Abstract
Background
The optimal dose of neoadjuvant radiation for locally advanced, resectable esophageal cancer remains controversial in the absence of randomized clinical trials, with conventional practice favoring the use of 50.4 vs. 41.4 Gy.
Methods
Retrospective analysis of adults with non-metastatic esophageal cancer in the National Cancer Database (2004–2015) treated with neoadjuvant chemoradiotherapy. Outcomes were compared between patients undergoing 41.4, 45, or 50.4 Gy. Primary outcome was overall survival. Secondary outcomes included T and N downstaging and perioperative mortality adjusted for demographics, clinicopathologic factors, and facility volume.
Results
Eight thousand eight hundred eighty-one patients were included: 439 (4.9%) received low-dose (41.4 Gy), 2194 (24.7%) received moderate-dose (45 Gy), and 6248 (70.4%) received high-dose (50.4 Gy) neoadjuvant radiation. Compared to high-dose, low-dose radiation was associated with superior median overall survival (52.6 vs. 40.7 months) and 5-year survival (48.3% vs. 40.2%), and lower unadjusted 90-day mortality (2.3% vs. 6.5%, all p ≤ 0.01). Multivariable proportional hazards models confirmed an increased hazard of death associated with high-dose radiation therapy (HR = 1.38, 95% CI 1.10–1.72, p = 0.005). There was no significant difference in T and/or N downstaging between low-dose vs. high-dose therapy (p > 0.1 for both). Patients receiving 45 Gy exhibited the lowest median overall survival (37.2 months) and 5-year survival (38.7%, log-rank p = 0.04).
Conclusions
Compared to 50.4 Gy, 41.4 Gy is associated with reduced perioperative mortality and superior overall survival with similar downstaging in locally advanced esophageal cancer. In the absence of randomized clinical data, our findings support the use of 41.4 Gy in patients with chemoradiation followed by esophagectomy. Prospective trials are warranted to further validate these results.
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References
Siegel, R.L., K.D. Miller, and A. Jemal, Cancer statistics, 2018. CA Cancer J Clin, 2018. 68(1): p. 7–30.
Shapiro, J., et al., Neoadjuvant chemoradiotherapy plus surgery versus surgery alone for oesophageal or junctional cancer (CROSS): long-term results of a randomised controlled trial. Lancet Oncol, 2015. 16(9): p. 1090–1098.
Cunningham, D., et al., Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med, 2006. 355(1): p. 11–20.
Ychou, M., et al., Perioperative chemotherapy compared with surgery alone for resectable gastroesophageal adenocarcinoma: an FNCLCC and FFCD multicenter phase III trial. J Clin Oncol, 2011. 29(13): p. 1715–21.
van Hagen, P., et al., Preoperative chemoradiotherapy for esophageal or junctional cancer. N Engl J Med, 2012. 366(22): p. 2074–84.
NCCN Clinical Practice Guidelines in Oncology: Esophageal and Esophagogastric Junction Cancers. Version 1.2017. 2017 [cited 2018 March 30, 2018]; Available from: http://www.nccn.org/professionals/physician_gls/pdf/esophageal.pdf.
Elliott DA, et al., Locally Advanced Esophageal Chemoradiation Therapy Practice Patterns: Results From a National Survey of ASTRO Members (Abstract). IJROBP, 2015. 93: p. S219.
Murro, D. and S. Jakate, Radiation esophagitis. Arch Pathol Lab Med, 2015. 139(6): p. 827–30.
Novak, J.M., et al., Effects of radiation on the human gastrointestinal tract. J Clin Gastroenterol, 1979. 1(1): p. 9–39.
Beukema, J.C., et al., Is cardiac toxicity a relevant issue in the radiation treatment of esophageal cancer?. Radiother Oncol, 2015. 114(1): p. 85–90.
Haque, W., et al., Radiation dose in neoadjuvant chemoradiation therapy for esophageal cancer: patterns of care and outcomes from the National Cancer Data Base. J Gastrointest Oncol, 2018. 9(1): p. 80–89.
Walsh, T.N., et al., A comparison of multimodal therapy and surgery for esophageal adenocarcinoma. N Engl J Med, 1996. 335(7): p. 462–7.
Urba, S.G., et al., Randomized trial of preoperative chemoradiation versus surgery alone in patients with locoregional esophageal carcinoma. J Clin Oncol, 2001. 19(2): p. 305–13.
Lee, J.L., et al., A single institutional phase III trial of preoperative chemotherapy with hyperfractionation radiotherapy plus surgery versus surgery alone for resectable esophageal squamous cell carcinoma. Ann Oncol, 2004. 15(6): p. 947–54.
Tepper, J., et al., Phase III trial of trimodality therapy with cisplatin, fluorouracil, radiotherapy, and surgery compared with surgery alone for esophageal cancer: CALGB 9781. J Clin Oncol, 2008. 26(7): p. 1086–92.
Burmeister, B.H., et al., Surgery alone versus chemoradiotherapy followed by surgery for resectable cancer of the oesophagus: a randomised controlled phase III trial. Lancet Oncol, 2005. 6(9): p. 659–68.
Mariette, C., et al., Surgery alone versus chemoradiotherapy followed by surgery for stage I and II esophageal cancer: final analysis of randomized controlled phase III trial FFCD 9901. J Clin Oncol, 2014. 32(23): p. 2416–22.
Kwa, S.L., et al., Radiation pneumonitis as a function of mean lung dose: an analysis of pooled data of 540 patients. Int J Radiat Oncol Biol Phys, 1998. 42(1): p. 1–9.
Vivekanandan, S., et al., The Impact of Cardiac Radiation Dosimetry on Survival After Radiation Therapy for Non-Small Cell Lung Cancer. Int J Radiat Oncol Biol Phys, 2017. 99(1): p. 51–60.
Wang, K., et al., Cardiac Toxicity After Radiotherapy for Stage III Non-Small-Cell Lung Cancer: Pooled Analysis of Dose-Escalation Trials Delivering 70 to 90 Gy. J Clin Oncol, 2017. 35(13): p. 1387–1394.
Speirs, C.K., et al., Heart Dose Is an Independent Dosimetric Predictor of Overall Survival in Locally Advanced Non-Small Cell Lung Cancer. J Thorac Oncol, 2017. 12(2): p. 293–301.
Bradley, J.D., et al., Standard-dose versus high-dose conformal radiotherapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non-small-cell lung cancer (RTOG 0617): a randomised, two-by-two factorial phase 3 study. Lancet Oncol, 2015. 16(2): p. 187–99.
Xi, M., et al., Comparing docetaxel plus cisplatin versus fluorouracil plus cisplatin in esophageal squamous cell carcinoma treated with neoadjuvant chemoradiotherapy. Jpn J Clin Oncol, 2017. 47(8): p. 683–689.
Almhanna, K., R. Shridhar, and K.L. Meredith, Neoadjuvant or adjuvant therapy for resectable esophageal cancer: is there a standard of care?. Cancer Control, 2013. 20(2): p. 89–96.
Nabavizadeh, N., et al., Preoperative carboplatin and paclitaxel-based chemoradiotherapy for esophageal carcinoma: results of a modified CROSS regimen utilizing radiation doses greater than 41.4 Gy. Dis Esophagus, 2016. 29(6): p. 614–20.
Munch, S., et al., Comparison of neoadjuvant chemoradiation with carboplatin/ paclitaxel or cisplatin/ 5-fluoruracil in patients with squamous cell carcinoma of the esophagus. Radiat Oncol, 2017. 12(1): p. 182.
Munch, S., et al., Comparison of definite chemoradiation therapy with carboplatin/paclitaxel or cisplatin/5-fluoruracil in patients with squamous cell carcinoma of the esophagus. Radiat Oncol, 2018. 13(1): p. 139.
Donahue, J.M., et al., Complete pathologic response after neoadjuvant chemoradiotherapy for esophageal cancer is associated with enhanced survival. Ann Thorac Surg, 2009. 87(2): p. 392–8; discussion 398-9.
Zanoni, A., et al., ypN0: Does It Matter How You Get There? Nodal Downstaging in Esophageal Cancer. Ann Surg Oncol, 2016. 23(Suppl 5): p. 998–1004.
Davies, A.R., et al., Tumor stage after neoadjuvant chemotherapy determines survival after surgery for adenocarcinoma of the esophagus and esophagogastric junction. J Clin Oncol, 2014. 32(27): p. 2983–90.
Kasten-Pisula, U., et al., The extreme radiosensitivity of the squamous cell carcinoma SKX is due to a defect in double-strand break repair. Radiother Oncol, 2009. 90(2): p. 257–64.
Korst, R.J., et al., Downstaging of T or N predicts long-term survival after preoperative chemotherapy and radical resection for esophageal carcinoma. Ann Thorac Surg, 2006. 82(2): p. 480–4; discussion 484-5.
Baan, R., et al., Carcinogenicity of alcoholic beverages. Lancet Oncol, 2007. 8(4): p. 292–3.
Morita, M., et al., Risk factors for esophageal cancer and the multiple occurrence of carcinoma in the upper aerodigestive tract. Surgery, 2002. 131(1 Suppl): p. S1–6.
Humans, I.W.G.o.t.E.o.C.R.t., Tobacco smoke and involuntary smoking. IARC Monogr Eval Carcinog Risks Hum, 2004. 83: p. 1–1438.
Wagner, T.D., N. Khushalani, and G.Y. Yang, Clinical T2N0M0 carcinoma of thoracic esophagus. J Thorac Dis, 2010. 2(1): p. 36–42.
Oppedijk, V., et al., Patterns of recurrence after surgery alone versus preoperative chemoradiotherapy and surgery in the CROSS trials. J Clin Oncol, 2014. 32(5): p. 385–91.
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Conflict of Interest
Julie A. Sosa, M.D., M.A., is a member of the Data Monitoring Committee for the Medullary Thyroid Cancer Consortium Registry supported by Novo Nordisk, GlaxoSmithKline, Astra Zeneca, and Eli Lilly. The other authors declare that they have no competing interests.
Additional information
This study was an oral presentation at the 12th Annual Academic Surgical Congress in Las Vegas, Nevada, 2017 and since has been updated to include data through 2015.
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Ji, K.S.Y., Thomas, S.M., Roman, S.A. et al. Low- vs. High-Dose Neoadjuvant Radiation in Trimodality Treatment of Locally Advanced Esophageal Cancer. J Gastrointest Surg 23, 885–894 (2019). https://doi.org/10.1007/s11605-018-4007-3
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DOI: https://doi.org/10.1007/s11605-018-4007-3