Role of radiotherapy in the management of hepatocellular carcinoma:A systematic review

Many patients with hepatocellular carcinoma(HCC) present with advanced disease,not amenable to curative therapies such as surgery,transplantation or radiofrequency ablation. Treatment options for this group of patients include transarterial chemoembolization(TACE) and radiation therapy. Especially TACE,delivering a highly concentrated dose of chemotherapy to tumor cells while minimizing systemic toxicity of chemotherapy,has given favorable results on local control and survival. Radiotherapy,as a therapeutic modality of internal radiation therapy with radioisotopes,has also achieved efficacious tumor control in advanced disease. On the contrary,the role of external beam radiotherapy for HCC has been limited in the past,due to the low tolerance of surrounding normal liver parenchyma. However,technological innovations in the field of radiotherapy treatment planning and delivery,have provided the means of delivering radical doses to the tumor,while sparing normal tissues. Advanced and highly conformal radiotherapy approaches such as stereotactic body radiotherapy and proton therapy,evaluated for efficacy and safety for HCC,report encouraging results. In this review,we present the role of radiotherapy in hepatocellular carcinoma patients not suitable for radical treatment.     

Potentiality of immunotherapy against hepatocellular carcinoma

Hepatocellular carcinoma(HCC),the predominant form of primary liver cancer,is the fifth most common cancer worldwide and the second leading cause of cancer-related death. Despite the high incidence,treatment options remain limited for advanced HCC,and as a result prognosis continues to be poor. Current therapeutic options,surgery,chemotherapy and radiotherapy,have only modest efficacy. New treatment modalities to prolong survival and to minimize the risk of adverse response are desperately needed for patients with advanced HCC. Tumor immunotherapy is a promising,novel treatment strategy that may lead to improvements in both treatment-associated toxicity and outcome. The strategies have developed in part through genomic studies that have yielded candidate target molecules and in part through basic biology studies that have defined the pathways and cell types regulating immune response. Here,we summarize the various types of HCC immunotherapy and argue that the newfound field of HCC immunotherapy might provide critical advantages in the effort to improve prognosis of patients with advanced HCC. Already several immunotherapies,such as tumor-associated antigen therapy,immune checkpoint inhibitors and cell transfer immunotherapy,have demonstrated safety and feasibility in HCC patients. Unfortunately,immunotherapy currently has low efficacy in advanced stage HCC patients; overcoming this chal lenge will place immunotherapy at the forefront of HCC treatment,possibly in the near future.     

Role of modern radiotherapy in managing patients with hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer. Several treatment options are available for managing HCC patients, classified roughly as local, local-regional, and systemic therapies. The high post-monotherapy recurrence rate of HCC urges the need for the use of combined modalities to increase tumor control and patient survival. Different international guidelines offer treatment recommendations based on different points of view and classification systems. Radiotherapy (RT) is a well-known local-regional treatment modality for managing many types of cancers, including HCC. However, only some of these treatment guidelines include RT, and the role of combined modalities is rarely mentioned. Hence, the present study reviewed clinical evidence for the use of different combined modalities in managing HCC, focusing on modern RT's role. Modern RT has an increased utility in managing HCC patients, mainly due to two driving forces. First, technological advancement (e.g., stereotactic body radiotherapy and advanced proton-beam therapy) enables precise delivery of radiation to increase tumor control and reduce side effects in the surrounding normal tissue. Second, the boom in developing target therapies and checkpoint-blockade immunotherapy prolongs overall survival in HCC patients, re-emphasizing the importance of local tumor control. Remarkably, RT combines with systemic therapies to generate the systemic therapy augmented by radiotherapy effect, a benefit now being actively investigated.     

Progress in the treatment of pulmonary metastases after liver transplantation for hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the fifth most common cancer in the world, and is the third leading cause of cancer-related death. Liver transplantation (LT) has become a curative treatment for patients with HCC. However, recurrence and metastasis after LT are the main factors reducing long-term survival in patients, and the lung is the most common site of metastasis after LT for HCC, although metastasis to liver, para-aortic lymph nodes and renal periphery are observed. Thus, the treatment of pulmonary metastases after LT for HCC has become a hot research topic, the successful treatment of pulmonary metastases can significantly prolong the survival of LT patients. Although single conventional treatment (chemotherapy, surgery and external beam radiation therapy), immunosuppression, image-guided minimally invasive therapy (radiofrequency ablation, microwave ablation, cryoablation, and brachytherapy) and molecular targeted drugs have had a significant effect, patients do not have durable remission and the long-term survival rate is disappointing. Therefore, improving existing treatments and identifying a more effective combination therapy are important research issues in the prevention and treatment of pulmonary metastases after LT for HCC. The paper reviewed single conventional treatments, new treatments, and combination therapy, to provide a basis for the best treatment of these patients.     

Indications of external radiotherapy for hepatocellular carcinoma from updated clinical guidelines: Diverse global viewpoints

significantly vary among regions.Modern standard treatments commonly require multidisciplinary approaches,including applications of up-to date medicine and advanced procedures,and necessitate the support of socioeconomic systems.For these reasons,a number of clinical guidelines for HCC from different associations and regions have been presented.External beam radiation therapy was contraindicated for HCC until a few decades ago,but with the development of new technologies,its application has rapidly increased as selective irradiation for tumorous lesions became possible.Most of the guidelines had been opposed or indifferent to radiotherapy in the past,but several guidelines have introduced indications and recommendations for radiotherapy in their updated versions.This review will discuss the characteristics of important guidelines and their contents regarding radiotherapy and will also provide guidance to physicians who are considering applications of locoregional modalities that include radiotherapy.     

肝细胞癌细胞免疫治疗的研究进展

肝细胞癌(HCC)的治疗目前主要采用以手术为主、配合局部放疗和化疗的综合治疗措施,但多数患者经综合治疗后也容易复发,缺乏有效的治疗药物和手段,总体治疗效果并不理想。越来越多的证据表明,肝癌的发生、发展、转移和复发与机体免疫系统有密切的关系。因此,免疫治疗特别是细胞免疫治疗可以调节机体免疫功能,诱导特异性肿瘤免疫,达到治疗肝癌、减少肝癌复发和转移的目的,已成为肝癌综合治疗的重要组成部分。对细胞免疫治疗在HCC中的临床前研究和临床试验取得的成果进行综述,并讨论当前存在的问题。     

Intraoperative radiotherapy and bypass surgery for unresectable pancreatic cancer

BACKGROUND/AIMS: Conflicting results have been reported concerning the usefulness of radiotherapy for unresectable pancreatic cancer. We evaluated the clinical efficacy of intraoperative radiotherapy and/or external beam radiotherapy in combination with bypass surgery. METHODOLOGY: Twenty-six patients with unresectable pancreatic cancer (16 in Stage II-III and 10 in Stage IV) were treated with intraoperative radiotherapy plus external beam radiotherapy (16 patients) or intraoperative radiotherapy alone (10 patients). The dose of intraoperative radiotherapy was either 25 or 30 Gy and the external beam radiotherapy dose was 31-60 Gy. The feasibility and clinical outcome were analyzed. RESULTS: The median survival time for Stage II-III and Stage IV were 11.5 and 6.5 months, respectively. The difference between Stage II-III and Stage IV in survival patterns was statistically significant (P < 0.05). For Stage II-III patients, the survival curves between the groups of intraoperative radiotherapy plus external beam radiotherapy and intraoperative radiotherapy alone were not significantly different, and only performance status was a significant factor in the prognosis (P < 0.05). Gastrointestinal bleeding was noted in 8%, but did not occur in the patients treated with an external beam radiotherapy dose less than 50 Gy. Palliative radiation was successfully performed to relieve pain, jaundice and appetite-loss and to shorten the hospital stay. CONCLUSIONS: The combination therapy with intraoperative radiotherapy and bypass surgery is considered to be tolerable and effective for unresectable pancreatic cancer, and also may improve the quality of life of the patients.     

质子刀放射治疗肝细胞癌的研究进展

随着对正常组织耐受能力的研究的不断深入和放疗技术的发展,针对大部分肝细胞癌（HCC）患者伴有的肝硬化,肿瘤体积大、多发且伴有血管浸润,甚至出现门静脉癌栓等现状,放射治疗便成为HCC降级治疗及辅助治疗的重要手段。其中质子刀（PBT）作为一种较新型的放疗方法取得了较为显著的临床效果。介绍了PBT治疗HCC的生物学特性及其临床疗效和毒性副作用。前期的研究结果表明PBT对于局部照射剂量具有良好的控制作用,可降低对健康肝细胞及周围正常组织的毒性。但目前的临床研究显示PBT应用于HCC也存在着一些禁忌证,值得进一步界定。     

Radiotherapy for hepatocellular carcinoma: Systematic review of radiobiology and modeling projections indicate reconsideration of its use

Background and Aims: External beam radiotherapy currently has a limited role in the treatment of hepatocellular carcinoma (HCC). The purpose of this article was to review available radiobiological data on HCC and normal liver and incorporate these data into radiobiological models that may be used to explain and improve treatment. Methods: Volume doubling times of HCC were described and used to demonstrate growth of HCC with time, assuming both exponential and logistic growth. Radiosensitivity of HCC was described and used to demonstrate the probability of uncomplicated tumor control as tumor size increases. The relationship between tolerance of liver to irradiation and volume irradiated was examined. Results: The median volume doubling time for untreated HCC was 130 days. HCC have a long period of subclinical growth. Radiosensitivity of HCC lies within the range of other tumors commonly treated with radiotherapy. When treating small volumes of normal liver, relatively high doses may be used with low risk of late radiation damage. There is a high probability of sterilizing subclinical disease and small HCC with tolerable radiation doses. Conclusion: New radiobiological data, modeling, emerging clinical data and the advantages offered by standard external beam radiotherapy techniques suggest the need for reconsidering the use of radiotherapy and for new trials.     

Clinical outcome and toxicity of radiotherapy for inferior vena cava tumor thrombus in HCC patients: A retrospective study

Hepatocellular carcinoma (HCC) involving the inferior vena cava rarely occurs, but its prognosis is extremely poor, with no established treatment to date. This study aimed to analyze the clinical outcome and toxicity of radiotherapy (RT) targeting inferior vena cava tumor thrombus (IVCTT) in HCC patients.From November 2011 to July 2020, medical record of 19 HCC patients who were treated with RT for IVCTT was retrospectively reviewed. RT was delivered using 3-dimensional conformal radiation therapy, intensity-modulated radiation therapy, and stereotactic body radiation therapy. The median radiation dose was 50 Gy (range, 45–55.8 Gy) for intensity-modulated radiation therapy and three-dimensional conformal radiotherapy. Stereotactic body radiation therapy was performed in 5 patients, for a total of 32 Gy in 4 fractions.The median follow-up duration was 8.1 months (range, 3.3–26.5 months). The median overall survival was 9.4 months (range, 3.7–26.5 months), and the 1-year overall survival rate was 37.1%. Eight of 19 patients (42.1%) had extrahepatic metastasis at the start of RT. Six of 11 patients (54.5%) who did not have extrahepatic metastasis at the start of RT showed extrahepatic metastasis after RT. The major cause of death was progression of extrahepatic metastasis (11 patients, 57.9%). The overall response rate of IVCTT for RT was 84.2%, and the local control rate at the time of the last follow-up was 89.4%. After RT, the most common first progression site was the lungs (9 patients, 47.4%). Most toxicities were grade 1 to 2 gastrointestinal (26.3%) and liver enzyme elevation (68.4%). Three patients occurred pulmonary embolism after RT later than 5 months after.RT is a feasible and safe local therapy for IVCTT, with favorable tumor control and acceptable toxicity. Extrahepatic metastasis is the major progression pattern and a leading cause of death in patients treated with RT. The combination of effective systemic therapy with RT may have to be considered.     

Technical advances in external radiotherapy for hepatocellular carcinoma

Radiotherapy techniques have substantially improved in the last two decades. After the introduction of 3-dimensional conformal radiotherapy, radiotherapy has been increasingly used for the treatment of hepatocellular carcinoma(HCC). Currently, more advanced techniques, including intensity-modulated radiotherapy(IMRT), stereotactic ablative body radiotherapy(SABR), and charged particle therapy, are used for the treatment of HCC. IMRT can escalate the tumor dose while sparing the normal tissue even though the tumor is large or located near critical organs. SABR can deliver a very high radiation dose to small HCCs in a few fractions, leading to high local control rates of 84%-100%. Various advanced imaging modalities are used for radiotherapy planning and delivery to improve the precision of radiotherapy. These advanced techniques enable the delivery of high dose radiotherapy for early to advanced HCCs without increasing the radiation-induced toxicities. However, as there have been no effective tools for the prediction of the response to radiotherapy or recurrences within or outside the radiation field, future studies should focus on selecting the patients who will benefit from radiotherapy.     

The effectiveness of particle radiotherapy for hepatocellular carcinoma associated with inferior vena cava tumor thrombus

Background

The prognosis of patients who have hepatocellular carcinoma (HCC) associated with inferior vena cava tumor thrombus (IVCTT) is very poor, and effective treatment modalities are extremely limited. The objective of this study was to determine the therapeutic efficacy of particle radiotherapy for HCC with IVCTT.

Methods

Between June 2001 and January 2009, 16 evaluable patients who had HCC with IVCTT were treated with particle radiotherapy. They were divided into 2 groups: 6 were treated with curative intent; 10 with palliative intent. The local tumor control rates, overall survival rates, and toxicities were evaluated.

Results

All tumors treated with particle radiotherapy remained controlled without local recurrence at the last follow-up. The overall survival rates for the 16 patients at 1 and 3?years were 61.1 and 36.7%, respectively. We observed a significant difference in the survival rates according to treatment policy. The median survival time was 25.4?months for patients treated with curative intent and 7.7?months for those treated with palliative intent. The one-year survival rates were 100.0 and 33.3%, respectively. No Grade 3 or higher treatment-related toxicities were observed.

Conclusions

Particle radiotherapy is thought to be potentially effective and safe for HCC with IVCTT. Considering the current lack of effective and less-invasive local therapy for HCC with IVCTT, particle radiotherapy may therefore be an attractive new therapeutic approach for this type of HCC.     

细胞免疫治疗原发性肝癌的现状及展望

原发性肝癌患者病程进展快,多数病人确诊时已难以手术切除,且肝癌对放疗、化疗不敏感,因此其总体治疗效果不理想。目前,在肝癌生物治疗的基础及临床研究中,细胞生物治疗已经显示出了潜在的疗效及良好的发展前景。     

Unresectable stage III non-small-cell lung cancer: Have we made any progress?

Lung cancer is responsible for the most cancer deaths worldwide with an incidence that is still rising. One third of patients have unresectable stage IIIA or stage IIIB disease. The standard of care for locally advanced disease in patients with good performance status consists of combined modality therapy in particular concurrent chemoradiotherapy. But despite a lot of efforts done in the past, local control and survival of patients with unresectable stage III non-small-cell lung cancer (NSCLC) remains poor. Improving outcomes for patients with unresectable stage III NSCLC has therefore been an area of ongoing research. Research has focused on improving systemic therapy, improving radiation therapy or adding a maintenance therapy to consolidate the initial therapy. Also implementation of newer targeted therapies and immunotherapy has been investigated as well as the option of prophylactic cranial irradiation. This article reviews the latest literature on improving local control and preventing distant metastases. It seems that we have reached a plateau with conventional chemotherapy. Radiotherapy dose escalation did not improve outcome although increasing radiation dose-intensity with new radiotherapy techniques and the use of newer agents, e.g., immunotherapy might be promising. In the future well-designed clinical trials are necessary to prove those promising results.     

A meta-analysis of adjuvant therapy after potentially curative treatment for hepatocellular carcinoma

BACKGROUND:

The high recurrence rate of hepatocellular carcinoma (HCC) after potentially curative treatment determines the long-term prognosis.

OBJECTIVE:

To evaluate the efficacy and safety of adjuvant therapies in patients with HCC who have undergone hepatic resection, transplantation or locoregional ablation therapy.

METHODS:

Several databases were searched to identify randomized controlled trials (RCTs) fulfilling the predefined selection criteria. Meta-analyses were performed to estimate the effects of adjuvant therapies of any modality on recurrence-free survival (RFS) and overall survival (OS).

RESULTS:

Eight adjuvant modalities were identified from 27 eligible RCTs conducted predominantly in Asian populations comparing adjuvant with no adjuvant therapy. Adjuvant chemotherapy, internal radiation and heparanase inhibitor PI-88 therapy failed to improve RFS or OS, while interferon (IFN) therapy yielded significant survival results. The findings of adjuvant vitamin analogue therapy required further examination. Adjuvant adoptive immunotherapy conferred significant benefit for RFS but not for OS. Although cancer vaccine therapy and radioimmunotherapy may improve survival after radical surgery, the results were from single, small-scale trials. Severe side effects were observed in the studies of adjuvant chemotherapy and of IFN therapy.

CONCLUSIONS:

Adjuvant IFN therapy can improve both RFS and OS; however, the benefits of using this agent should be weighed against its side effects. Combination of systemic and transhepatic arterial chemotherapy is not recommended for HCC after potentially curative treatment. Other adjuvant therapies produce limited success for survival. Additional RCTs with proper design are required to establish the role of adjuvant therapies for HCC.     

Proton therapy for hepatocellular carcinoma:Current knowledges and future perspectives

Hepatocellular carcinoma(HCC) is the second leading cause of cancer-related death, as few patients can be treated with currently available curative local modalities. In patients with HCC where curative modalities are not feasible, radiation therapy(RT) has emerged as an alternative or combination therapy. With the development of various technologies, RT has been increasingly used for the management of HCC. Among these advances, proton beam therapy(PBT) has several unique physical properties that give it a finite range in a distal direction, and thus no exit dose along the beam path. Therefore, PBT has dosimetric advantages compared with X-ray therapy for the treatment of HCC. Indeed, various reports in the literature have described the favorable clinical outcomes and improved safety of PBT for HCC patients compared with X-ray therapy. However, there are some technical issues regarding the use of PBT in HCC, including uncertainty of organ motion and inaccuracy during calculation of tissue density and beam range, all of which may reduce the robustness of a PBT treatment plan. In this review, we discuss the physical properties, current clinical data, technical issues, and future perspectives on PBT for the treatment of HCC.     

Combination of immunotherapy and radiotherapy in the treatment of brain metastases from non-small cell lung cancer

It was commonly assumed in the past that blood-brain barrier could efficiently prohibit penetration of large peptide molecules, such as monoclonal antibodies, including programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors. This belief has been recently revised by studies that demonstrate the presence of functional lymphatic vessels lining the dural sinuses. Furthermore, the activated circulating T cells have been shown to cross the blood-brain barrier. Such observations created strong rationale for attempts of immunotherapy for patients with brain metastases, used either alone or in combination with radiotherapy. The expected benefit from immunotherapy particularly refers to patients without targetable “driver” mutations who are not considered as candidates for novel targeted therapies. Current inference on efficacy and safety of combination of immunotherapy and radiotherapy in the treatment of brain metastases from non-small cell lung cancer (NSCLC) origins, in most, from the retrospective studies. The existing data suggest that use of immune checkpoint inhibitors (ICIs) with brain radiotherapy improves patients outcome, compared to brain radiotherapy alone. The available data also suggest that concurrent use of ICI and stereotactic radiation therapy (SRT) for brain metastases from NSCLC is tolerable and appears more effective than sequential combination of radiotherapy and ICI. Use of steroids appeared detrimental. Since a dependence between the risk of adverse events and type of ICI therapy as well as tumor pathology was found, further studies are required to establish optimal dosage, selection of drugs and sequence of ICI and brain radiotherapy in patients with brain metastases from NSCLC.     

Will the collaboration of surgery and external radiotherapy open new avenues for hepatocellular carcinoma with portal vein thrombosis?

Portal invasion of hepatocellular carcinoma(HCC)occurs in 12.5%-40%of patients diagnosed with cancer and yields poor clinical outcomes.Since it is a common cause of inoperability,sorafenib was regarded as the standard treatment for HCC in the Barcelona Clinic of Liver Cancer guidelines.However,the median survival of the Asian population was only approximately 6 mo,and the tumor response rate was less than moderate(<5%).Various locoregional modalities were performed,including external beam radiotherapy(EBRT),transarterial chemoembolization,hepatic arterial infusion chemotherapy,and surgery,alone or in combination.Among them,EBRT is a noninvasive method and can safely treat tumors involving the major vessels.Palliative EBRT has been commonly performed,especially in East Asian countries,where locally invasive HCC is highly prevalent.Although surgery is not commonly indicated,pioneering studies have demonstrated encouraging results in recent decades.Furthermore,the combination of neo-or adjuvant EBRT and surgery has been recently used and has significantly improved the outcomes of HCC patients,as reported in a few randomized studies.Regarding systemic modality,a combination of novel immunotherapy and vascular endothelial growth factor inhibitor showed results superior to that of sorafenib as a first-line agent.Future clinical trials investigating the combined use of these novel agents,surgery,and EBRT are expected to improve the prognosis of HCC with portal invasion.     

Radiotherapy in the treatment of pancreatic cancer.

In the last two decades, we have witnessed revolutionary advances in pancreatic imaging as well as increased availability of megavoltage radiotherapy equipment and sophisticated radiotherapy planning devices. Several advances in the radiotherapy of pancreatic cancer have been made for the patient with resectable disease. Postoperative radiotherapy combined with chemotherapy confers a survival advantage after 'curative' resection. Preoperative and intraoperative intraoperative radiotherapy may do the same, but this requires further evaluation. Preoperative irradiation may improve the resectability rate, but the clinical data are still very limited. For locally unresectable disease, PHD radiotherapy with adjuvant 5-FU should now be the standard treatment in suitable cases with a median survival time of about one year. High LET radiation beams have failed to produce improved survival in two prospective randomized studies. Intraoperative radiotherapy is an effective means of pain control and enhances control of local disease, but has not been shown to improve survival rate significantly. Interstitial radiotherapy also improves local control, but it is associated with a high mortality rate and an even higher major complication rate. Wide-area radiation therapy and preoperative radiotherapy both seem to show promise in this group of patients. Patients with metastatic disease should be treated palliatively on an individual basis.     

The long-term efficacy of conservative surgery and radiotherapy in the control of pituitary adenomas

OBJECTIVES We assessed the long-term efficacy and toxicity of conservative surgery and radiotherapy in the control of pituitary adenomas. DESIGN Retrospective study of patients treated at the Royal Marsden Hospital. PATIENTS Four hundred and eleven patients with pituitary adenomas treated with conventional external beam radiotherapy at the Royal Marsden Hospital between 1962 and 1986. Two hundred and fifty-two patients had clinically non-functioning pituitary adenomas, 131 had hormone secreting tumours and in 28 patients the secretory status was not known. Three hundred and thirty-eight patients had surgical intervention of whom only 11 had complete tumour excision. All patients received conventional fractionated external beam radiotherapy to a dose of 45–50Gy in 25–30 fractions. MEASUREMENTS Actuarial progression free survival and overall survival and assessment of toxicity, particularly in terms of vision, requirement for hormone replacement therapy and incidence of second tumours. RESULTS The actuarial progression free survival was 94% at 10 years and 88% at 20 years for all patients and 97% at 10 years and 92% at 20 years for patients with clinically non-functioning adenomas. Only secretory status was an independent prognostic factor for disease control. The 10 and 20-year survivals for all patients were 77 and 58% respectively. When compared with the normal population the relative risk of death was 1 76 (P<0 001) and no prognostic factors for survival were identified. The morbidity of radiotherapy was low. Visual deterioration, assumed to be radiation induced, occurred in 1–5% of patients and the risk of second brain tumour was 1.9% at 20 years. Fifty per cent of patients received hormone replacement therapy by 19 years. CONCLUSION Conventional external beam radiotherapy as described here combined with conservative surgery is safe and effective in the control of pitutary adenomas. These results should form a baseline for comparison with new treatment strategies.