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© 2000 American Society for Clinical Oncology Phase II Trial of Up-Front Accelerated Thoracic Radiotherapy Combined With Chemotherapy and Optional Up-Front Prophylactic Cranial Irradiation in Limited Small-Cell Lung CancerByFrom the Hôpitaux UniversitairesGeneva, Switzerland, and Centre Hospitalier Universitaire Albert Michallon, Grenoble, France. Address reprint requests to Anne Hügli, MD, Division d’Oncologie, Hôpital Cantonal de Genève, 24 Rue Micheli-du-Crest, 1211 Genève 14, Switzerland; email Anne.Huegli{at}hcuge.ch
PURPOSE: To investigate the feasibility and outcome of bifractionated, up-front thoracic radiotherapy (TR) (45 Gy in 30 fractions of 1.5 Gy twice daily over 3 weeks) combined with chemotherapy (CT) (six cycles of cisplatin and etoposide) and optional low-dose, up-front prophylactic cranial irradiation (18 Gy in 10 fractions of 1.8 Gy twice daily over 5 days) in limited small-cell lung cancer. PATIENTS AND METHODS: CT (etoposide 100 mg/m2 for 3 days and cisplatin 25 mg/m2 for 3 days) was started on day 8 or 15 after the first TR treatment. In the five subsequent cycles, cisplatin was given as a single 100-mg/m2 dose on day 1 every 4 weeks. A total of 52 patients were entered (41 men and 11 women); the median age was 55 years (range, 33 to 67 years). World Health Organization performance status was 0 in 34 patients, 1 in 16 patients, and 2 in two patients. Thirty-six patients (69%) received the full planned six cycles of CT. RESULTS: All treated patients were assessable for response. Thirty-one patients (60%) achieved a complete response, and 16 (30%) had a partial response. One-, 3-, and 4-year survival rates were 74% (95% confidence interval [CI], 60% to 84%), 34% (95% CI, 21% to 49%), and 32% (95 CI, 16% to 46%), respectively. The median survival time was 18 months. Event-free survival at 1 year was 45% (95% CI, 32% to 58%) and at 3 years, 30% (95% CI, 18% to 44%). The main radiation-related acute toxicity was esophageal: 38% of the patients experienced grade 3 or 4 acute toxicity. CT was well tolerated. Although grade 3/4 neutropenia was observed in 86% of the patients, only 4% presented with associated fever. Grade 3/4 nausea and vomiting was seen in 35% of patients. CONCLUSION: This trial demonstrates that up-front accelerated TR associated with CT is feasible, has acceptable toxicity, and shows considerable long-term survival potential.
IN LIMITED-DISEASE small-cell lung cancer, thoracic radiotherapy (TR) combined with chemotherapy (CT) improves local control and survival compared with CT alone.1-2 In recent years, a search for optimal timing between systemic treatment and TR has been undertaken in order to improve response rates and lower toxicity. Concurrent versus sequential chemoradiotherapy schedules have been tested.3-8 Further studies have involved TR given early in the treatment program compared with TR given toward the end of CT.9-12 A recent randomized study showed that accelerated (twice-daily) TR (45 Gy) starting simultaneously with the first cycle of CT improved survival rates when compared with the same total dose given in single daily fractions.13 The rational for early use of TR is based on the hypothesis that it could decrease the risk of dissemination of otherwise potentially drug-resistant cells, thus increasing chances of cure, as long as it does not compromise systemic treatment. So far, this hypothesis remains to be proven. The trial presented here is the second of two studies that were started in the 1980s to test the potential benefits of up-front TR before CT. An improved tumor response was expected as a consequence of two mechanisms: first, optimally avoiding the potential induction of radioresistant clones resulting from up-front CT,14 and second, associating the first cycle of CT with TR in the phase of putative higher tumor-cell proliferation rate (ie, week 2 to week 3 after starting TR).15,16 The first study, involving 29 patients, delivered 20 Gy (twice-daily schedule, over 1 week) of up-front TR 1 week before the start of CT (six cycles of cisplatin, doxorubicin, and etoposide).17,18 Excellent results were obtained despite the "low" TR dose, ie, 96% overall response rate and 31% survival rate at 6 years (95% confidence interval [CI], 16% to 50%). In view of these good results and excellent tolerance, a second trial was undertaken using a more standard dose of TR (45 Gy in twice-daily fractions), with part of the dose being given up front. Feasibility, tolerance, and cure potential were assessed. In addition, low-dose, up-front, accelerated prophylactic cranial irradiation (PCI) (18 Gy) was optional. The results of this study are reported in this article.
Between July 1993 and May 1998, 52 previously untreated patients with histologically or cytologically documented limited small-cell lung cancer were included in this study. Patients characteristics are described in Table 1.
Limited-stage disease was defined as tumor confined to one hemithorax with or without hilar and/or mediastinal and/or supraclavicular nodes and at least one measurable or assessable lesion. Patients with either pleural or pericardial effusions were excluded. Additional inclusion criteria were age less than 70 years, World Health Organization (WHO) performance status of 0 to 2, and adequate hematologic and renal function (ie, WBC count > 3,000/µL, platelet count > 100,000/µL, and serum creatinine level < 130 µmol/L). Adequate pulmonary function with a forced expiratory volume greater than 1.5 L was required. Initial staging included a clinical examination, complete blood count, serum chemistry analysis (electrolyte, AST, ALT, alkaline phosphatase, bilirubin, glucose, and albumin levels), an ECG, pulmonary function tests, chest x-ray, thoracic computed tomographic scan, bronchoscopy, biopsy, liver ultrasound or abdominal computed tomographic scan, isotopic bone scan, and brain computed tomographic scan. The planned 20-week treatment program started with a 3-week period of up-front external TR, with CT starting with the second (ie, day 8) or third week (ie, day 15) of TR (Fig 1). In one center, optional up-front, low-dose PCI was given to 19 patients during the first week of TR and CT was started on day 15; in the other center, no PCI was delivered and CT was started on day 8. A total TR dose of 45 Gy was delivered in 30 fractions (1.5 Gy/fraction twice a day, 5 d/wk for 3 weeks). A total PCI dose of 18 Gy was delivered in 10 fractions (1.8 Gy/fraction twice a day over a 5-day period). The interval between daily fractions was at least 6 hours for both TR and PCI. It was planned that TR would be administered to the existing gross disease (primary and nodal) as defined in the chest x-ray and thoracic computed tomographic scan images at diagnosis. The treatment volume included the gross disease with a 2- to 3-cm margin of normal surrounding tissue. Standard simulation and two-dimensional planning were recommended. During the first 2 weeks, TR was delivered with the patient in a supine position with a set of two anterior and posterior, parallel, and opposed fields. An off-cord technique with a pair of oblique fields to the same target volume was used for the third week of TR. Radiotherapy of megavoltage quality (ie, cobalt-60 or 4- to 10-MV x-rays) was used. PCI was delivered to the whole brain and meninges with two lateral, parallel, and opposed fields. The inferior field margin generously included the base of the skull down to the C2/C3 interspace.
All patients received CT with etoposide and cisplatin every 21 days for six courses. The first cycle, with concurrent TR, was planned to deliver a daily dose of cisplatin 25 mg/m2 intravenously and etoposide 100 mg/m2 intravenously on days 1, 2, and 3. For the five subsequent cycles, cisplatin 100 mg/m2 was given only on day 1 while the dose and administration schedule of etoposide was left unchanged. In case of neutropenia less than 2,000/µL, thrombocytopenia less than 100,000/µL, esophagitis greater than grade 2, and serum creatinine levels greater than 130 µmol/L on day 1 of each subsequent cycle, a 1-week treatment delay was allowed. If toxicity lasted for 2 weeks or longer, a dose reduction was undertaken or treatment was stopped completely in agreement with each center’s policy. Patients were monitored for radiation-induced acute toxicity (WHO–Eastern Cooperative Oncology Group criteria) weekly during the treatment interval and at 6 and 12 weeks thereafter. Weekly blood tests were performed during the CT interval, and the worst toxicity was scored. Nonhematologic toxicity was also graded according to the WHO criteria for each cycle, and the worst grade was reported. Late toxicity was evaluated every month during the first year after TR and every 3 months thereafter. Response was evaluated at day 21 and after every two cycles of CT with a chest x-ray. A thoracic computed tomographic scan was performed, in addition to the chest x-ray, at treatment completion (or interruption). Response was evaluated according to WHO standard criteria. No patient was lost to follow-up, performed on December 15th, 1998. The first site of relapse was either locoregional or distant. A distinction between CNS and non-CNS distant treatment failures was made.
Statistical Analysis
Treatment Delivery All patients but one received TR as planned, without cessation or interruption. A lung abscess after 28.5 Gy was the reason for a definitive interruption of TR in this one patient. He was subsequently operated upon, and no tumor was found in the pneumonectomy specimen. This patient remains disease-free 4 years later. Thirty-six patients (69%) received the full planned six cycles of CT. Seven patients (13%) received at least four cycles. Reasons for CT interruption were fear of potential neurotoxicity in one patient who presented with a paraneoplastic neuropathy at diagnosis and who obtained a complete response after two cycles, tumor progression in two patients, and toxicity in four (one patient with WHO grade 2 esophagitis, one with WHO grade 1 infection, one with polyneuropathy, and one with bone marrow toxicity). Nine patients (17%) received less than four CT cycles for the following reasons: one experienced disease progression while on treatment; two had an early polyneuropathy and received a CT regimen without cisplatin; one patient underwent bilobectomy after three cycles of CT (the resection specimen was tumor-free), and one patient had only three cycles of CT for unknown reasons (at his last follow-up, 19 months after the diagnosis, he remained in complete remission). The remaining four patients died during treatment (one patient died with cytomegalovirus colitis after the first cycle, one died in status epilepticus after two cycles [he had not received PCI], one had a lethal hemoptysis after two cycles on day 67 of the treatment [a pathologic examination was not performed, so disease progression v toxicity could not be assessed], and one committed suicide after three cycles). Cisplatin was reduced to less than 90% of the planned dosage in 36% of the patients who received six cycles of treatment and in one patient who received less than six cycles. Etoposide was reduced to less than 90% of the planned dosage in 11% of the patients who received six cycles of treatment and in none of the others. CT was started on day 8 in 28 patients and on day 15 in 22. It was delayed to day 48 in one patient because of radiation-induced grade 3 esophagitis and to day 54 in the patient with the lung abscess treated by surgery. No differences in toxicity or efficacy were observed among the patients who started their treatment on day 8 or day 15.
Toxicity
CT was well tolerated. Although, grade 3/4 neutropenia was observed in 87% of patients, only 4% presented with associated fever. Grade 3/4 nausea and vomiting were seen in 35% of patients. Because of peripheral polyneuropathy and ototoxicity, two patients had to be switched to a non–cisplatin-based regimen. A mean weight loss of 3.4 kg (ranging from an 8-kg gain to a 28-kg loss) was observed. Fifty percent of this population had weight variations ranging from a gain of 0.6 kg to a loss of 7 kg.
Response
Survival and Pattern of Failure
The combined TR and CT regimen presented above proved to be effective in successfully treating patients with limited-stage small-cell lung cancer, yielding a 90% response rate and a 4-year survival rate of 32%. Compared with CT alone, combined treatment has been shown to significantly reduce the local failure rate and to have a beneficial effect, though modest, on survival.1,2 Finding the optimal timing of TR and CT may provide further improvements in survival. There are data supporting the principle of giving TR early in the treatment schedule rather than at the end of the CT program.9-12 This may imply that early use of radiotherapy decreases the chances of dissemination of drug-resistant cells, thereby positively influencing survival. In addition, twice-a-day accelerated TR given early has been tested in limited-disease small-cell lung cancer with the objective of overcoming tumor repopulation by shortening the overall treatment time. This issue has been studied in a randomized trial comparing twice-daily with once-daily fractions which demonstrated that bifractionated TR had a significantly favorable impact on survival at the dose levels compared.13 As mentioned above, our group previously tested up-front TR,17,18 an approach whose feasibility and efficacy are also addressed in the present trial. Both schedules aimed to avoid CT cross-resistance and to deliver simultaneous TR and CT during the phase of accelerated repopulation thought to occur 7 to 15 days after the beginning of radiotherapy.15,16 Both trials have shown good feasibility and good long-term results (31% overall survival at 6 years for the first study and 32% at 4 years for the present study). Similar local failure rates were observed in both studies (12% in the first study and 13% in the present one). However, in our previous study, acute toxicity was less marked. With 20 Gy, no cases of severe radiation-induced esophagitis or lung toxicity were observed. In the present study, severe acute esophageal toxicity (grade 3 or 4) was observed in 38% of patients, a rate similar to the 32% esophageal acute toxicity reported in the accelerated TR arm of Turrisi et al’s randomized trial13 cited above. Increasing the TR dose from 20 Gy to 45 Gy seemed to induce more toxicity without modifying long-term survival. With regard to CT regimens, cisplatin plus etoposide was shown in randomized trials to be superior to non–platinum-based regimens and less toxic than cyclophosphamide, doxorubicin, and vincristine.23 Anthracyclines could not be safely combined with standard-dose TR.24,25 We therefore changed regimens between our first and second study: platinum, doxorubicin, and vincristine (PAV) were replaced by the etoposide-platinum (EP) combination. Nevertheless, it could be highlighted that with 20-Gy up-front TR followed by PAV, no acute or late lung and skin toxicities were observed. Whether 20-Gy TR followed by PAV is similar to 20-Gy TR followed by EP remains questionable. Nowadays, EP is considered the standard regimen in limited small-cell lung cancer. Four cycles of CT, as given by Turrisi et al,13 are probably sufficient, although there are no randomized data comparing four and six cycles. PCI has been shown to significantly reduce CNS disease progression,26-28 and a recently published meta-analysis has suggested an additional benefit in improving survival in this disease.29 Unfortunately, a high CNS late morbidity may be expected, mainly as a result of the use of large radiation fractions and the additive effect of CT.30,31 The timing between the two treatments may be even more critical in this regard.32 Animal studies have shown that cranial irradiation can alter the permeability of the blood-brain barrier for polar substances.33 We reasoned that low-dose PCI early in the treatment schedule before the start of CT may increase the permeability of the blood-brain barrier to CT products but at the same time avoid the synergistic mechanisms of toxicity. As for TR, a larger antitumor effect might also be expected from the irradiation of tumor cells before exposure to the potential cross-resistance–inducing effect of up-front CT. In the present study, among patients who received 18 Gy of PCI, a statistically nonsignificant reduction in brain recurrences was observed and no long-term toxicity was seen. In conclusion, delivery of TR twice daily up front in combination with cisplatin and etoposide CT is feasible and has a marked curative potential. Nevertheless, increasing the TR dose from 20 to 45 Gy may not necessarily improve long-term survival but certainly increases toxicity. Whether up-front TR at a lower dosage is associated with a more favorable therapeutic ratio should be tested in a randomized trial. Up-front PCI to 18 Gy preceding CT may have further curative potential with minimal or no toxicity. This issue should also be investigated in a phase III trial.
1. Warde P, Payne D: Does thoracic irradiation improve survival and local control in limited-stage small-cell carcinoma of the lung? A meta-analysis. J Clin Oncol 10:890-895, 1992[Abstract] 2. Pignon JP, Arriagada R, Ihde DC, et al: A meta-analysis of thoracic radiotherapy for small-cell lung cancer. N Engl J Med 327:1618-1624, 1992[Abstract] 3. McCracken JD, Janaki LM, Crowley JJ, et al: Concurrent chemotherapy/radiotherapy for limited small-cell lung carcinoma: A Southwest Oncology Group study. J Clin Oncol 8:892-898, 1990[Abstract]
4.
Johnson DH, Bass D, Einhorn LH, et al: Combination chemotherapy with or without thoracic radiotherapy in limited-stage small-cell lung cancer: A randomized trial of the Southeastern Cancer Study Group. J Clin Oncol 11:1223-1229, 1993
5.
Johnson DH, Turrisi AT, Chang AY, et al: Alternating chemotherapy and twice-daily thoracic radiotherapy in limited-stage small-cell lung cancer: A pilot study of the Eastern Cooperative Oncology Group. J Clin Oncol 11:879-884, 1993
6.
Johnson BE, Bridges JD, Sobczeck M, et al: Patients with limited-stage small-cell lung cancer treated with concurrent twice-daily chest radiotherapy and etoposide/cisplatin followed by cyclophosphamide, doxorubicin, and vincristine. J Clin Oncol 14:806-813, 1996 7. Gregor A, Drings P, Burghouts J, et al: Randomized trial of alternating versus sequential radiotherapy/chemotherapy in limited-disease patients with small-cell lung cancer: A European Organization for Research and Treatment of Cancer Lung Cancer Cooperative Group study. J Clin Oncol 15:2840-2849, 1997[Abstract] 8. Nielsen OS, Fode K, Bentzen SM, et al: Timing of radiotherapy and chemotherapy in limited stage small cell lung cancer: Final Analysis. Eur J Cancer 27:182, 1994 (suppl 2) (abstr)
9.
Murray N, Coy P, Pater JL, et al: Importance of timing for thoracic irradiation in the combined modality treatment of limited-stage small-cell lung cancer. J Clin Oncol 11:336-344, 1993 10. Perry MC, Eaton WL, Propert KJ, et al: Chemotherapy with or without radiation therapy in limited small-cell carcinoma of the lung. N Engl J Med 316:912-918, 1987[Abstract] 11. Perry MC, Herndon JE III, Eaton WL, et al: Thoracic radiation therapy added to chemotherapy for small-cell lung cancer: An update of Cancer and Leukemia Group B study 8083. J Clin Oncol 16:2466-2467, 1998[Abstract] 12. Work E, Nielsen OS, Bentzen SM, et al: Randomized study of initial versus late chest irradiation combined with chemotherapy in limited-stage small-cell lung cancer. J Clin Oncol 15:3030-3037, 1997[Abstract]
13.
Turrisi AT, Kim K, Blum R, et al: Twice-daily compared with once-daily thoracic radiotherapy in limited small-cell lung cancer treated concurrently with cisplatin and etoposide. N Engl J Med 340:265-271, 1999 14. Nishio K, Nakamura T, Koh Y, et al: Drug resistance in lung cancer. Curr Opin Oncol 11:109-115, 1999[Medline] 15. Fowler JF: The phantom of tumor treatment: Continually rapid proliferation unmasked. Radiother Oncolol 22:156-158, 1991 16. Trott KR, Kummermehr J: Accelerated repopulation in tumors and normal tissues. Radiother Oncol 22:159-160, 1991[Medline]
17.
Bonnefoi H, Zulian G, Mirimanoff RO, et al: Priming low-dose chest radiotherapy followed by CT for small-cell lung cancer. Ann Oncol 5:771-772, 1994 18. Hösli P, Bonnefoi H, Mirimanoff RO, et al: Effect of low-dose chest irradiation before chemotherapy on rate of local failure in small-cell lung cancer. Int J Radiat Oncol Biol Phys 41:287-289, 1998[Medline] 19. Kaplan EL, Meier P: Nonparametric estimation for incomplete observations. J Am Stat Assoc 53:457-481, 1958 20. Dorey FJ, Korn EL: Effective sample size for confidence intervals for survival probabilities. Stat Med 6:679-687, 1987[Medline] 21. Rothman KJ: Simulation of confidence limits for the cumulative probability of survival in life table analysis. J Chron Dis 76:312-319, 1978 22. Efron B: Censored data and the bootstrap. J Am Stat Assoc 76:312-319, 1981
23.
Fukuoka M, Furuse K, Saijo N, et al: Randomized trial of cyclophosphamide, doxorubicin, and vincristine versus cisplatin and etoposide versus alternation of these regimens in small-cell lung cancer. J Natl Cancer Inst 83:855-861, 1991 24. Perez CA, Einhorn L, Oldham RK, et al: Randomized trial of radiotherapy to the thorax in limited small-cell carcinoma of the lungtreated with multiagent chemotherapy and elective brain irradiation: A preliminary report. J Clin Oncol 2:1200-1208, 1984[Abstract] 25. Greco FA, Brereton HD, Kent H, et al: Adriamycin and enhanced radiation reaction in normal esophagus and skin. Ann Intern Med 85:294-298, 1976 26. Gregor A, Cull A, Stephens RJ, et al: Prophylactic cranial irradiation is indicated following complete response to induction therapy in small cell lung cancer: Results of a multicentre randomised trial—United Kingdom Coordinating Committee for Cancer Research (UKCCCR) and the European Organization for Research and Treatment of Cancer. Eur J Cancer 33:1752-1758, 1997
27.
Arriagada R, Le Chevalier T, Borie F, et al: Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. J Natl Cancer Inst 87:183-190, 1995
28.
Shaw EG, Su JQ, Eagan RT, et al: Prophylactic cranial irradiation in complete responders with small-cell lung cancer: Analysis of the Mayo Clinic and North Central Cancer Treatment Group data base. J Clin Oncol 12:2327-2332, 1994
29.
Aupérin A, Arriagada R, Pignon JP, et al: Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. N Engl J Med 341:476-484, 1999 30. Lee JS, Umsawasadi T, Lee YY, et al: Neurotoxicity in long-term survivors of small cell lung cancer. Int J Radiat Oncol Biol Phys 12:313-320, 1986[Medline] 31. Fleck JF, Einhorn LH, Lauer RC, et al: Is prophylactic cranial irradiation indicated in small cell lung cancer? J Clin Oncol 8:209-214, 1990[Abstract] 32. Turrisi AT, Glover DJ: Thoracic radiotherapy variables: Influence on local control in small cell lung cancer limited disease. Int J Radiat Oncol Biol Phys 19:1473-1479, 1990[Medline] 33. Griffin TW, Rasey JS, Bleyer WA: The effect of photon irradiation on blood-brain barrier permeability to methotrexate in mice. Cancer 40:1109-1111, 1977 Submitted July 29, 1999; accepted December 15, 1999.
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Copyright © 2000 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
) was given for a total of 18 Gy in 10 fractions (1.8 Gy/fraction twice a day). Chest radiotherapy (
) was given for a total of 45 Gy in 30 fractions (1.5 Gy/fraction twice a day, 5 days a week for 3 weeks). CT (
) consisted of cisplatin 25 mg/m2 intravenously on days 1, 2, and 3 and etoposide 100 mg/m2 on days 1, 2, and 3 (for cycle 1) and cisplatin 100 mg/m2 intravenously on day 1 and etoposide 100 mg/m2 on days 1, 2, and 3 (for cycles 2 through 6).
