Meta‐analysis comparing upfront surgery with neoadjuvant treatment in patients with resectable or borderline resectable pancreatic cancer. BJS 2018; 105: 946-958.

Published: 30th April 2018

Authors: E. Versteijne, J. A. Vogel, M. G. Besselink, O. R. C. Busch, J. W. Wilmink, J. G. Daams et al.

Background

Studies comparing upfront surgery with neoadjuvant treatment in pancreatic cancer may report only patients who underwent resection and so survival will be skewed. The aim of this study was to report survival by intention to treat in a comparison of upfront surgery versus neoadjuvant treatment in resectable or borderline resectable pancreatic cancer.

Method

MEDLINE, Embase and the Cochrane Library were searched for studies reporting median overall survival by intention to treat in patients with resectable or borderline resectable pancreatic cancer treated with or without neoadjuvant treatment. Secondary outcomes included overall and R0 resection rate, pathological lymph node rate, reasons for unresectability and toxicity of neoadjuvant treatment.

Results

In total, 38 studies were included with 3484 patients, of whom 1738 (49·9 per cent) had neoadjuvant treatment. The weighted median overall survival by intention to treat was 18·8 months for neoadjuvant treatment and 14·8 months for upfront surgery; the difference was larger among patients whose tumours were resected (26·1 versus 15·0 months respectively). The overall resection rate was lower with neoadjuvant treatment than with upfront surgery (66·0 versus 81·3 per cent; P < 0·001), but the R0 rate was higher (86·8 (95 per cent c.i. 84·6 to 88·7) versus 66·9 (64·2 to 69·6) per cent; P < 0·001). Reported by intention to treat, the R0 rates were 58·0 and 54·9 per cent respectively (P = 0·088). The pathological lymph node rate was 43·8 per cent after neoadjuvant therapy and 64·8 per cent in the upfront surgery group (P < 0·001). Toxicity of at least grade III was reported in up to 64 per cent of the patients.

Conclusion

Neoadjuvant treatment appears to improve overall survival by intention to treat, despite lower overall resection rates for resectable or borderline resectable pancreatic cancer.

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2 Comments

Elena Rangelova

4 months ago

The meta-analysis by Versteijne et al., neoadjuvant oncologic treatment (NAT) for resectable/borderline-resectable pancreatic cancer (R-BRPC), gave a significant survival advantage to upfront surgery (S) both in the intention-to-treat analysis and for the patients undergoing resection.

As exciting the finding appears, the conclusion should be interpreted with care. First, NAT comprises of mixture of regimens, including FOLFIRINOX, which overrules significantly gemcitabine in terms of survival for locally advanced PC (1). The advantage of FOLFIRINOX could be erroneously translated as a benefit of the whole group of chemotherapy.

Second, In the NAT group, adjuvant chemotherapy (ACT) was not even reported in 17/35 studies, and it is still the gold standard (2). The argument that patients may not receive ACT due to deconditioning after surgery is invalid, since patients who are too old or sick for ACT would be so even for NAT. Thus, there is already a selection bias in the NAT group. Also, FOLFIRINOX is not part of ACT, although a recent trial showed clear superiority to standard ACT even postoperatively (3).

Furthermore, there is a paradoxically higher resection rate for BR- over R-PC suggesting a discrepancy in the technical possibility for radical surgical resection among the studies. Resection itself has undoubtedly the highest impact on survival for PC.

Is it really the timing or the type of chemotherapy that makes a difference for survival after radical surgery? There are no trials comparing neoadjuvant to adjuvant FOLFIRINOX for R-BRPC. Until we have this data all meta-analysis performed will be biased.

Rangelova E
Valente R
Del Chiaro M

Pancreatic Unit at Dept of Upper GI Cancer
Karolinska University Hospital, K42
14186 Stockholm
Sweden
Elena.Rangelova@ki.se

References:
1. Suker M, Beumer BR, Sadot E, Marthey L, Faris JE, Mellon EA, El-Rayes BF, Wang-Gillam A, Lacy G, Hosein PJ, Moorcraft SY, Conroy T, Hohla F, Allen P, Taieb J, Hong TS, Shridhar R, Chau I, van Eijk CH, Koerkamp BG. FOLFIRINOX for locally advanced pancreatic cancer: a systemic review and patient-level meta-analysis. Lancet Oncol 2016; 18: 801-10.
2. Neoptolemos JP, Palmer DH, Ghaneh P, Psarelli EE, Valle JW, Halloran CM, Faluyi O, O’Reilly DA, Cunningham D, Wadsley J, Darby S, Meyer T, Gillmore R, Anthoney A, Lind P, Glimelius B, Falk S, Izbicki JR, Middleton GW, Cummins S, Ross PJ, Wasan H, McDonald A, Crosby T, Ma YT, Patel K, Sheriff D, Soomal R, Borg D, Sothi S, Hammel P, Hackert T, Jackson R, Bchler MW, European Study Group for Pancreatic Cancer. Lancet 2017; 389(10073):1011-1024.
3. Conroy T, Hammel P, Hebbar M, Abdelghani MB, Wei AC, Raoul J-L, Chone L, Francois E, Artru P, Biagi JJ, Lecomte T, Assenat E, Faroux R, Ychou M, Volet J, Sauvanet A, Jouffroy-Zeller C, RAT P, Castan F, Bachet J-B. Unicancer GI PRODIGE 24/CCTG PA.6 trial: a multicentre international randomized phase III trial of adjuvant mFOLFIRINOX versus gemcitabine (gem) in patients with resected pancreatic ductal adenocarcinomas. Abstract LBA4001, presented at ASCO meeting June 4th, 2018.

    Eva Versteijne

    2 weeks ago

    We thank dr Rangelova et al. for their critical appraisal of our review.

    Our review suggest a benefit of neoadjuvant treatment over upfront surgery for borderline resectable pancreatic cancer in median overall survival reported by intention to treat. We agree that these conclusions should be interpreted with care due to heterogeneity in neoadjuvant schedules and resectability criteria. But since only 3.4% of the 1,738 patients received neoadjuvant FOLFIRINOX this cannot be the cause of the difference found.

    In many neoadjuvant studies, all chemoradiotherapy is given preoperatively. But even if not, many pancreatic cancer patients do not receive adjuvant chemotherapy due to postoperative complications, or early disease progression. In the PREOPANC trial, recently presented at ASCO, only 48% of patients in the immediate surgery group started adjuvant chemotherapy, compared to 46% in the neoadjuvant treatment group. This strongly suggests that a higher proportion of patients is able to receive neoadjuvant treatment than adjuvant treatment (1, 2). The trial presented at ASCO, as all adjuvant trials, recruited patients fit enough to undergo (FOLFIRINOX) chemotherapy after a successful resection of their pancreatic cancer (3). This is a much more favourable patient selection than in neoadjuvant treatment studies.

    Hence, we do think that the benefit suggested in our meta-analysis is attributable to the timing of the chemoradiotherapy rather than the variation in schedules applied. We do hope that final results of the PREOPANC trial will provide randomized evidence to support this. We started the PREOPANC-2 trial to investigate the role of neoadjuvant FOLFIRINOX.

    Eva Versteijne
    Geertjan van Tienhoven

    Department of Radiation Oncology
    Cancer Centre Amsterdam
    Academic Medical Centre
    Meibergdreef 9
    1105 AZ, Amsterdam
    The Netherlands
    e.versteijne@amc.uva.nl

    References:
    1. Versteijne E, van Eijck CH, Punt CJ, Suker M, Zwinderman AH, Dohmen MA, Groothuis KB, Busch OR, Besselink MG, de Hingh IH, Ten Tije AJ, Patijn GA, Bonsing BA, de Vos-Geelen J, Klaase JM, Festen S, Boerma D, Erdmann JI, Molenaar IQ, van der Harst E, van der Kolk MB, Rasch CR, van Tienhoven G. Preoperative radiochemotherapy versus immediate surgery for resectable and borderline resectable pancreatic cancer (PREOPANC trial): study protocol for a multicentre randomized controlled trial. Trials 2016;17(1): 127.
    2. Van Tienhoven G, Versteijne E, Suker M, Groothuis KB, Busch OR, Bonsing BA, de Hingh IH, Festen S, Patijn GA, de Vos -Geelen J, Zwinderman AH, Punt CJ, van Eijck CH. Preoperative chemoradiotherapy versus immediate surgery for resectable and borderline resectable pancreatic cancer (PREOPANC-1) : A randomized, controlled, multicenter phase III trial. Abstract LBA4002, presented at ASCO meeting June 4th, 2018
    3. Conroy T, Hammel P, Hebbar M, Abdelghani MB, Wei AC, Raoul J-L, Chone L, Francois E, Artru P, Biagi JJ, Lecomte T, Assenat E, Faroux R, Ychou M, Volet J, Sauvanet A, Jouffroy-Zeller C, RAT P, Castan F, Bachet J-B. Unicancer GI PRODIGE 24/CCTG PA.6 trial: a multicentre international randomized phase III trial of adjuvant mFOLFIRINOX versus gemcitabine (gem) in patients with resected pancreatic ductal adenocarcinomas. Abstract LBA4001, presented at ASCO meeting June 4th, 2018.