LONG-TERM RESULTS OF A PHASE III TRIAL COMPARING ONCE-DAILY RADIOTHERAPY WITH TWICE-DAILY RADIOTHERAPY IN LIMITED- STAGE SMALL-CELL LUNG CANCER

Transcription

1 doi: /j.ijrobp Int. J. Radiation Oncology Biol. Phys., Vol. 59, No. 4, pp , 2004 Copyright 2004 Elsevier Inc. Printed in the USA. All rights reserved /04/$ see front matter CLINICAL INVESTIGATION Lung LONG-TERM RESULTS OF A PHASE III TRIAL COMPARING ONCE-DAILY RADIOTHERAPY WITH TWICE-DAILY RADIOTHERAPY IN LIMITED- STAGE SMALL-CELL LUNG CANCER STEVEN E. SCHILD, M.D.,* JAMES A. BONNER, M.D.,* THOMAS G. SHANAHAN, M.D., BURKE J. BROOKS, M.D., RANDOLPH S. MARKS, M.D.,* SUSAN M. GEYER, PH.D.,* SHAUNA L. HILLMAN, M.S., GIST H. FARR, JR., M.D., HENRY D. TAZELAAR, M.D.,* JAMES E. KROOK, M.D., FRANCOIS J. GEOFFROY, M.D., MUHAMMAD SALIM, M.D., ROBERT M. ARUSELL, M.D., # JAMES A. MAILLIARD, M.D.,** PAUL L. SCHAEFER, M.D., AND JAMES R. JETT, M.D.* *Mayo Clinic and Mayo Foundation, Rochester, MN; Carle Cancer Center CCOP, Urbana, IL; Ochsner CCOP, New Orleans, LA; Duluth CCOP, Duluth, MN; Illinois Oncology Research Association CCOP, Peoria, IL; Saskatchewan Cancer Foundation (Saskatoon Cancer Centre, Saskatoon, Saskatchewan, Canada and Allan Blair Cancer Centre, Regina, Saskatchewan, Canada; # Meritcare Hospital CCOP, Fargo, ND; **Missouri Valley Cancer Consortium, Omaha, NE; Toledo Community Hospital Oncology Program CCOP, Toledo, OH Purpose: This Phase III study was performed to determine whether twice-daily (b.i.d.) radiotherapy (RT) resulted in better survival than once-daily (q.d.) RT for patients with limited-stage small-cell lung cancer (LD-SCLC). Methods and Materials: A total of 310 patients with LD-SCLC initially received three cycles of etoposide and cisplatin. Subsequently, the 261 patients without significant progression were randomized to two cycles of etoposide and cisplatin plus either q.d. RT (50.4 Gy in 28 fractions) or split-course b.i.d. RT (24 Gy in 16 fractions, a 2.5-week break, and 24 Gy in 16 fractions) to the chest. Patients then received a sixth cycle of etoposide and cisplatin followed by prophylactic cranial RT. Results: Follow-up ranged from 4.6 to 11.9 years (median, 7.4 years). The median survival and 5-year survival rate from randomization was 20.6 months and 21% for patients who received q.d. RT compared with 20.6 months and 22% for those who received b.i.d. RT (p 0.68), respectively. No statistically significant differences were found in the rates of progression (p 0.68), intrathoracic failure (p 0.45), in-field failure (p 0.62), or distant failure (p 0.82) between the two treatment arms. No statistically significant difference was found in the overall rate of Grade 3 or worse (p 0.83) or Grade 4 or worse toxicity (p 0.95). Grade 3 or worse esophagitis (p 0.05) was more common in the b.i.d. arm. Grade 5 toxicity occurred in 4 (3%) of 130 patients who received b.i.d. RT compared with 0 (0%) of 131 who received q.d. RT (p 0.04). Conclusion: Although this study did not demonstrate an advantage to split-course b.i.d. RT, the long-term survival was favorable, likely reflecting the positive influences of concurrent combined modality therapy and prophylactic cranial RT Elsevier Inc. Small-cell lung cancer, Dose fractionation, Radiotherapy, Randomized prospective study, Limited stage. Reprints requests to: Steven E. Schild, M.D., Mayo Clinic, Desk R, E. Shea Blvd., Scottsdale, AZ Tel: (480) ; Fax: (480) ; sschild@mayo.edu Presented at the 39th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, June 1, 2003 and the 10th World Conference on Lung Cancer, Vancouver, BC, Aug 11, This study was conducted as a collaborative trial of the North Central Cancer Treatment Group and Mayo Clinic and was supported in part by Public Health Service Grants CA-15083, CA-25224, CA , CA-35269, CA-35113, CA-37417, CA-63849, CA-35415, CA-35195, CA-52352, CA-35103, CA-35448, CA-35272, CA-35101, CA-60276, CA-63848, and CA from the National Cancer Institute, Department of Health and Human Services. Acknowledgments The authors thank Jennifer Frank for her assistance in conducting this study. Additional participating institutions included Cedar Rapids Oncology Project CCOP, Cedar Rapids, IA (Martin Wiesenfeld, M.D.); Siouxland Hematology- Oncology Associates, Sioux City, IA (John C. Michalak, M.D.); Geisinger Clinic & Medical Center CCOP, Danville, PA (Suresh Nair, M.D.); Sioux Community Cancer Consortium, Sioux Falls, SD (Loren K. Tschetter, M.D.); Medcenter One Health Systems, Mid Dakota Clinic, Bismarck, ND (Ferdinand Addo, M.D.); Altru Health Systems, Grand Forks, ND (Tudor Dentchev, M.D.); Iowa Oncology Research Association CCOP, Des Moines, IA (Roscoe F. Morton, M.D.); Rapid City Regional Oncology Group, Rapid City, SD (Larry P. Ebbert, M.D.); CentraCare Clinic, St. Cloud, MN (Harold E. Windschitl, M.D.); Scottsdale CCOP, Scottsdale, AZ (Tom Fitch, M.D.); Michigan Cancer Consortium CCOP, Ann Arbor, MI (Philip J. Stella, M.D.). Received Sep 18, 2003, and in revised form Dec 29, Accepted for publication Jan 7,

2 944 I. J. Radiation Oncology Biology Physics Volume 59, Number 4, 2004 INTRODUCTION Lung cancer was diagnosed in an estimated 171,900 people in 2003 and caused an estimated 157,200 deaths in the United States (1). About 20% of patients with lung cancer have small-cell lung cancer (SCLC) and, of these, 30% have limited-stage disease (LD-SCLC) (2). Small-cell lung cancer is a rapidly proliferating tumor that is responsive to chemotherapy. Radiotherapy (RT) also has a central role in the treatment of LD-SCLC. In 1992, two meta-analyses were published regarding the role of thoracic RT in addition to chemotherapy (2, 3). They were based on randomized prospective studies that compared chemotherapy alone with chemotherapy plus thoracic RT. Pignon et al. (3) reported a 3-year survival rate of 14.3% with combined modality therapy compared with 8.9% with chemotherapy alone (p 0.001). This 5.4% difference in 3-year survival was identical to the 5.4% difference in 2-year survival (p 0.001) reported by Warde and Payne (2). Although a 5.4% difference may seem rather small, it represented a 61% increase in the 3-year survival rate of 8.9% achieved with chemotherapy alone (3). In addition to thoracic RT, prophylactic cranial irradiation (PCI) has been shown to influence survival positively in patients with a complete response (CR). Auperin et al. (4) published a meta-analysis that included data from seven randomized prospective studies comparing PCI with no PCI after a CR. As in the thoracic RT meta-analyses, the 3-year survival rate was 5.4% better for those who received PCI at 20.7% compared with 15.3% for those who did not receive PCI (p 0.01) (4). In an attempt to improve the outcome of patients with LD-SCLC, various alterations in the radiation-related variables have been investigated. It was hypothesized that because SCLC is a rapidly proliferating tumor, twice-daily (b.i.d.) RT might be more effective than once-daily (q.d.) RT. Mayo Clinic investigators performed a pilot study for patients with LD-SCLC that included etoposide plus cisplatin (EP) for a total of six cycles (5). During Cycles 5 and 6, split-course b.i.d. RT was administered that included the delivery of 24 Gy in 16 fractions followed by a 2.5-week break and an additional 24 Gy in 16 fractions. A treatment break was included because severe esophagitis was anticipated with a program that included 1.5-Gy fractions b.i.d. plus concurrent radiosensitizing chemotherapy. They reported a median survival of 26 months and 2-year survival rate of 55%. These results appeared promising, and this Phase III study (North Central Cancer Treatment Group [NCCTG] ) was launched comparing EP plus either q.d. RT or split-course b.i.d. RT. Turrisi et al. (6) also performed a randomized prospective study to compare chemotherapy plus either b.i.d. RT or q.d. RT. Their initial report showed no advantage to b.i.d. RT compared with q.d. RT. However, with longer follow-up (median, 8 years), Turrisi et al. (6) reported a significant survival advantage for b.i.d. RT. Therefore, it was important that the NCCTG study be reevaluated with longterm follow-up to see whether b.i.d. RT provided an advantage that was not apparent in the initial analysis, which included 3-year survival rates (7). METHODS AND MATERIALS The following procedures were performed before therapy: history and physical examination, complete blood cell count, serum chemistry studies (bilirubin, aspartate aminotransferase, alkaline phosphatase, creatinine, calcium), CT of the head, chest, and upper abdomen, pulmonary function tests, bone scan, electrocardiography, bone marrow biopsy, pregnancy test for fertile women, and a radiation oncology consultation. Patients participating in this study met the following eligibility criteria: pathologic confirmation of LD-SCLC, white blood cell count 3500/ L, platelet count 100,000/ L, hemoglobin of 9.5 g/dl, serum creatinine two times or less the upper limits of normal (ULN), normal total bilirubin level, aspartate aminotransferase or alkaline phosphatase less than three times the ULN, forced expiratory volume in 1 s 1 L; and Eastern Cooperative Oncology Group (ECOG) performance status 2. Limited disease was defined as SCLC limited to a hemithorax or the ipsilateral supraclavicular fossa and encompassed within a reasonable RT field as defined by a radiation oncologist. Patients were excluded from the study if they had had a myocardial infarction within 3 months or had uncontrolled congestive heart failure, uncontrolled arrhythmia, more than a minimal pleural effusion, another recent malignancy, received prior therapy for this malignancy, weight loss 10% within the past 3 months, or were pregnant or lactating. No age restriction was included for participation in this study. Each participating institution s institutional review board reviewed and approved this study. The experimental nature of the study was explained to all patients and each provided written informed consent before treatment. The tumor response to therapy was determined by the changes in the sum of the products of the greatest perpendicular diameters of all indicator lesions. A CR was the complete disappearance of all indicator lesions. A partial response was the decrease by 50% in this measure, and progression was an increase of 25%. Stable disease was defined as a decrease of 50% or an increase of 25% of this parameter. All patients received six cycles of EP, each of 3 days duration and separated by 28 days. Each day of chemotherapy consisted of 30 mg/m 2 of cisplatin given i.v. for min followed by 130 mg/m 2 of etoposide given i.v. for 45 min. The etoposide dose was reduced to 100 mg/m 2 for Cycles 4 6. After the initial three cycles of EP, patients underwent restaging with all the initial tests, except for the bone marrow biopsy, electrocardiography, and pregnancy test. Randomization to q.d. RT or b.i.d. RT was then performed in the patients who met the following requirements: thoracic disease that was still encompassed within reasonable RT

3 b.i.d. RT vs. q.d. RT for LD-SCLC S. E. SCHILD et al. 945 ports, ECOG performance status 2, white blood cell count 3500/ L, platelet count 100,000/ L, hemoglobin 9.5 g/dl, creatinine less than two times the ULN, forced expiratory volume in 1 s 1.0 L, other chemistry values (bilirubin, aspartate aminotransferase, alkaline phosphatase) less than three times the ULN, and no distant metastases other than brain metastases. Patients were stratified at the time of randomization for the following factors: measurable vs. assessable disease, performance status, amount of weight loss, age, gender, and tumor response. Thoracic RT was delivered with 4 10-MV X-rays using custom blocks. Qd RT included the delivery of 50.4 Gy in 28 fractions delivered on weekdays for a total of 38 days. The initial 39.6 Gy was delivered with AP PA fields. The final 10.8 Gy was delivered with oblique fields that excluded the spinal cord. The EP was continued during RT for Cycles 4 and 5 and began on the first day of RT. b.i.d. RT included the delivery of 48 Gy in 32 fractions. Treatment was given on weekdays at least 4 h apart. After the initial 24 Gy, RT was held for 2.5 weeks and then resumed 28 days after beginning RT to coincide with the fifth cycle of EP. AP PA fields were used for the first 33 Gy followed by obliques fields that excluded the spinal cord for the last 15 Gy. The spinal cord was limited to a maximal dose of 37 Gy with b.i.d. RT and 45 Gy with q.d. RT. Radiotherapy was administered to postchemotherapy volumes, which included the primary tumor, ipsilateral hilum, mediastinum, and supraclavicular volumes with a 2-cm margin between these structures and the block edge. If a CR was achieved before RT, treatment was directed to the ipsilateral hilum, mediastinum, and supraclavicular volumes. The oblique fields were directed to the same structures with angles ranging from 30 to 45 from a line perpendicular to the treatment table and included the ipsilateral supraclavicular volume only if persistent disease was present in this region. No tissue inhomogeneity corrections were made, and the irradiated volume received between 95% and 110% of the prescribed dose. After the thoracic RT, the sixth cycle of EP was given, followed by restaging. PCI was then administered to all patients with a CR. This included the delivery of 30 Gy in 15 daily treatments given on weekdays with 4 6-MV photons using opposed lateral fields delivered to the mid-plane or isocenter. For patients with failure in the brain at any time during treatment but disease that stayed limited in all other respects, therapeutic brain RT was administered. In this situation, the whole brain received 30 Gy in 15 fractions followed by a boost dose of an additional 20 Gy in 10 fractions to the metastasis plus 2 cm if solitary and to the entire brain if multiple. After the first course of chemotherapy, the doses were modified according to renal, hematologic, or neurologic toxicity. A nadir of leukocytes and platelets to a level 1500/ L or 50,000/ L, respectively, resulted in a 30% reduction of the etoposide dose at the next cycle. Retreatment was not initiated until the leukocyte and platelet count was 3500/ L and 100,000/ L. Cisplatin doses were decreased by 50% if the creatinine level rose to times the institutional ULN or Grade 2 neuropathy had occurred. Cisplatin was discontinued if the creatinine level exceeded two times the ULN or Grade 3 or worse neuropathy had occurred. Treatment was held if Grade 2 or worse esophagitis or Grade 3 or worse pneumonitis had occurred until the toxicity had decreased to Grade 1 or Grade 2, respectively. Follow-up was performed at 4-month intervals for the first year and 6-month intervals thereafter. These evaluations included history and physical examination, chemistry panel, complete blood cell count, and chest X-rays. This Phase III study was performed to assess whether survival was significantly better with the use of this program of b.i.d. RT compared with q.d. RT. The power analysis indicated that 240 patients needed to be randomized for an 80% power to detect a 50% improvement in median survival from the expected 15 months to 22.5 months. Furthermore, 240 patients would have provided a 95% power to detect an increase in the local control rate from 50% to 70% at 2 years. The survival and progression rates were calculated using the Kaplan-Meier method, and differences between the rates were evaluated using the log rank test (8, 9). Cumulative incidence methods, which account for competing events, were used to determine the rates of in-field, intrathoracic, brain, and distant failure. Toxicity was based on the Common Toxicity Criteria (version 1). We evaluated the incidence and severity of hematologic, nonhematologic, and overall toxicity. The incidence of Grade 3 or greater and Grade 4 or greater toxicity was compared across groups using the chi-square test or Fisher s exact test when appropriate. Statistical significance was declared at p RESULTS Patient characteristics This trial was open for accrual between September 1990 and November Of the 324 patients who were enrolled in this study, 14 patients were ineligible, leaving 310 assessable patients. All patients received six cycles of EP, each cycle separated by 28 days. Each cycle included 3 days of EP. After the first three cycles of EP, randomization to EP plus q.d. RT or EP plus b.i.d. RT was performed in the 261 patients who met the requirements previously described. Of these 261 patients, 111 (43%) were women and 150 (57%) were men. Patient age ranged from 37 to 81 years (median, 63 years). PCI was then administered to the 154 patients with a CR. The treatment arms were well balanced regarding the following patient characteristics: age, gender, performance status, disease status, weight loss, and response to chemotherapy (Table 1). Follow-up in survivors ranged from 4.6 to 11.9 years (median, 7.4 years). Of the 310 eligible patients, 228 assessable patients died. Tumor control and patient survival No statistically significant difference was found in the tumor progression rates when stratified by RT fractionation pattern (b.i.d. RT vs. q.d. RT). The 2- and 5-year progres-

4 946 I. J. Radiation Oncology Biology Physics Volume 59, Number 4, 2004 Table 1. Baseline characteristics of randomized patients Characteristic QDRT (n 131) BIDRT (n 130) Total (n 261) p* Age (y) 0.78 n Mean Median Range Gender 0.86 Female 55 (42) 56 (43) 111 (43) Male 76 (58) 74 (57) 150 (57) Performance score (95) 121 (93) 245 (94) 2 7 (5) 9 (7) 16 (6) Disease status 0.96 Measurable 51 (39) 51 (39) 102 (39) Assessable 80 (61) 79 (61) 159 (61) Weight loss since registration % 115 (88) 116 (89) 231 (89) 5 10% 15 (11) 13 (10) 28 (11) 10% 1 (1) 1 (1) 2 (1) Response to chemotherapy 0.78 Better than stable disease 122 (93) 123 (95) 245 (94) Stable 7 (5) 6 (5) 13 (5) Local Progression 1 (1) 1 (1) 2 (1) Brain metastases 1 (1) 0 (0) 1 (0) Data in parentheses are percentages. * Rank-sum p value for age; chi-square p values for all others. sion-free rate was 30.8% and 21% for the b.i.d. RT arm vs. 31.3% and 19.8% in the q.d. RT arm (p 0.68; Fig. 1). The 5-year in-field failure rate was 32% for the b.i.d. RT group compared with 34% for the q.d. RT group (p 0.62; Fig. 2). The 5-year intrathoracic failure rate was 36% for the b.i.d. RT group compared with 40% for the q.d. RT group (p 0.45; Fig. 3). The 5-year distant failure rate was 36% for patients who received b.i.d. RT compared with 37% for those who received q.d. RT (p 0.82; Fig. 4) The brain failure rate, in the 154 patients who underwent PCI, was 11% in the b.i.d. RT group vs. 9% in the q.d. RT group (p 0.68; Fig. 5). Fig. 1. Freedom from tumor progression by radiotherapy (RT) fractionation pattern. BID RT twice a day RT; QD RT once a day RT.

5 b.i.d. RT vs. q.d. RT for LD-SCLC S. E. SCHILD et al. 947 Fig. 2. Incidence of in-field progression by radiotherapy (RT) fractionation pattern. BID RT twice a day RT; QD RT once a day RT. The median survival and 2-year and 5-year survival rate for all 310 eligible patients from the initial date of registration was 20.9 months and 44%, and 20.4%, respectively. For the patients who were randomized, no statistically significant difference in survival was found according to the RT fractionation pattern (b.i.d. RT vs. q.d. RT; p 0.68). The median survival from the date of randomization was 20.6 months with either b.i.d. RT or q.d. RT. The 2- and 5-year survival rate was 44% and 22% in patients who received b.i.d. RT compared with 44.3% and 21% in those who received q.d. RT, respectively (p 0.68; Fig. 6). Toxicity Toxicity was evaluated using the National Cancer Institute Common Toxicity Criteria (version 1). The occurrence of overall, hematologic, and nonhematologic toxicity was compared between the treatment arms (Table 2). No statistically significant differences were found, with the exception of Grade 3 or worse nonhematologic toxicity and Grade 5 toxicity, which were significantly more common in patients who received b.i.d. RT. The most common Grade 3 or worse toxicity was myelosuppression, followed by nausea, vomiting, pulmonary tox- Fig. 3. Incidence of intrathoracic progression by radiotherapy (RT) fractionation pattern. BID RT twice a day RT; QD RT once a day RT.

6 948 I. J. Radiation Oncology Biology Physics Volume 59, Number 4, 2004 Fig. 4. Incidence of distant failure by radiotherapy (RT) fractionation pattern. BID RT twice a day RT; QD RT once a day RT. icity, and esophagitis (Table 3). The only specific toxicities found to be more common with b.i.d. RT were Grade 3 or worse thrombocytopenia (p 0.03) and Grade 3 or worse esophagitis (p 0.05). Of the 261 patients, 4 (2%) died of treatment-related toxicity (Grade 5 toxicity). Grade 5 toxicity occurred in 4 (3%) of the 130 who received b.i.d. RT compared with none (0%) of the 131 who received q.d. RT (p 0.04). These deaths occurred from pneumonitis in 3 patients and infection in 1 patient. DISCUSSION The role of thoracic RT has been established in the treatment of LD-SCLC (2, 3). Because SCLC has a high proliferation rate, it was theorized that SCLC might be more responsive to b.i.d. RT than q.d. RT. This observation has been reported in randomized prospective studies of headand-neck malignancies, which also have a high mitotic rate (10). The ECOG in a combined intergroup effort with the Radiation Therapy Oncology Group (RTOG) and the Southwest Oncology Group performed a Phase III trial that compared EP plus q.d. RT with EP plus b.i.d. RT (6). This trial, reported by Turrisi et al. (6) had two important differences with the present study. The RT was started during the first cycle of chemotherapy, and b.i.d. RT was given in a continuous fashion without a treatment break. Although the preliminary report from that Intergroup study revealed no Fig. 5. Incidence of brain failure by radiotherapy (RT) fractionation pattern only in patients who received prophylactic cranial irradiation (n 154). BID RT twice a day RT; QD RT once a day RT.

7 b.i.d. RT vs. q.d. RT for LD-SCLC S. E. SCHILD et al. 949 Fig. 6. Survival by radiotherapy (RT) fractionation pattern. BID RT twice a day RT; QD RT once a day RT. clear advantage for b.i.d. RT, a later analysis with a median follow-up of 8 years revealed a statistically significant advantage for b.i.d. RT. The intrathoracic failure rate was 52% for patients who received q.d. RT compared with 36% for those who had b.i.d. RT (p 0.06). These intrathoracic failure rates were similar to those of the present study, 40% with q.d. RT and 36% with b.i.d. RT. Their median survival time and 5-year survival rate was 19 months and 16%, respectively, for those who received q.d. RT compared with 23 months and 26%, respectively, for those who received b.i.d. RT (p 0.04). The median survival was 20 months and the 5-year survival rate was 23% for their entire cohort. Although the present study did not find an advantage for split-course b.i.d. RT, the survival of the 310 patients who were registered in the present study was almost identical, with a median survival of 20.9 months and 5-year survival rate of 20.4%. Esophagitis occurred more often in patients who received b.i.d. RT in both studies. Of the patients in the ECOG/Intergroup study who received b.i.d. RT, 32% had Grade 3 or worse esophagitis compared with 16% for those who received q.d. RT (p 0.001). The present study revealed an increase in both Grade 3 or worse and Grade 5 nonhematologic toxicity with b.i.d. RT. The overall risk of dying of toxicity was 3% in the b.i.d. RT arms of both studies. The present study was unable to detect an advantage for b.i.d. RT compared with q.d. RT. One explanation for this finding relates to the use of a split-course RT fractionation pattern. It appears that split-course b.i.d. RT results in a similar outcome as q.d. RT when used to treat either SCLC or non small-cell lung cancer. The NCCTG performed a companion study in patients with Stage III non small-cell lung cancer. Patients were randomized to receive either standard q.d. RT (60 Gy in 30 daily fractions) or splitcourse b.i.d. RT (30 Gy in 20 fractions b.i.d. followed by a 2-week break and then 30 Gy in 20 fractions b.i.d.). Both Table 2. Toxicity Toxicity QDRT (n 131) BIDRT (n 130) Total (n 261) p* Hematologic n (%) n (%) n (%) Grade (90) 116 (89) 234 (90) 0.82 Grade 4 57 (44) 55 (42) 112 (43) 0.84 Nonhematologic Grade 3 51 (39) 71 (55) 123 (47) 0.01 Grade 4 12 (9) 18 (14) 30 (11) 0.24 Grade 5 0 (0) 4 (3) 4 (2) 0.04 Any Grade (92) 120 (92) 240 (92) 0.83 Grade 4 61 (47) 61 (47) 122 (47) 0.95 Grade 5 0 (0) 4 (3) 4 (2) 0.04 Abbreviations: QDRT once-daily radiotherapy; BIDRT twice-daily radiotherapy. Data in parentheses are percentages. * Chi-square p values.

8 950 I. J. Radiation Oncology Biology Physics Volume 59, Number 4, 2004 Table 3. Specific toxicities Grade 3 Grade 4 p (Fisher s exact test) Toxicity type QDRT BIDRT QDRT BIDRT Grade 3 Grade 4 n (%) n (%) n (%) n (%) Leukopenia 112 (86) 114 (88) 47 (36) 46 (35) Thrombocytopenia 77 (59) 58 (45) 30 (23) 26 (20) Nausea 22 (17) 22 (17) 1 (1) 0 (0) Vomiting 16 (12) 19 (15) 9 (7) 7 (5) Esophagitis 7 (5) 16 (12) 0 (0) 0 (0) 0.05 N/A RT pneumonitis 6 (5) 8 (6) 0 (0) 3 (2) Lethargy 4 (3) 10 (8) 0 (0) 0 (0) 0.11 N/A Infection 3 (2) 5 (4) 1 (1) 2 (2) Cardiac 1 (1) 5 (4) 0 (0) 2 (2) Dermatitis 3 (2) 0 (0) 1 (1) 0 (0) Abbreviations as in Table 2. arms included EP during RT. No statistically significant differences were found between the q.d. RT and b.i.d. RT arms in terms of overall survival (median 14 and 15 months, respectively, p 0.4) or the cumulative incidence of local failure (2-year rate 45% and 41%, respectively, p 0.6) (11). There have been similar findings regarding RT fractionation in head-and-neck cancers. Although the initial pilot studies of split-course b.i.d. RT for head-and-neck cancers were also promising, data are now available refuting the value of this approach (10). The RTOG recently conducted a Phase III randomized trial in patients with locally advanced squamous cell carcinoma of the head and neck that compared various RT regimens (10). These patients were randomly assigned to receive RT delivered with standard fractionation at 2 Gy/fraction/d to 70 Gy in 35 fractions within 7 weeks; hyperfractionation at 1.2 Gy/fraction, b.i.d., to 81.6 Gy in 68 fractions within 7 weeks; accelerated fractionation with split at 1.6 Gy/fraction, b.i.d., to 67.2 Gy in 42 fractions within 6 weeks, including a 2-week rest after 38.4 Gy; or accelerated fractionation with concomitant boost at 1.8 Gy/fraction/d and 1.5 Gy/fraction/d to a boost field as a second daily treatment for the last 12 treatment days to 72 Gy in 42 fractions within 6 weeks. None of the patients received chemotherapy. Patients treated with hyperfractionation and accelerated fractionation with concomitant boost had better locoregional control (p and p 0.050, respectively) than those treated with standard fractionation. The RT program of accelerated fractionation with a treatment break provided no benefit compared with standard fractionation. The outcome of this RTOG headand-neck study suggested that b.i.d. RT without a break was more effective than q.d. RT. The present study included a treatment break in the b.i.d. RT arm, which may have decreased its efficacy. During the treatment break, cancer cells may have multiplied or developed greater radiation resistance. The findings of the two randomized prospective studies comparing q.d. RT and b.i.d. RT for LD-SCLC (the present study and the ECOG/Intergroup trial), lead one to conclude that continuous-course b.i.d. RT is better than q.d. RT, but split-course b.i.d. RT is not (6). On the basis of these findings, the NCCTG initiated a Phase I II study (N9923) for LD-SCLC that included concurrent chemotherapy and b.i.d. RT without a treatment break. This pilot study included escalating doses of b.i.d. RT given in 1.2-Gy fractions. The total dose of thoracic RT began at 48 Gy, with increases in 6-Gy increments as tolerated. PCI was administered after the chemotherapy and thoracic RT. This RT approach is similar to the 1.2-Gy b.i.d. fractionation pattern used in the RTOG head-and-neck study that achieved better results than q.d. RT and split-course b.i.d. RT (10). Future SCLC studies will investigate other RT parameters, newer imaging modalities, novel combinations of chemotherapy, and molecularly targeted therapy. RT research should attempt to determine the optimal dose-fractionation patterns, treatment volumes, delivery systems, and planning techniques. The current study evaluated one program of split-course b.i.d. RT that yielded an outcome similar to q.d. RT. The 5-year survival rate achieved in this study surpassed our previous efforts at the NCCTG and was similar to those achieved in other recent cooperative group trials (6, 12, 13). On the basis of the findings of the ECOG/Intergroup study and an NCCTG pilot study, the NCCTG has initiated a pilot study that included continuous-course b.i.d. RT (6, 14). REFERENCES 1. Jemal A, Murray T, Samuels A, et al. Cancer statistics CA Cancer J Clin 2003;53: 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 1992;10: Pignon JP, Arriagada R, Ihde DC, et al. A meta-analysis of

9 b.i.d. RT vs. q.d. RT for LD-SCLC S. E. SCHILD et al. 951 thoracic radiotherapy for small-cell lung cancer. N Engl J Med 1992;327: for the PCI Overview Collaborative Group, Auperin A, Arriagada R, Pignon JP, et al. Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. N Engl J Med 1999;342: Frytak S, Shaw EG, Jett JR, et al. Infusion cisplatin chemotherapy and hyperfractionated thoracic radiotherapy for smallcell lung cancer. Am J Clin Oncol 1996;19: Turrisi AT, Kyungmann K, Blum R, et al. Twice-daily compared with once-daily thoracic radiotherapy in limited smallcell lung cancer treated concurrently with cisplatin and etoposide. N Engl J Med 1999;340: Bonner JA, Sloan JA, Shanahan TG, et al. Phase III comparison of twice-daily split course irradiation versus once-daily irradiation for patients with limited stage small-cell lung carcinoma. J Clin Oncol 1999;17: Kaplan EL, Meier P. Non-parametric estimation from incomplete observations. J Am Stat Soc 1958;53: 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 1977; 35: Fu KK, Pajak TF, Trotti A, et al. A Radiation Therapy Oncology Group (RTOG) phase III randomized study to compare hyperfractionation and two variants of accelerated fractionation to standard fractionation radiotherapy for head and neck squamous cell carcinomas: First report of RTOG Int J Radiat Oncol Biol Phys 2000;48: Schild SE, Stella PJ, Geyer SM, et al. Phase III trial comparing chemotherapy plus once-daily or twice-daily radiotherapy in stage III non-small cell lung cancer (NSCLC). Int J Radiat Oncol Biol Phys 2002;54: Takada M, Fukuoka M, Kawahara M, et al. Phase III study of concurrent versus sequential thoracic radiotherapy in combination with cisplatin and etoposide for limited-stage small cell lung cancer: Results of the Japan Clinical Oncology Group study J Clin Oncol 2002;20: Sundstrom S, Bremnes RM, Kaasa S, et al. Cisplatin and etoposide regimen is superior to cyclophosphamide, epirubicin, and vincristine regimen in small cell lung cancer: Results from a randomized phase III trial with 5 years follow-up. J Clin Oncol 2002;20: Bonner JA, Hillman S, Vigliotti A, et al. High dose, twicedaily thoracic radiotherapy (TRT) with daily chemotherapy in limited stage small cell lung cancer [Abstract]. Lung Cancer 2003;41(suppl. 2):24.

10 本文献由 学霸图书馆 - 文献云下载 收集自网络, 仅供学习交流使用 学霸图书馆 ( 是一个 整合众多图书馆数据库资源, 提供一站式文献检索和下载服务 的 24 小时在线不限 IP 图书馆 图书馆致力于便利 促进学习与科研, 提供最强文献下载服务 图书馆导航 : 图书馆首页文献云下载图书馆入口外文数据库大全疑难文献辅助工具