- Email: [email protected]
Phase II study of hyperfractionated radiotherapy and concurrent weekly alternating chemotherapy in limited-stage small cell lung cancer
Lung Cancer 22 (1998) 39 – 44
Phase II study of hyperfractionated radiotherapy and concurrent weekly alternating chemotherapy in limited-stage small cell lung cancer Muhammad A. Ali a, Michael J. Kraut a, Manuel Valdivieso a, Arnold M. Herskovic b, Wei Du a, Gregory P. Kalemkerian a,* a b
Department of Internal Medicine, Wayne State Uni6ersity and the Barbara Ann Karmanos Cancer Institute, Detroit, MI, USA Department of Radiation Oncology, Wayne State Uni6ersity and the Barbara Ann Karmanos Cancer Institute, Detroit, MI, USA Received 26 April 1998; received in revised form 20 July 1998; accepted 25 August 1998
Abstract Despite recent advances in combined modality therapy, long-term survival remains elusive in most patients with limited-stage small cell lung cancer (SCLC). The present study was designed to evaluate the activity and toxicity of concurrent hyperfractionated radiotherapy and weekly, alternating-regimen chemotherapy. Twelve patients with limited-stage SCLC and performance status 0-1 were treated with cyclophosphamide 250 mg/m2, etoposide 100 mg/m2, and cisplatin 50 mg/m2 on day 1 every other week, and vincristine 1 mg/m2 on day 8, and ifosfamide 1.2 mg/m2 on days 8 and 9 every other week. Hyperfractionated thoracic radiotherapy, consisting of three daily doses of 1.1 Gy for 20 days to a total dose of 66 Gy, was started on day 1 of chemotherapy. Ten patients (83%) exhibited an objective response (9 CRs and 1 PR) with a median duration of response of 8.6 months. Two complete responders died at 50 and 53 months without evidence of progression and two remain alive and free of SCLC at 73 and 87 months. Median survival was 19.8 months with 2- and 5-year survival rates of 50 and 17%, respectively. Severe toxicity, including grade 3–4 esophagitis (67%) and granulocytopenia (83%), as well as debilitating fatigue and pneumonitis, prompted early termination of the trial. Hyperfractionated radiotherapy and concurrent weekly alternating-regimen chemotherapy resulted in promising response and survival rates, but induced excessive toxicity, in patients with limited-stage SCLC. © 1998 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Small cell lung cancer; Chemotherapy; Radiotherapy; Hyperfractionation; Combined modality therapy; Experimental therapeutics
* Corresponding author. Present address: Harper Hospital, Hudson 5, 3990 John R, Detroit, MI, 48201, USA. Tel.: +1 313 7452357; fax: + 1 313 9930559; e-mail: [email protected] 0169-5002/98/$ - see front matter © 1998 Elsevier Science Ireland Ltd. All rights reserved. PII S0169-5002(98)00064-6
40
M.A. Ali et al. / Lung Cancer 22 (1998) 39–44
1. Introduction Small cell lung cancer (SCLC) is characterized by early metastatic potential with only one-third of patients presenting with limited-stage disease. Although SCLC is responsive to initial therapy, most patients relapse and die with treatment-resistant disease. In limited-stage disease, treatment with combination chemotherapy plus thoracic radiation therapy results in an overall response rate of 80–95%, with a five-year survival rate of 15 – 20% [1]. A variety of chemotherapy strategies employing alternating non-cross-resistant or doseintense regimens have been studied in an attempt to improve the outcome of patients with SCLC. We previously demonstrated that outpatient weekly chemotherapy with etoposide, doxorubicin, cyclophosphamide, and vincristine was both effective and well-tolerated in patients with SCLC [2]. The present study was designed to build on this experience by adding two active agents, ifosfamide and cisplatin, in a weekly alternating schedule, and eliminating doxorubicin, in order to minimize toxicity during concurrent irradiation. Two recent meta-analyses confirmed a significant survival benefit for patients with limited-stage SCLC receiving both radiation and chemotherapy [3,4], with early concurrent regimens appearing to be superior to sequential regimens [5]. Hyperfractionated radiotherapy schemes have been developed to reduce the toxicity of combined-modality therapy and have yielded impressive preliminary results [6]. In addition, early data from a trial of single-modality hyperfractionated radiotherapy in non-SCLC suggested less toxicity with three daily dose fractions [7]. Based on these data, the current study was designed to evaluate the activity and toxicity of weekly alternating-regimen chemotherapy plus three fraction/day hyperfractionated radiotherapy in patients with limited-stage SCLC.
2. Patients and methods
2.1. Patients Patients with histologically documented limited-stage SCLC were entered onto the study be-
tween May 1990 and August 1992. Staging consisted of a bone scan, bilateral bone marrow biopsies, and CT scans of the chest, abdomen, and brain. Limited-stage SCLC was defined as disease confined to one hemithorax including hilar, mediastinal, and ipsilateral supraclavicular lymph nodes. Eligibility criteria also included: Zubrod performance status 0–2; expected survival of at least 8 weeks; no history of invasive malignancy within 5 years; WBC \ 3.0× 103/dl; platelets \ 100×103/dl; serum creatinine B 1.5 mg/dl; and no prior radiation or chemotherapy. All patients signed a written informed consent approved by the local institutional review board.
2.2. Treatment plan All patients were treated with hyperfractionated radiotherapy and weekly alternating chemotherapy as outlined in Table 1. Patients were hydrated with 1 l of saline +mannitol 12.5–25 mg IV before and after cisplatin. Mesna 240 mg/m2 IV was administered immediately prior to and 4 h after each dose of ifosfamide, and an oral dose of Mesna 480 mg/m2 was given 8 h. after each dose of ifosfamide. Hyperfractionated radiotherapy was started on day 1 of the first week of chemotherapy and continued 5 days per week for 20 days to a total dose of 66 Gy to the primary tumor and 44 Gy to the mediastinum and involved lymph nodes (Table 1). The large radioTable 1 Treatment plan Day
Treatment
1
Cyclophosphamide 250 mg/m2 Etoposide 100 mg/m2 Cisplatin 50 50 mg/m2
Â Ã Ì Ã Repeat every other week Å
8
Ifosfamide 1.2 gm/m2 Vincristine 1 mg/m2 Ifosfamide 1.2 gm/m2
Â Ã Ì Repeat every other week à Å
9 1–20
Radiotherapy (Gy) 08.00 h-large field 1.1 Â Ã 12.00 h-small field 1.1 Ì Monday–Friday each week 16.00 h-large field 1.1 Ã Å
M.A. Ali et al. / Lung Cancer 22 (1998) 39–44
therapy field encompassed the ipsilateral supraclavicular and bilateral mediastinal and hilar lymph nodes, and was treated with 1.1 Gy twice a day by oblique fields with at least 8 h between fractions. The small field was defined as the radiographically-visible primary tumor with a margin of 1.0–1.5 cm without encompassing any part of the spinal cord or esophagus, and was treated with 1.1 Gy once a day at least 4 h from any large field treatment. The maximum allowed dose to the spinal cord was 50 Gy and to the esophagus was 60 Gy. Patients were evaluated radiographically for response every 4 weeks. Patients who achieved a complete response (CR) received chemotherapy for 26 weeks or until progression, while patients who achieved a partial response (PR) were treated with chemotherapy until progression of disease. Response was defined as follows: CR, complete disappearance of all clinical evidence of tumor for a minimum of 4 weeks; PR, 50% or greater decrease in the product of the diameters of measured lesions for at least 4 weeks without an increase in size of any area of known disease or appearance of new areas of disease; and progression, increase of at least 50% in the size of any lesion, appearance of new lesions, or clearly progressive skeletal involvement documented by bone scan. Duration of response was defined as the first documentation of response until the first sign of relapse. Survival was measured from the start of treatment until date of death or last follow-up. The distribution of overall survival was estimated by the method of Kaplan and Meier [8] and median survival was calculated directly from the survival curve by linear interpolation. Toxicity was evaluated according to the common toxicity criteria. A two-stage design was utilized to allow early termination of the study if excessive toxicity occurred.
3. Results
3.1. Patient characteristics and treatment The 12 patients with limited-stage SCLC who were entered onto the study had a median age of 67 years (range, 54– 73) and 67% were male. All
41
Table 2 Toxicity Common toxicity criteria grade
Leukopenia Neutropenia Anemia Thrombocytopenia Infection/fever Esophagitis Mucositis Nausea/vomiting Pneumonitis Neurologic Dermatitis
1
2
3
4
— — 1 6 — — — — — 4 9
1 2 5 1 1 4 5 8 1 1 2
7 7 4 — — 4 3 1 — 2 1
4 3 — 1 — 4 4 1 1 — —
patients were smokers and all had a pre-treatment performance status of 0–1 with only two (17%) reporting greater than 10% weight loss. The mean and median duration of weekly alternating chemotherapy was 17 weeks (range 6–20). Three patients (25%) were treated for 6–12 weeks, three (25%) for 14–16 weeks, and six (50%) for 18–20 weeks. Eleven patients (92%) had treatment delayed due to toxicity and seven patients (59%) had dose reductions of 25 (five patients) or 50% (two patients).
3.2. Toxicity The major toxicities were myelosuppression and esophagitis (Table 2). Grade 3–4 leukopenia and granulocytopenia occurred in 11 (92%) and ten (83%) patients, respectively. Grade 3–4 non-hematologic toxicity consisted primarily of esophagitis and mucositis, occurring in eight (67%) and seven (58%) patients, respectively, during the combined-modality phase of therapy. This excessive esophageal toxicity led to the termination of the study after completion of the first stage of accrual. All patients experienced debilitating fatigue which resulted in discontinuation of therapy in ten patients (83%) prior to completion of the planned 26 weeks of chemotherapy. The other two patients progressed prior to week 26. Symptomatic radiation pneumonitis was noted in two patients within 2 months of completion of irradia-
42
M.A. Ali et al. / Lung Cancer 22 (1998) 39–44
tion and contributed to the death of one patient. One patient developed acute myelogenous leukemia (AML) at 53 months.
3.3. Response and sur6i6al Ten patients (83%) exhibited an objective response, 9 (75%) with a CR and one (8%) with a PR. The median duration of response was 8.6 months. Five patients relapsed after achieving an initial CR, three with brain metastases and two with local recurrence. None of the responders received prophylactic cranial irradiation. Three responders died without evidence of progression: one of myocardial infarction after 50 months in CR; one in an automobile accident after 53 months in CR, and shortly after the diagnosis of AML; and one of pneumonitis and heart failure after 3 months in PR. The latter patient represents the only case of treatment-related mortality in this study. Two patients remain alive without evidence of recurrent SCLC at 73 and 87 months. One of these patients underwent resection of a second primary squamous cell lung carcinoma at 4 years and then developed a locally-advanced third primary adenocarcinoma of the lung at 7 years. The median survival for all 12 patients was 19.8 months, and 1, 2, and 5 year overall survival rates were 67, 50, and 17%, respectively.
4. Discussion In the present study, weekly alternating-regimen chemotherapy with concurrent hyperfractionated radiotherapy resulted in overall and complete response rates of 83 and 75%, respectively, and a median survival of 19.8 months in previously untreated patients with limited-stage SCLC. Although the interpretation of response and survival data in this trial are limited by the small sample size, our results appear to be comparable to those of prior combined-modality regimens in this population. Current standard therapy in patients with limited-stage SCLC produces overall response rates of 80 – 95%, with complete response rates of 50 – 60%, median survival times of 12–20 months, and 2 year disease-free survival
rates of 15–40%. The fact that most patients still relapse and die from treatment-resistant disease has led to the development of treatment strategies utilizing alternating-regimen chemotherapy and dose-intense drug delivery. Goldie and Coldman hypothesized that the development of drug-resistant clones could be minimized by early exposure to as many active agents as possible [9]. However, in clinical trials, increasing the number of drugs usually required significant dose reductions of active agents. Strategies employing alternating noncross-resistant regimens were developed to avoid this problem and maximize drug delivery [10]. Although this approach has resulted in increased toxicity, improvements in survival have not been clearly demonstrated [11]. The benefit of thoracic radiation therapy in limited-stage SCLC has recently been confirmed in two meta-analyses that revealed a small, but statistically significant, improvement in overall survival with combined-modality therapy [3,4]. However, combined-modality therapy also increased the incidence and severity of esophageal, pulmonary, and hematologic toxicity, leading to the development of hyperfractionated radiation therapy schemes aimed at reducing the toxicity and increasing local control. Phase I and II trials of hyperfractionated radiotherapy have yielded impressive results with relatively low toxicity [12– 14], and a recent phase III trial has suggested a survival advantage in limited-stage SCLC [15]. The high risk of second primary malignancies in long-term survivors of SCLC has been well documented [16–18]. In the present study, one long-term survivor developed two subsequent non-SCLCs and another patient developed secondary AML. The risk of secondary leukemia after treatment for SCLC appears to be related to prolonged exposure to alkylating agents, and possibly to radiation therapy [19]. Although the current regimen was not prolonged, it did contain two alkylators along with etoposide and radiation therapy, all of which have leukemogenic potential. In the present study, the concurrent use of weekly alternating chemotherapy in combination with hyperfractionated radiotherapy yielded favorable response and survival results, at the expense of excessive treatment-related morbidity. A
M.A. Ali et al. / Lung Cancer 22 (1998) 39–44
recent trial of hyperfractionated radiation plus carboplatin and etoposide resulted in a 2% incidence of pneumonitis and a 27% incidence of grade 3–4 esophagitis with a low rate of grade 4 toxicity [20]. The high rate and grade of esophageal toxicity in the present trial was likely due to the concurrent use of large radiation fields and intensive chemotherapy. Despite attempts to minimize esophageal exposure by use of a smallfield midday dose and a relatively low total mediastinal dose, the short interval between doses dictated by a three dose per day schedule may have critically limited normal tissue recovery time and contributed to toxicity. Similarly, pneumonitis may have been exacerbated by the large field size and short dosing interval used in this trial. Future studies of combined-modality approaches utilizing accelerated or hyperfractionated radiotherapy should consider the use of limited fields encompassing involved sites and should incrementally intensify chemotherapy in a phase I-type fashion to avoid the excessive toxicity observed in this trial.
Acknowledgements The authors are grateful to Dr Mary L. Varterasian for review of the manuscript, Daryn Smith for statistical assistance, and the Charlotte A. Woody Lung Cancer Research Fund for continued support.
References [1] Ihde DC. Small cell lung cancer: state of the art therapy 1994. Chest 1995;107:243S–8S. [2] Valdivieso M, Wozniak A, Flaherty L, Pazdur R, Herskovic A, Heilbrun L, Redman B, Martino S, Baker L. Efficacy of weekly chemotherapy for small cell lung cancer (Abstr.). Proc Am Soc Clin Oncol 1990;9:238. [3] Pignon JP, Arriagada R, Ihde DC, Johnson DH, Perry MC, Souhami RL, Brodin O, Joss RA, Kies MS, Lebeau B, Onoshi T, Østerlind K, Tattersall MHN, Wagner H. A meta-analysis of thoracic radiotherapy for small-cell lung cancer. New Engl J Med 1992;327:1618–24. [4] Warde P, Payne D. Does thoracic irradiation improves survival and local control in limited-stage SCLC? A metaanalysis. J Clin Oncol 1992;10:890–5.
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[5] Murray N, Coy P, Pater JL, Hodson I, Arnold A, Zee BC, Payne D, Kostashuk EC, Evans WK, Dixon P, Sadura A, Feld R, Levitt M, Wierzbicki R, Ayoub J, Maroun JA, Wilson KS. Importance of timing for thoracic irradiation in the combined modality treatment of limited-stage small-cell lung cancer. J Clin Oncol 1993;11:336 – 44. [6] Johnson BE, Bridges JD, Sobczeck M, Gray J, Linnoila RI, Gazdar AF, Hankins L, Steinberg SM, Edison M, Frame JN, Pass H, Nesbitt J, Holden D, Mulshine JL, Glatstein E, Ihde DC. Patients with limited-stage smallcell lung cancer treated with concurrent twice-daily chest radiotherapy and etoposide/cisplatin followed by cyclophosphamide, doxorubicin, and vincristine. J Clin Oncol 1996;14:806 – 13. [7] Herskovic A, Orton C, Seyedsadr M, Lattin P, Kraut M, Han I, Han S, Ahmad K, Holt J. Initial experience with a practical hyperfractionated accelerated radiotherapy regimen. Int J Radiat Oncol Biol Phys 1991;21:1275 – 81. [8] Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Statist Assoc 1958;53: 457 – 81. [9] Goldie JH, Coldman AJ. A mathematical model for relating sensitivity of tumors to their spontaneous mutation rate. Cancer Treat Rep 1979;63:1727 – 33. [10] Tayler CW, Crowley J, Williamson SK, Miller TP, Taylor SA, Giri TGS, Stephens RL, Livingston RB. Treatment of small cell lung cancer with an alternating chemotherapy regimen given at weekly intervals: a Southwest oncology group pilot study. J Clin Oncol 1990;8:1811 – 7. [11] Sculier JP, Paesmans M, Bureau G, Dabouis G, Libert P, Vandermoten G, Van Cutsem O, Berchier MC, Ries F, Michel J, Sergysels R, Mommen P, Klastersky J. Multiple-day weekly chemotherapy versus standard combination regimens in small cell lung cancer: a phase III randomized study conducted by the European lung cancer working party. J Clin Oncol 1993;11:1858 – 65. [12] Johnson D, Turrisi A, Chang A, Blum R, Bonomi P, Ettinger D, Wagner H. Alternating chemotherapy and twice daily thoracic radiotherapy in limited-stage SCLC: a pilot study of the eastern co-operative oncology group. J Clin Oncol 1993;11:879 – 84. [13] Mornex F, Trillet V, Chauvin F, Ardiet JM, Schmitt T, Romestaing P, Carrie C, Mahe M, Mornex JF, Fournel P, Souquet PJ, Boniface E, Vincent M, Piperno D, Rebattu P, Gerard JP. Hyperfractionated radiotherapy alternating with multi-drug chemotherapy in the treatment of limited small-cell lung cancer. Int J Radiat Oncol Biol Phys 1990;19:23 – 30. [14] Turrisi A, Glover D, Mason B. A preliminary report: concurrent twice daily radiotherapy plus platinumetoposide chemotherapy for limited small cell lung cancer. Int J Radiat Oncol Biol Phys 1988;15:183 – 7. [15] Turrisi A, Kim K, Sause W, Komaki R, Wagner H, Aisner S, Livingston R, Blum R, Johnson D. Observationa after 5 year follow-up of Intergroup trial 0096: 4 cycles of cisplatin, etoposide, and concurrent 45 Gy tho-
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racic radiotherapy given in daily or twice-daily fractions. (Abstr.). Proc Am Soc Clin Oncol 1998;17:457a. [16] Østerlind K, Hansen HH, Hansen M, Dombernowsky P. Mortality and morbidity in long-term surviving patients treated with chemotherapy with or without irradiation for small-cell lung cancer. J Clin Oncol 1986;4:1044–52. [17] Heyne KH, Lippman SM, Lee JJ, Lee JS, Hong WK. The incidence of second primary tumors in long-term survivors of small-cell lung cancer. J Clin Oncol 1992;10:1519 – 24. [18] Richardson GE, Tucker MA, Venzon DJ, Linnoila I, Phelps R, Phares JC, Edison M, Ihde DC, Johnson BE. Smoking cessation after successful treatment of small-cell
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lung cancer is associated with fewer smoking-related second primary cancers. Ann Intern Med 1993;119:383 – 90. [19] Sagman U, Lishner M, Maki E, Sheperd FA, Haddad R, Evans WK, DeBoer G, Payne D, Pringle JF, Yeoh JL, Ginsberg R, Feld R. Second primary malignancies following diagnosis of small cell lung cancer. J Clin Oncol 1992;10:1525 – 33. [20] Jeremic B, Shibamoto Y, Acimovic L, Milisavljevic S. Initial versus delayed accelerated hyperfractionated radiation therapy and concurrent chemotherapy in limited small-cell lung cancer: a randomized study. J Clin Oncol 1997;15:893 – 900.
Phase II study of hyperfractionated radiotherapy and concurrent weekly alternating chemotherapy in limited-stage small cell lung cancer Muhammad A. Ali a, Michael J. Kraut a, Manuel Valdivieso a, Arnold M. Herskovic b, Wei Du a, Gregory P. Kalemkerian a,* a b
Department of Internal Medicine, Wayne State Uni6ersity and the Barbara Ann Karmanos Cancer Institute, Detroit, MI, USA Department of Radiation Oncology, Wayne State Uni6ersity and the Barbara Ann Karmanos Cancer Institute, Detroit, MI, USA Received 26 April 1998; received in revised form 20 July 1998; accepted 25 August 1998
Abstract Despite recent advances in combined modality therapy, long-term survival remains elusive in most patients with limited-stage small cell lung cancer (SCLC). The present study was designed to evaluate the activity and toxicity of concurrent hyperfractionated radiotherapy and weekly, alternating-regimen chemotherapy. Twelve patients with limited-stage SCLC and performance status 0-1 were treated with cyclophosphamide 250 mg/m2, etoposide 100 mg/m2, and cisplatin 50 mg/m2 on day 1 every other week, and vincristine 1 mg/m2 on day 8, and ifosfamide 1.2 mg/m2 on days 8 and 9 every other week. Hyperfractionated thoracic radiotherapy, consisting of three daily doses of 1.1 Gy for 20 days to a total dose of 66 Gy, was started on day 1 of chemotherapy. Ten patients (83%) exhibited an objective response (9 CRs and 1 PR) with a median duration of response of 8.6 months. Two complete responders died at 50 and 53 months without evidence of progression and two remain alive and free of SCLC at 73 and 87 months. Median survival was 19.8 months with 2- and 5-year survival rates of 50 and 17%, respectively. Severe toxicity, including grade 3–4 esophagitis (67%) and granulocytopenia (83%), as well as debilitating fatigue and pneumonitis, prompted early termination of the trial. Hyperfractionated radiotherapy and concurrent weekly alternating-regimen chemotherapy resulted in promising response and survival rates, but induced excessive toxicity, in patients with limited-stage SCLC. © 1998 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Small cell lung cancer; Chemotherapy; Radiotherapy; Hyperfractionation; Combined modality therapy; Experimental therapeutics
* Corresponding author. Present address: Harper Hospital, Hudson 5, 3990 John R, Detroit, MI, 48201, USA. Tel.: +1 313 7452357; fax: + 1 313 9930559; e-mail: [email protected] 0169-5002/98/$ - see front matter © 1998 Elsevier Science Ireland Ltd. All rights reserved. PII S0169-5002(98)00064-6
40
M.A. Ali et al. / Lung Cancer 22 (1998) 39–44
1. Introduction Small cell lung cancer (SCLC) is characterized by early metastatic potential with only one-third of patients presenting with limited-stage disease. Although SCLC is responsive to initial therapy, most patients relapse and die with treatment-resistant disease. In limited-stage disease, treatment with combination chemotherapy plus thoracic radiation therapy results in an overall response rate of 80–95%, with a five-year survival rate of 15 – 20% [1]. A variety of chemotherapy strategies employing alternating non-cross-resistant or doseintense regimens have been studied in an attempt to improve the outcome of patients with SCLC. We previously demonstrated that outpatient weekly chemotherapy with etoposide, doxorubicin, cyclophosphamide, and vincristine was both effective and well-tolerated in patients with SCLC [2]. The present study was designed to build on this experience by adding two active agents, ifosfamide and cisplatin, in a weekly alternating schedule, and eliminating doxorubicin, in order to minimize toxicity during concurrent irradiation. Two recent meta-analyses confirmed a significant survival benefit for patients with limited-stage SCLC receiving both radiation and chemotherapy [3,4], with early concurrent regimens appearing to be superior to sequential regimens [5]. Hyperfractionated radiotherapy schemes have been developed to reduce the toxicity of combined-modality therapy and have yielded impressive preliminary results [6]. In addition, early data from a trial of single-modality hyperfractionated radiotherapy in non-SCLC suggested less toxicity with three daily dose fractions [7]. Based on these data, the current study was designed to evaluate the activity and toxicity of weekly alternating-regimen chemotherapy plus three fraction/day hyperfractionated radiotherapy in patients with limited-stage SCLC.
2. Patients and methods
2.1. Patients Patients with histologically documented limited-stage SCLC were entered onto the study be-
tween May 1990 and August 1992. Staging consisted of a bone scan, bilateral bone marrow biopsies, and CT scans of the chest, abdomen, and brain. Limited-stage SCLC was defined as disease confined to one hemithorax including hilar, mediastinal, and ipsilateral supraclavicular lymph nodes. Eligibility criteria also included: Zubrod performance status 0–2; expected survival of at least 8 weeks; no history of invasive malignancy within 5 years; WBC \ 3.0× 103/dl; platelets \ 100×103/dl; serum creatinine B 1.5 mg/dl; and no prior radiation or chemotherapy. All patients signed a written informed consent approved by the local institutional review board.
2.2. Treatment plan All patients were treated with hyperfractionated radiotherapy and weekly alternating chemotherapy as outlined in Table 1. Patients were hydrated with 1 l of saline +mannitol 12.5–25 mg IV before and after cisplatin. Mesna 240 mg/m2 IV was administered immediately prior to and 4 h after each dose of ifosfamide, and an oral dose of Mesna 480 mg/m2 was given 8 h. after each dose of ifosfamide. Hyperfractionated radiotherapy was started on day 1 of the first week of chemotherapy and continued 5 days per week for 20 days to a total dose of 66 Gy to the primary tumor and 44 Gy to the mediastinum and involved lymph nodes (Table 1). The large radioTable 1 Treatment plan Day
Treatment
1
Cyclophosphamide 250 mg/m2 Etoposide 100 mg/m2 Cisplatin 50 50 mg/m2
Â Ã Ì Ã Repeat every other week Å
8
Ifosfamide 1.2 gm/m2 Vincristine 1 mg/m2 Ifosfamide 1.2 gm/m2
Â Ã Ì Repeat every other week à Å
9 1–20
Radiotherapy (Gy) 08.00 h-large field 1.1 Â Ã 12.00 h-small field 1.1 Ì Monday–Friday each week 16.00 h-large field 1.1 Ã Å
M.A. Ali et al. / Lung Cancer 22 (1998) 39–44
therapy field encompassed the ipsilateral supraclavicular and bilateral mediastinal and hilar lymph nodes, and was treated with 1.1 Gy twice a day by oblique fields with at least 8 h between fractions. The small field was defined as the radiographically-visible primary tumor with a margin of 1.0–1.5 cm without encompassing any part of the spinal cord or esophagus, and was treated with 1.1 Gy once a day at least 4 h from any large field treatment. The maximum allowed dose to the spinal cord was 50 Gy and to the esophagus was 60 Gy. Patients were evaluated radiographically for response every 4 weeks. Patients who achieved a complete response (CR) received chemotherapy for 26 weeks or until progression, while patients who achieved a partial response (PR) were treated with chemotherapy until progression of disease. Response was defined as follows: CR, complete disappearance of all clinical evidence of tumor for a minimum of 4 weeks; PR, 50% or greater decrease in the product of the diameters of measured lesions for at least 4 weeks without an increase in size of any area of known disease or appearance of new areas of disease; and progression, increase of at least 50% in the size of any lesion, appearance of new lesions, or clearly progressive skeletal involvement documented by bone scan. Duration of response was defined as the first documentation of response until the first sign of relapse. Survival was measured from the start of treatment until date of death or last follow-up. The distribution of overall survival was estimated by the method of Kaplan and Meier [8] and median survival was calculated directly from the survival curve by linear interpolation. Toxicity was evaluated according to the common toxicity criteria. A two-stage design was utilized to allow early termination of the study if excessive toxicity occurred.
3. Results
3.1. Patient characteristics and treatment The 12 patients with limited-stage SCLC who were entered onto the study had a median age of 67 years (range, 54– 73) and 67% were male. All
41
Table 2 Toxicity Common toxicity criteria grade
Leukopenia Neutropenia Anemia Thrombocytopenia Infection/fever Esophagitis Mucositis Nausea/vomiting Pneumonitis Neurologic Dermatitis
1
2
3
4
— — 1 6 — — — — — 4 9
1 2 5 1 1 4 5 8 1 1 2
7 7 4 — — 4 3 1 — 2 1
4 3 — 1 — 4 4 1 1 — —
patients were smokers and all had a pre-treatment performance status of 0–1 with only two (17%) reporting greater than 10% weight loss. The mean and median duration of weekly alternating chemotherapy was 17 weeks (range 6–20). Three patients (25%) were treated for 6–12 weeks, three (25%) for 14–16 weeks, and six (50%) for 18–20 weeks. Eleven patients (92%) had treatment delayed due to toxicity and seven patients (59%) had dose reductions of 25 (five patients) or 50% (two patients).
3.2. Toxicity The major toxicities were myelosuppression and esophagitis (Table 2). Grade 3–4 leukopenia and granulocytopenia occurred in 11 (92%) and ten (83%) patients, respectively. Grade 3–4 non-hematologic toxicity consisted primarily of esophagitis and mucositis, occurring in eight (67%) and seven (58%) patients, respectively, during the combined-modality phase of therapy. This excessive esophageal toxicity led to the termination of the study after completion of the first stage of accrual. All patients experienced debilitating fatigue which resulted in discontinuation of therapy in ten patients (83%) prior to completion of the planned 26 weeks of chemotherapy. The other two patients progressed prior to week 26. Symptomatic radiation pneumonitis was noted in two patients within 2 months of completion of irradia-
42
M.A. Ali et al. / Lung Cancer 22 (1998) 39–44
tion and contributed to the death of one patient. One patient developed acute myelogenous leukemia (AML) at 53 months.
3.3. Response and sur6i6al Ten patients (83%) exhibited an objective response, 9 (75%) with a CR and one (8%) with a PR. The median duration of response was 8.6 months. Five patients relapsed after achieving an initial CR, three with brain metastases and two with local recurrence. None of the responders received prophylactic cranial irradiation. Three responders died without evidence of progression: one of myocardial infarction after 50 months in CR; one in an automobile accident after 53 months in CR, and shortly after the diagnosis of AML; and one of pneumonitis and heart failure after 3 months in PR. The latter patient represents the only case of treatment-related mortality in this study. Two patients remain alive without evidence of recurrent SCLC at 73 and 87 months. One of these patients underwent resection of a second primary squamous cell lung carcinoma at 4 years and then developed a locally-advanced third primary adenocarcinoma of the lung at 7 years. The median survival for all 12 patients was 19.8 months, and 1, 2, and 5 year overall survival rates were 67, 50, and 17%, respectively.
4. Discussion In the present study, weekly alternating-regimen chemotherapy with concurrent hyperfractionated radiotherapy resulted in overall and complete response rates of 83 and 75%, respectively, and a median survival of 19.8 months in previously untreated patients with limited-stage SCLC. Although the interpretation of response and survival data in this trial are limited by the small sample size, our results appear to be comparable to those of prior combined-modality regimens in this population. Current standard therapy in patients with limited-stage SCLC produces overall response rates of 80 – 95%, with complete response rates of 50 – 60%, median survival times of 12–20 months, and 2 year disease-free survival
rates of 15–40%. The fact that most patients still relapse and die from treatment-resistant disease has led to the development of treatment strategies utilizing alternating-regimen chemotherapy and dose-intense drug delivery. Goldie and Coldman hypothesized that the development of drug-resistant clones could be minimized by early exposure to as many active agents as possible [9]. However, in clinical trials, increasing the number of drugs usually required significant dose reductions of active agents. Strategies employing alternating noncross-resistant regimens were developed to avoid this problem and maximize drug delivery [10]. Although this approach has resulted in increased toxicity, improvements in survival have not been clearly demonstrated [11]. The benefit of thoracic radiation therapy in limited-stage SCLC has recently been confirmed in two meta-analyses that revealed a small, but statistically significant, improvement in overall survival with combined-modality therapy [3,4]. However, combined-modality therapy also increased the incidence and severity of esophageal, pulmonary, and hematologic toxicity, leading to the development of hyperfractionated radiation therapy schemes aimed at reducing the toxicity and increasing local control. Phase I and II trials of hyperfractionated radiotherapy have yielded impressive results with relatively low toxicity [12– 14], and a recent phase III trial has suggested a survival advantage in limited-stage SCLC [15]. The high risk of second primary malignancies in long-term survivors of SCLC has been well documented [16–18]. In the present study, one long-term survivor developed two subsequent non-SCLCs and another patient developed secondary AML. The risk of secondary leukemia after treatment for SCLC appears to be related to prolonged exposure to alkylating agents, and possibly to radiation therapy [19]. Although the current regimen was not prolonged, it did contain two alkylators along with etoposide and radiation therapy, all of which have leukemogenic potential. In the present study, the concurrent use of weekly alternating chemotherapy in combination with hyperfractionated radiotherapy yielded favorable response and survival results, at the expense of excessive treatment-related morbidity. A
M.A. Ali et al. / Lung Cancer 22 (1998) 39–44
recent trial of hyperfractionated radiation plus carboplatin and etoposide resulted in a 2% incidence of pneumonitis and a 27% incidence of grade 3–4 esophagitis with a low rate of grade 4 toxicity [20]. The high rate and grade of esophageal toxicity in the present trial was likely due to the concurrent use of large radiation fields and intensive chemotherapy. Despite attempts to minimize esophageal exposure by use of a smallfield midday dose and a relatively low total mediastinal dose, the short interval between doses dictated by a three dose per day schedule may have critically limited normal tissue recovery time and contributed to toxicity. Similarly, pneumonitis may have been exacerbated by the large field size and short dosing interval used in this trial. Future studies of combined-modality approaches utilizing accelerated or hyperfractionated radiotherapy should consider the use of limited fields encompassing involved sites and should incrementally intensify chemotherapy in a phase I-type fashion to avoid the excessive toxicity observed in this trial.
Acknowledgements The authors are grateful to Dr Mary L. Varterasian for review of the manuscript, Daryn Smith for statistical assistance, and the Charlotte A. Woody Lung Cancer Research Fund for continued support.
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