Liver cancer is the 6th most prevalent malignant tumor in the world with poor prognosis and ranks 3rd in cancer-related mortality, with approximately 600,000 deaths from liver cancer each year. [1] Radiation therapy is one of the important treatment modalities for inoperable resectable liver cancer, and external irradiation is somewhat limited in the treatment of liver cancer due to the effect of photons on the surrounding normal liver tissue. The clinical advantage of proton therapy compared with photon therapy is the significant reduction of the irradiated dose to the patient, the absence of dose behind the Bragg peak of proton therapy, and the superior physics of the Bragg peak that allows the focal high-energy release of the proton beam in the tissue, making it possible to perform a precise range of maximum kill in liver cancer tissue. Compared to photon external irradiation, proton therapy reduces the irradiated dose by 60%. The relative biological effect (RBE) of protons relative to photon therapy is 1.1, i.e., the biological effect of 1 Gy of proton therapy is equivalent to 1.1 Gy of photon therapy, and the inherent physics of protons allows proton therapy to improve local control of tumors in liver cancer by increasing the irradiation dose to the tumor while avoiding unnecessary irradiation of normal liver tissue. [This paper systematically reviews the clinical application of proton therapy in the treatment of liver cancer.
I. Clinical studies of proton therapy for liver cancer
(I) Proton therapy for liver cancer
1. Clinical analysis of proton therapy for hepatocellular carcinoma
The overall survival rates at 1, 3 and 5 years were 89.5% (95% CI, 85.7-93.1%), 64.7% (95% CI, 56.6-72.9%), and 44.6% (95% CI, 29.7-59.5%) for proton therapy in 318 patients with hepatocellular carcinoma (HCC) from 2001 to 2007, respectively, as analyzed retrospectively by the University of Tsukuba, Japan. Child-Pugh liver function (hazard ratio [HR], 2.84; P < .01), T-stage (HR, 1.94; P < .05), PS score (HR, 2.12; P < .01), and planned target volume (HR, 2.12; P < .05) significantly affected survival. The 3- and 5-year survival rates were 69.1% (95% CI, 59.9-78.3%) and 55.9% (95% CI, 41.5-70.3%), respectively, for patients with Child-Pugh A liver function class; and 51.9% (95% CI, 32.3 -71.5%) and 44.9% (95% CI, -71.5%), respectively, for patients with Child-Pugh B liver function class. The 3-year and 5-year survival rates were 51.9% (95% CI, 32.3-71.5%) and 44.5% (95% CI, 23.1-65.8%), respectively, for patients with Child-Pugh B. Their study showed that proton therapy is safe and effective for patients with HCC. [3]
Mizumoto M et al. compared 3 different dose fractions of proton therapy for HCC in 266 HCC patients, divided into 3 groups: group A, 66 GyE, 10 doses; group B, 72.6 GyE, 22 doses; and group C, 77 GyE, 35 doses. the overall survival rates at 1, 3, and 5 years were: 87%, 61%, and 48%, respectively (median survival time was 4.2 years). Local control rates at 1, 3, and 5 years were 98%, 87%, and 81%, respectively. local control rates were better for all three dose fractionation modalities. The selection of different dose fractionation modalities according to the different sites of tumors in the liver is beneficial in reducing late toxic side effects. [4]
Fukumitsu N prospectively analyzed 51 patients with HCC treated with large-split protons. All of these patients had masses larger than 2 cm and not close to the hepatic hilum or gastrointestinal tract. The treatment dose was 66 GyE in 10 treatment sessions. The overall survival rates at 3 and 5 years after treatment were 49.2% and 38.7%, and the local control rates at 3 and 5 years were 94.5% and 87.8%. Blood AFP decreased significantly after treatment. three patients experienced delayed toxicities greater than or equal to grade 2, and there were no treatment-related deaths. Their study showed that large split proton therapy is safe and effective for HCC larger than 2 cm not close to the hepatic portal and gastrointestinal tract. [5] DeLaney TF et al. also concluded that large-split proton therapy is safe and cost-effective for selective hepatocellular carcinoma. [6]
Chiba T et al. retrospectively studied 162 patients with proton-treated HCC at a median proton therapy dose of 72 Gy/16 F. The overall 5-year survival rate was 23.5%. For 192 lesions in 162 patients, the 5-year local control rate was 86.9%. For patients with mild hepatic impairment and single tumors, the 5-year survival rate was 53.5%. Proton therapy is safe, effective, tolerable, and reproducible, and radical or palliative proton therapy is feasible regardless of the size and location of the intrahepatic tumor, inadequate blood supply to the tumor, vascular infiltration, or impaired liver function. [7]
Hata M retrospectively analyzed 21 patients with HCC who chose to undergo proton therapy because they were unsuitable for other treatments due to the combination of other diseases (4 cases of renal failure, 2 cases of severe heart disease, 9 cases of severe cirrhosis, 1 case of aplastic anemia, 1 case of large abdominal aneurysm, and 4 cases with bleeding tendencies or unresectable tumors). The objective efficiency rate was 81%, the 5-year control rate of primary foci was 93%, the 2-year overall and disease-specific survival rates were 62% and 82%, respectively, and the 5-year overall and disease-specific survival rates were 33% and 67%, respectively, with no treatment-related side effects greater than or equal to grade 3. Thus, proton therapy is effective and safe for patients who have limited treatment options due to other diseases or causes. [8]
A phase 2 clinical trial at Loma Linda University in the United States studied the safety and efficacy of proton therapy for HCC. A total of 76 patients with HCC were enrolled, and the median disease-free progression survival was 36 months, with a 3-year disease-free survival rate of 60% by the Milan criteria. 18 patients subsequently underwent liver transplantation, and of these patients, complete remission of pathology was found in 6 (33%), and 7 (39%) patients had microscopic residuals. Their results suggest that proton therapy is an effective local treatment modality for patients with non-surgical resectable HCC. [9]
The phase II clinical trial by Kawashima M et al. enrolled 30 patients with HCC. Therefore, all patients had cirrhosis, including 20 patients with liver function Child-Pugh A and 10 patients with Child-Pugh B. The dose of proton therapy was 76 GyE/5W, 3.8 GyE/F, and 4F per week. The median follow-up period was 31 months (16-54 months), and only one patient had recurrence of the primary focus, with a 2-year no local tumor progression rate of 96% (95% CI: 88%-100%). The 2-year overall survival rate was 66% (48%-84%). 8 patients developed proton therapy-induced hepatic insufficiency, 8 patients developed grade 3 leukopenia, 7 patients developed grade 3 thrombocytopenia, 1 patient developed grade 3 total bilirubin increase, and 5 patients developed transaminase abnormalities. There were no grade 4 toxic side effects. Their results show that proton therapy for HCC provides excellent control of the primary tumor with minimal acute toxic side effects. [10] Mizumoto M et al. studied 53 patients with HCC whose tumors were less than 2 cm from the hepatic hilum at a treatment dose of 72.6 GyE/22 F. The 3-year survival rate was 45.1% and the 3-year local control rate was 86.0%, with survival prognostic correlates such as Child-Pugh score, tumor number, and AFP level. There were no treatment-related late toxicities greater than or equal to grade 2. Their results showed that proton therapy 72.6 GyE/22F was effective and safe for HCC adjacent to the hepatic portal. [11]
2. proton therapy for hepatocellular carcinoma in the elderly
Hata M studied the prognosis of 21 elderly (greater than or equal to 80 years) HCC patients treated with proton therapy, with 3-year local recurrence-free survival and disease-free progression rates of 100% and 72%, and 3-year overall survival, disease-specific survival, and disease-free progression survival rates of: 62%, 88%, and 51%, respectively. There were no treatment-related toxicities greater than or equal to grade 3. Thus, proton therapy is effective and safe for elderly HCC patients, improving patient survival through local control of the tumor. [12]
3. proton therapy for giant hepatocellular carcinoma
To evaluate whether proton therapy is safe and effective in the treatment of giant liver tumors, Sugahara S et al. studied proton therapy in 22 patients with HCC with tumor diameter greater than 10 cm. Eleven of these cases were associated with portal vein cancer thrombosis. The median dose was 72.6GyE/22F (47.3-89.1GyE/10-35F). The median follow-up was 13.4 months (1.5-85 months). 2-year tumor control rate was 87%, 1-year overall and disease-free progression survival was 64% and 62%, and 2-year overall and disease-free progression survival was 36% and 24%. The predominant mode of recurrence was field recurrence with intrahepatic irradiation. There were no late-onset treatment-related toxic reactions greater than or equal to grade 3. They concluded that due to the properties of the Bragg peak, proton therapy has good conformability, allowing large intrahepatic tumors in HCC patients to receive high doses of radiation therapy but without increasing the amount of surrounding normal liver tissue exposed. They therefore concluded that proton therapy is safe and effective for HCC patients with large tumors. [13]
4. Proton therapy for hepatocellular carcinoma with severe cirrhosis or ascites
Hata M et al. studied 19 patients with Child-Pugh C cirrhosis at a total dose of 50-84 Gy/10-24 F. The 1-year overall and disease-free survival rates were 53% and 47%, and the 2-year overall and disease-free survival rates were both 42%. Status score and Child-Pugh score were prognostic factors for survival, with no treatment-related toxicities greater than or equal to grade 3. In patients with relatively good systemic status and liver function, proton therapy improves survival. [14] Hata M et al. showed that three patients with HCC with uncontrollable ascites treated with proton 24Gy single-shot radiation remained progression-free at 13 and 30 months in two patients, respectively. There were no treatment-related toxic side effects greater than or equal to grade 3. Their findings suggest that single high-dose precision proton therapy is acceptable for HCC patients with massive ascites. [15]
5. Proton therapy again for recurrence after proton therapy for hepatocellular carcinoma
Hashimoto T et al. analyzed 27 patients with HCC who relapsed after proton therapy and received proton therapy again. The median time between the first treatment and re-treatment was 24.5 months (range 3.3-79.8 months) The median total dose was 72 Gy/16F for the first treatment and 66 Gy/16F for the re-treatment. 5-year survival rate and median survival time were 55.6% and 62.2 months (from the first treatment), respectively. 1 case of Child-Pugh B and 1 patient with Child-Pugh C developed severe liver failure. Therefore it is safe to re-proton therapy after relapse in HCC patients not located at the hepatic margin as well as in those with hepatic function Child-Pugh A. [16]
6. Comparison of the results of proton therapy and carbon ion therapy for liver cancer
Of 343 HCC patients at Kobe University in Japan, 242 patients received proton therapy and 101 patients received carbon ion therapy. For all patients, the 5-year local control rate and overall survival rate were 90.8% and 38.2%. For the 242 patients treated with proton therapy, the 5-year local control and overall survival rates were 90.2% and 38%, and for the 101 patients treated with carbon ion therapy, the 5-year local control and overall survival rates were 93% and 36.3%. There was no difference between proton therapy and carbon ion therapy. Univariate analysis showed that tumor size was an independent risk factor for local recurrence for proton therapy, carbon ion therapy, and all patients. Multifactorial analysis showed that tumor size was the only independent risk factor for local recurrence in proton therapy and in the whole group of patients. Both univariate and multifactorial analyses showed that Child-Pugh class was the only independent risk factor for proton therapy, carbon ion therapy, and overall survival for the entire group of patients. No patients died from treatment-related toxicity. Their results suggest that the outcomes of proton therapy and carbon ion therapy for HCC are similar. [17]
7. effect of respiratory motion on proton therapy for hepatocellular carcinoma
The effect of respiratory motion cannot be ignored in proton therapy for liver cancer either, because irregular respiratory rhythms have a greater impact on the geometric accuracy of proton therapy for liver tumors. [18] Oshiro Y et al. studied 30 patients with liver cancer treated with proton therapy and found that end-expiration had better reproducibility than end-inspiration, a finding that facilitated more precise breath-synchronized proton therapy. [19]
For proton therapy efficacy assessment, it has been reported that contrast-enhanced color Doppler ultrasound is a valid modality for HCC proton therapy efficacy assessment. [20]
(B) Proton therapy for hepatocellular carcinoma thrombus
1. Proton therapy for portal cancer thrombosis
Sugahara S retrospectively analyzed the efficacy of proton therapy in 35 cases of advanced HCC with portal cancer embolism. The median dose was 72.6 GyE/22F, and the treatment target area included primary tumor in the liver and portal vein thrombus. 2-year and 5-year local progression-free survival rates were 46% and 20%, respectively. The median local disease-free progression survival time was 21 months. Three patients had acute phase toxicities greater than or equal to grade 3 and no patients had delayed toxicities greater than or equal to grade 3. Their study showed that proton therapy improves local control and prolongs survival in patients with HCC with portal cancer thrombosis. [21] Hata M et al. analyzed 12 patients (clinical stage T3-T4N0M0) with HCC with portal vein trunk or large branch carcinoma thrombi treated with 50-72 Gy/10-22 F for primary tumor and carcinoma thrombus proton therapy. 2- and 5-year disease-free survival rates were 67% and 24%, and median disease-free survival time was 2.3 years. No toxic side effects greater than or equal to grade 3 were identified. Proton therapy is feasible and effective in patients with HCC with portal carcinoma thrombosis, significantly improving local control and survival in these patients. [22] Experts from Kanazawa University, Japan, reported a patient with HCC with a primary tumor of 8.8 cm with portal cancer thrombus who was treated with irinotecan arterial infusion chemotherapy followed by proton radiotherapy with a survival of 6 years. [23]
Mayahara H et al. reported a case of HCC patient with marginal recurrence after 12 months of carbon ion 52.5GyE/8F treatment with portal vein carcinoma thrombus, which was reviewed after 3 months of 60GyE/22F proton therapy, and the recurrent tumor was reduced and the portal vein carcinoma thrombus disappeared without serious complications, and there was no further recurrence for 27 months (from the first treatment). [24]
2. Proton therapy for inferior vena cava carcinoma thrombosis
Mizumoto M et al. reported three patients with HCC with inferior vena cava carcinoma thrombosis treated with 50-70 Gy/10-35F for primary tumors in the liver and inferior vena cava carcinoma thrombosis, and the survival time of the three patients was 13-55 months without treatment-related toxic side effects greater than or equal to grade 3. Thus proton therapy is safe and effective in patients with HCC with inferior vena cava carcinoma thrombosis. [25]
II. Toxic and side effects of proton therapy for hepatocellular carcinoma
(A) Effects of proton therapy for hepatocellular carcinoma on liver function
The University of Tsukuba, Japan, analyzed the liver function of 259 patients with proton-treated hepatocellular carcinoma from 2001 to 2007, and the results showed that liver function after proton therapy for hepatocellular carcinoma was related to the percentage of unirradiated normal liver tissue, V0, V10, V20, V30 and Child-Pugh liver function classification, [26]
Proton-based stereotactic radiation therapy (SBRT) for solitary hepatic metastatic tumors reduces the dose of irradiated normal liver tissue as well as reduces the average irradiated dose to the liver. [27] For unresectable HCC, Kawashima M et al. evaluated proton therapy-induced hepatic insufficiency (PHI) using DVH maps and 15-minute indocyanine-green retention rate (ICGR15). They analyzed 60 patients and five patients developed PHI, all with V30 greater than 25%. 3-year local progression-free survival and overall survival rates were 90% and 56%, respectively. three patients developed gastrointestinal toxic reactions greater than or equal to grade 2. Their results showed that ICGR15 and V30 were effective in predicting the risk of developing PHI. [28] It has been reported that for HCC, proton therapy reduces the irradiated dose to normal liver tissue and non-hepatic tissue (e.g., spinal cord, right kidney, and stomach) compared to 3D conformal radiotherapy Compared with intensity-modulated conformal radiotherapy (IMRT), proton therapy also reduced the dose to normal liver tissue, the right kidney, and the stomach. [29] Toramatsu C et al. compared IMRT and proton therapy with radiographic liver disease and found that the average risk of radiographic liver disease in IMRT-treated HCC was 94.5% when the GTV diameter was greater than 6.3 cm, whereas the risk of radiographic liver disease in proton therapy was 6.2%. Therefore, proton therapy for HCC is safer, especially for HCC with a diameter greater than 6.3 cm.[30]
(ii) Effects of proton therapy for hepatocellular carcinoma on other normal tissues
The median survival time was 33.9 months (95% CI: 10.8-57.0 months), the 3-year overall survival rate was 50.0%, and the 3-year disease-free survival rate was 88.1%. 3 patients (6.4%) had grade 2 GI bleeding and 1 patient (2.1%) had grade 3 GI bleeding. Grade 3 GI bleeding was observed in 3 (6.4%) patients and Grade 3 GI bleeding in 1 (2.1%) patient. Proton therapy is effective for HCC in the adjacent GI tract, but should be used with caution. [31] Komatsu S et al. reported that for large HCC in the adjacent gastrointestinal tract that is not surgically resectable, a protective spacer can be surgically placed between the liver and the gastrointestinal tract followed by proton therapy, and they reported a disease-free survival time of more than 2 years in patients treated with this approach. [32]
Wang X, an MD Anderson investigator, et al. compared the dosimetric advantages of proton therapy versus photon therapy for liver cancer. They found that proton therapy significantly reduced V30 and mean liver dose, and gastric and duodenal V45 were also significantly lower than photon therapy, as were V40 and V50 in the heart and the maximum irradiated dose in the spinal cord. Compared to photon therapy, proton therapy completely avoids one kidney and exposes the other kidney to a lower dose (usually the left kidney). Proton therapy resulted in a significant reduction in the average dose to the patient’s whole body and vital organs. Their findings demonstrate dosimetrically that proton therapy is superior to photon therapy for HCC. [33]
Kanemoto A et al. retrospectively analyzed rib damage after large split proton therapy in 67 HCC patients. The proton irradiation dose was 66 GyE/10 F. A total of 310 ribs were irradiated with protons in 67 patients, resulting in fractures in a total of 27 (8.7%) ribs in 11 patients (16.4%). The results showed that V60 was the most statistically significant parameter for assessing rib fractures after large split proton therapy for HCC. [34]
(iii) Proton therapy and second primary tumor
Studies from the Department of Radiotherapy at MD Anderson Cancer Center have shown that in patients with HCC, proton therapy reduces the risk of radiotherapy-related second primary tumors compared with photon therapy. [35] MD Anderson investigators Taddei PJ et al. reported the effects of stray radiation (Stray Radiation) on patients with HCC treated with protons. The effective dose of stray radiation was 370 mSv, with 61% of this dose coming from neutrons outside the patient’s body and 39% from neutrons inside the patient’s body. The results showed that the risk of fatal second primary tumors from stray radiation was 1.2%. Their study provides a baseline level assessment of the dose and associated risk of stray radiation to adult HCC patients treated with proton therapy. It also provides new evidence for the suitability of proton therapy for HCC treatment.