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Phase II Study of Etoposide and Cisplatin With Concurrent Twice-Daily Thoracic Radiotherapy Followed by Irinotecan and Cisplatin in Patients With Limited-Disease Small-Cell Lung Cancer: West Japan Thoracic Oncology Group 9902

Hiroshi Saito, Yoshiki Takada, Yukito Ichinose, Kenji Eguchi, Shinzoh Kudoh, Kaoru Matsui, Kazuhiko Nakagawa, Minoru Takada, Shunichi Negoro, Kenji Tamura, Masahiko Ando, Takuhito Tada, Masahiro Fukuoka

From the Department of Respiratory Medicine, Aichi Cancer Center Aichi Hospital, Okazaki, Aichi; Departments of Thoracic Oncology and Respiratory Medicine, Hyogo Medical Center for Adults, Akashi, Hyogo; Department of Thoracic Oncology, National Hospital Organization Kyushu Cancer Center, Fukuoka; Department of Internal Medicine, National Hospital Organization Shikoku Cancer Center, Matsuyama, Ehime; Department of Respiratory Medicine, Osaka City University Hospital; Department of Thoracic Malignancy, Osaka Prefectural Medical Center for Respiratory and Allergic Diseases, Habikino; Department of Medical Oncology, Kinki University School of Medicine, Osakasayama; Department of Pulmonary Medicine, Rinku General Medical Center, Izumisano; Department of Radiology, Osaka Prefectural Medical Center for Respiratory and Allergic Diseases, Habikino, Osaka; Department of Medical Oncology, Kinki University School of Medicine, Nara Hospital, Ikoma, Nara; and the Health Service, Kyoto University, Kyoto, Japan

Address reprint requests to Hiroshi Saito, MD, Department of Respiratory Medicine, Aichi Cancer Center Aichi Hospital, 18 Kuriyado Kake-machi, Okazaki Aichi 444-0011, Japan; e-mail: hsaito{at}sun-inet.or.jp

	ABSTRACT

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Purpose: We initially conducted a randomized phase II study to compare irinotecan and cisplatin (IP) versus irinotecan, cisplatin, and etoposide (IPE) after etoposide and cisplatin (EP) with concurrent twice-daily thoracic radiotherapy (TRT) in limited-disease small-cell lung cancer (LD-SCLC). We amended the protocol to evaluate IP after EP with concurrent twice-daily TRT in a single-arm phase II study because of an unacceptable toxicity in IPE.

Patients and Methods: Previously untreated patients with LD-SCLC were treated intravenously with etoposide 100 mg/m² on days 1 through 3 and cisplatin 80 mg/m² on day 1 with concurrent twice-daily TRT (1.5 Gy per fraction, a total dose of 45 Gy) beginning on day 2 followed by three cycles of irinotecan 60 mg/m² on days 1, 8, and 15 and cisplatin 60 mg/m² on day 1 of a 4-week cycle.

Results: Of the 51 patients enrolled, 49 patients were assessable for response and toxicity. The overall response rate and complete response rate were 88% and 41%, respectively. The median survival time for all patients was 23 months. The 2-year and 3-year survival rates were 49% and 29.7%, respectively. The median progression-free survival was 11.8 months. The major toxicities observed were neutropenia (grade 4, 84%), febrile neutropenia (grade 3, 31%), infection (grade 3 to 4, 33%), electrolytes imbalance (grade 3 to 4, 20%), and diarrhea (grade 3 to 4, 14%).

Conclusion: EP with concurrent twice-daily TRT followed by the consolidation of IP appears to be an active regimen which deserves further phase III testing in patients with LD-SCLC.

	INTRODUCTION

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Small-cell lung cancer (SCLC), which accounts for approximately 15% of all lung cancer cases, is clinically categorized as the two stages, limited disease and extensive disease. Two meta-analyses have shown the combined modality of chemotherapy and thoracic radiotherapy (TRT) to improve the survival of patients with limited-disease (LD-) SCLC in comparison to chemotherapy alone.^1,2 The schedule, dose, and fractionation of TRT have previously been examined in patients with LD-SCLC in several randomized controlled studies.^3-7 On the basis of the results of these studies, etoposide and cisplatin (EP) with concurrent twice-daily TRT is currently a standard care for the treatment for LD-SCLC. However, the 5-year survival rate is less than 30%, and most patients experience a relapse of the primary tumor or distant metastasis.^3-6 To further improve the therapeutic efficacy, one approach is to develop a new chemoradiotherapy regimen incorporating with a novel active agent.

Irinotecan hydrochloride, a camptothecin derivative, is among the most active chemotherapeutic agents against SCLC with a response rate of 37% as a single agent.⁸ A randomized phase III study revealed that irinotecan and cisplatin (IP) was superior to EP in patients with extensive-disease SCLC (ED-SCLC).⁹ However, the role of IP in the treatment of LD-SCLC remains to be defined. To clarify the role of this combination regimen in LD-SCLC, we initially conducted a randomized phase II study to compare two consolidation chemotherapy regimens, IP versus irinotecan, cisplatin and etoposide (IPE), after EP with concurrent twice-daily TRT in LD-SCLC.¹⁰ However, EP with concurrent twice-daily TRT followed by IPE was not feasible because of unacceptable toxicity including grade 4 neutropenia (92%), grade 4 diarrhea (25%), grade 4 infection (25%) and one treatment-related death. We therefore amended the protocol to evaluate EP with concurrent twice-daily TRT followed by consolidation therapy with IP in a single-arm phase II study and herein report the results of this study.

	PATIENTS AND METHODS

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Eligibility Criteria
Patients with histologically or cytologically confirmed LD-SCLC (stage I disease was excluded) were eligible for this study. A limited stage was defined as disease confined to one hemithorax, the mediastinum, and the bilateral supraclavicular area. Cases with a small amount of pleural effusion and a negative cytology were included in the limited-stage group. Other eligibility criteria included the following: no prior chemotherapy or radiotherapy; measurable disease; Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2; age between 20 and 70 years; life expectancy of at least 3 months; adequate baseline organ function defined as leukocyte count ranging from 4,000 to 12,000/mm³, hemoglobin concentration of at least 9.5 g/dL, platelet count at least 100,000/mm³, AST and ALT 2.0x the upper limit of the normal range (ULN) or less, serum total bilirubin 1.5 mg/dL or less, serum creatinine ULN or less, 24-hour creatinine clearance of at least 60 mL/min, and PaO₂ at rest of at least 70 mmHg. The radiation portal should be equal or less than half of one lung.

The patients were ineligible if they had the following criteria: interstitial pneumonitis or pulmonary fibrosis; other respiratory diseases that precluded TRT; malignant pleural effusion or malignant pericardial effusion; active concomitant or a recent (< 3 years) history of any malignancy; uncontrolled angina pectoris, myocardial infarction less than 3 months before the enrollment or congestive heart failure; uncontrolled diabetes mellitus or hypertension; severe infection; intestinal paralysis or obstruction; pregnancy or lactation; or other serious concomitant medical conditions. The study protocol was approved by each institutional review board for clinical use. All patients gave their written informed consent before enrollment.

Study Evaluation
The pretreatment baseline evaluation included a complete medical history and physical examination, a CBC, blood chemistry studies, flexible bronchoscopy, electrocardiography, chest radiography, computed tomography of the chest, computed tomography or ultrasound study of the abdomen, computed tomography or magnetic resonance imaging of the brain, bone scintigraphy and bone marrow aspiration with or without biopsy. A CBC and blood chemistry studies were repeated every week. At the end of the study, all of these studies except for flexible bronchoscopy and bone marrow aspiration were repeated unless the patient had stable or progressive disease.

Treatment Schedule
The patients initially received induction chemoradiotherapy consisting of etoposide 100 mg/m² on day 1 through 3 and cisplatin 80 mg/m² on day 1 with concurrent twice-daily TRT. After the induction chemoradiotherapy, the patients received three cycles of consolidation chemotherapy consisting of irinotecan 60 mg/m² on days 1, 8, and 15 and cisplatin 60 mg/m² on days 1. Consolidation chemotherapy was repeated every 4 weeks for three cycles.

The first cycle of consolidation chemotherapy was begun 4 week after the initiation of induction chemoradiotherapy if the leukocyte count was at least 4,000/mm³; the platelet count was at least 100,000/mm³; AST and ALT 2.0x ULN or less; serum bilirubin 1.5 mg/dL or less; serum creatinine of ULN or less; the patient did not have fever ( 38°C), diarrhea within the past 24 hours, or intestinal paralysis or obstruction; and PaO₂ of at least 70 mmHg. The subsequent cycle of consolidation chemotherapy was repeated if the leukocyte count was at least 3,500/mm³; the platelet count was at least 100,000/mm³; AST and ALT 2.0x ULN or less; serum bilirubin 1.5 mg/dL or less; serum creatinine ULN or less; the patient did not have fever ( 38°C), diarrhea within the past 24 hours, or intestinal paralysis or obstruction. The use of granulocyte colony-stimulating factor (GCSF) was recommended after day 4. However, its administration was withheld on the day of administration of irinotecan.

TRT was performed with 6 MV or higher photons from a linear accelerator and began on day 2 of the induction chemoradiotherapy. Patients received 1.5 Gy per fraction twice daily with at least a 4-hour interval (preferably a 6-hour interval or more) between each fraction over a 3-week period (a total dose of 45 Gy). A radiation field included the primary tumor, the bilateral mediastinal and ipsilateral hilar lymph nodes with a margin of 1.5 to 2.0 cm. Radiation to the supraclavicular lymph nodes was administered only if they were involved. The inferior border extended 5 cm below the carina or to a level including ipsilateral hilar structures, whichever was lower. After initial irradiation with a dose of 30 Gy, off-cord (ie, the spinal cord was outside the field) oblique boost fields were used. The radiation field in the afternoon was not different from that in the morning. Computed tomography planning was not required and lung density corrections were not performed. Prophylactic cranial irradiation (PCI) was administered to the patients achieving complete response or good partial response with a total dose of 25 Gy in 10 fractions.

Dose Modification
Dose modification based on the toxicity of the induction chemoradiotherapy was not allowed at the time of the first administration of IP. In each cycle of IP, irinotecan on day 8 or 15 was withheld if a leukocyte count of less than 2,000/mm³ or a platelet count of less than 50,000/mm³ was determined, or if a patient had fever ( 38°C) or grade 2 or higher hepatotoxicity or any diarrhea within the last 24 hours or intestinal paralysis or obstruction. In the second and the third cycle of consolidation chemotherapy, the dose modification was made as follows. If a leukocyte nadir count of less than 1,000/mm³ or a neutrophil nadir count of less than 500/mm³ for 3 or more days or if febrile neutropenia developed or if a platelet nadir count of less than 25,000/mm³ was observed or if grade 2 hepatotoxicity or diarrhea was observed, irinotecan was decreased by 10 mg/m² in the subsequent cycle, if grade 2 or lower renal toxicity was observed during the previous course of treatment, only cisplatin decreased by 25%, if grade 3 or higher nonhematologic toxicity (excluding nausea, vomiting, and hair loss) developed, then cisplatin decreased by 25% and irinotecan decreased by 10 mg/m² in the following cycle. The patients were removed from the study if the following toxicities were observed: grade 4 diarrhea; grade 3 or higher renal toxicity or creatinine of at least 2.0 mg/dL; grade 3 or higher hepatotoxicity; grade 2 or higher pulmonary toxicity or PaO₂ at rest less than 60 mmHg.

Evaluation
The Response Evaluation Criteria in Solid Tumors (RECIST) were used for the response assessment.¹¹ Toxicity was evaluated according to the National Cancer Institute–Common Toxicity Criteria (version 2.0). An extramural review was conducted to validate the eligibility of the patients, staging, and response.

Statistical Analysis
The primary end point of this study was the 2-year survival rate. We calculated the sample size based on Fleming’s single-stage design of the phase II study.¹² We set a 2-year survival rate of 35% as a baseline survival rate and 20% as the high level of interest with a power of 0.9 at a one-sided significance level of .05, requiring an accrual of 53 eligible patients. The study was initially begun as a randomized phase II study to compare two consolidation arms, namely IP versus IPE after concurrent chemoradiotherapy. Because of the unacceptable toxicity in the triplet regimen, the study was modified to a single-arm phase II study to evaluate IP after EP with concurrent TRT and 11 patients in the IP arm were included in the analysis of this study.

The duration of survival was measured from the day of entry onto the study, and the overall survival curve and progression-free survival curve were calculated according to the method of Kaplan and Meier.¹³

	RESULTS

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Patients Characteristics
Between February 2000 and November 2002, 51 patients were enrolled onto this study. Table 1 lists the baseline characteristics of the patients. Two patients were considered to be ineligible because a secondary primary tumor was found after the administration of EP with concurrent TRT. Therefore, 49 patients were assessable for response and toxicity.

Response and Survival
On an intention-to-treat basis, the overall response rates and the complete response rates were 88% (95% CI, 78.6% to 96.9%) and 41%, respectively. After a median follow-up of 29.9 months, the median survival time for all patients was 23 months (Fig 1). The 2-year and 3-year survival rates were 49% and 29.7%, respectively. The median progression-free survival was 11.8 months (Fig 2).

View larger version (6K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Kaplan-Meier survival curve of 49 eligible patients with limited-disease small-cell lung cancer. The median survival time was 23 months, and the 2-year and 3-year survival rates were 49% and 29.7%, respectively.

View larger version (7K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Kaplan-Meier progression-free survival curve of 49 eligible patients with limited-disease small-cell lung cancer. The median progression-free survival time was 11.8 months.

	DISCUSSION

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Although a potential approach is to substitute irinotecan for etoposide in the combination of EP with concurrent TRT, we did not combine IP concurrently with TRT because two phase I studies demonstrated that combining IP with concurrent TRT was not feasible when the full dose of irinotecan was administered on days 1, 8, and 15.^16,17 On the basis of these results, we administered IP as consolidation therapy after EP with concurrent twice-daily TRT. After this article was initially submitted, Langer et al¹⁸ reported phase I study of once every 3 weeks scheduling of IP with concurrent twice-daily TRT (45 Gy) or once-daily TRT (70 Gy) in patients with LD-SCLC, thus concluding that IP with concurrent twice-daily TRT was safe and feasible. A further evaluation of this regimen is thus warranted.

One group evaluated IP administered as an induction followed by EP with concurrent twice-daily TRT.¹⁹ Their results are comparable to those of our study and EP with concurrent twice-daily TRT.^3-6 However, this regimen was highly myelotoxic (grade 4 neutropenia, 91%) with febrile neutropenia in 60% of the patients. Furthermore, early TRT is an important issue to obtain the improved outcome in LD-SCLC. Recent meta-analyses revealed that when platinum-based chemotherapy was concurrent with TRT in LD-SCLC, an improved survival was associated with early TRT.^20-22 Another group evaluated the addition of paclitaxel to EP with concurrent TRT.²³ Although their results are comparable to those of our study and EP with concurrent twice-daily TRT,^3-6 they concluded that the triplet regimen would not further improve the survival outcome in patients with LD-SCLC.

Esophagitis is a toxicity of a particular concern in concurrent chemoradiotherapy. We observed grade 3 or 4 esophagitis in one patient (2%), whereas the JCOG9903 trial reported it in 7% of the patients. These figures contrast with those in the studies evaluating etoposide and a platinum with concurrent twice-daily TRT (9% to 32%).^3-7 The substitution of irinotecan for etoposide may reduce the incidence of grade 3 or 4 esophagitis. Furthermore, a lower incidence of esophagitis has been noted in a Japanese trial.⁴ A possible explanation for this includes differences in the chemotherapy interval (once every 4 weeks v once every 3 weeks) and in ethnic background. Neutropenia was the most prominent toxicity in this study and its incidence is higher than that in the Turrisi et al study.³ However, no toxic death resulting from neutropenia was observed. Diarrhea was the most troublesome nonhematologic toxicity of irinotecan and one of the major causes for treatment discontinuation in this study.

Brain metastasis as an initial site of relapse was observed in 33% of our patients. The JCOG9903 trial reported brain metastasis in 37% of their patients. These rates were higher than those in the studies evaluating etoposide and a platinum with concurrent twice-daily TRT.^4,7 The rate of local recurrence solely was observed in only one patient and none in the JCOG9903 trial. This contrasts with the higher rate of distant failure either with or without local failure in these two studies (77% and 67%, respectively). These increased rates of distant failure including brain metastasis may be partly explained by insufficient administration of IP as consolidation.

A limitation of this study is the treatment feasibility. In this study, 53% of the patients completed the entire treatment and 69% received two or more cycles of IP. The respective values were 58% and 73% in the JCOG9903 trial.¹⁴ In contrast, Takada et al reported that 86% of the patients completed the treatment in EP with concurrent twice-daily TRT.⁴ Although the optimal duration of consolidation chemotherapy remains unclear, we consider that at least two cycles of IP is clinically meaningful in view of encouraging survival outcomes in these phase II studies. Whether the relatively low completion rate of IP causes increased distant metastasis and detrimentally affects the outcome will be addressed by the ongoing phase III study. To improve the feasibility, certain supportive measures including the prophylactic GCSF and/or antidiarrheal measures²⁴ and different dose scheduling (eg, 3-weekly scheduling of IP) should be considered in future studies.

In conclusion, EP with concurrent twice-daily TRT followed by the consolidation of IP appears to be active in patients with LD-SCLC, thus supporting the conduct of the currently ongoing phase III study to compare EP with concurrent twice-daily TRT followed by the consolidation of either EP or IP.

	Appendix

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The following principal investigators and institutions also participated in this study: Yasufumi Yamaji, MD, Mitoyo General Hospital, Kagawa; Masashi Yamamoto, MD, Nagoya Ekisaikai Hospital, Aichi; Toshiyuki Sawa, MD, Gifu Municipal Hospital, Gifu; Yoshiro Tanio, MD, OPHO Osaka Prefectural General Hospital, Osaka; Takashi Nakano, MD, Hyogo Medical College, Hyogo; Yoichi Nakanishi, MD, Kyushu University School of Medicine, Fukuoka; Hiroshi Semba, MD, Kumamoto Regional Medical Center, Kumamoto, Japan.

	Authors’ Disclosures of Potential Conflicts of Interest

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The authors indicated no potential conflicts of interest.

	Author Contributions

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... Author Contributions REFERENCES

 

Conception and design: Hiroshi Saito, Shunichi Negoro, Masahiro Fukuoka Administrative support: Masahiro Fukuoka Provision of study materials or patients: Hiroshi Saito, Yoshiki Takada, Yukito Ichinose, Kenji Eguchi, Shinzoh Kudoh, Kaoru Matsui, Kazuhiko Nakagawa, Minoru Takada, Shunichi Negoro, Kenji Tamura, Takuhito Tada, Masahiro Fukuoka Collection and assembly of data: Kazuhiko Nakagawa, Kenji Tamura Data analysis and interpretation: Hiroshi Saito, Kazuhiko Nakagawa, Kenji Tamura, Masahiko Ando Manuscript writing: Hiroshi Saito, Masahiko Ando, Takuhito Tada Final approval of manuscript: Hiroshi Saito, Yoshiki Takada, Yukito Ichinose, Kenji Eguchi, Shinzoh Kudoh, Kaoru Matsui, Kazuhiko Nakagawa, Minoru Takada, Shunichi Negoro, Kenji Tamura, Masahiko Ando, Takuhito Tada, Masahiro Fukuoka

 

	ACKNOWLEDGMENTS

 
We thank Kazumi Kubota for data management and Brian Quinn for his critical review.

	NOTES

 
Presented in part at the 39th Annual Meeting of the American Society of Clinical Oncology, May 31-June 3, 2003, Chicago, IL, and the 40th Annual Meeting of the American Society of Clinical Oncology, June 5-8, 2004, New Orleans, LA.

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

	REFERENCES

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Submitted May 3, 2006; accepted September 7, 2006.

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