Radiotherapy is an essential component of cancer therapy. Carbon ion radiotherapy (CIRT) promises to improve outcomes compared with standard of care in many cancers. Nevertheless, clinicians often observe in-field recurrence after CIRT. This indicates the presence of a subset of cancers that harbor intrinsic resistance to CIRT. Thus, the development of methods to identify and sensitize CIRT-resistant cancers is needed. To address this issue, we analyzed a unique donor-matched pair of clinical specimens: a treatment-naïve tumor, and the tumor that recurred locally after CIRT in the same patient. Exon sequencing of 409 cancer-related genes identified enrichment of somatic mutations in FGFR3 and FGFR4 in the recurrent tumor compared with the treatment-naïve tumor, indicating a pivotal role for FGFR signaling in cancer cell survival through CIRT. Inhibition of FGFR using the clinically available pan-FGFR inhibitor LY2874455 sensitized multiple cancer cell lines to carbon ions at 3 Gy (RBE: relative biological effectiveness), the daily dose prescribed to the patient. The sensitizer enhancement ratio was 1.66 ± 0.17, 1.27 ± 0.09, and 1.20 ± 0.18 in A549, H1299, and H1703 cells, respectively. Our data indicate the potential usefulness of the analytical pipeline employed in this pilot study to identify targetable mutations associated with resistance to CIRT, and of LY21874455 as a sensitizer for CIRT-resistant cancers. The results warrant validation in larger cohorts.

To evaluate the effects of dose-averaged linear energy transfer (LET_d) profiles on local control of pancreatic cancer treated with carbon ion radiotherapy (CIRT). Data from patients with inoperable pancreatic cancer, treated with CIRT and concurrent chemotherapy between 2013 and 2021, were analyzed retrospectively. The prescribed dose was 55.2 Gy (relative biological effectiveness), administered in 12 fractions. The LET_d of CIRT plans were calculated using a previously reported in-house pipeline. The association between tumor LET_d profiles and local recurrence (LR) was analyzed. The study analyzed 106 patients. The 2-year cumulative LR rate was 20.2% (95% confidence interval [CI], 12.8%-28.9%). Analysis of LET_d parameters using a Fine-Gray regression model showed that the minimum LET_d (L_min) for the clinical target volume (CTV) had a significant effect on LR (p = 0.023). According to the cutoff value of 42.2 keV/μm, determined by time-dependent Receiver Operating Characteristic analysis at 18 months, patients with low CTV L_min had a significantly greater cumulative LR rate than those with high CTV L_min (p = 0.020; 2-year cumulative LR rate, 32.4% [95% CI, 16.6%-49.3%] vs. 12.7% [95% CI, 5.8%-22.5%]). Cause-specific proportional hazards models identified CTV L_min as a significant predictor of LR (hazard ratio, 0.83 [95% CI, 0.71-0.98], p = 0.030). CTV L_min showed a strong significant negative correlation with CTV (p < 0.0001, r = -0.52). This is the largest study investigating the association between tumor LET_d profiles and local control post-CIRT. The results suggest that low LET_d within the CTV is associated with poor local control in patients with pancreatic cancer treated with CIRT.

This study aimed to first elucidate prostate-specific antigen (PSA) kinetics in prostate cancer patients treated with carbon ion radiotherapy (CIRT). From 2010 to 2015, 131 patients with prostate adenocarcinoma treated with CIRT (57.6 Gy relative biological effectiveness (RBE) in 16 fractions) alone were recruited. PSA was measured at 1, 2, 3, 6, 9, 12, 15, 18, 21, 24, 30, 36, 42, 48, 54, and 60 months post-CIRT. PSA bounce was defined as PSA increase over a cutoff followed by spontaneous decrease to or below the pre-bounce nadir. PSA failure was determined using the Phoenix criteria (nadir + 2.0 ng/mL). As a result, non-failure-associated temporary increase in PSA exhibited two distinct patterns, namely a classical bounce and a surge at one month. PSA bounce of ≥0.2 ng/mL was observed in 55.7% of the patients. Bounce amplitude was <2.0 ng/mL in 97.6% of cases. Bounce occurred significantly earlier than PSA failure. Younger age was a significant predictor of bounce occurrence. Bounce positivity was a significant predictor of favorable 5-year PSA failure-free survival. Meanwhile, a PSA surge of ≥0.2 ng/mL was observed in 67.9% of patients. Surge amplitude was significantly larger than bounce amplitude. Larger prostate volume was a significant predictor of PSA surge occurrence. PSA surge positivity did not significantly predict PSA failure. In summary, PSA bounce was distinguishable from PSA failure with regard to timing of occurrence and amplitude (earlier and lower for bounce, respectively). These data are useful for post-CIRT surveillance of prostate cancer patients.