We conducted this study hypothesizing that, in patients with stage III NSCLC undergoing PBT, irradiation of bone tissues might cause lymphopenia owing to depletion of progenitor cells, which would, in turn, reduce antitumor immunity and thereby influence survival. Our findings revealed that bone V5 and lung V5 correlated with lymphopenia and that lymphopenia was significantly associated with survival rates. In this study, however, there was no significant impact of bone V5 on survival rates, but lung V5 affected to DMFS on the multivariate analysis.
In RT with concurrent chemotherapy for NSCLC, it has been pointed out that low-dose irradiation of the thoracic vertebral body is associated with grade ≥ 3 leukopenia, which can result in poor survival and control rates owing to incomplete chemotherapy or treatment that could not be performed as planned . Some studies have also reported that doses to the bone were related to the survival rate in CRT for other primary tumors or with radiation alone [26, 27]. In the present study, the lymphocyte count tended to decrease with increasing bone irradiation doses, but lung V5 rather than bone V5 strongly correlated with lymphopenia. Conceivably, lung V5 irradiation doses increased relative to the bone V5 irradiation dose, and it is possible that lymphopenia, caused by the increase in doses to the bone, may be a spurious correlation (Fig. 4). However, there was no significant difference in the survival rate related to irradiation doses to the bone. In the present study, the thoracic vertebrae (Th1 to Th10), the sternum, and the first to seventh ribs were contoured as bones. Hayman et al. reported that the relative contribution of the thoracic vertebra, sternum, and ribs/clavicle to the active proliferating bone marrow was approximately 20%, 3%, and 9%, respectively . Thus, one reason that bone irradiation may not have a large effect on the survival rate could be that myelosuppression is mainly caused by the concurrent use of chemotherapy.
In the current study, we examined not only ALC but also NLR as lymphocyte-related factors, as there are various reports describing how these factors relate to the prognosis of surgery and systemic treatment [9, 10, 29]. It has been reported that inflammatory cytokines are involved in cancer progression and associated with chemotherapy [30, 31]. Furthermore, high NLR levels are inflammatory markers that are one of the poor prognostic factors for programmed cell death receptor-1 (PD-1) inhibitor treatment in patients with lung cancer [30, 31]. Likewise, high NLR was a predictive factor for lower PFS and DMFS on multivariable analysis in the present study. Therefore, because the standard treatment for locally advanced lung cancer is CRT and immune checkpoint inhibitor therapy, it is important to reduce lymphopenia during RT.
Radiation pneumonitis (RP) is a potentially life-threatening adverse event in chest RT, and lung V20 is frequently used as an index of RP [32–35]. The National Comprehensive Cancer Network Guidelines have described lung V5 as an RP risk factor; however, owing to the increased use of IMRT and the results of the RTOG 0617 study, the description of lung V5 has been removed from the guidelines regarding dose constraints in lung cancer treatment [35, 36]. In the present study, lung V5 strongly correlated with lymphopenia and have a significant impact on DMFS. This suggests that while lung V5 does not often reduce the survival rate due to RP, it may inhibit a patient’s anticancer immunity in association with lymphopenia. In the PACFIC study, it is suggested that distant metastases might be reduced by maintaining anti-tumor immunity, in which lymphocytes play an important role . Thus, careful attention should be paid not only to lung V20 but also to lung V5 in the treatment planning for NSCLC.
Nowadays, irradiation doses to the heart are known to be important in NSCLC patients treated with CRT. In the RTOG 0617 study, heart V5 was identified as a prognostic factor for OS . In the present study, heart V5 was significantly associated with OS in univariable analysis. Unlike IMRT, PBT has the advantage of concentrating high doses of irradiation on the CTV while avoiding low doses to the lung and heart . Therefore, in the treatment of lung cancer, PBT is considered to be more useful than IMRT because it can lower lung V20 and heart V5 exposure while suppressing the increase of lung V5. In chest irradiation with concurrent chemotherapy for esophageal cancer, PBT has advantages over IMRT in terms of lymphopenia and survival rate, and a prospective study is being conducted [12, 37, 38]. In lung cancer, a randomized control trial comparing passive-scattering PBT and IMRT for locally advanced NSCLC did not prove the superiority of PBT because, despite PBT, DVHs of the lung and heart remained extremely high . We speculate that in this randomized control trial, technical deficiencies in the delivery of the PBT probably affected the results because RP and local failure rates at 12 months for patients enrolled before versus after the trial midpoint were 31.0% and 13.1%, respectively (p = 0.027). Therefore, the results of the NRG 1308 trial, which compares PBT and IMRT and is focused on low doses to at-risk organs and lymphopenia, are highly anticipated to shed light on this important issue .
The major limitations of the current study are its retrospective nature, small number of participants, clinical heterogeneity, and long period of patient accrual. The number of the patients with severe lymphopenia (ALCmin ≤ 200/µL) was also small, although there was a significant difference in survivals between the patients with and without severe lymphopenia. However, the PBT protocol, such as the definition of the CTV, prescription dose and fractionation, beam arrangement, treatment machine, and methods of respiratory-motion management, has not changed over the study period. Spot-scanning irradiation techniques have become widespread but passive-scattering PBT plans have been still carried at our facility. Furthermore, chemotherapy regimens were not identical although all patients received concurrent platinum-doublet chemotherapy. Large multicenter prospective studies, such as RTOG 1308, are required to address the abovementioned limitations and resolve the question of whether PBT could significantly improve OS in patients with stage III unresectable locally advanced NSCLC.