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  • br Discussion br Clinical studies


    Clinical studies of CCRT reported in LAPC patients are summa-rized in Supplementary Table 1. For 3-dimensional conformal radiotherapy (3DCRT), the OS ranges from 2.8 to 13% at 2 years and the MST ranges from 10.3 to 15.8 months [21–25]. As for intensity modulated radiotherapy (IMRT), the OS range is 22– 32.9% at 2 years and MST ranges from 15.3 to 22.6 months with two recently published reports of IMRT indicating MSTs of over 20 months [25–28]. In an IMRT study that delivered a 60–66 Gy dose to a macroscopic tumor using a simultaneous and integrated boost technique, the MST was 19 months and the median time to local recurrence was 13 months [29]. Stereotactic body radiother-apy succeeded in shortening the treatment Bortezomib and the MST ranged from 10.6 to 15 months [30–32]. A large cohort study with
    Number of patients OS from OS from LC from LC from
    Site of recurrence Death of disease Adverse events
    CCRT initial Tx CCRT initial Tx local/distant/both
    (median) (median) (median) (median)
    Adverse events
    Hematologic Leukopenia
    Thrombocytopenia 24 6 2
    Gastrointestinal Nausea
    Gastric ulcer
    Abbreviations: OS: overall survival, LC: local control, Tx: treatment, Y: years, M: months.
    Grade of upper table shows the maximum grade of each patient.
    Grade of lower table shows every events.
    40 PBT for unresectable LAPC
    Fig. 1. Survival curves. (a) Overall survival rate. (b) Local control rate.
    Table 3
    Analysis of prognostic factors.
    OS LC
    Univariate Univariate
    * Significant.
    propensity matching reported that the outcome of SBRT was not inferior to IMRT and was at least improved over conventional radi-ation techniques [33]. As for proton beam therapy (PBT), some dosimetry studies have confirmed a physical advantage of proton beams over photon beams, namely a tissue-sparing benefit, leading to the idea that outcomes may be improved by safely increasing proton beam doses [34,35]. In the clinical PBT studies, the OS ranges from 31 to 45% at 2 years with an MST between 18.4 and 22.3 months although the reports are very few and the patient cohort was smaller than in photon beam studies [16,36,37]. Our data, in which the 2-year OS is 50.8% with MST of 25.6 months, is numerically superior to photon RT and equivalent or superior to PBT even when borderline resectable patients are omitted and only unresectable LAPC patients are analyzed. Moreover, the 1-year/2-year OS and LC were 67.1%/11% and 49.2%/0%, respectively, while MST and median time to local recurrence were 15.7 and 10.6 months, respectively, for 25 patients who received conven-tional photon chemoradiotherapy (50–50.4 Gy) at our institute at the same time as this study. These data suggest that PBT has a potential of superior anti-tumor effect over existing RT for the treatment of unresectable LAPC patients [21–33].
    Reasoning for the superiority of PBT is based on higher dose delivery, as patients with higher doses had a significantly longer 
    OS compared to conventional dosing. However, it is premature to state that higher doses universally lead to better outcomes as the challenging 67.5 GyE protocol still risks high dose exposure to the GI tract. Therefore, although the classification numbers may shrink, there needs to be a more detailed examination of the rela-tionship between irradiation dose and outcome. To this end, our study used 50 GyE, 54 to 60 GyE and 67.5GyE classifications and, as a result, we found that higher doses did trend toward longer LC and OS.
    During the study period, a total of 19 patients experienced Grade 3 or 4 acute adverse events. However, these events were hematologic and can be explained by chemotherapy. As for gas-trointestinal events, no patient suffered from more than a grade 2 event, lending credence the lower acute toxicity of PBT. Further-more, no patient manifested a late GI-related adverse event of more than Grade 3, reinforcing the idea of CCRT using proton beams as a relatively less adverse modality compared to more aggressive therapies. In the previous study of Nichols et al. [38], it was verified that PBT in the range of 50.4–59.4 GyE was safely performed without any grade 3 GI toxicity. However, with regard to the 67.5 GyE in 25 fractions protocol, Takatori, et al. [39] reported PBT-induced ulcers in 45/91 patients from the same insti-tute as the Terashima, et al. study [16]. Although we cannot directly compare treatment planning and methods in detail, the main difference between the Terashima, et al. study and ours is in the definition of the CTV. They included the primary tumor plus metastatic regional lymph nodes with prophylactic regions con-taining the drainage lymph nodes and paraaortic lymph nodes. Their CTV also involved peripheral regions surrounding the CA and SMA. Our CTV, on the other hand, contained the primary tumor plus only metastatic regional lymph nodes and peripheral regions surrounding the CA or SMA in cases of lesions which had invaded around the vessels. Non-metastatic regional lymph nodes for pro-phylactic irradiation were not included in our CTV. It may be pos-sible that differences in the irradiation field caused less severe adverse events in our study. In parts other than treatment plan-ning, routine use of proton-pump inhibitors and fasting before treatment might help to alleviate severe adverse events.