Abstract
Aim: To examine patterns of clinical practice in locally advanced esophageal cancer among US radiation oncologists after publication of the CROSS trial. Materials and Methods: US radiation oncologists were surveyed on 13 questions pertaining to the management of esophageal cancer. Respondents' demographics and their clinical rationale were analyzed for statistical association with their treatment recommendations. Results: Few respondents (15%) offered the CROSS regimen to patients considered suitable surgical candidates, while a near-equivalent number (16%) prescribed between 41.4 and 50.4 Gy contingent upon radiation planning parameters. Among respondents who prescribed 50.4 Gy, 50% and 17% reported concurrent administration of carboplatin/paclitaxel and cisplatin/5-FU, respectively. Higher radiation doses, over 50.4 Gy, were utilized by 15% and 38% of respondents for borderline surgical candidates and candidates unfit for surgery, respectively. The majority of respondents believed that higher complete pathological response and R0 resection would be achieved, as well as higher toxicity conferred using 50.4 Gy instead of 41.4 Gy. A clinical trial comparing 41.4 Gy to 50.4 Gy with concurrent carboplatin/paclitaxel was supported by 76% of respondents. Conclusion: Despite results from the CROSS trial, the majority of responding US radiation oncologists do not offer 41.4 Gy with concurrent chemotherapy for surgically-fit patients with locally advanced esophageal cancer, believing that a higher dose will translate to improved response.
Esophageal cancer predominantly manifests as a locally aggressive malignancy, ranking it globally as the sixth leading cause of cancer-related deaths (1). In 2018, there will be an estimated 17,290 individuals diagnosed with esophageal cancer with estimated deaths of 15,850 patients (2). Its clinical behavior has correspondingly shifted therapeutic management from a single modality to more aggressive tri-modality therapy (TMT) in the form of pre-operative chemoradiation (3-6).
CALGB 9781 was one of the initial prospective evaluations of preoperative chemoradiation, which randomized esophageal cancer patients to concurrent 50.4 Gy, cisplatin, and 5-fluorouracil followed by surgery versus surgery alone. With significant improvement in median overall survival (OS) to 4.5 years with TMT compared to 1.8 years in the surgery-alone arm, the current standard radiation dose was extrapolated from this study (4). However, this trial closed early due to poor accrual and reported on only 56, out of 500 planned patients, who were treated in the pre-intensity modulated radiation therapy (IMRT) era. The CROSS trial is the most recent randomized trial elucidating the role of preoperative (TMT), and it reported on a larger number of operable patients (n=368) randomized to surgery alone versus 41.4 Gy, carboplatin, and paclitaxel, followed by surgery. TMT with radiation dose at 41.4 Gy conferred a median OS of 49.4 months versus 24.0 months among surgery-alone patients. Furthermore, a R0 resection was achieved in 92% with TMT compared to 29% in the surgery alone patients (5).
As the CROSS trial did not specifically address dose de-escalation compared to the North American standard radiation dose, the adoption of the CROSS regimen has been met with uncertainty (7). In this light, we implemented a survey to ascertain the management of esophageal cancer among US radiation oncologists after the publication of the CROSS regimen.
Materials and Methods
Study population. Institutional Review Board approval was obtained for formulation and dissemination of an electronic email-based survey. A national database of radiation oncology personnel including attending and resident physicians was used to invite participation; respondents were assured anonymity. No honorarium for survey completion was offered. In the pre-determined interval of data acquisition and final analysis, we received 296 evaluable responses.
Survey design. The survey was comprised of thirteen questions. The initial five questions addressed respondent demographics. Questions 6-8 asked respondents to choose their preferred treatment option for patients considered good, borderline, or unresectable surgical candidates. The remaining questions addressed physicians' beliefs in regard to radiation dose, 50.4 Gy vs. 41.4 Gy, its effect on toxicity, pathologic complete response, R0 resection and the physician's willingness to enroll to a trial comparing 41.4 Gy vs. 50.4 Gy with concurrent carboplatin/paclitaxel. Data were securely collected and stored using the institutional Research Electronic Data Capture (REDCAP) (8).
Statistical analysis. Descriptive statistics were applied to report basic respondent characteristics. Univariate and multivariate nominal logistic regression analysis was performed to examine final treatment recommendations based on physician-respondent characteristics and clinico-pathologic rationale. Application of statistical tests was performed with senior departmental biostatisticians. All p-values were two-sided. In an attempt to reduce false positive results, an alpha level of 0.01 declared statistical significance. JMP Version 12 (Cary, NC) was used for statistical analysis.
Results
Physician demographics. Physician demographics included year since completing residency, practicing setting, practice region, and approximation of definitive esophageal cases seen over the last year are summarized in Table I. Over half (56%) of the respondents were over 10 years from completion of residency, while the majority of the remainder were either new graduates or less than 10 years from completion of residency. Sixty-one percent treated greater than five definitive cases of esophageal cancer within the previous calendar year. The response rates between academic and private practice centers were similar.
Management recommendations. Radiation oncologist recommendations based on surgeon-evaluated operative candidacy are summarized in Table II. The most common pre-operative or definitive regimen administrated across all patients is carboplatin/paclitaxel in combination with 50.4 Gy. Chemoradiation to 50.4 Gy with concurrent cisplatin/5-FU is used by 17%, 19% and 23% of respondents for good, borderline and poor surgical candidates, respectively. Few (15%) respondents recommend the CROSS regimen for good surgical candidates. For resectable candidates, dosimetric planning parameters influenced 16% of respondents on their use of either 41.4 or 50.4 Gy. Dose escalation beyond 50.4 Gy with concurrent chemotherapy is prescribed by 15% and 38% of physicians for borderline surgical candidates and poor surgical candidates, respectively.
Characteristics of 296 US radiation oncologists who responded to the survey.
Factors influencing recommendations. Eighty-five percent (n=251) of respondents held the opinion that 50.4 Gy yields a higher pathologic complete response rate than 41.4 Gy. On multivariate analysis, these subset of respondents were more likely to prescribe doses higher than 41. 4 Gy for good surgical candidates, and private practice physicians were more likely than academic radiation oncologists to hold this opinion. There was a trend toward significance among physicians in closer temporal proximity, namely less than 10 years, to their training to hold the opposite view (Table III).
Sixty-six percent (n=195) of respondents believe 50.4 Gy increases the likelihood of R0 resection compared to 41.4 Gy. The significant influences on this opinion were similar to those observed regarding higher dose and pathologic response. The additional distinct significant parameter was that physicians with less than 10 years of post-residency experience were less likely to believe doses higher than 41.4 Gy would lead to higher likelihood of R0 resection (Table IV).
Recommended treatments by US radiation oncologists based on patient's surgical candidacy.
Correlation between physician's belief that 50.4 Gy of radiation therapy yields a higher pathological complete response compared to 41.4 Gy and respondent's characteristics.
Fifty-four percent (n=158) of respondents believe that 50.4 Gy causes more toxicity than 41. 4 Gy. Multivariate analysis determined that physicians early in their career (<10 years practicing) were significantly more likely to believe 50.4 Gy causes more toxicity than 41.4 Gy (p=0.01) (Table V).
Correlation between physician's belief that 50.4 Gy of radiation therapy increases resectability and the likelihood of R0 resection compared to 41.4 Gy and respondent's characteristics.
Interest in a prospective comparison of 50.4 vs. 41.4 Gy in esophageal tri-modality therapy. Seventy-six percent (n=223) of respondents were willing to enroll patients in a neoadjuvant chemoradiotherapy clinical trial comparing 41.4 Gy to 50.4 Gy with concurrent carboplatin/paclitaxel in locally advanced esophageal cancer (Table VI). Physicians early in their career were more willing to enroll to a trial addressing this question (p<0.001). There was no significant correlation between common radiation doses used in physician practice and willingness to enroll in a clinical trial comparing 41.4 Gy, including those that commonly treated to doses >50.4 Gy (Table VI).
Correlation between physician's belief that 50.4 Gy of radiation therapy would cause more toxicity compared to 41.4 Gy and respondent's characteristics.
Discussion
Tri-modality therapy is the standard of care for patients with resectable locally advanced esophageal cancer (4-6, 9-15). In the United States, 50.4 Gy with concurrent cisplatin/5-FU was adopted nearly two decades ago as the standard treatment.
The more contemporary investigation of TMT in the CROSS trial implemented a lower dose of radiation of 41.4 Gy with concurrent carboplatin/paclitaxel chemotherapy. Despite the lower radiation dose, this TMT regimen maintained superior efficacy over surgery, appears to be similar in efficacy, and better tolerated than cisplatin/5-FU and 50.4 Gy (5, 15). Nevertheless, a substantially low number (15%) of US radiation oncologists implement the CROSS regimen in good surgical candidates who are receiving neoadjuvant chemoradiotherapy. However, physicians have changed the concurrent chemotherapy to carboplatin/paclitaxel while maintaining the higher radiation dose of 50.4 Gy with thoughts that the higher radiation dose increases the likelihood of R0 resection and pathological complete response; while possibly leading to higher toxicity (16). These data also support enrolling on a clinical trial comparing 41.4 Gy versus 50.4 Gy in neoadjuvant chemoradiotherapy.
Correlation between physician's willingness to enroll a patient with operable esophageal cancer on a randomized trial of 41.4 vs. 50.4 Gy of radiation therapy with concurrent chemotherapy and respondent's characteristics.
This study revealed insights into why US providers may continue to use higher doses of radiotherapy while changing the chemotherapy backbone to the better tolerated CROSS regimen. The respondents to the survey were evenly distributed in age, location, practice location and time from training. Data are challenging to extrapolate to all practicing radiation oncologists in the US, but can serve as an indicator of current practice patterns.
US practicing radiation oncologist continue to practice and believe that higher radiation dose correlates to a high likelihood of tumor response; however, there are insufficient data to support this conclusion, especially in the era following RTOG 0617, which failed to show a benefit of radiation dose escalation in non-small cell lung cancer. While the data from this survey supports enrollment in a clinical trial comparing 50.4 Gy to 41.4 Gy with concurrent carboplatin/paclitaxel; this is a costly endeavor that would require a considerable number of patients to accurately assess a difference between the two radiotherapy doses. This is a question that may be answered in the future with hospital or population-based databases.
Conclusion
This study reports the current practice patterns among US radiation oncologists for patients with locally advanced esophageal cancer: poor adoption of the CROSS regimen for resectable patients due to beliefs of improved pathological complete response rate and R0 resection with a higher radiation dose.
Acknowledgements
REDCap was used in data acquisition (1 UL1 RR024140 01).
- Received September 11, 2018.
- Revision received September 24, 2018.
- Accepted September 28, 2018.
- Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved
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