Journal of Clinical Oncology, Vol 16, 3528-3536, Copyright © 1998 by American Society of Clinical Oncology
Phase I study to determine the maximum-tolerated dose of radiation in standard daily and hyperfractionated-accelerated twice-daily radiation schedules with concurrent chemotherapy for limited-stage small-cell lung cancer
NC Choi, JE Herndon 2nd, J Rosenman, RW Carey, CT Chung, S Bernard, L Leone, S Seagren and M Green
Department of Radiation Oncology, Massachusetts General Hospital, Boston 02114, USA. choi.noah@mgh.harvard.edu
PURPOSE: An improvement in radiation dose schedule is necessary to increase
local tumor control and survival in limited-stage small-cell lung cancer.
The goal of this study was to determine the maximum- tolerated dose (MTD)
of radiation (RT) in both standard daily and hyperfractionated-accelerated
(HA) twice-daily RT schedules in concurrent chemoradiation. METHODS: The
study design consisted of a sequential dose escalation in both daily and HA
twice-daily RT regimens. RT dose to the initial volume was kept at 40 to
40.5 Gy, while it was gradually increased to the boost volume by adding a
7% to 11 % increment of total dose to subsequent cohorts. The MTD was
defined as the radiation dose level at one cohort below that which resulted
in more than 33% of patients experiencing grade > or = 4 acute
esophagitis and/or grade > or = 3 pulmonary toxicity. The study plan
included nine cohorts, five on HA twice-daily and four on daily regimens
for the dose escalation. Chemotherapy consisted of three cycles of
cisplatin 33 mg/m2/d on days 1 to 3 over 30 minutes, cyclophosphamide 500
mg/m2 on day 1 intravenously (IV) over 1 hour, and etoposide 80 mg/m2/d on
days 1 to 3 over 1 hour every 3 weeks (PCE) and two cycles of PE. RT was
started at the initiation of the fourth cycle of chemotherapy. RESULTS:
Fifty patients were enrolled onto the study. The median age was 60 years
(range, 38-79), sex ratio 2.3:1 for male to female, weight loss less than
5% in 73%, and performance score 0 to 1 in 94% and 2 in 6% of patients. In
HA twice-daily RT, grade > or = 4 acute esophagitis was noted in two of
five (40%), two of seven (29%), four of six (67%), and five of six patients
(86%) at 50 (1.25 Gy twice daily), 45, 50, and 55.5 Gy in 1.5 Gy twice
daily, 5 d/wk, respectively. Grade > or = 3 pulmonary toxicity was not
seen in any of these 24 patients. Therefore, the MTD for HA twice-daily RT
was judged to be 45 Gy in 30 fractions over 3 weeks. In daily RT, grade
> or = 4 acute esophagitis was noted in zero of four, zero of four, one
of five (20%), and two of six patients (33%) at 56, 60, 66, and 70 Gy on a
schedule of 2 Gy per fraction per day, five fractions per week. Grade >
or = 3 pneumonitis was not observed in any of the 19 patients. Thus, the
MTD for daily RT was judged to be at least 70 Gy in 35 fractions over 7
weeks. Grade 4 granulocytopenia and thrombocytopenia were observed in 53%
and 6% of patients, respectively, during the first three cycles of PCE.
During chemotherapy cycles 4 to 5, grade 4 granulocytopenia and
thrombocytopenia were noted in 43% and 29% of patients at 45 Gy in 30
fractions over 3 weeks (MTD) by HA twice-daily RT and 50% and 17% at 70 Gy
in 35 fractions over 7 weeks (MTD) by daily RT, respectively. The overall
tumor response consisted of complete remission (CR) in 51% (24 of 47),
partial remission (PR) in 38% (1 8 of 47), and stable disease in 2% (one of
47). The median survival time of all patients was 24.4 months and 2- and
3-year survival rates were 53% and 28%, respectively. With regard to the
different radiation schedules, 2- and 3-year survival rates were 52% and
25% for the HA twice-daily and 54% and 35% for the daily RT cohorts.
CONCLUSION: The MTD of HA twice-daily RT was determined to be 45 Gy in 30
fractions over 3 weeks, while it was judged to be at least 70 Gy in 35
fractions over 7 weeks for daily RT. A phase III randomized trial to
compare standard daily RT with HA twice- daily RT at their MTD for local
tumor control and survival would be a sensible research in searching for a
more effective RT dose-schedule than those that are being used currently.
This article has been cited by other articles:
|
|
|
|
 
M. A. Socinski and J. A. Bogart
Limited-Stage Small-Cell Lung Cancer: The Current Status of Combined-Modality Therapy
J. Clin. Oncol.,
September 10, 2007;
25(26):
4137 - 4145.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. R. Simon and A. Turrisi
Management of Small Cell Lung Cancer: ACCP Evidence-Based Clinical Practice Guidelines (2nd Edition)
Chest,
September 1, 2007;
132(3_suppl):
324S - 339S.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. E. Lally, J. J. Urbanic, A. W. Blackstock, A. A. Miller, and M. C. Perry
Small Cell Lung Cancer: Have We Made Any Progress Over the Last 25 Years?
Oncologist,
September 1, 2007;
12(9):
1096 - 1104.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. A. Bogart, S. L. Seagren, and A. Glicksman
Radiation oncology research in the cancer and leukemia group B.
Clin. Cancer Res.,
June 1, 2006;
12(11):
3628s - 3634s.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. Thatcher, W. Qian, P. I. Clark, P. Hopwood, R. J. Sambrook, R. Owens, R. J. Stephens, and D. J. Girling
Ifosfamide, Carboplatin, and Etoposide With Midcycle Vincristine Versus Standard Chemotherapy in Patients With Small-Cell Lung Cancer and Good Performance Status: Clinical and Quality-of-Life Results of the British Medical Research Council Multicenter Randomized LU21 Trial
J. Clin. Oncol.,
November 20, 2005;
23(33):
8371 - 8379.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Q.-T. Le, J. McCoy, S. Williamson, J. Ryu, L. E. Gaspar, M. J. Edelman, S. R. Dakhil, S. D. Sides, J. J. Crowley, and D. R. Gandara
Phase I Study of Tirapazamine Plus Cisplatin/Etoposide and Concurrent Thoracic Radiotherapy in Limited-Stage Small Cell Lung Cancer (S0004): A Southwest Oncology Group Study
Clin. Cancer Res.,
August 15, 2004;
10(16):
5418 - 5424.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A Price
Lung cancer * 5: State of the art radiotherapy for lung cancer
Thorax,
May 1, 2003;
58(5):
447 - 452.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. H. Johnson
"The Guard Dies, It Does Not Surrender!" Progress in the Management of Small-Cell Lung Cancer?
J. Clin. Oncol.,
December 15, 2002;
20(24):
4618 - 4620.
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Osterlind
Chemotherapy in small cell lung cancer
Eur. Respir. J.,
December 1, 2001;
18(6):
1026 - 1043.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. Komaki, M. H. Chasen, W. D. Travis, J. B. Putnam, F. V. Fossella, R. W. Byhardt, and J. Y. Ro
Oncodiagnosis Panel: 1999: Cancer of the Lung: Oncodiagnosis
RadioGraphics,
November 1, 2001;
21(6):
1573 - 1596.
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Elias
Hematopoietic Stem Cell Transplantation for Small Cell Lung Cancer*
Chest,
December 1, 1999;
116(suppl_3):
531S - 538S.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. Abadir, C. Orton, J. G. Armstrong, D. A. Laber, A. T. Turrisi, K. Kim, and D. H. Johnson
Radiotherapy for Small-Cell Lung Cancer
N. Engl. J. Med.,
June 24, 1999;
340(25):
2002 - 2004.
[Full Text]
|
|
|
|
|
|
|
A. Elias, J. Ibrahim, A. T. Skarin, C. Wheeler, M. McCauley, L. Ayash, P. Richardson, L. Schnipper, K. H. Antman, and E. Frei III
Dose-Intensive Therapy for Limited-Stage Small-Cell Lung Cancer: Long-Term Outcome
J. Clin. Oncol.,
April 1, 1999;
17(4):
1175 - 1175.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. T. Turrisi, K. Kim, R. Blum, W. T. Sause, R. B. Livingston, R. Komaki, H. Wagner, S. Aisner, and D. H. Johnson
Twice-Daily Compared with Once-Daily Thoracic Radiotherapy in Limited Small-Cell Lung Cancer Treated Concurrently with Cisplatin and Etoposide
N. Engl. J. Med.,
January 28, 1999;
340(4):
265 - 271.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
