Current Status of Radiation Sensitization by Fluoropyrimidines

Numerous clinical studies suggest that the combination of the fluoropyridimine fluorouracil and radiation is a more effective treatment for many cancers, especially gastrointestinal tumors, than is either modality alone. Also, the combination of fluorouracil and radiation has greatly expanded the possibilities for organ-preserving treatments, for example, in patients with bladder cancer. Another fluoropyridimine, floxuridine, administered via the hepatic artery, has been used in combination with irradiation in the treatment of patients with intrahepatic cancers and may prolong survival in patients with unresectable hepatobiliary malignancies. The beneficial effects of combining fluoropyrimidines and radiation are thought to be due to radiosensitization. More studies are needed to clarify the mechanism(s) of radiosensitization so as to optimize regimens in which the fluoropyrimidines are used.

Introduction

The fluoropyrimidines fluorouracil (5-FU) and floxuridine (5-fluoro-2'-deoxyuridine, FdUrd [FUDR]) are the most widely used radiation sensitizers in clinical practice. A large number of retrospective and prospective studies have suggested that the combination of fluorouracil and radiation is a more efficacious treatment for many malignancies (particularly gastrointestinal cancers) than either modality alone, and it has been hypothesized that the benefit from this combination is due to radiosensitization. In addition, the related nucleoside floxuridine has been used in combination with low-dose whole liver irradiation and with high-dose partial liver irradiation in the treatment of patients with intrahepatic malignancies.

In this article, we will briefly summarize laboratory studies aimed at determining the mechanism of fluoro- pyrimidine-mediated radiosensitization. (for more detailed reviews, readers are directed to references 1-3). We will then focus on clinical studies demonstrating the efficacy of the combination of radiation and fluoropyrimidines.

Fluoropyrimidine Cytotoxicity

DNA-Mediated Mechanisms

Fluorouracil and floxuridine are analogs of uracil and deoxyuridine, respectively (Figure 1). These compounds are metabolized to form fluorodeoxyuridine monophosphate (FdUMP) (Figure 2), which is ultimately responsible for the DNA-directed effects of both drugs. Fluorodeoxyuridine monophosphate, along with a folate cofactor, binds to and irreversibly inhibits thymidylate synthase (TS), the enzyme responsible for the conversion of deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP). Thymidylate synthase inhibition leads to depletion of the product dTMP (and, ultimately, thymidine triphosphate) and to the accumulation of the substrate dUMP and other deoxyuridine nucleotides, particularly deoxyuridine triphosphate (dUTP). The resultant increase in the ratio of dUTP to deoxythymidine triphosphate (dTTP) results in misincorporation of dUTP into DNA. The importance of dUTP levels in cytotoxicity is suggested by the finding that human colon cancer cells transfected with the dUTPase gene, which express increased enzyme activity, are relatively protected from floxuridine cytotoxicity [4].

Prolonged TS inhibition leads ultimately to DNA fragmentation and cell death. Two patterns of DNA fragmentation have been noted. The first involves the production of a wide spectrum of fragments with molecular weights ranging from 50 Kb to 5 Mb, and is associated with a morphologic pattern consistent with necrosis. The second pattern results in discrete fragments weighing between 50 and 200 Kb. It resembles programmed cell death (ie, apoptosis), and suggests that the formation of oligosomal ladders is not an essential part of this phenomenon [5].

RNA-Mediated Mechanisms

Whereas clinically achievable concentrations of floxuridine produce only DNA-mediated cytotoxicity, fluorouracil can also kill cells by RNA-dependent mechanisms. Flurouracil can be metabolized to fluorouracil monophosphate (FUMP) and ultimately to fluorouracil triphosphate (FUTP), which is incorporated into RNA in place of UTP. This misincorporation of FUTP can affect several critical aspects of messenger RNA (mRNA) function (including transcription, translation, and splicing).

The relative importance of DNA- vs RNA-mediated cytotoxicity varies considerably from one cell line to another. Leucovorin can act as a folate cofactor and increase the binding of fluorouracil to TS (see above), which tends to increase fluorouracil's DNA-directed actions.

Fluoropyrimidine-Radiation Interactions

Initial cell culture studies with fluorouracil suggested that sensitization occurred when cells were exposed to cytotoxic drug concentrations after irradiation [1]. Other investigators have studied floxuridine, with its single mode of action rather than the more complex fluorouracil with its RNA- and DNA-directed actions. Floxuridine is a potent radiosensitizer of human colon cancer cells [6,7] (Figure 3). Floxuridine exposure prior to radiation produces significantly greater radiosensitization than treatment after irradiation.

Radiosensitization by floxuridine is related to TS inhibition, and is accompanied by both a decrease in DNA double-strand break [6] and sublethal damage repair [8]. These findings probably also describe fluorouracil-mediated radiosensitization, since it appears to derive from the drug's DNA-directed effects [9]. Also, leucovorin potentiates fluorouracil radiosensitization [2], presumably by increasing TS inhibition.

Various mechanisms have been proposed for fluoropyrimidine-mediated radiosensitization. These include:

• Alterations in the nucleotide pools;
• Redistribution of cells to a relatively radiosensitive phase of the cell cycle (ie, cells accumulate at the relatively radiosensitive G1/S boundary following exposure to floxuridine); and
• Fluorodeoxyuridine triphosphate incorporation into DNA.

Although each of these proposed mechanisms may play a role, none alone explains fluoropyrimidine-radiation interactions.10 Furthermore, recent evidence11 is inconsistent with the hypothesis that cytotoxicity and radio- sensitization are closely correlated [2,12]. We recently proposed that sensitization depends on the inappropriate progression of cells through the G1/S boundary and into S phase during exposure to fluoropyrimidines [10,11]. Research into the mechanisms of fluoropyrimidine-induced cytotoxicity and sensitization is driven by the need to develop methods of overcoming clinical drug resistance.

Clinical Uses of Fluoropyrimidine Radiosensitization

The addition of fluorouracil (alone or combined with other chemotherapeutic agents) to radiation improves local control and survival in a number of malignancies. Furthermore, the combination of fluorouracil and radiation has significantly expanded the possibilities for organ-preserving treatments. Finally, the high hepatic extraction of floxuridine delivered via the hepatic artery permits extremely high regional drug levels, which offers a unique potential role for sensitization of intrahepatic cancers. In the following sections, we will discuss these uses of fluoropyrimidines as radiation sensitizers.

Rectal Cancer

The benefit of combining fluorouracil and irradiation in the treatment of locally advanced rectal cancer has been clearly demonstrated in randomized trials. The Gastrointestinal Tumor Study Group (GITSG) randomized 227 patients with stage B2 and C rectal adenocarcinoma to no adjuvant treatment, chemotherapy alone (fluorouracil and oral semustine [methyl-CCNU]), radiotherapy alone, or radiotherapy with semustine and fluorouracil given on the first and last 3 days of radiotherapy [13]. Although neither adjuvant chemotherapy nor radiotherapy alone increased survival, patients treated with combined-modality therapy survived significantly longer than those who received no adjuvant therapy.

A North Central Cancer Treatment Group (NCCTG) study also demonstrated the superiority of combined chemoradiation over radiation alone in the adjuvant treatment of rectal carcinoma [14]. In this trial, 204 patients who had undergone potentially curative resection of Dukes' B2 and C rectal carcinoma were randomized to receive either postoperative radiation alone or identical postoperative radiation with concurrent fluorouracil and semustine. In confirmation of the GITSG trial, the NCCTG results demonstrated significantly improved local control and survival in the combined chemotherapy and radiotherapy arm. Based on these data, a National Institutes of Health Consensus Development Conference concluded that the combination of postoperative chemotherapy and radiation improved local tumor control and survival in stage II and III rectal cancer (Dukes' B2 and C) [15].

Recent trials on the adjuvant treatment of rectal cancer have focused on optimizing the chemoradiation regimens utilized. The NCCTG recently reported the results of a randomized trial of 660 patients with stage II or III rectal cancer, which demonstrated the superiority of continuous-infusion fluorouracil over bolus fluorouracil [16]. Furthermore, when given concurrently with radiation, systemic therapy consisting of fluorouracil plus semustine was no more effective than a higher dose of fluorouracil given alone. This finding confirmed earlier suggestions that the chief benefit of combined-modality therapy derived from fluorouracil, rather than semustine [17]. The lack of benefit of semustine, combined with reports of its leukemogenic potential, have resulted in the elimination of this drug from adjuvant therapy.

Pancreatic Cancer

In addition to its beneficial effects in rectal carcinoma, the combination of fluorouracil plus radiotherapy improves the outcome of patients with pancreatic carcinoma. The GITSG performed a trial randomizing 106 patients with unresectable, histologically confirmed adenocarcinoma of the pancreas to 6,000 cGy of radiation alone, the same dose of radiation plus fluorouracil, or 4,000 cGy of radiation plus fluorouracil [18]. Despite the fact that radiation was given in split-course fashion and fluorouracil was given by bolus, the results of the study demonstrated that the addition of fluorouracil to radiation improved survival in patients with localized unresectable pancreatic cancer from 20 to 40 weeks.

Similarly, in another GITSG trial, patients with resectable pancreatic cancer who received chemotherapy plus radiation (4,000 cGy) had significantly better survival than patients who received radiation only (median survival, 20 vs 11 months) [19]. This improved survival among resected patients given combined-modality therapy was confirmed in an independent trial [20].

Bladder Cancer

Much of the published data on the use of chemotherapy combined with radiation in organ-sparing regimens for invasive bladder cancer have focused on regimens employing methotrexate, cisplatin (Platinol), and vinblastine [21]. However, several phase II trials have also demonstrated the efficacy of fluorouracil with concurrent radiation in these patients. Rotman et al reported the results of a pilot study in which 19 patients with locally advanced bladder cancer confined to the pelvis who were medically ineligible for or refused cystectomy were treated with continuous-infusion fluorouracil and concurrent radiotherapy [22]. Treatment response was assessed at 3 months by cystoscopy, biopsy, and urine cytology. Overall, treatment was well tolerated, and resulted in a complete response rate of 89% and a 5-year survival rate of 60%. Of the nine patients who had died at the time the study report was published, seven died of metastatic disease and two died of intercurrent disease. All nine patients had biopsy-proven tumor-free bladders at the time of death.

Russell et al also described the results of a phase I/II trial in which 34 patients with invasive bladder cancer (16 of whom had T3 lesions and 9, T4 lesions) were treated with radiation combined with continuous-infusion fluorouracil [23]. Following two cycles of infusional fluorouracil and 4,000 cGy of radiation, patients underwent repeat cystoscopy and biopsy. Those with an incomplete pathologic response were treated with cystectomy, while those without residual tumor were given an additional cycle of fluorouracil and radiation. The actuarial cancer-specific survival rate was 64% at 45 months, and the rate of freedom from relapse of invasive cancer was 54%. Furthermore, 24/34 patients retained intact bladders, with 20/24 reporting normal voiding. Of the 18 patients who were potential candidates for surgical resection, 13/16 who underwent pathologic restaging after two cycles of chemoradiation had no histologic evidence of residual tumor.

These studies demonstrate that concurrent fluorouracil and radiation offers a reasonable alternative for patients with invasive bladder cancer who refuse surgery or who are medically inoperable. Although it would be interesting to compare these organ-preserving approaches to radical cystectomy directly, we are unaware of any randomized trials that address this important question.

Anal Cancer

An important application of definitive concurrent chemotherapy and radiation is in the treatment of anal cancer. Because of the poor results of radical surgery for anal cancer (up to 40% recurrence rate after surgical management, with approximately 75% of patients suffering treatment failure in the pelvis alone) [24], Nigro et al initiated a pilot study in which 28 patients were treated with what was conceived as preoperative chemotherapy (fluorouracil and mitomycin [Mutamycin]) and pelvic radiotherapy followed by radical surgery (abdominoperineal resection) [25]. The results of the pilot study suggested that this chemoradiation regimen was highly effective and that abdominoperineal resection was not required, provided that the anal lesion disappeared, as determined by examination and local excision of the scar.

This approach has been confirmed at multiple centers, using slightly different regimens [26-28]. For instance, John et al reported that of 22 patients (13 with T3 or T4 lesions), 20 were alive and had no evidence of disease at a median follow-up of 45 months, while two patients died without evidence of disease at 7 months [27]. In contrast to the findings in rectal cancer that the addition of semustine to concurrent fluorouracil and radiation did not alter outcome, retrospective analyses suggest that the omission of mitomycin from the anal cancer regimen leads to decreased local control [28].

Esophageal Cancer

Encouraged by the success in squamous cell carcinoma of the anus, several investigators evaluated the efficacy of chemotherapy (fluorouracil and cisplatin) and radiation as preoperative treatment for squamous cell carcinoma of the esophagus. In a pilot study, Herskovic et al treated 22 patients with split-course radiation and concurrent fluorouracil and cisplatin. A pathologic complete response was achieved in 24% of patients, and median survival was 22 months. Based on a comparison of these patients with historical controls, whose median survival was 9.8 months after treatment with a preoperative chemoradiation regimen, these investigators concluded that there was no obvious benefit from planned esophagectomy [29].

Encouraging results in the treatment of esophageal cancer were also reported in a phase II trial from the University of Michigan. Forastiere et al reported a 24% pathologic complete response rate in patients treated with an intensive 3-week regimen of twice-daily radiation with concurrent fluorouracil, cisplatin, and vinblastine followed by transhiatal esophagectomy. Median survival in this study was 29 months. Furthermore, 34% of patients overall and 60% of those with pathologic complete responses were alive at 5 years. These 5-year survival results were double those reported from major surgical series, albeit with a highly selected patient population [30]. However, a preliminary analysis of a phase III trial comparing this form of chemoradiotherapy and surgery with surgery alone suggests that these approaches are not significantly different [30a].

Efforts have also been made to study the use of radiation with or without chemotherapy as definitive treatment for patients with inoperable esophageal cancer. Coia et al treated 50 patients with concurrent continuous-infusion fluorouracil, mitomycin, and radiation. The complete response rate (as assessed by barium swallow or endoscopy with or without biopsy at 1 to 3 months after completion of treatment) was 87%, with 1-, 2-, and 5-year actuarial survival rates of 68%, 47%, and 32%, respectively [31].

Herskovic et al reported the results of an intergroup study in which patients with squamous cell carcinoma or adenocarcinoma of the thoracic esophagus were randomized to receive radiation alone or a lower dose of radiation with concomitant fluorouracil and cisplatin. The trial was terminated when an interim analysis revealed significantly increased survival in the group receiving combined chemotherapy and radiation [32]. The improved local control in the combined-modality group is compatible with the concept of radiosensitization, since the radiation dose used in this group was lower.

Intrahepatic Cancer

Floxuridine has also been used in combination with radiation in phase I/II clinical trials in the treatment of primary and metastatic intrahepatic cancers. Hepatic arterial chemotherapy can generate high regional drug concentrations, thereby maximizing the drug exposure of the tumor while minimizing systemic toxicity [33]. This differential effect between intrahepatic tumors and normal tissue is achieved because floxuridine is actively metabolized by the liver, and also because tumors derive their blood supply chiefly from the hepatic artery, whereas the normal liver receives blood from the portal vein. The combination of hepatic arterial fluorouracil or floxuridine with whole liver radiation can palliate a large proportion of patients who have hepatic metastases, and might improve survival in patients with limited disease (Table 1) [34-40].

We have used hepatic arterial floxuridine and focal liver radiation to treat patients with primary hepatobiliary cancers [41]. In this trial, 26 patients with unresectable nonmetastatic primary hepato- biliary cancers received hepatic arterial floxuridine and concurrent hyperfractionated radiation (1.5 to 1.65 Gy per fraction twice daily). The dose of radiation depended on the fraction of normal liver that was spared a significant radiation dose; ie, patients with more extensive disease received lower doses of radiation to larger portions of the liver, while those with more localized disease received high-dose focal liver irradiation.

Patients who received high-dose focal liver irradiation fared better than those given low-dose whole liver irradiation. Objective responses to treatment were seen in 11/11 patients treated with focal radiation vs only 1/6 patients who received whole liver irradiation. The median survival of patients treated with focal liver irradiation was 19 months, as compared with 4 months in those treated with whole liver irradiation. Particularly noteworthy was the actuarial freedom from hepatobiliary progression in patients with localized disease of 72% at 24 months. These early results (Figure 4) appear to be sustained with a median potential follow-up of 4 years (Robertson, unpublished data, 1995).

We have used an identical regimen to that described above to treat patients with colorectal cancer metastatic to the liver. However, the results were inferior to those obtained in primary hepatobiliary tumors [35]. This finding was somewhat unexpected, since hepatic arterial floxuridine has a known role and response rate for colorectal metastases but no established role in the treatment of primary hepatobiliary tumors.

Conclusions

The combination of fluorouracil (alone or in conjunction with other chemotherapeutic agents) and concurrent radiation therapy improves survival or permits organ preservation in a number of malignancies (see Tables 2 and 3 ) [13,14,16,18,19,22,23,25,30,41,42]. Furthermore, the combination of hepatic arterial floxuridine and radiation may increase the survival of patients with unresectable hepatobiliary malignancies.

Although the concurrent administration of fluoropyrimidines and radiation therapy has an established role in the management of multiple malignancies, further studies focusing on the mechanism of radiosensitization by fluoropyrimidines are needed to optimize regimens employing fluoropyrimidines as radiosensitizers. In particular, the explosion of basic findings concerning the control of cell cycle checkpoints, combined with our finding that fluoropyrimidine-mediated radiosensitization may depend on these checkpoints, offers the potential for a wider effective application of combination therapy.

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