Presenter: Stephen Swisher, MD Presenter's Affiliation: MD Anderson Cancer Center Type of Session: Scientific
Prior studies (RTOG 8501) have demonstrated that chemoradiation is more effective than radiation alone in the treatment of esophageal cancer. However, in this study the majority of patients had squamous cell carcinoma and at present the most common histology is adenocarcinoma. There was also still a high rate of locoregional recurrence.
To improve on the results from RTOG 8501, other studies (INT 0123) have tried to escalate the radiation dose with concurrent chemotherapy. Others (INT 0122) have added neoadjuvant chemotherapy and escalated both dose and chemotherapy intensity to try and improve outcomes. However, there was no significant improvement in either study and there was increased toxicity.
In order to investigate new ways to improve outcomes this study incorporates induction chemotherapy with the addition of paclitaxel to 5-FU and cisplatin followed by concurrent chemoradiation. Additionally, this study sought to determine outcomes in a cohort of patients with a large proportion of adenocarcinomas.
Chemoradiation was used as definitive treatment for the esophageal cancer. There was to be selective surgical salvage for residual or recurrent disease.
Materials and Methods
The present study (RTOG 0246) is a prospective phase II study of 43 patients accrued from September 2003 to March 2006.
40 patients were eligible for analysis.
Patients had to have tumors more advanced than T1, N0 and have no evidence of metastatic disease to be enrolled in this study. All patients had to have resectable disease.
5-FU was given at a dose of 650 mg/m2/day with cisplatin at a dose of 15 mg/m2/day and paclitaxel 200 mg/m2/day for two cycles.
5-FU 300 mg/m2/day daily. Cisplatin was given at a dose of 15 mg/m2/day for the first five days of radiation treatment.
Radiation was given concurrently in 180 cGy fractions to a final dose of 50.4 Gy.
After definitive chemoradiation, patients were monitored for recurrent or residual disease with serial chest and abdomen CT scans and endoscopic ultrasound (EUS). PET surveillance was optional.
Salvage surgery was recommended for patients with recurrent or residual disease who did not have distant disease.
The primary endpoint of this study was 1 year overall survival. This study was designed to be powered to detect a change in 1 year overall survival from 60 to 77.5% with a target accrual of 38 patients. Secondary endpoints were locoregional control, toxicity, and feasibility of this treatment in patients with adenocarcinoma.
83% of patients were male and the median age of patients was 60 (42-81 years old).
73% of patients had adenocarcinomas
Pretreatment clinical stage:
75% of patients had T3 or T4 disease.
70% had N1 disease
Median follow up 22 months
40 patients were treated with induction chemotherapy and one died during induction chemotherapy. Two more patients died after induction chemotherapy but prior to the start of chemoradiation.
Hence 37 patients (93%) went on to chemoradiation. One patient is thought to have died of pulmonary toxicity related to treatment.
17 (43%) patients were found to have residual disease after treatment with chemoradiation (1.1 to 3.9 months after chemoradiation). One patient died during surgery. The remaining 16 all had pathological evidence of residual disease.
Two additional patients insisted on surgery. One was found to have a pathological complete response and the other had residual disease.
During surveillance after definitive chemoradiation an additional three patients (5-16 months after chemoradiation) were suspected to have recurrent disease and underwent resection.
Toxicity was similar to previous studies with 66% of patients having grade 3 or 4 toxicity.
One year survival was 71%, with 17 patients alive with no evidence of disease. Of the 17 patients who are alive with no evidence of disease, 12 had salvage surgery while five had definitive chemoradiation alone.
While the one year survival did not reach the threshold that the study was powered for, the results (71%) compare favorably with historical data (~52% with adenocarcinoma and ~60% for adenocarcinoma/squamous cell carcinoma). The one year survival from this study is better than a previous study of trimodality therapy by Walsh, and has comparable survival compared with a trimodality study by Urba.
These findings suggest that selective surgery after treatment with definitive chemoradiation is a feasible approach to treating adenocarcinoma of the esophagus.
Anal cancer has served as a model for organ preservation with chemoradiation followed by salvage surgery as necessary in the GI system. Early data looking at combined treatment of rectal cancers suggest that higher pathological complete response rates are seen when radiation is used concurrently with new chemotherapy regimens and biological agents. If these pathological complete response rates continue to improve, it may be reasonable to consider definitive concurrent chemoradiation followed by salvage surgery as necessary. This study applies this concept to esophageal cancer. This study provides an interesting start for considering organ preservation of the esophagus. However, in the current study about half (19) of patients still went on to have surgery either for recurrence or residual disease. Furthermore, two insisted on surgery of which one had residual disease. This would suggest that the complete response rate was ~50%. The majority of patients still alive with no evidence of disease underwent surgery (12/17). These findings are promising, but suggest that like rectal, other systemic agents should be considered to improve complete response rates. Furthermore, with more aggressive support, it may be possible to treat patients to higher doses and further improve pathological complete response rates. That being said, 12 of 20 patients who had surgery are free of disease suggesting that the delay in surgery may not compromise disease control and the use of salvage therapy at the time of recurrence may spare some patients from surgery.
Surgery is thought to add improved local control after chemoradiation. This study asked the interesting question of whether it is necessary to perform surgery for all patients immediately or whether, with surveillance; we can detect patients with recurrence and only operate on those patients. It is still early in follow up, but the results from this study are encouraging with one year survival comparable to previous studies of trimodality treatment. Unfortunately, at present they have not completed analysis of patients with recurrent disease to determine if patients were failing predominantly locoregionally or distantly. This would allow a comparison to historical local recurrence data to see if local control appears similar after definitive chemoradiation and surgery. Though still clearly investigational this study presents an intriguing beginning for organ sparing therapy for esophageal cancers.
Partially funded by an unrestricted educational grant from Bristol-Myers Squibb.
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