In elderly patients, aggressive treatment to malignant tumor is sometimes avoided because of age-associated functional decline, their severe comorbidities, or poor cognitive function [12]. This tendency is almost the same in pancreatic carcinoma [13–15]. In contrast, some studies reported that surgery or chemotherapy could prolong OS for elderly patients with pancreatic carcinoma [14–16]. With regard to chemoradiotherapy for the elderly with LAPC, Miyamoto et al. suggested that the outcomes of patients treated with CCRT were similar to those of historical controls. However, the patients in those studies were treated mainly with 5-FU and three-dimensional conformal radiotherapy (3D-CRT) [17]. Our study evaluated hypofractionated CCRT using IMRT with high-dose gemcitabine for the elderly.
Based on several previous studies, the MST ranged from 8.6 to 16.6 months and the median PFS ranged from 6.0 to 12.0 months in LAPC patients treated with CCRT among all ages [2, 18–22]. Among elderly patients, Miyamoto et al. demonstrated that the MST was 8.6 months in 24 LAPC patients treated with CCRT using 3D-CRT [17]. Several previous CCRT studies for LAPC are summarized in Table 6. Our study showed that the MST and median PFS were 20.4 and 13.5 months respectively, which were not inferior to the results of those previous reports about CCRT. Kuroda et al. reported that chemotherapy alone which consisted of mostly GEM-based regimens for elderly pancreatic carcinoma patients resulted in 9.0 months (274 days) of MST in 519 pancreatic carcinoma patients (approximately 28.3% of which were LAPC patients) [15]. Although, it is difficult to compare with that study because it included patients who had systematic metastasis. Compared with these studies, our treatment resulted in favorable survival outcomes, in spite of their elderly age. Our previous study suggested that full dose gemcitabine and hypofractionated dose escalation with IMRT improved treatment outcomes, which could be applicable to elderly patients [7]. In addition, some recent studies demonstrated that high-dose radiation was a prediction factor to prolong OS of patients with LAPC [23, 24]. In this study, we used hypofractionated dose of 48 Gy in 15 fractions, of which biological equivalent dose is almost equal to the conventional standard treatment dose (50.4–54 Gy in fractions of 1.8 Gy) by calculating with α/β value of 10. However, considering short overall treatment time, 48 Gy in 15 fractions is more potent than conventional standard treatment dose and could contribute to the better local control, which could lead to favorable survival outcomes.
As mentioned above, the OS and PFS were good; moreover, toxicity was also acceptable. Except one patient with pseudoaneurysm, grade 3 or higher non-hematologic adverse events induced by radiotherapy were not observed, and grade 3 non-hematologic toxicities occurred in merely two patients because of chemotherapy although all patients were ≥ 75 years (Table 5). The reason why our treatment strategy was less toxic is that, firstly, the dose reduction to surrounding normal organ with IMRT, which was demonstrated in our previous study [7]. Second, in induction chemotherapy, the dose and the interval of concurrent or maintenance chemotherapy could be adjusted. From Table 3, many of the patients needed reduction of chemotherapy dose or extension of chemotherapy interval because of adverse events or their PS. In fact, hematologic side effects seemed less toxic during CCRT than induction chemotherapy, especially in neutropenia (Table 5). The major aim of induction chemotherapy in our protocol was to select patients who have adequate tolerability of concurrent chemoradiotherapy and secure time for planning IMRT [25]. Further, as some previous studies described, it could contribute to increasing the completion rate of CCRT by using the adjusted dose of chemotherapy in reference to the dose of induction chemotherapy [19, 26]. As shown above, we adopted induction chemotherapy before our CCRT using IMRT protocol.
According to Table 3, the recurrence pattern was mainly distant metastasis; the number of distant metastasis was eight among 15 patients; while locoregional recurrence was four among 15 patients. This trend was shown by several previous studies [2, 27]. In a LAP07 study, OS was not prolonged compared with chemotherapy alone, in spite of improving local control treated with CRT. The reason why local control could not improve OS may be because of the existence of occult metastasis for LAPC patients at the time of initial diagnosis; hence, systematic treatment is required for LAPC [1]. Conversely, local treatment could prolong OS among patients with no occult metastasis. Besides, local recurrence can cause obstructive cholangitis, duodenal obstruction, bleeding, or cancer pain. Therefore, improving local control by adding radiotherapy to chemotherapy should be meaningful with LAPC patients if this treatment was acceptable. Since toxicity was not severe as we mentioned above, additional hypofractionated radiotherapy using IMRT may be good choice for elderly LAPC patients.
As this study was a retrospective and a single arm analysis, there are several limitations. First, this analysis did not directly compare the results between CCRT and chemotherapy alone or between IMRT and 3D-CRT for LAPC patients. Further we could not perform univariate or multivariate analyses for analyzing the prognostic factors, since our sample size is small. A large number of randomized control trials are desirable to explore the most feasible therapy for elderly patients with LAPC. Second, the assessment of toxicities may be inaccurate; especially low-grade toxicity may be underestimated because of the incomplete record of side effects since this was a retrospective analysis. We did not undercount severe toxicity, which should be obviously recorded, as it required additional medical care. Third, as the PS of all patients were 0 or 1 in this study because the patients were selected by our tumor board, and this result cannot be simply applied to all elderly patients. In other words, this treatment may be suitable for elderly patients with good PS, who are tolerable for the chemoradiotherapy.
To the best of our knowledge, this is the first study to evaluate the outcomes and tolerability with hypofractionated CCRT using IMRT for the elderly patients with LAPC. The results were favorable; moreover, considering the target was elderly people, hypofractionation may be meaningful because of its short treatment period. Since long period of hospitalization could induce disability such as cognitive decline or dementia in the elderly, short treatment should be preferable. As the incidence of elderly patients with pancreatic carcinoma is increasing, we should further investigate the ideal treatments including other modalities for LAPC patients.