Neoadjuvant therapy superior to upfront surgery in pancreatic cancer

May 2022 Clinical Practice Jolien Blokken

Until recently, the benefit of neoadjuvant chemoradiotherapy in resectable and borderline resectable cancer over upfront surgery remained controversial. Long-term results of the phase III PREOPANC trial now demonstrated that 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.

Pancreatic cancer is the fourth leading cause of cancer-related death in Europe. Approximately 15% of patients present with resectable or borderline resectable pancreatic cancer, with surgery followed by chemotherapy as the mainstay of treatment. Although adjuvant chemotherapy improves overall survival (OS) in patients with resected pancreatic cancer, about 50% of patients do not receive adjuvant chemotherapy because of early recurrence, surgical complications or clinical deterioration. Neo-adjuvant therapy may increase the proportion of patients that actually receive chemotherapy and thereby improve survival. Therefore, the phase III PREOPANC trial aimed to determine whether neoadjuvant gemcitabine-based chemoradiotherapy improves OS compared with upfront surgery, both followed by adjuvant gemcitabine in patients with resectable and borderline resectable pancreatic cancer. At a median follow-up of 27 months, no statistically significant difference in OS was observed. Recently, the long-term results of the PREOPANC trial were published.

PREOPANC study design

PREOPANC is a multicentre, randomised controlled trial conducted in 16 centres in the Netherlands. Eligible patients had pathologically confirmed resectable or borderline resectable pancreatic cancer without evidence of distant metastases, a WHO performance status of 0 or 1 and adequate haematologic, hepatic, and renal function. Patients were randomly assigned (1:1) to neoadjuvant gemcitabine-based chemoradiotherapy followed by surgery or to upfront surgery, both followed by adjuvant gemcitabine. Chemoradiotherapy consisted of three cycles of gemcitabine and radiotherapy. The first and third cycles had a duration of 3 weeks with gemcitabine once weekly in the first 2 weeks at a dose of 1,000 mg/m2. The second cycle had a duration of 4 weeks with gemcitabine once weekly in the first 3 weeks at a dose of 1,000 mg/m2, combined with hypofractionated radiotherapy of the pancreatic tumour and radiologically suspected lymph nodes at a dose of 36 Gy in 15 fractions (five fractions per week). Patients were re-staged within 4 weeks after the last dose of chemotherapy. When the CT scan showed no metastases or locally unresectable disease, patients were scheduled for surgical exploration within 4-6 weeks after the last chemotherapy. Patients in the upfront surgery group were scheduled for surgical exploration no later than 4 weeks after random assignment.

Results

In total, 248 patients were enrolled in the study: 120 were assigned to neoadjuvant chemoradiotherapy and 128 to upfront surgery. Two patients (one in each group) withdrew consent, leaving 119 patients in the neoadjuvant chemoradiotherapy group and 127 in the upfront surgery group for the ITT analyses. In the neoadjuvant chemoradiotherapy group, 81% of patients with pancreatic cancer started adjuvant chemotherapy, of whom 62% completed all cycles. In the upfront surgery group, 79% of patients with pancreatic cancer started adjuvant chemotherapy, of whom 54% completed all cycles. The median OS by ITT was 15.7 months in the neoadjuvant chemoradiotherapy group and 14.3 months in the upfront surgery group (HR[95%CI]: 0.73[0.56-0.96], p= 0.025). Survival estimates at 3 and 5 years were 27.7% and 20.5%, respectively, for the neoadjuvant chemoradiotherapy group and 16.5% and 6.5%, respectively, for the upfront surgery group. The effect of neoadjuvant chemoradiotherapy on OS was consistent across subgroups of baseline age, sex, WHO performance, resectability, tumour size and CA 19-9 level. The secondary time-to-event outcomes disease-free survival (HR[95%CI]: 0.69[0.53-0.91], p= 0.009), locoregional failure-free survival (HR[95%CI]: 0.57[0.39-0.83], p= 0.004), and distant metastases-free interval (HR[95%CI]: 0.74[0.54-1.03], p= 0.070) were also in favour of the neoadjuvant chemoradiotherapy group.

Serious adverse events occurred in 52% of patients in the neoadjuvant chemoradiotherapy group and in 41% of patients in the upfront surgery group (p= 0.096). Major surgical complications and postoperative mortality were not different between both groups.

Conclusion

The PREOPANC trial demonstrated that neoadjuvant therapy is superior to upfront surgery in pancreatic cancer. Neoadjuvant gemcitabine-based chemoradiotherapy followed by surgery and adjuvant gemcitabine improves overall survival compared with upfront surgery and adjuvant gemcitabine in patients with resectable and borderline resectable pancreatic cancer.

Reference

Versteijne E, van Dam JB, Suker M, et al. Neoadjuvant Chemoradiotherapy Versus Upfront Surgery for Resectable and Borderline Resectable Pancreatic Cancer: Long-Term Results of the Dutch randomized PREOPANC Trial. J Clin Oncol. 2022;40(11):1220-30.

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