Fluorinated pyrimidines have long been used as radiosensitizers in combined-modality therapy for solid tumors. Nonetheless, the most commonly used drug, 5-fluorouracil (5-FU), is inconvenient to administer, particularly
ABSTRACT: Fluorinated pyrimidines have long been used as radiosensitizers in combined-modality therapy for solid tumors. Nonetheless, the most commonly used drug, 5-fluorouracil (5-FU), is inconvenient to administer, particularly when given by continuous intravenous infusion. Continuous infusion 5-FU does offer a survival advantage over bolus in the treatment of large bowel tumors. This holds true regardless of whether radiation therapy is concomitantly given. UFT, a combination of uracil and tegafur (in a molar ratio of 4:1), is an attractive alternative. Trials to date suggest at least chemotherapeutic equivalence compared to 5-fluorouracil, and UFT is much simpler to administer. UFT is administered orally and can safely be combined with oral leucovorin. There is profound scientific rationale for using UFT with radiation therapy, and early trials in gastrointestinal malignancies demonstrate the safety and efficacy of the combination. Further studies will determine the optimal timing and uses for concomitant UFT and radiation therapy. [ONCOLOGY 13(Suppl 5):47-54, 1999]
The use of concomitant chemoradiotherapy has a strong theoretical and practical rationale, and combined-modality treatment has proven effective for a variety of human solid malignancies. Multiple prospective randomized trials have demonstrated improved local control and survival for patients with locally advanced, nonmetastatic gastrointestinal malignancies treated with 5-fluorouracil (5-FU)based chemoradiotherapy, compared to 5-FU or radiation therapy alone. While the mechanism(s) for the interaction has not been precisely defined, chemotherapy may increase the activity of radiation therapy through direct and selective eradication of radioresistant cells or through a cellular interaction with radiation therapy, leading to inhibition of structural repair and resulting in decreased radioresistance.
5-FU appears to be a more effective radiosensitizer when given by continuous intravenous infusion; however, that mode of administration is cumbersome. Uracil and tegafur (in a molar ratio of 4:1 [UFT]), an oral 5-FU prodrug, behaves pharmacologically like continuous intravenous infusion 5-FU and is a logical choice for combination with radiation therapy. This article reviews the structure and activity of both 5-FU and UFT, the use of fluoropyrimidines with radiation therapy, and ongoing trials of UFT as a component in combined-modality therapy.
5-FU has been a mainstay in the solid tumor chemotherapy armamentarium for more than 40 years. During this time, numerous attempts to bolster its effectiveness have been made, both by changing the route of administration and through modulation by codelivery with other agents. Despite these attempts, reported response rates remain low, and administration remains burdensome, requiring intravenous access and multiple patient clinic visits per cycle.
5-FU is a rationally designed compound synthesized by Heidelberger several decades ago. It belongs to the antimetabolite class of antineoplastics and is a pyrimidine antagonist that resembles uracil, substituting fluorine for hydrogen at position 5 (Figure 1). At least three major mechanisms of action have been postulated for 5-FU, all involving activation by metabolism to various nucleotides.[2,3] 5-FU is converted to 5-fluoro-2¢deoxyuridine (FUdR) by thymidine phosphorylase. FUdR is then further phosphorylated by thymidine kinase to 5-fluoro-2¢deoxyuridine monophosphate (FdUMP). FdUMP forms a stable covalent compound with thymidylate synthase, leading to the inhibition of that enzyme with subsequently decreased de novo synthesis of thymidine monophosphate (dTMP). This ultimately results in substandard DNA synthesis and repair.
A controversial proposed mechanism of action involves 5-FU incorporation through fluorodeoxyuridine triphosphate (FdUTP) into DNA. DNA synthesized in the presence of 5-FU has a markedly smaller strand size and is more prone to strand breaks. This fragility may result from the actual excision of 5-FU from the DNA or may be related to inefficient repair of normally occurring trauma. However, the extent to which this incorporation is related to cytotoxicity, particularly the magnitude of the effect from thymidylate synthase inhibition, continues to be debated.
Finally, 5-FU is somewhat unique in that it is extensively incorporated through fluorouridine triphosphate (FUTP) into all classes of RNA, where it leads to misprocessing and/or misfunction. This clearly correlates with cytotoxicity in various solid tumor cell lines.
5-FU is not convenient to administer. Oral bioavailability varies from 28% to 100%. Conventional IV bolus dosing leads to short periods (less than a few hours) during which plasma concentrations are above the putative cytotoxic level. Thymidylate synthase inhibition in particular is S-phase dependent, so the 6- to 20-minute half-life following bolus administration does not seem to overlap cell division for most of a bulky solid tumor and should not be the major mechanism of action for bolus 5-FU.
Continuous IV infusion is a logical choice to overcome the short half-life of the drug. Continuous intravenous infusion clearly has a different spectrum of toxicity than bolus administration, as well as a different maximum tolerated dose and achievable dose intensity. Cells resistant to bolus 5-FU occasionally remain sensitive to continuous intravenous infusion, suggesting there may actually be a different mechanism of action for that delivery system or that it leads to a shift in the relative importance of each of the three potential mechanisms for 5-FU discussed above. An alternate explanation is that patients receiving continuous intravenous infusion 5-FU achieve a 3- to 4-fold increase in cumulative dose vs bolus.
Continuous intravenous infusion 5-FU, administered during radiation therapy in the adjuvant treatment of rectal cancer, clearly leads to improved survival over bolus therapy. However, even in the absence of radiation therapy, continuous intravenous infusion 5-FU remains superior for the treatment of metastatic large bowel tumors. A recent meta-analysis comparing the administration of 5-FU by continuous intravenous infusion vs bolus found the response rate was significantly higher for continuous intravenous infusion (22% vs 14%), which translated to a small overall survival benefit (hazards ratio 0.88). However, continuous intravenous infusion 5-FU is even more inconvenient to administer, requiring a secure form of venous access, as well as the use of an ambulatory infusion pump.
Heidelberger and colleagues discovered that growth inhibitory doses of radiation therapy in rodent tumors were made cytotoxic by the addition of 5-FU. Conversely, ineffective 5-FU regimens became active with the addition of a single fraction of radiation therapy. These synergistic effects have subsequently been confirmed by many other investigators, using both in vitro and in vivo models.[9-15] Randomized trials have demonstrated that the combination of 5-FU and radiation therapy significantly improves local control and survival for patients with a wide variety of solid tumors, compared to radiation therapy or chemotherapy alone.[16-18]
The mechanism of 5-FU radiosensitization is poorly understood, and the best timing for administration of the two modalities is not precisely defined. There are several possible explanations for radiation sensitization by 5-FU, and more than one type of interaction is possible. FdUMP-mediated inhibition of thymidylate synthase with resulting thymidine triphosphate (dTTP) pool depletion, enhanced DNA damage, interference with DNA repair, and cell-cycle effects all may contribute to radiosensitization. Indeed, some in vitro models have shown that 5-FU increases the steepness of the radiation survival curve, while others have demonstrated that 5-FU reduces the shoulder of the curve (which represents the capacity for DNA repair) without affecting the slope. The underlying mechanisms for the 5-FU/radiation-therapy interaction may be influenced by drug dose, timing of administration, and duration of 5-FU exposure.
Byfield et al reported that combined treatment with 5-FU and radiation therapy leads to time-dependent and dose-dependent enhancement of cell killing in HeLa cervical cancer and HT-29 colon cancer cells. Enhanced radiosensitization was dependent on cell exposure to 5-FU for periods longer than the cell-doubling time. Optimal effects were observed when cells were exposed to 5-FU for 48 hours following radiation therapy, with little or no synergy observed when the drug was given either before or for 3 to 24 hours after radiation therapy. The authors concluded that radiation therapy enhancement was not related to either an infliction of additional acute damage by drug in the immediate postradiation-therapy period or to an inhibitory effect on repair of sublethal radiation- therapyinduced damage.
Other investigators have suggested that alternate timing and modes of 5-FU administration can also lead to radiosensitization. Smalley and associates reported that 5-FU modulation of radiosensitivity in DU-145 human prostate cancer cells was evident with radiation therapy delivered during a 1-hour pulse of 5-FU, as well as with radiation therapy given either immediately before 5-FU or 17 hours after 5-FU. Using a solid tumor model, Loony and associates observed that maximal inhibition of tumor growth occurred when 5-FU was administered 4 days after radiation therapy, with this combination being 2.5-fold more effective than that expected if effects were merely additive. Beaupain and colleagues showed the administration of 5-FU preceding radiation therapy to be the most effective schedule in growth inhibition of human pulmonary cancer nodules maintained in continuous organotypic culture. Weinberg and associates found no schedule dependency for 5-FU/radiation-therapy enhancement in an in vitro squamous cell carcinoma model, though there was clear dose dependency. These studies clearly demonstrate that there is substantial heterogeneity in cell radiosensitivity modulation by 5-FU.
FUdR is an interesting drug with which to study fluoropyrimidine-mediated radiosensitization. As a radiosensitizer, FUdR is effective in concentrations at which it would only achieve thymidylate synthase inhibition and would not demonstrate the more complex interactions other fluoropyrimidines show with DNA and RNA. Clearly, FUdR has been shown to be a potent radiosensitizer of HT-29 and HuTu80 human colon cancer cells.[23,24] Although sensitization has been produced under a wide range of exposure conditions, FUdR is substantially more effective when it precedes radiation therapy for 2 hours compared with when it follows radiation therapy. Sensitization correlates with thymidylate synthase inhibition and depletion of dTTP pools, and is blocked by coincubation with thymidine. However, 8- or 24-hour pre-exposures to low concentrations of FUdR can also enhance radiation-therapyinduced DNA damage, apparently by inhibiting repair of DNA double-strand breaks.
Both 5-FU and FUdR treatment arrest S-phase cells and block cells in early S-phase (G1/S interphase) 16 to 32 hours following fluoropyrimidine exposure. Early S-phase is thought to represent a relatively radiosensitive portion of the cell cycle, but some investigators have found that the fraction of cells in early S-phase is a weak predictor of radiation therapy enhancement. Lawrence and colleagues demonstrated that HT-29 cells with blocked S-phase progression are not radiosensitized by FUdR. Using a population of synchronized HT-29 cells, McGinn and associates examined radiation therapy survival data with FUdR and concluded early S-phase delay is not the primary means of radiosensitization, although there is an association between early S-phase enrichment and radiosensitization. Overall, experts suggest radiosensitization is partially but not completely due to redistribution of cells through the cell cycle, or at least to an alteration of the G1/S check point.
Gastrointestinal oncology chemoradiation schedules commonly employ 5-FU boluses during the first and last weeks of radiation therapy. Following IV bolus injection of conventional 5-FU doses (400 to 600 mg/m²), the drug is rapidly metabolized at both hepatic and extra-hepatic sites and quickly disappears from plasma. However, continuous intravenous infusion 5-FU at doses of 500 to 1,000 mg/m² results in sustained, measurable steady-state plasma concentrations (1 mM to 5 mM). Based on preclinical data, 5-FU is probably a more effective radiosensitizer when administered for prolonged periods during or following radiation therapy.
There are potential clinical advantages to this 5-FU administration schedule. OConnell and colleagues reported a prospective randomized trial assessing protracted venous infusion vs bolus administration of 5-FU in patients with fully resected rectal cancer (Table 1). Patients received 5-FU as a rapid IV injection (500 mg/m²) on days 1 to 5, 36 to 40, 134 to 138, and 169 to 173 following surgery. All received radiation therapy beginning on day 64, administered in 1.8-Gy fractions over 5 weeks to a total dose of 45 Gy, with subsequent boost doses of 5.4 to 9 Gy. During pelvic radiation therapy, patients received 5-FU, randomly divided between bolus administration (500 mg/m² rapid IV injection daily for 3 days during weeks 1 and 5 of radiation therapy) vs protracted venous infusion at 225 mg/m² per day during the entire radiation therapy period. Patients receiving protracted venous infusion had significant decreases in overall rate of tumor relapse and rate of distant metastases, as well as improvement in time to relapse and overall survival. Interestingly, there was a decrease in local recurrences with protracted venous infusion, although this was not statistically significant. The authors were unsure whether the overall beneficial effect was from improved cytotoxicity of infusional 5-FU (radiosensitization) or merely from the larger overall chemotherapy doses the protracted venous infusion patients received.
UFT can potentially overcome the inherent problems of 5-FU. Tegafur (FT; ftorafur; 1-[tetrahydro-2-furanyl]-5-fluorouracil) is a furanyl nucleoside analog of FUdR. It is essentially a prodrug that is metabolized via hepatic microsomes to 5-FU (Figure 2). Early Russian trials administering tegafur IV showed activity in a variety of solid tumors. Lack of myelosuppression in early trials was encouraging, but gastrointestinal toxicity (commonly seen with fluoropyrimidines) and a new side effect, neurotoxicity, limited development in the United States.[30,31]
Unlike 5-FU, however, tegafur is highly lipophilic and offers nearly complete oral bioavailability. Andersen and associates demonstrated that oral tegafur was similar to IV bolus 5-FU in terms of response rate and survival in patients with colorectal cancer, and the oral agent demonstrated less leukopenia and stomatitis. Japanese investigators, using small divided daily oral doses over prolonged periods, also showed activity and safety in the treatment of a variety of solid tumors.
Uracil appears to inhibit hepatic dihydropyrimidine dehydrogenase (dihydrouracil dehydrogenase), a 5-FU catabolic enzyme (Figure 2). Coadministration with tegafur leads to 5- to 10- fold increases in intratumoral 5-FU concentrations, compared with the administration of tegafur or 5-FU alone. Phase I trials in the United States evaluating UFT used an administration schedule similar to the Japanese schedules, adopting multiple daily doses for prolonged periods. M. D. Anderson Cancer Center tested a 5-day schedule repeated every 21 days, as well as a 28-day schedule repeated every 35 days. UFT was given at 8-hour intervals in both trials. Granulocytopenia was the dose-limiting toxicity on the 5-day schedule, which occurred at a dose of 900 mg/m² per day. Diarrhea was dose limiting on the more protracted schedule, seen in three of six patients receiving 450 mg/m² per day and three of eight patients receiving 400 mg/m² per day. No patient receiving 360 mg/m² per day developed severe diarrhea.
Pooled data from a phase II study conducted at 104 Japanese institutions included 665 patients who received oral UFT in total daily doses ranging from 300 to 600 mg for more than 4 weeks. Hematologic toxicity was rare, occurring in fewer than 7% of patients. Gastrointestinal toxicity included anorexia (24%), nausea/vomiting (13%), and diarrhea (11%). Neurologic toxicity was extremely rare (2%). Responses were seen in greater than 19% of those with gastric cancer, breast neoplasms, and those with cancers of the pancreas, biliary tree, liver, and large bowel. Retrospective comparison with 1,502 patients treated with tegafur alone showed significantly less gastrointestinal toxicity for patients receiving UFT.
In the United States, phase II dosing trials have evaluated 800 mg/m² daily of UFT using a 5-day schedule, and 360 mg/m² daily of UFT over a 28-day period. Preliminary reports suggest these doses cause no neutropenia or diarrhea. Pazdur and associates also assessed plasma-concentration data for 5-FU following administration of either protracted low-dose IV 5-FU or UFT 370 mg/m² daily (divided into three doses administered every 8 hours) for 28 consecutive days.[36,37] UFT generated higher maximum plasma levels and a similar area under the plasma concentration-time curve.
UFT With Leucovorin
Leucovorin has been used as a modulator of bolus 5-FU for years, and its combination with UFT may be even more attractive. Folates stabilize the FdUMP-thymidylate synthase complex, and their addition to 5-FU in the treatment of advanced colorectal cancer leads to an improved response rate over 5-FU alone (although only a questionable improvement in survival). Since the thymidylate synthase-inhibitory effect of 5-FU is speculated to assume more importance with continuous intravenous infusion than with bolus administration, leucovorin should enhance the cytotoxicity of UFT as well. In addition, in an HT-29 human colon cancer cell model, Lawrence showed that pre-incubation with leucovorin increases the effectiveness of both FUdR and 5-FU as radiosensitizers (Figure 3).[39,40] The increase in radiation-therapy sensitivity was associated with a decrease in the repair of radiation- therapyinduced DNA double-strand breaks. Oral leucovorin is available and can be administered on the same schedule as UFT.
The 28-day UFT regimen with leucovorin has been tested extensively in the United States. Pazdur and associates performed a phase I trial with fixed-dose leucovorin (150 mg/day administered in three divided doses), with diarrhea being the dose-limiting toxicity for UFT administered at 400 mg/m² per day. Multiple phase I, II, and III trials have now been reported, in general showing comparable activity to 5-FU/leucovorin and specifically showing activity against tumors of the colon/rectum[42,43] and breast. The UFT/leucovorin combination has also been added to cisplatin (Platinol) and etoposide (VePesid), demonstrating activity against nonsmall cell-lung cancer and gastric cancer, respectively.[45,46]
UFT With Radiation Therapy
UFT is a logical choice for combination with radiation therapy, given the sustained levels of 5-FU achieved with chronic oral UFT administration. Preclinical and clinical data exist for tegafur combined with radiation therapy. Byfield and colleagues exposed a human cervical cancer cell line (HeLa) to external-beam radiation therapy (.75 Gy/min), alone and with two different concentrations of tegafur (3 mg/mL and 30 mg/mL) and assessed colony formation. The drug promoted additive cell kill without affecting the shoulder or slope of the radiation-therapy survival curve. This lack of radiosensitization probably reflected a lack of metabolism of tegafur to 5-FU in the culture dish.
Byfield also performed a phase I trial of oral tegafur with simultaneous radiation therapy in 15 patients with advanced gastrointestinal cancers. Patients received tegafur 1 to 2.5 g/m² per day (in 3 divided doses) for 5 days; the drug was then discontinued until resolution of toxicity, and the cycle was repeated. Radiation therapy generally was administered as four 2.5-Gy fractions on 4 consecutive days and repeated after 10 days, to a total dose of 20 to 60 Gy (median, 45 Gy). This combination was substantially toxic, with ubiquitous nausea/vomiting and some lower gastrointestinal tract complaints. Central nervous system toxicity and stomatitis were rare, however, and neutropenia was not seen. The maximum cyclical 5-day tegafur dose was 2 g/m², more than can be tolerated when tegafur is administered on a continuous basis. However, the investigators suggested that this schedule was too short to achieve maximum radiosensitization (in part because of the low 5-FU concentrations achieved).
Few clinical trials evaluating UFT plus radiation therapy have been reported in the non-Japanese literature. Japanese investigators have published reports of tegafur or UFT given with radiation therapy for a variety of head and neck cancers, brain metastases from nonsmall-cell lung cancer, and gastroesophageal cancers.[48-52] In the United States, phase I trials of UFT with radiation therapy are ongoing (Table 2). Investigators at M. D. Anderson Cancer Center are conducting an open-label phase I trial assessing UFT/radiation therapy plus leucovorin in potentially resectable rectal cancer. Major objectives include determining the maximum tolerated dose and dose-limiting toxicity of oral UFT with leucovorin when given with full-dose radiation therapy before resection and when given without radiation therapy following surgery. In addition, investigators will evaluate whether the UFT/radiation therapy regimen represents a less expensive and/or less toxic regimen than standard preoperative 5-FU/radiation therapy. Eligible patients include those with a Zubrod performance status of 0 to 2 and biopsy-proven rectal cancer (T3/T4 and/or ³ N1, MO) who would otherwise be candidates for standard preoperative chemoradiation and resection. The preoperative phase includes pelvic radiation therapy, beginning on day 1 and administered at 1.8-Gy fractions, 5 days per week over 5 weeks, to a total dose of 45 Gy. UFT is administered daily in three divided doses on the days of radiation therapy; patients also receive leucovorin 30 mg with each UFT dose. The starting dose for the first cohort was 250 mg/m² per day (50 mg less than the standard maximum tolerated dose without radiation therapy), and doses have been escalated by 50 mg/m² day per cohort. Surgery is performed 4 to 6 weeks after completion of chemoradiation. Four to 6 weeks following resection, patients start the first of four courses of UFT with leucovorin 30 mg (90 mg/day). Courses consist of 28 days of treatment with a 1-week break between cycles. Postoperative UFT doses also start at 250 mg/m² daily. In a preliminary report including six patients enrolled at dose level 1 and three patients at dose level 2 (300 mg/m²/day), no grade 4 toxicity has been observed, although grade 3 diarrhea was seen in one patient at level 2. One patient at each level had a pathologic complete response at the time of surgery.
Investigators at Memorial Sloan-Kettering Cancer Center are also assessing UFT in combination with radiation therapy for rectal cancer. Their trial (Figure 4) will potentially serve as a future comparison arm with the current Intergroup study, the latter of which is testing whether continuous intravenous infusion 5-FU delivered for all six postoperative cycles is better than continuous intravenous infusion 5-FU administered only during radiation therapy, with the remaining four cycles (two before radiation therapy and two following radiation therapy) given by IV bolus. UFT, with a mechanism of action simulating continuous intravenous infusion 5-FU, is again a logical substitution. The Memorial Sloan-Kettering Cancer Center trial is determining the maximum tolerated dose of UFT with fixed-dose leucovorin and concurrent radiation therapy. Fixed doses of both UFT and leucovorin are administered following completion of concurrent UFT/leucovorin/radiation therapy. Investigators recently reached the third UFT dose level of 275 mg/m² per day, with no major toxicities reported to date (B. Minsky, MD, unpublished data, July 1998).
Oregon Health Sciences University and Vanderbilt Cancer Center investigators have proposed a phase I study of UFT with cisplatin, leucovorin, and radiation therapy in the treatment of potentially resectable esophageal cancer (Figure 5). Patients with biopsy-proven squamous cell or adenocarcinoma and an Eastern Cooperative Oncology Group performance status of 2 or less will receive preoperative and postoperative chemotherapy with preoperative radiation therapy. Preoperative radiation therapy will consist of 45 Gy (1.8 Gy/day, 5 days/week for 25 fractions). Presurgical chemotherapy will include cisplatin 80 mg/m² IV, days 1 and 28, and leucovorin 30 mg orally, three times daily, days 1 through 35. UFT will be given at levels shown in Figure 5, in three daily doses, on days 1 through 35. This schedule was selected to best simulate the use of continuous intravenous infusion 5-FU during radiation therapy. After maximal downstaging, surgical resection, and 4 to 6 weeks of postoperative recovery, patients will receive two additional chemotherapy cycles of cisplatin 80 mg/m², days 1 and 29, and leucovorin 30 mg orally three times daily, days 1 through 21 and 29 through 50. UFT dosing will begin at 300 mg/m² per day and will change as shown in Figure 5. This trial is under evaluation by Vanderbilt Cancer Center and Oregon Health Sciences University regulatory committees and should open in late 1999.
New drug development in oncology can take either of two different paths. One relates to identifying agents or combinations with novel mechanisms of action, looking to improve response rates and survival over existing regimens. The other tries to make standard therapy more convenient to administer. UFT, a combination of tegafur and uracil, represents the latter. It is an oral agent that mimics the pharmacokinetics of continuous intravenous infusion 5-FU, without requiring the patient to undergo central line placement or to wear an ambulatory infusion pump. Early trials suggest it demonstrates comparable efficacy to IV 5-FU.
The combination of UFT with radiation therapy is extremely logical. Fluoropyrimidines are clinically effective radiosensitizers and have been used with concomitant radiation therapy for decades. Continuous-infusion 5-FU appears to be more effective with radiation therapy, and this mode of administration is easily mimicked with prolonged oral UFT administration. Early trials suggest UFT may be safely combined with radiation therapy in the treatment of gastrointestinal malignancies. Further studies are necessary to best outline its use as well as its ultimate efficacy.
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