Pancreatic Adenocarcinoma: Update on Neoadjuvant and Adjuvant Treatment
The benefit of radiation therapy in the treatment of locally advanced pancreatic cancer was further explored by the Fédération Francophone de Cancérologie Digestive 2000-01 phase 3 trial. This study compared induction chemoradiotherapy (60 Gy, 2 Gy/fraction; concomitant fluorouracil infusion, 300 mg/m2/day, days 1–5 for 6 weeks; cisplatin, 20 mg/m2/day, days 1–5 during weeks 1 and 5) to gemcitabine alone (1000 mg/m2 weekly for 7 weeks) followed by maintenance gemcitabine in both arms.36 Unexpectedly, the median OS was significantly shorter in the chemoradiotherapy arm than in the chemotherapy alone arm (8.6 months versus 13 months, respectively, P = 0.03) and the combination arm had more toxicities. The phase 3 open-label LAP07 study explored the role of radiation therapy in patients with locally advanced pancreatic cancer who had controlled disease after 4 months of induction therapy.37 LAP07 had 2 randomizations: first, patients with locally advanced pancreatic cancer were assigned to receive weekly gemcitabine alone (1000 mg/m2) or this same dose of gemcitabine plus erlotinib 100 mg/day; second, patients with progression-free disease (61% of initial cohort) after 4 months of therapy were assigned to receive 2 months of the same chemotherapy or chemoradiotherapy (54 Gy plus capecitabine). This study showed that the addition of erlotinib to gemcitabine did not improve survival and in fact affected survival adversely. Of note, no survival benefit was observed after the first randomization from chemotherapy to consolidating chemoradiotherapy. Chemoradiotherapy achieved better locoregional tumor control with significantly less local tumor progression (32% versus 46%, P < 0.03) and no increase in toxicity. Based on prior moderate-quality evidence, guidelines recommend consolidative chemoradiotherapy only for surgical resection candidates following induction chemotherapy; for those who are not surgical candidates, guidelines recommend continuing systemic therapy.26,28,29
Gemcitabine and fluorouracil-based chemotherapies were the standard induction regimens until evidence from studies of metastatic systemic treatment protocols with FOLFIRINOX (ACCORD trial38) and nanoparticle albumin-bound paclitaxel (nab-paclitaxel) plus gemcitabine (MPACT trial39) was extrapolated to clinical practice. These regimens were shown to achieve higher objective response rates when compared to single-agent gemcitabine in patients with metastatic pancreatic cancer. Due to the broad heterogeneity of results in small retrospective series with neoadjuvant trials in borderline resectable pancreatic cancer, the quality of the evidence is low and any recommendation is limited. Many individual series have demonstrated improved complete resection rates and promising survival rates. In the largest single-institution retrospective review of patients with borderline resectable pancreatic adenocarcinoma who completed neoadjuvant gemcitabine-based chemoradiotherapy (50 Gy in 28 fractions or 30 Gy in 10 fractions), 94% achieved a margin-negative pancreatectomy; the median OS in those who completed preoperative therapy and had surgery was 40 months, with a 5-year OS of 36%.40 A meta-analysis by Andriulli and colleagues included 20 prospective studies of patients with initially resectable (366 lesions) or unresectable (341 lesions) disease who were treated with neoadjuvant/preoperative gemcitabine with or without radiotherapy.41 In the group with initially unresectable disease, 39% underwent surgery after restaging and 68% of explored patients were resected; the R0 resection rate was 60%. After restaging, 91% of patients with resectable disease underwent surgery, with 82% of explored patients undergoing surgical resection and 89% of these achieving R0 resection. The estimated 1- and 2-year survival probabilities after resection among patients with initially unresectable disease were 86.3% and 54.2%.41
The largest single-institution retrospective review of FOLFIRINOX (fluorouracil, oxaliplatin, irinotecan, and leucovorin), an alternative to gemcitabine, for neoadjuvant induction therapy for patients with locally advanced unresectable disease was conducted at Memorial Sloan Kettering Cancer Center. In this study (n = 101), 31% of patients initially deemed unresectable who completed FOLFIRINOX induction therapy with or without chemoradiation underwent resection. The R0 resection rate in these patients was 55%, and patients who did not progress during induction FOLFIRINOX therapy had a median OS of 26 months.42 A systematic review and meta-analysis of FOLFIRINOX chemotherapy with or without radiotherapy in patients with locally advanced unresectable pancreatic cancer reported that 25.9% of patients underwent resection after FOLFIRINOX therapy, and the R0 resection rate in these patients was 78.4%.43 The median OS in this study was 24.2 months, which was longer than the previously reported median OS rates for gemcitabine.
There is no strong evidence published for the use of combination nab-paclitaxel plus gemcitabine in the neoadjuvant setting, but it is used in clinical practice based on evidence from the MPACT trial, which showed the combination improved OS and progression-free survival in patients with metastatic pancreatic cancer.39 An early-phase 1-arm clinical trial of neoadjuvant gemcitabine, docetaxel, and capecitabine (GTX) followed by radiotherapy showed an increased response rate and survival for locally advanced disease; however, the NCCN expert panel has reached a consensus but not a uniform recommendation regarding this regimen due to significant toxicities and low patient accrual.26 Selected patients with pancreatic cancer with BRCA1/2 mutations are more sensitive to platinum-based chemotherapy. Although studies of neoadjuvant platinum-based chemotherapy in this population have not been reported, the NCCN guidelines list it as an alternative option based on extrapolated data.26 A clinical trial of gemcitabine, nab-paclitaxel, and cisplatin in the neoadjuvant setting in patients with resectable pancreatic cancer is currently enrolling patients (NGC triple regimen NCT0339257).
Summary
Chemotherapy alone or followed by chemoradiotherapy may be used as initial treatment for patients with borderline and unresectable pancreatic adenocarcinoma without distant metastases who are potential surgical candidates. Chemoradiotherapy remains a preferred treatment option for patients with poorly controlled pain from local tumor invasion, in view of the well-documented analgesic palliative effect of radiation therapy. FOLFIRINOX with or without radiation therapy may offer the highest documented response rates, but it also results in higher rates of treatment-related toxicities. FOLFIRINOX can be offered to selected fit patients (< 65 years old, no comorbidity contraindication, good functional status [ECOG 0–1]) who can tolerate triple therapy with a more toxic adverse-effect profile. A clinical trial evaluating neoadjuvant FOLFIRINOX with or without preoperative chemoradiotherapy in patients with borderline resectable pancreatic cancer is ongoing (PANDAS-PRODIGE 44, NCT02676349). Gemcitabine with or without radiation therapy is a tolerable combination, although it is potentially more toxic when combined with radiation. The addition of nab-paclitaxel to gemcitabine without radiation may emerge as a preferred neoadjuvant treatment for selected patients; a clinical trial investigating this modality in patients with resectable and borderline resectable disease is ongoing (NCT02723331).
