<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT02254681</url>
  </required_header>
  <id_info>
    <org_study_id>VPSR-1401</org_study_id>
    <nct_id>NCT02254681</nct_id>
  </id_info>
  <brief_title>Low-Dose Radiation Therapy to the Whole Liver With Gemcitabine and Cisplatin in IHC</brief_title>
  <official_title>A Phase 2 Study of Low-Dose Fractionated Radiation Therapy to the Whole Liver in Combination With Gemcitabine and Cisplatin in Locally Advanced Mass-Forming Intrahepatic Cholangiocarcinoma</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Allina Health System</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Allina Health System</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The overall goal of this study is to determine the safety and efficacy of combination&#xD;
      treatment of low-dose fractionated radiation therapy with gemcitabine-cisplatin chemotherapy&#xD;
      for locally advanced mass forming intra-hepatic cholangiocarcinoma.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Intrahepatic cholangiocarcinoma (IHC) are cancers with pathologic features of biliary tract&#xD;
      differentiation which arise from intrahepatic bile ducts and/or trans-differentiation of&#xD;
      hepatocytes. IHC is the second most common primary liver cancer and its incidence and&#xD;
      mortality rates are increasing both worldwide and in the United States. Approximately 80% of&#xD;
      IHC in the Western hemisphere is the mass-forming type. Liver disease represents the major&#xD;
      obstacle to long-term survival among patients with IHC. While partial hepatectomy offers the&#xD;
      only hope of cure, less than 30% of IHC are resectable at initial presentation.2 Most&#xD;
      patients have locally advanced disease (e.g. multi-focal tumors, major vascular invasion,&#xD;
      local invasion of surrounding organs, and/or regional lymph node metastasis). Each of these&#xD;
      factors portends poor 5-year survival (~20%) after surgical extirpation and are thus&#xD;
      considered unresectable disease by most surgeons in the current era. Moreover, the liver is&#xD;
      the most common site of disease recurrence after resection of IHC as 60-80% of initial&#xD;
      disease recurrence occurs in the liver remnant.&#xD;
&#xD;
      Published response rates to preoperative or definitive radiation therapy (RT) for&#xD;
      cholangiocarcinoma appear to be relatively high. For instance, a complete response proportion&#xD;
      of 48% was recently reported for perihilar cholangiocarcinoma patients who received&#xD;
      preoperative chemoradiation followed by liver transplant. Moreover, small series have&#xD;
      demonstrated superior progression free and overall survival with the combination of external&#xD;
      beam RT and chemotherapy compared to that derived from chemotherapy alone for many&#xD;
      unresectable hepatic malignancies, including IHC, colorectal cancer liver metastases, and&#xD;
      hepatocellular carcinoma. For example, addition of external beam RT to cisplatin chemotherapy&#xD;
      was associated with prolonged progression free (median 4.3 vs. 1.9 months, p=0.001) and&#xD;
      overall (median 9.3 vs. 6.2 months, p=0.048) survival compared to cisplatin alone among 92&#xD;
      total patients with unresectable IHC. Traditional thoughts in radiation biology of tumors&#xD;
      suggested that doses of at least 1.2 Gy were required to overcome the initial shoulder of the&#xD;
      cell survival curve. In practice, the standard dose per fraction is considered to be&#xD;
      0.015-0.022 Gy per fraction although the vast majority of patients are treated with either&#xD;
      1.8 Gy or 2 Gy fractions.&#xD;
&#xD;
      Laboratory and clinical data suggest that a new paradigm using LDFRT as a chemopotentiator&#xD;
      may allow full-dose drug therapy with improved efficacy without adding to the toxicity of the&#xD;
      systemic treatment. This chemopotentiating effect is possible through a phenomenon known as&#xD;
      hyper-radiation sensitivity (HRS) by which there is more effective tumor cell killing than&#xD;
      would be predicted when using doses per fraction below 1 Gy. This is followed by a change in&#xD;
      slope of the survival response with increasing doses per fraction, indicating increased&#xD;
      radioresistance (IRR). This HRS phenomenon was first described by Joiner and colleagues in&#xD;
      the Gray Laboratory in 1986 and has since been well described by a number of other&#xD;
      laboratories. It also has been documented in the clinical setting; in a study by Harney et&#xD;
      al., patients with paired cutaneous metastases from sarcoma and melanoma had longer time to&#xD;
      tumor regrowth after LDFRT than with conventional radiation. In vitro studies have&#xD;
      established a link between HRS/IRR and evasion of the early G2/M cell cycle checkpoint.&#xD;
      Exaggerated HRS/IRR responses were found for enriched populations of G2 phase cells in one&#xD;
      study, indicating that the mechanism likely involved events in the G2 phase of the cell&#xD;
      cycle. Two G2 checkpoints have been described, and the more recently discovered &quot;early&quot;&#xD;
      checkpoint is rapidly activated after radiation exposure. It is believed to prevent cell&#xD;
      cycle progression through G2 of cells with unrepaired radiation-induced DNA damage. The&#xD;
      signaling cascade regulating the early G2/M checkpoint is initiated through ATM activity.&#xD;
      Joiner and colleagues have shown that inhibition of ChK1 and Chk2, two proteins integral to&#xD;
      the G2/M transition, can influence the cell-cycle response to low-dose radiation. It is&#xD;
      believed that failure of the cell to repair DNA damage in G2-phase cells leads to increased&#xD;
      apoptosis. Nonetheless, inhibition of ChK1 and ChK2 also lead to IRR at radiation doses &gt; 0.2&#xD;
      Gy. This is consistent with reports indicating that low dose radiation can stimulate repair&#xD;
      of DNA damage. Interestingly, low dose radiation can also stimulate antioxidant capacity,&#xD;
      apoptosis, and induction of immune responses, which collectively may provide effective local&#xD;
      tumor control. In addition, hypoxia and nitric oxide levels can also affect cells sensitivity&#xD;
      to radiation. Reduction of nitric oxide level enhances the radiosensitivity of hypoxic&#xD;
      non-small cell lung cancer. Therefore, the identification of cellular pathways that are&#xD;
      responsive to low dose radiation and their contribution to chemopotentiation is highly&#xD;
      significant because this will provide a better measurement of the therapeutic response and&#xD;
      contribute to the rational design of mechanism-based clinical trials.&#xD;
&#xD;
      Based on promising preclinical data, clinical studies have been performed in a variety of&#xD;
      cancer types with LDFRT in addition to standard chemotherapy. Investigators at the University&#xD;
      of Kentucky published their experience using carboplatin and paclitaxel with 4 fractions of&#xD;
      0.8 Gy each in locally advanced head and neck cancer patients. They observed toxicities&#xD;
      similar to those expected from chemotherapy alone and concluded that the addition of LDFRT&#xD;
      was &quot;extremely well tolerated.&quot; Moreover, they reported excellent response rates. Regine et&#xD;
      al. conducted a phase I trial of low dose abdominal RT (0.6 vs. 0.7 Gy fractions, total 8&#xD;
      fractions) and gemcitabine 1,250 mg/m2 among patients with unresectable pancreatic/small&#xD;
      bowel carcinomas. The authors concluded that abdominal LDFRT using 0.6 Gy fractions was well&#xD;
      tolerated when given concurrently with full-dose gemcitabine. A multi-institutional phase II&#xD;
      trial using this regimen suggested improved efficacy of the combined regimen in improving&#xD;
      overall survival. Sixty-one percent of enrolled patients experienced at least stable disease,&#xD;
      and median survival in this poor prognosis population was 13 months. More importantly, no&#xD;
      additional toxicity was observed with LDFRT other than that expected from the high dose of&#xD;
      gemcitabine (personal communication, manuscript in preparation). More recently, Wrenn et al.&#xD;
      demonstrated tolerability of concomitant low-dose whole-abdominal RT and full-dose cisplatin&#xD;
      in optimally debulked stage III/IV endometrial cancer patients.&#xD;
&#xD;
      Currently, there are no prospective studies evaluating the efficacy of concomitant gem-cis&#xD;
      and RT for locally advanced IHC regarding disease response or post-operative intrahepatic&#xD;
      disease recurrence. Prior full dose external beam RT is an accepted contraindication to liver&#xD;
      resection due to development of advanced fibrosis and intrahepatic biliary sclerosis.&#xD;
      However, no studies have evaluated the influence of preoperative LDFRT on outcomes after&#xD;
      partial hepatectomy. Case reports of safe liver resection after antecedent radioembolization&#xD;
      suggest that LDFRT may not adversely affect postoperative outcomes. LDFRT to the entire liver&#xD;
      and portal lymph node basin is advantageous compared to tumor directed therapy as the former&#xD;
      treats occult disease representing the most common site of disease recurrence after partial&#xD;
      hepatectomy and progression after chemotherapy.&#xD;
&#xD;
      Based on data from the ABC trial establishing gem-cis as the standard of care for locally&#xD;
      advanced and/or metastatic cholangiocarcinoma, the primary goal of this phase II study is to&#xD;
      explore the safety and efficacy of using a combination of LDFRT as a chemopotentiator and&#xD;
      concurrent gem-cis for mass-forming IHC.&#xD;
&#xD;
      The pivotal Advanced Biliary Tract Cancer (ABC) Trial established combination&#xD;
      gemcitabine-cisplatin (gem-cis) therapy as the standard of care for patients with locally&#xD;
      advanced and/or metastatic IHC. While the majority of patients experience initial disease&#xD;
      stabilization after therapy (e.g. stable disease, partial response, or complete response)&#xD;
      partial or complete response occurs in only approximately 20% of patients. Smaller trials&#xD;
      comprising other chemotherapeutics with or without anti-biologic agents report similar&#xD;
      results. Moreover, disease stabilization is short lived with median progression free survival&#xD;
      of only six-eight months. Thus, there is a pressing need for more effective liver directed&#xD;
      therapy for locally advanced disease.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    lack of funding&#xD;
  </why_stopped>
  <start_date>September 2014</start_date>
  <completion_date type="Actual">September 2016</completion_date>
  <primary_completion_date type="Actual">September 2016</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Number of Participants With Radiographic Disease Response After Combination Low-dose Radiotherapy and Gemcitabine-cisplatin.</measure>
    <time_frame>16 weeks after treatment start</time_frame>
    <description>Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by CT/MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), &gt;=30% decrease in the sum of the longest diameter of target lesions; Progressive Disease (PD), At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study).</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Number of Participants With Adverse Events.</measure>
    <time_frame>up to 16 weeks after treatment start</time_frame>
    <description>Number of participants with adverse events during combined low-dose radiotherapy and gemcitabine-cisplatin treatment.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Number of Participants With Post-operative Complications After Partial Hepatectomy After Antecedent Combination Low-dose Radiotherapy and Gemcitabine-cisplatin.</measure>
    <time_frame>up to 90 days after partial hepatectomy</time_frame>
    <description>Measured post-operative complications include (but not limited to) bile leak, liver failure, ascites, infection, any organ failure or insufficiency, venous thromboembolism, and mortality.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Participants With Histologic Disease Response After Combination Low-dose Radiotherapy and Gemcitabine-cisplatin.</measure>
    <time_frame>16 weeks after start of first treatment</time_frame>
    <description>Tumor tissue will be obtained by either biopsy or liver resection after combination chemoradiotherapy. Histologic response will be determined by extent of viable tumor, tumor necrosis, and surrounding fibrosis.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Participants With Injury to the Background Liver After Combination Low-dose Radiotherapy and Gemcitabine-cisplatin.</measure>
    <time_frame>16 weeks after start of first treatment.</time_frame>
    <description>Background (non-tumor bearing) liver tissue will be obtained by either biopsy or liver resection after combination chemoradiotherapy. Histologic markers of Radiation Induced Liver disease will be measured.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Participants With Intrahepatic Recurrence After Partial Hepatectomy With Antecedent Combination Low-dose Radiotherapy and Gemcitabine-cisplatin.</measure>
    <time_frame>From date of partial hepatectomy until date of first documented recurrence or date of death from any cause, assessed up to 24 months.</time_frame>
    <description>To determine the number of participants with Intrahepatic recurrence assessed by RECIST criteria using MRI of the abdomen with intravenous gadolinium contrast.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Participants With Intrahepatic Disease Progression After Treatment With Combination Low-dose Radiotherapy and Gemcitabine-cisplatin.</measure>
    <time_frame>From date of first treatment until date of first documented progression or date of death from any cause, which ever comes first, assessed up to 24 months.</time_frame>
    <description>To determine the number of participants with Intrahepatic disease progression assessed by MRI of the abdomen with intravenous gadolinium contrast using RECIST criteria.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">6</enrollment>
  <condition>Intrahepatic Cholangiocarcinoma</condition>
  <arm_group>
    <arm_group_label>Treatment</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Four three-week treatment cycles. Gemcitabine (1000 gm/m^2) and cisplatin (25 mg/m^2) administered on days one and eight of each cycle. Whole liver and portal lymph node basin low dose radiotherapy on days one, two, eight, and nine of each cycle.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Gemcitabine</intervention_name>
    <arm_group_label>Treatment</arm_group_label>
    <other_name>Gemzar</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Cisplatin</intervention_name>
    <arm_group_label>Treatment</arm_group_label>
    <other_name>Platinol</other_name>
  </intervention>
  <intervention>
    <intervention_type>Radiation</intervention_type>
    <intervention_name>low dose radiotherapy</intervention_name>
    <description>Whole liver and portal lymph node basin low dose radiotherapy</description>
    <arm_group_label>Treatment</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Histologic diagnosis of mass-forming IHC. OR&#xD;
&#xD;
          -  Histologic diagnosis of adenocarcinoma of the liver in setting of negative&#xD;
             colonoscopy, upper endoscopy, mammography (females), or cross-sectional imaging for&#xD;
             primary disease.&#xD;
&#xD;
          -  Patients must have measurable disease, defined as at least one lesion that can be&#xD;
             accurately measured in at least one dimension as ≥10 mm (≥1 cm) with spiral CT scan,&#xD;
             MRI. See Section 8 for the evaluation of measurable disease.&#xD;
&#xD;
          -  Locally advanced disease (portal lymph node disease, multifocal intrahepatic lesions,&#xD;
             or major vascular invasion) AND no evidence of omental, peritoneal, or pelvic&#xD;
             metastases.&#xD;
&#xD;
          -  Other sites of metastatic disease (e.g. lung, distant lymph nodes, bone) are allowed.&#xD;
&#xD;
          -  No prior chemotherapy, radiotherapy, or surgical therapy.&#xD;
&#xD;
          -  ECOG performance status ≤ 1 (Karnofsky ≥70%). See Appendix A.&#xD;
&#xD;
          -  Life expectancy of greater than six months.&#xD;
&#xD;
          -  Patients must have normal organ and marrow function as defined below:&#xD;
&#xD;
          -  leukocytes≥3,000/mcL&#xD;
&#xD;
          -  absolute neutrophil count≥1,500/mcL&#xD;
&#xD;
          -  platelets ≥100,000/mcL&#xD;
&#xD;
          -  hemoglobin≥9.0 g/dL&#xD;
&#xD;
          -  total bilirubin≤2.0 mg/dL&#xD;
&#xD;
          -  AST(SGOT)/ALT(SGPT)≤3 × institutional upper limit of normal&#xD;
&#xD;
          -  creatinine within normal institutional limits OR&#xD;
&#xD;
          -  creatinine clearance≥60 mL/min/1.73 m2 for patients with creatinine levels above&#xD;
             institutional normal&#xD;
&#xD;
          -  int'l normalized ratio&lt;1.8&#xD;
&#xD;
          -  systolic blood pressure≤160 mmHg&#xD;
&#xD;
          -  diastolic blood pressure ≥90 mmHg&#xD;
&#xD;
          -  For women of child-bearing potential, negative serum pregnancy test within 14 days&#xD;
             prior to registration.&#xD;
&#xD;
          -  Women of childbearing age and male participants.&#xD;
&#xD;
          -  Ability to understand and the willingness to sign a written informed consent document.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Prior chemotherapy, surgical therapy, or radiotherapy for IHC.&#xD;
&#xD;
          -  Patients who are receiving any other investigational agents or have been treated with&#xD;
             any other therapeutic clinical protocols within 30 days prior to study entry or during&#xD;
             participation in the study.&#xD;
&#xD;
          -  Patients with known brain metastases will be excluded from this clinical trial because&#xD;
             of their poor prognosis and because they often develop progressive neurologic&#xD;
             dysfunction that would confound the evaluation of neurologic and other adverse events.&#xD;
&#xD;
          -  History of allergic reactions attributed to compounds of similar chemical or biologic&#xD;
             composition to gemcitabine or cisplatin.&#xD;
&#xD;
          -  Prior invasive malignancy (except for non-melanomatous skin cancer, low grade prostate&#xD;
             cancer, and in situ cervical cancer) unless disease free for ≥ two years.&#xD;
&#xD;
          -  Periductal infiltrating, intraductal, or poorly differentiated neuroendocrine (e.g.&#xD;
             high grade, small, or large cell) tumor histology.&#xD;
&#xD;
          -  Prior abdominal radiotherapy.&#xD;
&#xD;
          -  Cirrhosis, primary sclerosing cholangitis, hepatitis viral infection (documented by&#xD;
             positive serology and antigen serologic testing), or other background liver diseases.&#xD;
&#xD;
          -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active&#xD;
             infection; unstable angina and/or congestive heart failure within the last 6 months;&#xD;
             transmural myocardial infarction within the last 6 months; New York Heart Association&#xD;
             grade II or greater congestive heart failure requiring hospitalization within 12&#xD;
             months prior to registration; history of stroke, cerebral vascular accident or&#xD;
             transient ischemic attack within 6 months; serious and inadequately controlled cardiac&#xD;
             arrhythmia; significant vascular disease (e.g.;, high risk aortic aneurysm, history of&#xD;
             aortic dissection) or clinically significant peripheral vascular disease; evidence of&#xD;
             bleeding diathesis or coagulopathy; serious or non-healing wound, ulcer, or bone&#xD;
             fracture or history of abdominal fistula, gastrointestinal perforation or&#xD;
             intra-abdominal abscess, major surgical procedure or significant traumatic injury&#xD;
             within 28 days prior to registration; bacterial or fungal infection requiring&#xD;
             intravenous antibiotics at the time of registration; chronic obstructive pulmonary&#xD;
             disease exacerbation or other respiratory illness requiring hospitalization or&#xD;
             precluding study therapy at the time of registration; active connective tissue&#xD;
             disorders, such as lupus or scleroderma, that in the opinion of the treating physician&#xD;
             may put the patient at high risk for radiation toxicity; any other major medical&#xD;
             illnesses or psychiatric impairments that in the investigator's opinion will prevent&#xD;
             administration or completion of protocol therapy; cognitive impairment that precludes&#xD;
             a patient from acting as his or her own agent to provide informed consent.&#xD;
&#xD;
          -  Pregnant or breast feeding women.&#xD;
&#xD;
          -  Men and women of childbearing potential who are sexually active and not willing/able&#xD;
             to use medically acceptable forms of contraception.&#xD;
&#xD;
          -  Acquired immune deficiency syndrome (AIDS) based upon current CDC definition. Note,&#xD;
             however, that HIV testing is not required for entry into this protocol. The need to&#xD;
             exclude patients with AIDS from this protocol is necessary because the treatments&#xD;
             involved in this protocol are significantly immunosuppressive.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>99 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Srinevas K Reddy, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Allina Health System</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Virginia Piper Cancer Institute</name>
      <address>
        <city>Minneapolis</city>
        <state>Minnesota</state>
        <zip>55407</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <reference>
    <citation>Bridgewater J, Galle PR, Khan SA, Llovet JM, Park JW, Patel T, Pawlik TM, Gores GJ. Guidelines for the diagnosis and management of intrahepatic cholangiocarcinoma. J Hepatol. 2014 Jun;60(6):1268-89. doi: 10.1016/j.jhep.2014.01.021. Epub 2014 Mar 27. No abstract available.</citation>
    <PMID>24681130</PMID>
  </reference>
  <reference>
    <citation>Rizvi S, Gores GJ. Pathogenesis, diagnosis, and management of cholangiocarcinoma. Gastroenterology. 2013 Dec;145(6):1215-29. doi: 10.1053/j.gastro.2013.10.013. Epub 2013 Oct 15.</citation>
    <PMID>24140396</PMID>
  </reference>
  <reference>
    <citation>de Jong MC, Nathan H, Sotiropoulos GC, Paul A, Alexandrescu S, Marques H, Pulitano C, Barroso E, Clary BM, Aldrighetti L, Ferrone CR, Zhu AX, Bauer TW, Walters DM, Gamblin TC, Nguyen KT, Turley R, Popescu I, Hubert C, Meyer S, Schulick RD, Choti MA, Gigot JF, Mentha G, Pawlik TM. Intrahepatic cholangiocarcinoma: an international multi-institutional analysis of prognostic factors and lymph node assessment. J Clin Oncol. 2011 Aug 10;29(23):3140-5. doi: 10.1200/JCO.2011.35.6519. Epub 2011 Jul 5.</citation>
    <PMID>21730269</PMID>
  </reference>
  <reference>
    <citation>Endo I, Gonen M, Yopp AC, Dalal KM, Zhou Q, Klimstra D, D'Angelica M, DeMatteo RP, Fong Y, Schwartz L, Kemeny N, O'Reilly E, Abou-Alfa GK, Shimada H, Blumgart LH, Jarnagin WR. Intrahepatic cholangiocarcinoma: rising frequency, improved survival, and determinants of outcome after resection. Ann Surg. 2008 Jul;248(1):84-96. doi: 10.1097/SLA.0b013e318176c4d3.</citation>
    <PMID>18580211</PMID>
  </reference>
  <reference>
    <citation>Lang H, Sotiropoulos GC, Sgourakis G, Schmitz KJ, Paul A, Hilgard P, Zopf T, Trarbach T, Malago M, Baba HA, Broelsch CE. Operations for intrahepatic cholangiocarcinoma: single-institution experience of 158 patients. J Am Coll Surg. 2009 Feb;208(2):218-28. doi: 10.1016/j.jamcollsurg.2008.10.017.</citation>
    <PMID>19228533</PMID>
  </reference>
  <reference>
    <citation>Choi SB, Kim KS, Choi JY, Park SW, Choi JS, Lee WJ, Chung JB. The prognosis and survival outcome of intrahepatic cholangiocarcinoma following surgical resection: association of lymph node metastasis and lymph node dissection with survival. Ann Surg Oncol. 2009 Nov;16(11):3048-56. doi: 10.1245/s10434-009-0631-1. Epub 2009 Jul 22.</citation>
    <PMID>19626372</PMID>
  </reference>
  <reference>
    <citation>Paik KY, Jung JC, Heo JS, Choi SH, Choi DW, Kim YI. What prognostic factors are important for resected intrahepatic cholangiocarcinoma? J Gastroenterol Hepatol. 2008 May;23(5):766-70. doi: 10.1111/j.1440-1746.2007.05040.x. Epub 2007 Sep 12.</citation>
    <PMID>17868336</PMID>
  </reference>
  <reference>
    <citation>Nakagohri T, Kinoshita T, Konishi M, Takahashi S, Gotohda N. Surgical outcome and prognostic factors in intrahepatic cholangiocarcinoma. World J Surg. 2008 Dec;32(12):2675-80. doi: 10.1007/s00268-008-9778-3.</citation>
    <PMID>18843437</PMID>
  </reference>
  <reference>
    <citation>Tamandl D, Herberger B, Gruenberger B, Puhalla H, Klinger M, Gruenberger T. Influence of hepatic resection margin on recurrence and survival in intrahepatic cholangiocarcinoma. Ann Surg Oncol. 2008 Oct;15(10):2787-94. doi: 10.1245/s10434-008-0081-1. Epub 2008 Aug 7.</citation>
    <PMID>18685896</PMID>
  </reference>
  <reference>
    <citation>Valle J, Wasan H, Palmer DH, Cunningham D, Anthoney A, Maraveyas A, Madhusudan S, Iveson T, Hughes S, Pereira SP, Roughton M, Bridgewater J; ABC-02 Trial Investigators. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med. 2010 Apr 8;362(14):1273-81. doi: 10.1056/NEJMoa0908721.</citation>
    <PMID>20375404</PMID>
  </reference>
  <reference>
    <citation>Woo SM, Lee WJ, Kim JH, Kim DH, Han SS, Park SJ, Kim TH, Lee JH, Koh YH, Hong EK. Gemcitabine plus cisplatin versus capecitabine plus cisplatin as first-line chemotherapy for advanced biliary tract cancer: a retrospective cohort study. Chemotherapy. 2013;59(3):232-8. doi: 10.1159/000354539. Epub 2013 Dec 13.</citation>
    <PMID>24356333</PMID>
  </reference>
  <reference>
    <citation>Alberts SR, Al-Khatib H, Mahoney MR, Burgart L, Cera PJ, Flynn PJ, Finch TR, Levitt R, Windschitl HE, Knost JA, Tschetter LK. Gemcitabine, 5-fluorouracil, and leucovorin in advanced biliary tract and gallbladder carcinoma: a North Central Cancer Treatment Group phase II trial. Cancer. 2005 Jan 1;103(1):111-8. doi: 10.1002/cncr.20753.</citation>
    <PMID>15558814</PMID>
  </reference>
  <reference>
    <citation>Jensen LH, Lindebjerg J, Ploen J, Hansen TF, Jakobsen A. Phase II marker-driven trial of panitumumab and chemotherapy in KRAS wild-type biliary tract cancer. Ann Oncol. 2012 Sep;23(9):2341-2346. doi: 10.1093/annonc/mds008. Epub 2012 Feb 23.</citation>
    <PMID>22367707</PMID>
  </reference>
  <reference>
    <citation>Lubner SJ, Mahoney MR, Kolesar JL, Loconte NK, Kim GP, Pitot HC, Philip PA, Picus J, Yong WP, Horvath L, Van Hazel G, Erlichman CE, Holen KD. Report of a multicenter phase II trial testing a combination of biweekly bevacizumab and daily erlotinib in patients with unresectable biliary cancer: a phase II Consortium study. J Clin Oncol. 2010 Jul 20;28(21):3491-7. doi: 10.1200/JCO.2010.28.4075. Epub 2010 Jun 7.</citation>
    <PMID>20530271</PMID>
  </reference>
  <reference>
    <citation>Darwish Murad S, Kim WR, Harnois DM, Douglas DD, Burton J, Kulik LM, Botha JF, Mezrich JD, Chapman WC, Schwartz JJ, Hong JC, Emond JC, Jeon H, Rosen CB, Gores GJ, Heimbach JK. Efficacy of neoadjuvant chemoradiation, followed by liver transplantation, for perihilar cholangiocarcinoma at 12 US centers. Gastroenterology. 2012 Jul;143(1):88-98.e3; quiz e14. doi: 10.1053/j.gastro.2012.04.008. Epub 2012 Apr 12.</citation>
    <PMID>22504095</PMID>
  </reference>
  <reference>
    <citation>Kim YI, Park JW, Kim BH, Woo SM, Kim TH, Koh YH, Lee WJ, Kim CM. Outcomes of concurrent chemoradiotherapy versus chemotherapy alone for advanced-stage unresectable intrahepatic cholangiocarcinoma. Radiat Oncol. 2013 Dec 21;8:292. doi: 10.1186/1748-717X-8-292.</citation>
    <PMID>24359879</PMID>
  </reference>
  <reference>
    <citation>Ben-Josef E, Normolle D, Ensminger WD, Walker S, Tatro D, Ten Haken RK, Knol J, Dawson LA, Pan C, Lawrence TS. Phase II trial of high-dose conformal radiation therapy with concurrent hepatic artery floxuridine for unresectable intrahepatic malignancies. J Clin Oncol. 2005 Dec 1;23(34):8739-47. doi: 10.1200/JCO.2005.01.5354.</citation>
    <PMID>16314634</PMID>
  </reference>
  <reference>
    <citation>Servajean C, Gilabert M, Piana G, Monges G, Delpero JR, Brenot I, Raoul JL. One case of intrahepatic cholangiocarcinoma amenable to resection after radioembolization. World J Gastroenterol. 2014 May 7;20(17):5131-4. doi: 10.3748/wjg.v20.i17.5131.</citation>
    <PMID>24803830</PMID>
  </reference>
  <reference>
    <citation>Vouche M, Lewandowski RJ, Atassi R, Memon K, Gates VL, Ryu RK, Gaba RC, Mulcahy MF, Baker T, Sato K, Hickey R, Ganger D, Riaz A, Fryer J, Caicedo JC, Abecassis M, Kulik L, Salem R. Radiation lobectomy: time-dependent analysis of future liver remnant volume in unresectable liver cancer as a bridge to resection. J Hepatol. 2013 Nov;59(5):1029-36. doi: 10.1016/j.jhep.2013.06.015. Epub 2013 Jun 25.</citation>
    <PMID>23811303</PMID>
  </reference>
  <reference>
    <citation>Inarrairaegui M, Pardo F, Bilbao JI, Rotellar F, Benito A, D'Avola D, Herrero JI, Rodriguez M, Marti P, Zozaya G, Dominguez I, Quiroga J, Sangro B. Response to radioembolization with yttrium-90 resin microspheres may allow surgical treatment with curative intent and prolonged survival in previously unresectable hepatocellular carcinoma. Eur J Surg Oncol. 2012 Jul;38(7):594-601. doi: 10.1016/j.ejso.2012.02.189. Epub 2012 Mar 21.</citation>
    <PMID>22440743</PMID>
  </reference>
  <reference>
    <citation>Mullen JT, Ribero D, Reddy SK, Donadon M, Zorzi D, Gautam S, Abdalla EK, Curley SA, Capussotti L, Clary BM, Vauthey JN. Hepatic insufficiency and mortality in 1,059 noncirrhotic patients undergoing major hepatectomy. J Am Coll Surg. 2007 May;204(5):854-62; discussion 862-4. doi: 10.1016/j.jamcollsurg.2006.12.032. Epub 2007 Feb 15.</citation>
    <PMID>17481498</PMID>
  </reference>
  <reference>
    <citation>Marples B, Wouters BG, Collis SJ, Chalmers AJ, Joiner MC. Low-dose hyper-radiosensitivity: a consequence of ineffective cell cycle arrest of radiation-damaged G2-phase cells. Radiat Res. 2004 Mar;161(3):247-55. doi: 10.1667/rr3130.</citation>
    <PMID>14982490</PMID>
  </reference>
  <reference>
    <citation>Short SC, Woodcock M, Marples B, Joiner MC. Effects of cell cycle phase on low-dose hyper-radiosensitivity. Int J Radiat Biol. 2003 Feb;79(2):99-105.</citation>
    <PMID>12569013</PMID>
  </reference>
  <reference>
    <citation>Joiner MC, Marples B, Lambin P, Short SC, Turesson I. Low-dose hypersensitivity: current status and possible mechanisms. Int J Radiat Oncol Biol Phys. 2001 Feb 1;49(2):379-89. doi: 10.1016/s0360-3016(00)01471-1.</citation>
    <PMID>11173131</PMID>
  </reference>
  <reference>
    <citation>Kunos CA, Sill MW, Buekers TE, Walker JL, Schilder JM, Yamada SD, Waggoner SE, Mohiuddin M, Fracasso PM. Low-dose abdominal radiation as a docetaxel chemosensitizer for recurrent epithelial ovarian cancer: a phase I study of the Gynecologic Oncology Group. Gynecol Oncol. 2011 Feb;120(2):224-8. doi: 10.1016/j.ygyno.2010.10.018.</citation>
    <PMID>21075438</PMID>
  </reference>
  <reference>
    <citation>Arnold SM, Regine WF, Ahmed MM, Valentino J, Spring P, Kudrimoti M, Kenady D, Desimone P, Mohiuddin M. Low-dose fractionated radiation as a chemopotentiator of neoadjuvant paclitaxel and carboplatin for locally advanced squamous cell carcinoma of the head and neck: results of a new treatment paradigm. Int J Radiat Oncol Biol Phys. 2004 Apr 1;58(5):1411-7. doi: 10.1016/j.ijrobp.2003.09.019.</citation>
    <PMID>15050317</PMID>
  </reference>
  <reference>
    <citation>Harney J, Short SC, Shah N, Joiner M, Saunders MI. Low dose hyper-radiosensitivity in metastatic tumors. Int J Radiat Oncol Biol Phys. 2004 Jul 15;59(4):1190-5. doi: 10.1016/j.ijrobp.2003.12.029.</citation>
    <PMID>15234055</PMID>
  </reference>
  <reference>
    <citation>Joiner MC, Denekamp J. The effect of small radiation doses on mouse skin. Br J Cancer Suppl. 1986;7:63-6. No abstract available.</citation>
    <PMID>3459542</PMID>
  </reference>
  <reference>
    <citation>Krueger SA, Wilson GD, Piasentin E, Joiner MC, Marples B. The effects of G2-phase enrichment and checkpoint abrogation on low-dose hyper-radiosensitivity. Int J Radiat Oncol Biol Phys. 2010 Aug 1;77(5):1509-17. doi: 10.1016/j.ijrobp.2010.01.028.</citation>
    <PMID>20637979</PMID>
  </reference>
  <reference>
    <citation>Marples B, Wouters BG, Joiner MC. An association between the radiation-induced arrest of G2-phase cells and low-dose hyper-radiosensitivity: a plausible underlying mechanism? Radiat Res. 2003 Jul;160(1):38-45. doi: 10.1667/rr3013.</citation>
    <PMID>12816521</PMID>
  </reference>
  <reference>
    <citation>Regine WF, Hanna N, Garofalo MC, Doyle A, Arnold S, Kataria R, Sims J, Tan M, Mohiuddin M. Low-dose radiotherapy as a chemopotentiator of gemcitabine in tumors of the pancreas or small bowel: a phase I study exploring a new treatment paradigm. Int J Radiat Oncol Biol Phys. 2007 May 1;68(1):172-7. doi: 10.1016/j.ijrobp.2006.11.045. Epub 2007 Feb 2.</citation>
    <PMID>17276612</PMID>
  </reference>
  <reference>
    <citation>Wrenn DC, Saigal K, Lucci JA 3rd, Pearson MJ, Simpkins F, Schuman S, Twiggs LB, Walker GR, Wolfson AH. A Phase I Study using low-dose fractionated whole abdominal radiotherapy as a chemopotentiator to full-dose cisplatin for optimally debulked stage III/IV carcinoma of the endometrium. Gynecol Oncol. 2011 Jul;122(1):59-62. doi: 10.1016/j.ygyno.2011.03.007. Epub 2011 Apr 6.</citation>
    <PMID>21474169</PMID>
  </reference>
  <reference>
    <citation>Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47. doi: 10.1016/j.ejca.2008.10.026.</citation>
    <PMID>19097774</PMID>
  </reference>
  <verification_date>October 2018</verification_date>
  <study_first_submitted>September 30, 2014</study_first_submitted>
  <study_first_submitted_qc>October 1, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 2, 2014</study_first_posted>
  <results_first_submitted>March 14, 2018</results_first_submitted>
  <results_first_submitted_qc>October 2, 2018</results_first_submitted_qc>
  <results_first_posted type="Actual">October 3, 2018</results_first_posted>
  <last_update_submitted>October 2, 2018</last_update_submitted>
  <last_update_submitted_qc>October 2, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">October 3, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>low-dose radiotherapy</keyword>
  <keyword>gemcitabine</keyword>
  <keyword>cisplatin</keyword>
  <keyword>cholangiocarcinoma</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Cholangiocarcinoma</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Gemcitabine</mesh_term>
  </intervention_browse>

  <clinical_results>

    <participant_flow>
      <recruitment_details>6 subjects recruited from 9/2014-12/2015</recruitment_details>
      <group_list>
        <group group_id="P1">
          <title>Treatment</title>
          <description>Four three-week treatment cycles. Gemcitabine (1000 gm/m^2) and cisplatin (25 mg/m^2) administered on days one and eight of each cycle. Whole liver and portal lymph node basin low dose radiotherapy on days one, two, eight, and nine of each cycle.&#xD;
Gemcitabine&#xD;
Cisplatin&#xD;
Low dose whole liver and portal lymph node basin radiotherapy</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="6"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="6"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Lack of Efficacy</title>
              <participants_list>
                <participants group_id="P1" count="6"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Treatment</title>
          <description>Four three-week treatment cycles. Gemcitabine (1000 gm/m^2) and cisplatin (25 mg/m^2) administered on days one and eight of each cycle. Whole liver and portal lymph node basin low dose radiotherapy on days one, two, eight, and nine of each cycle.&#xD;
Gemcitabine&#xD;
Cisplatin&#xD;
Low dose whole liver and portal lymph node basin radiotherapy</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="6"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="64" spread="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="4"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Ethnicity (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="5"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Number of Participants With Radiographic Disease Response After Combination Low-dose Radiotherapy and Gemcitabine-cisplatin.</title>
        <description>Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by CT/MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), &gt;=30% decrease in the sum of the longest diameter of target lesions; Progressive Disease (PD), At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study).</description>
        <time_frame>16 weeks after treatment start</time_frame>
        <population>decision was made to close the study due to the futility of the regimen in the first 6 subjects, as well as the lack of funding to complete the study.</population>
        <group_list>
          <group group_id="O1">
            <title>Treatment</title>
            <description>Four three-week treatment cycles. Gemcitabine (1000 gm/m^2) and cisplatin (25 mg/m^2) administered on days one and eight of each cycle. Whole liver and portal lymph node basin low dose radiotherapy on days one, two, eight, and nine of each cycle.&#xD;
Gemcitabine&#xD;
Cisplatin&#xD;
Low dose whole liver and portal lymph node basin radiotherapy&#xD;
decision was made to close the study due to the futility of the regimen in the first 6 subjects, as well as the lack of funding to complete the study.</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With Radiographic Disease Response After Combination Low-dose Radiotherapy and Gemcitabine-cisplatin.</title>
          <description>Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by CT/MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), &gt;=30% decrease in the sum of the longest diameter of target lesions; Progressive Disease (PD), At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study).</description>
          <population>decision was made to close the study due to the futility of the regimen in the first 6 subjects, as well as the lack of funding to complete the study.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="6"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Stable Disease</title>
                  <measurement_list>
                    <measurement group_id="O1" value="5"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Partial Response</title>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Number of Participants With Adverse Events.</title>
        <description>Number of participants with adverse events during combined low-dose radiotherapy and gemcitabine-cisplatin treatment.</description>
        <time_frame>up to 16 weeks after treatment start</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Treatment</title>
            <description>Four three-week treatment cycles. Gemcitabine (1000 gm/m^2) and cisplatin (25 mg/m^2) administered on days one and eight of each cycle. Whole liver and portal lymph node basin low dose radiotherapy on days one, two, eight, and nine of each cycle.&#xD;
Gemcitabine&#xD;
Cisplatin&#xD;
Low dose whole liver and portal lymph node basin radiotherapy&#xD;
decision was made to close the study due to the futility of the regimen in the first 6 subjects, as well as the lack of funding to complete the study.</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With Adverse Events.</title>
          <description>Number of participants with adverse events during combined low-dose radiotherapy and gemcitabine-cisplatin treatment.</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="6"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Study related Adverse events</title>
                  <measurement_list>
                    <measurement group_id="O1" value="6"/>
                  </measurement_list>
                </category>
                <category>
                  <title>No study related Adverse Events</title>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Participants With Post-operative Complications After Partial Hepatectomy After Antecedent Combination Low-dose Radiotherapy and Gemcitabine-cisplatin.</title>
        <description>Measured post-operative complications include (but not limited to) bile leak, liver failure, ascites, infection, any organ failure or insufficiency, venous thromboembolism, and mortality.</description>
        <time_frame>up to 90 days after partial hepatectomy</time_frame>
        <population>1 of 6 subjects had surgery therefore only 1 subject was analyzed for post-operative complications.</population>
        <group_list>
          <group group_id="O1">
            <title>Treatment</title>
            <description>Four three-week treatment cycles. Gemcitabine (1000 gm/m^2) and cisplatin (25 mg/m^2) administered on days one and eight of each cycle. Whole liver and portal lymph node basin low dose radiotherapy on days one, two, eight, and nine of each cycle.&#xD;
Gemcitabine&#xD;
Cisplatin&#xD;
Low dose whole liver and portal lymph node basin radiotherapy&#xD;
decision was made to close the study due to the futility of the regimen in the first 6 subjects, as well as the lack of funding to complete the study.</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With Post-operative Complications After Partial Hepatectomy After Antecedent Combination Low-dose Radiotherapy and Gemcitabine-cisplatin.</title>
          <description>Measured post-operative complications include (but not limited to) bile leak, liver failure, ascites, infection, any organ failure or insufficiency, venous thromboembolism, and mortality.</description>
          <population>1 of 6 subjects had surgery therefore only 1 subject was analyzed for post-operative complications.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="1"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Participants With Histologic Disease Response After Combination Low-dose Radiotherapy and Gemcitabine-cisplatin.</title>
        <description>Tumor tissue will be obtained by either biopsy or liver resection after combination chemoradiotherapy. Histologic response will be determined by extent of viable tumor, tumor necrosis, and surrounding fibrosis.</description>
        <time_frame>16 weeks after start of first treatment</time_frame>
        <population>data not collected</population>
        <group_list>
          <group group_id="O1">
            <title>Treatment</title>
            <description>Four three-week treatment cycles. Gemcitabine (1000 gm/m^2) and cisplatin (25 mg/m^2) administered on days one and eight of each cycle. Whole liver and portal lymph node basin low dose radiotherapy on days one, two, eight, and nine of each cycle.&#xD;
Gemcitabine&#xD;
Cisplatin&#xD;
Low dose whole liver and portal lymph node basin radiotherapy&#xD;
decision was made to close the study due to the futility of the regimen in the first 6 subjects, as well as the lack of funding to complete the study.</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With Histologic Disease Response After Combination Low-dose Radiotherapy and Gemcitabine-cisplatin.</title>
          <description>Tumor tissue will be obtained by either biopsy or liver resection after combination chemoradiotherapy. Histologic response will be determined by extent of viable tumor, tumor necrosis, and surrounding fibrosis.</description>
          <population>data not collected</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Participants With Injury to the Background Liver After Combination Low-dose Radiotherapy and Gemcitabine-cisplatin.</title>
        <description>Background (non-tumor bearing) liver tissue will be obtained by either biopsy or liver resection after combination chemoradiotherapy. Histologic markers of Radiation Induced Liver disease will be measured.</description>
        <time_frame>16 weeks after start of first treatment.</time_frame>
        <population>data not collected</population>
        <group_list>
          <group group_id="O1">
            <title>Treatment</title>
            <description>Four three-week treatment cycles. Gemcitabine (1000 gm/m^2) and cisplatin (25 mg/m^2) administered on days one and eight of each cycle. Whole liver and portal lymph node basin low dose radiotherapy on days one, two, eight, and nine of each cycle.&#xD;
Gemcitabine&#xD;
Cisplatin&#xD;
Low dose whole liver and portal lymph node basin radiotherapy&#xD;
decision was made to close the study due to the futility of the regimen in the first 6 subjects, as well as the lack of funding to complete the study.</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With Injury to the Background Liver After Combination Low-dose Radiotherapy and Gemcitabine-cisplatin.</title>
          <description>Background (non-tumor bearing) liver tissue will be obtained by either biopsy or liver resection after combination chemoradiotherapy. Histologic markers of Radiation Induced Liver disease will be measured.</description>
          <population>data not collected</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Participants With Intrahepatic Recurrence After Partial Hepatectomy With Antecedent Combination Low-dose Radiotherapy and Gemcitabine-cisplatin.</title>
        <description>To determine the number of participants with Intrahepatic recurrence assessed by RECIST criteria using MRI of the abdomen with intravenous gadolinium contrast.</description>
        <time_frame>From date of partial hepatectomy until date of first documented recurrence or date of death from any cause, assessed up to 24 months.</time_frame>
        <population>Only 1 of the 6 subjects had surgery to assess recurrence after hepatectomy.</population>
        <group_list>
          <group group_id="O1">
            <title>Treatment</title>
            <description>Four three-week treatment cycles. Gemcitabine (1000 gm/m^2) and cisplatin (25 mg/m^2) administered on days one and eight of each cycle. Whole liver and portal lymph node basin low dose radiotherapy on days one, two, eight, and nine of each cycle.&#xD;
Gemcitabine&#xD;
Cisplatin&#xD;
liver and portal lymph node low dose Radiotherapy</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With Intrahepatic Recurrence After Partial Hepatectomy With Antecedent Combination Low-dose Radiotherapy and Gemcitabine-cisplatin.</title>
          <description>To determine the number of participants with Intrahepatic recurrence assessed by RECIST criteria using MRI of the abdomen with intravenous gadolinium contrast.</description>
          <population>Only 1 of the 6 subjects had surgery to assess recurrence after hepatectomy.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="1"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Participants With Intrahepatic Disease Progression After Treatment With Combination Low-dose Radiotherapy and Gemcitabine-cisplatin.</title>
        <description>To determine the number of participants with Intrahepatic disease progression assessed by MRI of the abdomen with intravenous gadolinium contrast using RECIST criteria.</description>
        <time_frame>From date of first treatment until date of first documented progression or date of death from any cause, which ever comes first, assessed up to 24 months.</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Treatment</title>
            <description>Four three-week treatment cycles. Gemcitabine (1000 gm/m^2) and cisplatin (25 mg/m^2) administered on days one and eight of each cycle. Whole liver and portal lymph node basin low dose radiotherapy on days one, two, eight, and nine of each cycle.&#xD;
Gemcitabine&#xD;
Cisplatin&#xD;
Low dose whole liver and portal lymph node basin radiotherapy&#xD;
decision was made to close the study due to the futility of the regimen in the first 6 subjects, as well as the lack of funding to complete the study.</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With Intrahepatic Disease Progression After Treatment With Combination Low-dose Radiotherapy and Gemcitabine-cisplatin.</title>
          <description>To determine the number of participants with Intrahepatic disease progression assessed by MRI of the abdomen with intravenous gadolinium contrast using RECIST criteria.</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="6"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>1.5 years</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Treatment</title>
          <description>Four three-week treatment cycles. Gemcitabine (1000 gm/m^2) and cisplatin (25 mg/m^2) administered on days one and eight of each cycle. Whole liver and portal lymph node basin low dose radiotherapy on days one, two, eight, and nine of each cycle.&#xD;
Gemcitabine&#xD;
Cisplatin&#xD;
Low dose whole liver and portal lymph node basin radiotherapy</description>
        </group>
      </group_list>
      <serious_events>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Hepatobiliary disorders</title>
            <event_list>
              <event>
                <sub_title>cholelithiasis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>anemia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>nausea</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>pain</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>neutropenia</sub_title>
                <counts group_id="E1" events="4" subjects_affected="4" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>thrombocytopenia</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>hypomagnesemia</sub_title>
                <counts group_id="E1" events="5" subjects_affected="3" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>hyponatremia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>All Principal Investigators ARE employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Srinevas K. Reddy</name_or_title>
      <organization>Allina Health</organization>
      <phone>612-863-8716</phone>
      <email>laura.rockwell@allina.com</email>
    </point_of_contact>
  </clinical_results>
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT02254681
org study id: VPSR-1401
nct id: NCT02254681
lead sponsor: 
has dmc: Yes
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.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Number of Participants With Radiographic Disease Response After Combination Low-dose Radiotherapy and Gemcitabine-cisplatin.
time frame: 16 weeks after treatment start
description: Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by CT/MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Progressive Disease (PD), At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study).
measure: Number of Participants With Adverse Events.
time frame: up to 16 weeks after treatment start
description: Number of participants with adverse events during combined low-dose radiotherapy and gemcitabine-cisplatin treatment.
measure: Number of Participants With Post-operative Complications After Partial Hepatectomy After Antecedent Combination Low-dose Radiotherapy and Gemcitabine-cisplatin.
time frame: up to 90 days after partial hepatectomy
description: Measured post-operative complications include (but not limited to) bile leak, liver failure, ascites, infection, any organ failure or insufficiency, venous thromboembolism, and mortality.
measure: Number of Participants With Histologic Disease Response After Combination Low-dose Radiotherapy and Gemcitabine-cisplatin.
time frame: 16 weeks after start of first treatment
description: Tumor tissue will be obtained by either biopsy or liver resection after combination chemoradiotherapy. Histologic response will be determined by extent of viable tumor, tumor necrosis, and surrounding fibrosis.
measure: Number of Participants With Injury to the Background Liver After Combination Low-dose Radiotherapy and Gemcitabine-cisplatin.
time frame: 16 weeks after start of first treatment.
description: Background (non-tumor bearing) liver tissue will be obtained by either biopsy or liver resection after combination chemoradiotherapy. Histologic markers of Radiation Induced Liver disease will be measured.
measure: Number of Participants With Intrahepatic Recurrence After Partial Hepatectomy With Antecedent Combination Low-dose Radiotherapy and Gemcitabine-cisplatin.
time frame: From date of partial hepatectomy until date of first documented recurrence or date of death from any cause, assessed up to 24 months.
description: To determine the number of participants with Intrahepatic recurrence assessed by RECIST criteria using MRI of the abdomen with intravenous gadolinium contrast.
measure: Number of Participants With Intrahepatic Disease Progression After Treatment With Combination Low-dose Radiotherapy and Gemcitabine-cisplatin.
time frame: From date of first treatment until date of first documented progression or date of death from any cause, which ever comes first, assessed up to 24 months.
description: To determine the number of participants with Intrahepatic disease progression assessed by MRI of the abdomen with intravenous gadolinium contrast using RECIST criteria.
arm group label: Treatment
arm group type: Experimental
description: Four three-week treatment cycles. Gemcitabine (1000 gm/m^2) and cisplatin (25 mg/m^2) administered on days one and eight of each cycle. Whole liver and portal lymph node basin low dose radiotherapy on days one, two, eight, and nine of each cycle.
intervention type: Drug
intervention name: Gemcitabine
arm group label: Treatment
other name: Gemzar
intervention type: Drug
intervention name: Cisplatin
arm group label: Treatment
other name: Platinol
intervention type: Radiation
intervention name: low dose radiotherapy
description: Whole liver and portal lymph node basin low dose radiotherapy
arm group label: Treatment
criteria: 
gender: All
minimum age: 18 Years
maximum age: 99 Years
healthy volunteers: No
last name: Srinevas K Reddy, MD
role: Principal Investigator
affiliation: Allina Health System
facility: 
country: United States
citation: Bridgewater J, Galle PR, Khan SA, Llovet JM, Park JW, Patel T, Pawlik TM, Gores GJ. Guidelines for the diagnosis and management of intrahepatic cholangiocarcinoma. J Hepatol. 2014 Jun;60(6):1268-89. doi: 10.1016/j.jhep.2014.01.021. Epub 2014 Mar 27. No abstract available.
PMID: 24681130
citation: Rizvi S, Gores GJ. Pathogenesis, diagnosis, and management of cholangiocarcinoma. Gastroenterology. 2013 Dec;145(6):1215-29. doi: 10.1053/j.gastro.2013.10.013. Epub 2013 Oct 15.
PMID: 24140396
citation: de Jong MC, Nathan H, Sotiropoulos GC, Paul A, Alexandrescu S, Marques H, Pulitano C, Barroso E, Clary BM, Aldrighetti L, Ferrone CR, Zhu AX, Bauer TW, Walters DM, Gamblin TC, Nguyen KT, Turley R, Popescu I, Hubert C, Meyer S, Schulick RD, Choti MA, Gigot JF, Mentha G, Pawlik TM. Intrahepatic cholangiocarcinoma: an international multi-institutional analysis of prognostic factors and lymph node assessment. J Clin Oncol. 2011 Aug 10;29(23):3140-5. doi: 10.1200/JCO.2011.35.6519. Epub 2011 Jul 5.
PMID: 21730269
citation: Endo I, Gonen M, Yopp AC, Dalal KM, Zhou Q, Klimstra D, D'Angelica M, DeMatteo RP, Fong Y, Schwartz L, Kemeny N, O'Reilly E, Abou-Alfa GK, Shimada H, Blumgart LH, Jarnagin WR. Intrahepatic cholangiocarcinoma: rising frequency, improved survival, and determinants of outcome after resection. Ann Surg. 2008 Jul;248(1):84-96. doi: 10.1097/SLA.0b013e318176c4d3.
PMID: 18580211
citation: Lang H, Sotiropoulos GC, Sgourakis G, Schmitz KJ, Paul A, Hilgard P, Zopf T, Trarbach T, Malago M, Baba HA, Broelsch CE. Operations for intrahepatic cholangiocarcinoma: single-institution experience of 158 patients. J Am Coll Surg. 2009 Feb;208(2):218-28. doi: 10.1016/j.jamcollsurg.2008.10.017.
PMID: 19228533
citation: Choi SB, Kim KS, Choi JY, Park SW, Choi JS, Lee WJ, Chung JB. The prognosis and survival outcome of intrahepatic cholangiocarcinoma following surgical resection: association of lymph node metastasis and lymph node dissection with survival. Ann Surg Oncol. 2009 Nov;16(11):3048-56. doi: 10.1245/s10434-009-0631-1. Epub 2009 Jul 22.
PMID: 19626372
citation: Paik KY, Jung JC, Heo JS, Choi SH, Choi DW, Kim YI. What prognostic factors are important for resected intrahepatic cholangiocarcinoma? J Gastroenterol Hepatol. 2008 May;23(5):766-70. doi: 10.1111/j.1440-1746.2007.05040.x. Epub 2007 Sep 12.
PMID: 17868336
citation: Nakagohri T, Kinoshita T, Konishi M, Takahashi S, Gotohda N. Surgical outcome and prognostic factors in intrahepatic cholangiocarcinoma. World J Surg. 2008 Dec;32(12):2675-80. doi: 10.1007/s00268-008-9778-3.
PMID: 18843437
citation: Tamandl D, Herberger B, Gruenberger B, Puhalla H, Klinger M, Gruenberger T. Influence of hepatic resection margin on recurrence and survival in intrahepatic cholangiocarcinoma. Ann Surg Oncol. 2008 Oct;15(10):2787-94. doi: 10.1245/s10434-008-0081-1. Epub 2008 Aug 7.
PMID: 18685896
citation: Valle J, Wasan H, Palmer DH, Cunningham D, Anthoney A, Maraveyas A, Madhusudan S, Iveson T, Hughes S, Pereira SP, Roughton M, Bridgewater J; ABC-02 Trial Investigators. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med. 2010 Apr 8;362(14):1273-81. doi: 10.1056/NEJMoa0908721.
PMID: 20375404
citation: Woo SM, Lee WJ, Kim JH, Kim DH, Han SS, Park SJ, Kim TH, Lee JH, Koh YH, Hong EK. Gemcitabine plus cisplatin versus capecitabine plus cisplatin as first-line chemotherapy for advanced biliary tract cancer: a retrospective cohort study. Chemotherapy. 2013;59(3):232-8. doi: 10.1159/000354539. Epub 2013 Dec 13.
PMID: 24356333
citation: Alberts SR, Al-Khatib H, Mahoney MR, Burgart L, Cera PJ, Flynn PJ, Finch TR, Levitt R, Windschitl HE, Knost JA, Tschetter LK. Gemcitabine, 5-fluorouracil, and leucovorin in advanced biliary tract and gallbladder carcinoma: a North Central Cancer Treatment Group phase II trial. Cancer. 2005 Jan 1;103(1):111-8. doi: 10.1002/cncr.20753.
PMID: 15558814
citation: Jensen LH, Lindebjerg J, Ploen J, Hansen TF, Jakobsen A. Phase II marker-driven trial of panitumumab and chemotherapy in KRAS wild-type biliary tract cancer. Ann Oncol. 2012 Sep;23(9):2341-2346. doi: 10.1093/annonc/mds008. Epub 2012 Feb 23.
PMID: 22367707
citation: Lubner SJ, Mahoney MR, Kolesar JL, Loconte NK, Kim GP, Pitot HC, Philip PA, Picus J, Yong WP, Horvath L, Van Hazel G, Erlichman CE, Holen KD. Report of a multicenter phase II trial testing a combination of biweekly bevacizumab and daily erlotinib in patients with unresectable biliary cancer: a phase II Consortium study. J Clin Oncol. 2010 Jul 20;28(21):3491-7. doi: 10.1200/JCO.2010.28.4075. Epub 2010 Jun 7.
PMID: 20530271
citation: Darwish Murad S, Kim WR, Harnois DM, Douglas DD, Burton J, Kulik LM, Botha JF, Mezrich JD, Chapman WC, Schwartz JJ, Hong JC, Emond JC, Jeon H, Rosen CB, Gores GJ, Heimbach JK. Efficacy of neoadjuvant chemoradiation, followed by liver transplantation, for perihilar cholangiocarcinoma at 12 US centers. Gastroenterology. 2012 Jul;143(1):88-98.e3; quiz e14. doi: 10.1053/j.gastro.2012.04.008. Epub 2012 Apr 12.
PMID: 22504095
citation: Kim YI, Park JW, Kim BH, Woo SM, Kim TH, Koh YH, Lee WJ, Kim CM. Outcomes of concurrent chemoradiotherapy versus chemotherapy alone for advanced-stage unresectable intrahepatic cholangiocarcinoma. Radiat Oncol. 2013 Dec 21;8:292. doi: 10.1186/1748-717X-8-292.
PMID: 24359879
citation: Ben-Josef E, Normolle D, Ensminger WD, Walker S, Tatro D, Ten Haken RK, Knol J, Dawson LA, Pan C, Lawrence TS. Phase II trial of high-dose conformal radiation therapy with concurrent hepatic artery floxuridine for unresectable intrahepatic malignancies. J Clin Oncol. 2005 Dec 1;23(34):8739-47. doi: 10.1200/JCO.2005.01.5354.
PMID: 16314634
citation: Servajean C, Gilabert M, Piana G, Monges G, Delpero JR, Brenot I, Raoul JL. One case of intrahepatic cholangiocarcinoma amenable to resection after radioembolization. World J Gastroenterol. 2014 May 7;20(17):5131-4. doi: 10.3748/wjg.v20.i17.5131.
PMID: 24803830
citation: Vouche M, Lewandowski RJ, Atassi R, Memon K, Gates VL, Ryu RK, Gaba RC, Mulcahy MF, Baker T, Sato K, Hickey R, Ganger D, Riaz A, Fryer J, Caicedo JC, Abecassis M, Kulik L, Salem R. Radiation lobectomy: time-dependent analysis of future liver remnant volume in unresectable liver cancer as a bridge to resection. J Hepatol. 2013 Nov;59(5):1029-36. doi: 10.1016/j.jhep.2013.06.015. Epub 2013 Jun 25.
PMID: 23811303
citation: Inarrairaegui M, Pardo F, Bilbao JI, Rotellar F, Benito A, D'Avola D, Herrero JI, Rodriguez M, Marti P, Zozaya G, Dominguez I, Quiroga J, Sangro B. Response to radioembolization with yttrium-90 resin microspheres may allow surgical treatment with curative intent and prolonged survival in previously unresectable hepatocellular carcinoma. Eur J Surg Oncol. 2012 Jul;38(7):594-601. doi: 10.1016/j.ejso.2012.02.189. Epub 2012 Mar 21.
PMID: 22440743
citation: Mullen JT, Ribero D, Reddy SK, Donadon M, Zorzi D, Gautam S, Abdalla EK, Curley SA, Capussotti L, Clary BM, Vauthey JN. Hepatic insufficiency and mortality in 1,059 noncirrhotic patients undergoing major hepatectomy. J Am Coll Surg. 2007 May;204(5):854-62; discussion 862-4. doi: 10.1016/j.jamcollsurg.2006.12.032. Epub 2007 Feb 15.
PMID: 17481498
citation: Marples B, Wouters BG, Collis SJ, Chalmers AJ, Joiner MC. Low-dose hyper-radiosensitivity: a consequence of ineffective cell cycle arrest of radiation-damaged G2-phase cells. Radiat Res. 2004 Mar;161(3):247-55. doi: 10.1667/rr3130.
PMID: 14982490
citation: Short SC, Woodcock M, Marples B, Joiner MC. Effects of cell cycle phase on low-dose hyper-radiosensitivity. Int J Radiat Biol. 2003 Feb;79(2):99-105.
PMID: 12569013
citation: Joiner MC, Marples B, Lambin P, Short SC, Turesson I. Low-dose hypersensitivity: current status and possible mechanisms. Int J Radiat Oncol Biol Phys. 2001 Feb 1;49(2):379-89. doi: 10.1016/s0360-3016(00)01471-1.
PMID: 11173131
citation: Kunos CA, Sill MW, Buekers TE, Walker JL, Schilder JM, Yamada SD, Waggoner SE, Mohiuddin M, Fracasso PM. Low-dose abdominal radiation as a docetaxel chemosensitizer for recurrent epithelial ovarian cancer: a phase I study of the Gynecologic Oncology Group. Gynecol Oncol. 2011 Feb;120(2):224-8. doi: 10.1016/j.ygyno.2010.10.018.
PMID: 21075438
citation: Arnold SM, Regine WF, Ahmed MM, Valentino J, Spring P, Kudrimoti M, Kenady D, Desimone P, Mohiuddin M. Low-dose fractionated radiation as a chemopotentiator of neoadjuvant paclitaxel and carboplatin for locally advanced squamous cell carcinoma of the head and neck: results of a new treatment paradigm. Int J Radiat Oncol Biol Phys. 2004 Apr 1;58(5):1411-7. doi: 10.1016/j.ijrobp.2003.09.019.
PMID: 15050317
citation: Harney J, Short SC, Shah N, Joiner M, Saunders MI. Low dose hyper-radiosensitivity in metastatic tumors. Int J Radiat Oncol Biol Phys. 2004 Jul 15;59(4):1190-5. doi: 10.1016/j.ijrobp.2003.12.029.
PMID: 15234055
citation: Joiner MC, Denekamp J. The effect of small radiation doses on mouse skin. Br J Cancer Suppl. 1986;7:63-6. No abstract available.
PMID: 3459542
citation: Krueger SA, Wilson GD, Piasentin E, Joiner MC, Marples B. The effects of G2-phase enrichment and checkpoint abrogation on low-dose hyper-radiosensitivity. Int J Radiat Oncol Biol Phys. 2010 Aug 1;77(5):1509-17. doi: 10.1016/j.ijrobp.2010.01.028.
PMID: 20637979
citation: Marples B, Wouters BG, Joiner MC. An association between the radiation-induced arrest of G2-phase cells and low-dose hyper-radiosensitivity: a plausible underlying mechanism? Radiat Res. 2003 Jul;160(1):38-45. doi: 10.1667/rr3013.
PMID: 12816521
citation: Regine WF, Hanna N, Garofalo MC, Doyle A, Arnold S, Kataria R, Sims J, Tan M, Mohiuddin M. Low-dose radiotherapy as a chemopotentiator of gemcitabine in tumors of the pancreas or small bowel: a phase I study exploring a new treatment paradigm. Int J Radiat Oncol Biol Phys. 2007 May 1;68(1):172-7. doi: 10.1016/j.ijrobp.2006.11.045. Epub 2007 Feb 2.
PMID: 17276612
citation: Wrenn DC, Saigal K, Lucci JA 3rd, Pearson MJ, Simpkins F, Schuman S, Twiggs LB, Walker GR, Wolfson AH. A Phase I Study using low-dose fractionated whole abdominal radiotherapy as a chemopotentiator to full-dose cisplatin for optimally debulked stage III/IV carcinoma of the endometrium. Gynecol Oncol. 2011 Jul;122(1):59-62. doi: 10.1016/j.ygyno.2011.03.007. Epub 2011 Apr 6.
PMID: 21474169
citation: Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47. doi: 10.1016/j.ejca.2008.10.026.
PMID: 19097774
responsible party type: Sponsor
mesh term: Cholangiocarcinoma
mesh term: Gemcitabine
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 