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Journal of Clinical Oncology, Vol 17, Issue 10 (October), 1999: 3276-3282
© 1999 American Society for Clinical Oncology

Sequential Biochemical Modulation of Fluorouracil With Folinic Acid, N-Phosphonacetyl-L-Aspartic Acid, and Interferon Alfa-2a in Advanced Colorectal Cancer

Melanie E Royce, William McGarry, Beth Bready, Shaker R. Dakhil, Robert J. Belt, J. Wendall Goodwin, Richard Gray, Paulo M. Hoff, Rodger Winn, Richard Pazdur

From the Division of Medicine and Division of Pharmacy, The University of Texas M.D. Anderson Cancer Center, Houston, TX; Wichita Community Cancer Oncology Program, Wichita, and Kansas City Community Cancer Oncology Program, Kansas City, KS; The Helen and Harry Gray Cancer Institute at Good Samaritan Medical Center, West Palm Beach, FL; Ozarks Regional Community Cancer Oncology Program, Springfield, MO; and Atlanta Regional Community Cancer Oncology Program, Atlanta, GA.

Address reprint requests to Richard Pazdur, MD, Box 92, Section of Gastrointestinal Medical Oncology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030; email rpazdur{at}mdanderson.org


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
PURPOSE: Several agents have been evaluated for their effect as biochemical modulators of fluorouracil (5-FU) in the treatment of metastatic colorectal carcinoma. In this study, we used folinic acid (FA), N-phosphonacetyl-L-aspartic acid (PALA), and recombinant interferon alfa-2a (IFN{alpha}-2a) in a sequential order to assess the efficacy of this approach in patients with metastatic colorectal carcinoma.

PATIENTS AND METHODS: Forty-four patients with metastatic colorectal carcinoma were enrolled onto the study. The treatment course consisted of three cycles: (cycle 1) FA 20 mg/m2 followed by 5-FU 425 mg/m2 on days 1 to 5; (cycle 2) PALA 250 mg/m2 on days 29, 36, 43, and 50 and 5-FU 2,600 mg/m2 as a 24-hour infusion on days 30, 37, 44, and 51; and (cycle 3) IFN{alpha}-2a 9 million units (MU) three times a week for 5 weeks beginning on day 57, with a continuous infusion of 5-FU 750 mg/m2 on days 57 to 61, and then weekly bolus of 5-FU 750mg/m2/wk on days 71, 78, and 85. Response was determined after cycle 3.

RESULTS: All patients had a Zubrod performance status >= 2, measurable disease, and had received no prior chemotherapy for their metastatic disease. A total of 212 cycles were given. Thirty-six patients were assessable for response. No complete responses were seen. Seven patients had a partial response, eight had stable disease, and 15 had progressive disease. The median duration of response was 25 weeks, and the median survival was 53 weeks. Grade 3 and 4 toxic effects included granulocytopenia, stomatitis, diarrhea, rash, nausea, and fatigue.

CONCLUSION: This trial provided no evidence that sequential biochemical modulation of 5-FU in patients with metastatic colorectal carcinoma had any therapeutic advantage over conventional treatment regimens of 5-FU plus FA.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
COLORECTAL CARCINOMA is the third leading cause of cancer death in the United States. Approximately 131,000 new cases will be diagnosed in 1999, and an estimated 55,000 people will die of the disease yearly.1 Fluorouracil (5-FU) remains the primary agent used in the treatment of advanced colorectal carcinoma, with response rates of 10% to 15%.2 Several trials have looked at agents that biochemically modulate 5-FU to increase its efficacy.3 These biochemical modulators have included folinic acid (FA),4-6 N-phosphonacetyl-L-aspartic acid (PALA),7,8 recombinant interferon alfa-2a (IFN{alpha}-2a),9-13 sequential methotrexate,14-16 and trimetrexate.17,18

Tumor response to 5-FU therapy generally occurs early, with a median time to response of 6 weeks.9,19 Unfortunately, duration of response is typically short, with a median survival time of 10 to 13 months.20 After disease progression despite initial 5-FU treatment, subsequent attempts to treat patients with 5-FU–based regimens by changing 5-FU dose, schedule, or biochemical modulator has resulted in few objective responses and median survival time of 8.5 months.21

In initial phase II trials, when FA, PALA, or IFN{alpha}-2a were used as biochemical modulators of 5-FU, response rates exceeded 40%.4-13 In the current phase II study, we used these three modulators in a sequential manner, anticipating enhancement of the efficacy of 5-FU before the development of resistance to 5-FU and subsequent disease progression. The order of administration of the various regimens was chosen for two reasons. First, we wanted to exploit the differing mechanisms of biochemical modulation of FA, PALA, and IFN{alpha}-2a on DNA and RNA synthesis. These agents seem to work independently as modulators of 5-FU. Second, we placed the most toxic regimen last to minimize schedule delays because of adverse events.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patients
Forty-four patients were enrolled onto this study. Informed consent was obtained in writing from all patients according to institutional guidelines. Eligibility criteria included histologic proof of metastatic colorectal carcinoma and the presence of at least one bidimensionally measurable lesion on computed tomography scan. Patients with brain metastasis were eligible provided the lesions were controlled for 6 months (requiring no therapy) and were not life threatening and other measurable disease existed. Patients had to be at least 16 years old. Women had to have no childbearing potential or using adequate contraception and have a negative pregnancy test at study entry. Patients also were required to meet the following criteria: Zubrod performance status score >= 2; adequate bone marrow, renal, and hepatic function as evidenced by absolute granulocyte count >= 1,500 cells/µL, platelet count >= 100,000 cells/µL, creatinine >= 1.5 mg /dL, serum bilirubin >= 1.5 mg /dL, and ALT >= 4 times the upper limit of normal; and no serious intercurrent medical illnesses. Patients could not have received prior chemotherapy for metastatic colorectal carcinoma. Patients who had received adjuvant chemotherapy were eligible if treatment was completed 6 months before study entry. Patients with second primary malignancies were excluded except for patients with completely excised basal cell carcinoma or a prior malignancy treated curatively with no evidence of disease for at least 5 years.

Treatment Plan
This was a single-arm, nonrandomized trial of sequential biochemical modulation of 5-FU with FA, PALA, and IFN{alpha}-2a in patients with untreated metastatic colorectal cancer. The three cycles in each course were administered sequentially as follows:

    •Cycle 1: FA + 5-FU22:
       —FA 20 mg/m2/d by intravenous piggyback (IVPB) over 15 minutes on days 1 to 5
       —5-FU 425 mg/m2/d IVPB over 15 minutes on days 1 to 5, immediately after FA

    •Cycle 2: PALA + 5-FU7 (begins on day 29):
       —PALA 250 mg/m2 IVPB over 15 to 30 minutes on days 29, 36, 43, and 50 —5-FU 2,600 mg/m2 continuous intravenous infusion over 24 hours on days 30, 37, 44, and 51, administered 24 hours after PALA.

    •Cycle 3: IFN{alpha}-2a + 5-FU9 (begins on day 57):
       —IFN{alpha}-2a 9 million units (MU) subcutaneously three times a week for 5 weeks
       —5-FU 750 mg/m2 continuous intravenous infusion on days 57 to 61, then 5-FU 750 mg/m2 intravenous bolus on days 71, 78, and 85

If patients experienced only National Cancer Institute (NCI) grade 1 hematologic toxicity, the dose of 5-FU was increased by 15%. The 5-FU dose was reduced by 25% for patients experiencing NCI grade 3 or 4 toxicity. In these dose modifications, the doses of FA and PALA were unchanged from the initial doses of 20 mg/m2 and 250 mg/m2, respectively. In cycle 3 (5-FU + IFN{alpha}-2a), the IFN{alpha}-2a dose was reduced by 25% for patients experiencing NCI grade 3 or 4 constitutional symptoms (ie, fatigue, anorexia, and malaise). Dose modifications were made only for the cycle designated either during the cycle being administered or during that cycle in subsequent courses. Dose modifications did not cross the boundaries of the different cycles in a course. Standard supportive care was given to patients experiencing moderate to severe side effects.

Weekly complete blood counts, including platelet counts and WBC differentials, were conducted to determine the level of myelosuppression. Before each cycle, a complete chemistry panel including electrolytes, standard 12-channel screening profile, and carcinoembryonic antigen were obtained. After each course of therapy (one course = cycle 1 + 2 + 3), all lesions were measured bidimensionally and assessed for changes by computed tomography to evaluate treatment response. Treatment was continued until disease progression became evident or side effects became intolerable.

Statistical Design
The Simon design for phase II trials was used.23 It was assumed that a response probability of 55% or greater in patients with metastatic colorectal carcinoma was of interest. Further testing was not pursued if the response rate was 40% or less. Initially, 38 patients were accrued. If 16 or fewer of the 38 patients responded to treatment, the study would be terminated, and it would be concluded that the regimen had no added therapeutic efficacy over conventional 5-FU regimens. However, if 17 or more responses were noted in the initial cohort of 38 patients, then 50 additional eligible patients would be accrued. Forty-one or more responses among the 88 patients was considered evidence warranting further study of the regimen, provided other factors, such as toxicity and survival, also seemed favorable. This design had a 10% false-positive rate and a 55% probability of early termination if the tumor response rate was >= 40%.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Patient Characteristics
Patient characteristics are listed in Table 1. The median age was 61 years (range, 32 to 81 years). The median Zubrod performance status score was 1. Forty-two patients had a histologic diagnosis of adenocarcinoma. The major sites of metastatic disease were liver, lung, soft tissue, and lymph node. Three patients had received no prior treatment; the others had previously undergone one or more of the following treatments: surgery (41 patients), radiation therapy (12 patients), and adjuvant chemotherapy (10 patients). Prior adjuvant chemotherapy included: 5-FU alone (four patients), 5-FU and levamisole (three patients), 5-FU and FA (two patients), and 5-FU, FA, and IFN{alpha}-2a (one patient).


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  		Table 1. Patient Characteristics
 

Treatment and Response
The number of treatment cycles given per course is listed in Table 2. A total of 212 cycles were delivered during the trial (median, four cycles; range, one to 12 cycles). All 44 patients received cycle 1 (5-FU + FA) at the initial 5-FU dose (425 mg/m2). In subsequent courses of 5-FU + FA, the dose of 5-FU was modified in 17 patients; 11 patients received a 15% dose increase (488.75 mg/m2), and six patients received a 25% dose reduction (318.75 mg/m2). Forty patients went on to receive cycle 2 (5-FU + PALA) at the initial 5-FU dose (2,600 mg/m2). In subsequent courses of 5-FU + PALA, 11 patients had 5-FU dose modification; six patients received a 15% dose increase (2,990 mg/m2), and five patients received a 25% dose reduction (1950 mg/m2). Thirty-seven patients went on to receive cycle 3 (5-FU + IFN{alpha}-2a) to complete a full course of the planned treatment. In subsequent courses of 5-FU + IFN{alpha}-2a, 13 patients had the following dose modifications: one patient received a 15% dose increase in 5-FU (862.5 mg/m2) and no change in IFN{alpha}-2a dose (9 MU); 10 patients received a 25% dose reduction in 5-FU (562.5 mg/m2) and no change in IFN{alpha}-2a dose; and two patients received a 25% dose reduction in IFN{alpha}-2a (6.75 MU) and no change in the 5-FU dose (750 mg/m2).


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  		Table 2. Treatment Summary
 

All 44 patients enrolled onto the study were assessable for toxic effects, but only 36 were assessable for response. Eight patients did not complete a full course; these patients were treated as nonresponders in the response analysis. Of these, five patients refused further treatment; one patient was removed from the study for noncompliance; one patient was removed from the study because of intercurrent illness (alcohol abuse/dependence); and in one patient, grade 4 exfoliative dermatitis developed after cycle 1. No complete responses were noted. Seven patients (16%) had a partial response, eight (18%) had stable disease, and 15 (34%) had progressive disease. The overall intent-to-treat response rate was 16% (95% confidence interval [CI], 7% to 30%). The median duration of response was 25 weeks, and the median survival time was 53 weeks.

Toxicity
The hematologic toxic effects are listed in Table 3. In cycle 1 (5-FU + FA), a total of 18 patients had grade 3 or 4 granulocytopenia. The median granulocyte nadir occurred at day 12, with a median duration of granulocyte suppression of 7 days (range, 2 to 14 days). One patient each experienced grade 3 anemia and thrombocytopenia, with no grade 4 seen. In cycle 2 (5-FU + PALA), a total of three patients had grade 3 or 4 granulocytopenia. The median granulocyte nadir occurred at day 51, with a median duration of granulocyte suppression of 7 days (range, 7 to 21 days). No grade 3 or 4 anemia or thrombocytopenia was noted. Finally, for cycle 3 (5-FU + IFN{alpha}-2a), 13 patients had grade 3 or 4 granulocytopenia. The median granulocyte nadir occurred at day 78, with a median duration of granulocyte suppression of 10 days (range, 3 to 28 days). One patient experienced grade 3 anemia. Likewise, only one patient had grade 3 thrombocytopenia. No grade 4 anemia or thrombocytopenia was noted.


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  		Table 3. Hematologic Toxic Effects (n = 44)
 

Nonhematologic toxic effects are listed by grade for each cycle in Tables 4, 5, and 6. Stomatitis, rash, diarrhea, hand-foot syndrome, and vomiting were the grade 4 toxic effects reported. The other severe (grade 3) toxic effects were nausea, fatigue, and motor dysfunction (manifested mainly as weakness). The grade 1 and 2 toxic effects were stomatitis, nausea, diarrhea, rash, fatigue, vomiting, alopecia, drug fever, motor dysfunction, anorexia, sensory dysfunction (manifested mainly as paresthesia), flu-like symptoms, weight loss, headache, and myalgias/arthralgias. Cerebellar dysfunction was rare, and when it occurred, it was mild; no ataxia was noted.


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  		Table 4. Common Acute Nonhematologic Toxic Effects, Cycle 1*
 

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  		Table 5. Common Acute Nonhematologic Toxic Effects, Cycle 2*
 

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  		Table 6. Common Acute Nonhematologic Toxic Effects, Cycle 3*
 

Most of the observed toxic effects occurred in cycle 3, with 34%, 7%, and 59% grade 3 and 4 toxic effects observed in cycles 1, 2, and 3, respectively. Grade 3 or 4 toxic effects for patients who completed at least one treatment course (cycle 1 + 2 + 3) are listed in Table 7.


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  		Table 7. Toxic Effects After a Treatment Course, Cycles 1 + 2 + 3 (n = 37)
 


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Since its introduction into clinical use, 5-FU has remained the most extensively prescribed agent for the treatment of colorectal cancer, and over the past decade, numerous attempts have been made to increase its efficacy. Efforts to improve the therapeutic efficacy of 5-FU have focused, in part, on biochemical modulation to produce selective enhancement of its cytotoxicity. Among the agents that have been used are FA, PALA, IFN{alpha}-2a, sequential methotrexate, and trimetrexate.3

In the 1970s, the reaction mechanism of fluorodeoxyuridylate with thymidylate synthase was characterized and was shown to generate an analogous ternary complex, with a greatly increased affinity for the enzyme, which ultimately resulted in impairment of DNA synthesis.24 FA enhances the cytotoxic activity of 5-FU by expanding the intracellular pools of reduced folate, thereby potentiating ternary complex formation and stabilization.25 The increased therapeutic effect of 5-FU + FA has been documented in various preclinical model systems.26,27 Based on the observations, clinical trials were performed to test the efficacy of 5-FU + FA in patients with metastatic colorectal carcinoma.6,28-30 A meta-analysis of nine randomized clinical trials of 5-FU + FA showed a significant benefit of this regimen compared with single-agent 5-FU in terms of response rate (23% v 11%, respectively), without discernible improvement of overall survival (median survival, 11.5 v 11 months, respectively).31 Comparing two commonly used schedules of 5-FU + FA, Buroker et al32 found that an intensive course of 5-FU plus low-dose FA was associated with significantly more frequent and severe leukopenia and stomatitis, whereas a weekly course of 5-FU plus high-dose FA was associated with significantly more frequent and severe diarrhea. There were no significant differences in therapeutic efficacy between the regimens with respect to response rate, survival, and palliative effects.

In vitro studies have shown that inhibition of de novo pyrimidine biosynthesis, such as by PALA via the enzyme aspartate transcarbamylase,33 results in enhancement of 5-FU cytotoxicity.34 The biochemical basis for the synergy noted between 5-FU and PALA in preclinical studies35,36 involves either increase in the 5-fluorouridine triphosphate/uridine triphosphate ratio in PALA-treated tumor cells, resulting in increased incorporation of 5-fluorouridine triphosphate into RNA,37 or enhanced generation of fluorodeoxyuridylate from 5-FU, resulting in increased inhibition of thymidylate synthase and DNA synthesis inhibition.38 Several clinical studies of 5-FU + PALA have been performed based on this previously described synergy.7,39 Ardalan et al,7 in a randomized phase I and II study of 5-FU + PALA versus single-agent 5-FU, noted therapeutic response favoring the combination arm, with a response rate of 46%. Myelosuppression and ataxia were the dose-limiting toxic effects. O'Dwyer et al,40 subsequently reported a confirmatory phase II study in patients with metastatic colorectal carcinoma using the same regimen, with similar response rates and minimal toxic effects. Despite previously observed response rates, however, the addition of PALA to 5-FU did not seem to improve survival in patients with metastatic colorectal carcinoma.41

IFN{alpha}-2a alone is not active in the treatment of colorectal cancer.27 However, a dose-related potentiation by IFN{alpha}-2a of the cytotoxicity of 5-FU to a colon cancer cell line has been demonstrated.42 The exact mechanism for the interaction is not clear, but several mechanisms have been proposed.43 5-FU and IFN{alpha}-2a have been combined in clinical trials to determine the therapeutic efficacy of the combination. Wadler et al9 first clinically demonstrated the effectiveness of 5-FU + IFN{alpha}-2a in patients with metastatic colorectal carcinoma. Their study produced an impressive response rate of 76% but with severe toxicities, including one treatment-related death. Other investigators have not been able to confirm such a high response rate, yielding response rates ranging from 26% to 42%.10,11 Toxic effects from this regimen include stomatitis, diarrhea, leukopenia, and neurotoxicity. In addition, IFN{alpha}-2a has specific side effects, such as fever, weight loss, and flu-like symptoms. In randomized phase III trials, no significant difference in response rate or overall survival were seen by the addition of IFN{alpha}-2a.12,44-47 Furthermore, the National Surgical Adjuvant Breast and Bowel Project Trial C-05 also failed to show cytotoxic improvement when IFN{alpha}-2a was added to 5-FU + FA as treatment for patients with stage II and III colon carcinoma.48 Hence, despite the initial enthusiasm, 5-FU + IFN{alpha}-2a regimens have failed to show improved efficacy over other 5-FU–based regimens as treatment for colorectal carcinoma either in metastatic disease or an adjuvant setting.

In this study, we used three agents in a sequential order (FA, followed by PALA, and then IFN{alpha}-2a) to biochemically modulate 5-FU as treatment for patients with metastatic colorectal carcinoma. The rationale for early sequential biomodulation is to achieve the greatest cytotoxic activity before the development of 5-FU–resistant cells, with the goal of improving the therapeutic efficacy of 5-FU. Previously, attempts at combining these modulators in a single treatment regimen have not provided significant therapeutic advantage over conventional 5-FU treatment regimens.16,17,49 Unfortunately, our attempt at sequential modulation likewise resulted in no improvement in efficacy. The response rates, duration of response, and median survival were similar to those obtained from other treatment regimens combining 5-FU with a single modulator. As expected, the toxicity profile for each cycle among patients in this study was similar to that reported in the literature, with the most toxicity seen in the 5-FU + IFN{alpha}-2a cycle.

Because efforts thus far to further modulate 5-FU in the treatment of metastatic colorectal carcinoma have met with disappointment, future studies aimed at improving the therapeutic efficacy of 5-FU, which inherently performs poorly in the metastatic setting,50 will need to focus on novel combination regimens with newer drugs. A few examples of such newer drugs are oxaliplatin, irinotecan, and other agents, such as capecitabine (Xeloda; Roche, Nutley, NJ), UFT plus oral leucovorin (Orzel; Bristol-Myers Squibb, Princeton, NJ), and eniluracil plus oral 5-FU (Glaxo-Wellcome, Research Triangle Park, NC). These novel agents alone and in combination may provide more promising routes of clinical investigation in this disease.


   ACKNOWLEDGMENTS
 
Supported in part by grants no. CA45809 and CA16672 from the National Cancer Institute, Bethesda, MD.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
1. Landis SH, Murray T, Bolden S, et al: Cancer statistics. CA Cancer J Clin48:6-30, 1998[Abstract]

2. Pazdur R, Coia LR, Wagman LD, et al: Colorectal and anal cancers, in Pazdur R, Coia LR, Hoskins WJ, et al (eds): Cancer Management: A Multidisciplinary Approach. Huntington, NY, PRR, Inc, 1998, pp 65-88

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12. Hill M, Norman A, Cunningham D, et al: Royal Marsden phase III trial of fluorouracil with or without interferon alfa-2b in advanced colorectal cancer. J Clin Oncol13:1297-1302, 1995[Abstract]

13. Kim J, Zhi J, Satoh H, et al: Pharmacokinetics of recombinant human interferon-alfa-2a combined with 5-fluorouracil in patients with advanced colorectal carcinoma. Anticancer Drugs9:689-696, 1998[Medline]

14. Ajani JA, Kanojia MD, Bedikian AV: High dose methotrexate and 5-fluorouracil in patients with advanced colorectal carcinoma: A randomized study of two pretreatment intervals. Am J Clin Oncol12:335-338, 1989[Medline]

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16. Valone FH, Friedman MA, Wittlinger PS, et al: Treatment of patients with advanced colorectal carcinomas with fluorouracil alone, high dose leucovorin plus fluorouracil, or sequential methotrexate, fluorouracil, and leucovorin: A randomized trial of the Northern California Oncology Group. J Clin Oncol7:1427-1436, 1989[Abstract]

17. Conti JA, Kemeny N, Sieter K, et al: Trial of sequential trimetrexate, fluorouracil and high dose leucovorin in previously treated patients with gastrointestinal carcinoma. J Clin Oncol12:695-700, 1994[Abstract]

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Submitted January 28, 1999; accepted June 4, 1999.


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