The role of radiotherapy in the treatment of liver metastases

Radiotherapy has historically played a minor role in the treatment of patients with unresectable liver metastases from colorectal cancer and other malignancies. This can be attributed chiefly to the low tolerance of the whole liver to radiation. High-precision radiotherapy planning techniques have allowed much higher doses of radiation to be delivered safely to focal liver metastases, while sparing most of the normal liver. When combined with hepatic arterial fluorodeoxyuridine, high-dose focal liver radiotherapy is associated with excellent response rates, local control, and survival in patients with unresectable liver metastases from colorectal cancer. Radiotherapy, with and without concurrent systemic chemotherapy, has also been used with encouraging outcomes for patients with liver metastases from colorectal cancer and other cancers. There appears to be a radiation dose response for liver metastases; tumors treated with doses of 70 Gy or greater are likelier to have durable local control. Advancements in tumor imaging, in radiotherapy techniques that will allow the safe delivery of higher doses of radiation, and in novel tumor radiation sensitizers and normal tissue radioprotectors should substantially improve the outcome of patients with unresectable liver metastases treated with radiotherapy.     

Clinical Results of the Combination of Radiation and Fluoropyrimidines in the Treatment of Intrahepatic Cancer

Radiation therapy has played a minor role in the conventional management of patients with unresectable primary hepatobiliary malignancies and liver metastases. This can be attributed to normal tissue toxicity, which has limited the dose of radiation that can be safely administered, and imaging limitations, which have prevented focal irradiation of involved regions. Trials of whole-liver irradiation with and without 5-fluorouracil (5-FU) or fluorodeoxyuridine (fur) suggest that the addition of fluoropyrimidines results in a slight increase in the median survival without an increase in radiation-induced liver disease (RILD). The development of three-dimensional radiotherapy techniques has now allowed high-dose focal irradiation to be safely delivered, which, when combined with hepatic arterial fur, produces a much higher rate of response and, in some cases, prolonged survival particularly for patients with primary hepatobiliary cancers. Further investigations into the optimal methods of combining the fluoropyrimidines and radiation to permit higher doses of both agents to be delivered as well as methods of protecting the normal liver are expected to yield significant improvement in the outcome of treatment for patients with intrahepatic malignancies.     

Escalated focal liver radiation and concurrent hepatic artery fluorodeoxyuridine for unresectable intrahepatic malignancies.

PURPOSE: To evaluate the response, time to progression, survival, and impact of radiation (RT) dose on survival in patients with intrahepatic malignancies treated on a phase I trial of escalated focal liver RT. PATIENTS AND METHODS: From April 1996 to January 1998, 43 patients with unresectable intrahepatic hepatobiliary cancer (HB; 27 patients) and colorectal liver metastases (LM; 16 patients) were treated with high-dose conformal RT. The median tumor size was 10 x 10 x 8 cm. The median RT dose was 58.5 Gy (range, 28.5 to 90 Gy), 1.5 Gy twice daily, with concurrent continuous-infusion hepatic arterial fluorodeoxyuridine (0.2 mg/kg/d) during the first 4 weeks of RT. RESULTS: The response rate in 25 assessable patients was 68% (16 partial and one complete response). With a median potential follow-up period of 26.5 months, the median times to progression for all tumors, LM, and HB were 6, 8, and 3 months, respectively. The median survival times of all patients, patients with LM, and patients with HB were 16, 18, and 11 months, respectively. On multivariate analyses, escalated RT dose was independently associated with improved progression-free and overall survival. The median survival of patients treated with 70 Gy or more has not yet been reached (16.4+ months), compared with 11.6 months in patients treated with lower RT doses (P =.0003). CONCLUSION: The excellent response rate, prolonged intrahepatic control, and improved survival in patients treated with RT doses of 70 Gy or more motivate continuation of dose-escalation studies for patients with intrahepatic malignancies.     

Long-term follow-up of patients of intrahepatic malignancies treated with iodine-125 brachytherapy

PURPOSE: We investigated the role of intraoperative iodine-125 (125I) brachytherapy as a treatment option for unresectable primary and metastatic liver tumors. METHODS AND MATERIALS: Between 1989 and 2002, 64 patients with unresectable or residual disease after surgical resection for intrahepatic malignancies underwent 160-Gy permanent 125I brachytherapy. RESULTS: The median length of follow-up was 13.2 years. The overall 1-year, 3-year, and 5-year actuarial intrahepatic local control rates were 44%, 22%, and 22%, respectively, with a median time to liver recurrence of 9 months (95% CI, 6-12 months). The 5-year actuarial intrahepatic control was higher for patients with solitary metastasis (38%) than for those with multiple metastases (6%, p = 0.04). The 1-year, 3-year, and 5-year actuarial overall survival rates were 73%, 23%, and 5%, respectively (median, 20 months; 95% CI, 16-24; longest survival, 7.5 years). Overall survival was higher for patients with smaller-volume implants (p = 0.003) and for patients without prior liver resection (p = 0.002). No mortality occurred. Radiation-related complications were minimal. CONCLUSIONS: For select patients with unresectable primary and metastatic liver tumors for whom curative surgical resection is not an option, 125I brachytherapy is a safe and effective alternative to other locally ablative techniques and can provide long-term local control and increased survival.     

Phase II trial of high-dose conformal radiation therapy with concurrent hepatic artery floxuridine for unresectable intrahepatic malignancies.

PURPOSE: A phase II trial was conducted to determine if high-dose radiation with concurrent hepatic arterial floxuridine would improve survival in patients with unresectable intrahepatic malignancies. PATIENTS AND METHODS: Three-dimensional conformal high-dose radiation therapy was delivered concurrently with hepatic arterial floxuridine in 128 patients. The radiation dose was based on a normal-tissue complication probability model and subjected the patient to an estimated maximum risk of radiation-induced liver disease of 10% to 15%. The study design provided more than 80% power to detect a two-fold increase in median survival compared with historical controls at a 5% significance level. RESULTS: The median radiation dose delivered was 60.75 Gy (1.5-Gy fractions bid). At a median follow-up time of 16 months (26 months in patients who were alive) the median survival was 15.8 months (95% CI, 12.6 to 18.3 months), significantly longer than in the historical control. The actuarial 3-year survival was 17%. The total dose was the only significant predictor of survival. Primary hepatobiliary tumors had a significantly greater tendency to remain confined to the liver than did colorectal cancer metastases. Overall toxicity was acceptable, with 27 patients (21%) and 11 patients (9%) developing grade 3 and 4 toxicity, respectively, and one treatment-related death. CONCLUSION: The results suggest that, compared with historical controls, high-dose focal liver irradiation with hepatic artery floxuridine prolongs survival in patients with unresectable chemotherapy-refractory metastatic colorectal cancer and primary hepatobiliary tumors. This provides a rationale for intensification of local therapy for unresectable hepatobiliary cancers and integration of this regimen with newer systemic therapy for patients with colorectal cancer.     

Radiotherapy of liver malignancies. From whole liver irradiation to stereotactic hypofractionated radiotherapy

AIMS AND BACKGROUND: Until recently radiotherapy of hepatic malignancies has played a limited role due to the well-known limited radiotolerance of the liver. The aim of this paper is to review the available data on the risk of radiation-induced liver disease (RILD) and to define the modern role of radiotherapy in the management of patients with metastatic or primary liver malignancies. METHODS: The advent of three-dimensional conformal treatment planning with dose-volume histogram analysis has made the study of partial liver irradiation possible. Limited portions of the liver may withstand high doses of radiation with minimal risk of RILD. Patients with solitary unresectable liver tumors may be treated with high-dose radiotherapy with curative intent. Recently, the feasibility of stereotactically guided treatment techniques with a single fraction or few treatment sessions has been explored in numerous institutions. RESULTS: The radiation tolerance of the whole liver found by several investigations is in the order of approximately 30 Gy, which seriously restricts its clinical application. The role of whole liver irradiation therefore appears of limited benefit in the palliation of patients with multiple liver metastases. The use of three-dimensional conformal techniques has made partial liver irradiation possible to doses in the 70-80 Gy range with conventional fractionation. At least two published series have reported improved local control and survival rates with dose escalation with three-dimensional conformal radiotherapy in patients with unresectable liver metastases. Similar outcomes have been recently reported with single dose (or hypofractionated) stereotactic radiotherapy both in metastatic and primary hepatic malignancies with minimal morbidity. Accurate target delineation and treatment reproducibility are the key to the success of this novel treatment approach, and specific treatment planning techniques and patient setup procedures must be developed to implement it. CONCLUSIONS: Stereotactic high-dose radiotherapy is technically feasible for the treatment of inoperable liver malignancies, with the potential of high local control and low morbidity. Definitive evidence on the clinical advantages of this technique over other more established treatments can only be gathered from well-designed clinical studies.     

Radiation therapy for hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide, and its incidence is on the rise. The primary therapy is resection or liver transplant, but only a minority of patients present with resectable disease. Historically, radiotherapy has not played a significant role in the treatment of liver malignancies because of the low tolerance of the whole liver to radiation. With improvements in 3-dimensional conformal radiotherapy and intensity-modulated radiotherapy, higher doses of radiation can be delivered to target lesions with low doses to the noninvolved liver; thus, experience in the use of radiation for the treatment of focal HCC has increased. At the same time, our understanding of the relationships between radiation dose and volume and the risk of classic radiation-induced liver disease and other toxicities more likely to occur in HCC patients has improved considerably. These developments have led to a body of evidence that now supports the careful use of radiotherapy for unresectable HCC. The rationale for studying radiotherapy in a randomized trial is strong.     

Radiation therapy for intrahepatic malignancies

Historically, radiation was not used in the management of hepatocellular carcinoma and liver metastasis because of the low tolerance of the liver to radiation. More recently, improvements in radiation delivery using advanced techniques, such as 3D conformal radiation therapy, intensity-modulated radiation therapy, image-guided radiation therapy, stereotactic body radiation therapy, proton-beam therapy and internal radiation therapy, have enabled partial and selective irradiation of the liver with promising response rates and toxicity profiles. This review will discuss the different techniques of radiation that can now be used to treat intrahepatic malignancies and the important clinical studies in the medical literature.     

Pathologic response and microdosimetry of Y microspheres in man: Review of four explanted whole livers

INTRODUCTION: Radioactive microsphere (90)Y therapy is increasingly used for primary and metastatic solid tumors in the liver. We present an analysis of 4 explanted livers previously treated with (90)Y microsphere agents (glass or resin). One tumor nodule was analyzed with submillimeter three-dimensional microdosimetry. METHODS AND MATERIALS: Four patients received hepatic artery delivery of (90)Y microspheres for unresectable hepatocellular and colon cancers. Whole livers were explanted as part of lifesaving cadaveric transplant in 2 patients with hepatoma. These patients had received glass microspheres as a procedural bridge to transplant. Autopsy was performed on 2 patients with colon cancer who died of progressive metastatic disease and who had been treated with resin microspheres. Complete pathologic review was performed on each whole liver, including estimation of the response of the tumor to therapy, distribution of microspheres in the tumor and normal liver tissues, and normal-tissue radiation response. A biopsy taken from the edge of a tumor nodule was sectioned serially for three-dimensional radiation dosimetry analyses. Three-dimensional microsphere coordinates within the biopsy specimen were used to calculate dosage using a three-dimensional dose kernel. Isodose coverage of tumor and normal liver areas and total dose delivered were determined. RESULTS: Preferential and heterogeneous deposition of microspheres was noted at the edge of tumor nodules compared with the center portion of the tumor or normal liver parenchyma. Both glass and resin microspheres delivered high cumulative doses to the tumor, which varied from 100 Gy to more than 3000 Gy. No veno-occlusive disease or widespread radiation hepatitis was seen. CONCLUSION: Microsphere ((90)Y) therapy delivers high numbers of spheres with resulting high total doses of radiation, preferentially in the periphery of tumors. Normal liver parenchyma showed little radiation effect away from the tumors. Heterogeneous high-dose regions in the tumor were produced by both glass and resin microspheres.     

A clinical-pharmacological evaluation of percutaneous isolated hepatic infusion of doxorubicin in patients with unresectable liver tumors

A dose escalation study of hepatic arterial infusion of doxorubicin during hemodynamic isolation of the liver (the Delcath system) was conducted to: 1) study the pharmacokinetics of regional doxorubicin therapy, and 2) define therapeutic efficacy in the treatment of unresectable liver tumors. Eighteen patients with unresectable primary or metastatic tumor in the liver were treated with 57 procedures. Pharmacokinetic studies were performed on all treatments. Hepatic extraction ratio of doxorubicin remained constant at 60.3+/-12.1%. independent of the dose escalation. The calculated intrahepatic concentration of doxorubicin ranged from 30 to 88 microg/ml when the dosage of doxorubicin was escalated from 50 to 120 mg/m2. Dose-limiting systemic toxicity (grade 4 myelosuppression) was observed at 120 mg/m2. Twelve of 14 patients who received more than one treatment at 90 or 120 mg/m2 were evaluable for disease response: there were 4 partial responses, 3 minor responses, I stable disease, and 4 progressive disease. The median overall survival of responders was 23 months, and for nonresponders it was 8 months. We have demonstrated a dose-response effect of hepatic infusion of doxorubicin at 90 and 120 mg/m2 in advanced hepatic malignancies. The isolated hepatic perfusion system improves the therapeutic index of doxorubicin and provides pharmacologic justification for its use in the treatment of unresectable hepatic malignancies, especially metastatic melanoma and sarcoma.     

Radiotherapy for unresectable hepatic malignancies

The management of hepatic malignancies, primary or metastatic, is an increasingly common problem in clinical practice. Unfortunately, most patients present with unresectable disease for which there is no universally accepted standard therapy. Radiotherapy is gaining importance in the management of these tumors and in this article we will review the advancements made in this field recently. Increased understanding of the relationship between radiation dose and volume and the risk of radiation-induced liver disease (RILD) has allowed delivery of high-dose focal liver radiation with encouraging results. A recent US phase II trial suggests a radiation dose-dependent improvement in survival when compared to historical controls. Others have reported favorable experience with moderate-dose external-beam radiotherapy, stereotactic hypofractionated radiotherapy, and radiopharmaceuticals.     

Review article: Biliary tree malignancies

Radiation therapy is used as definitive treatment for unresectable bile duct tumors, or as adjuvant therapy after resection. External beam irradiation of 45–50 Gy is generally given whenever feasible. Intraluminal brachytherapy is a useful technique to deliver higher doses of radiation to the tumor while respecting the tolerance of the surrounding normal tissues. Brachytherapy can be given at a high dose rate or low dose rate via an in-dwelling biliary drainage catheter to boost external beam doses. Brachytherapy alone is reserved for palliative therapy. Techniques should be implemented with care to make them not only effective but safe. The long-term efficacy and morbidity of this mode of radiation should be studied further. Only large prospective trials can lead to resolution of some of the questions yet unsolved in treatment of these challenging malignancies. J. Surg. Oncol. 1998;67:203–210. © 1998 Wiley-Liss, Inc.     

Non-surgical treatment of hilar cholangiocarcinoma

Cancer of the biliary confluence also known as hilar cholangiocarcinoma (HC) or Klatskin tumor, is a rare type of neoplastic disease constituting approximately 40%-60% of intrahepatic malignancies, and 2% of all cancers. The prognosis is extremely poor and the majority of Klatskin tumors are deemed unresectable upon diagnosis. Most patients with unresectable bile duct cancer die within the first year after diagnosis, due to hepatic failure, and/or infectious complications secondary to biliary obstruction. Curative treatments include surgical resection and liver transplantation in highly selected patients. Nevertheless, very few patients are eligible for surgery or transplant at the time of diagnosis. For patients with unresectable HC, radiotherapy, chemotherapy, photodynamic therapy, and liver-directed minimally invasive procedures such as percutaneous image-guided ablation and intra-arterial chemoembolization are recommended treatment options. This review focuses on currently available treatment options for unresectable HC and discusses future perspectives that could optimize outcomes.     

肝脏术中超声的临床价值

目的总结肝脏术中超声的优越性,准确诊断病变,提高原发性肝肿瘤的手术切除率。方法采用高频率５．０ＭＨｚ探头,探头置于肝表面,观察肿物大小、数量、部位与血管的关系。结果４２例原发性肝肿瘤,２９例经术中超声定位后切除肿瘤;４例术中超声发现肿物与大血管关系密切,无法切除;６例术中发现多发病灶。结论术中超声较经腹超声和术中探查敏感,其优越性为：（１）定位准确,能提高手术切除率;（２）可确定肿瘤与血管关系;（３）弥补术前影像检查的不足;（４）术中可进行肝脓肿开窗术及肝囊肿介入治疗。     

Radiotherapeutic strategies in the management of hepatocellular carcinoma

Although potentially curative therapies for hepatocellular carcinoma (HCC) are well established, they are offered only to a limited number of patients. For advanced HCC, sorafenib is now the treatment of choice. Radiotherapy technology has evolved remarkably during the past decade and can be precisely delivered, thereby permitting higher doses to the tumor and reduced doses to surrounding normal tissues. According to the Korean Liver Cancer Study Group (KLCSG) practice guidelines, radiation therapy is considered appropriate for unresectable, locally advanced HCC without extrahepatic metastasis, Child-Pugh class A or B, and tumors occupying less than two thirds of the liver with level II evidence. In this review, we discuss the radiotherapeutic strategies for each clinical setting in patients with HCC.     

Overview: Where does radiation therapy fit in the spectrum of liver cancer local-regional therapies?

Experience with radiation therapy for the treatment of hepatocellular carcinoma (HCC) and liver metastases has increased rapidly in the past decade. This is principally because of advances in imaging and radiation techniques that can conform high doses to focal cancers and to a better understanding of how to avoid radiation-induced liver toxicity. Guidelines on how to use radiation therapy safely are becoming more clearly established, and reports of tumor control at 2 to 5 years show the potential for cure after radiation therapy for early-stage HCC and liver metastases. For both HCC and liver metastases, the best outcomes after radiation therapy are found in patients with fewer than 3 lesions that are <6 cm in size, with intact liver function and no extrahepatic metastases. There is a strong rationale for using radiation therapy in patients unsuitable for or with expected poor outcomes after standard local-regional therapies. These patients tend to have advanced tumors (large, multifocal, or invading vessels) and/or impaired liver function, reducing the chance of cure and increasing the chance of toxicity. In these patients, the benefits of radiation therapy over systemic therapy or best supportive therapy should be established in randomized trials.     

Liver Transplantation for Malignancies

Liver transplantation (LT) has become an acceptable and effective treatment for selected patients with hepatocellular carcinoma with excellent outcomes. More recently, LT has been tried in different primary and secondary malignancies of the liver. The outcomes of LT for very selected group of patients with hilar cholangiocarcinoma (CCA) have been promising. Excellent results have been reported in LT for patients with unresectable hepatic epithelioid hemangioendothelioma (HEHE). In contrast to excellent results after LT for HEHE, results of LT for angiosarcoma have been disappointing with no long-term survivors. Hepatoblastoma (HB) is the most common primary liver cancer in pediatric age group. Long-term outcomes after LT in patients with unresectable tumor and good response to chemotherapy have been promising. Indication for LT for hepatic metastasis from neuroendocrine tumors (NETs) is mainly for patients with unresectable tumors and for palliation of medically uncontrollable symptoms. Posttransplant survival in those patients with low tumor activity index is excellent, despite recurrence of the tumor. More recent limited outcomes data on LT for unresectable hepatic metastases from colorectal cancer have claimed some survival benefit compared to the previous reports. However, due to the high rate of tumor recurrence in a very short time after LT, especially in the era of organ shortage, this indication has not been favored by the transplant community.     

Isolation perfusion of the liver

Thousands of patients die annually from unresectable metastatic or primary hepatic cancers confined to liver. Isolated hepatic perfusion (IHP) is a regional treatment strategy in which the vascular supply to the liver is isolated and perfused with a therapeutic regimen using an extracorporeal circuit consisting of a reservoir, heat exchanger, and oxygenator. Drug doses that would cause severe toxicities if delivered systemically can be confined to the liver by isolated hepatic perfusion, resulting in the ability to intensify treatment to the cancer-burdened region of the body. Agents and mechanisms commonly used in IHP include melphaIan, hyperthermia, and tumor necrosis factor. IHP appears to be efficacious for patients with advanced disease, as reflected by large tumor size, high number of lesions, or significant overall tumor burden in the liver. In addition, responses are observed for patients whose cancer is refractory to systemic and hepatic arterial infusion chemotherapy. Recent clinical trials have demonstrated that IHP has anti-tumor efficacy against primary hepatic neoplasms and metastases from various primary tumors, such as colorectal carcinoma, ocular melanoma, and neuroendocrine tumors. Current studies demonstrate that combining hepatic arterial infusion with floxuridine after IHP for patients with colorectal cancer metastases is associated with significant and durable response rates. Continued clinical evaluation is warranted for the use of IHP in the treatment of unresectable liver metastases.     

p53 mutations as a possible predictor of response to chemotherapy in metastatic colorectal carcinomas

Although intrahepatic infusion therapy with 5-flourouracil for unresectable colorectal liver metastases may lead to improved overall survival for some patients, it is not clear why a response is not observed in others. Gene alterations in oncogenes or tumor-suppressor genes are critical events in tumor formation, and some of them could play a role in the process of drug resistance. The tumor-suppressor gene p53, which is known to trigger cell arrest or apoptosis in response to DNA damage, is found to be mutated in a wide range of human tumors. The aim of this work is to establish whether a relationship is found between p53 mutations and survival in patients undergoing adjuvant chemotheraphy for advanced Dukes' D colorectal cancers. Seventeen tumors from patients treated with 5-fluorouracil regimen via intrahepatic infusion for unresectable colorectal hepatic metastasis were considered. p53 mutations from tumor DNA were detected, after amplification by PCR of exons 5 to 8, by non-radioactive single-strand conformation polymorphism and direct DNA sequencing. Patients with mutated p53 colorectal tumors had short survival, whereas prolonged survival was associated with the presence of wild-type p53 (p = 0.019). Our data suggest that mutated p53 colorectal tumors had a weak response, or even no response, to chemotherapeutic treatment. Routine assessment of p53 status would be helpful in selecting patients with only wild-type p53 gene who have a predictably better response to chemotherapy. © 1996 Wiley-Liss, Inc.