Cooper JS, Guo MD, Herskovic A, Macdonald JS, Martenson, Jr JA, Al-Sarraf M, Byhardt R, Russell AH, Beitler JJ, Spencer S, Asbell SO, Graham MV, Leichman LL. Chemoradiotherapy of Locally Advanced Esophageal CancerLong-term Follow-up of a Prospective Randomized Trial (RTOG 85-01). JAMA. 1999;281(17):1623-1627. doi:10.1001/jama.281.17.1623
Author Affiliations: Department of Radiation Oncology, New York University, New York, NY (Dr Cooper); Radiation Therapy Oncology Group Headquarters, Philadelphia, Pa (Dr Guo); Department of Radiation Oncology, Wayne State University, Detroit, Mich (Dr Herskovic); Department of Medical Oncology, St Vincent's Cancer Center, New York, NY (Dr Macdonald); Department of Radiation Oncology, Mayo Clinic, Rochester, Minn (Dr Martenson); Department of Medical Oncology, Providence Cancer Center, Southfield, Mich (Dr Al-Sarraf); Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee (Dr Byhardt); Department of Radiation Oncology, Radiation Oncology Center, Sacramento, Calif (Dr Russell); Department of Radiation Oncology, Albert Einstein College of Medicine, New York, NY (Dr Beitler); Department of Radiation Oncology, University of Alabama, Birmingham (Dr Spencer); Department of Radiation Oncology, Albert Einstein Medical Center, Philadelphia (Dr Asbell); Department of Radiation Oncology, Washington University, St Louis, Mo (Dr Graham); and Department of Medical Oncology, Roswell Park Cancer Institute, Buffalo, NY (Dr Leichman).
Context Carcinoma of the esophagus traditionally has been
treated by surgery or radiation therapy (RT), but 5-year overall
survival rates have been only 5% to 10%. We previously reported
results of a study conducted from January 1986 to April 1990 of
combined chemotherapy and RT vs RT alone when an interim analysis
revealed significant benefit for combined therapy.
Objective To report the long-term outcomes of a previously
reported trial designed to determine if adding chemotherapy during RT
improves the survival rate of patients with esophageal carcinoma.
Design Randomized controlled trial conducted 1985 to 1990 with
follow-up of at least 5 years, followed by a prospective cohort study
conducted between May 1990 and April 1991.
Setting Multi-institution participation, ranging from tertiary
academic referral centers to general community practices.
Patients Patients had squamous cell or adenocarcinoma of the
esophagus, T1-3 N0-1 M0, adequate renal and bone marrow reserve, and a
Karnofsky score of at least 50.
Interventions Combined modality therapy (n=134):
50 Gy in 25 fractions over 5 weeks, plus cisplatin intravenously on the
first day of weeks 1, 5, 8, and 11, and fluorouracil, 1
g/m2 per day by continuous infusion on the first 4 days of
weeks 1, 5, 8, and 11. In the randomized study, combined therapy was
compared with RT only (n=62): 64 Gy in 32 fractions
over 6.4 weeks.
Main Outcome Measures Overall survival, patterns of failure, and
Results Combined therapy significantly increased overall survival
compared with RT alone. In the randomized part of the trial, at 5 years
of follow-up the overall survival for combined therapy was 26% (95%
confidence interval [CI], 15%-37%) compared with 0% following RT.
In the succeeding nonrandomized part, combined therapy produced a
5-year overall survival of 14% (95% CI, 6%-23%). Persistence of
disease (despite therapy) was the most common mode of treatment
failure; however, it was less common in the groups receiving combined
therapy (34/130 [26%]) than in the group treated with RT only (23/62
[37%]). Severe acute toxic effects also were greater in the combined
therapy groups. There were no significant differences in severe late
toxic effects between the groups. However, chemotherapy could be
administered as planned in only 89 (68%) of 130 patients (10% had
life-threatening toxic effects with combined therapy vs 2% in the RT
Conclusion Combined therapy increases the survival of
patients who have squamous cell or adenocarcinoma of the esophagus,
T1-3 N0-1 M0, compared with RT alone.
The risk of
esophageal cancer is growing; over the past 20 years the incidence rate
has increased 14.8%.1 Moreover, carcinomas of the
esophagus have been among the most resistant to treatment. Mean
survival following traditional therapy has approximated only 9 months.
Earlam and Cuhna-Melo's2 1980 review of 122 articles
describing the surgical care of 83,783 cases of squamous cell
carcinoma of the esophagus revealed a paltry 5-year survival rate of
4%. Their subsequent review of the role of radiation therapy (RT)
found an almost equally dismal rate of 6%.3 While
improvements in technique have occurred and more modern surgical series
tend to report survival rates in the 20% range, at least some
investigators believe the major explanation for this has been earlier
detection of tumors.4 The first evidence that the
integration of chemotherapy with RT could improve outcome surfaced in
the early 1980s.
Several pilot studies using cisplatin and
fluorouracil suggested that median survival could be lenghtened
to 13 months.5- 11
In 1985, the Radiation Therapy Oncology Group (RTOG) launched
RTOG 85-01, a prospective, randomized, phase 3 trial testing the
hypothesis that concurrent chemoradiotherapy followed by adjuvant
chemotherapy could improve the overall survival rate of patients who
had carcinoma of the thoracic esophagus (without evidence of distant
disease) compared with RT alone. Initially, the study allowed only
squamous cell tumors, but adenocarcinomas were included after October
1986. To facilitate completion of the trial, the Southwest Oncology
Group and the North Central Cancer Treatment Group collaboratively
enrolled patients. Thus, the results reflect a diverse spectrum of
patients and clinical settings for cancer care.
In early 1990, a preplanned interim analysis (detailed below) resulted
in early termination of the random allocation of treatment because the
group receiving combined modality therapy was surviving significantly
longer. Thereafter, a separate cohort of patients who would have been
eligible for participation in the trial were prospectively registered
and treated only with combined modality therapy.
Preliminary results of this trial have been published
elsewhere12,13; however, we report the long-term survival
beyond 5 years and the first as detailed by the CONSORT
Patients were eligible for this trial if they had
nondisseminated squamous or adenocarcinoma of the thoracic esophagus
and a normal tracheobronchial tree, white blood cell count of at least
4.0 × 109/L, a platelet count of at least 10.0 ×
109/L, serum creatinine level no greater than 133 µmol/L
(1.5 mg/dL), and serum urea nitrogen level no greater than 7.85 mmol/L
(22 mg/dL) (and/or creatinine clearance at least 1.0 mL/s [60
mL/min]), Karnofsky score of at least 50, no prior or concurrent other
malignancy, and no prior chest irradiation or chemotherapy.
The combined modality therapy consisted of cisplatin, 75
mg/m2 intravenously, on the first day of weeks 1, 5, 8, and
11. The patients were given a continuous infusion of fluorouracil, 1
g/m2, for the first 4 days of weeks 1, 5, 8, and 11. From
the supraclavicular fossae to the esophagogastric junction, radiation
was delivered at 30 Gy in 15 fractions over 3 weeks starting on day 1,
followed by 20 Gy in 10 fractions over 2 weeks to the initial tumor
length plus a 5-cm margin. The RT consisted of 50 Gy in 25 fractions
over 5 weeks to the tumor plus a 5-cm margin cephalad and caudad
(including the supraclavicular fossae for lesions of the middle and
upper third of the thoracic esophagus) starting on day 1 and followed
by 14 Gy in 7 fractions over 1.4 weeks including the initial tumor
length with a 5-cm margin cephalad and caudad.
The primary outcome measure for this study was overall survival.
Secondary end points were patterns of treatment failure, and acute and
late (ie, more than 90 days from initiation of treatment) toxic
Target size was projected based on the estimate that 2-year
survival in the group getting RT alone would be 10%. A 20%
improvement in survival (ie, from 10% to 30%) was sought with
combined modality therapy. A 2-tailed test was used because of the
possibility that the addition of chemotherapy would be so toxic that
survival would be shortened. Sample size calculations were designed to
detect this difference with a type I error of .05, a statistical power
of 0.90, and an assumption that up to 10% of patients subsequently
would be deemed ineligible and/or have inadequate follow-up. This
resulted in a total planned sample size of 150.
The date of randomization was used as the starting point for all time
to event variables. Persistence of tumor was counted as an immediate
local failure. Time to local failure was estimated by the cumulative
incidence approach and
compared with the Gray statistic.15
Estimates of survival rates were derived by the Kaplan-Meier
method,16 and comparisons were made using the log-rank
statistic.17 All statistical comparisons were made with
2-tailed tests on an intent-to-treat basis.
Interim analysis of survival data was scheduled for the next
semi-annual RTOG meeting after data for 56 cases were available. The
O'Brien-Fleming method18 was applied to account for
multiple interim analyses. If either treatment group had a highly
significant improvement in survival (log-rank test, P<.005),
a recommendation was to be made to discontinue patient accrual.
At an interim analysis in May 1990 (90 evaluable cases had been
accrued), the survival rates were statistically different at
P=.005 (2-sided log-rank test) and favored the
combined modality therapy arm. After consultation with clinicians and
statisticians at the National Cancer Institute, a decision was made to
suspend randomization and assign all patients to combined modality
This protocol was approved by the National Cancer
Institute, each of the participating national cooperative groups,
and the individual review boards of each of the participating
institutions. Patients provided signed informed consent prior to
randomization of care.
Randomization was done centrally at RTOG headquarters, balancing
histology, tumor size, and weight loss among institutions.
A total of 129 patients were enrolled between January 1986 and April
1990 when a planned interim analysis revealed a difference that
satisfied the "early stopping rule." Over the next year, 73
consecutive patients were treated uniformly by chemoradiotherapy.
Figure 1 and Figure 2 indicate that chemoradiotherapy had
greater noncompliance than RT. All but 2 patients (lost to follow-up at
3.25 and 4.94 years) have now been followed up for a minimum of 5
Analysis of pretreatment characteristics revealed no
statistically significant differences in the baseline features between
the randomized cohorts.13 The nonrandomized group had
relatively fewer T2 tumors (more T1 and more T3); otherwise, the groups
were not significantly different.
Long-term overall survival was associated with combined modality
therapy (Table 1). By 5 years, 26%
(95% confidence interval [CI], 15%-37%) of the randomized combined
modality group and 14% (95% CI, 6%-23%) of the nonrandomized
combined modality group were alive vs none in the RT group. Our data
are now sufficiently mature to conclude that 22% of the randomized
combined modality group survived at least 8 years following therapy, to
project that the 10-year survival rate may be as high as 20% and to
observe that no deaths that occurred after 5 years were due to
esophageal cancer, indicating that these patients are truly cured of
their disease (not merely palliated for a longer time). There were no
statistical differences in survival related to histology in those
patients treated with combined modality therapy (Table 2).
Persistence of disease was the greatest cause of treatment
failure in every group of patients (Table 3). However, it was 40% more common in the
group receiving RT alone (37% following RT only; 25% and 28%
following combined modality therapy in the randomized and nonrandomized
cohorts, respectively). Moreover, chemoradiotherapy appeared to
prevent, not merely delay, the local growth of tumor (Figure 3).
Eight percent of the cohort randomly assigned to combined modality
therapy experienced acute life-threatening (ie, grade 4) toxic effects
on the RTOG acute morbidity scale and an additional 2% died as a
direct consequence of treatment. In contrast, only 2% of patients
receiving RT alone experienced acute grade 4 toxic effects and there
were no fatalities due to toxic effects. Interestingly, the
nonrandomized combined modality group experienced a lower grade 4 rate
(4% vs 8%) and no fatalities, perhaps reflecting greater experience
with this management plan (despite receiving more drugs).13
In contrast, once patients survived more than 90 days based on time
from the beginning of treatment, there were no significant differences
in (late RTOG scale) toxic effects between the groups (Table 4).
Carcinoma of the esophagus has been highly lethal even though distant
metastases do not occur in the majority of patients until late in the
course of their disease. Instead, carcinomas of the esophagus tend to
spread axially, up and down the length of the organ and to regional
lymphatics, producing their morbidity and mortality from local-regional
effects. Consequently, the essential hypothesis of this trial was that
concurrently administered chemotherapy would act as a promoter of the
local-regional effects of RT as well as having direct cytotoxic effects
on its own. The decreased incidence of
persistent disease seen in this trial can be viewed
as evidence that this hypothesis is correct. In fact, the trial may
well have handicapped the efficacy of chemoradiation by using a smaller
dose of RT than was used for patients treated by RT alone (50 Gy vs 64
In addition, chemotherapy appears to have eradicated some
presumably subclinical distant metastases. Distant metastases (with or
without local-regional disease) accounted for the first site of
treatment failure in 30% of the RT group vs 16% in the randomized
combined modality therapy group and 26% in the nonrandomized combined
modality therapy group. This difference was evident even though the
increased life-span of patients who received chemotherapy placed them
at a longer (ie, greater) risk of developing distant metastases.
The 5-year minimum follow-up of patients first reported in this article
is critical for its proper interpretation. Based solely on the
preliminary findings of this trial, it was tenable to think that
combined modality therapy merely delays the time to failure (local,
regional, or distant). The long-term durability of the multimodality
therapy reported herein demonstrates that this regimen truly cures more
patients than does RT alone.
The reproducibility of the outcome in a separate, but similarly
selected, group of consecutively accrued patients who were treated by
combined modality therapy further demonstrates the value of
chemoradiotherapy in the treatment of patients who have esophageal
cancer. It seems reasonable to conclude that chemoradiotherapy now
should be considered a standard of care for patients who have carcinoma
of the esophagus.
Our trial did not address the potential role of surgery in
combination with chemoradiotherapy. There is some evidence that
chemoradiotherapy prior to surgery is feasible and more efficacious
than surgery alone. For example, Walsh et al19
prospectively tested surgery alone vs multimodality therapy for
esophageal adenocarcinoma (2 courses of fluorouracil and cisplatin plus
concurrent RT followed by surgery). Median survival time following
surgery alone was 11 months compared with 16 months following
multimodal therapy (P=.01). Results appeared
durable because 3-year survival was only 6% following surgery alone vs
32% following multimodal therapy (P=.01). The
authors concluded multimodal treatment is superior to surgery alone for
patients with resectable adenocarcinoma of the esophagus. Since
local-regional persistence of disease accounted for the majority of
treatment failures in our trial, surgery might be able to eradicate
some of these tumors.