Low-Dose Radiation Therapy to the Whole Liver With Gemcitabine and Cisplatin in IHC

Intrahepatic cholangiocarcinoma (IHC) are cancers with pathologic features of biliary tract differentiation which arise from intrahepatic bile ducts and/or trans-differentiation of hepatocytes. IHC is the second most common primary liver cancer and its incidence and mortality rates are increasing both worldwide and in the United States. Approximately 80% of IHC in the Western hemisphere is the mass-forming type. Liver disease represents the major obstacle to long-term survival among patients with IHC. While partial hepatectomy offers the only hope of cure, less than 30% of IHC are resectable at initial presentation.2 Most patients have locally advanced disease (e.g. multi-focal tumors, major vascular invasion, local invasion of surrounding organs, and/or regional lymph node metastasis). Each of these factors portends poor 5-year survival (~20%) after surgical extirpation and are thus considered unresectable disease by most surgeons in the current era. Moreover, the liver is the most common site of disease recurrence after resection of IHC as 60-80% of initial disease recurrence occurs in the liver remnant.

Published response rates to preoperative or definitive radiation therapy (RT) for cholangiocarcinoma appear to be relatively high. For instance, a complete response proportion of 48% was recently reported for perihilar cholangiocarcinoma patients who received preoperative chemoradiation followed by liver transplant. Moreover, small series have demonstrated superior progression free and overall survival with the combination of external beam RT and chemotherapy compared to that derived from chemotherapy alone for many unresectable hepatic malignancies, including IHC, colorectal cancer liver metastases, and hepatocellular carcinoma. For example, addition of external beam RT to cisplatin chemotherapy was associated with prolonged progression free (median 4.3 vs. 1.9 months, p=0.001) and overall (median 9.3 vs. 6.2 months, p=0.048) survival compared to cisplatin alone among 92 total patients with unresectable IHC. Traditional thoughts in radiation biology of tumors suggested that doses of at least 1.2 Gy were required to overcome the initial shoulder of the cell survival curve. In practice, the standard dose per fraction is considered to be 0.015-0.022 Gy per fraction although the vast majority of patients are treated with either 1.8 Gy or 2 Gy fractions.

Laboratory and clinical data suggest that a new paradigm using LDFRT as a chemopotentiator may allow full-dose drug therapy with improved efficacy without adding to the toxicity of the systemic treatment. This chemopotentiating effect is possible through a phenomenon known as hyper-radiation sensitivity (HRS) by which there is more effective tumor cell killing than would be predicted when using doses per fraction below 1 Gy. This is followed by a change in slope of the survival response with increasing doses per fraction, indicating increased radioresistance (IRR). This HRS phenomenon was first described by Joiner and colleagues in the Gray Laboratory in 1986 and has since been well described by a number of other laboratories. It also has been documented in the clinical setting; in a study by Harney et al., patients with paired cutaneous metastases from sarcoma and melanoma had longer time to tumor regrowth after LDFRT than with conventional radiation. In vitro studies have established a link between HRS/IRR and evasion of the early G2/M cell cycle checkpoint. Exaggerated HRS/IRR responses were found for enriched populations of G2 phase cells in one study, indicating that the mechanism likely involved events in the G2 phase of the cell cycle. Two G2 checkpoints have been described, and the more recently discovered "early" checkpoint is rapidly activated after radiation exposure. It is believed to prevent cell cycle progression through G2 of cells with unrepaired radiation-induced DNA damage. The signaling cascade regulating the early G2/M checkpoint is initiated through ATM activity. Joiner and colleagues have shown that inhibition of ChK1 and Chk2, two proteins integral to the G2/M transition, can influence the cell-cycle response to low-dose radiation. It is believed that failure of the cell to repair DNA damage in G2-phase cells leads to increased apoptosis. Nonetheless, inhibition of ChK1 and ChK2 also lead to IRR at radiation doses > 0.2 Gy. This is consistent with reports indicating that low dose radiation can stimulate repair of DNA damage. Interestingly, low dose radiation can also stimulate antioxidant capacity, apoptosis, and induction of immune responses, which collectively may provide effective local tumor control. In addition, hypoxia and nitric oxide levels can also affect cells sensitivity to radiation. Reduction of nitric oxide level enhances the radiosensitivity of hypoxic non-small cell lung cancer. Therefore, the identification of cellular pathways that are responsive to low dose radiation and their contribution to chemopotentiation is highly significant because this will provide a better measurement of the therapeutic response and contribute to the rational design of mechanism-based clinical trials.

Based on promising preclinical data, clinical studies have been performed in a variety of cancer types with LDFRT in addition to standard chemotherapy. Investigators at the University of Kentucky published their experience using carboplatin and paclitaxel with 4 fractions of 0.8 Gy each in locally advanced head and neck cancer patients. They observed toxicities similar to those expected from chemotherapy alone and concluded that the addition of LDFRT was "extremely well tolerated." Moreover, they reported excellent response rates. Regine et al. conducted a phase I trial of low dose abdominal RT (0.6 vs. 0.7 Gy fractions, total 8 fractions) and gemcitabine 1,250 mg/m2 among patients with unresectable pancreatic/small bowel carcinomas. The authors concluded that abdominal LDFRT using 0.6 Gy fractions was well tolerated when given concurrently with full-dose gemcitabine. A multi-institutional phase II trial using this regimen suggested improved efficacy of the combined regimen in improving overall survival. Sixty-one percent of enrolled patients experienced at least stable disease, and median survival in this poor prognosis population was 13 months. More importantly, no additional toxicity was observed with LDFRT other than that expected from the high dose of gemcitabine (personal communication, manuscript in preparation). More recently, Wrenn et al. demonstrated tolerability of concomitant low-dose whole-abdominal RT and full-dose cisplatin in optimally debulked stage III/IV endometrial cancer patients.

Currently, there are no prospective studies evaluating the efficacy of concomitant gem-cis and RT for locally advanced IHC regarding disease response or post-operative intrahepatic disease recurrence. Prior full dose external beam RT is an accepted contraindication to liver resection due to development of advanced fibrosis and intrahepatic biliary sclerosis. However, no studies have evaluated the influence of preoperative LDFRT on outcomes after partial hepatectomy. Case reports of safe liver resection after antecedent radioembolization suggest that LDFRT may not adversely affect postoperative outcomes. LDFRT to the entire liver and portal lymph node basin is advantageous compared to tumor directed therapy as the former treats occult disease representing the most common site of disease recurrence after partial hepatectomy and progression after chemotherapy.

Based on data from the ABC trial establishing gem-cis as the standard of care for locally advanced and/or metastatic cholangiocarcinoma, the primary goal of this phase II study is to explore the safety and efficacy of using a combination of LDFRT as a chemopotentiator and concurrent gem-cis for mass-forming IHC.

The pivotal Advanced Biliary Tract Cancer (ABC) Trial established combination gemcitabine-cisplatin (gem-cis) therapy as the standard of care for patients with locally advanced and/or metastatic IHC. While the majority of patients experience initial disease stabilization after therapy (e.g. stable disease, partial response, or complete response) partial or complete response occurs in only approximately 20% of patients. Smaller trials comprising other chemotherapeutics with or without anti-biologic agents report similar results. Moreover, disease stabilization is short lived with median progression free survival of only six-eight months. Thus, there is a pressing need for more effective liver directed therapy for locally advanced disease.