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Table of Contents
Year : 2021  |  Volume : 4  |  Issue : 3  |  Page : 538-540

Radiation therapy in esophageal cancer: Shifting paradigms

Department of Radiation Oncology, Max Institute of Cancer Care, Nanavati Hospital, Mumbai, Maharashtra, India

Date of Submission05-Sep-2021
Date of Decision11-Sep-2021
Date of Acceptance18-Sep-2021
Date of Web Publication08-Oct-2021

Correspondence Address:
Kaustav Talapatra
Department of Radiation Oncology, Max Institute of Cancer Care, Nanavati Hospital, Mumbai, Maharashtra
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/crst.crst_217_21

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How to cite this article:
Talapatra K. Radiation therapy in esophageal cancer: Shifting paradigms. Cancer Res Stat Treat 2021;4:538-40

How to cite this URL:
Talapatra K. Radiation therapy in esophageal cancer: Shifting paradigms. Cancer Res Stat Treat [serial online] 2021 [cited 2021 Dec 4];4:538-40. Available from: https://www.crstonline.com/text.asp?2021/4/3/538/327798

The esophagus is placed anatomically within a zone of complexity pertinent to structures and functions which poses various challenges to the radiation oncologist in appropriately planning radiotherapy for a patient of esophageal cancer.

In the last few years, radiation has found an important place in the treatment of esophageal cancer. The trend and the focus are also shifting from surgery only treatment to multimodality treatment. The Intergroup 0116 trial established the benefit of post-operative concurrent chemoradiation in patients with gastric and gastroesophageal junction tumors.[1]

The CROSS protocol used a lower dose of radiotherapy with concurrent weekly carboplatin and paclitaxel. Between 2004 and 2008, this study randomly assigned 366 patients to receive either surgery alone or pre-operative chemoradiation with paclitaxel, carboplatin, and concurrent radiation to a dose of 41.4 Gy in 23 fractions. The majority of patients (75%) were diagnosed with adenocarcinoma. Chemoradiation was beneficial for patients with both squamous and adenocarcinoma (although the effect size was larger in squamous tumors, the R0 resection rates were greatly enhanced, and the incidence of pathologic complete response following chemoradiotherapy was 29%).[2] At 5 years, the locoregional recurrence rate was 14% in patients who received neoadjuvant treatment, compared to 34% in individuals who underwent surgery alone.

In summary, these analyses convincingly suggest that concurrent chemoradiotherapy improves survival in patients with locally advanced, non-metastatic esophageal carcinoma, in both the surgically resectable and unresectable scenarios.

While contradicting evidence suggests that neoadjuvant chemotherapy alone may provide a survival benefit, a summary of the data from limited prospective studies comparing pre-operative chemoradiotherapy to chemotherapy alone indicates a benefit from the inclusion of radiation therapy.[3],[4]

In the current issue, Dora et al.[5] have made a commendable attempt at comparing two radiotherapy techniques, conformal and volumetric modulated arc therapy (VMAT) which is extremely pertinent in the modern era of radiotherapy. The study demonstrated a decrease in the cardiac doses in the VMAT technique which is an important finding. However, considering the retrospective nature of the study with a small number of patients, an assessment of the overall survival and disease-free survival outcomes may not be justifiable in the larger perspective.

Delineation is done on the planning fluorodeoxyglucose-positron emission tomography (FDG-PET)/computed tomography (CT) and includes all the available information (e.g., endoscopy, endoscopic ultrasound [EUS], endobronchial ultrasound [EBUS], diagnostic FDG-PET/CT, biopsy, magnetic resonance imaging [MRI], and ultrasound).[6]

The gross tumor volume (GTV) should encompass the primary tumor (with the esophageal wall) as seen on the planning FDG-PET/CT scan and includes all the available information (e.g., endoscopy, EUS, diagnostic FDG-PET/CT, MRI, and fiducial markers). It includes the entire esophageal wall but does not include the peri-esophageal fat. The GTV must include the involved lymph nodes defined as pathological at any time before the radiation therapy. Lymph nodes that appear to be new on the planning FDG-PET/CT compared to the diagnostic FDG-PET/CT, suspected to be malignant lymph nodes, have to be included in GTVn. Fine-needle aspiration cytology (FNAC) is recommended in case of doubt and when it would have an impact on the delineation of the target volume.

The clinical target volume (CTV) is proposed to be oriented along the esophagus instead of being a simple geometric expansion.

The clinical target volume = GTVp + 1.0 cm radially and 3.0 cm craniocaudally along the esophageal wall. CTV is corrected for anatomy (muscles, bones, large vessels, and organs at risk [OARs]) if there is no invasion.

Proximal tumors: The CTV is proposed not to extend above the level of the cricoid cartilage unless there is gross disease at that level.

Lower esophagus and gastroesophageal junction: The CTV is restricted to 2.0 cm distal to the tumor.

The nodal CTV is proposed to include the grossly involved nodes with an expansion of 1.0 cm in all directions and the lymph node stations at that level. It involves the lymph node stations along the CTV primary as long as they are within 3.0 cm craniocaudally from the grossly involved primary tumor.

Nodal CTV is corrected for anatomy (muscles, bones, large vessels, and OARs) if there is no invasion.

The final CTV is sum of the primary and nodal CTV and is expanded to include potential gaps between the CTVs – esophagus and the lymph node station at that level are proposed to be included. If the distance of the gap is more than 3.0 cm, the decision to expand the CTV total or to irradiate two separate volumes is up to the treating physician.

An extensive elective nodal volume can be omitted, and only the involved lymph node stations are proposed to be additionally irradiated.

Various dosage schedules have been explored in the treatment of esophageal cancer. RTOG 85-01 proposed 50 Gy as the recommended dose with concomitant systemic therapy in the definitive setting.[7],[8] Given the high rate of persistence and local recurrence despite the use of concomitant chemotherapy, it was assumed that higher radiation doses might improve outcomes. This resulted in a phase III intergroup trial (INT 0123) in which the RTOG 85-01 chemoradiation dose (adjusted to 50.4 Gy from 50 Gy) was compared to a higher dose of 64.8 Gy employing the same concurrent chemotherapy regimen. 86% of the patients enrolled had squamous cell carcinoma. There was no difference in the 2-year survivals between the two arms in this trial. Moreover, 11 treatment-related deaths occurred in individuals assigned to the high dosage arm, compared to 2 in the standard-dose group. However, even the 11 deaths in the high-dose group occurred before the patients received a dosage of 50.4 Gy.[9] The ARTDECO study randomized patients with medically inoperable or unresectable carcinoma of the esophagus. The study compared the dose of 50.4 Gy at 1.8 Gy/fraction over 5.5 weeks to the primary tumor and regional lymph nodes vs. the higher dose of 61.6 Gy to the primary tumor with concurrent paclitaxel and carboplatin administered as 6 weekly cycles. At a median follow-up of 50 months, the primary endpoint of local progression-free survival (LPFS) was not significantly different between the 2 arms.[10]

Overall, the findings of RTOG 85-01, INT 0123, and ARTDECO study confirm 50.4 Gy in 28 fractions as the standard radiotherapy dose for definitive chemoradiation. Nonetheless, there is continued interest in increasing radiation doses to improve complete response rates and decrease local recurrence rates, especially for patients who are medically inoperable or who have cervical or more proximal tumors which would require a morbid laryngopharyngectomy surgery. Cervical tumors are substantially similar to hypopharyngeal malignancies, and despite a dearth of prospective randomized trials, modest retrospective, and prospective data indicate that higher radiation doses of 60 Gy or more are feasible in this circumstance.[11],[12],[13]

The predominant failure pattern for esophageal squamous cell carcinoma is local in-field or distant failures. Regional nodal recurrence (out-of-field) is infrequent in the absence of elective node irradiation.[6]

A high rate of nodal involvement characterizes esophageal cancer, and its pattern of spread is not always predictable. Skip nodal metastases are also frequently observed. Hence, the biological behavior of this disease makes it difficult to define in advance the extent of coverage of elective nodal irradiation. If distant lymph node areas are irradiated prophylactically, patients would then experience more severe radiation complications and have a poorer treatment tolerance. This forms the basis for omitting elective nodal irradiation in patients with esophageal squamous cell carcinoma.

The goal of radiation planning should always be minimizing esophageal toxicity, lung toxicity, and cardiotoxicity. It is pertinent to note that point doses are equally important as dose constraints relied on volume during radiotherapy plan analysis and approval. In the neoadjuvant chemoradiotherapy setting, the surgical anastomosis site is of paramount significance and hence must be taken into consideration.

The last decade has witnessed several advances in radiation techniques for the treatment of esophageal cancer. Incorporation of imaging tools such as PET/CT, 4D CT, and modern planning software has enhanced the scope for radiation oncologists to achieve critical goals in terms of target delineation, critical organ sparing, and dose delivery. Identification of biomarkers with respect to radiation would be the future goal, and there are exciting times ahead in the space of radiation treatment in esophageal malignancies.

  References Top

Smalley SR, Benedetti JK, Haller DG, Hundahl SA, Estes NC, Ajani JA, et al. Updated analysis of SWOG-directed intergroup study 0116: A phase III trial of adjuvant radiochemotherapy versus observation after curative gastric cancer resection. J Clin Oncol 2012;30:2327-33.  Back to cited text no. 1
van Hagen P, Hulshof MC, van Lanschot JJ, Steyerberg EW, van Berge Henegouwen MI, Wijnhoven BP, et al. Preoperative chemoradiotherapy for esophageal or junctional cancer. N Engl J Med 2012;366:2074-84.  Back to cited text no. 2
Sjoquist KM, Burmeister BH, Smithers BM, Zalcberg JR, Simes RJ, Barbour A, et al. Survival after neoadjuvant chemotherapy or chemoradiotherapy for resectable oesophageal carcinoma: An updated meta-analysis. Lancet Oncol 2011;12:681-92.  Back to cited text no. 3
Stahl M, Walz MK, Stuschke M, Lehmann N, Meyer HJ, Riera-Knorrenschild J, et al. Phase III comparison of preoperative chemotherapy compared with chemoradiotherapy in patients with locally advanced adenocarcinoma of the esophagogastric junction. J Clin Oncol 2009;27:851-6.  Back to cited text no. 4
Dora T, Deshmukh J, Chatterjee A, Goel A, Bose S, Singh A, et al. Conformal vs vmat technique in high dose concurrent chemoradiotherapy of carcinoma esophagus: A retrospective analysis. Cancer Res Stat Treat 2021;4:456-65.  Back to cited text no. 5
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Zhao KL, Ma JB, Liu G, Wu KL, Shi XH, Jiang GL. Three-dimensional conformal radiation therapy for esophageal squamous cell carcinoma: Is elective nodal irradiation necessary? Int J Radiat Oncol Biol Phys 2010;76:446-51.  Back to cited text no. 6
Herskovic A, Martz K, al-Sarraf M, Leichman L, Brindle J, Vaitkevicius V, et al. Combined chemotherapy and radiotherapy compared with radiotherapy alone in patients with cancer of the esophagus. N Engl J Med 1992;326:1593-8.  Back to cited text no. 7
Cooper JS, Guo MD, Herskovic A, Macdonald JS, Martenson JA Jr., Al-Sarraf M, 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;281:1623-7.  Back to cited text no. 8
Minsky BD, Pajak TF, Ginsberg RJ, Pisansky TM, Martenson J, Komaki R, 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;20:1167-74.  Back to cited text no. 9
Hulshof MC, Geijsen ED, Rozema T, Oppedijk V, Buijsen J, Neelis KJ, et al. Randomized Study on Dose Escalation in Definitive Chemoradiation for Patients With Locally Advanced Esophageal Cancer (ARTDECO Study). J Clin Oncol 2021;39:2816-24.  Back to cited text no. 10
Zenda S, Kojima T, Kato K, Izumi S, Ozawa T, Kiyota N, et al. Multicenter phase 2 study of cisplatin and 5-fluorouracil with concurrent radiation therapy as an organ preservation approach in patients with squamous cell carcinoma of the cervical esophagus. Int J Radiat Oncol Biol Phys 2016;96:976-84.  Back to cited text no. 11
Burmeister BH, Dickie G, Smithers BM, Hodge R, Morton K. Thirty-four patients with carcinoma of the cervical esophagus treated with chemoradiation therapy. Arch Otolaryngol Head Neck Surg 2000;126:205-8.  Back to cited text no. 12
Zhang P, Xi M, Zhao L, Qiu B, Liu H, Hu YH, et al. Clinical efficacy and failure pattern in patients with cervical esophageal cancer treated with definitive chemoradiotherapy. Radiother Oncol 2015;116:257-61.  Back to cited text no. 13


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