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© 1999 American Society for Clinical Oncology Randomized Study of CODE Versus Alternating CAV/EP for Extensive-Stage Small-Cell Lung Cancer: An Intergroup Study of the National Cancer Institute of Canada Clinical Trials Group and the Southwest Oncology GroupFrom the National Cancer Institute of Canada Clinical Trials Group, Kingston, Ontario, Canada; and the Southwest Oncology Group, San Antonio, TX. Address reprint requests to Nevin Murray MD, British Columbia Cancer Agency, 600 West 10th Ave, Vancouver, British Columbia, Canada V5Z 4E6; email nmurray{at}bccancer.bc.ca
PURPOSE: To determine whether an intensive weekly chemotherapy regimen plus thoracic irradiation is superior to standard chemotherapy in the treatment of extensive-stage small-cell lung cancer (ESCLC). PATIENTS AND METHODS: Patients with ESCLC were considered eligible for the study if they were younger than 68 years, had a performance status of 0 to 2, and were free of brain metastases. Patients were randomized to receive cisplatin, vincristine, doxorubicin, and etoposide (CODE) or alternating cyclophosphamide, doxorubicin, vincristine/etoposide and cisplatin (CAV/EP). Consolidative thoracic irradiation and prophylactic cranial irradiation were given to patients responding to CODE and according to investigator discretion on the CAV/EP arm. RESULTS: The fidelity of drug delivery on both drug regimens was equal, and more than 70% of all patients received the intended protocol chemotherapy. Although rates of neutropenic fever were similar, nine (8.2%) of 110 patients on the CODE arm died during chemotherapy, whereas one (0.9%) of 109 patients died on the CAV/EP arm. Response rates after chemotherapy were higher (P = .006) with CODE (87%) than with CAV/EP (70%). However, progression-free survival (median of 0.66 years on both arms) and overall survival (median, 0.98 years for CODE and 0.91 years for CAV/EP) were not statistically different. CONCLUSION: The CODE regimen increased two-fold the received dose-intensity of four of the most active drugs in small-cell lung cancer compared with the standard CAV/EP regimen while maintaining an approximately equal total dose. Despite supportive care (but not routine prophylactic use of granulocyte colony-stimulating factor), there was excessive toxic mortality with the CODE regimen. The response rate with CODE was higher than that of CAV/EP, but progression-free and overall survival were not significantly improved. In view of increased toxicity and similar efficacy, the CODE chemotherapy regimen is not recommended for treatment of ESCLC.
TWO MAJOR THEMES in cancer chemotherapeutic innovation include drug selection and manipulation of drug delivery. Drug selection for small-cell lung cancer (SCLC) chemotherapy regimens has usually involved permutations of five drugs or their analogs, including cyclophosphamide, doxorubicin, vincristine, etoposide, and cisplatin. A number of regimens have been declared standard.1 Investigations of more intense delivery of standard chemotherapy regimens such as cyclophosphamide, doxorubicin, and vincristine (CAV)2,3 or etoposide and cisplatin (EP)4 in extensive-stage SCLC (ESCLC) have not generated data to support administration of chemotherapy above dose levels that cause moderately severe myelosuppression. However, dose-intensity below standard levels seems to be detrimental.5,6 Because of overlapping toxicity, potential advantages of drug diversity by selection of more drugs within a regimen may be undermined by suboptimal dose-intensity of component agents. The rationale for development of the cisplatin, vincristine, doxorubicin, and etoposide (CODE) regimen7 was to increase overall relative dose-intensity by delivering four drugs at standard intensity rather than increasing the delivery of two or three drugs within a combination above standard intensity. This weekly protocol alternates myelosuppressive and nonmyelosuppressive therapy weeks and includes administration of corticosteroids and prophylactic antibiotics as supportive care. The CODE regimen is designed to deliver as much cisplatin, more doxorubicin, more vincristine, and more etoposide in 9 weeks as the alternating CAV/EP regimen does in 18 weeks (Table 1). The CODE regimen does not include cyclophosphamide. In the Vancouver pilot study,7 patients responding to CODE without residual disease outside the chest after chemotherapy received consolidative thoracic irradiation (TI) and prophylactic cranial irradiation (PCI). The Vancouver study population was a select group with good performance status, and patients older than 65 years of age were excluded. The complete response rate after combined-modality therapy was 48% (thoracic response assigned by chest radiograph rather than computed tomography [CT] scan), median survival was 55 weeks, 2-year survival was 24%, and 5-year survival was 10%.9 Treatment-related deaths occurred in two (2.3%) of 85 patients. These results seemed superior to published ESCLC outcomes (median survival of 30 to 40 weeks and 2-year survival < 5%) from phase III studies performed by large cooperative groups.10-12
Based on these considerations, the National Cancer Institute of Canada Clinical Trials Group (NCIC-CTG) and the Southwest Oncology Group (SWOG) agreed to conduct a phase III trial comparing CODE chemotherapy plus consolidative irradiation for responders with alternating CAV/EP plus consolidative irradiation at the discretion of the investigator. Although the contribution of TI to the outcomes observed in the CODE pilot study was uncertain, investigators sought to determine whether this combined-modality regimen could improve the prognosis of patients with ESCLC and confirm whether a small proportion of patients could achieve long-term survival.
Eligibility and Evaluation All eligible patients had histologic or cytologic proof of SCLC with measurable or not measurable but assessable disease. Extensive stage disease was defined as tumor spread beyond the primary site, mediastinum, and ipsilateral supraclavicular nodes. For patients classified as ESCLC only because of pleural effusion, the effusion had to be easily visible on chest radiograph rather than on CT scan only (cytologic proof was not required). Other eligibility requirements included the following: age less than 68 years, Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 for NCIC-CTG centers and 0 or 1 for SWOG centers, granulocytes  2.0 x 109/L, platelets 150 x 109/L, bilirubin 1.5 times the upper limit of normal, creatinine the upper limit of normal, and albumin lower limit of normal. Ineligibility criteria included the following: previous chemotherapy or radiotherapy, prior malignant tumor other than a nonmelanoma skin tumor, brain metastases, recent (< 3 months) myocardial infarction, and diabetes mellitus (intolerance of corticosteroids). Pretreatment studies included history and physical examination, chest radiography, and routine blood tests including the following: complete blood cell count, bilirubin, AST, alkaline phosphatase, lactate dehydrogenase (LDH), creatinine, albumin, sodium, potassium, calcium, random blood sugar, and CEA. All patients had chest radiographs and CT examination of the abdomen and head plus radionuclide bone scans. Health-related quality-of-life (HRQOL) assessment was performed using the self-report European Organization for Research and Treatment of Cancer QLQ-C30,13 which was completed within 7 days before randomization by patients at Canadian centers but was optional at SWOG centers. During treatment, blood counts, chest radiographs, and quality-of-life (QOL) assessments were performed every 3 weeks; complete blood cell counts and creatinine assessments were performed weekly on patients receiving CODE. All abnormal scans were repeated 3 weeks after chemotherapy completion. After completion of all therapy, patients had follow-up examinations at intervals of 3 months with a history, physical examination, chemistry panel, and chest x-ray until disease progression or death.
Chemotherapy
Radiotherapy
Evaluation of Response and Survival Survival time was measured from the date of randomization until death, and progression-free survival was measured from the day of randomization to the time when disease progression was first documented. Toxicities were graded according to NCIC-CTG expanded common toxicity criteria.
Statistical Analysis Drug delivery was described by the cumulative dose plot methodology described by Coppin.14 Generalized Wilcoxon and log-rank statistics were used to compare survival experience between the two arms. A Cox proportional hazards model was used to assess prognostic factors and treatment effect after controlling for important prognostic variables. Response rates and toxicities between the two treatment arms were compared by Fisher's exact test. Logistic regression was used to assess and adjust for prognostic factors with respect to complete response. The HRQOL score comparisons were performed at baseline (week = 0), and the "intended" weeks 4, 7, 10, 13, 16, and 19 assessments using the Wilcoxon rank-sum test. The analysis was also performed using a growth curve model as described by Zee15 to assess the repeated measures of domain scores and symptom scores. A test of treatment-by-time interaction was performed to detect significant differences in QOL profiles between the two treatment arms. The significance tests between the two treatment arms at weeks 3, 6, 9, 12, and 15 were performed within the growth curve model to illustrate the differences between the two arms at various time points. Both cross-section analysis and growth curve models have similar results in this analysis.
The study was activated in July 1992 and terminated early in April 1996. The recommendation made by the Data and Safety Monitoring Committee of the NCIC-CTG at the time of interim analysis was to continue accrual but closely monitor the rate of toxic deaths in the study. The study was later terminated as a result of the recommendation made by the Data and Safety Monitoring Committee after an additional toxic death on the CODE arm had been observed. Two hundred twenty patients were randomized. Canadian centers entered 77 patients and SWOG entered 143 patients. Only one patient was considered ineligible because of an elevated bilirubin level. The total number of eligible patients was 109 on the CAV/EP arm and 110 on the CODE arm. Patient characteristics are listed in Table 2. The median age of the two arms was identical at 59.3 years. One third of the patient population was female. Ninety percent had ECOG performance status of 0 (30%) or 1 (60%). Multiple sites of extensive-stage disease were present in 72.5% of CAV/EP patients versus 80% of CODE patients. Forty-four percent of CAV/EP patients had liver metastases compared with 56.4% on CODE (P = .079). Elevated LDH values were present in approximately 60% of patients and were equally distributed between the two arms.
Chemotherapy Delivery
Radiotherapy
Toxicity
One patient had grade 3 pulmonary toxicity after TI on the CAV/EP arm. Toxicity from PCI was not different than expected.
Response and Survival
Median progression-free survival was 0.66 years on both treatment arms (Fig 3A). Ten percent of patients on both arms were progression-free at 2 years. Median overall survival was 0.98 years for patients treated with CODE compared with 0.91 years for patients treated with CAV/EP (P = NS) (Fig 3B). Approximately 18% of patients on both arms were alive at 2 years. The hazards ratio is 0.89 in favor of the CODE arm, with a 95% confidence interval of 0.67 to 1.18. In a stratified Cox regression model adjusted for liver involvement, elevated LDH, initial granulocytes, and sex, the treatment difference remains nonsignificant (P = .349).
HRQOL
The importance of high chemotherapy dose-intensity in the palliative setting remains a largely unproven concept. The putative advantage of the experimental CODE chemotherapy regimen in this trial was doubling the dose-intensity of four of the most active drugs for SCLC while maintaining total dose of these agents equal to or greater to the control arm of alternating CAV/EP. Conceptually, delivery of chemotherapy by the CODE regimen may be compared to the accelerated fractionation method for delivery of radiotherapy16 in that chemotherapy was delivered in somewhat smaller doses on a more frequent basis to a similar total dose over a shorter period of time than that of standard therapy. The structure of CODE involved weekly chemotherapy administration, and although other weekly regimens for SCLC have been tested in phase III trials,17,18 these other regimens did not deliver chemotherapy more intensively than standard regimens as measured by published dose-intensity comparison methodology.9 Despite termination of this trial before the original sample size was entered, sufficient patients were accrued to evaluate the regimens in an adequate fashion. The fidelity of the chemotherapy delivery on both arms was good, with approximately 70% of patients receiving all chemotherapy intended with few delays or reductions. The doubling of dose-intensity on the CODE regimen was associated with a significant increase in the overall response rate to 87% compared with 70% on the standard arm (P = .006). Nevertheless, progression-free survival and overall survival were not improved. One hypothesis consistent with this outcome is that intensive chemotherapy may eliminate chemosensitive tumor more quickly than standard regimens, and when this occurs before resistant elements become dominant, a higher response rate after completion of chemotherapy may be assigned. However, survival may be determined by the progression tempo of the chemotherapy-resistant tumor population. Even though one phase II study19 demonstrated CODE to have a response rate of 88% in relapsed SCLC, increased dose-intensity as delivered by this regimen was unable to sufficiently overcome chemotherapy resistance to increase survival. The International Association for the Study of Lung Cancer Workshop on SCLC stated that a fatal treatment toxic mortality rate of 5% could be justified in potentially curable cases.20 The chemotherapy-related mortality rate of 8.2% (nine of 110 patients) on the CODE regimen was unacceptably high compared with 1% (one of 109 patients) on the CAV/EP regimen. Oral prophylactic antibiotics and corticosteroids were inadequate supportive care to protect patients from the toxicity of CODE in this intergroup study. Fukuoka et al21 compared CODE chemotherapy alone with CODE plus G-CSF in a randomized trial of ESCLC. Patients on the CODE plus G-CSF arm not only received increased chemotherapy dose-intensity (P = .03) but also had a significant (P = .004) improvement in survival (median of 59 weeks on CODE plus G-CSF versus 32 weeks for CODE alone). A subsequent ESCLC phase III trial of ESCLC comparing CODE plus G-CSF versus CAV/EP demonstrated a higher response rate and slightly better survival duration for CODE plus G-CSF (median survival, 11.9 months) versus CAV/EP (median survival, 10.6 months), but differences were not statistically significant.22 Routine use of prophylactic G-CSF on the CODE arm of the NCIC-SWOG trial may have diminished toxic mortality and produced a small survival gain, but, like the Furuse trial,22 it is unlikely to have resulted in a major therapeutic gain. In view of the excessive toxicity demonstrated, the CODE regimen is not recommended for treatment of ESCLC. Median survival of approximately 1 year and 2-year survival of approximately 20% for the ESCLC patient population treated in this phase III study is similar to that of the pilot study of CODE plus radiotherapy.9 These results are better than the 8- to 10-month median survival and the less than 5% 2-year survival rate usually reported in phase II or III trials of ESCLC.10-12 Because the improved survival in this study cannot be attributed to improved treatment, it may be associated with patient prognostic factors. The eligibility criteria excluded elderly patients older than 67 years, but the median age of 59 years is similar to that of other trials, as is the range of metastatic sites and initial LDH values. The powerful prognostic factor that is different in this trial compared with some others10-12 is the distribution of initial performance status. Because of the intensive chemotherapy included in this trial, patients with ECOG performance status of 3 were excluded, and only 10% of patients entered had ECOG performance status of 2. Historically, 20% to 40% of patients in ESCLC phase III study populations have had performance status of 2 and 10% to 15% have had performance status of 3. When ESCLC patients are selected for investigation using performance status criteria (ECOG 0 and 1) that are now widely accepted for studies of advanced non–small-cell lung cancer,23,24 survival will be superior to expectations based on previous studies. The influence of performance status selection is crucial for interpretation of phase II trials of intensive therapy and new agents for ESCLC. TI was given sequentially after chemotherapy to 27% of patients after CAV/EP and to 43% of patients after CODE. Radiotherapy toxicity was not different than expected, but the largest differences in HRQOL between the two treatment groups was found at approximately the time when TI and PBI had been given to patients on CODE. Data from this trial do not confirm or refute a benefit from consolidative radiotherapy for patients that respond well to chemotherapy for ESCLC. Long-term survival results from this trial will be examined later, but any differences observed cannot become statistically significant. It is also uncertain whether the deterioration in global QOL, physical functioning, and fatigue seen in patients on CODE was entirely or only partly secondary to TI and PBI. Radiation therapy may only have added to an accumulating HRQOL burden. Like other similarly designed trials,2-4 this study concludes that standard combination chemotherapy protocols that cause moderately severe myelosuppression are as efficacious and less toxic than intensive regimens for the treatment of ESCLC. It seems improbable that reconfiguration of drugs used in this trial would result in a significant improvement for these patients. Although these results do not necessarily contradict trials25,26 that have demonstrated improved outcome with more intensive therapy for limited SCLC patients, confirmatory trials that show worthwhile survival improvement are mandatory to justify increased toxicity in this curable patient population.
Presented in part at the 33rd Annual Meeting of the American Society of Clinical Oncology, May 17-20, 1997, Denver, CO.
1. Ihde DH: Chemotherapy for lung cancer. N Engl J Med327:1434-1441, 1992[Medline] 2. Figueredo AT, Hryniuk WM, Strautmanis I, et al: Cotrimoxazole prophylaxis during high-dose chemotherapy of small-cell lung cancer. J Clin Oncol3:54-64, 1985[Abstract]
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Johnson DH, Einhorn LH, Birch R, et al: A randomized comparison of high-dose versus conventional-dose cyclophosphamide, doxorubicin, and vincristine for extensive-stage small-cell lung cancer: A phase III trial of the Southeastern Cancer Study Group. J Clin Oncol5:1731-1738, 1987
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Ihde DH, Mulshine JL, Kramer BS, et al: Prospective randomized comparison of high-dose and standard-dose etoposide and cisplatin chemotherapy in patients with extensive-stage small-cell lung cancer. J Clin Oncol12:2022-2034, 1994 5. Cohen MH, Creaven PJ, Fossieck BE, et al: Intensive chemotherapy of small cell bronchogenic carcinoma. Cancer Treat Rep61:348-354, 1977 6. Murray N: Importance of dose and dose intensity in the treatment of small-cell lung cancer. Cancer Chemother Pharmacol 40:S58-S63, 1997 (suppl) 7. Murray N, Shah A, Osoba D, et al: Intensive weekly chemotherapy for the treatment of extensive-stage small-cell lung cancer. J Clin Oncol9:1632-1638, 1991[Abstract]
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Hande KR, Bennett RB, Krozley MG: Improved bioavailability with low dose oral etoposide. J Clin Oncol11:374-7, 1993 9. Murray N: Weekly chemotherapy for small cell lung cancer. Lung Cancer11:138-139, 1994 (suppl 2) 10. Livingston RB, Schulman S, Mira JG, et al: Combined alkylators and multiple-site irradiation for extensive small cell lung cancer: A Southwest Oncology Group study. Cancer Treat Rep70:1395-1401, 1986[Medline] 11. Evans WK, Feld R, Murray N, et al: Superiority of alternating non-cross resistant chemotherapy in extensive small cell lung cancer. Ann Intern Med107:451-458, 1987 12. Roth BJ, Johnson DH, Einhorn LH, et al: Randomized study of cyclophosphamide, doxorubicin, and vincristine versus etoposide and cisplatin versus alternation of these two regimens in extensive small-cell lung cancer: A phase III trial of the Southeastern Cancer Study Group. J Clin Oncol 282-291, 1992
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Aaronson NK, Ahmedzai S, Bergman B, et al: The European Organization for Research and Treatment of Cancer QLQ-C30: A quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst85:365-376, 1993 14. Coppin C: The description of chemotherapy delivery: Options and pitfalls. Semin Oncol14:34-42, 1987 (suppl 4) 15. Zee B: Growth curve model analysis for quality of life data. Stat Med17:757-766, 1998[Medline] 16. Withers HR: Biological basis of radiation therapy for cancer. Lancet339:156-163, 1992[Medline]
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Sculier JP, Paesmans M, Bureau G, et al: Multiple-drug weekly chemotherapy versus standard combination regimen in small-cell lung cancer: A phase III randomized study conducted by the European Lung Cancer Working Party. J Clin Oncol11:1858-1865, 1993
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Souhami RL, Rudd R, Ruiz de Elvira MCet al: Randomized trial comparing weekly versus 3-week chemotherapy in small-cell lung cancer: A Cancer Research Campaign Trial. J Clin Oncol12:1806-1813, 1994
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Kubota K, Nishiwaki Y, Kakinuma R, et al: Dose-intensive weekly chemotherapy for treatment of relapsed small-cell lung cancer. J Clin Oncol15:292-296, 1997 20. Aisner J, Alberto P, Bitran J, et al: Role of chemotherapy in small cell lung cancer: A consensus report of the International Association for the Study of Lung Cancer Workshop. Cancer Treat Rep67:37-43, 1983[Medline] 21. Fukuoka M, Masuda N, Negoro S, et al: CODE chemotherapy with and without granulocyte colony-stimulating factor in small-cell lung cancer. Br J Cancer75:306-309, 1997[Medline] 22. Furuse K, Kubota K, Nishiwaki Y, et al: Phase III study of dose intensive weekly chemotherapy with recombinant human granulocyte-colony stimulating factor versus standard chemotherapy in extensive disease small cell lung cancer. J Clin Oncol16:2126-2132, 1998[Abstract] 23. Wozniak AJ, Crowley JJ, Balcerzak SP, et al: Randomized phase III trial of cisplatin (CDDP) vs. CDDP plus navelbine (NVB) in treatment of advanced non-small cell lung cancer (NSCLC): Report of a Southwest Oncology Group Study (SWOG-9308). J Clin Oncol16:2459-2465, 1998[Abstract] 24. Bonomi P, Kim K, Chang A, et al: Phase III trial comparing etoposide (E) cisplatin (C) versus Taxol (T) with cisplatin-G-CSF(G) versus Taxol-cisplatin in advanced non-small cell lung cancer. An Eastern Cooperative Oncology Group (ECOG) trial. Proc Am Soc Clin Oncol15:382, 1996 (abstr 1145)
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Arriagada R, Le Chevalier T, Pignon JP, et al: Initial chemotherapeutic doses and survival in patients with limited small-cell lung cancer. N Engl J Med329:1848-1852, 1993 26. Mehta C, Vogl SE: High-dose cyclophosphamide in the induction therapy of small cell lung cancer: Minor improvements in rate of remission and survival. Proc Am Assoc Cancer Res23:155, 1982 (abstr 612) Submitted November 12, 1998; accepted March 30, 1999.
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Copyright © 1999 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
