Influence of induction chemotherapy in trimodality therapy-eligible oesophageal cancer patients: secondary analysis of a randomised trial

Yusuke Shimodaira, Rebecca S Slack, Kazuto Harada, Hsiang-Chun Chen, Tara Sagebiel, Manoop S Bhutani, Jeffrey H Lee, Brian Weston, Elena Elimova, Quan Lin, Fatemeh G Amlashi, Dilsa Mizrak Kaya, Mariela A Blum, Jack A Roth, Stephen G Swisher, Heath D Skinner, Wayne L Hofstetter, Jane E Rogers, Jaennette Mares, Irene Thomas, Dipen M Maru, Ritsuko Komaki, Garrett Walsh, Jaffer A Ajani, Yusuke Shimodaira, Rebecca S Slack, Kazuto Harada, Hsiang-Chun Chen, Tara Sagebiel, Manoop S Bhutani, Jeffrey H Lee, Brian Weston, Elena Elimova, Quan Lin, Fatemeh G Amlashi, Dilsa Mizrak Kaya, Mariela A Blum, Jack A Roth, Stephen G Swisher, Heath D Skinner, Wayne L Hofstetter, Jane E Rogers, Jaennette Mares, Irene Thomas, Dipen M Maru, Ritsuko Komaki, Garrett Walsh, Jaffer A Ajani

Abstract

Background: A randomised phase 2 trial of trimodality with or without induction chemotherapy (IC) in oesophageal cancer (EC) patients showed no advantage in overall survival (OS) or pathologic complete response rate. To identify subsets that might benefit from IC, a secondary analysis was done.

Methods: The trial had accrued 126 patients (NCT 00525915). Recursive partitioning and proportional hazards regression with interactions were performed.

Results: The median follow-up of surviving patients was 6.7 years and the median OS duration was 3.8 years (95% confidence interval (CI), 2.6-5.8 years). OS was associated with tumour length (P=0.03), cT (P=0.02), cN (P=0.04), clinical stage (P=0.01), and tumour grade (P<0.001). The effect of IC differed according to tumour grade. Among patients with well or moderately differentiated (WMD) ECs (n=59), the 5-year survival rate was 74% with IC and 50% without IC, P=0.001. IC had no effect on OS of patients with poorly differentiated (PD) ECs (31% and 28%, respectively; interaction, P=0.04; IC, P=0.03). In the multivariate reduced model, WMD with IC was an independent prognosticator for better OS (HR=0.41, 95% CI, 0.25-0.67; P=<0.001). The following four EC phenotypes emerged for OS: (1) very high risk (PD, cN2/N3), (2) high risk (PD, cN0/N1, stage cIII), (3) moderate risk (PD, cN0/N1, stage cI/II or WMD without IC), and (4) low risk (WMD with IC). The 5-year survival rates were 11%, 27%, 48%, and 74%, respectively (P<0.001).

Conclusions: Our data show that IC significantly prolonged OS of WMD EC patients who undergo trimodality; prospective evaluation is needed.

Trial registration: ClinicalTrials.gov NCT00525915.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Kaplan–Meier OS curve. (A) OS for the entire patient population (B) OS by treatment arm. (C) OS by treatment arm and tumour grade. Well, well- to-moderately differentiated tumour; poor, poorly differentiated tumour.
Figure 2
Figure 2
Four subgroups based on risk differential. (A) Tree diagram of the patient subgroups based on risk differential identified using recursive partitioning analysis (RPA). (B) OS by Risk Groups Identified by RPA.

References

    1. Ajani JA, D'Amico TA, Almhanna K, Bentrem DJ, Besh S, Chao J, Das P, Denlinger C, Fanta P, Fuchs CS, Gerdes H, Glasgow RE, Hayman JA, Hochwald S, Hofstetter WL, Ilson DH, Jaroszewski D, Jasperson K, Keswani RN, Kleinberg LR, Korn WM, Leong S, Lockhart AC, Mulcahy MF, Orringer MB, Posey JA, Poultsides GA, Sasson AR, Scott WJ, Strong VE, Varghese TK Jr, Washington MK, Willett CG, Wright CD, Zelman D, McMillian N, Sundar H National comprehensive cancer n (2015) Esophageal and esophagogastric junction cancers, version 1. 2015. J Natl Compr Canc Netw 13(2): 194–227.
    1. Ajani JA, Xiao L, Roth JA, Hofstetter WL, Walsh G, Komaki R, Liao Z, Rice DC, Vaporciyan AA, Maru DM, Lee JH, Bhutani MS, Eid A, Yao JC, Phan AP, Halpin A, Suzuki A, Taketa T, Thall PF, Swisher SG (2013) A phase II randomized trial of induction chemotherapy versus no induction chemotherapy followed by preoperative chemoradiation in patients with esophageal cancer. Ann Oncol 24(11): 2844–2849.
    1. Breiman L, Friedman J, Olshen R, Stone C (1984) Classification and Regression Trees. Chapman and Hall/CRC.
    1. Chirieac LR, Swisher SG, Correa AM, Ajani JA, Komaki RR, Rashid A, Hamilton SR, Wu TT (2005) Signet-ring cell or mucinous histology after preoperative chemoradiation and survival in patients with esophageal or esophagogastric junction adenocarcinoma. Clin Cancer Res 11(6): 2229–2236.
    1. Cox DR (1972) Regression models and life-tables. J R Stat Soc Series B Methodol 34(2): 187–220.
    1. Cunningham D, Allum WH, Stenning SP, Thompson JN, Van de Velde CJ, Nicolson M, Scarffe JH, Lofts FJ, Falk SJ, Iveson TJ, Smith DB, Langley RE, Verma M, Weeden S, Chua YJ, Participants MT (2006) Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med 355(1): 11–20.
    1. Idelevich E, Kashtan H, Klein Y, Buevich V, Baruch NB, Dinerman M, Tokar M, Kundel Y, Brenner B (2012) Prospective phase II study of neoadjuvant therapy with cisplatin, 5-fluorouracil, and bevacizumab for locally advanced resectable esophageal cancer. Onkologie 35(7-8): 427–431.
    1. Kaplan EL, Meier P (1958) Nonparametric Estimation from Incomplete Oservations. J Am Stat Assoc 53(282): 457–481.
    1. Mantel N (1966) Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep 50(3): 163–170.
    1. Oppedijk V, van der Gaast A, van Lanschot JJ, van Hagen P, van Os R, van Rij CM, van der Sangen MJ, Beukema JC, Rutten H, Spruit PH, Reinders JG, Richel DJ, van Berge Henegouwen MI, Hulshof MC (2014) Patterns of recurrence after surgery alone versus preoperative chemoradiotherapy and surgery in the CROSS trials. J Clin Oncol 32(5): 385–391.
    1. Pocock SJ, Simon R (1975) Sequential treatment assignment with balancing for prognostic factors in the controlled clinical trial. Biometrics 31(1): 103–115.
    1. Ruhstaller T, Pless M, Dietrich D, Kranzbuehler H, von Moos R, Moosmann P, Montemurro M, Schneider PM, Rauch D, Gautschi O, Mingrone W, Widmer L, Inauen R, Brauchli P, Hess V (2011) Cetuximab in combination with chemoradiotherapy before surgery in patients with resectable, locally advanced esophageal carcinoma: a prospective, multicenter phase IB/II Trial (SAKK 75/06). J Clin Oncol 29(6): 626–631.
    1. Siegel RL, Miller KD, Jemal A (2016) Cancer statistics, 2016. CA Cancer J Clin 66(1): 7–30.
    1. Stahl M, Mihaljevic AL, Moehler M, Kanzler S, Hoehler T, Thuss-Patience PC, Moenig SP, Kunzmann V, Schroll S, Lordick F, Meyer H-J, Sandermann A, Schumacher C, Wilke H (2015) Perioperative chemotherapy with ECX +/- panitumumab in locally advanced gastroesophageal adenocarcinomas (GEA): A randomized study of the Arbeitsgemeinschaft Internistische Onkologie and the Chirurgische Arbeitsgemeinschaft Onkologie of the German Cancer Society. Journal of Clinical Oncology 33(3_suppl): 104.
    1. Stahl M, Mariette C, Haustermans K, Cervantes A, Arnold D ESMO Guidelines Working Group (2013) Oesophageal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 24(Suppl 6): vi51–vi56.
    1. Taketa T, Sudo K, Correa AM, Wadhwa R, Shiozaki H, Elimova E, Campagna MC, Blum MA, Skinner HD, Komaki RU, Lee JH, Bhutani MS, Weston BR, Rice DC, Swisher SG, Maru DM, Hofstetter WL, Ajani JA (2014) Post-chemoradiation surgical pathology stage can customize the surveillance strategy in patients with esophageal adenocarcinoma. J Natl Compr Canc Netw 12(8): 1139–1144.
    1. Therneau TM, Atkinson EJ (1997) An introduction to recursive partitioning using the RPART routines: Report no. 61. Available at: .
    1. van Hagen P, Hulshof MC, van Lanschot JJ, Steyerberg EW, van Berge Henegouwen MI, Wijnhoven BP, Richel DJ, Nieuwenhuijzen GA, Hospers GA, Bonenkamp JJ, Cuesta MA, Blaisse RJ, Busch OR, ten Kate FJ, Creemers GJ, Punt CJ, Plukker JT, Verheul HM, Spillenaar Bilgen EJ, van Dekken H, van der Sangen MJ, Rozema T, Biermann K, Beukema JC, Piet AH, van Rij CM, Reinders JG, Tilanus HW, van der Gaast A Group C (2012) Preoperative chemoradiotherapy for esophageal or junctional cancer. N Engl J Med 366(22): 2074–2084.
    1. Wu TT, Chirieac LR, Abraham SC, Krasinskas AM, Wang H, Rashid A, Correa AM, Hofstetter WL, Ajani JA, Swisher SG (2007) Excellent interobserver agreement on grading the extent of residual carcinoma after preoperative chemoradiation in esophageal and esophagogastric junction carcinoma: a reliable predictor for patient outcome. Am J Surg Pathol 31(1): 58–64.

Source: PubMed

スポンサーと協力者

医学的状態

薬物療法

3
購読する