Commentary (Putnam): Primary Combined-Modality Therapy for Esophageal Cancer

Commentary (Putnam): Primary Combined-Modality Therapy for Esophageal Cancer

In this issue of ONCOLOGY, Dr. Minsky provides a compelling argument for combined-modality therapy (ie, chemotherapy and radiation therapy) for esophageal carcinoma. The need for sustained improvements in both local and systemic control is painfully real to our patients and to physicians treating this disease. In the United States, approximately 14,450 new cases of esophageal carcinoma will be diagnosed in 2006, and 13,770 patients—more than 75% male—will die of the disease.[1] According to the Surveillance, Epidemiology, and End Results (SEER) statistics, the 5-year survival rate for esophageal carcinoma based on stage at diagnosis (1995-2001) is 14.9% overall: 31.4% for local disease; 13.8 for regional disease, and 2.7 % for distant disease.[1] Combined-modality therapy for systemic control has become a well-accepted standard for unresectable or medically inoperable patients.[2]

Challenges of Combined-Modality Therapy

Combined-modality therapy has been used successfully to treat carcinoma of the esophagus.[3] In North America, most patients with this disease have distal adenocarcinoma of the esophagus, which may involve the gastro-esophageal junction. A meta-analysis of induction combined-modality therapy followed by resection noted that this treatment sequence improved 3-year survival and reduced local recurrence compared to resection alone.[4]

Although complete pathologic response is associated with improved survival following combined-modality therapy, we cannot consistently define which patients will have a complete response and which will have residual microscopic disease,[5] to select patients who would optimally benefit from resection. Esophagectomy after combined-modality therapy decreases locoregional recurrence compared to no resection[6] but may increase morbidity.

The recent MRC Adjuvant Gastric Infusional Chemotherapy (MAGIC) trial[7] noted that perioperative chemotherapy significantly improved resectability, progression-free survival, and overall survival in operable gastric and lower esophageal cancer patients. National Comprehensive Cancer Network (NCCN) guidelines recommend combined-modality therapy alone, or induction combined-modality therapy with resection.[2]

The use of combined-modality therapy in lieu of resection poses specific challenges, including:

• Inconsistent clinical staging prior to any therapeutic intervention.

• Variable systemic and local control without resection.

• Lack of any defined role of chemotherapy and radiation in early disease (eg, high-grade dysplasia, or stage T1, N0, M0).

• Lack of a standard evaluation of response to treatment.

• Subjective, rather than objective, measurement of dysphagia and symptom relief (ie, improvement of quality of life). Although the FACT-E has been commonly used, this assessment is designed for chemotherapy symptoms rather than surgical results. Recurrence of dysphagia (and recurrence of tumor) after combined-modality therapy alone may be inconsistently documented given the paucity of additional effective treatments.

• Consistency of follow-up and evaluation (after treatment), including detection and documentation of recurrence, and need for follow-up.

• Variable outcomes with increased costs.

Esophageal Resection

The morbidity and mortality of esophageal resection is well known, and a recent prospective randomized series suggests that a mortality of 6% (or lower) can be achieved.[8] Although induction chemotherapy was not shown to improve survival in this study, another recent study[9] demonstrated improved survival in patients receiving induction chemotherapy (16.8 vs 13.3 months for resection alone). Facility with the esophagectomy itself is a quality indicator, but the small number of patients seeking treatment diffuses experience in both combined-modality therapy and esophagectomy. Patients undergoing esophagectomy in hospitals performing fewer than five of these procedures per year have a mortality rate of 10% to 20%. Typically, these patients have the most consistently favorable outcomes at centers with surgeons who perform this operation frequently.[10] The surgeon who performs such esophageal procedures occasionally cannot consistently achieve acceptable rates of morbidity and mortality.

The surgeon must balance the risk of resection with the anticipated benefits of enhanced quality of life and better survival. Although the choice of operation does not significantly affect long-term survival,[11] the attendant risks in the early perioperative period (typically through 30 days after resection) and beyond must be minimized for resection advantages to be identified in clinical trials.


Clinical Trials

Excellent surgical results are required to eliminate compounding variables of surgical mortality. In addition, morbidity and mortality from combined-modality therapy must be accurately collected. The use of propensity analysis or a retrospective review of prospectively collected data is limited in that the refined and subjective judgment of the clinician can select optimal therapy for individual patients. This observation may be a result of access to high-volume centers with expertise in esophagectomy, aggressive medical oncologists using specific combination chemotherapy, and/or talented radiation oncologists using standard, conformal intensity-modulated radiation therapy or proton therapy for improved treatment.


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