Concurrent chemoradiotherapy using proton beams for unresectable locally advanced pancreatic cancer

Abstract

Background and purpose: We investigated clinical outcomes of proton beam concurrent chemoradiotherapy (CCRT) for unresectable, locally advanced pancreatic cancer (LAPC) patients. Materials and methods: Records from 42 unresectable LAPC patients (21 male and 21 female, 39-83 years old) with IIB/III clinical staging of 1/41 treated by proton beam CCRT were retrospectively reviewed. Twelve patients received a conventional 50 Gray equivalents (GyE) in 25 fractions protocol and 30 others received a higher dose protocol of 54.0-67.5 GyE in 25-33 fractions. Gemcitabine or S-1 (Tegafur, Gimeracil and Oteracil) was used concurrently. Toxicity, overall survival (OS) and local control (LC) were examined. Results: Acute adverse events of grades 1, 2, 3 and 4 were found in 4, 15, 17 and 2 patients, respectively. All grade 3 and 4 events were hematologic. Late adverse events of grades 1 and 2 were found in 3 and 2 patients, respectively. No late adverse effects of grade 3 or higher were observed. The 1-year/2-year OS rates from the start of CCRT were 77.8/50.8% with median survival time (MST) of 25.6 months. The 1year/2-year LC rate from CCRT start was 83.3/78.9% with a median time to local recurrence of more than 36 months. Total irradiation dose was the only significant factor in univariate analyses of OS and LC (p = 0.015 and 0.023, respectively). Conclusion: Proton beam CCRT lengthened survival periods compared to previous photon CCRT data and higher dose irradiation prolonged LC and OS for unresectable LAPC patients. Proton beam therapy is therefore safe and effective in these cases.

Clinical Limitations of Photon, Proton and Carbon Ion Therapy for Pancreatic Cancer

“…Maemura, et al's [71] comparative PT study of 25 patients (10 undergoing PT and 15 undergoing hyper-fractionated XRT) only had two patients develop grade ≥ 2 gastric ulcers, still appearing advantageous compared to XRT and C-ion regarding high grade haematological toxicity when gemcitabine was employed. In fact, Hiroshima, et al's [45] PT trial reported all grade ≥ 3 and 4 events were haematologic and correlated with full-dose gemcitabine and/or speculated as high doses to the spleen (as previously described in XRT studies [72,73]).…”

“…Established as a broad ranging anti-tumour treatment gemcitabine is the most widely recommended chemotherapy agent to reduce this risk of distant metastasis and regional recurrence, the major mode of LAPC treatment failure. However, administration of gemcitabine has been linked to a higher incidence of grade ≥ 3 haematological toxicities across chemoradiation trials (Tables 2-4 [45] PT trial reported all grade ≥ 3 and 4 events were haematologic and correlated with full-dose gemcitabine and/or speculated as high doses to the spleen (as previously described in XRT studies [72,73]). Developments in particle therapy have marginally improved MST, LC and OS in recent years, whilst marginally reducing the incidence and grade of GI toxicities compared to XRT (Figures 2 and 3).…”

“…A gap which may possibly be exploited by particle therapy and the further development of systemic therapies such as HAPs. Table 3 demonstrates an improved 2-year OS and MST ranging from 31-50.8% and 18.4-25.6 months [45,50]. The enhanced biological damage of PT radiation dose delivery compared to XRT (i.e., dose reporting) across the studies varies in terms of: RBE, cobalt Gray equivalents (CGE refers to absorbed dose × 1.1 (RBE) to express the biologic effective proton dose), Gray equivalents (GyE refers to proton physical dose (in Gray) × 1.1 (RBE)).…”

“…Combined with concurrent chemotherapy several SBRT studies experienced a trade-off of LC for late grade ≥ 2 GI toxicities [44]. Though the quick course is favourable for LAPC clinical management, surgery is still the only curative treatment [5,45]. SBRT studies, by Mellon, et al [46] and Chuong et al [37] demonstrated 51% and 56% of borderline resectable patients, respectively, were able to undergo post-SBRT resection with high complete resection rates.…”

“…As evident in Table 3, the clinical progress of combined particle therapy is vastly underexplored, and further studies are necessary to obtain more robust data on its effectiveness and toxicity. There needs to be a more detailed examination of the relationship between irradiation dose and outcome [45]. Patients often experienced more than one toxicity throughout their course of treatment (e.g., haematological and GI).…”