Efficacy
Locally advanced pancreatic cancer phase III trials
LAP 07
The LAP 07 trial was an international multicentre, open-label, unblinded, randomised phase III study of patients with locally advanced pancreatic cancer (LAPC).r The study was stratified to centre and performance status and used a 2-step randomisation process. The first step evaluated gemcitabine vs gemcitabine plus erlotinib as induction chemotherapy (CT) for 4 months. Patients with a tumour which was controlled proceeded to a second randomisation of either CT or chemoradiation therapy (CRT). The CRT involved 54 Gy in 30 fractions plus capecitabine. The planning target volume (PTV) margins used were 3 cm craniocaudally and 1.5 cm in the other directions.
Overall survival (OS) was not significantly different between CT (16.5 months) vs CRT (15.2 months) (p = 0.83). However, there were differences observed in time to re-initiation of therapy for CRT (159 days) vs CT (96 days) (p = 0.05) and differences in local tumour progression for CRT (32%) vs CT (46%) (p = 0.0001). The reasoning for induction therapy was to spare patients with rapidly progressive disease, while also selecting those that could potentially benefit from CRT. The trial had better median survival than other prospective studies (13 and 11 months). This suggests that induction CT selected patients with better prognosis and those excluded before second randomisation had median survival of 7.7 months. The secondary surgical resection rate was only 4% in this study.
Radiation therapy (RT) compliance may have contributed to the study outcomes, with only 32% of patients in the CRT arm treated per protocol. Toxicity was not substantially different between arms, although the study did not include patient-reported toxicity.
ECOG-4201
Loehrer et al. 2011 reported on the ECOG-4201 study which compared CT alone vs CRT in patients with localised unresectable pancreatic cancer.r The prescribed dose was 50.4 Gy in 28 fractions with concurrent gemcitabine. RT was delivered in two phases; phase one delivered 39.6 Gy in 22 fractions to initial large fields and phase two followed to deliver a total dose of 50.4 Gy to a reduced field (GTV + 2 cm margin).
The study was severely limited by poor accrual, enrolling only 74 of the planned 316 patients, resulting in poor statistical power. However, intention to treat analysis showed median survival was 9.2 months (CT) compared to 11.1 months (CRT) (p = 0.017). There was no difference in progression-free survival (PFS). This may be due to scans not being performed at adequate intervals, challenging precise measurement, and that this study was primarily designed to detect OS. There were no significant differences in quality of life between the two treatment arms after week 6 of treatment.
FFCD/SFRO 2008
The phase III FFCD/SFRO 2008 trial involved 119 patients with LAPC.r Patients were randomised either to induction gemcitabine alone or induction gemcitabine followed by CRT (60 Gy in 30 fractions and 5-FU infusion and cisplatin). Both arms were followed by maintenance gemcitabine until progression or toxicity. RT planning used a PTV expansion of the clinical target volume (CTV) + 2 cm margin in all directions.
OS was significantly reduced in the CRT arm, with a median of 8.6 months compared to 13 months in the gemcitabine alone arm (p = 0.03). More grade 3-4 toxicities were observed in the CRT arm. Patients in this group received fewer courses of maintenance therapy with gemcitabine. The survival difference became apparent after 8 months, suggesting that the toxicity did not directly contribute to death, but perhaps led to reduced tolerance for maintenance gemcitabine and that the RT dose used may have been too intense.
Locally advanced pancreatic cancer phase II trials
SCALOP
Mukherjee et al. reported on SCALOP, a phase II trial including 74 patients that compared capecitabine (n = 36) and gemcitabine (n = 38).r All patients received induction chemotherapy (gemcitabine and capecitabine). Patients with responding or stable disease (based on response evaluation criteria in solid tumors [RECIST] criteria), tumour diameter ≤6 cm and WHO performance status 0-1 were randomised to be given a further cycle of gemcitabine and capecitabine followed by CRT (50.4 Gy in 28 fractions) with either gemcitabine or capecitabine. Of the 34 patients in the capecitabine group who received CRT, 25 (74%) received the full protocol dose of RT, compared with 26 (68%) patients in the gemcitabine group. In the capecitabine vs gemcitabine group there was improved median survival (15.2 months vs 13.4 months, respectively) and 12 month OS (79.2% vs 64.2%, respectively).
Brunner et al. 2002 reported on a phase II trial of 29 patients given pre-operative CRT delivering 50.4 Gy in 28 fractions and a 5.4 Gy boost (in 3 fractions) with 5-FU and mitomycin C.r They reported a resectability rate of 37% (n = 10), OS of 50% (resected patients) vs 6% (non-resected patients) and a median OS of 9 months. No significant acute toxicity was reported.
Borderline resectable and resectable pancreatic cancer phase III trials
PREOPANC
The PREOPANC trial, reported in 2020, randomised 246 patients with borderline resectable pancreatic cancer (BRPC) to either upfront surgery or preoperative CRT (36 Gy in 15 fractions) with gemcitabine (1000 mg/m2) preceded and followed by 2 doses of gemcitabine.r The RT dose was based on an earlier phase II dose escalation trial.r This study used high dose gemcitabine and hence a lower dose of radiation therapy. RT involved simulation with 4DCT and IV contrast. There was no elective lymph node irradiation. Full dose CT was standard. Pre-operative CRT did not show a significant OS benefit, but secondary endpoints and pre-defined subgroup analysis suggest an advantage from the neoadjuvant approach. Median OS by intention to treat (ITT) was 16 months for neoadjuvant CRT vs 14.3 months with immediate surgery. The R0 resection rate was 71% vs 40% respectively (p <0.001). Neoadjuvant CRT was associated with significantly improved disease free survival (DFS) locoregional control and significantly lower rates of pathologic lymph nodes, perineural invasion and venous invasion. Patients who underwent tumour resection and received adjuvant CT showed improved OS with neoadjuvant CRT (35.2 months vs 19.8 months, p = 0.029).
Borderline resectable and resectable pancreatic cancer phase II trials
Jang et al. 2018 reported on the first prospective randomised control trial (RCT) evaluating the oncological benefits of a neoadjuvant strategy.r In this phase II/III multi-centre RCT, 110 patients with BRPC were to be randomised to neoadjuvant CRT (54 Gy) followed by surgery or upfront surgery followed by CRT in four large-volume centres in Korea. The trial accrued 58 patients and was terminated early due to statistical significance. In the ITT analysis, the 2-year survival and median survival was significantly better in the neoadjuvant CRT than the upfront surgery group (40.7%, 21 months vs 26.1%, 12 months with (HR 1.495, 95% CI: 0.66 – 3.36, p = 0.028]). R0 resection rate was also significantly higher in the neoadjuvant CRT group than upfront surgery (51.8% vs 26.1%, p = 0.004).
Murphy et al. 2019 reported on a phase II trial of total neoadjuvant therapy with FOLFIRINOX followed by individualised chemotherapy for BRPC (n = 49).r Patients were given 8 cycles of FOLFIRINOX and were then restaged. Patients with resolution of vascular involvement received short-course CRT (25 Gy delivered in 5 Gy fractions using protons) with capecitabine. Patients with persistent vascular involvement received long-course CRT with 5-FU or capecitabine. The R0 resection rate was reported as 61%.