Clinical data comparing proton and photon radiotherapy with curative intent for HCC are limited. In the present study, we found that after appropriately adjusting for prognostic variables, patients who received proton radiotherapy had significantly better OS, which may be driven by a higher BED and lower risk of RILD.
These results echo those of the MGH report. The study demonstrates survival benefits with proton therapy, which may be related to the decreased incidence of nonclassic RILD. It is always challenging for retrospective studies to minimize selection bias, especially when studying liver tumors, as both tumor characteristics and patients’ baseline liver function play a significant role in survival outcomes. The strength of the present study is the balanced variables after PSM. We matched not only tumor variables but also baseline liver function variables that could potentially affect radiation toxicity and outcomes, including the liver fibrosis score, Child-Pugh class, ALBI grade, and hepatitis infection status[10, 12]. Moreover, we only included patients who underwent radiotherapy as the primary treatment modality after diagnosis, therefore precluding the effect of previous treatment modalities, such as radiofrequency ablation (RFA), surgery, or chemotherapy. The disease entity is also quite different between the present study and the MGH report. Our patients presented with more advanced HCC with larger tumors (median diameter of 6.8 cm for the largest tumor vs. median gross tumor volume of 106~118 mL) and a higher ratio of multiple tumors (56.4~60% vs. 36~49%), HBV infection (61.8~65.5% vs. 5~12%), and tumor thrombosis (43.6~47.3% PVTT vs. 27~35%), which may have influenced the BED that could be safely delivered by photon radiotherapy, which is much lower in the present study than in the MGH report (median, 62.5 Gy vs. 80.4 Gy [RBE]).
For liver tumors, it has been well demonstrated that a higher radiation dose could result in better oncological outcomes. The prescribed dose varies among series depending on the tumor entity, radiotherapy technique, and combined treatment modalities. In the era of 3D conformal radiotherapy (3DCRT), Park et al. analyzed 158 HCC patients and found that a higher radiation dose predicted a better tumor response rate (29.3% for <40 Gy; 68.6% for 40–50 Gy, and 77.1% for >50). However, the radiation dose also seemed to be a determining factor for RILD (4.2% for <40 Gy; 5.9% for 40-50 Gy, and 8.4% for >50 Gy). Among patients with PVTT who were treated with 3DCRT, Toya et al. reported a better response rate (80.0% vs. 21.7%, p<0.001) and 1-year survival rate (59.3% vs. 29.2%, p=0.04) for those who received BED ≥58 Gy. In the era of intensity-modulated radiotherapy (IMRT), the radiation dose could be escalated safely by advanced techniques. Byun et al. analyzed 637 patients with Barcelona Clinic Liver Cancer (BCLC) stage C HCC who received IMRT with concurrent hepatic arterial 5-fluorouracil. A higher BED (≥72 Gy) significantly increased the 1-year local failure-free survival (95% vs. 78%; p= 0.008) and 1-year OS (62% vs. 51%; p= 0.03) rates. Chadha et al. reported a series of 46 HCC patients treated with proton radiotherapy. Patients receiving a BED ≥90 Gy (RBE) had signiﬁcantly better OS. In the present study, the BED was significantly higher in the proton group and would be an essential factor contributing to better OS.
RILD is a major concern of using radiotherapy to treat liver tumors. The risk of RILD may be related to the liver radiation dose, the dose distribution, and underlying liver disease. Investigations have tried to issue dose parameters to predict the risk of RILD. In the Quantitative Analyses of Normal Tissue Effects in the Clinic (QUANTEC) report, Charlie et al. recommended that for those receiving therapeutic partial liver radiotherapy, keeping the mean normal liver dose (liver minus gross tumor volume) <28 Gy for primary liver cancer and <32 Gy for liver metastases may reduce the risk of RILD to <5%. Although advanced radiotherapy techniques such as IMRT or volumetric modulated arc therapy (VMAT) could achieve more conformal target dose coverage and a higher target dose than 3DCRT, the low-dose region may be increased by the nature of the physical properties of X-rays. The increase in the low-dose region in the normal liver could potentially increase the risk of RILD. Son et al. reported an analysis of 72 patients treated with helical tomotherapy and hypofractionated radiotherapy (40-50 Gy in 10 fractions). Normal liver receiving a dose of more than 15 Gy (V15) was found to be a parameter capable of predicting the deterioration of hepatic function. Moreover, dosimetric studies have found that for liver tumors larger than 8 cm, IMRT or VMAT delivered a higher mean liver dose than 3DCRT. These findings highlight the difficulties of using photon radiotherapy to treat large liver tumors optimally.
The story could be changed by the superior physical properties of proton radiotherapy. A proton beam has a finite range of energy deposition with no exit dose after the target. This physical advantage, compared with photon beams, may allow a higher target dose to be achieved without the unwanted spread of low doses to the surrounding normal liver. In a dosimetric study, Wang et al. demonstrated that for liver tumors, proton radiotherapy could significantly lower the mean liver dose and volume of normal liver receiving a dose of more than 30 Gy (RBE) (V30) compared to photon radiotherapy. Toramatsu et al. also performed a dosimetric study to compare spot-scanning proton therapy (SSPT) and IMRT. They predicted the risk of RILD using the Lyman-normal-tissue complication probability model and found that the risk of RILD increased drastically between with IMRT but not SSPT for liver tumors 6.3-7.8 cm in diameter (RILD 94.5% for IMRT vs. 6.2% for SSPT for tumor size >6.3 cm), which indicated that HCC lesions could be more safely treated with proton therapy, especially HCC lesions greater than 6.3 cm in size. Moreover, patients with small normal liver volumes may potentially benefit from proton radiotherapy. Lee et al. analyzed 22 HCC patients with a small normal liver volume (< 800 cm3) who were treated with proton radiotherapy. The oncological results were a 1-year in-field local control rate of 95.5% and a 1-year OS rate of 81.8%; there were no cases of liver failure, and only one case of nonclassic RILD could be identified. In the present study, 83.4% (n=92) of the patients included in the PSM series had multiple tumors or a largest tumor size >5 cm, and the risk of RILD would therefore be high with photon radiotherapy. Nonetheless, with proton radiotherapy, albeit with a higher BED, the risk of RILD was significantly lower, which is attributed to the advantages of its physical properties.
The dose schemas used in the proton cohort are mainly modified from Proton Medical Research Center (Tsukuba, Japan) protocols. Briefly, 72.6 Gy (RBE) in 22 fractions or 66 Gy (RBE) in 10 fractions were prescribed, depending on the tumor location. The 72.6 Gy (RBE) protocol is preferred for tumors located within 2 cm of the gastrointestinal tract or porta hepatis. The physical advantage of the proton beam, which minimizes unwanted spreading of the dose to the surrounding normal liver, was that the prescribed doses in the proton cohort were quite uniform and mostly did not need to be tailored for large tumor volume HCC cases. On the contrary, in the photon cohort, large tumor volume may be an essential factor that resulted in higher unwanted doses spreading to the normal liver and therefore limited the tolerance of the prescribed dose. Consequently, photon dose prescriptions need to be tailored case by case for different tumor sizes or locations; therefore, the prescribed doses in the photon cohort were more diverse and lower than those in the proton cohort.
Our study does have potential limitations. Limited by the nature of the CGRD, we could only record the “size of the largest tumor” instead of the “total tumor volume.” Although the “size of the largest tumor” has been demonstrated to predict survival outcomes for HCC patients undergoing liver transplantation, this may result in uncertainties when assessing patients with multiple HCC lesions. The location of HCC is also an essential factor contributing to the dosimetric difference between photon and proton radiotherapy and could not be addressed in the present study. Although we generated balanced groups according to several variables by PSM, potential selection bias is still present due to the retrospective nature of the study. Patients treated with proton radiotherapy in our series were all treated at a single medical center, while patients treated with photon radiotherapy were treated at four different hospitals. There may be a bias related to differences in protocols and treatment techniques among different hospitals. Economically, photon therapy is covered by National Health Insurance (NHI) in our country, while proton therapy is an expensive technique not covered by NHI. This may lead to potential selection bias regarding socioeconomic status between the groups.