Regional and Systemic Therapies for Advanced Colorectal Carcinoma: Randomized Clinical Trial Results

ABSTRACT: The treatment of advanced colorectal cancer has been evaluated in a series of randomized trials, including infusional and modulated 5-fluorouracil (5-FU), and three meta-analyses encompassing trials of 5-FU plus leucovorin, continuous-infusion 5-FU, and intra-arterial fluoropyrimidines. A Southwest Oncology Group seven-arm phase II trial suggested that infusional 5-FU produced the most favorable toxicity spectrum and the longest survival, warranting further investigation in phase III trials. In a randomized phase III five-arm trial conducted by the Eastern Cooperative Oncology Group and the Cancer and Leukemia Group B, significant toxicity differences noted among the arms favored high-dose infusional 5-FU. In addition, the trial showed that 5-FU modulated by leucovorin or interferon was not more effective than 5-FU given as a 24-hour high-dose infusion weekly, and N-(phosphonacetyl)-L-aspartic acid did not enhance the activity of the weekly infusional 5-FU. Oral leucovorin provided no advantage over IV dosing. There was a significant difference in survival for patients with nonmeasurable disease (16.9 months) compared to those with measurable disease (12.6 months, P = .001). The Advanced Colorectal Cancer Meta-Analysis Project demonstrated a response advantage for patients receiving 5-FU plus leucovorin (23%) compared to those receiving bolus 5-FU (11%, P = 10-7); however, there was no survival advantage of 5-FU plus leucovorin over 5-FU alone (P = 0.57). The Meta-Analysis Group in Cancer showed that continuous-infusion 5-FU resulted in a statistically significantly higher response rate than bolus 5-FU (22% vs 14%, P = .0002). Overall survival also favored continuous-infusion 5-FU (P = .04). Continuous-infusion 5-FU was less toxic than bolus treatment. Data from six select randomized trials comparing hepatic intra-arterial infusion of FUDR to systemic therapy demonstrated a significant difference favoring intra-arterial therapy. Future directions for the treatment of advanced colorectal cancer include ongoing trials comparing low-dose vs high-dose infusional 5-FU, intra-arterial FUDR, leucovorin and dexamethasone vs systemic leucovorin plus 5-FU and proposed trials evaluating the dihydropyrimidine dehydrogenase inhibitor eniluracil plus oral 5-FU. Other drugs of interest include UFT, capecitabine, thymidylate synthase inhibitors, oxaliplatin, and irinotecan combinations. [ONCOLOGY 12(Suppl 7):28-34, 1998]

Introduction

Since the late 1980s, a series of randomized clinical trials, including meta-analyses, have assessed various schedules and combinations of 5-fluorouracil (5-FU)-based therapy for the treatment of advanced colorectal cancer. A smaller series of studies has evaluated the role of intra-arterial chemotherapy for patients with metastatic colorectal cancer to the liver. Results of these trials have helped define the appropriate comparison regimens for the next generation of studies using new agents, eg, irinotecan (CPT-11) and the oral dihydropyrimidine dehydrogenase (DPD) inhibitor eniluracil plus oral 5-FU. This review summarizes significant randomized trials and published meta-analyses involving advanced colorectal cancer, including trials of 5-FU plus leucovorin, continuous-infusion 5-FU, and intra-arterial fluoropyrimidines.

Background

The mechanism of action of 5-FU depends on two active metabolites, 5-fluorodeoxyuridine monophosphate (FdUMP) and fluorouracil triphosphate (FUTP). The intracellular conversion of 5-FU to FdUMP results in the inhibition of the enzyme thymidylate synthase (TS) through formation of the covalent ternary complex (TS-FdUMP and 5, 10 methylene tetrahydrofolate) (Figure 1).[1,2] For more than 10 years, randomized trials in colorectal cancer have focused on this particular 5-FU metabolic pathway, best exemplified by modulation of 5-FU by leucovorin. Preclinical investigations suggest that interferon-alfa biochemically modulates 5-FU by increasing intracellular levels of FdUMP and by binding to TS. Furthermore, continuous-infusion 5-FU results not only in a greater proportion of tumor cells exposed to the drug, but also may enhance cytotoxic activity by inhibition of TS. In contrast, N-(phosphonacetyl)-L-aspartic acid (PALA) blocks de novo pyrimidine synthesis pathways by inhibiting aspartate transcarbamylases. Combining PALA with 5-FU enhances tumor cytotoxicity by increasing the incorporation of 5-FU into RNA.

More recently, significant interest has focused on strategies to inhibit 5-FU degradation pathways. The major pathway of 5-FU catabolism is via the enzyme DPD, producing the inactive metabolite a-fluoro-b-alanine. The variability in oral bioavailability of 5-FU is due to substantial variation in DPD activity in the GI tract during first pass metabolism of the drug. Eniluracil is a potent irreversible inactivator of DPD, which substantially increases the plasma half-life and bioavailability of oral 5-FU.[3-7] This agent allows long-term oral administration of 5-FU, which may provide results similar to those achieved with continuous intravenous infusion 5-FU.

Randomized Trials of Systemic 5-FU

Results of two large randomized trials, assessing modulation of 5-FU and toxicities with various schedules and combinations, were recently reported.[8,9] The Southwest Oncology Group (SWOG) randomized phase II study included 620 patients who received one of seven 5-FU-based regimens, including bolus 5-FU, bolus 5-FU with either low-dose or high-dose leucovorin, protracted venous infusion 5-FU with or without low-dose leucovorin, and high-dose 24-hour infusional 5-FU with or without PALA (Figure 2).[8] The trial was designed to screen these regimens and to select those producing the best response or survival for a randomized phase III confirmatory study.

Results showed that patient characteristics were comparable in all treatment groups. The majority of patients had an ECOG performance status of 0-1 and most had not received previous adjuvant therapy. Differences in toxicities were noted among the treatment groups. In particular, more patients (47%) who received bolus 5-FU with or without low-dose leucovorin experienced grade 3 and 4 granulocytopenia compared with patients (1%) who received low-dose continuous-infusion 5-FU with or without leucovorin. Diarrhea occurred most frequently in patients receiving high-dose leucovorin.

Seventy-one percent of accrued patients had measurable disease. Confirmed response rates ranged from 13% to 24% (15% to 29% when unconfirmed responses were included). At a median follow-up duration of 37 months, there was minimal difference among the seven regimens with respect to progression-free survival. A survival trend was noted, however, favoring the low-dose continuous infusion and 24-hour infusion 5-FU regimens, whereas patients who received PALA plus high-dose infusional 5-FU had a shorter survival duration. Overall survival ranged from 13 to 15 months for all treatments. Interpretation of these results is complex because, paradoxically, patients receiving single-agent bolus 5-FU had higher than expected response and survival rates as compared with historical data (29% vs an expected response of 11%). No clear explanation accounts for this high response rate, though it is possible that patients with excellent performance status and metastatic disease were diagnosed earlier than those in previous trials. Variations in response rate may also be secondary to dose intensity. For example, only 48% of patients receiving high-dose leucovorin received 100% of the planned dose, usually due to toxicity. The authors concluded that infusional 5-FU produced the most favorable toxicity spectrum and the longest survival, warranting further investigation in phase III trials.

The Eastern Cooperative Oncology Group (ECOG) in collaboration with the Cancer and Leukemia Group B (CALGB) recently accrued 1,072 patients in a five-arm randomized phase III trial designed to evaluate the role of biochemical modulation therapy for patients with advanced colorectal cancer (Figure 3).[9] Among evaluable patients, 62% were male and 38% female; 65% had measurable disease (701 patients) and 35% had nonmeasurable disease (371 patients). Performance status (ECOG) was 0 in 53% and 1 or 2 in 47% of patients. Hepatic metastases were present in 74% of patients, and 89% (955 patients) had received no previous chemotherapy.

Four pair-wise comparisons were included in the analysis; high-dose infusional 5-FU vs PALA with the infusion, 5-FU with IV vs oral leucovorin, high-dose infusional 5-FU vs 5-FU and IV leucovorin, and 5-FU and IV leucovorin vs 5-FU and interferon. A preliminary analysis demonstrated no significant survival differences among the comparisons (median survival range, 11.9 to 15.3 months). Significant differences in toxicity, however, were apparent. The 5-FU and interferon regimen produced more grade 3 or 4 toxicities and stomatitis (26%) compared with the other four regimens. The incidence of severe diarrhea was significantly increased in patients receiving leucovorin-containing regimens; up to 36% of patients receiving IV leucovorin experienced grade 3 or 4 diarrhea. Overall, the high-dose infusional 5-FU arms produced significantly less grade 3 or 4 toxicity compared with the leucovorin- and interferon-based regimens.

Significant differences in survival by patient characteristics were also noted. For example, median survival was 16.9 months for patients with nonmeasurable disease compared with 12.6 months for those with measurable disease (P = .0001). Likewise, median survival was 15.9 months in patients with a performance status of 0 and 11.9 months if performance status was ³ 1 (P = .0001). Furthermore, patients with hepatic metastases had a median survival of 13.3 months vs 15.7 months for those without hepatic metastases (P = .0002).

In summary, the results of this large definitive trial demonstrated that 5-FU modulated by leucovorin or interferon was more toxic and not more effective than 5-FU given as a 24-hour high-dose infusion weekly. Oral leucovorin provided no advantage over IV dosing. The use of PALA at this dosing schedule did not enhance the activity of weekly infusional 5-FU. In addition, this trial confirmed that the presence of measurable disease, hepatic metastases, or disease-related symptoms is associated with a poorer prognosis.

Meta-Analyses: Leucovorin, Continuous-Infusion 5-FU

Two published meta-analyses have addressed the effect of 5-FU treatment on objective tumor response and survival in advanced colorectal cancer. One compares 5-FU and leucovorin vs 5-FU alone; and the other, 5-FU via continuous intravenous infusion vs bolus administration.[10,11]

The Advanced Colorectal Cancer Meta-Analysis Project included nine randomized trials comparing 5-FU alone to IV leucovorin and 5-FU, given either weekly or daily for 5 days. A tenth trial conducted by the North Central Cancer Treatment Group (NCCTG)/Mayo Clinic was included using published results for response and survival analyses. Individual patient data were not available from this trial. The numbers of patients varied from 53 to 382 patients per trial, all with measurable disease. The eligibility and response criteria used in the trials were comparable. Differences in the patient populations between trials included fewer patients with liver metastases only in the two US trials (Northern California Oncology Group [NCOG], City of Hope) compared with the others; and in eight of the nine trials, more than two thirds of the patients had a good performance status (< 2) while in one trial (Bologna) almost three fourths of patients had performance status ³ 2. Finally, fewer patients in the NCOG trial than in the other trials had rectal primary tumors.

Overall, 1,381 patients were randomized in the nine clinical trials. The mean follow-up was 13 months. Objective responses were seen in 11% of patients receiving 5-FU and 23% of those receiving 5-FU + leucovorin (P < 10-7) (Figure 4). The odds ratios favored the 5-FU and leucovorin combination in seven of the nine trials (odds ratio ranges, 0.18 to 1.21). There was no survival advantage of 5-FU + leucovorin over 5-FU alone (P = .57) (Figure 5).

An evaluation of individual prognostic factors demonstrated that patients with a good performance status or metastases confined to the liver had significantly better survival (P <10^-9 and P = .046, respectively). In contrast, the NCCTG/Mayo trial showed improved objective tumor responses for patients receiving leucovorin-containing regimens and a statistically significant advantage in overall survival for both high-dose and low-dose leucovorin (P = .037 and P = .050, respectively). Survival benefit, however, was limited to patients with nonmeasurable disease.

One conclusion of this trial was that tumor response is not a valid surrogate end point for survival when planning clinical trials for advanced colorectal cancer. Hypotheses to explain why the response benefit with 5-FU + leucovorin did not translate into improved survival included the following: The response duration may have been too brief to affect survival, and/or the response rate to 5-FU + leucovorin may have been too small to affect survival, since 75% of patients did not respond. Therefore, even with the meta-analysis, there may have been too few patients to detect significant survival differences between treatment groups. Another question is whether there was a crossover effect for patients who received 5-FU + leucovorin after progressing on 5-FU therapy.

The Meta-Analysis Group in Cancer recently published an analysis of 1,219 patients entered onto six randomized trials, each comparing continuous-infusion 5-FU given at various schedules with bolus 5-FU, usually administered daily× 5.[11] In two of the trials, leucovorin was added to both the infusion and bolus regimens. Results showed that continuous-infusion 5-FU resulted in a statistically significantly higher response rate than bolus 5-FU (22% vs 14%; overall response odds ratio, .55; 95% confidence interval [CI], .41-.75; P = .0002) (Figure 6). Overall survival was also significantly higher for patients receiving continuous-infusion 5-FU (overall hazards ratio, .88; 95% CI, .78-.99, P = .04) (Figure 7).

Multivariate analysis demonstrated that patients with good performance status had improved tumor response and survival (P < .0001, P < .0001, respectively), and that patients with rectal cancer as the primary tumor site had improved survival compared with those with colon cancer (P = .0003). Therefore, significant predictors of tumor response were treatment and performance status, and significant predictors of survival were treatment, performance status, and primary tumor site. Grade 3 or 4 hematologic toxicity occurred more frequently in patients receiving 5-FU bolus therapy (31% vs 4%; P < 10^-16). Erythrodysaesthesia was seen more frequently in the continuous-infusion 5-FU-treated group (34% vs 13%; P < 10^-7). The authors concluded that continuous-infusion 5-FU was superior to 5-FU bolus therapy, both for tumor response and survival (though the magnitude of the survival benefit was small), and that continuous-infusion 5-FU was less toxic than bolus treatment.

Hepatic Artery Infusion

For more than 30 years, there has been interest in using intra-arterial fluoropyrimidine therapy to treat patients with isolated metastases confined to the liver. Floxuridine (FUDR) has been the drug of choice for intra-arterial administration because of extensive first-pass extraction in the liver, resulting in high intrahepatic drug concentrations and less systemic toxicity. Although numerous studies have been published, most—including those comparing intra-arterial and systemic therapy—have had insufficient power to detect survival differences. With this in mind, a meta-analysis that included six randomized trials that met select inclusion criteria has been published.[12] The meta-analysis included only prospective randomized trials comparing intra-arterial regional chemotherapy to systemic treatment (limited to 5-FU or FUDR regimens). Disease had to have been biopsy proven and isolated to the liver, and survival reports were required from time of randomization until death. The data analysis demonstrated a significant difference favoring intra-arterial therapy in 1-year survival (12.9%; P = .002) and 2-year survival (7.5%, P = .026) (Figure 8). The 1- and 2-year survival was greater when crossover of treatment was not allowed (19.1% [P = .001], 8.6% [P = .049], respectively, in the hepatic artery infusion group).

The authors believe that these results confirm the survival trend previously suggested in the literature; however, the individual trials were underpowered to detect a survival benefit, which ranged from 8% to 13%. Other criticisms of the individual trials were as follows: Some of the trials allowed patients who progressed after systemic therapy to receive crossover treatment via hepatic artery infusion, thus hindering analysis of survival benefits with regional therapy. At least one trial permitted the treating physician to determine whether systemic 5-FU would be administered, and the systemic therapy may have been suboptimal compared with present standards.

The meta-analysis did not include one randomized study of 100 patients who received either FUDR by hepatic artery infusion or conventional symptom palliation.[13] Patient demographics were similar in both trial arms, and all patients had excellent performance status. This trial demonstrated an overall survival benefit for patients receiving hepatic artery infusion compared with controls (median, 405 days vs 226 days, P = .03). There was a similar significant prolongation in normal quality survival in the hepatic artery infusion group for patient symptoms, anxiety, and depression (P = .04 for each category). The reduction in size of metastases (measured by computed tomography scan) (P = .001) and decrease in carcinoembryonic antigen level (P = .006) was significantly better for the treated patients. In addition, toxicity in the hepatic artery infusion group was consistent with that observed in other studies, and included gastritis, cannula erosion, pump pocket infection, and catheter dislodgment. No treatment-related hepatic toxicity, as measured by bilirubin and serum aspartate aminotransferase levels, was observed.

Future Directions

The published data cited above confirm that the standard of care for patients with metastatic colorectal cancer includes treatment with 5-FU/leucovorin combinations and infusional 5-FU. A regimen may be chosen based on toxicity considerations and patient convenience. For example, infusion systems may be too expensive or inconvenient for some patients. In addition, there is renewed interest in the role of hepatic artery infusion therapy, particularly based on the demonstrated benefits of this treatment compared with symptom palliation.

Other randomized clinical trials are under way to build upon these results. For example, SWOG and ECOG are comparing continuous low-dose infusional 5-FU (300 mg/m² daily) with intermittent high-dose 5-FU (2,600 mg/m² over 24 hours given weekly) in 700 patients. This trial, which will be completed in 1999, will define the optimal 5-FU infusion schedule. CALGB and ECOG are comparing hepatic artery infusion (FUDR 0.15 mg/kg/day, leucovorin 8 mg/m²/day, dexamethasone 20 mg, days 1-14) with systemic low-dose leucovorin (20 mg/m²/day) + 5-FU (425 mg/m²/day, days 1-5). This trial of 340 patients, which does not permit crossover, will be the largest randomized trial comparing systemic vs intra-arterial therapy. In addition, results are pending from an ECOG/SWOG randomized trial comparing intra-arterial FUDR plus systemic infusional 5-FU vs observation for patients with resected liver metastases, which should better define management of such patients. Another trial of great interest is the National Cancer Institute of Canada/NCCTG randomized phase III trial evaluating immediate vs delayed therapy with 5-FU and leucovorin for patients with asymptomatic advanced colorectal cancer. This study should confirm whether there is a survival benefit for good performance status patients who receive chemotherapy at the time of diagnosis.

Although standards of treatment have been defined, the overall response and survival for patients with advanced colorectal cancer remains suboptimal. Thus, numerous trials are exploring the activity and clinical benefits of agents such as oral 5-FU prodrugs (eg, uracil and tegafur [UFT], capecitabine), DPD inhibitors (eniluracil), thymidylate synthase inhibitors (raltitrexed [Tomudex], AG-337, MTA [LY231514]), topoisomerase I inhibitors (irinotecan, 9-aminocamptothecin), and platinum analogs (oxaliplatin).

Prolonged administration of oral compounds such as eniluracil plus oral 5-FU are of particular interest because they may replace continuous-infusion 5-FU, thus avoiding the complexities of an infusion pump drug delivery system while maintaining efficacy with limited toxicity. The ease of oral administration and excellent toxicity profiles invite the development of future drug combinations and combined-modality approaches with radiation. ECOG has recently completed a phase II trial of eniluracil (10 mg/m² PO) with 5-FU (1.0 mg/m² PO), both given bid for 28 days to previously treated and untreated advanced colorectal cancer patients. SWOG is conducting a trial of the same regimen for patients with advanced fluorouracil-resistant colorectal cancer. A phase II trial being conducted by CALGB will build upon the extensive experience with leucovorin modulation of 5-FU by evaluating a 7-day regimen of eniluracil (50 mg PO, days 1-7) with 5-FU (20 mg/m² PO, days 2-6) and leucovorin (50 mg PO, days 2-6). In early 1999, ECOG and SWOG will begin a randomized phase III trial comparing the 28-day schedule of oral 5-FU + eniluracil (1.15 mg/m² and 15 mg/m², respectively) vs protracted venous infusion 5-FU (300 mg/m²/day) in previously untreated patients. In addition, results of a recently completed study of oral UFT vs intravenous 5-FU and leucovorin are pending.

Randomized trials evaluating the role of irinotecan are of continuing interest. Cunningham recently reported results of a study comparing irinotecan (350 mg/m²every 3 weeks) vs best supportive care for patients who progressed after receiving 5-FU.[14] Among 279 randomized patients, baseline characteristics were well balanced except that performance status was significantly better in the irinotecan group. With a median follow-up of 13 months, overall 1-year survival was 36.2% for irinotecan patients vs 13.8% for the best supportive care group (P = .0001). In addition, survival without performance status deterioration or without weight loss, and pain-free survival were significantly improved in the irinotecan group. Furthermore, a randomized phase III trial including 267 patients compared irinotecan (350 mg/m² every 3 weeks) with infusional 5-FU-based regimens selected prospectively by each participating center.[15] Patients had to have had progressive disease during previous 5-FU treatment. With a median follow-up of 15 months, progression-free survival and overall survival improved for the irinotecan patients (P = .029 and P = .035, respectively). Results of another large randomized phase III trial comparing irinotecan (125 mg/m² weekly × 4) vs irinotecan + 5-FU vs leucovorin + 5-FU are pending. Several other irinotecan combinations and schedules are in development, including combinations with oral 5-FU-based regimens.

In summary, a series of well-designed, randomized phase III trials and meta-analyses of treatment of advanced colorectal cancer have been conducted in the past decade. Data generated from these important projects have provided critical information addressing toxicity, quality of life, response, and survival. These studies have defined the comparative regimens for future randomized trials and have encouraged the development of oral agents and other new combinations.

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