Proton beam therapy for hepatocellular carcinoma

Introduction: Radiation therapy is an effective treatment option for hepatocellular carcinoma (HCC) patients. However, radiotherapy for HCC still has limited recognition as a standard treatment option in international consensus guidelines due to a paucity of randomized controlled trials and the risk of hepatotoxicity, which is primarily mediated by baseline liver function and dose delivered to non-tumor liver cells. Proton beam therapy (PBT) may offer advantages over photon-based radiation treatments through its dosimetric characteristic of sparing more liver volume at low to moderate doses. PBT has the potential to reduce radiation-related hepatotoxicity and allow for tumor dose escalation.

Areas covered: This article reviews the clinical rationale for using PBT for HCC patients and clinical outcome and toxicity data from retrospective and prospective studies. PBT-specific technical challenges for these tumors and appropriate selection of patients to be treated with PBT are discussed.

Expert commentary: Local control, overall survival, and toxicity results are promising for liver PBT. Future studies, including ongoing randomized cooperative group trials, will aim to determine the incremental benefit of PBT over photons and which patients are most suitable for PBT.     

Proton beam therapy for hepatocellular carcinoma

BACKGROUND:

The authors have published a series of studies evaluating the safety and efficacy of proton beam therapy for the treatment of hepatocellular carcinoma in a variety of clinical settings. In the current study, they retrospectively reviewed their entire experience treating hepatocellular carcinoma patients with proton beam therapy at their hospital‐based facility at the University of Tsukuba.

METHODS:

From November 2001 to December 2007, 333 patients with hepatocellular carcinoma were treated with proton beam therapy at the University of Tsukuba. A total of 318 patients were included in this study. Total dose delivered and fractionation scheme were determined by protocols that varied based on location of tumor. Survival rates and prognostic factors were assessed.

RESULTS:

Overall actuarial survival rates at 1‐year, 3‐years, and 5‐years were 89.5% (95% confidence interval [95% CI], 85.7‐93.1%), 64.7% (95% CI, 56.6‐72.9%), and 44.6% (95% CI, 29.7‐59.5%), respectively. Child‐Pugh liver function (hazards ratio [HR], 2.84; P < .01), T stage (HR, 1.94; P < .05), performance status (HR, 2.12; P < .01), and planning target volume (HR, 2.12; P < .05) significantly impacted survival. The 3‐year 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 disease and 51.9% (95% CI, 32.3‐71.5%) and 44.5% (95% CI, 23.1‐65.8%), respectively, for patients with Child‐Pugh B disease. The actuarial survival rates of patients with Child‐Pugh class A were statistically different between groups of planned target volume ≤125 mL and >125 mL (P < .05).

CONCLUSIONS:

The authors have shown proton beam therapy to be both safe and effective for the treatment of patients with hepatocellular carcinoma. They strongly recommend the consideration of proton beam therapy in patients for whom other treatment options are risky or contraindicated. Cancer 2009. © 2009 American Cancer Society.     

Proton beam therapy for aged patients with hepatocellular carcinoma

PURPOSE: To investigate the safety and efficacy of proton beam therapy for aged patients with hepatocellular carcinoma (HCC). METHODS AND MATERIALS: Twenty-one patients aged > or =80 years with HCC underwent proton beam therapy. At the time of irradiation, patient age ranged from 80 to 85 years (median, 81 years). Hepatic tumors were solitary in 17 patients and multiple in 4. Tumor size ranged from 10 to 135 mm (median, 40 mm) in maximum diameter. Ten, 5, and 6 patients received proton beam irradiation with total doses of 60 Gy in 10 fractions, 66 Gy in 22 fractions, and 70 Gy in 35 fractions, respectively, according to tumor location. RESULTS: All irradiated tumors were controlled during the follow-up period of 6-49 months (median, 16 months). Five patients showed new hepatic tumors outside the irradiated volume, 2-13 months after treatment, and 1 of them also had lung metastasis. The local progression-free and disease-free rates were 100% and 72% at 3 years, respectively. Of 21 patients, 7 died 6-49 months after treatment; 2 patients each died of trauma and old age, and 1 patient each died of HCC, pneumonia, and arrhythmia. The 3-year overall, cause-specific, and disease-free survival rates were 62%, 88%, and 51%, respectively. No therapy-related toxicity of Grade > or = 3 but thrombocytopenia in 2 patients was observed. CONCLUSIONS: Proton beam therapy seems to be tolerable, effective, and safe for aged patients with HCC. It may contribute to prolonged survival due to tumor control.     

Proton beam therapy for hepatocellular carcinoma with limited treatment options

BACKGROUND: The authors conducted a retrospective review to define the usefulness of proton beam therapy for patients who had hepatocellular carcinoma (HCC) with limited treatment options. METHODS: Twenty-one patients with HCC for whom other treatment modalities either were contraindicative or were unfeasible because of coexisting diseases and unfavorable conditions received proton beam therapy. Four patients had renal failure, 2 patients had severe heart disease, 9 patients had severe cirrhosis, 1 patient had aplastic anemia, 1 patient had a dissecting abdominal aortic aneurysm before treatment, and 4 patients had bleeding tendency or unresectable tumors. Moreover, 2 of the latter 4 patients were allergic to iodine, and 2 other patients were unable to be catheterized for transcatheter arterial chemoembolization. Hepatic tumors were solitary in 14 patients and multiple in 7 patients, and the tumors ranged in greatest dimension from 25 mm to 100 mm (median, 40 mm). No patient had regional lymph node or distant metastasis. Total doses of 63 grays (Gy) to 84 Gy (median, 73 Gy) in 13 to 27 fractions (median, 18 fractions) were used for tumor treatments. RESULTS: All but 1 of the irradiated tumors were controlled at a median follow-up of 3.3 years. The objective response rate was 81%, and the primary site-control rate was 93% at 5 years. Eleven patients had intrahepatic recurrences, and 2 patients had distant metastases in the lungs. Four of 11 patients with intrahepatic recurrences received a second course of proton beam therapy, and all recurrent tumors were controlled. The overall and cause-specific survival rates were 62% and 82% at 2 years, respectively, and 33% and 67% at 5 years, respectively. Grade > or =3 therapy-related toxicities were not observed. CONCLUSIONS: Proton beam therapy was safe and effective for a variety of patients with HCC. The current results suggested that this method was tolerable and effective, even for patients with HCC who had limited treatment options.     

Proton therapy for hepatocellular carcinoma

Proton radiotherapy has seen an increasing role in the treatment of hepatocellular carcinoma(HCC).Historically,external beam radiotherapy has played a very limited role in HCC due to a high incidence of toxicity to surrounding normal structures.The ability to deliver a high dose of radiation to the tumor is a key factor in improving outcomes in HCC.Advances in photon radiotherapy have improved dose conformity and allowed dose escalation to the tumor.However,despite these advances there is still a large volume of normal liver that receives a considerable radiation dose during treatment.Proton beams do not have an exit dose along the beam path once they enter the body.The inherent physical attributes of proton radiotherapy offer a way to maximize tumor control via dose escalation while avoiding excessive radiation to the remaining liver,thus increasing biological effectiveness.In this review we discuss the physical attributes and rationale for proton radiotherapy in HCC.We also review recent literature regarding clinical outcomes of using proton radiotherapy for the treatment of HCC.     

Proton beam therapy for hepatocellular carcinoma with portal vein tumor thrombus

BACKGROUND: Treatment modalities for patients with hepatocellular carcinoma (HCC) who have portal vein tumor thrombus (PVTT) are limited and controversial; furthermore, the prognosis for these patients is extremely poor. The authors conducted a retrospective review to determine the role of proton beam therapy in the treatment of patients who had HCC with PVTT. METHODS: Twelve patients with HCC who had tumor thrombus in the main trunk or major branches of the portal vein (clinical T3-T4N0M0) were treated with proton beam therapy. At the time they received proton beam irradiation, patients ranged in age from 42 years to 80 years (median, 62 years), and their tumors ranged in size from 40 mm to 110 mm (median, 60 mm) in greatest dimension. A total dose of 50-72 gray (Gy) (median, 55 Gy) in 10-22 fractions was delivered to the tumors, including PVTT. RESULTS: All tumors that were treated with proton beam therapy remained controlled at a median follow-up of 2.3 years (range, 0.3-7.3 years). Among 12 patients, 10 patients had new liver tumors outside the irradiated volume 0.1-2.4 years after proton beam therapy, and 3 patients also had distant metastases; consequently, 8 patients died of disease, and 2 patients were salvaged by further therapies. The remaining two patients were alive with no evidence of disease 4.3 years and 6.4 years after proton beam therapy. The progression-free survival rates were 67% at 2 years and 24% at 5 years. The median progression-free survival was 2.3 years. According to the Acute Radiation Morbidity Scoring Criteria (Radiation Therapy Oncology Group), therapy-related toxicity > or = Grade 3 was not observed. CONCLUSIONS: Proton beam therapy for patients with HCC who had PVTT was feasible and effective. It appeared to improve survival and local control significantly for these patients.     

Proton beam therapy for hepatocellular carcinoma adjacent to the porta hepatis

PURPOSE: To evaluate the efficacy and safety of proton beam therapy (PBT) for patients with hepatocellular carcinoma (HCC) located adjacent to the porta hepatis. METHODS AND MATERIALS: Subjects of the study were 53 patients with HCC located within 2 cm of the main portal vein. All patients had tumor confined to the radiation field with no evidence of metastatic disease. All patients had hepatic function levels of a Child-Pugh score of 10 or less, Eastern Cooperative Oncology Group performance status of 2 or less, and no uncontrolled ascites. Patients underwent PBT of 72.6 GyE in 22 fractions from Sept 2001 to Dec 2004. RESULTS: After 3 years, the actuarial survival rate was 45.1% and local control rate was 86.0%. Prognostic factors for survival included Child-Pugh score, number of tumors, and alpha-fetoprotein levels. No late treatment-related toxicity of Grade 2 or higher was observed. CONCLUSIONS: The PBT delivering 72.6 GyE in 22 fractions appears to be effective and safe for HCC adjacent to the porta hepatis.     

Systemic therapy for advanced hepatocellular carcinoma: a review

Hepatocellular carcinoma (HCC) is a common cause of cancer mortality worldwide. Whilst local treatments are useful in selected patients, they are not suitable for many with advanced disease. Here, we review phase II and III trials for systemic therapy of advanced disease, finding no strong evidence that any chemotherapy, hormonal therapy, or immunotherapy regimen trialled to date benefits survival in this setting. Many trials were inadequately powered, single centre, and enrolled highly selected patients. From this review, we cannot recommend any therapeutic approach in these patients outside of a clinical trial setting. Including an untreated control arm in clinical trials in HCC is still justified. Every effort should be made to enroll these patients into adequately powered trials, and promising phase II results must be tested in a multicentre phase III setting, preferably against a placebo control arm. Prevention of hepatitis B and C remains vital to decrease deaths from HCC.     

Proton beam therapy for hepatocellular carcinoma with inferior vena cava tumor thrombus: report of three cases

Three patients with hepatocellular carcinoma (HCC) and inferior vena cava tumor thrombus (IVCTT) were treated using proton beam therapy at the University of Tsukuba, Japan. A total dose of 50-70 Gy in 10-35 fractions was given to the primary tumor and IVCTT. All the patients survived for more than 1 year from the beginning of proton beam therapy (13-55 months) and no treatment-related toxicity of grade 3 or higher was observed. These cases suggest that proton beam therapy is safe and effective for patients with HCC associated with IVCTT.     

Repeated proton beam therapy for hepatocellular carcinoma

PURPOSE: To retrospectively evaluate the safety and effectiveness of repeated proton beam therapy for newly developed or recurrent hepatocellular carcinoma (HCC). METHODS AND MATERIALS: From June 1989 through July 2000, 225 patients with HCC underwent their first course of proton beam therapy at the University of Tsukuba. Of them, 27 with 68 lesions who had undergone two or more courses were retrospectively reviewed in this study. Median interval between the first and second course was 24.5 months (range 3.3-79.8 months). Median total dose of 72 Gy in 16 fractions and 66 Gy in 16 fractions were given for the first course and the rest of the courses, respectively. RESULTS: The 5-year survival rate and median survival period from the beginning of the first course for the 27 patients were 55.6% and 62.2 months, respectively. Five-year local control rate for the 68 lesions was 87.8%. Of the patients, 1 with Child-Pugh class B and another with class C before the last course suffered from acute hepatic failure. CONCLUSIONS: Repeated proton beam therapy for HCC is safe when the patient has a target in the peripheral region of the liver and liver function is Child-Pugh class A.     

Proton beam therapy for locally advanced lung cancer: A review

Protons interact with human tissue differently than do photons and these differences can be exploited in an attempt to improve the care of lung cancer patients. This review examines proton beam therapy (PBT) as a component of a combined modality program for locally advanced lung cancers. It was specifically written for the non-radiation oncologist who desires greater understanding of this newer treatment modality. This review describes and compares photon (X-ray) radiotherapy (XRT) to PBT. The physical differences of these beams are described and the clinical literature is reviewed. Protons can be used to create treatment plans delivering significantly lower doses of radiation to the adjacent organs at risk (lungs, esophagus, and bone marrow) than photons. Clinically, PBT combined with chemotherapy has resulted in low rates of toxicity compared to XRT. Early results suggest a possible improvement in survival. The clinical results of proton therapy in lung cancer patients reveal relatively low rates of toxicity and possible survival benefits. One randomized study is being performed and another is planned to clarify the clinical differences in patient outcome for PBT compared to XRT. Along with the development of better systemic therapy, newer forms of radiotherapy such as PBT should positively impact the care of lung cancer patients. This review provides the reader with the current status of this new technology in treating locally advanced lung cancer.     

Proton beam radiotherapy versus transarterial chemoembolization for hepatocellular carcinoma: Results of a randomized clinical trial

Background

This study compares survival rates, recurrence patterns, toxicity, and treatment cost in patients with hepatocellular carcinoma (HCC) treated with either transarterial chemoembolization (TACE) or proton beam radiotherapy (PBT).

Methods

Subjects with untreated HCC meeting Milan or San Francisco transplant criteria were recruited. Subjects were randomized to receive PBT (n = 36) or TACE (n = 40). Proton therapy was administered in 15 fractions over 3 weeks to a total dose of 70.2 Gy. TACE was repeated until complete or maximal response. The primary outcome measure was overall survival (OS). Secondary end points were progression-free survival (PFS), local control (LC), toxicity, and cost.

Results

Of the 76 randomized patients, 74 were assessed for outcome measures. The 2-year OS for PBT versus TACE was similar at 68%, 95% confidence interval (CI), 0.54–0.86, and 65%, 95% CI, 0.52–0.83 (p = .80), however, median PFS was improved for PBT versus TACE (not reached vs. 12 months, p = .002). LC was improved with PBT versus TACE (hazard ratio, 5.64; 95% CI, 1.78–17.9, p = .003). Days of posttreatment hospitalization were 24 for PBT and 166 for TACE (p < .001). Total mean cost per patient for treatment and posttreatment care revealed a 28% cost savings for PBT.

Conclusions

PBT and TACE yielded similar OS for treatment of HCC, but PFS and LC were improved with PBT compared to TACE. Patients treated with PBT required fewer courses of treatment, fewer posttreatment hospitalization days, and reduced cost of treatment compared to TACE. These data support the use of PBT as a viable treatment alternative to TACE for patients with HCC within transplant criteria.     

Multimodality treatment for patients with hepatocellular carcinoma: a single institution retrospective series.

BACKGROUND: The main therapeutic options for hepatocellular carcinoma (HCC) are hepatic resection, transcatheter arterial embolization (TAE), percutaneous ethanol injection therapy (PEIT) and regional chemotherapy (RC). METHODS: This study retrospectively examined the results of primary treatment of 600 patients with hepatocellular carcinoma selected according to the treatment guidelines of our facility and the results of various combination therapies for recurrent cases. The selection criteria of therapeutic options included the number and size of tumours and hepatic function. RESULTS: The selected primary treatment was hepatic resection for 53.7% of the cases, TAE for 31.5%, PEIT for 8.2% and RC for 6.6%,. The treatment for post-resection recurrence was TAE alone for 62.4% of the cases, TAE + RC for 4.0%, PEIT for 15.2%, TAE + PEIT alone for 4.8%, RC for 8.0% and hepatic resection for 5.6%. The treatment for post-TAE recurrence was TAE alone for 83% of the cases, TAE + PEIT for 9%, TAE + RC for 3%, RC alone for 3% and PEIT alone for 2%. For post-PEIT, therapy was PEIT alone for 71.4% of the cases and PEIT + TAE for 28.6%. For post-RC, RC alone was used for 92.5% and RC + PEIT for 7.5%. The cumulative 3 and 5-year survival rates were 84.4% and 70.6%, respectively for stage I; 61.5% and 48.6% for stage II; 52.7% and 20.5% for stage III; and 22.8% and 17.1% for stage IVA. The cumulative 5 and 7-year survival rates after the primary treatments were 52.% and 40.1%, respectively, for hepatic resection; 46.5% and 38.7%, for TAE; 49.6% and 33.1% for PEIT; and 16.7% and 8.3% for RC. CONCLUSIONS: To improve the treatment results for HCC, early detection is essential and various modalities of treatments in combination should be used for recurrence after primary treatment.     

Proton beam therapy for inoperable recurrence of bronchial high-grade mucoepidermoid carcinoma

We report the case of a 17-year-old patient who received four courses of proton beam therapy for inoperable recurrent high-grade bronchial mucoepidermoid carcinoma of the chest wall and lymph nodes. The equivalent doses in conventional fractionation of 79.2-80.6 Gy were applied to the tumor from the first to third courses of proton beam therapy; the hemi-chest wall was also irradiated prophylactically in the third course. The irradiated tumor recurred marginally and liver metastasis developed, but tumor size within the irradiated field was suppressed. Proton beam therapy was also applied to the marginally recurrent tumor in the fourth course. The patient died of cancer about 5 years after the first course of proton beam therapy-about 9 years after the initial diagnosis and surgery. Repeated irradiation of the mediastinum and chest wall with photon radiotherapy is often limited by side-effects in the heart, esophagus and spinal cord. However, no severe late complications in critical organs were detected in this case. Only a Grade 2 skin reaction and lymphatic edema were observed. Therefore, high-dose proton beam therapy may be an option as a salvage therapy with less toxicity to normal tissues compared with photon radiotherapy and provide an alternative to repeated surgery.     

回顾性分析162例T4期胃癌术后结果

Objective  

There is controversy about the best therapeutic surgical approach for treatment of patients with T4 gastric cancer. We evaluated the survival benefit of resection in this group of patients.     

Survival rate in patients with hepatocellular carcinoma: a retrospective analysis of 389 patients

Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide. However, treatment options are limited and often inefficient. The aim of this study was to determine current survival rates for patients diagnosed with HCC and to identify prognostic factors, which will help in choosing optimal therapies for individual patients. A retrospective analysis of medical records was performed on 389 patients who were identified through the central tumour registry at our institution from 1998 to 2003. Clinical parameters, treatments received and survival curves from time of diagnosis were analysed. Overall median survival was 11 months. Liver cirrhosis was diagnosed in 80.5% of all patients. A total of 170 patients received transarterial chemoembolisation (TACE) and/or percutaneous ethanol injections (PEI) with a median survival rate of 16 months for patients receiving TACE, 11 months for patients receiving PEI and 24 months for patients receiving TACE followed by PEI. Independent negative prognostic parameters for survival were the presence of portal vein thrombosis, advanced liver cirrhosis (Child-Pugh score B or C) and a score of >2. This study will help to estimate survival rates for patients with HCC according to their clinical status at diagnosis and the treatments received.     

Proton beam therapy in rectal cancer: A systematic review and meta-analysis

IntroductionLocally advanced rectal cancer is often treated with neoadjuvant chemoradiotherapy and surgery. Radiotherapy carries significant risk of toxicity to organs at risk (OAR). Proton beam therapy (PBT) has demonstrated to be effective in other cancers, delivering equivalent dosimetric radiation but with the benefit of improved sparing of OAR. This review compares dosimetric irradiation of OAR and oncological outcomes for PBT versus conventional photon-based radiotherapy in locally advanced rectal cancer.MethodsAn electronic literature search was performed for studies with comparative cohorts receiving proton beam therapy and photon-based radiotherapy for rectal cancer.ResultsEight articles with a total of 127 patients met the inclusion criteria. There was significantly less irradiated small bowel with PBT compared to three-dimensional conformal radiation therapy (3DCRT) and intensity-modulated radiation therapy (IMRT) (MD -17.01, CI [-24.06, −9.96], p < 0.00001 and MD -6.96, CI [-12.99, −0.94], p = 0.02, respectively). Similar dosimetric results were observed for bladder and pelvic bone marrow. Three studies reported clinical and oncological results for PBT in recurrent rectal cancer with overall survival reported as 43 %, 68 % and 77.2 %, and one study in primary rectal cancer with 100 % disease free survival.ConclusionPBT treatment plans revealed significantly less irradiation of OAR for rectal cancer compared to conventional photon-based radiotherapy. Trials for recurrent rectal cancer and PBT have shown promising results. There are currently no ongoing clinical trials for primary rectal cancer and PBT. More research is required to validate its potential role in dose escalation, higher complete response rate and organ preservation without increasing toxicity.