Download Final Results of Phase III Trial in Regionally

Final Results of Phase III Trial in Regionally Advanced
Unresectable Non-Small Cell Lung Cancer*
Radiation Therapy Oncology Group, Eastern
Cooperative Oncology Group, and Southwest
Oncology Group
William Sause, MD, FCCP; Patricia Kolesar; Samuel Taylor IV, MD;
David Johnson, MD; Robert Livingston, MD; Ritsuko Komaki, MD;
Bahman Emami, MD; Walter Curran, Jr., MD; Roger Byhardt, MD;
A. Rashid Dar, MD; and Andrew Turrisi III, MD
Study objectives: The purpose of this phase III clinical trial was to test whether chemotherapy
followed by radiation therapy resulted in superior survival to either hyperfractionated radiation
or standard radiation in surgically unresectable non-small cell lung cancer.
Design: Patients were prospectively randomized to 2 months of cisplatin, vinblastine chemotherapy followed by 60 Gy of radiation at 2.0 Gy per fraction or 1.2 Gy per fraction radiation delivered
twice daily to a total dose of 69.6 Gy, or 2.0 Gy per fraction of radiation once daily to 60 Gy.
Patients were enrolled from January 1989 through January 1992, and followed for a potential
minimum period of 5 years.
Setting: This trial was an intergroup National Cancer Institute–funded trial within the Radiation
Therapy Oncology Group, the Eastern Cooperative Oncology Group, and the Southwest
Oncology Group.
Patients: Patients with surgically unresectable non-small cell lung cancer, clinical stage II, IIIA,
and IIIB, were required to have a Karnofsky Performance Status of > 70 and a weight loss of
< 5% for 3 months before study entry. Four hundred ninety patients were registered on trial, of
which 458 patients were eligible.
Conclusion: Overall survival was statistically superior for the patients receiving chemotherapy
and radiation vs the other two arms of the study. The twice-daily radiation therapy arm, although
better, was not statistically superior in survival for those patients receiving standard radiation.
Median survival for standard radiation was 11.4 months; for chemotherapy and irradiation, 13.2
months; and for hyperfractionated irradiation, 12 months. The respective 5-year survivals were
5% for standard radiation therapy, 8% for chemotherapy followed by radiation therapy, and 6%
for hyperfractionated irradiation.
(CHEST 2000; 117:358 –364)
Key words: chemotherapy; hyperfractionated radiation; lung cancer; phase III trial; radiation
Abbreviations: CALGB ⫽ Cancer and Leukemia Group B 8433; KPS ⫽ Karnofsky Performance Status;
RTOG ⫽ Radiation Therapy Oncology Group
*From the LDS Hospital Radiation Therapy, Salt Lake
City, UT (Dr. Sause); RTOG Headquarters, Philadelphia, PA
(Ms. Kolesar); Illinois Masonic Cancer Center, Chicago, IL
(Dr. Taylor); Radiation Oncology, Vanderbilt Clinic, Nashville, TN (Dr. Johnson); University of Washington Medical
Center, Seattle, WA (Dr. Livingston); Division of Radiation
Oncology, MD Anderson Center, Houston, TX (Dr. Komaki);
Department of Radiotherapy, Edward Hines VA Hospital,
Hines, IL (Dr. Emami); Department of Radiation Oncology,
Thomas Jefferson University Hospital/Bodine Treatment Center, Philadelphia PA (Dr. Curran); Department of Radiation
Oncology, Zablocki VA Hospital, Milwaukee, WI (Dr.
Byhardt); London Regional Cancer Center, London, Ontario,
Canada (Dr. Dar); and Department of Radiation Oncology,
Medical University of South Carolina, Charleston, SC (Dr.
Turrisi)
Supported by NIH grants U10 CA21661, CCOP U10 CA37422,
and STAT U10 CA32115 to the RTOG (Dr. Sause, Ms. Kolesar,
Drs. Taylor, Komaki, Emami, Curran, Byhardt, and Dar); CA
21115 and STAT CA23318 to the ECOG (Drs. Johnson and
Turrisi); and U10 CA58861 to the Southwest Oncology Group
(Dr. Livingston).
Manuscript received March 30, 1999; revision accepted September 8, 1999.
Correspondence to: William Sause, MD, FCCP, LDS Hospital
Radiation Therapy, 400 C St, Salt Lake City, UT 84143
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Clinical Investigations
egionally advanced non-small cell lung cancer
R represents
the most common presentation of the
most common cause of cancer death in the United
States.1 Survival for regionally advanced non-small
cell lung cancer is extremely poor. Controversy exists
as to whether nonsurgical treatment in these patients
is capable of substantially altering the course of the
disease. Local regional radiation therapy has represented the traditional approach in these patients,
inasmuch as it represents, at a minimum, a useful
palliative tool and has resulted in occasional longterm survival.2 In attempts to improve the survival in
these patients, many investigators have added cytotoxic chemotherapy to external beam irradiation.3–11
Several phase III trials have been equivalent,5,6,9 –11
but more recently, several trials have been positive in
favor of combined therapy.3,4,8,12 This trial was designed to confirm the results of Cancer and Leukemia Group B 8433 (CALGB),8 which used induction
chemotherapy followed by irradiation.
This trial was also designed to test hyperfractionated irradiation. Hyperfractionated irradiation is
treatment that delivers radiation more than once
daily at total daily doses similar to that of standard
radiation and with an increase in overall total dose. A
previous phase I/II Radiation Therapy Oncology
Group (RTOG) trial suggested that hyperfractionated irradiation represented a therapeutic advantage
to standard irradiation.13
An important component of this trial was preselection of patients for good performance. It has been
recognized that patients with excessive weight loss
and poor Karnofsky Performance Status (KPS) do
poorly with nonsurgical therapy.7,14 For this reason,
this trial, as well as many others, included only
patients with minimal weight loss and relatively good
performance status.
Materials and Methods
Methods have been previously described.12 Eligibility included
patients who were surgically inoperable with American Joint
Committee on Cancer stage II, IIIA, or IIIB non-small cell lung
cancer.15 Patients were required to have a KPS ⱖ 70 and a weight
loss of ⬍ 5% for 3 months before study entry, to be ⬎ 18 years of
age, and to have no metastatic disease. Surgical staging was not
required. Patients with pleural effusions were excluded from
study participation. Pretreatment evaluation required a complete
history and physical examination, chest radiograph with thoracic
and upper abdominal CT, and laboratory studies (including a
CBC count, platelet count, measurements of calcium and bilirubin concentrations, urine analysis, and liver function studies).
Pulmonary function tests consisting of vital capacity, FEV1, and
carbon monoxide diffusing capacity of the lung were required of
the patients. Patients who had received prior chemotherapy or
irradiation were excluded from study participation, and patients
who had undergone curative surgical procedures were also
excluded. Patients signed a study-specific consent form that had
been approved by the institutional review board and all participating institutions.
Statistical variables included histologic cell type, KPS, and
clinical stage. The sample size was selected to detect a 49%
improvement in median survival in the experimental arm, with a
p ⬍ 0.05 and a power of ⱖ 80%. Theoretically, this study would
observe an improvement from a standard treatment arm median
survival of 8.7 months to experimental treatment arm median
survival of 13 months. We determined that 161 patients would
need to be registered in each treatment arm to ensure a statistical
validity of our observation. Our total registered sample size would
be 483 patients for the lifetime of the study. The Study Monitoring Committee evaluated the study midway through accrual to
ensure that no one treatment arm was statistically superior and
that accrual could continue as planned.
The standard radiation therapy arm (arm 1) and the induction
chemotherapy arm (arm 2) had similarly delivered irradiation.
Irradiation was delivered at 2 Gy per fraction, 5 days a week, to
a total dose of 60 Gy. There were no corrections for lung
inhomogeneity. Regional lymphatics, including the supraclavicular lymph nodes when the primary tumor was in the upper lobes
or mainstem bronchus, were included in the initial radiation
volume. The field included a 2-cm margin on the ipsilateral hilar
lymph nodes and a 1-cm margin on the contralateral hilar lymph
nodes. The subcarinal lymph nodes were included to 5 cm below
the carina. The regional lymphatics were treated to a total dose of
50 Gy at 2 Gy per fraction followed by a boost dose to the primary
neoplasm and all lymph nodes ⬎ 2.5 cm in diameter visualized on
CT scan before chemotherapy. The boost dose included a 2-cm
margin around the radiographically visible tumor, and the dose
was continued to 60 Gy. The spinal cord dose was limited to 45
Gy in treatment arms 1 and 2 of the study and to 50 Gy in the
hyperfractionated arm (treatment arm 3). A posterior spinal cord
block was not allowed in any arms of this study. The hyperfractionated radiation therapy arm (arm 3) consisted of 1.2 Gy per
fraction delivered twice daily (consecutive days, 5 days per week
until total dose achieved) to a total dose of 69.6 Gy. The study
required treatments to be 4 to 6 h apart, with field reduction
occurring at 50.4 Gy. Field sizes and target volumes in arm 3
were similar to those in arms 1 and 2. The dosimetry staff and one
investigator (W.T.S.) at RTOG headquarters retrospectively reviewed all field arrangements, target volumes, and dosimetry.
Treatment arm 2, which consisted of cisplatin and vinblastine
before irradiation, required that irradiation began on day 50. The
cisplatin (100 mg/m2) was administered IV for a 30- to 60-min
period on days 1 and 29. Adequate hydration was begun 24 h
before the use of cisplatin. Vinblastine (5 mg/m2) was administered by IV bolus weekly for 5 consecutive weeks beginning on
day 1 with cisplatin. Dose modifications were incorporated into
the trial and were based on the granulocyte and platelet counts.
One of us (S.T.) retrospectively reviewed all flow sheets to
evaluate chemotherapy. Central pathology review was not required in this trial, inasmuch as previously conducted trials
established good concordance between institutional and central
reviews.16
After completion of treatment, patients were evaluated every 2
months for up to 6 months, then every 3 months for 2 years, then
every 6 months. Follow-up evaluation included a plain radiograph of the chest, liver function studies, and CBC counts. More
sophisticated work-up was performed only if indicated. Sites and
times of recurrence were to be documented. Survival and time to
incidence of toxic effects were measured from the date of
registration on study. In the computation of the time-adjusted
incidence of toxicity, a bias associated with censoring patients
who die without morbidity may occur; to correct for this bias,
conditional probabilities were used.17 Survival estimates were
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359
computed by the product-limit method.18 The time to treatment
morbidity and survival were plotted as a step function. Testing for
difference in survival distribution was performed using the
log-rank status19 and the generalized Wilcoxon test.20 The latter
test is more sensitive to an early difference in the survival
distributions. All statistical tests were two-sided.
The study opened on January 20, 1989, and closed on January
25, 1992, with a total accrual of 490 patients. RTOG institutions
placed 348 patients on trial; Eastern Cooperative Oncology
Group institutions, 115 patients; and Southwest Oncology Group
institutions, 27 patients. All patients were followed for a minimum of 5 years or until death. The potential minimum follow-up
was 5 years. Thirty-two of the 490 patients entered in the trial
were either ineligible or had no analyzable data, which resulted in
a study population of 458 patients (Table 1). Table 2 shows the
pretreatment characteristics of the patients. Approximately 45%
of the patients in all treatment arms had stage IIIA disease and
approximately 50% had stage IIIB disease. Twenty-three patients
had T3N0 tumors; 9 of these patients were treated by standard
radiation therapy, 9 by chemotherapy and irradiation, and 5 by
hyperfractionated radiation therapy. As noted in Table 2, tumor
stage and histology were uniformly divided in all treatment arms.
Two thirds of the patients had a KPS of 90 to 100.
Results
Compliance to protocol was acceptable. Approximately 80% of patients received treatment per protocol with minor variation of protocol delivery. Major
acceptable variations in treatment were seen in only
5% of patients registered on treatment. One hundred twenty-two of 151 patients had chemotherapy
delivered by protocol. Table 3 outlines the delivery
of systemic therapy. Toxicity was acceptable. There
were six grade 4 or worse acute radiotherapy-related
toxic events: four on the hyperfractionated radiation
arm, one on the standard radiation therapy arm, and
one on the chemotherapy plus radiation therapy arm.
Two of the four toxic effects of hyperfractionated
radiation therapy were secondary to esophagitis. Two
patients on trial died of pulmonary toxicity secondary
Table 1—Case Status*
Status
Standard RT
CT ⫹ RT
HFX RT
Total
Patients randomly
accrued, No.
Patients ineligible—
no protocol
therapy, No.
Eligible patients,
No.
Patients with no
registration form,
No.
Patients properly
entered and
eligible, No.
163
164
163
490
10
12
6
28
153
152
157
462
1
0
3
4
152
152
154
458
Table 2—Patient Characteristics by Assigned
Treatment*
Standard RT CT ⫹ RT HFX RT
(n ⫽ 152) (n ⫽ 152) (n ⫽ 154)
Characteristic
Sex
Male
Female
KPS
90–100
70–80
Histologic diagnosis
Squamous
Adenocarcinoma
Large cell
Squamous/adenocarcinoma
Carcinoma not otherwise
specified
Other
Unknown
T stage
T1
T2
T3
T4
TX
N stage
N0
N1
N2
N3
Unknown
AJCC stage
II
IIIA
IIIB
105 (69)
47 (31)
109 (72)
43 (28)
108 (70)
46 (30)
100 (66)
52 (34)
106 (70)
46 (30)
106 (69)
48 (31)
68 (45)
50 (33)
13 (8)
5 (3)
9 (6)
66 (43)
57 (38)
17 (11)
5 (3)
3 (2)
68 (44)
48 (31)
22 (14)
1 (1)
8 (5)
7 (5)
0
4 (3)
0
6 (4)
1 (1)
12 (8)
59 (39)
48 (31)
32 (21)
1 (1)
17 (11)
51 (34)
36 (24)
47 (31)
1
14 (9)
54 (37)
39 (25)
45 (29)
2
20 (13)
13 (9)
72 (47)
47 (31)
0
22 (15)
14 (9)
85 (56)
31 (20)
0
14 (9)
14 (9)
87 (57)
38 (24)
1
9 (6)
67 (44)
76 (50)
10 (6)
68 (45)
74 (48)
7 (4)
71 (46)
76 (50)
No. (%) of patients by treatment.
See footnote for Table 1 for abbreviations.
to irradiation, one patient on the chemotherapy plus
radiation therapy and one on the hyperfractionated
radiation arm. Two chemotherapy-related deaths
were reported. Both were secondary to infection
before the commencement of irradiation. Table 4
represents the toxicity.
Table 5 and Figure 1 reflects the survival for all
patients entered on trial, with a minimum potential
follow-up of 5 years. The median survival for those
Table 3—Delivery of Systemic Therapy*
*RT ⫽ radiation therapy; CT ⫽ chemotherapy; HFX ⫽ hyperfractionated
Vinblastine Courses
Cisplatin
None
1 Course
2 Courses
Total No. of patients
0
1
2
3
4
5
Total No. of
Patients
1
0
0
1
0
3
0
3
0
6
1
7
0
3
11
14
0
0
51
51
0
1
67
68
1
13
130
144
*Number of patients. Flow sheet not available for eight patients.
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Clinical Investigations
months. All toxic deaths secondary to chemotherapy
were in patients ⬎ 70 years. In the entire study, 66
patients were ⬎ 70 years, 214 between 60 and 70
years, and 172 ⬍ 60 years of age, well balanced
between treatment arms.
Chemotherapy and irradiation was most effective
for nonsquamous cell types, with a median survival
for standard irradiation of 11.4 months and for
radiation plus chemotherapy, 15.6 months. Although
not statistically significant, those patients with squamous cell carcinoma treated with hyperfractionated
irradiation exhibited a 9% 5-year survival compared
with 2% in each of the other treatment arms.
Table 4 —Acute and Late Toxicity*
Toxicity
RT
CT/RT
HFX/RT
Acute ⬎ grade III
radiation
Acute ⬎ grade III
chemotherapy
Late ⬎ grade III
radiation‡
1
1 (1 grade V†)
4 (1 grade V†)
77 (3 grade V†)
3
5 (1 grade V†)
5 (2 grade V†)
*No. of patients. See Table 1 footnote for abbreviations.
†All grade V toxicity (death) occurred in patients ⬎ 60 years of age.
‡Late toxicity is ⱖ 90 days after treatment.
receiving standard irradiation was 11.4 months, and
the 5-year survival was 5%. The median survival for
those receiving chemotherapy plus irradiation was
13.2 months, with a 5-year survival of 8%; those
patients who received hyperfractionated irradiation
experienced a median survival of 12 months with a
5-year survival of 6%. The log-ranked statistical
comparison indicated chemotherapy plus irradiation
resulted in a superior survival equal to p ⫽ 0.04.
Several patients were lost to follow-up resulting in
some discrepancies in survival denominator.
Subset analysis was performed to detect a subgroup of patients which may benefit more substantially from a particular arm of treatment. Analysis
was performed comparing histology and age to treatment, which failed to reveal any known predictive
factors other than age, which was statistically significant for those patients receiving cytotoxic chemotherapy (Figs 2–5). For patients ⬍ 60 years of age,
median survival for radiation therapy alone was 11.7
months; for hyperfractionated irradiation, 11.5
months; and for standard irradiation with chemotherapy, 15.4 months. On the other hand, for patients ⬎ 70 years of age, the survival was best with
standard radiation therapy alone, with a median
survival of 13.1 months. The median survival for
chemotherapy followed by irradiation was 10.9
Discussion
The purpose of this trial was to test the hypothesis
that either induction chemotherapy followed by irradiation or hyperfractionated irradiation would provide superior survival to standard irradiation in regionally advanced non-small cell lung cancer. This
trial represents the largest trial in North America
comparing standard irradiation to chemotherapy followed by irradiation in regionally advanced nonsmall cell lung cancer, and the only phase III trial
comparing hyperfractionated irradiation to standard
irradiation in regionally advanced non-small cell lung
cancer. Our trial suggests that aggressively applied,
nonsurgical treatment can statistically improve the
survival and alter the natural history of this disease.
In our trial, the patients who exhibited the best
survival were those patients treated with induction
chemotherapy followed by irradiation. This confirms
a previous study conducted by the CALGB in the
United States.8
Several studies have been conducted worldwide
comparing irradiation therapy alone with irradiation
therapy and chemotherapy.3–11 Although many of
these trials have been equivalent,5,6,9 –11 several of
the more recently conducted trials using cisplatin-
Table 5—Overall Survival by Treatment Arm for all Patients*
RT ⫹ CT
RT Alone
HFX
Years
% Alive
No. at Risk
% Alive
No. at Risk
% Alive
No. at Risk
0
1
2
3
4
5
Median
Dead/Total
p value
100
47
21
11
6
5
152
70
31
16
8
4
100
59
32
17
11
8
149†
88
47
25
14
10
100
52
24
14
9
6
149†
74
36
21
13
7
11.4 months
145/152
13.2 months
136/149
12 months
143/149
0.04
*See footnote for Table 1 for abbreviations.
†Three patients in the RT/CT group and five patients in the HFX group were lost to follow-up on study information.
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361
Figure 1. RTOG 8808 survival by treatment, all patients.
RT ⫽ radiation therapy; RT ⫹ CT ⫽ radiation therapy plus chemotherapy; HFX ⫽ hyperfractionated irradiation therapy.
Figure 3. RTOG 8808 survival by treatment, patients ⬎ 70 years
old. See Figure 1 for abbreviations.
based chemotherapy have been positive in favor of
combined therapy.3,4,8,12 One published meta-analysis also suggests that cisplatin-based chemotherapy
added to irradiation provides a statistical improvement in survival.21 The survival benefit noted in our
trial is substantially less impressive than that observed by the CALGB. The survival benefit in our
trial is more in line with previously conducted trials
in France3 and in Great Britain.9 The French trial
did reach statistical significance, whereas the recent
trial conducted by the Medical Research Council did
not reach statistical significance.
Because the benefits of combined therapy are
relatively small, we performed a subset analysis to
see whether we could discover a subgroup most
likely to benefit from aggressive treatment. Our
analysis suggests that age represented a factor that
may predict a better survival to cytotoxic chemotherapy and irradiation. Interestingly, those patients
⬎ 70 years of age seemed to benefit from the least
aggressive treatment arm. Only 66 patients ⬎ 70
years old were registered in the study. This makes
sound conclusions regarding this observation difficult. Underrepresentation of elderly on clinical trials
is not unique to this study.22 Interestingly, the
CALGB trial, which suggested a more dramatic
benefit to combined therapy, had a greater proportion of patients ⬍ 60 years of age (45%) and fewer
patients with squamous cell cancer (36%) in the
combined arm than our trial.23
One should note that all patients in this protocol
were selected for protocol participation. All patients
treated in this study had high performance status and
minimal weight loss before enrollment. Extrapolation
of this aggressive form of therapy to other clinical
subgroups may not be appropriate. The RTOG has also
attempted to analyze sites of failure to define the
reason for benefit to combined therapy.24 The results
of the sites of failure analysis are conflicting and
probably relate to the difficulty of performing accurate
sites of failure analysis in large intergroup trials containing patients with lung cancer.
This study failed to confirm a benefit of hyperfrac-
Figure 2. RTOG 8808 survival by treatment, patients ⬍ 60 years
old. See Figure 1 for abbreviations.
Figure 4. RTOG 8808 survival by treatment, patients with
non-squamous cell cancer. See Figure 1 for abbreviations.
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Clinical Investigations
Figure 5. RTOG 8808 survival by treatment, patients with
squamous cell cancer. See Figure 1 for abbreviations.
tionated irradiation. Although the median survival of
those patients treated with multiple daily fractions
was intermediate to those receiving combined therapy and standard irradiation, this failed to reach
statistical significance. Interestingly, in squamous
cell disease, the 5-year survival was 9% vs 2% in the
other two treatment arms. The Medical Research
Council of Great Britain25 has recently completed an
accelerated radiotherapy trial in regionally advanced
non-small cell lung cancer. In this trial, patients were
randomized to receive either standard irradiation or
irradiation delivered 150 cGy, three times per day
for 12 consecutive days. This aggressive approach
provided a statistical improvement in survival to
those patients on the experimental arm. Interestingly, approximately 80% of patients treated in the
Great Britain trial had squamous cell cancer. It may
be that aggressively applied irradiation would be
most beneficial in squamous cell disease, whereas
chemotherapy and irradiation may provide more
benefit in nonsquamous cell cancers, an observation
that will need confirmation in other clinical trials.
This large phase III trial does confirm our ability
to alter the natural history of regionally advanced
non-small cell lung cancer with aggressively applied
nonsurgical therapy. Although the degree of improvement is relatively small, the frequency of this
disease reflects a potential benefit to large numbers
of patients. Around the world, groups are enrolling
patients in clinical trials that are attempting to
improve on these results. Hopefully, refinements in
these observations will allow more selective and
more sophisticated application of aggressive nonsurgical therapies in patients with regionally advanced
non-small cell lung cancer.
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