Regional hyperthermia with cisplatin added to gemcitabine versus gemcitabine in patients with resected pancreatic ductal adenocarcinoma: The HEAT randomised clinical trial.

BACKGROUND: Regional hyperthermia (RHT) with cisplatin added to gemcitabine showed efficacy in gemcitabine-pre-treated patients with advanced pancreatic ductal adenocarcinoma. We conducted a randomised clinical trial to investigate RHT with cisplatin added to gemcitabine (GPH) compared with gemcitabine (G) in the adjuvant setting of resected pancreatic ductal adenocarcinoma. METHODS: This randomised, multicentre, open-label trial randomly assigned patients to either GPH (gemcitabine 1000 mg/m2 on day 1, 15 and cisplatin 25 mg/m2 with RHT on day 2, 3 and 15,16) or to G (gemcitabine 1000 mg/m2 on day 1,8,15), four-weekly over six cycles. Disease-free survival (DFS) was the primary end-point. Secondary end-points included overall survival (OS) and safety. RESULTS: A total of 117 eligible patients (median age, 63 years) were randomly allocated to treatment (57 GPH; 60 G). With a follow-up time of 56.6 months, the median DFS was 12.7 compared to 11.2 months for GPH and G, respectively (p = 0.394). Median post-recurrence survival was significantly prolonged in the GPH-group (15.3 versus 9.8 months; p = 0.031). Median OS reached 33.2 versus 25.2 months (p = 0.099) with 5-year survival rates of 28.4% versus 18.7%. Excluding eight patients who received additional capecitabine in the G-arm (investigators choice), median OS favoured GPH (p = 0.052). Adverse events CTCAE (Common Terminology Criteria for Adverse Events) grade ≥3 occurred in 61.5% (GPH) versus 63.6% (G) of patients. Two patients in the G-group died because of treatment-related toxic effects. CONCLUSIONS: The randomised controlled Hyperthermia European Adjuvant Trial study failed to demonstrate a significant difference in DFS. However, it suggests a difference in post-recurrence survival and a trend for improved OS. CLINICALTRIALS: gov, number NCT01077427.

Adjuvant therapy in pancreatic cancer: a critical appraisal.

Adenocarcinoma of the pancreas carries a grim prognosis. Surgery is currently the only curative option, but even the few patients undergoing complete resection of early localised disease run a high risk for relapse and death. Although numerous clinical trials have been conducted during the past 20 years to find an effective adjuvant treatment, thus far no general consensus on the most appropriate regimen has been reached. In a small randomised study performed in the 1980s by the GITSG (Gastrointestinal Tumor Study Group), encouraging results were obtained with fluorouracil (5-FU)-based split-course chemoradiotherapy, but these findings were not confirmed in a randomised study initiated some years later by the EORTC (European Organisation for Research and Treatment of Cancer). More recently, the ESPAC (European Study Group for Pancreatic Cancer)-1 trial even indicated a detrimental effect of chemoradiotherapy, while chemotherapy with 5-FU was shown to have a significant positive impact on long-term survival. However, this latter finding is in contrast to earlier studies of adjuvant chemotherapy with 5-FU combinations from Norway and Japan that did not suggest a prolonged beneficial effect of 5-FU on survival. Thus, the results for adjuvant regimens based on systemic 5-FU with or without external radiotherapy are conflicting. Clinical experience with intraoperative radiotherapy or regionally targeted chemotherapy to prevent local relapse, though encouraging, is still preliminary. More recently, gemcitabine, which is the most effective single agent in advanced pancreatic cancer, has also been evaluated in the adjuvant setting. The RTOG (Radiation Therapy Oncology Group)-9704 trial demonstrated that gemcitabine is superior to 5-FU as an addition to chemoradiotherapy, but the results did not allow conclusions about the value of radiation in the combined modality approach. The Charité Onkologie CONKO-001 is a randomised trial from Germany and Austria that compared adjuvant gemcitabine with observation alone. Gemcitabine was very well tolerated and almost doubled median disease-free survival and overall survival rate at 5 years, although the advantage in overall survival failed to reach statistical significance. In summary, the available data from randomised clinical trials of adjuvant therapy suggest that (i) chemoradiotherapy has no obvious advantage compared with chemotherapy alone; and (ii) chemotherapy with gemcitabine is effective and probably offers the best benefit-risk ratio of all currently available adjuvant treatment options.