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Originally published as JCO Early Release 10.1200/JCO.2002.12.111 on October 21 2002 © 2002 American Society for Clinical Oncology Cisplatin and Etoposide Regimen Is Superior to Cyclophosphamide, Epirubicin, and Vincristine Regimen in Small-Cell Lung Cancer: Results From a Randomized Phase III Trial With 5 Years’ Follow-UpByFrom the Departments of Oncology and Pulmonology, University Hospital of Trondheim, Trondheim; Departments of Oncology and Pulmonology, University Hospital of Tromsø, Tromsø; Departments of Oncology and Pulmonology, Ullevål Hospital, and Department of Oncology, Norwegian Radium Hospital, Oslo; Department of Pulmonology, Haukeland Hospital, Bergen; and Department of Internal Medicine, Østfold Sentralsykehus, Fredrikstad, Norway. This article was published ahead of print at www.jco.org.Address reprint requests to Roy M. Bremnes, MD, Department of Oncology, University Hospital of Tromsø, N-9038 Tromsø, Norway; email: roy.bremnes{at}unn.no
PURPOSE: To investigate whether chemotherapy with etoposide and cisplatin (EP) is superior to cyclophosphamide, epirubicin, and vincristine (CEV) in small-cell lung cancer (SCLC). PATIENTS AND METHODS: A total of 436 eligible patients were randomized to chemotherapy with EP (n = 218) or CEV (n = 218). Patients were stratified according to extent of disease (limited disease [LD], n = 214; extensive disease [ED], n = 222). The EP group received five courses of etoposide 100 mg/m2 intravenously (IV) and cisplatin 75 mg/m2 IV on day 1, followed by oral etoposide 200 mg/m2 daily on days 2 to 4. The CEV group received five courses of epirubicin 50 mg/m2, cyclophosphamide 1,000 mg/m2, and vincristine 2 mg, all IV on day 1. In addition, LD patients received thoracic radiotherapy concurrent with chemotherapy cycle 3, and those achieving complete remission during the treatment period received prophylactic cranial irradiation. RESULTS: The treatment groups were well balanced with regard to age, sex, and prognostic factors such as weight loss, and performance status. The 2- and 5-year survival rates in the EP arm (14% and 5%, P = .0004) were significantly higher compared with those in the CEV arm (6% and 2%). Among LD patients, median survival time was 14.5 months versus 9.7 months in the EP and CEV arms, respectively (P = .001). The 2- and 5-year survival rates of 25% and 10% in the EP arm compared with 8% and 3% in the CEV arm (P = .0001). For ED patients, there was no significant survival difference between the treatment arms. Quality-of-life assessments revealed no major differences between the randomized groups. CONCLUSION: EP is superior to CEV in LD-SCLC patients. In ED-SCLC patients, the benefits of EP and CEV chemotherapy seem equivalent, with similar survival time and quality of life.
SMALL-CELL LUNG cancer (SCLC) accounts for 20% to 25% of all lung cancers. At diagnosis, approximately 40% of the patients will present with limited-stage disease (LD), while 60% will have extensive-stage disease (ED). SCLC is highly sensitive to chemotherapy and for the last 25 years, combination chemotherapy has been the cornerstone in the treatment of this disease. However, after an initial response, most tumors will relapse and the majority of patients will eventually die from chemotherapy-resistant disease. Nevertheless, SCLC is a potentially curable disease, since 3% to 8% of the patients are long-term survivors.1-3 In LD-SCLC patients, the 5-year survival rate is 7% to 15%, whereas long-term survival is uncommon in ED patients.4,5 Combination chemotherapy is clearly superior to single-agent treatment in SCLC, and during the 1970s, the cyclophosphamide, anthracycline, and vincristine (CAV) regimen became the standard treatment.6 Later, cyclophosphamide-based regimens including etoposide seemed to be superior to CAV.7-9 In the mid-1980s, clinical trials with the combination of cisplatin and etoposide (EP regimen) as first-line treatment in SCLC demonstrated high efficacy, with complete response rates above 40% and median survival times of up to 14 months.10,11 Although randomized phase III studies failed to prove a definitive survival benefit compared with CAV,12-14 the EP regimen was better tolerated in combination with thoracic radiotherapy (TRT) and soon became the most frequently used chemotherapy regimen for SCLC.15,16 Recently, however, irinotecan in combination with cisplatin has in a phase III study shown superior survival in ED-SCLC when compared with the EP regimen.17 The value of TRT and prophylactic cranial irradiation (PCI) in LD-SCLC was still debated when the present study was initiated. Recently, two meta-analyses18,19 demonstrated a 14% improvement in median survival by adding TRT to combination chemotherapy. Another meta-analysis demonstrated that PCI, when administered to LD patients with a complete response (CR), improved the net overall 3-year survival rate by 5.4%, from 15.3% to 20.7%.20 In several studies it has also been shown that PCI reduces the risk of brain recurrences by more than 50%.21,22 Although TRT and PCI are part of the routine treatment of LD patients, these treatment modalities have not proven any survival benefit in ED patients. The presented randomized study was initiated in 1989 with the aim to evaluate whether the EP regimen was superior to the three-drug combination of cyclophosphamide, epirubicin, and vincristine (CEV). The primary end point was survival, with health-related quality of life (HRQOL) as the secondary end point. We present data from a minimum of 5 years of follow-up of these patients.
Patients From January 1989 through August 1994, 440 consecutive patients were included from 25 hospitals in Norway. Six hospitals contributed with 74% of the patients.
Eligibility Criteria The histologic diagnosis was established in accordance with standard procedures by the local pathologist according to the World Health Organization classification system for SCLC. There was no central review of the pathologic specimens. Cytologic specimens from bronchial brushings or fine-needle aspiration were accepted as a diagnostic criterion. The protocol was approved by the regional ethics committee. Before randomization, written informed consent was obtained from all patients.
Staging Patients were classified as having LD or ED. LD was defined as tumor confined to one hemithorax and adjacent nodes and lending itself to radiotherapy field sizes (portals) tolerated by normal tissue. If patients had metastatic disease beyond this area, they were considered ED patients.
Therapy According to the national guidelines, TRT was given as an anterior and posterior portal individually encompassing the regional mediastinal lymph nodes and the original tumor volume with a 1.5- to 2-cm margin. The supraclavicular region was not routinely treated unless palpable nodes or the primary tumor was located in the apical region of the lung. The radiation therapy was administered for 3 weeks between the third and fourth chemotherapy courses. The fractionation schedule was 15 fractions of 2.8 Gy once daily (total, 42 Gy). A 1.0-cm-wide filter was inserted in the posterior field to reduce the medulla dose to 2.6 Gy per fraction and thereby not exceed an ED value of 1,180 ret. PCI was administered to all LD patients classified as having a CR at restaging 4 weeks after chemotherapy ended. PCI was started within 2 weeks after restaging and was given as a total of 30 Gy to the whole brain (two opposing fields), using 2-Gy once-daily fractions (15 fractions). ED-SCLC patients did not receive radiotherapy as part of the routine treatment. However, chest or cranial irradiation was optional if severe symptoms could not be palliated by chemotherapy.
Evaluation and Follow-Up Detailed follow-up data of relapse pattern and treatment of relapse were available for 87% of the patients (CEV 88%, EP 85%). At the time of relapse, major symptomatic sites were registered.
HRQOL The HRQOL part of the study was optional. Patients were asked by the doctor to complete a baseline HRQOL questionnaire before the first chemotherapy course. Later questionnaires were mailed from the data centers directly to the patients (at 2, 6, 14, 22, 30, 38, 46, and 54 weeks). Patients still noncompliant after one reminder received no further questionnaires.
Statistical Methods
Categorical variables were analyzed using Pearson’s Differences regarding HRQOL were calculated using group scores of the mean values of each variable, and group differences were tested by mean of the Wilcoxon rank sum test. A difference of 10 or more in the 0 to 100 scale was regarded as clinically significant.27,28 A conservative P value of .01 was chosen in order to indicate statistical significance with all HRQOL estimates because of multiple comparisons.
Patients From January 1989 through August 1994, 440 patients were randomized. All eligible patients were included in the survival analysis on an intention-to-treat basis. The minimum follow-up was 5 years. Four patients were ineligible because of incorrect histologic diagnosis (non–small-cell lung cancer in three patients and low-grade primary pulmonary carcinoid in one patient). Thus, 436 patients were included in the analyses, with 218 patients in each treatment arm (Table 1). The median age was 64 years, 35% were female, and 65% were classified as having an ECOG performance status 0 or 1. Thirteen patients incorrectly randomized as ECOG 3 were included in the further analyses on an intention-to-treat basis. The treatment arms were well balanced with regard to sex, age, and performance status, as well as lactate dehydrogenase, alkaline phosphatase, and neuron-specific enolase.
Characteristics of patients with LD and ED are presented in Table 2 and Table 3, respectively. In the LD group, the median age was 64 years, 38% of patients were female, 77% had a performance status 0 to 1, and 54% reported some degree of recent weight loss. In the ED group, median age and sex distribution were equivalent to those of the LD group, while performance status (45% ECOG 2 to 3) and weight loss (70%) were worse. Major prognostic variables were well balanced in both subgroups. Approximately two thirds of the ED patients had symptoms of and verified metastatic disease to one site, while in one third of the patients metastases could be demonstrated at two or more sites. The distribution of metastasis is shown in Table 3; the liver was the most commonly involved organ (40%). Metastases were seen more frequently in the lung/pleura (P < .02) and brain (P < .05) in the CEV group, but there were no statistical differences between the treatment arms with regard to the other involved metastatic sites. Moreover, the number of involved metastatic sites was equal in the treatment groups.
Induction and Cross-Over Treatment The median number of administered induction chemotherapy courses was five in both groups, with a mean number of 4.2 and 4.0 courses in the CEV and EP arms, respectively. The planned number of chemotherapy courses (n = 5) was given to 69% of patients in the CEV arm and 65% in the EP arm. Induction treatment was terminated prematurely because of toxicity more often in the EP arm (19% v 7%) (P < .0001), whereas treatment termination because of progressive disease was more frequent in the CEV arm (24% v 16%) (P < .0001). Six patients, three in each treatment arm, did not receive any chemotherapy (rapid deterioration and death, n = 5; refused chemotherapy, n = 1). Seven percent (n = 30) of all patients were crossed over, 6% in the CEV group and 8% in the EP group. Cross-over from EP was mainly due to toxicity (93%), whereas progressive disease was the major reason (75%) for cross-over from CEV. The mean number of administered cross-over courses was similar in the CEV arm (mean, 2.3) and the EP arm (mean, 1.9). In the subgroups of LD and ED patients, the mean numbers of administered induction chemotherapy courses were 4.3 (CEV) and 4.2 (EP) versus 4.1 (CEV) and 3.9 (EP), respectively. There was no significant difference concerning chemotherapy intensity between the LD and ED groups, and 64% to 70% of these patients received the intended protocol chemotherapy. TRT was administered to 86% of all LD patients (CEV 83%, EP 88%). Twenty-four LD patients did not receive TRT because of disease progression, deterioration, or early death. PCI was administered to 20% of LD patients in the CEV arm and 23% in the EP arm.
Relapse Pattern and Palliative Treatment No differences were recorded with regard to palliative radiotherapy. It was administered when needed and judged beneficial to the patient (73 EP patients v 69 CEV patients). Forty-five percent of patients who developed brain metastases received palliative cranial irradiation. Palliative chest irradiation was administered to 17% in the ED group and 6% in the LD group. Local recurrences were more frequent among ED patients (54%) compared with LD patients (34%). Among LD patients, brain relapses occurred in 36% in the CEV arm and 53% in the EP arm (P = .06). For disease relapse, an equivalent number of chemotherapy courses were given in the LD (mean, 3.5) and ED (mean, 3.0) subgroups.
Survival
The EP regimen was superior to CEV in the LD group only (Figs 2 and 3). The median survival was 9.7 months in the CEV arm and 14.5 months in the EP arm (P = .001). The 2- and 5-year survival rates in the EP arm were 25% and 10%, respectively, compared with 8% and 3% in the CEV arm. The 5-year disease-specific survival rate among all LD patients was 8.5% (13% in the EP arm and 4% in the CEV arm).
A trend in survival benefit for the EP regimen was also seen in the ED patients, with a median survival of 6.5 months in the CEV group as compared with 8.4 months in the EP patients. The 2- and 5-year survival rates of 4% and 1%, respectively, were similar in the two treatment groups. In ED patients, the disease-specific 5-year survival rate was 2% in the EP group and 1% in the CEV group.
Quality-of-Life Analysis
Mean scores for all QLQ-C30 scales and single items at baseline and 2, 6, 14, 30, and 54 weeks are presented in Table 5. At week 6, emesis was significantly more pronounced in the EP than the CEV group. Furthermore, in the EP group, constipation was worse at week 2 and diarrhea worse at week 14 when compared with the CEV group. In other respects, there was no statistical difference between the groups. Data from all scheduled questionnaires for the physical function, global quality of life, fatigue, emesis, pain, and dyspnea scales are given in Fig 4.
Although EP has been the most frequently used chemotherapy regimen in SCLC since the early 1990s, neither the efficacy of cisplatin as single agent nor the superiority of the EP over CAV has been established in this malignancy. The rationale for combining cisplatin and etoposide in clinical studies was in fact originally based only on their synergistic activity in preclinical model systems.10,29 Acquired drug resistance has been a major problem in the treatment of SCLC. A number of randomized trials with alternating combination regimens have been performed in attempts to prove the validity of the Goldie-Coldman model.12,13,30-33 This model predicts maximum tumor kill if all effective agents are used as early as possible.34 In most of the studies, EP and CAV were used as alternating regimens. In only two of these studies12,13 could a modest advantage of the alternating approach over CAV be demonstrated. However, the advantage of the alternating treatment could be related just as much to the addition of a more active anticancer agent (EP) as to the alternating schedule itself. The aim of the present study was to address the question of whether the EP regimen, when compared with the CEV regimen, improves survival and HRQOL in SCLC patients. Since these were the primary end points, the lack of a central review of the objective response data, due to the high number of centers and long distances, was considered acceptable. The CEV regimen was chosen instead of CAV because epirubicin was regarded to be less cardiotoxic compared with doxorubicin.35 Given the national SCLC incidence rates (The Norwegian Cancer Registry) during the accrual period, and assuming that approximately 30% of the total number of patients with SCLC would be ineligible for the study because of highly advanced disease and/or poor performance status, it can be estimated that close to 40% of all "eligible" SCLC patients were randomized in this trial. The treatment arms in the present study were well balanced with regard to personal and clinical pretreatment characteristics, as well as induction therapy, cross-over therapy, and relapse therapy administered. Among ED patients, there were more brain and lung metastases detected in the CEV arm than in the EP arm. However, the number of metastatic sites presented may not fully account for all metastases because no screening for metastatic lesions was performed after the ED stage was confirmed. Thus, the numbers and distribution of metastases may not be the accurate figures, but we consider the data representative for the distribution of metastases between the treatment arms. In this randomized study, the EP regimen proved superior to the CEV regimen, with prolonged median and long-term survival for patients with LD and a similar degree of subjective side effects and symptomatic effects measured by the QLQ-C30. In ED patients, however, there was no significant difference in median survival time and long-term survival between the two groups. During the last decade, two randomized trials have investigated the survival benefit of EP and CAV therapy in SCLC patients.12,13 Roth et al13 treated 437 ED patients with CAV, EP, or alternating CAV/EP. In accordance with our results, they found no significant differences in survival between the two study arms. In a similar study performed by the Japanese Lung Cancer Chemotherapy Group,12 288 patients with LD-SCLC or ED-SCLC were treated in a three-armed trial with CAV, EP, or alternating CAV/EP. The investigators12 reported a significantly higher overall survival for LD patients receiving the alternating CAV/EP therapy (2-year survival, 30%) when compared with CAV (15%) or EP (21%). However, there was no statistically significant survival difference between the CAV and EP arms. The present study contains more than twice the number of patients in each group, which may explain in part the statistical difference between the two studies. It should also be noted that in contrast to the present study, none of the LD patients in the Japanese study received PCI. Chute et al36 reviewed all SCLC patients treated at the National Cancer Institute in the United States from 1973 to 1993. The patients were split into two groups based on the decade of diagnosis since cyclophosphamide-based chemotherapy was used in the period 1973 to 1983 and cisplatin-based chemotherapy in 1983 to 1993. In a multivariate analysis, a modest survival benefit was noted only in LD patients who received cisplatin-based chemotherapy. Their findings are in accordance with our survival data demonstrating longer survival in the EP arm among LD patients but no differences between the treatment arms in the ED group. The data also corroborate the results from two other recently published meta-analyses evaluating possible survival benefits from cisplatin-based or EP-based treatment in SCLC.37,38 Data from these studies support a 1-year survival improvement of at least 4% by using cisplatin-based chemotherapy in the treatment of SCLC. In a recent phase III study in LD-SCLC patients, Turrisi et al39 reported impressive survival data after four courses of EP combined with concurrent TRT, once or twice daily. TRT was administered concurrent with the first cycle, and optimal chemotherapy dose during radiotherapy was stressed. The 2-year and 5-year survival rates of the once-daily fractionation arm were 41% and 16%, respectively, versus 47% and 26% in the hyperfractionated arm. The findings by Turrisi et al emphasize the importance of adequate chemotherapy doses and optimal concurrent TRT. When this investigation was started in 1989, HRQOL assessments were optional. As a consequence, only 72% of the included patients were enrolled onto this part of the study. The treatment arms seemed, in general, to be equivalent with regard to HRQOL issues. The lack of long-term improvement in the functional and symptom scales may be related to the poor prognosis of SCLC and the substantial number of patients in both arms alive with advanced disease. Another explanation is that patients in both arms, irrespective of type of chemotherapy, received optimal palliative treatment. However, it should be emphasized that patients who received a cisplatin-based regimen did report more emesis when compared with the CEV patients. This is probably due to optimal antiemetic treatment including the use of 5-hydroxytryptamine-3 antagonists. In the present study, the survival time in ED patients was equivalent after EP and CEV treatment. On the basis of the survival results, recommendations pertaining to chemotherapy treatment of choice in ED-SCLC cannot be given. It is known that EP gives more acute toxicity in terms of nausea and vomiting when compared with CAV, yet the HRQOL assessments performed in this study showed that despite the acute chemotherapy-induced toxicity from the EP regimen, even ED patients reported similar results after EP as after CEV chemotherapy. However, the higher frequency of cross-over from the EP arm in this group of patients, primarily because of hematologic toxicity, may advise against EP as first-line treatment in ED-SCLC. Since the value of the meta-analyses can be no more than exploratory, the establishment of EP’s superiority over CEV in this randomized trial is fundamental for future standard treatment and clinical trials in SCLC patients. Furthermore, innovations in systemic therapy for this malignant disease should be tested in the potentially curable limited-stage group, even if the novel treatment shows little effect in extensive disease. For LD-SCLC patients, EP should be the standard treatment because of the superior survival. In addition, this regimen also combines more favorably with concurrent TRT than CAV. Given equivalent survival, the EP regimen may be a treatment choice in ED as well, since the HRQOL data were similar in the treatment arms.
Supported by the Norwegian Cancer Society. This study was initiated and performed by the Norwegian Lung Cancer Study Group. The secretarial assistance at the Clinical Research Office, Norwegian Radium Hospital, is greatly appreciated.
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2, adequate bone marrow and renal function (WBC count 
3,000/µL, platelet count 
2 test or the Fisher’s exact test. Continuous variables were analyzed using the Wilcoxon rank sum test and the Kruskal-Wallis test. Survival was calculated from randomization date, and the rates were calculated using the Kaplan-Meier product-limit method. The log-rank test was applied for comparison of survival. The effect of treatment at each assessment time was evaluated by using the nonparametric Mann-Whitney U test. The significance level was set at .05 using one-sided P values. 
