-related withdrawal due to nonhematologic toxicities included a topotecan patient with tumor lysis syndrome and two CAV patients with a decline in cardiac status.
Despite high response rates to initial chemotherapy, the majority of SCLC patients will progress within a year of completing therapy.17 The outlook for patients who receive second-line therapy is poor. Responses obtained are usually brief and median survival is generally less than 4 months.18 Phase II studies indicated that topotecan was active in patients with SCLC, particularly those with sensitive disease.11-13,19 In the present study, we compared single-agent topotecan with CAV in patients who progressed at least 60 days after initial therapy. The study was originally designed to recruit patients with at least 90 days between completion of first-line therapy and progression, but early in the study the criteria were amended to make topotecan available to a larger proportion of relapsed SCLC patients. The response rates were 24.3% (topotecan) and 18.3% (CAV) with median survival of 25.0 and 24.7 weeks, respectively. Although response in women was greater in this study, the European Organization for Research and Treatment of Cancer study reported by Ardizzoni et al11 showed a response rate of 25% in men versus 13.8% in women. The value of sex as a prognostic factor in previously treated SCLC remains unclear. Forty-five patients (43.3%) on the CAV arm had received cyclophosphamide and an anthracycline as part of their first-line regimen. Although we were concerned that these patients may have developed resistance to the regimen, the response rate in this group was 20.0%, which was similar to the response rate for the overall population. Time to response, time to progression, and response duration were similar for both groups. Significant benefit was seen in several symptoms as well as in interference with daily activity. Palliation of disease-related symptoms is an important objective of therapy, as these patients are not potentially curable. Hematologic toxicity was the predominant toxicity for both regimens, with grade 4 neutropenia occurring more frequently in patients in the CAV group and grade 4 thrombocytopenia and grade 3/4 anemia occurring more frequently in patients on the topotecan arm. The hematologic toxicity in patients on both arms, however, was of short duration, and clinically important sequelae of neutropenia did not increase with subsequent courses of therapy in either group. For patients in both groups, most nonhematologic toxicities were mild (grades 1 and 2). With the exception of neuropathy secondary to vincristine, these toxicities rarely caused dose reduction in either group. Worsening of LVEF occurred more frequently on the CAV arm, with two patients withdrawn because of cardiotoxicity, but no conclusions were reached due to insufficient LVEF data at the end of study. There is no standard regimen for SCLC after first-line therapy. CAV has been used in second-line therapy with response rates of 13% and 28% and median response durations of 26 and 24 weeks, respectively, in two studies.3,4 A 13% response rate was observed in 49 patients, with only 10% classified as "sensitive."3 Shepherd et al4 reported a 28% response rate and 15-week median survival in 29 patients, 45% with no response to prior chemotherapy. In a study comparing EP and CAV in patients who had received the alternate regimen as first-line therapy, the response rate was higher with EP, but overall survival was similar.1 Early studies with oral etoposide reported response rates as high as 45%, albeit with a modest survival of 14 weeks.20 Oral etoposide as a single agent has been compared with combination chemotherapy in first-line treatment of patients who were elderly or had poor performance status and was found to be inferior with respect to survival and overall quality of life.21,22 In one study, 171 patients received oral etoposide and 168 received combination chemotherapy, the majority with CAV. Survival was worse in the oral etoposide arm.21 A second study compared oral etoposide to alternating cycles of CAV and EP. One-year survival, median progression-free survival, and response rate were all statistically worse for oral etoposide, as was quality of life.22 Both studies were closed prematurely. A number of new cytotoxins have recently been shown to be active in SCLC, including taxanes, vinca alkaloids, and antimetabolites. A 34% response rate was observed in a phase II study of 36 previously untreated patients with SCLC who received paclitaxel 250 mg/m2 over 24 hours every 3 weeks for as many as four cycles.23 Kirschling et al24 used the same regimen combined with prophylactic G-CSF in previously untreated patients and reported a 41% response rate with a median survival of 6.6 months in 37 assessable patients. Neither study reported any complete responses. Docetaxel has been studied in both treated and untreated patients. Latreille et al25 reported a response rate of 8.3% in 12 chemo-naive patients using a dose of 75 mg/m2 as a 1-hour infusion every 3 weeks. Smyth et al26,27 used a dose of 100 mg/m2 of docetaxel and found a response rate of 25% in 28 assessable patients who had received prior chemotherapy. A trial of gemcitabine in 26 previously untreated patients found a 27% response rate.28 Vinorelbine achieved response rates of 12% and 16% in second-line patients with sensitive disease.29,30 In two studies from Japan, irinotecan had response rates of 50% in 16 patients, and 47% in 15 patients, but response durations were 46 and 58 days, respectively.31,32 A European study, in contrast, showed a response rate of 27% in 15 assessable patients.33 Although these new agents have demonstrated varying degrees of activity in SCLC, randomized studies are needed to determine their role in SCLC. Topotecan has also been studied as first-line treatment in SCLC. ECOG conducted a "Window of Opportunity" study with single-agent topotecan 2.0 mg/m2/d intravenously for 5 days every 21 days in patients with extensive disease. Approximately 70% of the patients received G-CSF support. Patients with no response after two cycles or partial response at four cycles were then given standard therapy with cisplatin and etoposide. Of 48 assessable patients, 19 (39%) achieved a partial response on topotecan. Median response duration was 4.8 months and median survival was 10.0 months.34 The Cancer and Leukemia Group B used combination cisplatin/topotecan and paclitaxel/topotecan in first-line SCLC, but these arms of the study were closed early because of toxicity.35,36 The paclitaxel/topotecan arm has been reopened with a reduced dose of paclitaxel. Despite the treatment-related deaths at the initial dose level, the median survival in the first group of patients was considered favorable enough to warrant further evaluation of the regimen after dosage adjustment (Mark R. Green, personal communication, 1998). Jett et al37 used a 5-day schedule of topotecan 1.0 mg/m2 followed by a 24-hour infusion of paclitaxel 135 mg/m2 on day 5 with G-CSF in previously untreated patients and obtained a response rate of 92% (11 of 12 patients) with acceptable toxicity. Eastern Cooperative Oncology Group is currently evaluating four cycles of topotecan as consolidation therapy versus observation after four cycles of standard platinum/etoposide therapy. Enrollment for this trial is ongoing. Of all the new chemotherapy agents, topotecan has undergone the most extensive evaluation in SCLC. It is clearly active in second-line SCLC and shows promise in first-line therapy. In vitro data show synergism of topotecan with many other drugs, including topoisomerase II inhibitors such as etoposide, and with DNA cross-linking agents such as alkylators and platinum compounds. Present development of topotecan in combination with cisplatin or carboplatin, the taxanes, and other agents is focusing on shorter schedules of topotecan, such as 3 days, and use on a weekly basis. Additionally, an oral formulation of topotecan is in development that may increase the ease of administration of the 5-day regimen. Preclinical data suggest that more prolonged exposure to topotecan may increase effectiveness. Hochster et al38 gave topotecan as a 21-day continuous infusion in second-line ovarian cancer patients and found a response rate of 43%, with considerably less toxicity. Whether prolonged administration will provide a benefit remains to be determined. If prolonged administration is found to be useful, the oral formulation may facilitate this schedule. In conclusion, we have reported that the efficacy of single-agent topotecan was similar to that of the three-drug combination of CAV, with improved control of several symptoms. Further study with topotecan in SCLC, including combination first-line therapy, is warranted.
We gratefully acknowledge the excellent contribution of Ruth Poulin in data analysis and manuscript preparation.
This study was supported by a grant from SmithKline Beecham Pharmaceuticals (study no. 104864/090). S.Z.F., J.B.K., G.R., and S.R.L. are employees of SmithKline Beecham Pharmaceuticals.
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ABSTRACT
INTRODUCTION
.043). Grade 4 neutropenia occurred in 37.8% of topotecan courses versus 51.4% of CAV courses (P < .001). Grade 4 thrombocytopenia and grade 3/4 anemia occurred more frequently with topotecan, occurring in 9.8% and 17.7% of topotecan courses versus 1.4% and 7.2% of CAV courses, respectively (P < .001 for both). Nonhematologic toxicities were generally grade 1 to 2 for both regimens. 
2 statistic was used to compare the percentages of patients in each treatment group who experienced sustained improvement over baseline. Patients were required to have both baseline and postbaseline measurements in order to assess a change. In the event that a patient had a missing baseline measurement and at least one nonmissing postbaseline measurement of "A Little Bit" or worse, the baseline value was imputed as "Not at All," and the patient was included in the analysis of that symptom. If symptom assessments were not recorded, algorithms were used to impute scores for the courses with the missing assessments. In addition, Kaplan-Meier estimates were obtained and tested using the log-rank test for the time to worsening for each symptom. The time to symptom worsening (measured in courses) was defined as the interval from the first dose of study medication until the first increase in the postbaseline assessment score. Patients not known to have experienced a worsening in that symptom were censored at their last symptom assessment. 
