In conclusion, the available data reveal that LC after DCRT for EC remains a problem and that most local failures occur within the primary tumor. This indicates that the standard RT dose (50.4 Gy in 28 fractions) may be inadequate to achieve a high probability for LC for some subgroup patients. It is warranted to explore potential ways of improving LC, including IMRT and VMAT techniques, radiation dose escalation, and the use of more effective dose fractionation strategies. Some studies have found that the use of a higher dose and late course of accelerated hyperfraction radiation may lead to better LC and survival for EC patients undergoing CRT. Nevertheless, there is no evidence from Phase III randomized trials to support the additional benefit of dose-escalated RT. Although there is a potential for better tumor LC, there is also an associated higher incidence of toxicity. Therefore, the higher radiation dose should be used with caution on an individual basis in patients with EC.
It has been reported that EC probably has variable sensitivities to CRT. Therefore further studies will be required to: 1) identify the factors involved in EC sensitivity to radiation; 2) determine the causes of recurrence and non-control from molecular biology perspectives; and 3) individually determine the target region of RT, fractionated dose, and total dose to increase both LC and survival rates and decrease the rates of metastasis in patients with EC.
This study was funded by the Natural Science Foundation of China (NSFC 81672995) and The Key Research and Development Program of Shandong Province (2016GSF201133).
The authors report no conflicts of interest in this work.
Yijun Luo,1,* Qingfeng Mao,2,3,* Xiaoli Wang,1 Jinming Yu,3 Minghuan Li3
1Department of Oncology, The People’s Hospital of Jiangxi, Nanchang, 2School of Medical and Life Sciences, University of Jinan-Shandong Academy of Medical Sciences, 3Department of Radiation Oncology and Radiology, Shandong Cancer Hospital Affiliated to Shandong University, Jinan, China
*These authors contributed equally to this work
1. Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65(2):87–108.
2. Kumagai K, Rouvelas I, Tsai JA, et al. Meta-analysis of postoperative morbidity and perioperative mortality in patients receiving neoadjuvant chemotherapy or chemoradiotherapy for resectable oesophageal and gastro-oesophageal junctional cancers. Br J Surg. 2014;101(4):321–338.
3. Wheeler JB, Reed CE. Epidemiology of esophageal cancer. Surg Clin North Am. 2012;92(5):1077–1087.
4. Ajani JA. Gastroesophageal cancers: progress and problems. J Natl Compr Canc Netw. 2008;6(9):813–814.
5. Song Y, Li L, Ou Y, et al. Identification of genomic alterations in oesophageal squamous cell cancer. Nature. 2014;509(7498):91–95.
6. Cooper JS, Guo MD, Herskovic A, et al. Chemoradiotherapy of locally advanced esophageal cancer: long-term follow-up of a prospective randomized trial (RTOG 85–01). Radiation Therapy Oncology Group. JAMA. 1999;281(17):1623–1627.
7. Minsky BD, Neuberg D, Kelsen DP, et al. Final report of intergroup trial 0122 (ECOG PE–289, RTOG 90-12): Phase II trial of neoadjuvant chemotherapy plus concurrent chemotherapy and high-dose radiation for squamous cell carcinoma of the esophagus. Int J Radiat Oncol Biol Phys. 1999;43(3):517–523.
8. Minsky BD, Pajak TF, Ginsberg RJ, et al. INT 0123 (Radiation Therapy Oncology Group 94–05) phase III trial of combined-modality therapy for esophageal cancer: high-dose versus standard-dose radiation therapy. J Clin Oncol. 2002;20(5):1167–1174.
9. Higuchi K, Koizumi W, Tanabe S, et al. Current management of esophageal squamous-cell carcinoma in Japan and other countries. Gastrointest Cancer Res. 2009;3(4):153–161.
10. Meng X, Wang J, Sun X, et al. Cetuximab in combination with chemoradiotherapy in Chinese patients with non-resectable, locally advanced esophageal squamous cell carcinoma: a prospective, multicenter phase II trail. Radiother Oncol. 2013;109(2):275–280.
11. Li M, Zhang X, Zhao F, Luo Y, Kong L, Yu J. Involved-field radiotherapy for esophageal squamous cell carcinoma: theory and practice. Radiat Oncol. 2016;11:18.
12. Bedenne L, Michel P, Bouché O, et al. Chemoradiation followed by surgery compared with chemoradiation alone in squamous cancer of the esophagus: FFCD 9102. J Clin Oncol. 2007;25(10):1160–1168.
13. Rawat S, Kumar G, Kakria A, Sharma MK, Chauhan D. Chemoradiotherapy in the management of locally advanced squamous cell carcinoma esophagus: is surgical resection required. J Gastrointest Cancer. 2013;44(3):277–284.
14. Pöttgen C, Stuschke M. Radiotherapy versus surgery within multimodality protocols for esophageal cancer a meta-analysis of the randomized trials. Cancer Treat Rev. 2012;38(6):599–604.
15. Kawaguchi Y, Nishiyama K, Miyagi K, Suzuki O, Ito Y, Nakamura S. Patterns of failure associated with involved field radiotherapy in patients with clinical stage I thoracic esophageal cancer. Jpn J Clin Oncol. 2011;41(8):1007–1012.
16. van Hagen P, Hulshof MC, van Lanschot JJ, et al. Preoperative chemoradiotherapy for esophageal or junctional cancer. N Engl J Med. 2012;366(22):2074–2084.
17. Kato K, Nakajima TE, Ito Y, et al. Phase II study of concurrent chemoradiotherapy at the dose of 50.4 Gy with elective nodal irradiation for Stage II–III esophageal carcinoma. Jpn J Clin Oncol. 2013;43(6):608–615.
18. Rohatgi PR, Swisher SG, Correa AM, et al. Failure patterns correlate with the proportion of residual carcinoma after preoperative chemoradiotherapy for carcinoma of the esophagus. Cancer. 2005;104(7):1349–1355.
19. Nakagawa S, Kanda T, Kosugi S, Ohashi M, Suzuki T, Hatakeyama K. Recurrence pattern of squamous cell carcinoma of the thoracic esophagus after extended radical esophagectomy with three-field lymphadenectomy. J Am Coll Surg. 2004;198(2):205–211.
20. Reid TD, Davies IL, Mason J, Roberts SA, Crosby TD, Lewis WG. Stage for stage comparison of recurrence patterns after definitive chemoradiotherapy or surgery for oesophageal carcinoma. Clin Oncol (R Coll Radiol). 2012;24(9):617–624.
21. Sugiyama M, Morita M, Yoshida R, et al. Patterns and time of recurrence after complete resection of esophageal cancer. Surg Today. 2012;42(8):752–758.
22. Fletcher GH. Clinical dose-response curves of human malignant epithelial tumours. Br J Radiol. 1973;46(541):1–12.
23. Li JC, Liu D, Chen MQ, et al. Different radiation treatment in esophageal carcinoma: a clinical comparative study. J BUON. 2012;17(3):512–516.
24. Chen YJ, Liu A, Han C, et al. Helical tomotherapy for radiotherapy in esophageal cancer: a preferred plan with better conformal target coverage and more homogeneous dose distribution. Med Dosim. 2007;32(3):166–171.
25. Leclerc M, Maingon P, Hamoir M, et al. A dose escalation study with intensity modulated radiation therapy (IMRT) in T2N0, T2N1, T3N0 squamous cell carcinomas (SCC) of the oropharynx, larynx and hypopharynx using a simultaneous integrated boost (SIB) approach. Radiother Oncol. 2013;106(3):333–340.
26. Yu WW, Zhu ZF, Fu XL, et al. Simultaneous integrated boost intensity-modulated radiotherapy in esophageal carcinoma: early results of a phase II study. Strahlenther Onkol. 2014;190(11):979–986.
27. Suh YG, Lee IJ, Koom WS, et al. High-dose versus standard-dose radiotherapy with concurrent chemotherapy in stages II–III esophageal cancer. Jpn J Clin Oncol. 2014;44(6):534–540.
28. He L, Allen PK, Potter A, et al. Re-evaluating the optimal radiation dose for definitive chemoradiotherapy for esophageal squamous cell carcinoma. J Thorac Oncol. 2014;9(9):1398–1405.
29. Zhang Z, Liao Z, Jin J, et al. Dose-response relationship in locoregional control for patients with stage II-III esophageal cancer treated with concurrent chemotherapy and radiotherapy. Int J Radiat Oncol Biol Phys. 2005;61(3):656–664.
30. Kim HJ, Suh YG, Lee YC, et al. Dose-response relationship between radiation dose and loco-regional control in patients with stage II–III esophageal cancer treated with definitive chemoradiotherapy. Cancer Res Treat. 2017;49(3):669–677.
31. Chen CY, Li CC, Chien CR. Does higher radiation dose lead to better outcome for non-operated localized esophageal squamous cell carcinoma patients who received concurrent chemoradiotherapy? A population based propensity-score matched analysis. Radiother Oncol. 2016;120(1):136–139.
32. Wolf MC, Zehentmayr F, Schmidt M, Hölzel D, Belka C. Treatment strategies for oesophageal cancer – time-trends and long term outcome data from a large tertiary referral centre. Radiat Oncol. 2012;7:60.
33. Semrau R, Herzog SL, Vallböhmer D, Kocher M, Hölscher AH, Müller RP. Prognostic factors in definitive radiochemotherapy of advanced inoperable esophageal cancer. Dis Esophagus. 2012;25(6):545–554.
34. Song T, Liang X, Fang M, Wu S. High–dose versus conventional-dose irradiation in cisplatin-based definitive concurrent chemoradiotherapy for esophageal cancer: a systematic review and pooled analysis. Expert Rev Anticancer Ther. 2015;15(10):1157–1169.
35. Yu W, Cai XW, Liu Q, et al. Safety of dose escalation by simultaneous integrated boosting radiation dose within the primary tumor guided by (18)FDG-PET/CT for esophageal cancer. Radiother Oncol. 2015;114(2):195–200.
36. Chen J, Guo H, Zhai T, et al. Radiation dose escalation by simultaneous modulated accelerated radiotherapy combined with chemotherapy for esophageal cancer: a phase II study. Oncotarget. 2016;7(16):22711–22719.
37. Withers HR, Taylor JM, Maciejewski B. The hazard of accelerated tumor clonogen repopulation during radiotherapy. Acta Oncol. 1988;27(2):131–146.
38. Trott KR. Cell repopulation and overall treatment time. Int J Radiat Oncol Biol Phys. 1990;19(4):1071–1075.
39. Jeremic B, Shibamoto Y, Acimovic L, et al. Accelerated hyperfractionated radiation therapy and concurrent 5-fluorouracil/cisplatin chemotherapy for locoregional squamous cell carcinoma of the thoracic esophagus: a phase II study. Int J Radiat Oncol Biol Phys. 1998;40(5):1061–1066.
40. Shi XH, Yao W, Liu T. Late course accelerated fractionation in radiotherapy of esophageal carcinoma. Radiother Oncol. 1999;51(1):21–26.
41. Zhao KL, Shi XH, Jiang GL, Wang Y. Late-course accelerated hyperfractionated radiotherapy for localized esophageal carcinoma. Int J Radiat Oncol Biol Phys. 2004;60(1):123–129.
42. Zhang YW, Chen L, Bai Y, Zheng X. Long-term outcomes of late course accelerated hyper-fractionated radiotherapy for localized esophageal carcinoma in Mainland China: a meta-analysis. Dis Esophagus. 2011;24(7):495–501.
43. Wang JH, Lu XJ, Zhou J, Wang F. A randomized controlled trial of conventional fraction and late course accelerated hyperfraction three-dimensional conformal radiotherapy for esophageal cancer. Cell Biochem Biophys. 2012;62(1):107–112.
44. Zhao KL, Shi XH, Jiang GL, et al. Late course accelerated hyperfractionated radiotherapy plus concurrent chemotherapy for squamous cell carcinoma of the esophagus: a phase III randomized study. Int J Radiat Oncol Biol Phys. 2005;62(4):1014–1020.
45. Tong DK, Law S, Kwong DL, Chan KW, Lam AK, Wong KH. Histological regression of squamous esophageal carcinoma assessed by percentage of residual viable cells after neoadjuvant chemoradiation is an important prognostic factor. Ann Surg Oncol. 2010;17(8):2184–2192.
46. Chao YK, Chan SC, Liu YH, et al. Pretreatment T3–4 stage is an adverse prognostic factor in patients with esophageal squamous cell carcinoma who achieve pathological complete response following preoperative chemoradiotherapy. Ann Surg. 2009;249(3):392–396.
47. Hammoud ZT, Kesler KA, Ferguson MK, et al. Survival outcomes of resected patients who demonstrate a pathologic complete response after neoadjuvant chemoradiation therapy for locally advanced esophageal cancer. Dis Esophagus. 2006;19(2):69–72.
48. Nishimura Y, Suzuki M, Nakamatsu K, Kanamori S, Yagyu Y, Shigeoka H. Prospective trial of concurrent chemoradiotherapy with protracted infusion of 5–fluorouracil and cisplatin for T4 esophageal cancer with or without fistula. Int J Radiat Oncol Biol Phys. 2002;53(1):134–139.
49. Hatt M, Le Pogam A, Visvikis D, Pradier O, Cheze Le Rest C. Impact of partial-volume effect correction on the predictive and prognostic value of baseline 18F-FDG PET images in esophageal cancer. J Nucl Med. 2012;53(1):12–20.
50. Muijs CT, Beukema JC, Pruim J, et al. A systematic review on the role of FDG-PET/CT in tumour delineation and radiotherapy planning in patients with esophageal cancer. Radiother Oncol. 2010;97(2):165–171.
51. Huh JW, Min JJ, Lee JH, Kim HR, Kim YJ. The predictive role of sequential FDG-PET/CT in response of locally advanced rectal cancer to neoadjuvant chemoradiation. Am J Clin Oncol. 2012;35(4):340–344.
52. Capirci C, Rubello D, Pasini F, et al. The role of dual-time combined 18–fluorodeoxyglucose positron emission tomography and computed tomography in the staging and restaging workup of locally advanced rectal cancer, treated with preoperative chemoradiation therapy and radical surgery. Int J Radiat Oncol Biol Phys. 2009;74(5):1461–1469.
53. Kato H, Fukuchi M, Miyazaki T, et al. Prediction of response to definitive chemoradiotherapy in esophageal cancer using positron emission tomography. Anticancer Res. 2007;27(4C):2627–2633.
54. Atsumi K, Nakamura K, Abe K, et al. Prediction of outcome with FDG-PET in definitive chemoradiotherapy for esophageal cancer. J Radiat Res. 2013;54(5):890–898.
55. Javeri H, Xiao L, Rohren E, et al. Influence of the baseline 18F-fluoro-2-deoxy-D-glucose positron emission tomography results on survival and pathologic response in patients with gastroesophageal cancer undergoing chemoradiation. Cancer. 2009;115(3):624–630.
56. Levine EA, Farmer MR, Clark P, et al. Predictive value of 18-fluoro-deoxy-glucose-positron emission tomography (18F-FDG-PET) in the identification of responders to chemoradiation therapy for the treatment of locally advanced esophageal cancer. Ann Surg. 2006;243(4):472–478.
57. Rizk NP, Tang L, Adusumilli PS, et al. Predictive value of initial PET-SUVmax in patients with locally advanced esophageal and gastroesophageal junction adenocarcinoma. J Thorac Oncol. 2009;4(7):875–879.
58. Larson SM, Erdi Y, Akhurst T, et al. Tumor treatment response based on visual and quantitative changes in global tumor glycolysis using PET–FDG imaging. The visual response score and the change in total lesion glycolysis. Clin Positron Imaging. 1999;2(3):159–171.
59. Chung MK, Jeong HS, Park SG, et al. Metabolic tumor volume of [18F]–fluorodeoxyglucose positron emission tomography/computed tomography predicts short-term outcome to radiotherapy with or without chemotherapy in pharyngeal cancer. Clin Cancer Res. 2009;15(18):5861–5868.
60. Roedl JB, Colen RR, Holalkere NS, Fischman AJ, Choi NC, Blake MA. Adenocarcinomas of the esophagus: response to chemoradiotherapy is associated with decrease of metabolic tumor volume as measured on PET–CT. Comparison to histopathologic and clinical response evaluation. Radiother Oncol. 2008;89(3):278–286.
61. Jayachandran P, Pai RK, Quon A, et al. Postchemoradiotherapy positron emission tomography predicts pathologic response and survival in patients with esophageal cancer. Int J Radiat Oncol Biol Phys. 2012;84(2):471–477.
62. Stiekema J, Vermeulen D, Vegt E, et al. Detecting interval metastases and response assessment using 18F-FDG PET/CT after neoadjuvant chemoradiotherapy for esophageal cancer. Clin Nucl Med. 2014;39(10):862–867.
63. Miles KA, Lee TY, Goh V, et al; Experimental Cancer Medicine Centre Imaging Network Group. Current status and guidelines for the assessment of tumour vascular support with dynamic contrast–enhanced computed tomography. Eur Radiol. 2012;22(7):1430–1441.
64. Bellomi M, Viotti S, Preda L, D’Andrea G, Bonello L, Petralia G. Perfusion CT in solid body-tumours. Part II: clinical applications and future development. Radiol Med. 2010;115(6):858–874. Italian.
65. Djuric-Stefanovic A, Micev M, Stojanovic-Rundic S, Pesko P, Saranovic Dj. Absolute CT perfusion parameter values after the neoadjuvant chemoradiotherapy of the squamous cell esophageal carcinoma correlate with the histopathologic tumor regression grade. Eur J Radiol. 2015;84(12):2477–2484.
66. Lundsgaard Hansen M, Fallentin E, Lauridsen C, et al. Computed tomography (CT) perfusion as an early predictive marker for treatment response to neoadjuvant chemotherapy in gastroesophageal junction cancer and gastric cancer a prospective study. PLoS One. 2014;9(5):e97605.
67. Hayano K, Okazumi S, Shuto K, et al. Perfusion CT can predict the response to chemoradiation therapy and survival in esophageal squamous cell carcinoma: initial clinical results. Oncol Rep. 2007;18(4):901–908.
68. Makari Y, Yasuda T, Doki Y, et al. Correlation between tumor blood flow assessed by perfusion CT and effect of neoadjuvant therapy in advanced esophageal cancers. J Surg Oncol. 2007;96(3):220–229.
69. Djuric-Stefanovic A, Saranovic D, Micev M, et al. Does the computed tomography perfusion imaging improve the diagnostic accuracy in the response evaluation of esophageal carcinoma to the neoadjuvant chemoradiotherapy? Preliminary study. J BUON. 2014;19(1):237–244.
70. Onal C, Torun N, Guler OC, Yildirim BA. Prognostic value of metabolic response measured by 18F-FDG-PET in oesophageal cancer patients treated with definitive chemoradiotherapy. Nucl Med Commun. 2016;37(12):1282–1289.
71. Cuenca X, Hennequin C, Hindié E, et al. Evaluation of early response to concomitant chemoradiotherapy by interim 18F-FDG PET/CT imaging in patients with locally advanced oesophageal carcinomas. Eur J Nucl Med Mol Imaging. 2013;40(4):477–485.
72. Javeri H, Xiao L, Rohren E, et al. The higher the decrease in the standardized uptake value of positron emission tomography after chemoradiation, the better the survival of patients with gastroesophageal adenocarcinoma. Cancer. 2009;115(22):5184–5192.
73. Stiles BM, Salzler G, Jorgensen A, et al. Complete metabolic response is not uniformly predictive of complete pathologic response after induction therapy for esophageal cancer. Ann Thorac Surg. 2013;96(5):1820–1825.
74. Young H, Baum R, Cremerius U, et al. Measurement of clinical and subclinical tumour response using [18F]–fluorodeoxyglucose and positron emission tomography: review and 1999 EORTC recommendations. European Organization for Research and Treatment of Cancer (EORTC) PET Study Group. Eur J Cancer. 1999;35(13):1773–1782.
75. Kim MK, Ryu JS, Kim SB, et al. Value of complete metabolic response by (18)F-fluorodeoxyglucose-positron emission tomography in oesophageal cancer for prediction of pathologic response and survival after preoperative chemoradiotherapy. Eur J Cancer. 2007;43(9):1385–1391.
76. Veit-Haibach P, Schmid D, Strobel K, et al. Combined PET/CT-perfusion in patients with head and neck cancers. Eur Radiol. 2013;23(1):163–173.
77. Goh V, Rodriguez-Justo M, Engledow A, et al. Assessment of the metabolic flow phenotype of primary colorectal cancer: correlations with microvessel density are influenced by the histological scoring method. Eur Radiol. 2012;22(8):1687–1692.
78. Goh V, Engledow A, Rodriguez-Justo M, et al. The flow-metabolic phenotype of primary colorectal cancer: assessment by integrated 18F-FDG PET/perfusion CT with histopathologic correlation. J Nucl Med. 2012;53(5):687–692.
79. Padhani AR, Miles KA. Multiparametric imaging of tumor response to therapy. Radiology. 2010;256(2):348–364.
Source: Cancer Management and Research.
Originally published December 29, 2017.