In the present study, grade 3 acute RP only occurred in one patient (3%). The incidence of grade 2 or 3 late RP after PT was 35%, while there were no cases of grade 4 or 5 late RP. Table 6 summarizes the frequencies of grade 3, 4, or 5 late RP in IP patients in previous studies [9, 10, 29, 30]. It was reported that RP occurred frequently in patients with IP, especially those with IPF. These studies suggest that X-ray irradiation may cause fatal pneumonia in IP patients. In the present study of PT, there were only two cases (6.9%) of grade 3 late RP, suggesting that PT is associated with a lower risk of fatal pneumonia among lung cancer patients with IP than X-ray therapy. This may be due to the physical characteristics of PT, as it reduces the doses delivered to the surrounding normal organs [11, 31].
Previous studies have shown that IPF patients with lung cancer have shorter survival times than patients with IPF alone [32, 33]. However, many treatment-related deaths have been reported in lung cancer patients with IPF. Surgery, such as lobectomy and biopsies, also worsens IPF. The reported postoperative IPF exacerbation rates range from 9.3–30% [7, 34, 35]. The risk of pulmonary toxicity from drug therapy, such as pemetrexed, has been reported to be approximately 3.5% in patients without IP, 12.0% in patients with IP, and up to 16.7% in patients with IPF [36]. In our study, 10 patients that exhibited the UIP pattern, which is suggestive of IPF, were treated with PT, and only one of them developed late grade 3 RP. There were no deaths associated with PT. Therefore, PT can be considered to be relatively safe. However, even narrowly localized radiotherapy for patients with IPF was reported to lead to marked variation in the frequency of RP [37]. Therefore, the necessity of interventions, including PT, should be carefully assessed in lung cancer patients with IPF.
Conventional radiotherapy for lung cancer patients with IP may be associated with a high risk of life-threatening pneumonia. SBRT may be safer if patients that were at high risk were excluded based on pretreatment CT evaluations or the measurement of biomarker levels [10, 29]. However, SBRT is generally used as a treatment option for early stage lung cancer, and treating large targets with SBRT is technically difficult [38, 39]. In our study, the median PTV of the patients treated with PT was large due to the inclusion of stage I to III patients, while the doses delivered to the lungs were kept low (Table 3). Our study suggests that the physical properties of PT are advantageous. The treatment of stage III lung cancer in IP patients carries a risk of life-threatening pneumonia, and PT is a safer treatment option for these patients.
QOL evaluations are important for comparing treatment modalities. Surgery is highly invasive and often leads to poor QOL. In a previous study, it was reported that patients’ QLQ-C30 scores had not returned to their preoperative levels at 6 months after lung cancer surgery [40]. Postoperative patients tend to experience persistent physical function problems, such as shortness of breath and pain in the arms and chest [41]. Reductions of 10% in the physical and mental component summary scores of the SF-36 from the baseline after lung cancer surgery have been reported to be associated with a high risk of death [42]. Although there is no consensus on what constitutes a significant difference in QOL data, a 10% difference in the SF-36 summary score is generally considered to be a clinically relevant difference. In our study, no significant reductions in HRQOL scores were seen after PT. As this study focused on lung cancer patients with IP, PT can be considered to be a less invasive treatment. However, the changes in QLQ-LC13 dyspnea scores seen at 3 months after radiotherapy have been shown to be correlated with lung V30Gy, V40Gy, V50Gy, and MLD values [43]. Previous studies have suggested that a lung V40Gy cut-off value of 11% exhibits good sensitivity and specificity as a predictor of dyspnea. Our results showed that grade 2 or 3 late pneumonia developed in patients with lung V40GyRBE values of > 11% (Table 4). The indications for PT for large PTV that require wide-field irradiation must be carefully judged in consideration of the risks and benefits.
This study had several limitations. Dosimetric analyses of the PTV showed that the D50% tended to be relatively well preserved, but D95% was sacrificed in some cases to ensure lung safety (Table 3). Sacrificing the PTV D95% in this manner may be clinically acceptable, but it may negatively affect long-term prognosis. We try to achieve both high PTV coverage and low lung exposure using respiratory-gated irradiation with gold marker implantation [6]. As another limitation, the HRQOL survey period was only 3 months. This was because in our prospective clinical studies the HRQOL surveys were scheduled to be conducted at 3 and 24 months after the PT. However, at 24 months sufficient data were not available for some patients due to the length of the follow-up period being too short or an HRQOL survey not being performed. Further case accumulation and multicenter trials will be needed to assess late toxicities. Finally, patient selection bias must also be considered. Only patients who were judged to be suitable for this costly treatment by a pulmonologist were referred to our facility. In Japan, PT for lung cancer is not covered by medical insurance, and only wealthy people can receive this treatment. Thus, the prognosis of the patients in our study may have been abnormally good, as the patients probably had access to adequate standard medical support in addition to PT.
Immune checkpoint inhibitors have been developed in recent years, and many patients will continue to be treated with them. In a prospective study in which nivolumab was administered to 6 NSCLC patients with mild IP, no life-threatening pneumonia occurred [44]. Even when they are used in combination with radiotherapy, there are many uncertainties regarding the risk of immune checkpoint inhibitors in patients with IP. There are also reports suggesting that a history of thoracic radiation is a risk factor for pneumonia during treatment with immune checkpoint inhibitors [45]. Our study showed that PT could reduce the radiation dose delivered to normal lung tissue, and the incidence of clinically problematic pneumonia was low. When immune checkpoint inhibitors need to be given to lung cancer patients with IP, PT could be useful for reducing the risk of adverse events. Therefore, at our facility, several IP patients with stage III NSCLC have been treated with durvalumab as maintenance therapy after chemotherapy combined with PT after approval was granted by the cancer board. The results of a prospective trial of this approach will also be reported in the future. We hope that PT can contribute to safer treatment in many lung cancer patients with IP.