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Original Contribution |

Chemoradiotherapy of Locally Advanced Esophageal Cancer:  Long-term Follow-up of a Prospective Randomized Trial (RTOG 85-01) FREE

Jay S. Cooper, MD; Matthew D. Guo, PhD; Arnold Herskovic, MD; John S. Macdonald, MD; James A. Martenson, Jr, MD; Muhyi Al-Sarraf, MD; Roger Byhardt, MD; Anthony H. Russell, MD; Jonathan J. Beitler, MD, MBA; Sharon Spencer, MD; Sucha O. Asbell, MD; Mary V. Graham, MD; Lawrence L. Leichman, MD
[+] Author Affiliations

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).


JAMA. 1999;281(17):1623-1627. doi:10.1001/jama.281.17.1623.
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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 toxic effects.

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 only group).

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.

Figures in this Article

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.511

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 statement.14

Protocol Population

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.

Interventions

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.

End Points

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 effects.

Target Size

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.

Statistical Analysis

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.

Prospectively Defined Stopping Rules

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 therapy.

Informed Consent

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.

Assignment

Randomization was done centrally at RTOG headquarters, balancing histology, tumor size, and weight loss among institutions.

Populations

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 years.

Figure 1. Progress of Patients Through the Randomized Part of the Trial
Graphic Jump Location
Of the 61 patients randomized to receive combined modality therapy, 37 received chemotherapy as planned and 56 received radiation therapy as planned so that 36 of the 61 received both therapies as planned. Randomization period was from January 1986 to April 1990.
Figure 2. Progress of Patients Through the Nonrandomized Part of the Trial
Graphic Jump Location
Of the 69 patients assigned to receive combined modality therapy, 52 received chemotherapy as planned and 64 received radiation therapy as planned so that 50 of the 69 received both therapies as planned. Nonrandomization period was from May 1990 to April 1991.

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.

Survival

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).

Table Graphic Jump LocationTable 1. Overall Survival by Treatment Group*
Table Graphic Jump LocationTable 2. Survival Estimates by Histologic Type After Combined Modality Therapy*
Patterns of Failure

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).

Table Graphic Jump LocationTable 3. Location of Disease at First Treatment Failure*
Figure 3. Percentage of Patients Developing Local Disease by Treatment Group in Intergroup Protocol 85-01
Graphic Jump Location
Time to local failure by treatment arm plotted by Kaplan-Meier method. Comparisons based on log-rank χ2 statistic. Persistent tumors were counted as treatment failure immediately.
Toxic Effects

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).

Table Graphic Jump LocationTable 4. Late Reactions by Treatment Group and by Anatomic Site*

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 Gy).

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.

Harras A, Edwards BK, Blot WJ, Gloecker Ries LA. Cancer Rates and Risks. 4th ed. Washington, DC: US Dept of Health and Human Services, Public Health Service, National Institutes of Health; 1996. NIH publication 96-691.
Earlam R, Cuhna-Melo JR. Oesophageal squamous cell carcinoma, I: a critical review of surgery.  Br J Surg.1980;67:381-390.
Earlam R, Cuhna-Melo JR. Oesophageal squamous cell carcinoma, II: a critical review of radiotherapy.  Br J Surg.1980;67:457-461.
Swisher SG, Hunt KK, Holmes EC.  et al.  Changes in the surgical management of esophageal cancer from 1970 to 1993.  Am J Surg.1995;169:609-614.
Leichman L, Steiger Z, Seydel HG.  et al.  Combined preoperative chemotherapy and radiation therapy for cancer of the esophagus: the Wayne State University, Southwest Oncology Group and Radiation Therapy Oncology Group experience.  Semin Oncol.1984;11:178-185.
Kelsen DP, Bains M, Hilaris B.  et al.  Combination chemotherapy of esophageal carcinoma using cisplatin, vindesine, and bleomycin.  Cancer.1982;49:1174-1177.
Leichman L, Berry BT. Experience with cisplatin in treatment regimens for esophageal cancer.  Semin Oncol.1991;18(suppl 3):64-72.
Forastiere AA. Treatinent of loco-regional esophageal cancer.  Semin Oncol.1992;19(suppl 11):57-63.
Al-Sarraf M. The current status of combined modality treatment containing chemotherapy in patients with esophageal cancer.  Int J Radiat Oncol Biol Phys.1990;19:813-815.
Poplin F, Fleming T, Leichman L.  et al.  Combined therapies for squamous cell carcinoma of the esophagus, a Southwest Oncology Group study (SWOG-8037).  J Clin Oncol.1987;5:622-628.
Seydel HG, Leichman L, Byhardt R.  et al.  Preoperative radiation and chemotherapy for localized squamous cell carcinoma of the esophagus: a RTOG study.  Int J Radiat Oncol Biol Phys.1988;14:33-35.
Herskovic A, Martz K, Al-Sarraf M.  et al.  Combined chemotherapy and radiotherapy compared with radiotherapy alone in patients with cancer of the esophagus.  N Engl J Med.1992;326:1593-1598.
Al-Sarraf M, Martz K, Herskovic A.  et al.  Progress report of combined chemoradiotherapy versus radiotherapy alone in patients with esophageal cancer: an intergroup study.  J Clin Oncol.1997;15:277-284.
Begg C, Cho M, Eastwood S.  et al.  Improving the quality of reporting of randomized controlled trials: the CONSORT statement.  JAMA.1996;276:637-639.
Gray RJ. A class of K-sample tests for comparing the cumulative incidence of a competing risk.  Ann Stat.1998;16:1141-1154.
Kaplan EL, Meier P. Non-parametric estimation from incomplete observations.  J Am Stat Assoc.1958;3:457-481.
Mantel N, Haenszel W. Statistical aspects of the analysis of data from retrospective studies of disease.  J Natl Cancer Inst.1959;22:719-748.
O'Brien PC, Fleming TR. A multiple testing procedure for clinical trials.  Biometrics.1979;35:549-556.
Walsh TN, Noonan N, Hollywood D.  et al.  A comparison of multimodal therapy and surgery for esophageal adenocarcinoma.  N Engl J Med.1996;335:462-467.

Figures

Figure 1. Progress of Patients Through the Randomized Part of the Trial
Graphic Jump Location
Of the 61 patients randomized to receive combined modality therapy, 37 received chemotherapy as planned and 56 received radiation therapy as planned so that 36 of the 61 received both therapies as planned. Randomization period was from January 1986 to April 1990.
Figure 2. Progress of Patients Through the Nonrandomized Part of the Trial
Graphic Jump Location
Of the 69 patients assigned to receive combined modality therapy, 52 received chemotherapy as planned and 64 received radiation therapy as planned so that 50 of the 69 received both therapies as planned. Nonrandomization period was from May 1990 to April 1991.
Figure 3. Percentage of Patients Developing Local Disease by Treatment Group in Intergroup Protocol 85-01
Graphic Jump Location
Time to local failure by treatment arm plotted by Kaplan-Meier method. Comparisons based on log-rank χ2 statistic. Persistent tumors were counted as treatment failure immediately.

Tables

Table Graphic Jump LocationTable 1. Overall Survival by Treatment Group*
Table Graphic Jump LocationTable 2. Survival Estimates by Histologic Type After Combined Modality Therapy*
Table Graphic Jump LocationTable 3. Location of Disease at First Treatment Failure*
Table Graphic Jump LocationTable 4. Late Reactions by Treatment Group and by Anatomic Site*

References

Harras A, Edwards BK, Blot WJ, Gloecker Ries LA. Cancer Rates and Risks. 4th ed. Washington, DC: US Dept of Health and Human Services, Public Health Service, National Institutes of Health; 1996. NIH publication 96-691.
Earlam R, Cuhna-Melo JR. Oesophageal squamous cell carcinoma, I: a critical review of surgery.  Br J Surg.1980;67:381-390.
Earlam R, Cuhna-Melo JR. Oesophageal squamous cell carcinoma, II: a critical review of radiotherapy.  Br J Surg.1980;67:457-461.
Swisher SG, Hunt KK, Holmes EC.  et al.  Changes in the surgical management of esophageal cancer from 1970 to 1993.  Am J Surg.1995;169:609-614.
Leichman L, Steiger Z, Seydel HG.  et al.  Combined preoperative chemotherapy and radiation therapy for cancer of the esophagus: the Wayne State University, Southwest Oncology Group and Radiation Therapy Oncology Group experience.  Semin Oncol.1984;11:178-185.
Kelsen DP, Bains M, Hilaris B.  et al.  Combination chemotherapy of esophageal carcinoma using cisplatin, vindesine, and bleomycin.  Cancer.1982;49:1174-1177.
Leichman L, Berry BT. Experience with cisplatin in treatment regimens for esophageal cancer.  Semin Oncol.1991;18(suppl 3):64-72.
Forastiere AA. Treatinent of loco-regional esophageal cancer.  Semin Oncol.1992;19(suppl 11):57-63.
Al-Sarraf M. The current status of combined modality treatment containing chemotherapy in patients with esophageal cancer.  Int J Radiat Oncol Biol Phys.1990;19:813-815.
Poplin F, Fleming T, Leichman L.  et al.  Combined therapies for squamous cell carcinoma of the esophagus, a Southwest Oncology Group study (SWOG-8037).  J Clin Oncol.1987;5:622-628.
Seydel HG, Leichman L, Byhardt R.  et al.  Preoperative radiation and chemotherapy for localized squamous cell carcinoma of the esophagus: a RTOG study.  Int J Radiat Oncol Biol Phys.1988;14:33-35.
Herskovic A, Martz K, Al-Sarraf M.  et al.  Combined chemotherapy and radiotherapy compared with radiotherapy alone in patients with cancer of the esophagus.  N Engl J Med.1992;326:1593-1598.
Al-Sarraf M, Martz K, Herskovic A.  et al.  Progress report of combined chemoradiotherapy versus radiotherapy alone in patients with esophageal cancer: an intergroup study.  J Clin Oncol.1997;15:277-284.
Begg C, Cho M, Eastwood S.  et al.  Improving the quality of reporting of randomized controlled trials: the CONSORT statement.  JAMA.1996;276:637-639.
Gray RJ. A class of K-sample tests for comparing the cumulative incidence of a competing risk.  Ann Stat.1998;16:1141-1154.
Kaplan EL, Meier P. Non-parametric estimation from incomplete observations.  J Am Stat Assoc.1958;3:457-481.
Mantel N, Haenszel W. Statistical aspects of the analysis of data from retrospective studies of disease.  J Natl Cancer Inst.1959;22:719-748.
O'Brien PC, Fleming TR. A multiple testing procedure for clinical trials.  Biometrics.1979;35:549-556.
Walsh TN, Noonan N, Hollywood D.  et al.  A comparison of multimodal therapy and surgery for esophageal adenocarcinoma.  N Engl J Med.1996;335:462-467.
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