Long-term results of a phase III trial comparing once-daily radiotherapy with twice-daily radiotherapy in limited-stage small-cell lung cancer

doi:10.1016/j.ijrobp.2004.01.055

International Journal of Radiation OncologyBiologyPhysics

Volume 59, Issue 4, 15 July 2004, Pages 943-951

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, 2003.

https://doi.org/10.1016/j.ijrobp.2004.01.055 Get rights and content

Abstract

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.

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] 89-20-52) 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 89-20-52 study be reevaluated with long-term 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).

Section snippets

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:

Patient characteristics

This trial was open for accrual between September 1990 and November 1996. 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%)

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 head-and-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

Acknowledgements

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,

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Patients above or equal to 70 years old tolerated concurrent twice-daily chemoradiotherapy and achieved similar disease control as younger patients, indicating older patients should receive the same treatment as younger patients.
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For LS-SCLC, OD conventional chemoradiation results in similar outcomes to BID chemoradiation. In contrast, hypofractionated radiotherapy was associated with a better OS and PFS than BID. Additional randomized phase III trials exploring hypofractionation with systemic therapy are warranted to validate our findings.
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^☆: 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-37404, 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-63826 from the National Cancer Institute, Department of Health and Human Services.

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Clinical investigation: lungLong-term results of a phase III trial comparing once-daily radiotherapy with twice-daily radiotherapy in limited-stage small-cell lung cancer☆

Abstract

Purpose

Methods and materials

Results

Conclusion

Introduction

Section snippets

Methods and materials

Patient characteristics

Discussion

Acknowledgements

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Cancer statistics 2003

CA Cancer J Clin

Does thoracic irradiation improve survival and local control in limited-stage small-cell carcinoma of the lung? A meta-analysis

J Clin Oncol

A meta-analysis of thoracic radiotherapy for small-cell lung cancer

N Engl J Med

Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission

N Engl J Med

Infusion cisplatin chemotherapy and hyperfractionated thoracic radiotherapy for small-cell lung cancer

Am J Clin Oncol

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☆