Int. J. Radiation Oncology Biol. Phys., Vol. 59, No. 2, pp.

460 – 468, 2004

Copyright © 2004 Elsevier Inc.
Printed in the USA. All rights reserved
0360-3016/04/$–see front matter

doi:10.1016/j.ijrobp.2003.10.021

CLINICAL INVESTIGATION Lung

70 GY THORACIC RADIOTHERAPY IS FEASIBLE CONCURRENT WITH

CHEMOTHERAPY FOR LIMITED-STAGE SMALL-CELL LUNG CANCER:
ANALYSIS OF CANCER AND LEUKEMIA GROUP B STUDY 39808

JEFFREY A. BOGART, M.D.,* JAMES E. HERNDON II, PH.D.,† ALAN P. LYSS, M.D.,‡
DOROTHY WATSON,† ANTONIUS A. MILLER,§ MICHAEL E. LEE,¶ ANDREW T. TURRISI, M.D.,㛳
㛳
AND MARK R. GREEN, M.D.

*Department of Radiation Oncology, Upstate Medical University, Syracuse, NY, †Cancer and Leukemia Group B Statistical Center,
Durham, NC; ‡Missouri Baptist Medical Center, St. Louis, MO; §Wake Forest University School of Medicine, Winston-Salem, NC;
¶
Virginia Oncology Associates, Norfolk, VA; 㛳Department of Radiation Oncology, Medical University of South Carolina,
Charleston, SC

Purpose: To prospectively evaluate the feasibility of delivering 70 Gy once-daily thoracic radiotherapy (TRT),
concurrent with chemotherapy, in the treatment of limited-stage small-cell lung cancer (L-SCLC).
Materials and Methods: Eligible patients received two cycles of induction paclitaxel (175 mg/m2 on Day 1) and
topotecan (1 mg/m2 on Days 1–5) with granulocyte colony stimulating factor support, followed by three cycles of
carboplatin (area under the curve ⴝ 5 on Day 1) and etoposide (100 mg/m2 on Days 1–3). TRT (70 Gy, 2 Gy/fx/7
weeks) was initiated with the first cycle of carboplatin and etoposide. Prophylactic cranial irradiation was offered
to patients achieving a complete response or good partial response.
Results: Ninety percent of patients (57 of 63) proceeded to protocol TRT. There was one treatment-related
fatality. Nonhematologic Grade 3/4 toxicities affecting more than 10% of patients, during or after TRT, were
dysphagia (16%/5%) and febrile neutropenia (12%/4%). The response rate to all therapy was 92% and the
median overall survival is 22.4 months (95% confidence interval 16.1, ⴥ). Twenty-eight patients remain alive with
a median follow-up of 24.7 months.
Conclusion: 70 Gy once-daily TRT can be delivered safely in the cooperative group setting for patients with
L-SCLC. Initial efficacy data are encouraging. The hypothesis that high-dose once-daily TRT results in
comparable or improved survival compared with twice-daily accelerated TRT warrants testing in a Phase III
trial. © 2004 Elsevier Inc.

Limited small-cell lung cancer, Radiation therapy, Multimodality therapy.

Reprint requests to: Jeffrey A. Bogart, M.D., Department of
Radiation Oncology, SUNY Upstate Medical University, 750 E.
Adams Street, Syracuse, NY 13210. Tel: (315) 464-5276; Fax:
(315) 464-5943; E-mail: BogartJ@Upstate.edu
Presented in part at the 44th Annual Meeting of the American
Society for Therapeutic Radiology and Oncology, New Orleans,
LA, October 2002, and the 37th Annual Meeting of the American
Society of Clinical Oncology, San Francisco, CA, May 2001.
Supported, in part, by grants from the National Cancer Institute
(CA31946) to the Cancer and Leukemia Group B (Richard L.
Schilsky, Chairman).
The contents of this manuscript are solely the responsibility of
the authors and do not necessarily represent the official views of
the National Cancer Institute.
Acknowledgments—The following institutions participated in the
study: CALGB Statistical Office, Durham, NC, Stephen George,
Ph.D., supported by CA33601; Dartmouth Medical School Norris
Cotton Cancer Center, Lebanon, NH, Marc S. Ernstoff, M.D.,
supported by CA04326; Duke University Medical Center,
Durham, NC, Jeffrey Crawford, M.D., supported by CA47577;
Green Mountain Oncology Group CCOP, Bennington, VT, H.
James Wallace Jr., M.D., supported by CA35091; Massachusetts
General Hospital, Boston, MA, Michael L. Grossbard, M.D., sup-
ported by CA12449; Mount Sinai School of Medicine, New York,
NY, Lewis R. Silverman, M.D., supported by CA04457; SUNY
Upstate Medical University, Syracuse, NY, Stephen Graziano,
M.D., supported by CA21060; The Ohio State University Medical
Center, Columbus, OH, Clara D. Bloomfield, M.D., supported by
CA77658; University of California at San Diego, San Diego, CA,
Stephen Seagren, M.D., supported by CA11789; University of
Chicago Medical Center, Chicago, IL, Gini Fleming, M.D., sup-
ported by CA41287; University of Maryland Cancer Center, Bal-
timore, MD, David Van Echo, M.D., supported by CA31983;
University of Massachusetts Medical Center, Worcester, MA,
Mary Ellen Taplin, M.D., supported by CA37135; University of
Minnesota, Minneapolis, MN, Bruce A. Peterson, M.D., supported
by CA16450; University of Missouri/Ellis Fischel Cancer Center,
Columbia, MO, Michael C. Perry, M.D., supported by CA12046;
University of Nebraska Medical Center, Omaha, NE, Anne Kess-
inger, M.D., supported by CA77298; University of Tennessee
Memphis, Memphis, TN, Harvey B. Niell, M.D., supported by
CA47555; Vermont Cancer Center, Burlington, VT, Hyman B.
Muss, M.D., supported by CA77406; Wake Forest University
School of Medicine, Winston-Salem, NC, David D. Hurd, M.D.,
supported by CA03927.
Received Apr 9, 2003, and in revised form Aug 12, 2003.
Accepted for publication Oct 15, 2003.

460
 70 Gy thoracic radiotherapy
INTRODUCTION
The integration of thoracic radiotherapy (TRT) with sys-
temic chemotherapy for the treatment of limited-stage
small-cell lung cancer (L-SCLC) has been a focus of intense
study. Two meta-analyses, published in the early 1990s,
confirmed that adding TRT to chemotherapy significantly
improved long-term survival for patients with L-SCLC (1,
2). A recent overview of prospective research in L-SCLC,
including 26 randomized clinical trials initiated by cooper-
ative groups in North America between 1972 and 1992,
found that only five studies showed statistically significant
survival prolongation in the experimental arm compared
with the control arm (3). Strikingly, all five studied some
aspect of thoracic radiation therapy. Several aspects of TRT,
including the optimal dose, schedule, duration, and timing
in the treatment of L-SCLC, have not been adequately
addressed and remain undefined.
Traditionally, modest total doses of radiation, ranging
from 45–50 Gy, have been employed because of the ob-
served responsiveness of small-cell lung cancer to radio-
therapy (4). However, a critical review of prospective liter-
ature reveals high rates of local tumor relapse associated
with modest-dose, conventionally fractionated TRT. For
example, intrathoracic relapse was observed in 75% of
patients treated with 45 Gy once-daily radiotherapy concur-
rent with cisplatin and etoposide chemotherapy in a modern
prospective Phase III trial (5).
Intensifying the radiotherapy course by accelerating the
time to complete treatment (while maintaining the same
nominal total radiation dose) appears to be an effective
strategy to improve outcomes for patients with L-SCLC. A
recent intergroup trial (INT-0096) randomized patients to
either conventional (180 cGy every day ⫻ 25 fractions [45
Gy in 5 weeks]) or hyperfractionated, accelerated dose (150
cGy twice daily ⫻ 30 fractions [45 Gy in 3 weeks]) TRT.
TRT was initiated with the first cycle of etoposide/cisplatin
chemotherapy. Long-term follow-up of this trial was re-
cently published (5). Statistically significant improvement
in overall survival and trends toward improved disease-free
survival and time to progression were noted for the accel-
erated TRT (5-year survival of 26% compared with only
16% for patients receiving conventional TRT). Patterns of
recurrence reflected improved local and local plus distant
recurrence rates with the accelerated irradiation, suggesting
that local treatment could have a significant impact on
outcome in L-SCLC. The major increased toxicity of the
accelerated regimen was a doubling of the severe acute
esophagitis rate.
An alternative approach to increasing the efficacy of
TRT, which has not been extensively explored in the treat-
ment of L-SCLC, is dose escalation with once-daily TRT.
Cancer and Leukemia Group B (CALGB) conducted a
Phase I limited-access trial (CALGB 8837), which demon-
strated that TRT doses between 56 Gy and 70 Gy were
tolerable when delivered with conventionally fractionated
radiotherapy (6). Long-term results of this trial are provoc-
● J. A. BOGART et al. 461
ative, because more than one-third of patients receiving
once daily TRT were alive at 6 years (7). Furthermore,
although the number of patients treated was small, a dose–
response relationship was suggested. We, therefore, theo-
rized that treatment with a high-dose once-daily regimen
might improve tumor control while providing a favorable
acute toxicity profile in comparison to modest dose, accel-
erated TRT. Thus one important objective in developing
CALGB 39808 was to assess the feasibility of delivering 70
Gy once-daily TRT in a group-wide setting.
METHODS AND MATERIALS
Eligibility
Requirements for protocol entry included histologically
or cytologically documented L-SCLC. Limited-stage dis-
ease category included disease restricted to one hemithorax
with regional lymph node metastases, including hilar, ipsi-
lateral, and contralateral mediastinal lymph nodes. Patients
with clinically suspected or confirmed supraclavicular
lymph node metastases and patients with pleural effusions
that were visible on plain chest radiographs were not eligi-
ble. Measurable disease was required, including any mass
reproducibly measured in a single dimension (the longest
diameter) or in two dimensions (two perpendicular diame-
ters) by physical examination or imaging study. Staging
evaluation included a posteroanterior and lateral chest X-
ray, computed tomography (CT), or magnetic resonance
imaging (MRI) scan of the chest, liver, and adrenal glands;
CT or MRI scan of the brain; and bone scan. Required initial
laboratory values included granulocytes ⱖ1,500/␮L, a
platelet count of at least 100,000/␮L, serum creatinine less
than the upper limit of normal, bilirubin ⬍1.5 mg/dl, and
SGOT (AST) ⬍2⫻ the upper limit of normal. The mini-
mum age for protocol entry was 18 years, Eastern Cooper-
ative Oncology Group performance status 0 –2 was re-
quired, and patients with prior cancer treated with either
radiotherapy or chemotherapy were not eligible. All patients
were evaluated by a medical oncologist and a radiation
oncologist before entry on study. Investigations were per-
formed after approval by a local Human Investigations
Committee. Informed consent was obtained from all pa-
tients. Patient registration was managed by the CALGB
Statistical Center.
Treatment plan
Patients received two cycles of induction chemotherapy
with topotecan and paclitaxel, with granulocyte colony
stimulating factor support, at 21-day intervals followed by
restaging evaluation with a chest X-ray and CT or MRI scan
of the chest, liver, and adrenal glands. Patients without
disease progression then received three cycles of consoli-
dation therapy with etoposide and carboplatin at 21-day
intervals, coincident with TRT. After a second restaging,
those patients who achieved complete response (CR) or
good partial response (PR) in the opinion of the investigator
were offered prophylactic cranial irradiation. Assessment of
462 I. J. Radiation Oncology ● Biology ● Physics
toxicity, according to the common toxicity criteria of the
National Cancer Institute, was performed at the start of each
chemotherapy cycle, and patients were evaluated weekly
while undergoing radiotherapy.
Induction chemotherapy
Induction chemotherapy consisted of topotecan (1 mg/
m2/day intravenously [IV] Days 1–5 and 22–26) and pacli-
taxel (175 mg/m2 IV over 3 hours Days 1 and 22). Granu-
locyte colony stimulating factor (5 ␮g/kg subcutaneously)
was given every day starting on Days 6 and 27 until the
postnadir absolute neutrophil count was ⱖ10,000/␮L.
Dexamethasone, diphenhydramine, and cimetidine were
given before paclitaxel administration.
Consolidation chemotherapy
Consolidation chemotherapy consisted of carboplatin
(area under the curve ⫽ 5) IV Days 43, 64, and 85 and
etoposide 100 mg/m2/day over 1 h IV Days 42– 44, 64 – 66,
and 85– 87.
Thoracic radiotherapy
All patients without evidence of progressive disease were
scheduled to begin TRT on Day 43 if absolute neutrophil
count ⬎1500/␮L and platelets ⬎100,000/␮L. If counts
were below these values, counts were repeated twice weekly
and TRT was started when granulocytes ⬎1500/␮L and
platelets ⬎100,000/␮L. Close monitoring of the patient’s
clinical condition and prompt institution of supportive care
were recommended. Sucralfate suspension (1 g by mouth
four times a day) and antifungal therapy (e.g., fluconazole
100 mg by mouth every day) were suggested at the onset of
radiotherapy in an effort to minimize symptomatic esoph-
agitis.
Thoracic radiotherapy planning was based on volumes
from the restaging chest CT obtained after induction che-
motherapy. Three-dimensional conformal radiotherapy
guidelines were incorporated, and treatment with either
two-dimensional or three-dimensional techniques was al-
lowed. The gross target volume (GTV) included residual
lung tumor after induction chemotherapy and involved
lymph node regions (both prechemotherapy and postchemo-
therapy). The initial clinical target volume (CTV) included
the GTV plus the ipsilateral hilar lymph nodes and medi-
astinal lymph node stations 3, 4, and 7 (e.g., precarinal,
lower paratracheal, and subcarinal). Mediastinal lymph
node stations 5 and 6 (e.g., aorta-pulmonary window and
para-aortic) were included in the GTV for left-sided tumors.
After a tumor dose of 44 Gy, the CTV included only the
GTV and ipsilateral hilar lymph nodes. The planning target
volume included the CTV ⫹ 1 cm. Treatment was pre-
scribed to the isocenter and tissue heterogeneity corrections
were not used. The maximum spinal cord dose was limited
to 50 Gy, no more than 50% of the combined lung volume
was allowed to receive 25 Gy, and the entire heart volume
had to receive less than 25 Gy. TRT planning data, includ-
ing copies of radiographic studies and simulation and ver-
Volume 59, Number 2, 2004
ification films for each field (with target volumes drawn on
the simulation films), photographs of the patient in the
treatment position, a dosimetry summary form including the
minimum and maximum dose and the planning target vol-
ume, copies of work sheets or printouts used for calcula-
tions, and copies of isodose distributions, was submitted for
review by the Quality Assurance Review Center during the
initial 3 days of treatment. In addition, copies of additional
simulation films and verification films with any major field
modifications, a copy of the patient’s radiotherapy record
including the prescription and daily and cumulative doses to
all required areas of reference points, and copies of isodoses
were submitted to Quality Assurance Review Center within
1 week of completing therapy. Interruption of TRT was
mandated for Grade 4 esophagitis or Grade 4 neutropenia
with fever, and therapy could be restarted when the accom-
panying toxicity declined to ⱕGrade 2.
Cranial radiotherapy
Prophylactic cranial irradiation (PCI) was recommended
after a CR or good PR to all therapy. PCI was scheduled to
start 3 to 5 weeks after completion of chemotherapy, and
concurrent PCI and chemotherapy was not allowed. The
dose and fractionation of PCI were at the discretion of the
individual investigator.
Follow-up and response measurement
After the completion of treatment, patients were sched-
uled for evaluation every 3 months for 2 years, then every
6 months for 3 years, and subsequently at 1-year intervals
for 5 additional years. At each follow-up visit, patients
underwent a medical history and physical examination,
complete blood count, and chest radiography. A CT or MRI
scan of the chest was obtained every 6 months for 2 years,
and then yearly for 2 additional years.
The criteria for CR were the disappearance of all disease,
including signs, symptoms, radiographic, and biochemical
changes related to the tumor. For patients with all disease
measurements in two dimensions, PR was defined as a
reduction of ⬎50% of the sum of the longest diameters of
all measured target lesions without the development of new
lesions or enlargement of any existing lesion. Stable disease
was defined as a ⬍50% reduction or ⬍25% increase in the
sum of the longest diameters of all measured target lesions
compared with the size present at entry on study without the
development of new lesions or enlargement of any existing
lesion. Objective progression or relapse was defined as an
increase in the sum of longest diameters of all measured
target lesions by ⱖ30% compared with the size present at
entry on study or, for those patients who responded, the size
at the time of maximum regression or the appearance of new
lesions or sites of disease.
For patients with disease measurements in one dimen-
sion, PR was defined as a reduction of ⬎30% of the sum of
the longest diameters of all measured target lesions without
the development of new lesions or enlargement of any
existing lesion. Stable disease was defined as a ⬍30%
 70 Gy thoracic radiotherapy ● J. A. BOGART et al. 463

reduction or ⬍30% increase in the sum of the longest Table 1. Patient characteristics
diameters of all measured target lesions compared with the
n
size present at entry on study without the development of
new lesions or enlargement of any existing lesion. Objective Gender
progression or relapse was defined as an increase in the Male 34 (54%)
product of two perpendicular diameters of any measured Female 29 (46%)
Age
lesion by ⱖ25% compared with the size present at entry on ⬍40 1 (2%)
study, or, for those patients who responded, the size at the 40–49 8 (13%)
time of maximum regression or the development of new 50–59 20 (32%)
lesions or sites of disease. 60–69 27 (43%)
70–79 7 (11%)
Median (minimum, maximum) 60 (42, 73)
Study design and statistical methods Race
A single-stage Phase II study design was used to deter- White 57 (90%)
mine whether a treatment regimen consisting of two cycles Hispanic 1 (2%)
of paclitaxel and topotecan followed by radiation-intensive Black 5 (8%)
consolidation chemotherapy has sufficient merit to compare Performance status
0 31 (49%)
against “standard” treatment for L-SCLC. With an accrual 1 29 (46%)
goal of 60 patients, the study was designed to have greater 2 3 (5%)
than 90% power to differentiate between a complete re- Weight loss (6 months)
sponse to the full chemoradiotherapy regimen of 50% and Unknown 2 (3%)
70% for a test conducted at the 0.05 level of significance. ⬍5% 40 (63%)
5%–10% 14 (22%)
Kaplan-Meier curves were used to describe overall sur- ⬎10% 7 (11%)
vival and failure-free survival. Survival time was defined as
the time between initiation of induction chemotherapy and
death. Failure-free survival time was computed as the time
between initiation of induction chemotherapy and disease exsanguination via the oral cavity. Nonhematologic Grade
progression or death. 3/4 toxicities reported in more than 10% of patients were
dysphagia (16%/5%) and febrile neutropenia (12%/4%).
Pulmonary toxicity was limited: 3 patients had Grade 3
RESULTS
dyspnea (5%) during chemoradiotherapy or in the follow-up
Seventy-five patients were enrolled on study between period. No Grade 4 pulmonary toxicity related to TRT has
March 15, 1999, and June 15, 2000. The initial 10 patients been reported. Grade 3/4 hematologic toxicity was common
were assigned to receive 60 Gy TRT to assess initial toler- during combined therapy, although only 1 patient required a
ability of the combined treatment plan and were not in- platelet transfusion and 2 patients required packed red blood
cluded in this analysis. Because treatment was deemed cell transfusion.
tolerable, the following 65 consecutive patients were as-
signed to receive 70 Gy TRT. One patient withdrew consent Response
before receiving any treatment and 1 patient was found to be The response to induction chemotherapy is shown in
ineligible because of metastasis to the left breast, leaving 63 Table 3a, and the best response to overall therapy in shown
patients for this analysis in Table 3b. Two complete (3%) and 47 partial (75%)
responses were documented after the two induction cycles
Patient characteristics of topotecan and paclitaxel. After the completion of all
Patient characteristics are shown in Table 1. There was a systemic therapy, 44% (28 of 63) of patients experienced a
slight male predominance, and the median age was 60 years. radiographic CR. Fifteen additional patients (24%) had a
Performance status was fairly evenly split between 0 and 1 “sustained PR,” defined as a radiographic PR without signs
with 5% performance status 2 patients. Weight loss in the 6 of disease progression for at least 6 months after completing
months before protocol entry was ⬎5% in 33% of patients therapy. Another 15 patients (24%) were considered con-
and ⬎10% in 11% of patients. ventional partial responders. The overall response rate was
92%.
Toxicity
Fifty-seven of 63 patients (90%) proceeded to TRT after Survival
induction chemotherapy and were available for evaluation Survival figures (Table 4) are calculated on a modified
of toxicity. Thirty-three patients received protocol PCI. intent-to-treat basis for all eligible patients assigned to re-
Toxicities reported during or after concurrent chemoradio- ceive 70 Gy TRT, regardless of whether TRT was actually
therapy are listed in Table 2. There was one lethal treat- given. With a median follow-up of 24.7 months, 28 of 63
ment-related toxicity. This patient discontinued TRT at 64 patients remain alive. The median overall survival and fail-
Gy, and was found to have expired at home because of ure-free survival are 22.4 months and 13.4 months, respec-
464 I. J. Radiation Oncology ● Biology ● Physics Volume 59, Number 2, 2004

Table 2. Toxic effects during or following concurrent therapy

Grade of adverse event

3 (severe) 4 (life threatening) 5 (lethal)

n % n % n % Total

Blood/bone marrow
Neutrophils/granulocytes 16 28% 25 44% 0 0% 57
Leukocytes 7 12% 4 7% 0 0% 57
Hemoglobin 10 18% 1 2% 0 0% 57
Lymphopenia 5 9% 1 2% 0 0% 57
Platelets 19 33% 3 5% 0 0% 57
Gastrointestinal
Dysphagia 9 16% 3 5% 0 0% 57
Infection/febrile neutropenia
Febrile neutropenia 7 12% 2 4% 0 0% 57
Pulmonary
Dyspnea 3 5% 0 0% 0 0% 57

tively. Two-year overall survival and failure-free survival
are 48% and 31%, respectively. Figures 1a and 1b illustrate
the Kaplan-Meier survival and failure-free survival curves
for patients assigned to receive 70 Gy. Mature data reflect-
ing patterns of relapse are not yet available. At the time of
this writing, however, only one relapse has been scored as
being within the initial prechemotherapy volume but outside
of the irradiated volume. Ten patients have relapsed locally
within the high-dose (e.g., 70 Gy) volume, whereas no
relapses have been limited to the low dose (e.g., 44 Gy)
volume.
DISCUSSION
The results of this multi-institutional prospective Phase II
trial demonstrate that 70 Gy every day TRT can be safely
delivered concurrent with chemotherapy in the treatment of
L-SCLC. The overall toxic effects of therapy are compara-
ble with other recent trials using more modest total doses of
TRT, and the incidence of severe esophagitis is reduced
compared with reports of accelerated TRT (5). Furthermore,
few patients developed acute or late respiratory toxic ef-
fects. The tolerability of the 70 Gy TRT used in this trial
may have been enhanced by several factors. For example,
radiotherapy treatment volumes were defined after two cy-
cles of induction chemotherapy. Because the response rate
to induction chemotherapy was 78%, induction therapy
Table 3a. Tumor response to induction chemotherapy
Response
CR 2 (3%)
PR 47 (75%)
Stable 12 (19%)
PD 1 (2%)
Early death* 1 (2%)
Overall response rate 49/63 (78%)
95% CI (64%, 88%)
served to limit the amount of functioning lung irradiated. In
addition, although elective nodal irradiation was employed,
only select mediastinal stations and the ipsilateral hilum
were routinely treated. Furthermore, three-dimensional con-
formal radiotherapy techniques were used in approximately
50% of patients, which may have reduced the volume of
normal tissue irradiated. Finally, the substitution of carbo-
platin for cisplatin may also have improved the tolerability
of chemoradiotherapy. In any event, our data suggest high-
dose every day TRT is achievable in a multi-institutional
setting.
The current outcome data from this trial are encouraging,
particularly in terms of median survival, 2-year overall
survival and 2-year failure-free survival. The overall (92%)
and complete (44%) radiographic response rates are com-
parable with other modern series in L-SCLC patient (5, 8).
Moreover, we observed a subset of patients with sustained
PR who had outcomes similar to CR patients. Post-TRT
fibrotic changes on radiographic exams may account for the
Table 3b. Best response to therapy
Response
CR 28 (44%)
sPR 15 (24%)
PR 15 (24%)
Stable 3 (5%)
PD 1 (2%)
Early death* 1 (2%)
CR or sPR rate 43/63 ⫽ 68%
95% CI (55%, 79%)
Overall response rate 58/63 ⫽ 92%
95% CI (81%, 98%)
Abbreviations: CR ⫽ complete response; PR ⫽ partial re-
sponse; PD ⫽ objective progression; CI ⫽ confidence interval;
sPR ⫽ sustained PR.
* Early deaths include patients who die within 50 days of
registration without reassessment of their disease. One patient
died, day 14 after first cycle of chemotherapy, of post obstructive
pneumonia. The death was not considered treatment related.
 70 Gy thoracic radiotherapy ● J. A. BOGART et al. 465

Table 4. Survival statistics

n Number of events Median (months) 2-year

Overall survival 63 35 22.4 (15.2, ⬁) 48% (37%, 63%)

Failure-free survival 63 43 13.4 (9.9, 29.9) 31% (22%, 45%)

Fig. 1. (a) Overall survival curve. (b) Failure-free survival curve.

466 I. J. Radiation Oncology ● Biology ● Physics Volume 59, Number 2, 2004

Table 5. Comparison of INT-0096 and CALGB 39808 be among the barriers to treating patients in multiple daily
sessions.
CALGB
Trial INT-0096 39808 High-dose daily TRT is frequently incorporated into clin-
ical practice, despite the fact that few Phase III trials in any
Thoracic radiotherapy regimen 45 Gy 70 Gy disease have demonstrated superiority for using higher than
twice daily every day “standard” total doses of conventionally fractionated radia-
Patient and tumor characteristics
Male 58% 54%
tion. A dose escalation trial for non–small-cell lung cancer,
Weight loss ⬎ 5% 18% 31% performed by the Radiation Therapy Oncology Group in the
Age, years (median) 61 60 1970s, demonstrated improved response rates and in-field
Supraclavicular adenopathy 4% 0 tumor control with higher doses of radiotherapy, but long-
Toxicity profile term survival was uniformly poor (12). More recently, a
Hematologic toxicity 87% 83%
Esophagitis 32% 21%
randomized Phase III trial showed no benefit from escalat-
Outcome ing the RT dose from 50.4 Gy to 64.8 Gy, concurrent with
Median overall survival 20.3 22.4 chemotherapy, in the treatment of locally advanced esoph-
months months ageal carcinoma (13). A Phase III randomized trial compar-
2-year overall survival 44% 48% ing 45 Gy twice daily with 70 Gy every day would be a
2-year DFS 29% 31%
critical test of the paradigm of dose escalation. If a greater
Abbreviation: DFS ⫽ disease-free survival. than 50% increase in nominal total dose did not translate
into a superior overall outcome, then the strategy of achiev-
ing a maximal dose of conventionally fractionated radio-
discrepancy between radiographic and true CR. This obser- therapy, employed in a multitude of prospective Phase I and
vation was made for patients receiving modest-dose accel- Phase II trials, would have to be reassessed.
erated TRT (but not conventional TRT) on INT-0096 (9). The induction regimen of paclitaxel and topotecan has
Therefore, the percentage of patients achieving a radio- been tested as first-line therapy in L-SCLC and in patients
graphic CR may not be an appropriate endpoint for trials with relapsed or refractory SCLC. Phase II studies have
incorporating aggressive TRT. reported a 46% response rate for topotecan in extensive-
Prolonged follow-up is necessary to fully evaluate the stage SCLC (14). Paclitaxel also has reported single-agent
efficacy of treatment for L-SCLC. For instance, in the initial activity rates in extensive stage SCLC of up to 34% (15). A
reports of INT-0096, there was no survival difference be- recent Phase II trial evaluating paclitaxel and topotecan as
tween treatment arms at approximately 2 years of follow-up, initial therapy for extensive SCLC demonstrated an overall
but a significant difference emerged with additional fol- response rate of 69% and a median survival of 9.9 months
low-up (5, 10). Similarly, the results of patients treated with (16). These results do not suggest an advantage to this
high-dose every day TRT on CALGB 8837 were reported to regimen compared to cisplatin and etoposide. Therefore, the
improve over time (6, 7). Keeping this in mind, a compar- contribution of this novel induction regimen to the favorable
ison of the experimental arm of INT-0096 and CALGB overall survival experience noted here is not easily dis-
39808 is shown in Table 5. In the two studies, the patient cerned.
and tumor characteristics were similar, with the exception of We substituted carboplatin in place of cisplatin during
a higher percentage of patients with weight loss on CALGB concurrent chemoradiotherapy for several reasons, includ-
39808 and a small number of patients with ipsilateral su- ing the ease of delivery of carboplatin compared with cis-
praclavicular adenopathy on the intergroup trial. Hemato- platin as well as the reduction in nonhematologic toxicity
logic toxicity appears similar, but there was less esophagitis noted with carboplatin. Although the substitution of carbo-
in the CALGB trial. Median survival at a median follow-up platin for cisplatin has been a contentious issue (17), the
of 2 years and other survival outcomes are comparable. results of three comparative trials have not demonstrated a
There are no relevant prospective comparative data to difference in efficacy between cisplatin and carboplatin in
evaluate the relative merits of conventional dose escalation the treatment of extensive small-cell lung cancer (18 –20).
and dose intensification with accelerated fractionation in Whether this result extends to the treatment L-SCLC re-
patients with L-SCLC. The results of a comparative trial mains unclear and is fertile ground for future research. The
would have important practical and biologic ramifications. value of the 70 Gy TRT regimen may even be considered
Despite a reported survival benefit, accelerated TRT has not somewhat more encouraging given the results obtained
been widely adopted in clinical practice. Patterns of care without the use of cisplatin.
data show that 10% of L-SCLC patients were treated with A cumulative total of five cycles of chemotherapy was
accelerated TRT during 1998 and 1999. Although the re- used, because this has been standard in CALGB trials for
sults of INT-0096 were published in 1999 in the New L-SCLC. Although the results of INT-0096, which em-
England Journal of Medicine, it is estimated that only ployed four cycles of chemotherapy, were particularly en-
approximately 25% of centers presently treat L-SCLC pa- couraging, the optimal number of chemotherapy cycles has
tients with accelerated TRT (11). The perceived severe not been studied prospectively for L-SCLC.
acute toxicity of twice-daily TRT and practical issues may Conclusions regarding the timing of TRT cannot be
 70 Gy thoracic radiotherapy
drawn from the results of this study. Prior randomized trials
have reported conflicting results. A study by the National
Cancer Institute of Canada randomized patients to receive
TRT (40 Gy/3 weeks) beginning concurrently with either
the second or the sixth cycle of chemotherapy (21). Overall
survival was superior in the arm that used the earlier irra-
diation, primarily because of a reduction in the development
of brain metastases. CALGB trial 8083 examined a com-
parison of TRT concurrent with the first cycle of chemo-
therapy and TRT initiated with the fourth chemotherapy
cycle. There was a trend toward improved survival with
cycle 4 radiotherapy compared with cycle 1 radiotherapy
(22). However, this study has been criticized because of
mandatory dose reductions of chemotherapy that dispropor-
tionately affected the early radiotherapy group. More recent
trials addressing the timing of TRT have not resolved the
issue (23–25).
The issue of optimum TRT volume in L-SCLC therapy
has not been extensively studied in comparative trials. Only
one trial, conducted by the Southwest Oncology Group,
prospectively studied TRT volume in relation to induction
chemotherapy. In that trial, patients with a partial response
to induction chemotherapy were randomized to receive TRT
encompassing either the initial tumor volume or the residual
tumor following induction chemotherapy (26). The extent
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