lack of funding

The overall goal of this study is to determine the safety and efficacy of combination treatment of low-dose fractionated radiation therapy with gemcitabine-cisplatin chemotherapy for locally advanced mass forming intra-hepatic cholangiocarcinoma.

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.

Inclusion Criteria:

• Histologic diagnosis of mass-forming IHC. OR
• Histologic diagnosis of adenocarcinoma of the liver in setting of negative colonoscopy, upper endoscopy, mammography (females), or cross-sectional imaging for primary disease.
• Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension as ≥10 mm (≥1 cm) with spiral CT scan, MRI. See Section 8 for the evaluation of measurable disease.
• Locally advanced disease (portal lymph node disease, multifocal intrahepatic lesions, or major vascular invasion) AND no evidence of omental, peritoneal, or pelvic metastases.
• Other sites of metastatic disease (e.g. lung, distant lymph nodes, bone) are allowed.
• No prior chemotherapy, radiotherapy, or surgical therapy.
• ECOG performance status ≤ 1 (Karnofsky ≥70%). See Appendix A.
• Life expectancy of greater than six months.
• Patients must have normal organ and marrow function as defined below:
• leukocytes≥3,000/mcL
• absolute neutrophil count≥1,500/mcL
• platelets ≥100,000/mcL
• hemoglobin≥9.0 g/dL
• total bilirubin≤2.0 mg/dL
• AST(SGOT)/ALT(SGPT)≤3 × institutional upper limit of normal
• creatinine within normal institutional limits OR
• creatinine clearance≥60 mL/min/1.73 m2 for patients with creatinine levels above institutional normal
• int'l normalized ratio<1.8
• systolic blood pressure≤160 mmHg
• diastolic blood pressure ≥90 mmHg
• For women of child-bearing potential, negative serum pregnancy test within 14 days prior to registration.
• Women of childbearing age and male participants.
• Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

• Prior chemotherapy, surgical therapy, or radiotherapy for IHC.
• Patients who are receiving any other investigational agents or have been treated with any other therapeutic clinical protocols within 30 days prior to study entry or during participation in the study.
• Patients with known brain metastases will be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to gemcitabine or cisplatin.
• Prior invasive malignancy (except for non-melanomatous skin cancer, low grade prostate cancer, and in situ cervical cancer) unless disease free for ≥ two years.
• Periductal infiltrating, intraductal, or poorly differentiated neuroendocrine (e.g. high grade, small, or large cell) tumor histology.
• Prior abdominal radiotherapy.
• Cirrhosis, primary sclerosing cholangitis, hepatitis viral infection (documented by positive serology and antigen serologic testing), or other background liver diseases.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection; unstable angina and/or congestive heart failure within the last 6 months; transmural myocardial infarction within the last 6 months; New York Heart Association grade II or greater congestive heart failure requiring hospitalization within 12 months prior to registration; history of stroke, cerebral vascular accident or transient ischemic attack within 6 months; serious and inadequately controlled cardiac arrhythmia; significant vascular disease (e.g.;, high risk aortic aneurysm, history of aortic dissection) or clinically significant peripheral vascular disease; evidence of bleeding diathesis or coagulopathy; serious or non-healing wound, ulcer, or bone fracture or history of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess, major surgical procedure or significant traumatic injury within 28 days prior to registration; bacterial or fungal infection requiring intravenous antibiotics at the time of registration; chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy at the time of registration; active connective tissue disorders, such as lupus or scleroderma, that in the opinion of the treating physician may put the patient at high risk for radiation toxicity; any other major medical illnesses or psychiatric impairments that in the investigator's opinion will prevent administration or completion of protocol therapy; cognitive impairment that precludes a patient from acting as his or her own agent to provide informed consent.
• Pregnant or breast feeding women.
• Men and women of childbearing potential who are sexually active and not willing/able to use medically acceptable forms of contraception.
• Acquired immune deficiency syndrome (AIDS) based upon current CDC definition. Note, however, that HIV testing is not required for entry into this protocol. The need to exclude patients with AIDS from this protocol is necessary because the treatments involved in this protocol are significantly immunosuppressive.

1.5 years