Advanced hepatobiliary and pancreatic cancers are incurable, and presently there is no standard chemotherapy or chemotherapeutic regimen for these diseases. In most studies, fluorouracil (5-FU) alone or 5-FU-based regimens have consistently yielded response rates of less than 20%. UFT (tegafur and uracil) has been studied extensively in Japan, and combined phase II data from 438 cancer patients treated with this drug indicate overall cancer response rates of 25% (pancreatic), 25% (gallbladder and bile duct), and 19% (liver). Retrospective analysis of one uncontrolled Japanese study showed that patients with pancreatic cancer who received UFT 400 to 600 mg/m2/day had significantly better overall survival than those who had not received UFT (P = .009). In addition, several case reports in the Japanese literature document complete remissions of primary hepatobiliary tumors after prolonged exposure to UFT.[3,4]
There have been no published reports of UFT in the treatment of pancreatic and hepatobiliary tumors in the United States, leading to initiation of this trial. The rationale for our trial is that oral UFT is more convenient to administer than intravenous 5-FU and its bioavailability is better and less erratic than that of oral 5-FU. Further, given the mild to moderate toxicity profile of UFT, it serves as a reasonable drug choice for palliation.
The primary objective of our trial is to determine the patient response to UFT by histologic category; specifically, hepatoma, cholangiocarcinoma/bile duct tumors, and pancreatic adenocarcinomas. Our secondary objective is to determine response duration, time to disease progression, overall survival, quality of life, and toxicity.
The study is designed as a single-arm, multicenter, open-label phase II trial. It has been initiated at eight sites (seven under the direction of the University of Chicago Phase II Consortium, which includes the University of Chicago Medical Center; Fort Wayne Medical Center, Fort Wayne Indiana; Michiana Hematology/Oncology, South Bend, Indiana; Lutheran General Hospital, Parkridge, Illinois; Oncology/Hematology Association, Peoria, Illinois; University of Illinois at Chicago; and Weiss Memorial Hospital, Chicago, Illinois). All registration and patient data management are coordinated through our central data management office at the University of Chicago.
Study Inclusion Criteria
Patients are required to have histologic or cytologic proof of locally advanced or metastatic hepatoma, cholangiocarcinoma or bile duct cancer, or pancreatic carcinoma. Eligibility also calls for bidimensionally measurable disease by computed tomography or ultrasound; at least 18 years of age; and a Karnofsky performance status of 60% or higher. Patients must have adequate organ function with an absolute neutrophil count of at least 1,500/µL, platelets of at least 100,000/µL (or at least 75,000/µL for those with hepatobiliary primary tumor), total bilirubin of 1.5 mg/dL or less (or, in the case of hepatobiliary primary tumor, no more than 2.0 × upper limits of normal), alanine aminotransferase and/or aspartate aminotransferase of no more than 2.5
´ upper limits of normal, albumin levels at least 2.5 mg/dL, and creatinine levels 2.0 mg/dL or less. Patients must be enrolled in the study within 10 weeks of documentation of metastatic disease. Patients with prior chemotherapy for metastatic disease are ineligible for enrollment in the study.
Schema of Study
Patients who meet the eligibility criteria are given oral UFT 300 mg/m2/day and leucovorin 90 mg/day for 28 days, repeated every 35 days. Physical examination and symptom assessment are done every 5 weeks and computed tomography scans are performed every 10 weeks. The patients are treated until the appearance of disease progression or unacceptable toxicity. If the disease is stable or responding, treatment may continue for as long as the patient and physician believe it is in the patients best interest.
The starting dose of UFT has been set at 300 mg/m2/day, divided into three doses, with leucovorin 90 mg/day, divided into three doses. If UFT dosing must be delayed, leucovorin also will be delayed. The leucovorin dose does not change. Treatment with UFT is continued until day 28. Treatment is not extended longer than 28 days from the start of the treatment cycle, regardless of whether UFT dosing has been delayed for toxicity. In consideration of hematologic toxicity, granulocyte levels of 1,000/µL or less or platelets of 50,000/µL or less call for delayed dosing of UFT and leucovorin until granulocytes recover to at least 1,500/µL and platelets to at least 100,000/µL. For nonhematologic toxicity, UFT and leucovorin dosing is delayed for toxicity grades 2 and greater and treatment is resumed when toxicity subsides to baseline or grade 1 or less.
Re-treatmenttreatment at the next cycleis initiated only if the granulocyte and platelet levels are at least 1,500µL and 100,000/µL, respectively, and all nonhematologic toxicity, other than alopecia, has reverted to baseline or grade 1 or less. If treatment is delayed for more than 2 weeks, the patient is discontinued from the study. For dose-level adjustment and subsequent dose modification of UFT and leucovorin, the dose is adjusted to the highest toxicity grade in the previous cycle; for example, if the highest toxicity level is within grades 0 to 2, the same dose level is chosen, but if toxicity reaches grade 3 or 4, the dose is decreased by one dose level. Once decreased, the dose cannot be increased again. Dose modifications based on dose level are shown in Table 1.
All patients are evaluable for toxicity from the time of first chemotherapy dose. All patients who undergo one or more treatment cycles are evaluable for response. Standard tumor measurements are used, although we also include patients with unidimensionally measurable tumors. In keeping with this definition:
- Complete response is defined as complete disappearance of the tumor for at least 4 weeks from documentation of the complete response;
- Partial response is defined as more than a 50% decrease in the sum of the products of the two largest perpendicular diameters of all measurable lesions, as determined 4 weeks apart consecutively;
- Stable disease describes neither a complete response nor a partial response, but also no objective progression;
- Progressive disease is defined as a 25% or greater increase in the size of any measurable lesion or the appearance of new lesions or ascites.
Time to response is measured from the first treatment day to the day the response is recorded, and time to progression from the first treatment day to the date of identification of progressive disease or death. Duration of response is measured from the date of response notation to the date of the first record of disease progression or death, and survival is measured from the first day of treatment to death.
Symptom and Quality of Life Assessments
Symptom assessment is performed every 5 weeks and includes: evaluation of pain using a Memorial Sloan-Kettering pain scale, analgesic consumption (documented in morphine equivalents), performance status (documented by the Karnofsky scale), weight, and time unable to perform baseline activities. A European Organization for Research and Treatment of Cancer QLQ-C30 form, which comprises 30 questions that measure function, status symptoms, and global health, is also used. Evaluation forms are answered by the patient alone in the clinic waiting area; forms are not sent home with the patient.
The primary end point of this study is to establish objective response rates in each of the three histologic categories: hepatoma, bile duct/cholangiocarcinoma, and pancreatic adenocarci- noma. Secondary end points are survival, time to progression, remission duration, quality of life, and toxicity. The median time to progression and remission duration will be estimated using the Kaplan-Meier method; and quality of life and toxicity will be described using appropriate descriptive analysis. The sample size is set by a Simon two-stage design: In stage 1, we expect to enroll 14 evaluable patients in each of the three histologic subgroups, with enrollment stopped if there are no responses. If no responseseither complete response or partial responseare observed, the patient enrollment in that group will be stopped with the conclusion that the treatment is not active. It is not likely to be 0.2 or greater. This ensures that the probability of stopping enrollment in a histologic group with a response rate of 0.2 or less is less than 0.05. If at least one patient responds among the initial 14 evaluable patients in a given histologic group, stage 2 will involve enrollment of an additional 11 patients, for a total of 25 patients in that group. This allows the response rate to be estimated for that group with a standard error of less than 0.10. The total number of patients in the study will be between 42 and 75.
All but one site opened in October 1996; LaGrange Hospital (outside our phase II consortium) was initiated in December 1996.
Results are very preliminary, as most patients enrolled are too early to evaluate for response (Table 2). One patient died of progressive gallbladder cancer while being treated with UFT and leucovorin. Another patient died during treatment due to a pulmonary embolus that was probably caused by the underlying tumor rather than by treatment.
1. Ota K, Taguchi T, Kimura K: Report on nationwide pooled data and cohort investigation in UFT phase II study. Cancer Chemother Pharmacol 22:333-338, 1988.
2. Ohashi O, Yamamoto M, Ishida H, et al: Retrospective analysis of postoperative chemotherapy with UFT against pancreatic cancer. Gan To Kagaku Ryoho 22:933-993, 1995.
3. Kitamura T, Maruyama T, Nakamura H, et al: Therapy of hepatocellular carcinoma with UFTclinical evaluation of its effect in the combination therapy with transcatheter arterial embolization or one shot therapy. Gan To Kagaku Ryoho 17:1467-1471, 1990.
4. Kurihara M: Clinical experience with UFT in Japan. Adv Exp Med Biol 339:243-251, 1993.