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The dose calculation algorithms used in Japan and Europe (local effect model, LEM) are different, so the total dose must be modified to ensure consistency

1. Japan : 55.2 GyE in 4.6 GyE per fraction in 12 fractions delivered 4 days a week. At least 90% of each CTV receives at least 95% of the prescribed dose, and 100% of the GTV V95 must receive at least 95% of the prescribed dose.
2. European: . Patients treated in Europe should receive 57.6 GyE in 4.8 GyE per fraction in 12 fractions delivered 4 days a week. At least 90% of CTV receives at least 95% of the prescribed dose, and 100% of the GTV V95 must receive at least 95% of the prescribed dose. This evaluation will occur in the LEM system

50.4-56 Gy in 1.8-2.0 Gy per fraction in 28 fractions delivered 5 days a week. The plan should be normalized such that 100% of the PTV receives at least 48.9 Gy (i.e. 97% of 50.4 Gy). In addition, 100% of the GTV should receive at least 50.4 Gy. The maximum dose allowed to a point volume (0.03 mL) is 115% of the prescribed dose.

Patient will receive CIRT daily, 4 days a week for a total of 12 fractions/treatments plus concurrent chemotherapy (gemcitabine) weekly for 3 weeks. Gemcitabine will be given intravenously over about 1 hour in the outpatient clinic. Within 6 weeks of completing radiotherapy, patient will start 4 cycles of chemotherapy. If the doctor chooses gemcitabine+nab-Paclitaxel, patient will receive gemcitabine and nab-paclitaxel intravenously once a week for 3 weeks then 1 week off, for a total of 4 cycles (16 weeks). If the doctor chooses FOLFIRINOX, then patient will receive oxaliplatin, irinotecan, infusional 5-fluorouracil, and possibly leucovorin, all intravenously, every 2 weeks, for a total of 16 weeks.

Carbon Ion Radiation Therapy (CIRT)

Patient will receive IMRT daily, 5 days a week for a total of 28 fractions/treatments plus concurrent chemotherapy (gemcitabine or capecitabine) weekly for 5 weeks. Gemcitabine will be given intravenously over about 1 hour in the outpatient clinic,within 6 weeks of completing radiotherapy,patient will start 4 cycles of chemotherapy. If the doctor chooses gemcitabine+nab-Paclitaxel, patient will receive gemcitabine and nab-paclitaxel intravenously once a week for 3 weeks then 1 week off, for a total of 4 cycles (16 weeks). If the doctor chooses FOLFIRINOX, then patient will receive oxaliplatin, irinotecan, infusional 5-fluorouracil, and possibly leucovorin, all intravenously, every 2 weeks, for a total of 16 weeks.

Intensity Modulated Radiation Therapy (IMRT)

David Sher, MD

To determine if carbon ion radiotherapy improves overall survival versus photon therapy in patients with locally advanced, unresectable pancreatic cancer

To compare the efficacy of carbon ion-based chemo radiotherapy with x-ray-based chemo radiotherapy for the treatment of locally advanced pancreatic adenocarcinoma by comparison of overall survival at 2 years following treatment.

Patient has 2 in 3 chance of receiving Arm A and 1 in 3 chance of receiving Arm B.

Arm A (chemoradiation takes place in Japan):

CIRT in 12 fractions/treatments plus concurrent gemcitabine, followed by 4 cycles of gemcitabine + nab-Paclitaxel, or until progression or intolerance of therapy

Arm B:

IMRT in 28 fractions plus concurrent gemcitabine or capecitabine, followed by 4 cycles of gemcitabine + nab-Paclitaxel, or until progression or intolerance of therapy

Per investigator discretion, patients may receive either:

1. Definitive treatment :
2. Neoadjuvant treatment:

Adjuvant chemotherapy 4 cycles of gemcitabine/nab-paclitaxel or FOLFIRNOX, Gemcitabine alone if these regimens are unavailable

Eligible patients will be randomized in a 2:1 fashion (carbon:photon) between carbon ion radiotherapy or intensity modulated radiation therapy. Assuming a 10% dropout risk, the study will have 82% power to detect an increase in 2-year survival from 22% to 48% with carbon ion radiotherapy.

Trial of Carbon Ion Versus Photon Radiotherapy for Locally Advanced, Unresectable Pancreatic Cancer

CIPHER: A Prospective, Multi-Center Randomized Phase 3 Trial of Carbon Ion Versus Conventional Radiation Therapy for Locally Advanced, Unresectable Pancreatic Cancer

To compare the efficacy of carbon ion-based chemoradiotherapy with x-ray-based chemoradiotherapy for the treatment of locally advanced pancreatic adenocarcinoma by comparison of overall survival following treatment.

To compare progression-free survival between x-ray-based and carbon-ion-based chemoradiotherapy treatment courses for locally advanced pancreatic adenocarcinoma

To compare patterns-of-failure between x-ray-based and carbon-ion-based chemoradiotherapy treatment courses for locally advanced pancreatic adenocarcinoma

To compare quality-of-life and toxicity outcomes between x-ray-based and carbon-ion-based chemoradiotherapy treatment courses for locally advanced pancreatic adenocarcinoma.The quality-of-life assessment will be performed during and after treatment. Patient-reported functional status will be assessed with the hepatobiliary subscales of the Functional Assessment of Cancer Therapy-Hepatobiliary (FACT-Hep).

Only adverse events assessed to be definitely, probably, or possibly related to protocol treatment will be considered. The rates of all Grade 3-5 adverse events, and death during or within 30 days of discontinuation of protocol treatment using CTCAE 5.0.

Spots Global Cancer Trial Database for carbon ion radiation therapy (cirt)