Triple modal treatment comprising with proton beam radiation, hyperthermia, and gemcitabine/nab-paclitaxel for locally advanced pancreatic cancer: a phase I/II study protocol (TT-LAP trial).

BACKGROUND: Locally advanced pancreatic ductal adenocarcinoma (PDAC), accounting for about 30% of PDAC patients, is difficult to cure by radical resection or systemic chemotherapy alone. A multidisciplinary strategy is required and our TT-LAP trial aims to evaluate whether triple-modal treatment with proton beam therapy (PBT), hyperthermia, and gemcitabine plus nab-paclitaxel is a safe and synergistically effective treatment for patients with locally advanced PDAC. METHODS: This trial is an interventional, open-label, non-randomized, single-center, single-arm phase I/II clinical trial organized and sponsored by the University of Tsukuba. Eligible patients who are diagnosed with locally advanced pancreatic cancer, including both borderline resectable (BR) and unresectable locally advanced (UR-LA) patients, and selected according to the inclusion and exclusion criteria will receive triple-modal treatment consisting of chemotherapy, hyperthermia, and proton beam radiation. Treatment induction will include 2 cycles of chemotherapy (gemcitabine plus nab-paclitaxel), proton beam therapy, and 6 total sessions of hyperthermia therapy. The initial 5 patients will move to phase II after adverse events are verified by a monitoring committee and safety is ensured. The primary endpoint is 2-year survival rate while secondary endpoints include adverse event rate, treatment completion rate, response rate, progression-free survival, overall survival, resection rate, pathologic response rate, and R0 (no pathologic cancer remnants) rate. The target sample size is set at 30 cases. DISCUSSION: The TT-LAP trial is the first to evaluate the safety and effectiveness (phases1/2) of triple-modal treatment comprised of proton beam therapy, hyperthermia, and gemcitabine/nab-paclitaxel for locally advanced pancreatic cancer. ETHICS AND DISSEMINATION: This protocol was approved by the Tsukuba University Clinical Research Review Board (reference number TCRB22-007). Results will be analyzed after study recruitment and follow-up are completed. Results will be presented at international meetings of interest in pancreatic cancer plus gastrointestinal, hepatobiliary, and pancreatic surgeries and published in peer-reviewed journals. TRIAL REGISTRATION: Japan Registry of Clinical Trials, jRCTs031220160. Registered 24 th June 2022, https://jrct.niph.go.jp/en-latest-detail/jRCTs031220160 .

Survival impact on triple-modal strategy comprising hyperthermia, external radiation, and chemotherapy for unresectable locally advanced (UR-LA) pancreatic ductal adenocarcinoma.

BACKGROUND: Present treatment strategy for unresectable locally advanced (UR-LA) pancreatic ductal adenocarcinoma (PDAC) patients is controversial. Hence, a triple-modal therapy, which is a multidisciplinary strategy, was designed for patients with UR-LA PDAC by adding hyperthermia to conventional chemoradiotherapy at our institution. In this study we aimed to evaluate the effectiveness of this strategy. METHODS: Data of 21 UR-LA PDAC patients who underwent the triple-modal treatment were retrospectively analyzed for evaluating the safety and oncological effect of the treatment. The treatment schedule included, five concurrent infusions of gemcitabine (800 mg/m2) followed by hyperthermia (1 h) and X-ray (2 Gy) or proton beam radiation (2.7 Gy) on days 1, 8, 15, 29, and 36. Additional radiotherapies applied a total dose of 50 Gy/25 fr for X-ray radiation or 67.5 Gy/25 fr for proton beam radiation. RESULTS: Median overall survival (OS) was 23.6 months. Conversion surgery was performed in 5 patients (23.8%), and a R0 margin could be achieved in 4 of them; however, their median OS (16.3 months) tended to be shorter than that of the patients who did not undergo resection (23.6 months, p = 0.562). Further, the median OS of patients who underwent proton beam radiation (28.0 months) was significantly longer than that of patients who underwent X-ray radiation (13.9 months, p = 0.045). Most adverse events were manageable, except for one grade 3 gastric ulcer. The median tumor size and marker reduction rates were -17% and -91%, respectively. The tumor responses were partial response, stable disease, and progressive disease in 3, 15, and 3 patients, respectively. CONCLUSION: Triple-modal strategy, especially when combined with proton beam radiation, is feasible and results in favorable survival outcomes in patients with UR-LA PDAC.

A phase I study on combined therapy with proton-beam radiotherapy and in situ tumor vaccination for locally advanced recurrent hepatocellular carcinoma.

BACKGROUND: Proton-beam radiotherapy (PBT) has been shown to be effective to hepatocellular carcinoma (HCC) as a nonsurgical local treatment option. However, HCC still remains as one of the most difficult cancers to be cured because of frequent recurrences. Thus, methods to inhibit the recurrence need to be explored. To prevent the HCC recurrence, we here report on a prospective phase I study of 'in situ' tumor vaccination using CalTUMP, a newly developed immunoadjuvant consisting of BCG extract bound to hydroxyapatite and microparticulated tuberculin, following local PBT for HCC. METHODS: Patients with locally advanced recurrent HCC, which had been heavily pretreated with various treatments, were enrolled. PBT was performed with the conventional method to the target HCC. Subsequently, CalTUMP was injected into the same irradiated-tumor three times at one-week intervals. Three dose-levels of CalTUMP (1/10, 1/3, and 1/1) were administered to 3 patients each. Vital signs, blood samples, ultrasound, and computed tomographic scans were monitored to evaluate the safety. RESULTS: Three intratumoral injections of CalTUMP following PBT (median dose: 72.6 GyE) were accomplished in 9 patients. Transient low-grade fever and minor laboratory changes were observed in 7 patients after CalTUMP injections. No other treatment-related adverse events were observed. Median progression-free survival was 6.0 months (range: 2.1-14.2) and 4 patients were progression-free for more than 1 year. CONCLUSIONS: Intratumoral injection of CalTUMP following PBT was feasible and safe in patients with heavily pre-treated HCC. Further clinical studies to evaluate the efficacy of this in situ tumor vaccination are warranted.