Neoadjuvant Chemoradiotherapy Versus Upfront Surgery for Resectable and Borderline Resectable Pancreatic Cancer: Long-Term Results of the Dutch Randomized PREOPANC Trial

Author(s): Eva Versteijne, MD, PhD¹; Jacob L. van Dam, MD²; Mustafa Suker, MD, PhD²; Quisette P. Janssen, MD²; Karin Groothuis, MSc³; Janine M. Akkermans-Vogelaar, BSc³; Marc G. Besselink, MD, PhD⁴; Bert A. Bonsing, MD, PhD⁵; Jeroen Buijsen, MD, PhD⁶; Olivier R. Busch, MD, PhD⁴; Geert-Jan M. Creemers, MD, PhD⁷; Ronald M. van Dam, MD, PhD^8,9,10; Ferry A. L. M. Eskens, MD, PhD¹¹; Sebastiaan Festen, MD, PhD¹²; Jan Willem B. de Groot, MD, PhD¹³; Bas Groot Koerkamp, MD, PhD²; Ignace H. de Hingh, MD, PhD¹⁴; Marjolein Y. V. Homs, MD, PhD¹¹; Jeanin E. van Hooft, MD, PhD^15,16; Emile D. Kerver, MD¹⁷; Saskia A. C. Luelmo, MD¹⁸; Karen J. Neelis, MD, PhD¹⁹; Joost Nuyttens, MD, PhD²⁰; Gabriel M. R. M. Paardekooper, MD²¹; Gijs A. Patijn, MD, PhD²²; Maurice J. C. van der Sangen, MD, PhD²³; Judith de Vos-Geelen, MD, PhD²⁴; Johanna W. Wilmink, MD, PhD²⁵; Aeilko H. Zwinderman, PhD²⁶; Cornelis J. Punt, MD, PhD²⁷; Geertjan van Tienhoven, MD, PhD¹; and Casper H. J. van Eijck, MD, PhD²; for the Dutch Pancreatic Cancer Group

Source: DOI: 10.1200/JCO.21.02233 Journal of Clinical Oncology 40, no. 11 (April 10, 2022) 1220-1230.

Dr. Lucio Gordan's Thoughts

Very interesting study which gives more support for preoperatory therapy in the setting of borderline resectable pancreatic cancer. The use of neodjuvant chemotherapy or chemoradiotherapy will likely increase overtime, as systemic options improve, even in pancreatic cancer. Optimal regimen is unknown as studies with other options such as Folfirinox, gemcitabine/albumin-bound paclitaxel are needed, post chemoradiotherapy.

PURPOSE

The benefit of neoadjuvant chemoradiotherapy in resectable and borderline resectable pancreatic cancer remains controversial. Initial results of the PREOPANC trial failed to demonstrate a statistically significant overall survival (OS) benefit. The long-term results are reported.

METHODS

In this multicenter, phase III trial, patients with resectable and borderline resectable pancreatic cancer were randomly assigned (1:1) to neoadjuvant chemoradiotherapy or upfront surgery in 16 Dutch centers. Neoadjuvant chemoradiotherapy consisted of three cycles of gemcitabine combined with 36 Gy radiotherapy in 15 fractions during the second cycle. After restaging, patients underwent surgery followed by four cycles of adjuvant gemcitabine. Patients in the upfront surgery group underwent surgery followed by six cycles of adjuvant gemcitabine. The primary outcome was OS by intention-to-treat. No safety data were collected beyond the initial report of the trial.

RESULTS

Between April 24, 2013, and July 25, 2017, 246 eligible patients were randomly assigned to neoadjuvant chemoradiotherapy (n = 119) and upfront surgery (n = 127). At a median follow-up of 59 months, the OS was better in the neoadjuvant chemoradiotherapy group than in the upfront surgery group (hazard ratio, 0.73; 95% CI, 0.56 to 0.96; P = .025). Although the difference in median survival was only 1.4 months (15.7 months v 14.3 months), the 5-year OS rate was 20.5% (95% CI, 14.2 to 29.8) with neoadjuvant chemoradiotherapy and 6.5% (95% CI, 3.1 to 13.7) with upfront surgery. The effect of neoadjuvant chemoradiotherapy was consistent across the prespecified subgroups, including resectable and borderline resectable pancreatic cancer.

CONCLUSION

Neoadjuvant gemcitabine-based chemoradiotherapy followed by surgery and adjuvant gemcitabine improves OS compared with upfront surgery and adjuvant gemcitabine in resectable and borderline resectable pancreatic cancer.

Author Affiliations

¹Department of Radiation Oncology, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands ²Department of Surgery, Erasmus MC Cancer Institute, Rotterdam, the Netherlands ³Clinical Research Department, Comprehensive Cancer Organisation the Netherlands (IKNL) Nijmegen, the Netherlands ⁴Department of Surgery, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands ⁵Department of Surgery, Leiden University Medical Center, Leiden, the Netherlands ⁶Department of Radiation Oncology (MAASTRO), GROW School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, the Netherlands ⁷Department of Medical Oncology, Catharina Hospital, Eindhoven, the Netherlands ⁸Department of Surgery, Maastricht University Medical Center, Maastricht, the Netherlands ⁹Department of General, Visceral and Transplant Surgery, University Hospital Aachen, Aachen, Germany ¹⁰GROW – School for Oncology and Developmental Biology, Maastricht University, the Netherlands ¹¹Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands ¹²Department of Surgery, OLVG, Amsterdam, the Netherlands ¹³Department of Medical Oncology, Isala Oncology Center, Zwolle, the Netherlands ¹⁴Department of Surgery, Catharina Hospital, Eindhoven, the Netherlands ¹⁵Department of Gastroenterology and Hepatology, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands ¹⁶Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, the Netherlands ¹⁷Department of Medical Oncology, OLVG, Amsterdam, the Netherlands ¹⁸Department of Medical Oncology, Leiden University Medical Center, Leiden, the Netherlands ¹⁹Department of Radiation Oncology, Leiden University Medical Center, Leiden, the Netherlands ²⁰Department of Radiation Oncology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands ²¹Department of Radiation Oncology, Isala Oncology Center, Zwolle, the Netherlands ²²Department of Surgery, Isala Oncology Center, Zwolle, the Netherlands ²³Department of Radiation Oncology, Catharina Hospital, Eindhoven, the Netherlands ²⁴Department of Internal Medicine, Division of Medical Oncology, GROW—School for Oncology and Developmental Biology, Maastricht UMC+, Maastricht, the Netherlands ²⁵Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands ²⁶Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands ²⁷Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Centre, Utrecht University, the Netherlands

Addition of Metastasis-Directed Therapy to Systemic Therapy for Oligometastatic Pancreatic Ductal Adenocarcinoma (EXTEND): A Multicenter, Randomized Phase II Trial

Interesting study using local therapy in metastatic pancreatic ductal adenocarcinoma (MPDAC) patients with <=5 metastatic sites. I would really like to see overall survival data here as I think progression-free survival (PFS) is a tricky endpoint to use in a trial like this. Most likely the study arm will take a lot longer to demonstrate progression if all lesions are ablated, but most important to me is the quality of life, survival and overall exposure to cytotoxic therapy; the last of which is likely much better with local therapy being utilized.

Safety and Efficacy of CT041 in Patients With Refractory Metastatic Pancreatic Cancer: A Pooled Analysis of Two Early-Phase Trials

CAR-T agent for refractory met-pancreas showing a median duration of response of 9.5 months. These treatments are far from widely available, but the proof of principle is nice to see in a disease that otherwise has not had responses to immunotherapy. Hopefully more agents to come.

Nimotuzumab Plus Gemcitabine for K-Ras Wild-Type Locally Advanced or Metastatic Pancreatic Cancer

Asian study of nimotuzumab (humanized EGFR-inhibitor) + gemcitabine (gem) vs. gem alone. The overall survival (OS) was 10.9 vs. 8.5 months in favor of the combination arm. While the OS difference is small, recall that the OS in the NALIRIFOX and FOLFIRINOX studies are similar. The safety profile of nimotuzumab + gemcitabine is superior to a triplet or double cytotoxic chemotherapy combination regimen. This drug is currently not available in the USA but is approved for nasopharyngeal carcinoma in China.

NALIRIFOX versus nab-paclitaxel and gemcitabine in treatment-naive patients with metastatic pancreatic ductal adenocarcinoma (NAPOLI 3): a randomised, open-label, phase 3 trial

You may have enrolled a patient in this trial, but it seems we may have a new first line regimen. Surprisingly toxicity simar in both arms, but there was improvement in PFS and OS (17% reduction in death) although it wasn’t statistically significant in OS.
More diarrhea with nalirifox, but more neutropenia with gem abraxane.

Adjuvant nab-Paclitaxel + Gemcitabine in Resected Pancreatic Ductal Adenocarcinoma: Results From a Randomized, Open-Label, Phase III Trial

Somewhat disappointing as this was a negative study, however it is still an option for patients who are not candidates for mFOLFIRINOX.