The impact of radiation therapy sequencing on survival and cardiopulmonary mortality in the combined modality treatment of patients with esophageal cancer

Abstract

BACKGROUND: The addition of chemoradiation (CRT) to surgery has been shown to improve survival in patients with esophageal cancer. In the current study, the authors determined whether the sequencing of CRT has an effect on survival and cardiopulmonary mortality in patients with esophageal cancer. METHODS: Patients with the following inclusion criteria were identified within 17 Surveillance, Epidemiology, and End Results registries from 1988 through 2007: adenocarcinoma or squamous cell carcinoma of the esophagus and having undergone esophagectomy. Patients who died within 90 days of surgery were excluded. Demographic, tumor, and survival data were compared between patients receiving preoperative and postoperative RT. Cox proportional hazards regression models were calculated to identify parameters associated with cause-specific survival and overall survival. A competing risk analysis was performed to account for death due to esophageal cancer in the calculation of cardiopulmonary mortality. RESULTS: Of 5512 patients, 1881 received preoperative RT, 901 received postoperative RT, and 2730 did not receive RT. Patients receiving preoperative RT had improved 5-year cause-specific survival (41% vs 31%; P < .0001) and overall survival (33% vs 23%; P < .0001) compared with those receiving postoperative RT. No differences in adjusted cardiopulmonary mortality were found between patients who received RT versus those who did not (8% vs 10% at 10 years; hazards ratio [HR] KEYWORDS: esophageal neoplasms, combined modality therapy, radiation oncology, survival, heart diseases, lung diseases. INTRODUCTIONIn patients with locally advanced esophageal cancer, the addition of chemoradiation (CRT) to surgery has shown improvements in overall survival (OS) when given preoperatively. [1][2][3][4][5][6] In the subset of patients with tumors of the gastroesophageal junction, CRT delivered postoperatively has also demonstrated a survival benefit. 7 To the best of our knowledge, no randomized controlled trials currently exist that compare the outcomes of the sequencing of CRT in relation to surgery in patients with esophageal cancer.Preoperative CRT is preferred over postoperative treatment in patients with other gastrointestinal malignancies such as rectal cancer, in whom preoperative CRT has been demonstrated to have a superior locoregional control rate, toxicity profile, and survival rate. 8,9 It is postulated that preoperative treatment is favored because of tumor downstaging and smaller radiation treatment fields. We hypothesized that preoperative RT is associated with decreased cardiopulmonary mortality from lower RT doses to the heart and lungs as well as improved survival outcomes compared with postoperative RT in patients with esophageal cancer.Using the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) database, we assessed differences in survival outcomes between patients treated with preoperative RT and those treated with postoperative RT and analyzed the effect of RT on heart and lung morbidity a...

Reply to When randomized trials and observational data disagree: The case of preoperative versus postoperative chemoradiotherapy for esophageal cancer

“…However, in our study, we conducted a thorough sensitivity analysis to assess the effects of unmeasured variables, such as clinical tumor staging. 2 A similar sensitivity analysis demonstrated that, even if the preoperative patients were half as likely to have comorbid disease as postoperative patients, our statistically significant results would hold.Palma et al suggest that some of the postoperative patients may have received radiotherapy for palliation of early recurrence after surgery, confounding the results. This is unlikely, because SEER data only capture first course of treatment information within 4 months of the cancer diagnosis, and the likelihood of patients developing recurrence within the first few months after surgery is less than 5% according to recent randomized data.…”

“…However, in our study, we conducted a thorough sensitivity analysis to assess the effects of unmeasured variables, such as clinical tumor staging. 2 A similar sensitivity analysis demonstrated that, even if the preoperative patients were half as likely to have comorbid disease as postoperative patients, our statistically significant results would hold.…”

Value of radiotherapy in addition to esophagectomy for stage II and III thoracic esophageal squamous cell carcinoma: Analysis of surveillance, epidemiology, and end results database

“…At presentation, more than one‐third of esophageal cancer patients have stage II or III disease . Multimodality treatments, including different combinations of radiotherapy and various chemotherapy regimens, may improve overall prognosis . Currently, preoperative chemoradiation followed by surgery is the most preferred treatment for stage II‐III thoracic esophageal squamous cell carcinoma (TESCC) of the middle or distal third .…”

“…various chemotherapy regimens, may improve overall prognosis. [4][5][6][7][8] Currently, preoperative chemoradiation followed by surgery is the most preferred treatment for stage II-III thoracic esophageal squamous cell carcinoma (TESCC) of the middle or distal third. [9][10][11] However, because of the pathological heterogeneity of patients enrolled in different studies, the survival benefit provided by preoperative chemoradiation has not yet been definitely established.…”

When randomized trials and observational data disagree: The case of preoperative versus postoperative chemoradiotherapy for esophageal cancer

“…We read with interest the recent study by Wojcieszynski and colleagues, who used the Surveillance, Epidemiology, and End Results (SEER) database to assess "whether the sequencing of chemoradiotherapy (CRT) has an effect on survival and cardiopulmonary mortality" for esophageal cancer. 1 Although chemotherapy data are not available in SEER, the authors use the delivery of radiotherapy (RT) as a surrogate for CRT, assuming that RT is "almost always administered concurrently with chemotherapy." 1 The findings are striking: the use of preoperative RT was associated with a 10% improvement in 5-year survival compared with postoperative RT (P < .0001).…”