UFT, Leucovorin, and Radiation Therapy: A Novel Approach to Treating Pancreatic
August 1, 1999
UFT, Leucovorin, and Radiation Therapy: A Novel Approach to Treating Pancreatic Cancer
By Hoyt Abner Childs III, MD, and Francisco Robert, MD
Randomized, prospective trials have established 5-fluorouracil (5-FU) based chemotherapy and radiation as acceptable treatment options for pancreatic cancer, both in the adjuvant setting and as definitive management of unresectable tumors. UFT is an oral anti-neoplastic agent that combines the 5-FU pro-drug Tegafur with Uracil in a 1:4 molar ratio. Uracil competitively inhibits the catabolism of 5-FU, resulting in increased plasma and tumor 5-FU concentrations. The prolonged elimination half life of 5-FU following UFT administration (7 hours) provides the basis for the use of this agent as a radiosensitizer. UFT and Leucovorin have been proven in phase II trials to have acceptable toxicity and response in colorectal cancers, and seem to afford a treatment alternative to infusional 5-FU. Because survival rates with pancreatic cancer are still quite poor, we hoped to find a more tolerable, and hopefully efficacious, treatment regimen for this disease.
Background
In 1998, there were 28,600 cases of pancreatic cancer, with an equal number of deaths, as reported by the American Cancer Society. Of these, fewer than 15% of the patients were candidates for curative resection, and unfortunately, only half of this 15% will have locally or regionally confined tumors. Even patients who undergo pancreatico- duodenectomy alone have a high incidence of local tumor recurrence (50-80%), with a median survival of only 12 months. However, there are prospective and retrospective data that address the use of multi-modality therapy in patients with localized pancreatic cancer. Both resectable and unresectable cases have been evaluated, and multi-modality therapy seems to improve survival duration as well as improve local regional tumor control in each situation. The best available data suggest that 5-FU-based chemotherapy and radiation confer the most significant benefits.
Two Gastrointestinal Study Group (GTSG) studies specifically address the treatment of pancreatic cancer with combined modality therapy. The first was conducted with resectable disease, and with a combined regimen of 5-FU chemotherapy and radiotherapy protocol given adjuvantly, median survival was increased from 10.9 months to 21 months in favor of the chemotherapy/radiotherapy group.1 This trial randomized resected patients either to no further therapy or irradiation and 5-FU chemotherapy. Twenty-two patients were observed and 23 received combined modality therapy consisting of 40 Gy in a six-week split course with 500mg/m2 of 5-FU on days 1-3 of each course. There was a statistical increase in survival (P < 0.05) in the treatment arm, with 42% of patients surviving two years and 14% surviving five years compared to 15% and 5% of controls, respectively. The GTSG then treated another 30 patients on the combined modality arm to verify the results.7
Another study by the GTSG was performed for unresectable disease and also similarly doubled median survival, increasing such survival from 5.2 months to 9.6 months in favor of the chemotherapy/radiotherapy group.2 The randomization was different in that it was a three-arm trial with radiation alone to 60 Gy split course as a control arm in 25 patients. The other two arms, 83 and 86 patients respectively, both received 5-FU chemotherapy with either 40 Gy or 60 Gy split-course radiation. The superior arm was found to be the 40 Gy and 5-FU arm because it demonstrated an increase in two-year survival from 5% to 10%, with acceptable toxicity. With an exception from the Eastern Cooperative Oncology Group, other studies from the Mayo Clinic, Duke University, and Thomas Jefferson University solidify the superiority of combined 5-FU chemoradiotherapy over either alone in the treatment of pancreatic cancer.2-10
5-FU has also been proven to act as a radiosensitizer. A basic biochemical (pre-clinical) prerequisite for 5-FU radiosensitization is that 5-FU must be present after each radiation exposure, the concentration of 5-FU must be high enough to yield a cytotoxic effect from the drug alone, and the duration of 5-FU must be at least one full cell cycle in length.11 Because of the short half-life of 5-FU (7-13 minutes), this prerequisite can be met only by continuously infused 5-FU. Continuous infusion 5-FU has been proven to be superior to bolus 5-FU in rectal cancer and, through a phase I study from the ECOG, may have promise in unresectable pancreatic cancer as well.18 As with other chemotherapies, 5-FU may also have spatial cooperation with radiotherapy treating distant sites of micro-metastatic disease while the radiation serves to treat the local disease.
UFT
UFT is an oral anti-neoplastic agent that combines the 5-FU pro-drug Tegafur (1-[2-tetrahydrofuryl]-5-fluorouracil) and Uracil in a molar ratio of 1:4. Tegafur is hydroxylated and converted to 5-FU by the hepatic microsomal enzymes and may lead to a sustained level of 5-FU in tumors. Uracil is also known to competitively inhibit the activity of hepatic dihydropyrimidine dehydrogenase, thus, blocking the catabolism of 5-FU and resulting in increased plasma and tumor concentrations. UFT thus has a longer half-life than 5-FU (7 hours) and this provides the basis for its use as a radiosensitizer. (See Figure 1.) Calcium Folinate (Leucovorin Calcium) may enhance the cytotoxic effect of UFT by stabilizing the covalent ternary enzyme complex (FdUMP/TS). (See Figure 2.) 5-FU inhibits thymidine synthase through its metabolite, 5-fluorodeoxyuridine 5’-monophosphate (FdUMP), which causes inhibition of the de novo production of thymidylate (dTMP) from deoxyuridine monophosphate (dUMP). Depletion of the thymidine triphosphate pool (dTTP) consequently interferes with DNA synthesis.
UFT has been tested in phase I and II studies from Japan and Spain in colorectal cancer and here in the United States at MD Anderson Cancer Center and Roswell Park Cancer Institute.12-15 Toxicity has proven to be fairly mild, with the dose-limiting toxicities occurring mainly at levels of 350 mg/m2 or higher. The toxicities that were noticed, although mild, included diarrhea, fatigue, nausea, and, more rarely, hematologic dysfunction. UFT has also been combined with cisplatin in the treatment of advanced non-small cell lung cancer, with the authors noting equivalent efficacy and reduced myelosuppresion compared with other cisplatin-based regimens.16
In 1994, one group of investigators at MD Anderson Cancer Center reported some of the first data from the United States regarding the use of UFT.14 After completing a phase I trial and determining the dose-limiting toxicity of diarrhea, they began a phase II trial in patients with metastatic colorectal cancer at 350 mg/m2 of daily UFT. This was given with 150 mg/d of Leucovorin, and both were divided every eight hours for 28 days. Of note, the dose of UFT was lowered during the protocol to 300 mg/m2, as a significant percentage of patients (5 of 7) developed prolonged grade 3 diarrhea. At a dose of 300 mg/m2, however, only four of 38 patients developed grade 3 diarrhea. Other significant toxicities included vomiting, abdominal cramping, and fatigue. The expected limiting side effects of intravenous regimens of 5-FU, namely neutropenia and severe oral mucositis, were not observed. The authors performed extensive pharmacokinetic studies and were not able to relate the parameters with the dose-limiting toxicity of diarrhea. The authors also report a 42% response rate and planned to test the regimen in a phase III trial. This trial was begun in 1995 and the authors plan to treat 600 patients with metastatic colorectal cancer with either 5-FU/LV or UFT/LV.15 They have, similar to our trial, lowered the dose of leucovorin as the absorption falls at doses higher than 75 mg.
Twenty-one patients have been enrolled in a phase II study conducted at Memorial Sloan-Kettering Cancer Center and at the University of Southern California with UFT and low-dose Leucovorin (15 mg/d).19 At a UFT dose of 350 mg/m2/d for 28 days followed by seven days of rest, grade 3 digestive events included nausea and vomiting. These events were possibly related to protocol therapy. Three patients also experienced grade 3 diarrhea that was probably related to protocol therapy and one additional patient had grade 4 diarrhea. Chemotherapy was stopped until diarrhea completely resolved and then was restarted at a reduced dose. No patient had greater than grade 3 myelosuppression. Four patients achieved a partial response and one more achieved complete response. A phase III trial between this therapy and conventional parenteral 5-FU and leucovorin was felt to be warranted.
One group of investigators recently reported on 144 patients with advanced colorectal cancer treated with 300 mg/m2 of UFT and 150 mg of leucovorin given three times a day for 28 days with a one week break.13 The incidence of diarrhea (15%) and vomiting (10%) was felt to be low, and coupled with the respectable percentage (59.5%) of patients who either had a response or stabilization of disease, the authors conclude that the regimen is active and recommendable.
UFT and Pancreatic Cancer
We have proposed a novel approach in the treatment of pancreatic cancer with a fully oral treatment option combined with conventional radiotherapy.17 This study is designed to determine the maximum tolerated dose (MTD) and dose limiting toxicities (DLT) of UFT and Leucovorin when given concurrently with conventional radiotherapy in patients with pancreatic cancer. The dose of UFT was begun at 150 mg/m2 divided in three equal doses. Patients were required to have been fasting, both one hour prior to and after each dosing. Calcium Follinate at 90 mg/d was also administered in three equally divided doses per day. Patients were treated with a 35-day regimen of chemotherapy concurrent with radiotherapy and there were no breaks in therapy. Patients were assigned to treatment with radiation therapy to 45 Gy at 180 cGy per day using a conformal technique. Great care was taken to use CT-based simulation and dosimetry to adequately cover the pancreas or the pancreatic bed with 3 cm of margin and the regional nodal tissue, including the pancreaticoduodenal, porta hepatic, celiac, and supra-pancreatic nodes as indicated.
Thirteen patients were enrolled, and 12 of these were evaluable for toxicity and response. Patients had a median age of 59 years, with 11 patients having an ECOG performance status of 0-1 and one patient having an ECOG performance status of 2. Median follow-up was 13 months. Using MD Anderson clinical-radiographic staging, six patients had stage I resectable disease and seven patients had stage II unresectable disease. Of the stage I patients, all were taken to laparotomy and found to have pathologic adenopathy. Patients were escalated through four dose levels to a dose of 300 mg/m2 of UFT.
We have noticed only minimal hematologic toxicity, although one patient was felt to have had a grade IV neutropenia on day 38, possibly related to therapy and/or infection. Mild to moderate (grades 0-II) nausea, anorexia, and fatigue were also observed. One patient developed grade IV vomiting due to morphine overdose. The major dose-limiting toxicity of diarrhea has been grade 0 in 6 patients, grade 1 in 3, and grade 2 in 2. One other patient developed grade 4 diarrhea on day 61 but we feel this is unrelated to protocol therapy. Four patients had progressive disease before or during therapy, but the median time to progression of the other eight was 15 months. The median overall survival was 12.5 months, with four of six surviving patients having greater than one year of follow-up with stable or no evidence of disease.
Conclusion and Future Directions
Our patients had a median survival of 12 months with a range of four to 19 months. As explained above, we have noted very little toxicity and especially little of the expected diarrhea. The potential benefits of the long bioavailability and oral delivery of UFT warrant further investigation as, compared to continuous 5-FU infusion regimens, survival seemed to be comparable to historical controls but without the added morbidity of a central venous catheter and a pump. We plan to expand the current protocol into a phase II trial starting at 300 mg/m2 per day of UFT evaluating both pharmacokinetic parameters and survival. (Dr. Childs is Resident in Radiation Oncology, and Dr. Robert is Professor in Hematology/Oncology, University of Alabama at Birmingham Comprehensive Cancer Center.)
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