Eyck, Ben M.

van Lanschot, J. Jan B.

Wijnhoven, Bas P.L.

English

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correspondenceReply to B. Li et alWe thank our colleagues Li and Chen1 for theircomments in response to our article.2 Indeed, there isstill no full consensus about the best treatment strategyfor locally advanced esophageal cancer and morespecifically about the optimal neoadjuvant regimen. Liand Chen1 argue that extended lymphadenectomy is acrucial part of treatment in these patients and that theneoadjuvant chemoradiotherapy as applied in theCROSS trial simply compensated for inadequate sur-gery. We feel that their viewpoint is not supported bythe available evidence.The overall survival benefit of patients who receivedneoadjuvant chemoradiotherapy persists for at least10 years. Surgical approach (transthoracic v tran-shiatal) did not affect this survival advantage.2 Li andChen1 argue that these results are not in line with ourearlier randomized HIVEX trial in which limited tran-shiatal resection was compared with extended trans-thoracic resection (exclusively in patients withadenocarcinoma).3,4 However, the HIVEX trial did notshow an overall benefit for the extended resection, butthe post hoc analyses showed a benefit only in patientswith a type-1 esophageal tumor and a limited numberof positive lymph nodes. We realize that this specificsubgroup is most relevant for our Asian colleagues whoare mainly confronted with type-1 esophageal patients(with squamous cell carcinoma).Also, Li and Chen1 argue that the results of CROSS areconflicting with their Fudan University ShanghaiCancer Center trial, in which a right-sided transtho-racic resection (with extended lymphadenectomy) iscompared with left-sided transthoracic resection (withlimited lymphadenectomy).5 In the surgery-alone armof the CROSS trial, however, the median number ofresected nodes (n 5 18, interquartile range [IQR] 13-27) was only marginally lower than that in the extendedlymphadenectomy arm of the Fudan trial (n5 22, IQR17-33), whereas the R0 radicality rate was comparable(69% v 68%, respectively).5,6 This is even morestriking, considering the fact that the patients in thesurgery-alone arm of the CROSS trial had substantiallymore advanced tumor stages than the patients in theFudan trial (pT3-4: 80% v 49%, pN1: 75% v 44%,respectively). Hence, we conclude that in the CROSStrial, the surgical part of the multimodality treatmentwas up to standards.What is the evidence that extended lymphadenectomycan add any survival benefit in patients who undergomultimodality treatment according to CROSS? In theoriginal CROSS trial, the number of resected lymphnodes was not associated with survival if patientsreceived chemoradiotherapy before surgery.7 Thisfinding was confirmed in a larger cohort study,showing no prognostic effect of transthoracic overtranshiatal resection in patients who were treated withthe CROSS regimen.8 Moreover, in a nationwide Dutchpropensity score–matched study including 1984 pa-tients, survival was comparable between thosewith $ 15 versus , 15 lymph nodes resected afterneoadjuvant chemoradiotherapy.9Finally, Li and Chen1 state that a difference in deathfrom other cause was observed in the CROSS trial andthat the proportion of deaths from other cause washigher than that in the Fudan trial. In the neoadjuvantchemoradiotherapy plus surgery arm, however, 18%of patients died from other cause (not 28%, as wronglycited by Li and Chen1) compared with 12% of patientsin the surgery-alone arm (cause-specific hazard ratio1.17; 95% CI, 0.68 to 1.99). Also, comparison of theproportion of deaths in the CROSS trial with those inthe Fudan trial should be done with caution since themedian follow-up of the Fudan trial was only68 months (IQR 62-82 months), whereas the medianfollow-up of the CROSS trial was 147 months (IQR134-157 months). Thus, patients in the CROSS trialran a substantially longer risk of dying.In conclusion, surgery in the CROSS trial can beconsidered as adequate. Addition of neoadjuvantchemoradiotherapy to such adequate surgery resultsin substantially improved survival even after 10 years offollow-up and, in these patients, more extended lymphnode dissection is probably not beneficial.Ben M. Eyck, MD, Bas P. L. Wijnhoven, MD, PhD,and J. Jan B. van Lanschot, MD, PhD; On behalf ofthe CROSS Study GroupDepartment of Surgery, Erasmus MC Cancer Institute,Erasmus University Medical Center, Rotterdam,the NetherlandsAUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OFINTERESTDisclosures provided by the authors are available with this article atDOI https://doi.org/10.1200/JCO.21.01543.REFERENCES1. Li B, Chen H: The best surgery should be applied for locally advancedesophageal cancer. J Clin Oncol 39:3189-3190, 20212. Eyck BM, van Lanschot JJB, Hulshof MCCM, et al: Ten-year outcomeof neoadjuvant chemoradiotherapy plus surgery for esophagealcancer: The randomized controlled CROSS trial. J Clin Oncol 39:1995-2004, 20213. Hulscher JB, van Sandick JW, de Boer AG, et al: Extendedtransthoracic resection compared with limited transhiatal resec-tion for adenocarcinoma of the esophagus. N Engl J Med 347:1662-1669, 20024. Omloo JM, Lagarde SM, Hulscher JB, et al: Extended transtho-racic resection compared with limited transhiatal resection for3190 Volume 39, Issue 28Downloaded from ascopubs.org by Erasmus Universiteit on November 11, 2021 from 154.059.124.038Copyright © 2021 American Society of Clinical Oncology. All rights reserved. adenocarcinoma of the mid/distal esophagus: Five-year survival of a ran-domized clinical trial. Ann Surg 246:992-1000, 2007; discussion 1000-10015. Li B, Hu H, Zhang Y, et al: Extended right thoracic approach com-pared with limited left thoracic approach for patients with middle andlower esophageal squamous cell carcinoma: Three-year survival of aprospective, randomized, open-label trial. Ann Surg 267:826-832,20186. van Hagen P, Hulshof MC, van Lanschot JJ, et al: Preoperative chemo-radiotherapy for esophageal or junctional cancer. N Engl J Med 366:2074-2084, 20127. Koen Talsma A, Shapiro J, Looman CW, et al: Lymph node retrieval duringesophagectomy with and without neoadjuvant chemoradiotherapy:Prognostic and therapeutic impact on survival. Ann Surg 260:786-792,2014; discussion 792-7838. Noordman BJ, van Klaveren D, van Berge Henegouwen MI, et al: Impact ofsurgical approach on long-term survival in esophageal adenocarcinomapatients with or without neoadjuvant chemoradiotherapy. Ann Surg 267:892-897, 20189. van der Werf LR, Marra E, Gisbertz SS, et al: A propensity score-matchedcohort study to evaluate the association of lymph node retrieval with long-term overall survival in patients with esophageal cancer. Ann Surg Oncol 28:133-141, 2021DOI: https://doi.org/10.1200/JCO.21.01543; Published at ascopubs.org/journal/jco on August 2, 2021.n n nJournal of Clinical Oncology 3191CorrespondenceDownloaded from ascopubs.org by Erasmus Universiteit on November 11, 2021 from 154.059.124.038Copyright © 2021 American Society of Clinical Oncology. All rights reserved. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTERESTReply to B. Li et alThe following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted.Relationships are self-held unless noted. I5 Immediate Family Member, Inst5My Institution. Relationships may not relate to the subject matter of this manuscript.For more information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/authors/author-center.Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).No potential conflicts of interest were reported.© 2021 by American Society of Clinical Oncology Volume 39, Issue 28CorrespondenceDownloaded from ascopubs.org by Erasmus Universiteit on November 11, 2021 from 154.059.124.038Copyright © 2021 American Society of Clinical Oncology. All rights reserved. 

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