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© 2001 American Society for Clinical Oncology Duration of Chemotherapy in Advanced Non–Small-Cell Lung Cancer: A Randomized Trial of Three Versus Six Courses of Mitomycin, Vinblastine, and CisplatinFrom the Royal Marsden National Health Service Trust, London and Surrey; Kent Cancer Centre, Maidstone; Imperial Cancer Research Fund Medical Oncology Unit, Churchill Hospital, Oxford; Aberdeen Royal Infirmary, Aberdeen; St George’s Hospital, London; and Royal Bournemouth Hospital, Bournemouth, United Kingdom. Address reprint requests to Ian Smith, MD, Royal Marsden National Health Service Trust, Downs Rd, Sutton, Surrey SM2 5PT, United Kingdom; email: ian.smith{at}rmh.nthames.nhs.uk
PURPOSE: So far there are no published data on optimal duration of chemotherapy for advanced non–small-cell lung cancer (NSCLC); six or more courses are usually recommended. We have carried out a multicenter randomized trial comparing three versus six courses of chemotherapy. PATIENTS AND METHODS: Patients with stage IIIb or IV NSCLC were randomized at start of treatment to receive either three or six courses of mitomycin 8 mg/m2 (courses 1, 2, 4, and 6), vinblastine 6 mg/m2, and cisplatin 50 mg/m2 (MVP) every 21 days. Treatment was stopped early in both arms for progressive disease or unacceptable toxicity. Key end points were overall survival, duration of symptom relief, and quality-of-life assessment using the European Organization for Research and Treatment of Cancer (EORTC) core questionnaire QLQ-C30 with lung cancer–specific module QLQ-LC13. RESULTS: Three hundred eight patients were randomized. Seventy-two percent of the 155 patients randomized to three courses completed treatment. In the 153 patients randomized to six courses, 73% completed three courses and 31% six courses. Median survival was 6 versus 7 months, respectively, and 1-year survival 22% versus 25% (P = .2). Median duration of symptom relief was 4.5 months (both arms), and 8% versus 18% had continuing symptom relief (P = .4). Quality-of-life parameters were the same or improved for patients randomized to only three courses, including significantly decreased fatigue (P = .03) and a trend toward decreased nausea and vomiting (P = .06). CONCLUSION: Our findings show no evidence for additional clinical benefit by continuing MVP chemotherapy beyond three courses. This challenges current orthodoxy of six courses or more. Further trials addressing duration of chemotherapy are now warranted, particularly with newer chemotherapy schedules.
PALLIATIVE CHEMOTHERAPY is now widely used in the treatment of advanced non–small-cell lung cancer (NSCLC). Most trials have shown a survival advantage over best supportive care,1-5 and this has been confirmed by a meta-analysis.6 Useful symptom relief and improved quality of life have also been demonstrated after chemotherapy,4,5,7 but overall clinical benefit so far remains modest. Current orthodoxy usually recommends that treatment should continue for at least six courses, and sometimes indefinitely until disease progression.1-3,5,8-11 Several recent trials have addressed the question of optimal drug selection,8-13 but the important issue of optimal duration of treatment has in contrast so far been largely ignored, despite the obvious quality of life and resource implications involved. In order to address this question, we started a trial in which patients with advanced NSCLC who had gained an objective or symptomatic response to three cycles of mitomycin, vinblastine, and cisplatin (MVP) chemotherapy were offered randomization to stop or to continue for a further three cycles.14 Accrual proved unexpectedly difficult, and most patients wished to continue treatment in the belief that more of the same must be better. This initial trial was therefore stopped and we designed a new trial in which randomization was carried out at the start of the treatment to three versus six courses of MVP chemotherapy. This design proved much more acceptable, with around 80% patient acceptance. The trial was expanded on a multicenter basis, and we report our results here.
Patients Patients with histologically or cytologically proven stage IIIB or IV NSCLC not previously treated with chemotherapy were offered entry onto this trial. Further inclusion criteria were World Health Organization (WHO) performance status (PS) 0 to 2; ability to give signed informed consent; pretreatment hemoglobin greater than 10 g/dL, WBC count greater than 3 x 109/L, and platelets greater than 100 x 1012/L; adequate renal function with chromium-51 (51Cr)–EDTA 60 mL/min or greater; and adequate liver function tests not more than two times normal unless caused by metastatic disease. Patients who had serious uncontrolled concomitant medical illness were excluded. Patients were recruited from May 1995 to November 1998 from six centers: the Royal Marsden Hospital, London; Kent Cancer Centre, Maidstone; Imperial Cancer Research Fund Medical Oncology Unit, Churchill Hospital, Oxford; Aberdeen Royal Infirmary, Aberdeen; St George’s Hospital, London; and Royal Bournemouth Hospital, Bournemouth.
Treatment Regimen No formal dose reduction was prescribed for hematologic toxicity or neutropenic fever, but treatment was delayed for 1 week if peripheral leucocyte count was less than 3 x 109/L, or platelets were less than 100 x 109/L. Patients with active infection at the time of second or subsequent courses were treated with antibiotics for 5 days, with a treatment delay of 1 week. Treatment was continued until the development of progressive disease, unacceptable toxicity, or to a maximum of three or six cycles (depending on randomization) in patients achieving objective response and/or symptomatic relief. Patients relapsing off treatment were allowed the option of restarting MVP if clinically appropriate.
Pretreatment Investigations
Assessment of Toxicity
Assessment of Objective Response
Assessment of Symptomatic Response
Quality of Life
Randomization Procedure
End Points and Statistical Considerations
The patient characteristics of the two treatment arms were compared by means of the Quality of life was summarized by five functional scales including physical functioning and emotional health, a global health status, and symptom scales (fatigue, nausea and vomiting, cough, pain, and dyspnea) as described in the EORTC QLQ-C30 scoring manual. All scales ranged from 0 to 100, with a high score representing better functioning and global health and a higher level of symptomatology. The mean values of each of the scales were plotted at 3-weekly intervals. For each patient, the AUC was calculated separately for two time periods (0 to 9 weeks to represent the effect of courses 1 to 3, and weeks 9 to 18 to represent the effects of courses 4 to 6 or no treatment). The AUCs were found to be normally distributed, and hence the treatment groups were compared by means of the two-sample t test.
Ethical Considerations
Patient Characteristics A total of 308 patients were entered onto the trial between May 1995 and November 1998 (310 were randomized but two turned out to be ineligible on further histologic evaluation and have been excluded from the analysis: one patient had malignant melanoma and one had a gastrointestinal primary tumor). Two hundred two eligible patients were male and 106 were female. Median age was 63 years (range, 27 to 82 years). PS was as follows: three patients PS 0, 224 patients PS 1, and 81 patients PS 2. One hundred forty-one patients were stage IIIB and 167 were stage IV. Twenty-two patients had relapsed after surgery, 53 patients had received previous radiotherapy to the chest, five patients had received CNS radiotherapy, and 20 patients had received radiotherapy for bony disease. Details including histologic subtypes are given in Table 1. There were no significant differences between the treatment arms.
Outcome After Randomization One hundred fifty-five patients were randomized to receive three courses of chemotherapy and 153 to receive six courses. The number of patients treated at each course is given in Table 2. Usually, treatment was discontinued because of evidence of objective or symptomatic progression, and in a minority because of toxicity or patient preference. Table 2 shows that very similar numbers in the two groups continued to course 2 (136 v 135 patients), and to course 3 (111 v 112 patients). For the 155 patients randomized to three courses, 111 patients (72%) completed treatment, including one erroneously given a fourth course. In the 153 patients randomized to six courses, 112 (73%) completed three courses, 87 (57%) completed four courses, 61 completed (40%) five courses, and 48 (31%) completed six courses.
Sixty-two patients were 70 years or older, of whom 35 were randomized to three courses and 27 to six. There was no significant difference in completion rates in this subgroup compared with younger patients.
Survival
Time to Disease Progression Median time to disease progression was 5 months for both arms (P = .4) ( Fig 3). Likewise, there was no significant difference in time to disease progression for the 178 patients "eligible" for treatment beyond three courses, as described above (P = .2).
Objective Response All patients except three stopping early for toxicity were included for assessment of objective response. Of 154 assessable patients randomized to three courses, one achieved CR and 46 PR (overall response rate [RR], 31%; 95% confidence interval [CI], 23% to 38%). Of 151 assessable patients randomized to six courses, after three courses two had achieved CR and 46 PR (overall RR, 32%; 95% CI, 24% to 39%). After six courses, three had achieved CR and 55 PR (overall RR, 38%; 95% CI, 31% to 46%). The difference in final response rate between three and six courses was not significant (P = .2). Median duration of response was 7 months (three courses) versus 8 months (six courses) (P = .2), and 22% had continuing response at 1 year (three courses) versus 23% (six courses). Likewise there was no significant difference in median response duration for the 178 patients "eligible" for treatment beyond three courses, as described above (P = .2)
Symptomatic Response Time to symptom progression is given in Fig 4. Median time to progression was 4 months for three courses versus 4.5 months for six courses (P = .7). Eleven percent (three courses) remained free of symptom progression at 1 year compared with 19% (six courses) (P = .7). Duration of symptom relief is given in Fig 5. Median duration of symptom relief was 4.5 months for both arms and 8% versus 18% had continuing symptom relief at 1 year (P = .4).
Exclusion of PS 2 Patients Patients with WHO PS 2 were eligible for inclusion in this study on the basis of our previous experience that PS 2 patients treated with MVP also have a chance of clinical benefit, although less so than those with PS 0 to 1.20 Recent practice elsewhere has, however, tended to exclude patients with PS 2 from phase III chemotherapy trials.21 Eighty-one patients were PS 2 at the start of treatment. When these are excluded from the analysis, there remains no difference in survival (P = .5) ( Fig 6), time to disease progression (P = .8), or response duration (P = .6) between three and six courses of treatment.
Quality of Life Quality-of-life parameters assessed at 3-week intervals until 18 weeks are shown graphically in Fig 7 using the following parameters: physical functioning, emotional well-being, global health, nausea and vomiting, fatigue, cough, dyspnea, and pain. As anticipated, no differences emerged between the two groups for the first 9 weeks (three courses). Subsequently, from weeks 9 to 18, patients randomized to continue on chemotherapy had significantly increased fatigue (P = .03) and a strong trend toward increased nausea and vomiting (P = .06). No correlation was found between increased fatigue and decline in hemoglobin levels. There was a nonsignificant trend toward improved global health, physical functioning, and emotional well-being in those randomized to three courses.
Toxicity Treatment-related toxicities are listed in Table 3 and are scored for worst toxicity, subgrouped as follows: (1) patients randomized to three courses of treatment, (2) courses 1 to 3 of patients randomized to six courses, and (3) courses 4 to 6 of patients randomized to six courses. These show that chemotherapy was in general well tolerated. There was no evidence for a significant increase in toxicity during courses 4 to 6 except for anemia; in contrast, constipation was significantly less (P = .005). Of patients receiving four or more courses, none required a dose reduction because of toxicity, one had a dose delay (1 week), and four stopped because of subjective toxicity. Toxicity was not formally measured after stopping chemotherapy in those randomized to three courses, but it is a reasonable assumption that most toxicities including infection, nausea, vomiting, mucositis, and diarrhea would be absent or at least much less than in those continuing treatment.
Relapse Off Treatment At the time of analysis, three patients randomized to three courses received further MVP on relapse, of whom one responded. Four patients randomized to six courses similarly received further MVP on relapse, of whom one responded.
Most studies on chemotherapy for advanced NSCLC use at least six courses of treatment,3,5,9-12 and some state that treatment should be continued indefinitely until disease progression.1,2,8,13 Current ongoing trials are continuing the same policy.22 Only one recent large trial of which we are aware explicitly restricted treatment to four courses.4 Our trial for the first time shows no significant clinical benefit for continuing chemotherapy with the MVP regimen beyond three courses in terms of symptom relief, objective response rate, survival, or quality of life. Indeed, patients randomized to three courses had an overall improvement in quality-of-life measures during the period in which those randomized to six courses were continuing treatment; specifically, a significant improvement was seen in fatigue coupled with a strong trend toward less nausea and vomiting. Global health, physical functioning, and emotional well-being were at least as good in those randomized to receive the shorter duration treatment, and it is a reasonable assumption that patients felt better without the side effects of chemotherapy prolonged for a further three courses. In addition, the potential resource and quality-of-life implications for three courses of chemotherapy compared with six are obvious. We are not aware of other randomized data addressing this issue in NSCLC, although the question has been addressed in other areas including, for example, the treatment of metastatic breast cancer.23 The optimal duration of chemotherapy in phase II trials for advanced NSCLC has been retrospectively assessed on the basis of the time taken to achieve response; the data indicated that more than 80% of patients had achieved response within 12 weeks of commencing treatment and 98% within 24 weeks.24 On the basis of this, the authors questioned the value of continuing phase II chemotherapy treatment beyond 12 weeks in the absence of a response. Although our findings challenge current orthodoxy on treatment duration, they should not be considered conclusive. First, several new drug combinations have been developed against NSCLC that have achieved higher response rates than standard schedules; these include cisplatin and vinorelbine,8 cisplatin and paclitaxel,9,13 cisplatin and gemcitabine,10,11 and carboplatin and paclitaxel.25 So far, however, most of these combinations have failed to show a significant survival advantage. It is possible that more than three courses of treatment with the newer drug combinations may prove of clinical benefit, although this is by no means certain given the modest gains so far. Further trials are required, to address this question. Second, randomization in this trial was on an intent-to-treat basis; in practice, this led to an inevitable fall-off with each course of treatment, usually because of progressive disease, such that only 72% to 73% of patients completed three courses in each arm, and only 31% of those randomized to six courses actually achieved this. This dilutional effect may have masked some benefit for continuation of chemotherapy in patients doing well after three courses. Initially, we had attempted to address this issue by starting a trial with randomization after three courses to stop or continue for a further three; in practice, only four of the first 17 eligible patients accepted randomization, with the remaining 13 wishing to continue chemotherapy.14 At that time patients had the reasonable belief that more of what was doing them good must be better. The results of the current trial argue against this, and might encourage patients to accept randomization after three courses in a future trial developed on the basis of the original design. Such a trial would, however, bring its own problems in terms of defining which subgroup of patients would be appropriate for going forward to randomization. In conclusion, this trial challenges standard practice of six or more courses of chemotherapy for advanced NSCLC. The resource and quality-of-life implications of shorter duration treatment are obvious, and further trials addressing this issue are now warranted.
1. Cormier Y, Bergeron D, La Forge J, et al: Benefits of polychemotherapy in advanced non small cell lung bronchogenic carcinoma. Cancer 50: 845-849, 1982[Medline] 2. Rapp E, Pater JL, Willan A, et al: Chemotherapy can prolong survival in patients with advanced non small cell lung cancer: Report of a Canadian multicentre randomized trial. J Clin Oncol 6: 633-641, 1988[Abstract]
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Non-Small Cell Lung Cancer Collaborative Group: Chemotherapy in non-small cell lung cancer: A meta-analysis using updated data on individual patients from 52 randomized trials. BMJ 311: 899-909, 1995 7. Ellis PA, Smith IE, Hardy JR, et al: Symptom relief with MVP (mitomycin C, vinblastine and cisplatin) chemotherapy in advanced non-small-cell lung cancer. Br J Cancer 71: 366-370, 1995[Medline] 8. Le Chevalier T, Brisgand D, Pujol JL, et al: Randomized study of Navelbine and cisplatin versus vindesine and cisplatin versus Navelbine alone in 612 patients with advanced non-small cell lung cancer (NSCLC). Bull Cancer 83: 385-394, 1996[Medline] 9. Giaccone G, Splinter TA, Debruyne C, et al: Randomized study of paclitaxel-cisplatin versus cisplatin-teniposide in patients with advanced non-small-cell lung cancer: The European Organization for Research and Treatment of Cancer Lung Cancer Cooperative Group. J Clin Oncol 16: 2133-2141, 1998[Abstract]
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Crino L, Scagliotti GV, Ricci S, et al: Gemcitabine and cisplatin versus mitomycin, ifosfamide, and cisplatin in advanced non-small cell lung cancer: A randomized phase III study of the Italian Lung Cancer Project. J Clin Oncol 17: 3522-3530, 1999 12. Kelly K, Crowley J, Bunn PA, et al: A randomized phase III trial of paclitaxel plus carboplatin (PC) versus vinorelbine plus cisplatin (VC) in untreated advanced non-small cell lung cancer (NSCLC): A Southwest Oncology Group (SWOG) trial. Proc Am Soc Clin Oncol 18: 461, 1999 (abstr 1777) 13. Bonomi P, Kim C, Kugler K, et al: Results of a phase III trial comparing taxol-cisplatin (TC) regimens to etoposide-cisplatin (EC) in non-small cell lung cancer (NSCLC). Lung Cancer 18: 10, 1997 (suppl 1, abstr 28) 14. Hickish TF, Smith IE, Middleton G, et al: Patient preference for extended palliative chemotherapy for non-small cell lung cancer. Lancet 345: 857-858, 1995 (letter)[Medline] 15. Miller AB, Hoogstraten B, Staquet M, et al: Reporting results of cancer treatment. Cancer 47: 207-214, 1981[Medline] 16. Kaplan EL, Meier P. Non parametric estimation from incomplete observation. J Am Stat Assoc 53:457-481, 1958
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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 Inst 85: 365-376, 1993 18. Bergman B, Aaronson NK, Ahmedzai S, et al: The EORTC QLQ-LC13: A modular supplement to the EORTC core quality of life questionnaire (QLQ-C30) for use in lung cancer clinical trials. Eur J Cancer 30A: 625-642, 1994 19. Peto R, Pike MC, Armitage P, et al: Design and analysis of randomized clinical trials requiring prolonged observation of each patient: II. Analysis and examples. Br J Cancer 35: 1-39, 1976 20. Hickish T, Smith IE, O’Brien MER, Ashley S, Middleton G: Clinical benefit from palliative chemotherapy in non-small cell lung cancer extends to the elderly and those with poor prognostic factors. Br J Cancer 78: 28-33, 1998[Medline] 21. Schiller JH, Harrington D, Sandler A, et al: A randomized phase III trial of four chemotherapy regimens in advanced non-small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 18: xx, 2000 (abstr 2) 22. CancerNet Physician Data Query, National Cancer Institute. Available at http: //www.hcfa.gov/pdq/pdq_treatment.shtml. Accessed on. 23. Coates A, Gebski V, Bishop JF, et al: Improving quality of life during chemotherapy for advanced breast cancer: A comparison of intermittent and continuous treatment strategies. N Engl J Med 317: 1490-1495, 1987[Abstract]
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Larsen H, Sorensen JB, Nielsen AL, et al: Evaluation of the optimal duration of chemotherapy in phase II trials for inoperable non-small-cell lung cancer (NSCLC). Ann Oncol 6: 993-997, 1995 25. Bunn PA Jr: Defining the role of paclitaxel in lung cancer: Summary of recent studies and implications for future directions. Semin Oncol 24: 153-162, 1997 (suppl 12)[Medline] Submitted June 20, 2000; accepted November 9, 2000. This article has been cited by other articles:
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ABSTRACT
INTRODUCTION
2 test with Yates’ correction of the Mann-Whitney test. Objective and symptomatic response rates were compared by means of the Mann-Whitney test with trend. Response duration and survival were measured from the date of first treatment and survival curves were generated by the method of Kaplan and Meier
) and six courses (
). (A) Global health; (B) physical functioning; (C) emotional well-being; (D) fatigue; (E) nausea and vomiting; (F) cough; (G) dyspnea; (H) pain.
