Cancer of the exocrine pancreas can still be considered an unsolved clinical problem. An epidemiological analysis from 2012 has shown that in Europe incidence equals mortality.1 Proton therapy could emerge as a new treatment option showing several advantages compared to standard radiotherapy.
The dismal outcome of pancreatic cancer is driven both by the high rate of patients that are already metastatic at diagnosis (or that develop metastases early in the course of their disease) and by the difficulties in achieving local control even in the non-metastatic patients. Aggressive chemotherapy can achieve a survival advantage both in metastatic and locally advanced cases.2 Radiotherapy has been used in the attempt to increase local control both preoperatively3 and postoperatively4 but its role as exclusive local treatment is still questionable.
Particle therapy with protons or carbon ions has several dosimetric advantages in comparison with standard radiotherapy with photons. Particles display an inverse depth dose profile with a finite range; therefore they can achieve a conformality that is similar to that of the most advanced photon-based techniques, while substantially reducing the integral dose to the patient and the middle and low dose bath. Carbon ions, besides their favorable physical properties, have a radiobiological advantage: in the last part of their track, they produce dense ionizations that create DNA damages that are very difficult to repair. These damages can kill cells almost independently from the oxygenation level. This is particularly relevant for pancreatic cancer as it is a disease with a thick fibrotic stroma and many hypoxic niches.
The use of proton and carbon ions in the treatment of pancreatic cancer has the potential to reduce the dose to the small bowel and stomach thus reducing the risk of acute and late gastro-intestinal toxicity. Moreover, the sparing of the healthy tissues, i. e. the bone marrow, but most importantly the spleen, can reduce hematological toxicity and improve tolerance to concomitant chemotherapy. Particle therapy can therefore be used to reduce toxicity and to increase the delivered dose and, at least for carbon ions, the radiobiological efficiency of the dose, in the attempt to improve local control.
Proton therapy in the U.S. and Japan
Proton therapy has been used in the preoperative treatment of pancreatic cancer mainly at Massachusetts General Hospital.5 An aggressive combination of chemotherapy with FOLFIRINOX (folinic acid, 5-fluorouacil, irinotecan, oxaliplatin), radio-chemotherapy (with protons or photons according to the availability) and surgery has achieved a 3-year overall survival (OS) in excess of 60 %, which is more than double of what is expected in this population.
Additionally, in the experience of the University of Florida, proton therapy concomitant to chemotherapy could convert a significant percentage of locally advanced cases to resectability without any increase in intra- and perioperative morbidity.6
Finally, carbon ion radiotherapy has been employed in Japan with excellent results both in the preoperative setting and for locally advanced cases. The initial results of the National Institute of Radiological Sciences in Chiba7, 8 have been recently confirmed in a prospective multi-centric study in Japan.9 In these series, 2-year OS in excess of 50 % has been reported for inoperable patients without surgery.
The Japanese experience is extremely relevant also in terms of target volume definition, which is based on an extensive review of pathological series assessing the risk of nodal involvement in each of the lymph-node station in the upper abdomen (according to the Japanese Pancreas Society [JPS] classification).10 The target volumes employed are also modified to account for the risk of perineural spread.
An international multi-centric prospective randomized phase III trial (CIPHER, ClinicalTrials.gov identifier: NCT03536182) of carbon ion radiotherapy vs. photons-intensity- modulated radiation therapy ( IMRT) in patients with locally advanced pancreatic cancer has been designed to verify this survival advantage. This trial will randomize patients with locally advanced pancreatic cancer to receive either IMRT with photons in their home country (USA, South Korea, Italy and Japan) or carbon ion radiotherapy in Japan and Italy.
Proton therapy in Austria
MedAustron is the only existing particle therapy facility and is capable of delivering both proton and carbon ion radiotherapy with active beam scanning in Austria (Fig. 1). Clinical activity has started with protons in December 2016 and with carbon ions in July 2019.
Treatment of upper abdomen with active scanning particle therapy is challenging because of organ motion. The strategy of MedAustron to cope with organ motion consists of mild uniform abdominal compression (achieved with the thermoplastic mask), 4D computed tomography (CT) at immobilization, robust planning, and quality assurance (QA) with frequent (every 1–2 weeks) 4D CTs and replanning when necessary. Selected cases of pancreatic cancer have already been treated at MedAustron. A pilot trial (PARC-MA-062019) is now open for recruitment in cooperation with AKH in Vienna and LKWN in Wiener Neustadt. In this prospective study, patients with borderline resectable pancreatic cancer will be treated with neoadjuvant chemotherapy with gemcitabine plus nabpaclitaxel followed by concomitant proton therapy and capecitabine and then surgery, when feasible.
This is the first step in the attempt to establish a nationwide cooperation with the double purpose of contributing to the creation of high-level evidence and of making particle therapy available for the routine clinical treatment of pancreatic cancer. Further studies are in the design phase, focusing on preoperative treatment of both operable and borderline resectable cases, but also considering possible innovative strategies for locally advanced disease. The participation in international trial (e.g. CIPHER) is also foreseen.