Fluorouracil/Leucovorin/Interferon α-2a in patients with advanced colorectal cancer. Effects of maintenance therapy on remission duration.

Transcription

1 Chapter 8 Fluorouracil/Leucovorin/Interferon α-2a in patients with advanced colorectal cancer. Effects of maintenance therapy on remission duration. Jan Buter, Harm A.M. Sinnige, Dirk Th. Sleijfer, Elisabeth G.E. de Vries, Pax.H.B. Willemse, Winette T.A. van der Graaf, René C.J. Verschueren 1 and Nanno H. Mulder Summary Departments of Medical Oncology and 1 Surgical Oncology University Hospital, Oostersingel 59, 9713 EZ Groningen,The Netherlands. Background: We reported earlier a phase II study of combination treatment with 5- fluorouracil (5-FU), leucovorin (LV), and interferon α-2a (IFN) in patients with previously untreated metastatic colorectal cancer (Sinnige et al., Eur J Cancer 1993; 29A: ). Therapy was on an outpatient basis and consisted of LV 60 mg p.o. q8h day 1-3, IFN 18x10 6 IU s.c. day 1-3, and bolus 5-FU 750 mg/m 2 i.v. day 2-3. Treatment was repeated every 14 days, till a maximum of 8 courses. A response rate of 54% (95% confidence interval (CI), 34%-72%) was observed. However, remission duration after cessation of therapy was short with a median duration of 5 months (range 2 to 13+). Methods: Subsequently entered patients reaching a remission on this induction treatment received maintenance therapy: the above described 3-day regimen every 6 weeks until progression, for a maximum of 2 years. Results: Fifty-three patients were enroled in the induction regimen and 18 out of 29 responding patients received maintenance treatment. In 50 assessable patients 3 CR and 26 PR were observed for a response rate of 58% (CI, 43-72%). Median remission duration of patients receiving maintenance therapy was 9.4 months (CI, months) compared to 4.7 months (CI, months) of patients without maintenance therapy (p=.032). Median overall survival of all patients was 16.6 months. Toxicity of maintenance therapy was confined to WHO grade 2. Conclusion: The high response rate of this 5-FU/LV/IFN regimen holds true in a larger group of patients. Moreover, maintenance therapy prolongs median remission duration in responding patients without adding significant toxicity. 125

2 Introduction Colorectal carcinoma is one of the major causes of cancer-related deaths in the western world. The prognosis of untreated patients with advanced disease is poor with a median survival time of 10 months (1). The results of chemotherapy in these patients have been disappointing. Single-agent therapy with 5-fluorouracil (5-FU) results in response rates of 15% with most responses being partial and non-lasting. Effects on survival, if any, are minimal (2, 3). Addition of leucovorin (LV) to 5-FU has shown to improve anticancer activity both preclinically and clinically by modulating the inhibition of the target enzyme thymidilate synthetase (4, 5). Other modulation studies have shown improved anticancer activity from the combination of interferon α-2a (IFN) and 5-FU. Several synergistic mechanisms for this combination have been proposed, including altered intracellular and serum pharmacokinetics of 5-FU induced by IFN (6, 7). We studied the combination of 5-FU, LV and IFN. This triple-drug combination showed improved cytotoxicity over the two-drug combinations in vitro (8, 9). We reported earlier on the first 28 assessable patients with previously untreated metastatic colorectal cancer in a phase II study with a response rate of 54% (95% confidence interval (CI), 34%-72%). Despite this high activity, remission duration after cessation of therapy was short with a median remission duration of 5 months (range 2-13+) (10). Since then, patient accrual has continued, but patients with an objective response now received maintenance courses every six weeks to a maximum of 2 years or until progression. To investigate the role of maintenance therapy on the remission duration and the overall survival, we compared the second cohort receiving maintenance courses with the first cohort receiving the induction treatment only. Patients and methods Patients with histologically documented bi-dimensionally measurable or assessable advanced colorectal carcinoma, a WHO performance status (PS) of 0 to 2, an age between 18 and 75 years, with no prior chemotherapy and no uncontrollable concomitant diseases were eligible. Additional eligibility criteria included a leucocyte count of > 3x10 9 /L, platelet count > 100x10 9 /L, serum creatinine < 200 µmol/l, and serum bilirubin < 100 mmol/l. Informed consent was obtained from all patients before the start of treatment and the study was approved by the Medical Ethical Committee of the University Hospital Groningen, The Netherlands. Appropriate radiologic examinations were obtained within 4 weeks of study-entry to serve as a baseline for serial evaluation of the patient s disease status. Serum levels of carcino-embryonic antigen (CEA) were determined before the start of treatment. After an interim analysis the protocol was amended and patients in the second cohort with an objective 126

3 Table 1. Patients characteristics N Patients 53 Male/female 28/25 Age(years) median 53 range Performance status Prior radiotherapy 4 Time from diagnosis (months) median 4 range 0-74 Primary tumor Colon 33 Rectum 20 Sites of disease* Liver only 38 Liver and lung 3 Liver and other site 9 Lung only 2 Abdominal 16 *Can be more than one site 127

4 response (CR or PR) after eight induction courses were given maintenance therapy. Their number was estimated on detecting a doubling of remission duration with a power of 0.80 and a p-value < Therapy was on an outpatient basis and consisted of leucovorin 60 mg orally every 8 hours on days 1 through 3, interferon α-2a (Roferon-α, Roche, Mijdrecht, The Netherlands) 18x10 6 IU subcutaneously on days 1 through 3, and 5-FU 750 mg/m 2 as an intravenous bolus infusion on days 2 and 3. Acetaminophen 500 mg orally every 4 to 6 hours was given for pyretic reactions on IFN. To diminish the severity of mucositis, the patients were instructed to use ice chips by mouth starting 5 minutes before 5-FU administration and continuing for 30 minutes after the end of the 5-FU infusion (11). An oral hygiene program was used consisting of frequent teeth cleaning and mouth rinses with saline followed by chlorhexidine gluconate 0.12%. Induction cycles were repeated every 14 days for 4 courses and treatment was repeated in responding patients to a maximum of 8 courses. Maintenance treatment consisted of the same 3 day schedule every 6 weeks until progression for a maximum of 2 years. Evaluation of response was performed after every four courses during the induction treatment and after every course during the maintenance treatment. A complete response (CR) required disappearance of all evidence of tumor for a minimum of four weeks, a partial response (PR) was registered when a 50% or greater decrease in the sum of the products of all perpendicular diameters of evaluable lesions was reached; patients with a response less than partial or an increase of less than 25% were classified as stable disease (SD). Progression (PD) was defined as an increase of more than 25% or the development of new lesions. Remission duration was measured from the end of the remission-induction treatment until the date of documented progression. Survival was measured from the first day of therapy to date of death. Toxicity was assessed before every new course according to WHO guidelines (12). Treatment was withheld for 1 week when toxicity from a prior course had not recovered to a WHO grade 1 or less, except for hand-foot syndrome and alopecia. In case of grade 2 or higher major organ toxicity and grade 3 or higher myelotoxicity, 5-FU dose was reduced with 25%. In case of a delay for more than 2 weeks or more than 50% dose reduction the patient went off study. Because of its short intermittent use, no dose modification for the IFN was foreseen. CEA serum levels were measured before every course. 128

5 Statistical analysis Estimates of survival and remission duration were calculated using the method of Kaplan and Maier (13). Differences between responding patients with or without maintenance therapy was calculated using the generalized Wilcoxon test (14). A two sided alpha level of 0.05 was considered statistically significant. The association between performance status and response was assessed with the Mantel test for trend (15). Table 2. Characteristics of responding patients with or without maintenance treatment. No maintenance treatment Maintenance treatment Patients CR 2 1 PR 9 17 Male/female 5/6 11/7 Age (years) Performance status Site of origin Time from diagnosis (months) Median Range Colon 5 9 Rectum 6 9 Primary Metastasis

6 Results Patients From November 1990 to November 1993, a total of 53 patients were enroled in the induction regimen. Patients characteristics are listed in table 1. Liver metastases were the predominant metastatic site (74% of patients). All patients are included in the analysis of remission duration and survival. The characteristics of responding patients receiving maintenance treatment (group B) or not (group A) are shown in table 2. Both groups were comparable for age, sex, primary tumor, and performance status. Response Three out of the 53 patients were not evaluable for response. Two of them died from unrelated causes after one treatment course. One patient developed tumor-associated obstruction ileus two weeks after a first course and died after surgery. Three CR and 26 PR were observed. The response rate in 50 assessable patients was 58% (CI, 43%-72%). An additional 16 patients had SD and 5 patients had PD. Responses occurred in the liver (N=24), lung (N=6), and three responses were observed in extrahepatic, intra-abdominal lesions. Response rate was correlated to performance status. Objective response rate (CR + PR) was 88% in 16 patients with a WHO performance status of 0 and 48% in 29 patients with PS 1, and 20% in 5 patients with PS of 2 (p=.002). The overall response rate was higher for patients with rectum (75%) than for patients with colon primaries (47%) (p=.043). No difference in response rate was observed between patients with or without prior radiotherapy, male or female gender, and late (> 1 year) or early (< 1 year) onset of metastasis after diagnosis of primary tumor. Pretreatment CEA levels were elevated in 36/50 assessable patients. Responses were observed in 22/36 patients with elevated CEA levels and in 6/14 patients with normal pretreatment CEA levels (N.S.). Serial measurements of CEA levels revealed an initial rise of CEA levels after the onset of chemotherapy in several patients, probably due to shedding of the epitopes into the circulation. Biochemical response of serum CEA levels correlated with the clinical response, with only 2/22 responding patients having sustained elevated CEA levels (p=.036). 130

7 Toxicity Toxicity during the induction therapy was significant and occurred in all patients, with mucositis, mild nausea and vomiting, diarrhea and leucopenia as the most frequently observed side effects (table 3). Mucositis occurred in 229/354 (65%) courses, nausea and vomiting grade 1 and 2 in 142/354 (40%), diarrhea in 134/354 (39%) courses, and leucopenia in 93/534 (26%). Hand-foot syndrome (HFS) occurred in 24 patients and alopecia grade 3 in 11 patients. HFS and alopecia were observed only after two or more courses. Neurological toxicity, primarily cerebellar toxicity, occurred in 5 patients. In 14 patients 25% dose reduction of 5- FU was necessary because of persistent toxicity (43 courses). Hospital admission was necessary for grade 3-4 mucositis (2 patients) and diarrhea (1 patient). Toxicity tended to accumulate during the induction treatment. After the end of the induction treatment toxicities resolved after a 4- to 6-week rest period. 131

8 Table 3. Toxicity occurring in 354 courses during induction treatment Toxicity WHO grade (%) Mucositis Diarrhea Vomiting Leucopenia Thrombocytopenia Anemia Maintenance treatment Eighteen responding patients received maintenance treatment for a total 80 courses (median 4, range 1-10). Toxicity during maintenance courses was low and consisted of mild mucositis and diarrhea, confined to a WHO grade 1-2 level in all patients. The overall survival of all 53 patients is shown in figure 1. With a median observation period of 19.7 months, no differences were yet observed in the survival times of both cohorts. Median survival time of all patients was 16.6 months (CI, months). Median remission duration of patients receiving maintenance therapy was 9.4 months (CI, months) compared to 4.7 months (CI, months) of the previous 11 responding patients without maintenance therapy (p=.033, figure 2). Legend to figure 1. Survival probability of all patients. Legend to figure 2. Probability of progression free survival of patients with (dashed line) or without (solid line) maintenance treatment (P=.033). 132

9 Figure 1. Figure

10 Discussion We reported earlier our experience with an outpatient combination treatment of 5-FU, oral LV and IFN in patients with previously untreated metastatic colorectal cancer (10). LV was administered orally because of the preferential uptake of the active l-isomer that may prevent possible competition of the inactive d-isomer in the serum (16). The dose of LV 60 mg, every 8 hours for 3 days was shown to result in serum concentrations of LV sufficiently high enough to modulate 5-FU cytotoxicity in vitro (10). Among the first 28 assessable patients a response rate of 54% (95% CI, 34%-72%) was observed. Despite this high activity, the remission duration after cessation of chemotherapy was however disappointing with a median duration of 5 months (range months). We therefore started maintenance courses for responding patients to attempt prolongation of remission duration. We report here our cumulative experience of a total of 53 patients. The high response rate of this regimen holds true in a larger group of patients, with a response rate of 58% (95% CI, 43%-72%) among 50 evaluable patients. Response was correlated to initial performance status. The response rate is achieved at the cost of significant toxicity, for which dose modifications were necessary in 26% of patients. Remission duration after the end of the induction treatment was prolonged in the cohort of patients who received maintenance treatment, when compared with the cohort of responders among the first 28 patients who only received the induction treatment. Remission duration was 4.7 and 9.4 months for both groups, respectively (p=.033). With a median observation duration of responding patients of 19.7 months no conclusions can be drawn on survival time in both subgroups. The median survival time of all 53 patients was 16.6 months. Toxicity during maintenance therapy was confined to grade 1-2 mucositis and was acceptable in all patients. In conclusion, a high response rate of 54% of this outpatient regimen in patients with advanced colorectal carcinoma in a single center phase II setting holds true in a larger group of patients. Maintenance treatment in responding patients may prolong remission duration without adding significant toxicity. To study the effects of treatment on survival, randomized controlled trials are necessary comparing induction/maintenance treatment to the standard options of treatment in this stage of colon cancer. 134

11 References 1. Silverman DT, Murray JL, Smart CR, Brown CC, Myers MH. Estimated median survival times of patients with colorectal cancer based on experience with 9,745 patients. Am J Surg 1977; 133: Moertel CG. Chemotherapy of gastrointestinal cancer. N Engl J Med 1978; 299: Davis HL. Chemotherapy for large bowel cancer. Cancer 1982; 50: Moran RG. Leucovorin enhancement of the effects of the fluoropyrimidines on thymidilate synthase. Cancer 1989; 63: Arbuck SG. Overview of clinical trials using 5-fluorouracil and leucovorin in the treatment of advanced colorectal cancer. Cancer 1989; 63: Wadler S, Schwartz EL. Antineoplastic activity of the combination of interferon and cytotoxic agents against experimental and human malignancies: a review. Cancer Res 1990; 50: Grem JL, McAtee N, Murphy RF, Balis FM, Steinberg SM, Hamilton JM, et al. A pilot study of interferon alfa-2a in combination with fluorouracil plus high-dose leucovorin in metastatic gastrointestinal carcinoma. J Clin Oncol 1991; 9: Houghton JA, Morton CL, Adkins DA, Rahman A. Locus of interaction among 5-fluorouracil, leucovorin, and interferon-α2a in colon carcinoma cells. Cancer Res 1993; 53: Sinnige HAM, Timmer-Bosscha H, Peters GF, De Vries EGE, Mulder NH. Combined modulation of leucovorin and α-2a interferon of fluoropyrimidine mediated growth inhibition. Anticancer Res 1993; 13: Sinnige HAM, Buter J, De Vries EGE, Uges DRA, Roenhorst HW, Verschueren RCJ, et al. Phase I-II study of the addition of α-2a interferon to 5-fluorouracil/leucovorin. Pharmacokinetic interaction of α-2a interferon and leucovorin. Eur J Cancer 1993; 29A: Mahood DJ, Dose AM, Loprinzi CL, Veeder MH, Athmann LM, Thernau JM, et al. Inhibition of fluorouracil-induced stomatitis by oral cryotherapy. J Clin Oncol 1991; 9: WHO Handbook for reporting results of cancer treatment. Den Haag: Martinus Nijhoff, Kaplan EL, Maier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958; 53: Breslow NE. Analysis of survival data under the proportional hazards model. Int Statist Rev 1975; 43: Mantel N. Chi-square tests with one degree of freedom: Extensions of the Mantel-Haenszel procedure. J Am Stat Assoc 1963; 58: Straw JA, Szapary D, Wynn WT. Pharmacokinetics of the diastereoisomers of leucovorin after intravenous and oral administration to normal subjects. Cancer Res 1984; 44: