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.

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.