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Year : 2022  |  Volume : 5  |  Issue : 1  |  Page : 169-171

Authors' reply to Bhattacharyya et al., Thammineedi et al., and Arun

Department of Radiation Oncology, Homi Bhabha Cancer Hospital, Civil Hospital Campus, Sangrur City, Punjab, India

Date of Submission01-Feb-2022
Date of Decision27-Feb-2022
Date of Acceptance01-Mar-2022
Date of Web Publication31-Mar-2022

Correspondence Address:
Tapas Kumar Dora
Department of Radiation Oncology, Homi Bhabha Cancer Hospital, Civil Hospital Campus, Sangrur City - 148 001, Punjab
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/crst.crst_65_22

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How to cite this article:
Dora TK, Aeron T, Chatterjee A, Deshmukh J. Authors' reply to Bhattacharyya et al., Thammineedi et al., and Arun. Cancer Res Stat Treat 2022;5:169-71

How to cite this URL:
Dora TK, Aeron T, Chatterjee A, Deshmukh J. Authors' reply to Bhattacharyya et al., Thammineedi et al., and Arun. Cancer Res Stat Treat [serial online] 2022 [cited 2022 May 21];5:169-71. Available from: https://www.crstonline.com/text.asp?2022/5/1/169/342405

We thank Bhattacharyya et al,[1] Thammineedi et al,[2] and Arun[3] for their interest in our study titled, “Neoadjuvant chemoradiotherapy followed by surgery for operable carcinoma esophagus: Ground reality in a tertiary care center of rural India - A retrospective audit”[4] and the accompanying editorial by Rajappa.[5] We completely agree with the surgical oncologist's viewpoint proposed by Arun[3] that video-assisted thoracoscopic surgery (VATS) could reduce morbidity in the organ preservation approach with preoperative chemoradiotherapy in operable esophageal cancer, with a high pathological complete remission rate and R0 resection rate for a predominantly squamous cell histology in the Indian subcontinent. Thammineedi et al.[2] have highlighted that the problem in the Indian scenario is refusal of surgery because of poor understanding due to lower socioeconomic background and misinterpretation of symptom improvement as disease cure, which leads to higher attrition rates during the follow-up period. Bhattacharyya et al.[1] have rightly commented that we failed to deliver the radical dose of up to 50.4 Gy in those who could not undergo surgery (group B) due to the lack of in-house thoracic surgical facility, and that the pathologic response rate could have been different if the 9 out of 55 patients who did not undergo surgery had received proper in-house surgical counseling. Moreover, despite repeated calling, we failed to document if patients in group B had any residual disease or recurrence. Therefore, we need to improve patient follow-up with timely tracking to ensure that patients undergo surgery; we also need to document the disease status of those who do not undergo surgery.

The baseline T and N stages along with composite staging, neoadjuvant chemoradiation details, and toxicities are shown in [Table 1]. This information was not included in the manuscript due to space limitations. All 55 patients were compliant and completed the full course of radiation. The range of radiotherapy duration was higher in group B as 3 out of 8 patients who had advanced inoperable disease on restaging were treated with a radical dose of 63 Gy when they presented to the hospital after a few weeks. In groups A and B, one patient each defaulted on concurrent chemotherapy after three cycles, and in group B, chemotherapy was discontinued after two cycles in one patient due to poor general condition. No patient required chemotherapy dose reduction due to toxicities.
Table 1: Clinical staging, chemoradiation, and toxicities in patients with locally advanced esophageal cancer who received neoadjuvant chemoradiotherapy as per the CROSS protocol

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Regarding the paradox in disease-free survival (DFS) pointed out by Bhattacharyya et al.,[1] we concede that we had similar concerns. However, we would like to point out that 16 patients in group B did not have any disease documentation by endoscopy or positron emission tomography (PET)-computed tomography (CT) as they were lost to follow-up. Hence, the DFS reported in our study may not be a true representation of the actual DFS as per definition. At best, it can be considered as clinical DFS, and the actual DFS could have been different with proper follow-up investigations in these patients. Similarly, Thammineedi et al.[2] have rightly pointed out that neoadjuvant chemoradiation alone with a suboptimal dose of 41.4 Gy cannot be considered a definitive radical treatment arm. However, surprisingly, the DFS was better in group B (those who did not complete surgery) than in group A (those who completed surgery). Our rationale to compare the above-mentioned groups was to highlight the fact that there is likely a cohort of patients who respond excellently to a 41.4 Gy dose. Therefore, we can implement the “wait and watch” strategy, as is done in carcinoma of the rectum and operable carcinoma esophagus, with evidence from two ongoing trials, SANO[6] and ESOTRATE.[7]

In our study,[4] the major reasons for not completing surgery in group B were advanced inoperable disease on restaging (n=8), unfit for surgery (n=5), feeling better so unwilling for surgery (n=8), and scared of surgery due to low self-confidence (n=1). All these reasons broadly fall into the following two categories: patients with advanced inoperable disease on restaging and those unfit for surgery who may have been overenthusiastically considered for surgery, even though they may not have been ideal candidates. If we had thoroughly screened all the patients upfront and evaluated the possibility of inoperability after induction therapy due to disease progression or becoming unfit for surgery due to low body weight or poor general condition, then we may not have planned these patients for the CROSS protocol. We strongly agree with the conclusion drawn in a recent article by Bhattacharyya et al.[8] that “CROSS protocol can be safely implemented in carefully selected (PET-CT–based disease assessment before starting treatment) patients with squamous cell carcinoma esophagus.” However, caution needs to be exercised when adopting the protocol for patients with more advanced disease and, more so, in resource-limited countries without strong screening programs.

Patients who refused surgery either because of fear or they were feeling better were probably good responders to chemoradiation, who should have been kept on active surveillance after a negative bite-on-bite biopsy, based on the results of two ongoing randomized trials.[6],[7] Here, the proposal by Thammineedi et al.[2] for a neoadjuvant dose of 50.4 Gy instead of 41.4 Gy appears reasonable, considering that the majority of Indian cases have squamous histology compared to 75% cases of adenocarcinoma in the CROSS study. However, 50.4 Gy is the proven radical dose for squamous histology as evidenced from the INT0123 study,[9] and this dose cannot be implemented in the neoadjuvant setting without randomized Phase III trial evidence, considering the additional risk of postoperative morbidities due to possible difficulties of surgical planes. Thus, the pertinent question is whether it is time to initiate a randomized trial limited to carcinoma esophagus of squamous histology comparing the neoadjuvant dose of 41.4 versus 50.4 Gy and surgery versus active surveillance based on the results of bite-on-bite biopsies.

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Conflicts of interest

There are no conflicts of interest.

  References Top

Bhattacharyya T, Mallick I, Singh MA. Neoadjuvant chemoradiation followed by surgery in operable carcinoma esophagus: Is the real-world scenario too far from clinical trial settings? Cancer Res Stat Treat 2022;5:166-7.  Back to cited text no. 1
  [Full text]  
Thammineedi SR, Patnaik SC, Nusrath S. Does the radiation dose in neoadjuvant chemoradiation in resectable esophageal carcinoma matter in the Indian scenario? Cancer Res Stat Treat 2022;5:167-9.  Back to cited text no. 2
  [Full text]  
HN A. Is CROSS the right approach for locally advanced esophageal cancer in India? Cancer Res Stat Treat 2022;5:165-6.  Back to cited text no. 3
Dora TK, Aeron T, Chatterjee A, Deshmukh J, Goel A, Bose S. Neoadjuvant chemoradiotherapy followed by surgery for operable carcinoma esophagus: Ground reality in a tertiary care center of rural India retrospective audit. Cancer Res Stat Treat 2021;4:647-55.  Back to cited text no. 4
  [Full text]  
Rajappa SJ. At crossroads with CROSS: Implementing the CROSS protocol in a resource-limited setting. Cancer Res Stat Treat 2021;4:734-6.  Back to cited text no. 5
  [Full text]  
Noordman BJ, Wijnhoven BP, Lagarde SM, Boonstra JJ, Coene PP, Dekker JW, et al. Neoadjuvant chemoradiotherapy plus surgery versus active surveillance for oesophageal cancer: A stepped wedge cluster randomised trial. BMC Cancer 2018;18:142.  Back to cited text no. 6
Bedenne L, Mariette C. Comparison of Systematic Surgery Versus Surveillance and Rescue Surgery in Operable Oesophageal Cancer with a Complete Clinical Response to Radiochemotherapy (Esostrate). Available from: https://clinicaltrials.gov/ct2/show/NCT02551458. [Last accessed on 2019 May 21].  Back to cited text no. 7
Bhattacharyya T, Arunsingh M, Chakraborty S, Harilal V, Sasidharan R, Saha S, et al. Can the CROSS protocol be safely implemented in real world scenario with broader eligibility criteria? Experience from a tertiary care centre in India. Ecancermedicalscience 2021;15:1291.  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


  [Table 1]


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