Affiliations of authors: J.-L. Pujol, X. Quantin, Centre Hôpital Universitaire Arnaud de Villeneuve, Montpellier, France; J.-P. Daurès, Institut Universitaire de la Recherche Clinique, Montpellier; A. Rivière, Centre Régional de Lutte contre le Cancer, François Baclesse, Caen, France; E. Quoix, Hôpital Universitaire de Strasbourg, France; V. Westeel, Hôpital Universitaire de Besançon, France; J.-L. Breton, Hôpital de Belfort, France; E. Lemarié, Hôpital Universitaire de Tours, France; M. Poudenx, Centre Régional de Lutte contre le Cancer, Antoine Lacassagne, Nice, France; B. Milleron, Hôpital Universitaire Tenon, Paris, France; D. Moro, Hôpital Universitaire de Grenoble, France; D. Diebieuvre, Hôpital de Vesoul, France; T. Le Chevalier, Institut Gustave Roussy, Villejuif, France.
Correspondence to: Jean-Louis Pujol, M.D., Hôpital Universitaire Arnaud de Villeneuve, 34295 Montpellier, Cedex 5 France (e-mail: pujol{at}cyber-sante.org).
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ABSTRACT |
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INTRODUCTION |
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Nevertheless, long-term results obtained with this combination remain disappointing. Despite the high chemosensitivity of the disease, the 2- and 5-year survivals are low because of the frequent occurrence of relapses due to chemoresistance developed by the patients (8). The circumvention of this secondary chemoresistance has been addressed by different treatment modalities. One approach consists of intensifying the induction treatment. There are two theoretical ways to improve the results of chemotherapy beyond a standard regimen (1). The first one is based on the hypothesis of Schabel et al. (9) suggesting that cell killing may be improved by increasing the doses of chemotherapy. The second way is derived from the classical Goldie and Coldman model (10). This model hypothesizes that the combination of different drugs with distinct cellular mechanisms is able to reduce the risk of emergence of the resistant clone. Dose-intensity strategies examine both hypotheses.
Is there really a possibility for dose intensification in the treatment of SCLC? The question still remains to be resolved. One study (11) suggested that a moderate increase in dose during the first chemotherapy cycle results in a statistically significant increase in 2-year survival. Two other studies (12,13) suggested that the shortening of the cycle duration improved the outcome of patients but disagreed about the use of hematopoietic growth factors in this setting. On the other hand, several studies (1416) have failed to demonstrate an improvement in survival. There is probably no single answer to the above-mentioned question, inasmuch as different approaches toward SCLC chemotherapy intensification actually exist: 1) moderate increase in dose, 2) high increase of dose intensity with peripheral progenitor cell support, 3) reduction of cycle duration (e.g., increased dose density), or 4) addition of drugs to a standard combination. The last method could be considered as a putative progress, depending on the presumed different and synergistic effects in the cell-killing mechanisms of the additional drugs and an acceptable increase in toxicity (10). Indirect comparisons between data published with the EP regimen (6,7,14) and data reporting survival in patients treated with the use of a four-drug combination (15,16) suggest that there might be some advantage in the approach consisting of drug addition. Studies (11,15) using a four-drug combination have been reported. The quadruplet regimen consisted of the addition of cyclophosphamide and anthracycline to the etoposidecisplatin doublet. This approach deserves further comparison with the standard regimen, in view of the promising results obtained in patients receiving these combinations.
Based on these data, our intergroup collaboration has resulted in a randomized trial conducted in patients with extensive SCLC. The tested hypothesis was that adding 4'-epidoxorubicin and cyclophosphamide to the standard EP combination could result in an improvement in survival.
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PATIENTS AND METHODS |
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Patients with newly diagnosed, histologically confirmed SCLC took part in this study. According to the U.S. Veterans Administration (currently referred to as the U.S. Department of Veterans Affairs) Lung Cancer Group (17), extensive disease was defined by criteria that are opposite to those defining the limited disease. Thus, the extensive disease is defined as a disease beyond one hemithorax, including mediastinal lymph nodes and/or supraclavicular lymph nodes. Therefore, patients with distant metastases and patients with malignant pleural effusion were considered to have extensive disease. Other eligibility criteria consisted of a performance status (PS) of 2 or less according to the World Health Organization (WHO); age below 75 years; weight loss of 10% or less during the previous 3 months; baseline neutrophil count of 2000/µL or more; platelet count of 100 000/µL or more; levels of bilirubin, alkaline phosphatase, aspartate aminotransferase, and alanine aminotransferase lower than twice the normal upper limits; serum sodium 125 mmol/L or higher; creatinine clearance of 60 mL/minute or higher; and left ventricular ejection fraction greater than 50%. In addition, at least one bidimensionally measurable lesion was recorded before inclusion in the study. None of the patients could have received previous treatment or have experienced a previous malignant disease except well-controlled basal cell skin cancer. No patient could have symptomatic brain metastases. (This criterion was also applied to patients with symptomatic brain metastases who were free of neurologic symptoms after successful corticosteroid treatment.) Signed informed consent had to be obtained from the patient before randomization, and the study was approved by the Montpellier University Hospital Medical Ethics Committee. In addition, the study has been registered in the U.S. National Cancer Institute CANCERLIT®/PDQ® database.
For all patients, evaluation before receiving any drug treatment included clinical examination, complete blood cell count, blood chemistry (including both lactate hydrogenase and neuron-specific enolase measurements), isotopic or echographic ventricular ejection measurement, standard chest x-ray, computed tomographic scan of chest and brain, computed tomography or ultrasonography of the upper abdomen, fiberoptic bronchoscopy, bone scan, and bone marrow biopsy.
Treatment
Patients were randomly assigned to receive either EP (etoposide at a dose of 100 mg/m2 on day 1 through day 3 and cisplatin at 100 mg/m2 on day 2) or PCDE (etoposide and cisplatin given as in EP plus cyclophosphamide at a dose of 400 mg/m2 on day 1 through day 3 and 4'-epidoxorubicin at 40 mg/m2 on day 1); cycles were repeated every 4 weeks, and a total of six courses were planned for both groups. Drug administration was standardized and did not differ from one arm to the other. In particular, there was no difference in either dose by cycle or schedule of administration for etoposide and cisplatin. The latter drug was administered as a 180-minute intravenous infusion in a 3% NaCl solution protected from light and a concomitant infusion of 250 mL of 10% mannitol with standard hydration. Prophylaxis of neutropenia with the use of growth factors was not allowed. Antiemetic therapy based on both corticosteroids and serotonin receptor (5HT-3) antagonists were similarly scheduled for both groups.
Each cycle started every 28 days if the neutrophil count was 2000/µL or higher and the platelet count was 100 000/µL or higher. When the blood cell counts on day 1 of a planned cycle indicated neutropenia and/or thrombocytopenia, the course was delayed for 8 days. Patients with persistent grade 1 or more neutropenia or thrombocytopenia after an 8-day delay and/or patients who had experienced a grade 3 or 4 infection and/or a grade 4 neutropenia lasting for 6 days or more received 75% of the planned doses (25% dose reduction). These dose reductions for myelotoxicity did not affect the cisplatin dosage. Full, projected doses of cisplatin were administered to patients with a creatinine clearance of more than 60 mL/minute. Patients with a creatinine clearance between 40 and 60 mL/minute received 50% of the projected doses, whereas no cisplatin was administered to patients with a creatinine clearance less than 40 mL/minute. Chemotherapy toxicity was assessed for each cycle according to the WHO scale (18).
At the end of the chemotherapy program, prophylactic cranial irradiation was recommended for patients with complete responses, whereas thoracic radiotherapy was recommended for patients with partial responses if residual tumor was confined to the chest. No maintenance therapy was applied to complete responders at the planned end of the treatment. The decision as to what treatment to propose to patients who had relapsed was left to the discretion of each center's policy.
Response Analysis and Assessment of Quality of Life
The patients were assessed after every other cycle and at the planned end of chemotherapy in the same way as before they entered the study. After completing the treatment program, the patients were followed-up every 3 months. Tumor response was evaluated with the use of the WHO recommendations (18). A complete response was defined as the complete disappearance of all lesions with a negative histology of repeat fiberoptic bronchoscopy biopsies. A partial response was defined as equal to or greater than a 50% reduction in the product of the two longest perpendicular diameters of the indicator lesions. Both partial and complete responses must have lasted a minimum of 4 weeks to be confirmed. No change was defined as a less than 50% reduction or a less than 25% increase in this product. Finally, progressive disease was defined as equal to or greater than a 25% increase in this product or the appearance of new lesions. The actual dose intensity for each drug was defined as the ratio of the administered dose per unit of time to the planned dose per unit of time (19). For each patient, we calculated the dose intensity by taking into account the actual time of treatment plus 4 weeks. The percent of cumulative chemotherapy dose actually received in each treatment group was calculated according to the following formula: (the mean cumulative dose received/the planned cumulative dose) x 100.
At the time of study entry, the quality of life of patients was assessed by use of the EORTC (European Organization for Research and Treatment of Cancer) QLQ (quality-of-life questionnaire)-C30 and the LC (lung cancer) module 13 quality-of-life scale. The quality of life was subsequently reassessed after completion of the first two cycles and at the end of the study program, even when the chemotherapy had to be discontinued early (20).
Statistical Considerations
Overall survival was the endpoint of this study. On the basis of our previous experience with the four-drug chemotherapy (15) and on the data in the literature regarding EP (6,7,14), we hypothesized that a 15% improvement in the 1-year survival could be achieved with the PCDE regimen. The planned accrual was 210 patients (153 events), taking into account a type 2 ( error) of 20% and a type 1 (
error) of 5% (both two-sided). No interim analysis was planned, and all of the analyses were done on an intent-to-treat basis.
Survival was defined as the time from the date of random assignment to the date of death. Time to progression was defined as the period lasting from the first day of treatment to the date of the first observation of progressive disease. Probability of survival was estimated by the KaplanMeier method (21), and the survival difference was analyzed by means of Wilcoxon and log-rank tests. Associations between the treatment groups, putative prognostic variables (age, sex, metastatic involvement of specific organ, alkaline phosphatase, lactate dehydrogenase, and neuron-specific enolase), and survival were tested in a Cox proportional hazards model (22). The selection of variables to be tested in the Cox model was made with the use of the results of univariate analysis, i.e., variables reaching at least a P level less than 5% with the log-rank test. This model was written after a Boolean coding of the significant variables. The forward procedure of variable selection was used to perform the multivariate regression Cox model. For each variable, the proportional hazards assumption was tested graphically and statistically with the use of time-dependent variables. A P value of less than .05 was considered to be statistically significant. SAS (SAS Institute, Inc., Cary, NC) and BMDP (BMDP Statistical Software, Inc., Los Angeles, CA) software packages were used.
The distribution of qualitative variables (such as response categories or grades of toxic events) between groups was compared with the use of the 2 test. When the calculated frequency of the categorical data of the contingency table did not allow the use of the
2 test, Fisher's exact test was used. Quantitative variables (such as absolute neutrophil count) were compared with the use of the MannWhitney U test. Stepwise logistical regression analysis was done to determine the statistically significant (P<.05) reasons for protocol discontinuation.
Toxicity was analyzed by the frequency distribution of grade 3 or 4 toxic events. In addition, we defined time to grade 4 neutropenia and time to grade 4 thrombocytopenia as the time from day 1 of treatment to the first onset of a neutrophil count of less than 500/µL and a platelet count of less than 25 000/µL. KaplanMeier estimates of the time to first grade 4 neutropenia or thrombocytopenia were constructed, and the log-rank test was applied to analyze the differences between groups. Quality of life was tested with the use of two-way analysis of variance (one factor and repeated measurements). The unbalanced repeated measures models with structured covariance matrices of the BMDP software (procedure 5V) have been applied to correct statistics for missing data and loss of sphericity. All statistical tests were two-sided.
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RESULTS |
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From March 1996 through March 1999, a total of 226 patients were enrolled by 19 institutions (see the "Appendix" section), 109 in the EP group and 117 in the PCDE group (Fig. 1). Six patients were found retrospectively to be ineligible (2.6% of the whole population; three in each group); reasons for ineligibility included limited disease (one patient), combined small-cellnon-small-cell lung cancer (one patient), hyperbilirubinemia (two patients), symptomatic brain metastases (one patient), and hyponatremia (one patient). One patient who was randomly assigned to the PCDE group actually received EP. He was analyzed in his allocated arm (PCDE). There was no statistical difference between the two groups when pretreatment variables were analyzed (Table 1
). The delay from random allocation to treatment did not differ from one group to the other, inasmuch as 95% of the patients received their first course of chemotherapy within 24 hours of randomization (mean delay of 1.5 and 1.2 days in the EP and PCDE groups, respectively; P = .78).
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The objective (complete plus partial) response rate was 76% (89 [25 with complete and 64 with partial responses] of 117) in the PCDE group compared with 61% (66 [14 with complete and 52 with partial responses] of 109) in the EP group (P = .02 for the difference in combined objective responses in the two groups). The complete response rate was also higher in the PCDE group than in the EP group (21% versus 13%, respectively), although the difference did not reach the criterion of statistical significance (P = .06). Early progressive disease (i.e., tumor progression disclosed at the time of the first tumor evaluation) was more frequently observed in the EP group than in the PCDE group (22% and 9%, respectively).
Seventy-five (64%) of 117 patients completed the six courses of chemotherapy in the PCDE arm, whereas only 58 (53%) of 109 patients completed the six courses in the EP arm (P = .09). It is interesting that the reason for protocol discontinuation statistically significantly differed between the two groups (Table 2): A higher proportion of patients randomly assigned to the EP regimen discontinued chemotherapy because of progressive disease when compared with the patients assigned to the PCDE regimen (32% and 9%, respectively; P<.0001). Conversely, discontinuation due to toxicity was higher in the PCDE group than in the EP group (15% and 5%, respectively; P = .007). Stepwise logistical regression analysis demonstrated that both above-mentioned variables were the only statistically significant determinants of protocol discontinuation.
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Treatment Toxicity
A higher rate of hematologic toxicity was observed in patients in the PCDE group than in patients in the EP group. In particular, febrile neutropenia was more frequently observed in the former group, and a similar trend was also observed regarding documented infections (Table 4). Transfusions of red blood cells and platelets and re-admission for antibiotic infusions statistically significantly affected more patients in the PCDE group than in the EP group. The cumulative duration of re-admission due to management of toxic events was statistically significantly longer in patients in the PCDE group than in those in the EP group; the mean duration in days was 8 (95% confidence interval [CI] = 6 to 10) for the PCDE group and 1.6 (95% CI = 0.6 to 2) for the EP group (P = .0001). Patients in the PCDE group had statistically significantly shorter times to grade 4 neutropenia and thrombocytopenia than patients in the EP group (respective median time to neutropenia: 0.5 and 3.5 months; log-rank test: P<.0001). A higher frequency of cardiac toxicity was also seen in the PCDE group, with one fatal myocardial infarction and eight nonsymptomatic left ventricular impairments requiring 4'-epidoxorubicin discontinuation. Other toxic events did not statistically significantly differ between the two groups.
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The main hematologic toxicity was analyzed according to the performance status. In the PCDE regimen, the proportion of grade 3 or 4 thrombocytopenia, febrile neutropenia, and documented infection did not statistically significantly differ according to PS. However, in the PCDE group, the toxicity-related death rate was statistically significantly higher in patients with a PS of 2 (five of 17, or 29%) compared with patients with a PS of 01 (six of 100, or 6%; P = .01). This difference affected only patients allocated to received the four-drug regimen, inasmuch as no difference in the rate of death from toxic effects was observed in the EP group according to the PS (8% for the group with a PS of 2 and 5% for the group with a PS of 01; P = .33).
Survival
Survival data were updated on October 1, 1999. At that time, the median follow-up was 2 years. A total of 196 deaths were observed, and one patient was lost to follow-up in the EP arm. Patients in the PCDE group proved to have a longer survival than patients in the EP group (1-year survival rate: 40% and 29%, respectively; 18-month survival rate: 18% and 9%, respectively; median survival: 10.5 and 9.3 months, respectively; log-rank: P = .0067; Fig. 3). According to the procedure described previously in the section entitled "Statistical Considerations," seven variables were selected as putative prognostic determinants to be tested in the regression hazards model (i.e., age, alkaline phosphatase, lactate dehydrogenase, neuron-specific enolase, performance status, bone marrow metastases, and treatment group). In the Cox model, the following variables were statistically significant determinants of a better prognosis: a serum neuron-specific enolase level at presentation lower than 25 ng/mL, a performance status of 0 or 1, and an allocation to the PCDE group, with a relative risk (RR) of 0.70 (95% CI = 0.51 to 0.95) (Table 5
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Quality of Life
The EORTC-QLQ-C30 and LC13 questionnaires were completed at the planned three instances. Seventy-four percent (n = 73) of the patients in the PCDE group and 64% (n = 55) of the patients in the EP group were able to complete the survey. The global health status of the EORTC QLQ-C30 scale statistically significantly improved during the treatment program, without any difference between the two groups. The initial mean value of status (with a value of 100 considered to be the best score) for patients randomly assigned to the EP group was 53 (95% CI = 48 to 57); it rose to 58 (95% CI = 53 to 64) at the end of therapy. In the PCDE group, the respective mean values of this status were 55 (95% CI = 51 to 59) and 61 (95% CI = 56 to 66) (P for time effect <.0002). These observed improvements were parallel (P for interaction = .9). Physical functioning and social functioning remained stable in both groups, whereas emotional functioning decreased slightly at the same time. With regard to the symptom scale, a decrease in most of the variables analyzed was seen. It is noteworthy that the decrease in pain and dyspnea statistically significantly differed according to randomization, inasmuch as the patients in the PCDE group achieved a better final score than the patients in the EP group (final score for pain [best score = 0] was 25 (95% CI = 18 to 33) and 15 (95% CI = 11 to 20) for patients in the EP and PCDE groups, respectively; P for treatment group effect = .011). When the lung cancer EORTC-QOL-LC module 13 was analyzed, all symptoms substantially affecting patients at the time of presentation (i.e., mean symptom score 25/100) abated in both arms. Randomization had no statistically significant effect on variables in this module, and an overall benefit was recorded in both treatment groups.
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DISCUSSION |
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Our study compared this doublet with a four-drug regimen consisting of the addition of cyclophosphamide and 4'-epidoxorubicin without any change in the EP dosage, schedule, and number of planned courses. The improvement in both overall survival and time to disease progression seemed to be in relationship to a higher response rate, as graphically suggested by Fig. 3. The higher hematologic toxicity of this four-drug regimen did not preclude patients from receiving the entire six-course chemotherapy program, insofar as a higher proportion received the four-drug regimen when compared with the EP group. Conversely, the shortest time to disease progression, as observed in the EP regimen, resulted in a lower achievement of the whole protocol. Cumulative dosages of drugs shared by the two regimens were the same for cisplatin and slightly lower for etoposide in the PCDE regimen. Taken as a whole, compliance with the planned cumulative doses remained satisfactory, despite the frequent need for dose reductions in patients assigned to the four-drug regimen group. This finding suggests that the observed differences in survival, response rate, and toxicity depend on the addition of both anthracycline and cyclophosphamide to the EP regimen.
In our study, the standard group received the EP combination every 4 weeks. Although there is no definite agreement regarding the schedule and doses of etoposide and cisplatin to be delivered in this combination (6,14), the 3-week EP schedule seems to be more frequently applied in recent years. One can, therefore, raise the question whether or not our EP regimen could be considered as a standard one. In our opinion, there are arguments for a positive answer. When a 3-week schedule is applied, an 80-mg/m2 dose of cisplatin by cycle is recommended, which results in an equivalent dose intensity when compared with 100 mg/m2 given every 4 weeks as delivered in our study. In addition, there is no clear evidence that the dose intensity of EP influences survival in patients with extensive SCLC (14). Finally, the survival data on patients randomly assigned to our EP regimen are similar to those observed in recent trials in which EP regimens were given every 3 weeks (28).
Our population has been accrued by a large intergroup composed of specialists from various hospitals and institutions. The main selection criteria of this study, i.e., age 75 years or younger, performance status of 02, and weight loss of 10% or less, could be regarded as standard ones and are usually applied in routine practice. The aim of the study was to test dose intensity in the subgroup of patients with extensive SCLC. Taking into account this unfavorable prognostic variable shared by all patients and additional well-known poor prognostic factors (i.e., PS equal to 2, high serum lactate dehydrogenase level, or high level of neuron-specific enolase), it is noteworthy that 65% of the patients presented with at least two unfavorable prognostic factors. This proportion included 21% of the whole population presenting with three or four of these factors. These criteria have been reported as belonging to a high-risk patient population (29). Therefore, one can consider the clinical significance of the reported increase in survival rate to be well-founded in regard to the population studied. Moreover, the lower rate of both local relapse and metastatic progression (except in the brain) in the four-drug regimen could be analyzed as a possible better control of the disease.
The 9% rate of toxicity-related deaths observed in the PCDE regimen made it compulsory to carry out a detailed analysis to identify, among this group, specific variables predictive of high risk of toxicity. Patients affected by extensive SCLC and presenting with a PS of 2 were at higher risk of toxicity-related death. These data suggest that the PCDE regimen might be considered as acceptable in a general community setting for patients who are affected by extensive SCLC and have a PS of less than 2.
The quality of life statistically significantly improved during the treatment program, without any difference between the groups. It is noteworthy that an almost equivalent proportion of patients completed the three questionnaires during therapy, allowing a comparison of the quality of life between the two groups. This observed improvement was parallel insofar as there was no statistical interaction between time and treatment group. The quality of life was evaluated with the well-established EORTC QLQ-C30-LC13 scale. With the use of this gradation, acute toxicity, such as myelosuppression, could be underevaluated by the global health scale, insofar as this item mainly evaluates the week preceding the quality-of-life assessment. Nevertheless, the better compliance with the treatment in patients allocated to the PCDE group than in patients assigned to the EP group suggested that acute toxicity did not jeopardize the improvement of symptoms such as dyspnea and pain.
Brain metastasis remained an important difficulty. At the time of the study design, in 1995, there was no clear evidence in favor of a survival advantage for patients receiving prophylactic cranial irradiation. Insofar as not all investigators were convinced of the benefit of this prophylactic therapy, it was only recommended by the protocol and, in fact, only a small proportion of patients in the two groups received it. Recently, a meta-analysis based on individual patient's data (30) yielded a positive answer to the question for complete responders. As is well-known, brain metastases mainly affect the subgroup of SCLC patients who benefit the most from induction therapy. This might explain why a higher proportion of patients in the PCDE group had this modality of relapse when compared with patients in the EP group.
Several studies (1315,31) failed to demonstrate a statistically significant relationship between chemotherapy intensity and patient outcome. However, one can observe that there are various designs aimed at chemotherapy intensification. Patients with SCLC, especially those affected by an extensive stage, frequently share comorbidity and multiple poor prognostic factors precluding certain very intensive approaches. For example, in a previous study where a high-dose, four-drug regimen plus granulocytemacrophage colony-stimulating factor was compared with standard doses of the same combination in the treatment of extensive SCLC, we failed to demonstrate any advantage in using the intensive regimen. However, it was concluded that this approach failed to deliver a higher dose-density chemotherapy, inasmuch as the cumulative dose of each drug for the entire program was statistically significantly lower in the high-dose group than in the group given the standard doses, suggesting insufficient hematopoietic support (14). Therefore, we suggest that, in the treatment of extensive SCLC, not all methods are successful with an increase in the dose intensity. Despite the fact that a substantial complete response rate could be achieved in this disease, cure remains the exception. One explanation is that the treatment is unable to kill all malignant cells. However, in other curable human malignancies, such as germ cell tumor, high doses with three drugs are better than EP (32). One can hypothesize that the younger age of the patients in this latter setting may explain the easier delivery of full doses leading to a high cure rate.
Some past strategies demonstrated that a clinically significant improvement in survival could be achieved in SCLC patients, depending on the use of moderate intensification techniques (1012). We suggest that the data from our study could be added to this body of data showing that a dose intensitysurvival relationship exists in SCLC even if this is only a narrow way to improve patient outcome.
This investigation supports a relationship between treatment intensity and the outcome of patients with extensive SCLC, insofar as PCDE yields a higher response rate and better survival than EP, without any detrimental effect on the quality of life during therapy.
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APPENDIX |
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NOTES |
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We thank Mrs. Jo Baïssus for help in preparing the manuscript and Dr. Farid Khial and Mrs. Marie Cécile Bozonnat for technical and statistical assistance.
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Manuscript received July 18, 2000; revised November 22, 2000; accepted December 27, 2000.
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