Background: Proton radiotherapy has a dosimetric advantage over photon radiotherapy. Many retrospective studies have shown promising results with proton radiotherapy in treating hepatocellular carcinoma (HCC). However, clinical evidence demonstrating the benefit of protons over photons is still limited. We therefore compared the clinical outcomes of the two modalities using medical research databases from our medical foundation. Methods: We conducted a propensity score-matched cohort study based on our multi-institution medical organization research database. From January 2007 to January 2018, a total of 413 patients (photon: 349; proton: 64) who were diagnosed with HCC and primarily treated with radiotherapy with curative intent were enrolled. Overall survival (OS) and radiation-induced liver disease (RILD) were assessed. Stratified analysis was also performed to evaluate the heterogeneous effects of the two arms. Results: A total of 110 patients (photon: 55; proton: 55) were analyzed in the propensity-matched series. The matched groups were balanced for baseline tumor risk factors. Cox regression analysis revealed a significant survival benefit in the proton group (p = 0.032, HR 0.56, 95% CI 0.33–0.96). The median overall survival in the proton group was not reached and that in the photon group was 17.4 months. The biological equivalent dose of radiotherapy was significantly higher in the proton group than in the photon group (median, 96.56 Gray [relative biological effectiveness] vs. 62.5 Gray, p < 0.001). The risk of RILD was significantly lower in the proton group (11.8% vs. 36%, p = 0.004). Conclusions: Proton radiotherapy could deliver a higher radiation dose than photon radiotherapy without increasing the risk of RILD and result in a better overall survival rate for those diagnosed with HCC and treated with radiotherapy with curative intent.

Atezolizumab plus bevacizumab (atezo-bev) has been recommended for advanced hepatocellular carcinoma (HCC). High-dose external beam radiotherapy (RT) is recognized for its excellent local tumor control. The efficacy and safety of concurrent atezo-bev with RT for highly advanced HCC has been minimally explored. In this preliminary retrospective study, we assessed patients with highly advanced HCC, characterized by Vp4 portal vein thrombosis or tumors exceeding 50% of liver volume, who received concurrent atezo-bev and RT (group A). Group A included 13 patients who received proton radiation at a dose of 72.6 GyE in 22 fractions, and one patient who received photon radiation at a dose of 54 Gy in 18 fractions. This group was compared with 34 similar patients treated atezo-bev alone as a control (group B). The primary objectives were to evaluate the objective response rate (ORR), overall survival (OS), and safety. Baseline characteristics were similar between groups, except for a higher incidence of Vp4 portal vein thrombosis in group A (78.6% vs. 21.4%, P = .05). Group A achieved a higher ORR (50.0% vs. 11.8%, P < .01) and a longer OS (not reached vs. 5.5 months, P = .01) after a median follow-up of 5.2 months. Multivariate analysis indicated that concurrent RT independently favored longer OS (hazard ratio: 0.18; 95% CI, 0.05-0.63, P < .01). Group A did not increase any grade adverse events (78.6% vs. 58.8%, P = .19) or severe adverse events of grade ≥ 3 (14.3% vs. 14.7%, P = .97) compared to group B. The concurrent high-dose external beam radiotherapy appears to safely enhance the effectiveness of atezolizumab plus bevacizumab for highly advanced patients with HCC. Further studies are warranted to confirm these findings.

Intensity modulated proton therapy (IMPT) with the vertebral artery (VA)-sparing technique has been initially proposed in our institution. This pilot study was conducted to compare the dose to VAs between IMPT and volumetric-modulated arc therapy (VMAT) for patients with nasopharyngeal carcinoma (NPC). A total of six patients with NPC treated by IMPT were enrolled in the study. Target volumes and organs at risk (OARs) were delineated, including 12 samples of right and left VAs, respectively, for each patient. Treatment planning by IMPT and dual-arc VMAT was carried out for comparison. The IMPT plan significantly reduced VA mean dose, V10, V20, V30, V40, and V50, compared to the VMAT plan in all 12 samples (p < 0.001). The average mean dose to VAs for IMPT was 35.2% (23.4–46.9%), which was less compared to VMAT (p < 0.001). Adequate dose coverage was achieved with both IMPT and VMAT plans for three different dose levels of target volumes for all patients. IMPT significantly reduces VA dose while maintaining adequate dose coverage of all target volumes. For patients with head and neck cancer who seek to preserve their blood flow to the brain in order to decrease late vascular and neurologic sequelae, IMPT should be considered. A prospective study with longer follow-up is ongoing to confirm our preliminary results.

This study evaluated the outcomes of hepatocellular carcinoma (HCC) patients with small normal liver volume (NLV) treated with proton beam therapy (PBT) and introduced estimated standard liver volume (eSLV) as a new constraint. HCC patients with NLV < 800 cm³ and no distant metastasis who received treatment in our proton center were included. The doses of PBT were mainly 72.6 Gray equivalents (GyE) in 22 fractions and 66 GyE in 10 fractions according to tumor locations. The Urata equation was used to calculate eSLV. Twenty-two patients were treated between November 2015 and December 2016. The 1-year progression-free and overall survival rates were 40.4% and 81.8%, respectively. The 1-year in-field failure-free rate was 95.5%. NLV ranged from 483.9 to 795.8 cm³ (median = 673.8 cm³), eSLV ranged from 889.3 to 1290.0 cm³ (median = 1104.5 cm³), and the resulting NLV/eSLV ratio ranged from 44.3 to 81.2% (median = 57.7%). Non-irradiated liver volume (NILV) ranged from 232.9 to 531.6 cm³ (median = 391.2 cm³). The NILV/eSLV ratio ranged from 21.2 to 48.0% (median = 33.3%). NLV in the patients who received <30 GyE (rV30) ranged from 319.1 to 633.3 cm³ (median = 488.2 cm³), and their rV30/eSLV ratio ranged from 30.7 to 58.0%. None of our patients developed liver failure. One patient with initial abnormal liver enzyme levels developed non-classic radiation-induced liver disease (RILD). From the viewpoint of minimal liver toxicity occurring in our patients with NLV < 800 cm³, conventional liver constraints involving the use of absolute volume could not accurately predict the risk of RILD. It is reasonable to start using individualized constraints with eSLV for HCC patients undergoing PBT. According to the study results, an NILV/eSLV ratio of >20% and an rV30/eSLV ratio of >30% are acceptable.