Journal of Gastrointestinal Surgery

, Volume 23, Issue 5, pp 885–894 | Cite as

Low- vs. High-Dose Neoadjuvant Radiation in Trimodality Treatment of Locally Advanced Esophageal Cancer

  • Keven S. Y. Ji
  • Samantha M. Thomas
  • Sanziana A. Roman
  • Brian Czito
  • Kevin L. AndersonJr.
  • Jessica Frakes
  • Mohamed A. Adam
  • Julie A. Sosa
  • Timothy J. RobinsonEmail author
Original Article



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.


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.


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).


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.


Esophageal neoplasms Chemoradiotherapy Neoadjuvant therapy 


Compliance with Ethical Standards

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.

Supplementary material

11605_2018_4007_MOESM1_ESM.pdf (11 kb)
Supplementary Figure 1 (PDF 10 kb)
11605_2018_4007_MOESM2_ESM.pdf (92 kb)
Supplementary Figure 2 (PDF 91 kb)
11605_2018_4007_MOESM3_ESM.docx (24 kb)
Supplementary Table 1 (DOCX 24 kb)
11605_2018_4007_MOESM4_ESM.docx (16 kb)
Supplementary Table 2 (DOCX 16 kb)
11605_2018_4007_MOESM5_ESM.docx (14 kb)
Supplementary Table 3 (DOCX 14 kb)
11605_2018_4007_MOESM6_ESM.docx (13 kb)
Supplementary Table 4 (DOCX 13 kb)
11605_2018_4007_MOESM7_ESM.docx (13 kb)
Supplementary Table 5 (DOCX 13 kb)
11605_2018_4007_MOESM8_ESM.docx (15 kb)
Supplementary Table 6 (DOCX 15 kb)
11605_2018_4007_MOESM9_ESM.docx (16 kb)
Supplementary Table 7 (DOCX 15 kb)


  1. 1.
    Siegel, R.L., K.D. Miller, and A. Jemal, Cancer statistics, 2018. CA Cancer J Clin, 2018. 68(1): p. 7–30.CrossRefGoogle Scholar
  2. 2.
    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.CrossRefGoogle Scholar
  3. 3.
    Cunningham, D., et al., Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med, 2006. 355(1): p. 11–20.CrossRefGoogle Scholar
  4. 4.
    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.CrossRefGoogle Scholar
  5. 5.
    van Hagen, P., et al., Preoperative chemoradiotherapy for esophageal or junctional cancer. N Engl J Med, 2012. 366(22): p. 2074–84.CrossRefGoogle Scholar
  6. 6.
    NCCN Clinical Practice Guidelines in Oncology: Esophageal and Esophagogastric Junction Cancers. Version 1.2017. 2017 [cited 2018 March 30, 2018]; Available from:
  7. 7.
    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.Google Scholar
  8. 8.
    Murro, D. and S. Jakate, Radiation esophagitis. Arch Pathol Lab Med, 2015. 139(6): p. 827–30.CrossRefGoogle Scholar
  9. 9.
    Novak, J.M., et al., Effects of radiation on the human gastrointestinal tract. J Clin Gastroenterol, 1979. 1(1): p. 9–39.CrossRefGoogle Scholar
  10. 10.
    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.CrossRefGoogle Scholar
  11. 11.
    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.CrossRefGoogle Scholar
  12. 12.
    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.CrossRefGoogle Scholar
  13. 13.
    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.CrossRefGoogle Scholar
  14. 14.
    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.CrossRefGoogle Scholar
  15. 15.
    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.CrossRefGoogle Scholar
  16. 16.
    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.CrossRefGoogle Scholar
  17. 17.
    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.CrossRefGoogle Scholar
  18. 18.
    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.CrossRefGoogle Scholar
  19. 19.
    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.CrossRefGoogle Scholar
  20. 20.
    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.CrossRefGoogle Scholar
  21. 21.
    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.CrossRefGoogle Scholar
  22. 22.
    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.CrossRefGoogle Scholar
  23. 23.
    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.CrossRefGoogle Scholar
  24. 24.
    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.CrossRefGoogle Scholar
  25. 25.
    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.CrossRefGoogle Scholar
  26. 26.
    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.CrossRefGoogle Scholar
  27. 27.
    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.CrossRefGoogle Scholar
  28. 28.
    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.CrossRefGoogle Scholar
  29. 29.
    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.CrossRefGoogle Scholar
  30. 30.
    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.CrossRefGoogle Scholar
  31. 31.
    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.CrossRefGoogle Scholar
  32. 32.
    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.CrossRefGoogle Scholar
  33. 33.
    Baan, R., et al., Carcinogenicity of alcoholic beverages. Lancet Oncol, 2007. 8(4): p. 292–3.CrossRefGoogle Scholar
  34. 34.
    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.CrossRefGoogle Scholar
  35. 35.
    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.Google Scholar
  36. 36.
    Wagner, T.D., N. Khushalani, and G.Y. Yang, Clinical T2N0M0 carcinoma of thoracic esophagus. J Thorac Dis, 2010. 2(1): p. 36–42.Google Scholar
  37. 37.
    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.CrossRefGoogle Scholar

Copyright information

© The Society for Surgery of the Alimentary Tract 2018

Authors and Affiliations

  • Keven S. Y. Ji
    • 1
  • Samantha M. Thomas
    • 2
    • 3
  • Sanziana A. Roman
    • 4
  • Brian Czito
    • 5
  • Kevin L. AndersonJr.
    • 1
  • Jessica Frakes
    • 6
  • Mohamed A. Adam
    • 7
  • Julie A. Sosa
    • 4
  • Timothy J. Robinson
    • 6
    Email author
  1. 1.Duke University School of MedicineDurhamUSA
  2. 2.Duke Cancer InstituteDurhamUSA
  3. 3.Department of Biostatistics & BioinformaticsDuke UniversityDurhamUSA
  4. 4.Department of SurgeryUniversity of California at San Francisco-UCSFSan FranciscoUSA
  5. 5.Department of Radiation OncologyDuke University Medical CenterDurhamUSA
  6. 6.Department of Radiation OncologyMoffitt Cancer CenterTampa BayUSA
  7. 7.Department of SurgeryDuke University Medical CenterDurhamUSA

Personalised recommendations