Clinical trialPhase 3Pancreatic cancer

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

J Clin Oncol · 2022246 eligible patients (119 neoadjuvant chemoradiotherapy, 127 upfront surgery)

Versteijne E, van Dam JL, Suker M, et al. J Clin Oncol. 2022. 40:1220-1230

Study type: Clinical trial
Study name: PREOPANC
Phase: Phase 3
Design: Multicentre randomised trial (16 centres in the Netherlands), 1:1 randomisation; long-term results (median follow-up 59 months)
Sample size: 246 eligible patients (119 neoadjuvant chemoradiotherapy, 127 upfront surgery)
Source: J Clin Oncol · 2022

In plain words

An important question in pancreatic cancer is whether it is better to have surgery first, or to have chemotherapy and radiotherapy before surgery. In this Dutch study, patients who had chemoradiotherapy before surgery had a better chance of being alive in the long term: after 5 years about 20% of them were alive, compared with about 6.5% of those who had surgery straight away. These results are one of the reasons that treatment before surgery is used more today, especially for borderline tumours.

Key results

HR 0.73

Overall survival (hazard ratio)

95% CI 0.56–0.96; P=.025; median follow-up 59 months

15.7 vs 14.3 months

Median overall survival

Difference in medians only 1.4 months

20.5% vs 6.5%

5-year overall survival

95% CI 14.2–29.8 and 3.1–13.7, respectively

71% vs 40%

R0 resection (initial report, JCO 2020)

51 of 72 vs 37 of 92 resected patients; P<.001 — Versteijne E et al, J Clin Oncol 2020 (doi:10.1200/JCO.19.02274)

Drugs in this study:Gemcitabine (Gemzar)

Dose and schedule cards

Neoadjuvant gemcitabine-based chemoradiotherapy (PREOPANC)

Resectable or borderline resectable pancreatic cancerCycle length: Every 28 daysOn the page “Pancreatic cancer” · Adjuvant (postoperative) and neoadjuvant (preoperative) therapy

Resectable or borderline resectable pancreatic cancer

Drug	Dose	Route	Schedule
Preoperative: 3 cycles of 28 days
Gemcitabine	1000 mg/m²	IV	Cycles 1 and 3: Days 1 and 8; Cycle 2: Days 1, 8 and 15
Hypofractionated radiotherapy	36 Gy in 15 fractions	External beam	During cycle 2 only
Postoperative: 4 cycles
Adjuvant gemcitabine		IV

Cycle length: Every 28 days
Duration: 3 cycles before surgery, surgery, then 4 cycles of adjuvant gemcitabine

Doses and schedule from PREOPANC-2 (chemoradiotherapy arm); survival evidence compared with upfront surgery: PREOPANC.

On the page “Pancreatic cancer” · Adjuvant (postoperative) and neoadjuvant (preoperative) therapy

Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.

Treatment arms and regimens

1Neoadjuvant chemoradiotherapy

3 cycles of 28 days of neoadjuvant gemcitabine (according to the description of the same regimen in PREOPANC-2: 1000 mg/m² IV on days 1, 8 and 15, and only on days 1 and 8 in the first and third cycles), with the second cycle combined with hypofractionated radiotherapy of 36 Gy in 15 fractions (15 × 2.4 Gy); after restaging, surgery followed by 4 cycles of adjuvant gemcitabine (dose not stated in the abstract).

2Upfront surgery (control group)

Upfront surgery followed by 6 cycles of adjuvant gemcitabine (dose not stated in the abstracts).

Source of the regimen details: PREOPANC abstracts (JCO 2020 and 2022): 3 cycles of gemcitabine, 36 Gy in 15 fractions (15 × 2.4 Gy) during the second cycle, 4 or 6 cycles of adjuvant gemcitabine; dose and days of neoadjuvant gemcitabine from the description of the same regimen in the PREOPANC-2 abstract (chemoradiotherapy arm; Lancet Oncol 2025); the adjuvant gemcitabine dose is not stated in the abstracts

Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.

Study population

Patients with resectable or borderline resectable pancreatic cancer.
Randomised between April 2013 and July 2017 at 16 Dutch centres.

Endpoints

Primary outcome: overall survival by intention to treat.

Secondary outcomes (initial 2020 report): resection rate, R0 resection, disease-free survival, locoregional failure-free interval and safety. No new safety data were collected for the long-term report.

Safety and side effects

No new safety data were collected for the long-term report. In the initial report (JCO 2020), the proportion of patients with serious adverse events was 52% in the preoperative chemoradiotherapy group versus 41% in the upfront surgery group (P=.096).

Clinical significance and place in guidelines

PREOPANC was the first randomised trial to show a long-term survival benefit of neoadjuvant therapy in resectable and borderline resectable pancreatic cancer, and it supports the "treatment-first" approach in borderline disease. However, its regimen (gemcitabine + radiotherapy) is now being compared with stronger combination regimens such as (m)FOLFIRINOX (the PREOPANC-2 and PREOPANC-3 trials). The ESMO 2023 guideline prefers induction therapy over upfront surgery in borderline disease [II, A], but does not recommend neoadjuvant therapy outside a clinical trial in resectable disease; NCCN also considers neoadjuvant therapy the approach preferred by most member institutions in borderline disease.

Limitations

The difference in median survival was small (1.4 months), and the benefit was seen mainly in the "tail" of the survival curve. The sample size was relatively small, and resectable and borderline patients were enrolled together. The systemic regimen (gemcitabine alone) is weak compared with current regimens, and no new safety data were collected for the long-term report. The upfront surgery group did not receive adjuvant mFOLFIRINOX, which is the standard today.

Original article (DOI)PubMed

This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.