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An Updated Report on the Pathologic Complete Response and Survival Outcome of Southwest Oncology Group (SWOG S0536): A Phase II Trial of Oxaliplatin (oxp) Plus Protracted Infusion 5-Fluorouracil (PIFU) and External Beam Radiation (EBRT) Prior to Surgery f
Reviewer: Samuel Swisher-McClure, MD
The Abramson Cancer Center of the University of Pennsylvania
Last Modified: November 1, 2010
Authors: L.P. Leichman, B. Goldman, C.R. Thomas, K.G. Billingsley, C.L. Corless, H. Lenz, S. Iqbal, J.K. Benedetti, P.J. Gold, C.D. Blanke.
Affiliations: Aptium Gastrointestinal Cancer Consortium. Palm Springs, CA. Southwest Oncology Group. Seattle, WA. Oregon Health Sciences University. Portland, OR. University of Southern California. Los Angeles, CA. Swedish Institute. Seattle, WA. University of British Columbia and British Cancer Agency. Vancouver, BC.
- Previously published randomized data support the use of neoadjuvant chemoradiation prior to surgery for patients with adenocarcinoma of the esophagus (Walsh et al. NEJM, 1996).
- Although neoadjuvant combined modality therapy (NACMTX) has become a standard of care in the United States, median overall survival (OS) for patients (PTS) with EA has changed little over the past 25 years.
- Progression free survival (PFS) and OS after NACMTX strongly correlate with extent of primary tumor response.
- Novel treatment regimen are needed and pathologic complete response (pCR) may be used as an early surrogate for efficacy of a given treatment regimen.
- Based on phase I data which established a tolerable dose schedule and reported a promising pCR rate of 81% (Khushalani et al. JCO, 2006), SWOG designed a phase II trial (S0356) to evaluate OXP with PI5FU and EBRT for patients with EA.
- Study Eligibility Criteria:
- Clinical stage II/III EA,
- ? 18 years
- Zubrod PS ? 2
- Standard hematologic/non-hematologic values
- Tumor ? 2 cm into the gastric cardia
- EUS was not required for staging unless there was no visible mass on CT scan.
- The Chemotherapy schedule was as follows:
- OXP 85 mg/m2 was given on days 1, 15, and 29.
- PI5FU 180 mg/m2/d was given on days 8-43.
- EBRT was initiated on day 8 and consisted of 25 fractions of 180 cGy/d, 5 days/week to total dose of 4500 c Gy.
- Surgery was planned 2-4 weeks after completion of NACMTx.
- There was then a second cycle of OXP/ PI5FU planned 4-6 weeks after Surgery.
- Objectives of the study included pCR ? 25%, acceptable toxicity, PFS, OS and exploration of molecular parameters relevant to pCR.
- Central pathology review of surgical specimens was mandated both pre-operatively and post-operatively.
- The trial used a 2-stage design; the trial was halted at 45 patients to review pCR rate; and then subsequently reopened to full accrual.
- A total of 98 patients were enrolled in the trial between 9/15/04 and 8/18/08.
- 6 patients were ineligible due to a diagnosis of Squamous Cell Carcinoma.
- 2 patients did not receive therapy (TX).
- Therefore a total of 90 patients were analyzed.
- The median age of the study population was 61.7 years.
- Of note, 84/90 patients (93%) enrolled in the trial were men.
- There were 4 treatment related deaths (4.5%) recorded.
- 2 of these deaths were thought to be directly related to NACMTX while 2 of the deaths were thought to have been related to surgical complications.
- Grade 3/4 toxicities were observed in 43% and 18% of patients respectively.
- The rates of specific Grade 3-4 toxicities were as follows: 39% GI, 22% Fatigue, 17% Pulmonary, 16% Hematologic, 14% Mucositis, 3% Neurologic.
- 77 patients (86%) were able to undergo surgery. The remaining patients either developed disease progression, refused surgery, or were denied surgery because of poor performance status.
- 30 patients (33%) had a pCR as determined by the treating institution. However, 4 of these patients were found to have residual cancer by central pathology review.
- Therefore the final reported pCR rate was 28.5 %.
- An additional 12 patients (10%) had very good treatment response with only residual in situ cancer or T1N0M0 found on final pathology.
- Only 40% of enrolled patients received the planned postoperative chemotherapy.
- The 3 year Overall Survival was found to be 48%.
- Among patients achieving pCR, 3 year OS was found to be 76%.
- The currently studied regimen of Neoadjuvant OXP/PIFU and RT for patients with EA has produced the highest pCR rate reported to date for a cooperative group trial.
- Significant but manageable non-hematologic toxicities were observed.
- Relatively few patients were able to tolerate post-operative chemotherapy. Therefore, future trials built on this platform should plan to complete all treatment before surgery.
- A significant number of cases initially thought to have had a pCR were overturned upon central pathology review. This highlights the importance for trials using pCR as an endpoint to require central pathology review.
- The regimen used in the current study provides a reasonable neoadjuvant combined modality treatment option for patients with adenocarcinoma of the esophagus.
- Further information regarding molecular correlates with clinical outcomes will be reported in future analyses.
- Neoadjuvant chemoradiation prior to esophagectomy provides significant benefit for patients with adenocarcinoma of the esophagus. However, the optimal chemotherapy regimen remains unknown.
- This study was a prospective single-arm phase II study enrolling 90 patients that examined combined modality therapy with OXP/PIFU plus RT prior to surgery.
- The observed pCR rate of 28.5 % is the highest reported to date in a cooperative group trial.
- The 3 year OS observed in patients who achieved a pCR was an impressive 76%.
- The observed toxicities were comparable with previously published experience in combined modality therapy for esophageal cancer. However, the toxicity results underscore the importance of aggressive supportive care for patients undergoing this type of therapy.
- The authors plan to further analyze molecular correlates associated with clinical outcomes in an effort to identify biomarkers that may be prognostic and associated with response to this treatment.
- Limitations of the study include:
- EUS was not required to evaluate T stage prior to treatment and therefore a detailed assessment of each patient's pre-treatment stage cannot be made.
- There were 4 treatment related deaths (4.5%) observed and Grade 3 toxicities were observed in close to half of patients. Therefore patients treated with this regimen should be carefully selected and extensively counseled regarding potential risks associated with treatment.
- The treatment regimen examined in this trial produced promising results that ultimately should be evaluated in the context of a phase III trial.