Failure patterns in patients with esophageal cancer treated with definitive chemoradiation

Localized esophageal carcinomas are highly aggressive and difficult to cure, as they often persist or recur after definitive chemoradiation. Esophageal cancer is the eighth most common causes of cancer, with 482,000 new cases and 407,000 deaths estimated worldwide in 2008, making it the sixth most common cause of death from cancer.1 The prevalence of esophageal cancer, specifically adenocarcinoma, in North America continues to increase in parallel with the growth in prevalence of obesity and gastroesophageal reflux disease leading to Barrett’s metaplasia.2-4 Although surgery continues to be the standard approach for most localized esophageal cancers, cure rates after surgery alone have been poor, with 3- to 5-year survival rates ranging from 6% to 35%.5-7 The current trimodality approach, combining chemotherapy, radiation therapy (RT), and surgery, has significantly improved prognosis,8 with several studies showing improved survival rates.9, 10 However, many patients cannot tolerate surgery or decline it; for such individuals, definitive chemoradiation is the standard approach. The combination of RT and chemotherapy has additive effects in terms of local control and overall survival in this select population.7, 9, 11, 12 However, the optimal dose of radiation for this purpose continues to be a topic of debate, with current recommendation is to use the same dose for preoperative RT as for definitive treatment, i.e., 50.4 Gy.13 Several studies have attempted to evaluate the potential benefit of dose-escalation for esophageal cancer. The largest such study Intergroup 0123 / Radiation Therapy Oncology Group 94-05,14 found that escalating the dose to 64.8 Gy did not improve survival or local-regional control yet may have contributed to increased morbidity. However, that study used two-dimensional conformal RT (2D-CRT) with a sequential boost for dose escalation, with larger margins for both the primary and high-dose volumes than are now considered standard practice. These large treatment fields may have resulted in excessive overall toxicity. Since that study was completed, advances in the technologies associated with tumor imaging and radiation planning and delivery have allowed improved accuracy. The use of highly conformal intensity-modulated radiation therapy (IMRT) has been demonstrated by several groups to provide additional flexibility in modifying dose distributions and improving normal tissue sparing.15 Compared with 2D-CRT, IMRT results in improved conformality and dose reduced to proximal critical structures. Further, use of a simultaneous integrated radiation boost with the IMRT offers the additional advantage of simultaneously delivering a higher dose to the primary tumor (at 2.2 Gy or 2.3 Gy per fraction) while lower conventional doses are used to treat subclinical disease or electively treated regions (at 1.8 Gy or 2.0 Gy per fraction).16 Nevertheless, despite these advances the doses used to treat esophageal cancer have remained the same. The principle of radiation dose escalation has translated into improved local control and enhanced survival for patients with other solid tumors, and one would anticipate similar benefits for patients with esophageal cancer, however, such studies have not been conducted.17-19 Since the current standard is to use the same RT dose for definitive and for preoperative therapy, we hypothesized that the treatment failure after definitive chemoradiation would occur in most patients within the gross tumor volume (GTV), where the tumor burden is largest. We sought here to document the sites of failure after standard-dose definitive chemoradiation therapy for esophageal cancer in terms of three commonly used radiation treatment volumes: GTV, the larger clinical target volume (CTV), and the still larger planning target volume (PTV). We further assessed a variety of patient- and disease-related characteristics for their potential utility as risk factors for identifying patterns of failure, reasoning that such factors would be useful in personalizing therapeutic approaches.