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Treatment of metastatic renal cell carcinoma with constant-rate floxuridine infusion plus recombinant α2b-interferon
Annals of Oncology 7: 601-605, 1996. O 1996 Kluwer Academic Publishers. Primed in the Netherlands.
Original article Treatment of metastatic renal cell carcinoma with constant-rate floxuridine infusion plus recombinant a2b-interferon A. Falcone,1 C. Cianci,1 E. Pfanner,1 S. Ricci,1 M. Lencioni,1 I. Brunetti,1 P. C. Giulianotti,2 L. Vannucci,2 F. Mosca2 & P. F. Conte 1 'U.O. Oncologia Medica, Ospedale S. Chiara; 7Istituto Chirurgia Generate e Sperimentale Universitd, Pisa, Italy
increase the initial FUDR does in 21 (50%) patients; the median FUDR dose intensity was 0.35 mg/kg/week (range Background: Floxuridine (FUDR) and a-interferon (IFN) are 0.18-0.54). Among 39 evaluable patients, 3 (7.5%) complete active agents in advanced renal cell carcinoma, with different and 10 (25.5%) partial responses were observed (response dose-limiting toxic effects and antitumor synergism in experi- rate 33%, 95% confidence interval (CI) 19%-50%) which mental models. The main purpose of this phase II study was lasted a median of 13 months (5.5-40+). Responses also to assess the activity and toxic effects of a combination of occurred in liver (2), in patients pretreated with systemic therapy (5) and in patients who had other unfavourable progFUDR and a2b-IFN in metastatic renal cell carcinoma. Patients and methods: Metastatic renal cell carcinoma nostic characteristics (7). Median progression-free and surpatients with measurable disease entered the study. FUDR vival times were 9 and 16 months, respectively. was administered as a constant-rate continuous infusion for Conclusions: In this study FUDR + a2b-IFN demonstrat14 days every 28 days at a starting daily dose of 0.1 mg/kg ed interesting activity in metastatic renal cell carcinoma, and with dose escalations of 0.025 mg/kg/day at each sub- showing promise also in patients with unfavourable prognossequent cycle if WHO >2 toxicity had not occurred. EFN- tic characteristics. The antitumor activity of FUDR and a2ba2b 10 x 1061.U. was administered intramuscularly 3 times IFN seems to be cumulative, but cumulative toxicity is also per week. observed. These results require confirmation in randomised Results: Forty-two patients entered the study and a total trials. of 272 cycles of FUDR + a2b-IFN were administered. In 41 evaluable patients WHO grade LQ-IV toxic effects included nausea and vomiting (22%), diarrhea (32%), stomatitis Key words: floxuridine, interferon, metastatic, renal carci(12%), fatigue (27%) and anorexia (12%). It was possible to noma, phase II Summary
Metastatic renal cell carcinoma (MRCC) is a poorprognosis disease with a median survival of approximately 8 months and a 5-year survival of less than 10% [1, 2]. There is no standard treatment for this neoplasm - one of the most chemo-resistant of all malignancies [3-5]. However, human cytokines such as a-interferon (a-IFN) and interleukin-2 (IL-2) have shown modest but reproducible results: response rates of approximately 10%-20% have been reported and some improvement in survival, in retrospective analyses, has been observed [6, 7|. Many different combinations of a-IFN and chemotherapy have been clinically evaluated, but no relevant benefits for combined regimens have been demonstrated [4, 5, 8, 9]. More recently, interest has been focused on the use of 5-fluoro-2deoxyuridine (FUDR), an S-phase fluoropyrimidine antimetabolite which is directly activated to 5-fluorodeoxyuridine-monophosphate (5-FdUMP). In fact, when administered as a continuous or circadian infu-
sion, responses have been observed in approximately 15%-20% of MRCC patients. The circadian infusion of FUDR has rendered it possible to significantly reduce toxicity and consequently to increase the maximum tolerable FUDR dose and dose-intensity when compared to a flat continuous infusion [10-13]; this observation was recently confirmed in a randomised study in advanced renal cancer patients [14]; however, preliminary results do not indicate a significantly improved activity in the circadian infusion arm [14]. Because of the demonstrated synergism between fluoropyrimidines and IFN [15-19] and their different dose-limiting toxicities, we previously conducted a preliminary evaluation of the combination of a2b-IFN, administered at 10 x 106 I.U. 3 times a week, and FUDR, administered as a 14-day flat continuous infusion every 28 days, in 16 metastatic renal carcinoma patients [20]. The study demonstrated that the combination was feasible, that the maximum tolerable dose of FUDR ranged between 0.1 and 0.175 mg/kg/d and that this treatment was active (33% response rate), with
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Introduction
602 responses observed also in patients pretreated with a-IFN + vinblastine. In the present study we extended these preliminary studies in 42 metastatic renal cancer patients to better define the clinical activity and toxicity of this new drug combination. Patients and methods Patient eligibility
Treatment and study design Eligible patients received recombinant a2b-IFN 10 x 106 l.U. intramuscularly 3 times a week, and FUDR at a starting daily dose of 0.100 mg/kg (in a minority of patients the starting FUDR daily dose was 0.075 or 0.125 mg/kg) administered as a constant-rate continuous infusion for 14 days every 28 days, through an implantable central venous catheter and an external volumetric pump (Pharmacia CADD-1, Pharmacia Deltec Inc., St. Paul, MN, USA). To improve IFN tolerability, most patients received concomitant therapy with acetaminophen and prednisolone (8 mg/day), which has been demonstrated to reduce LFN-induced toxic effects but not its efficacy [21, 22]. IFN therapy was temporarily interrupted and doses were subsequently reduced to 5 x 106 l.U. (and if not tolerated, to 3 x 106 l.U.) if intolerable IFN-related toxic effects (fever, fatigue and anorexia) had occurred. The FUDR dose was escalated at each subsequent cycle up to 0.025 mg/kg/day if FUDR-related World Health Organisation (WHO) gastrointestinal toxicity > grade 2 had occurred. After recovery from toxicity, FUDR therapy was resumed and continued at the dose immediately preceding the one which had caused > grade 2 toxicity. FUDR therapy was administered for a maximum of 12 cycles or until the onset of progressive disease. IFN therapy, if well tolerated, was continued until progressive disease was documented.
Assessability, toxicity and response criteria Pretreatment evaluation included history and physical examination, performance status assessment, complete blood cell with differential and platelet counts, complete blood profile, urine analysis, electrocardiogram, chest X-ray or computed tomography (CT) scan, abdominal CT scan and/or sonogram and any other examination necessary for evaluating metastatic sites. During treatment, physical examination and complete blood cell counts were repeated every two weeks, blood profile and urine analysis every 4 weeks, and sites of metastatic disease were evaluated every 8 weeks with radiographs or CT scan. Toxicity and responses were scored according to standard WHO criteria [23]. Duration of objective responses (CR and PR) as well as of minor responses and stable disease were calculated from the first day of treatment to the date of first observation of progressive disease or last examination.
This study was an open, non-randomised phase II trial and its main purpose was to assess the activity of a combination of FUDR and a2b-IFN in metastatic renal cell carcinoma. The optimal two-stage sequential sampling design described by Simon [24] was used to determine the number of patients to be included. The design parameters p0 (response rate in null hypothesis), pj (response rate in alternative hypothesis) and a and p" errors considered were 0.20, 0.40, 0.10 and 0.10, respectively. Therefore the first stage of the study required 17 patients and, if at least 3 objective responses were observed, the second stage required a total of 37 evaluable patients. If at least 10 patients responded after the second accrual stage the treatment was considered promising unless other factors indicated otherwise. Objective response rates between different subgroups of patients were compared using the standard x2 test. Tune to progression and survival distributions were calculated by using the KaplanMeier method and measured from the date of treatment start
Results A total of 42 consecutive patients with progressive metastatic renal cell carcinoma entered the study; their characteristics are summarised in Table 1. Classifying the patients into four risk subgroups as previously described by Palmer et al. [25] where ECOG PS, time from diagnosis to treatment and number of metastatic Table 1. Patient characteristics. No. of patients Median age (years) Range Female/male ECOG PS 0 1 2 3 Prior nephrectomy Prior systemic therapy Hormonotherapy a-IFN Chemotherapy Multiple pretreatment Sites of disease Lung/pleura Retro peritoneum Bone Liver Soft tissues Others Number of metastatic sites Single Multiple Median time from diagnosis to metastases (months) Range Median time from diagnosis to study entry (months) Range Risk group (Palmer) Very low Low Medium High
42 63 38-77 13/29 18 21 2 1 41 18 6 12 8 7 27 16 13 7 5 3 21 21 10 0-182 12 1-219 3 15 12 12
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Eligibility criteria included: histologicaUy proven diagnosis of renal cell carcinoma with recurrent or metastatic disease, Eastern Cooperative Oncology Group (ECOG) performance status < 3, measurable or evaluable disease, serum creatinine <3 mg/dl, serum bilirubin <1.5 mg/dl, transaminase <2.5 times normal values, leukocytes >3500 mm3 and platelets > 100,000 mm3. Prior nephrectomy in patients with synchronous metastatic disease was not considered an eligibility criteria; however, it was a standard treatment practice at our institution in all patients with an ECOG PS <2, a life expectancy >3 months and no major contraindications to surgery. Approval for the study was obtained from the local Ethics Committee, patients were informed of the nature of the study, gave their informed consent and were pre-registered before entry into the study.
Statistical considerations
603 among 6 patients in whom single interferon doses were reduced to 3 x 106 I.U. (P = 0.2). Of the remaining 26 patients 3 (7.5%) obtained minor responses, 15 (38.5%) had stable disease and 8 (21%) progressed (Table 3). Minor responses lasted a median of 13 months (range 4.5-13) and stable diseases lasted a median of 7 months (range 2-39+). Median progression-free and survival times estimated by the Kaplan-Meier method from the first day of treatment in all 42 of the study patients were 9 and 16 months, respectively; progression-free and overall survival distributions are shown in Figure 1. Table 2. Worst overall toxic effects (41 evaluable patients). Adverse effect
WHO grade ('%)
Nausea/vomiting Diarrhea Stomatitis Fever Leukopenia Fatigue* Anorexia*
I
n
ra
rv
20 17 27 7 22 7 5
37 20 19 27 15 30 17
15 22 10 0 0 27 12
7 10 2 0 0 -
* Grade t mild; grade II: moderate; grade HI: severe. Table 3. Responses to FUDR + a2b-IFN. Evaluable1 No. of patients 39 Proportion 100% Median duration Months Range
PR
CR 3 7.5%
MR 3 7.5%
10 25.5%
12.5 11-15.5
13 5.5-40+
13 4.5-13
SD
PD
15 38.5%
8 21%
7 2-39+
-
• Three patients were not evaluable because: 1 had radical surgery after 1st cycle, 1 refused therapy after 1 st cycle, 1 was lost to follow-up.
100 Entered 42
Progressed 35
Died 29
Figure I. Actuarial progression free and overall survival curves.
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sites are considered, 18 fell into the very low- or lowrisk groups and 24 into the medium- and high-risk groups. A total of 272 cycles of FUDR + a2b-IFN were administered, with a median of 6 cycles per patient. Forty-one patients are evaluable for toxicity (1 patient who died of the disease before toxicity could be assessed is not evaluable) and most frequent side effects included nausea, vomiting, diarrhea and stomatitis which developed during the second week of FUDR infusion or immediately after its end, flu-like symptoms which appeared in all patients mostly during the first 2 weeks of IFN therapy, and finally, fatigue and anorexia which were more common and severe in patients who received IFN for several months. No toxic deaths occurred, but 4 patients required hospitalisation because of severe diarrhea with dehydration. One of these patients, who experienced grade 4 diarrhea at the end of the first cycle with FUDR at 0.1 mg/kg/day, continued, after recovery, FUDR + IFN therapy with FUDR 0.075-0.100 mg/kg/day administered in circadian chronomodulated infusion (67% of total daily dose administered between 4 p.m. and midnight) this time without severe side effects. Because of fatigue and anorexia 20 (47%) patients required IFN dose reductions during the first 4 months of treatment and 4 (10%) after that period. In 21 (50%) patients the initial FUDR dose could be increased in the subsequent cycles, with the maximum FUDR dose ranging from 0.100 to 0.200 mg/kg/day (median 0.125 mg/kg/day). FUDR dose intensity during the entire treatment period was also calculated and ranged between 0.18 and 0.54 mg/kg/week (median 0.35 mg/kg/week). Thirty-nine patients are evaluable for response. Three patients are not evaluable because one underwent surgery after the first cycle of FUDR and was rendered disease-free, another refused further therapy after the first cycle and the last was lost to follow-up before first re-evaluation. Overall, 13 objective responses have been observed (response rate 33%, 95% CI 19%-50%) and of these 3 (7.5%) were complete and 10 (25.5%) partial (Table 3). Responses occurred in lung (9), liver (2), lymph nodes (3) and soft tissues (1); the median time to response was 3 months (range 1-9) and responses lasted a median of 13 months (range 5.5-40+). Two of the 3 complete responses occurred in lung and one in liver , and lasted 11 to 15.5 months. No significant correlation was found between FUDR dose-intensity and response (<0.35 mg/kg/ week: 7/19 (37%) vs. >0.35 mg/kg/week: 6/20 (30%); P- 0.90), between IFN dose and response '10 x 106 I.U.: 5/15 (33%) vs. <10 x 106 I.U.: 8/24 (33%)', between previous systemic therapy and response (previous therapy: 5/17 (29%) vs. no previous therapy: 8/22 (36%); P " 0.9) nor between the risk subgroups previously described by Palmer and response (very low + low risk: 6/17 (35%) vs. medium + high risk 7/22: (32%); P= 0.81). However, only 1 partial remission, 2 stable diseases and 3 progressions were observed
604 Discussion
Acknowledgements
The work was partially supported by a grant from the Associazione Italiana Ricerca Cancro. The authors thank the nurses and staff of the Division of Medical Oncology (S. Chiara Hospital, Pisa, Italy) for their assistance in conducting the study. References 1. De Forges A, Rey A, Klink M et al. Prognostic factors of adult renal carcinoma: Multivariate analyses. Semin Surg Oncol 1988; 4: 149-54. 2. Giuliani L, Giberti C, Martorana G et al. Radical extensive surgery for renal cell carcinoma; Long term results and prognostic factors. J Urol 1990; 143:468-74. 3. Yagoda A, Abi-Rached B, Petrylak D. Chemotherapy for advanced renal-cell carcinoma: 1983-1993. Semin Oncol 1995; 22: 42-60. 4. WM Linehan WM, Shipley WV, Parkinson DR. Cancer of the
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Despite the accumulation of knowledge about cancer biology results in the therapy of metastatic renal carcinoma are still discouraging [3-5]. Interferon-a and IL-2 are the most widely used treatments, but objective responses are obtained in only 10%-20% of the patients and the impact of these compounds on the natural history of the disease is limited [3-7]. Of the chemotherapeutic agents, FUDR has recently demonstrated modest, but definitive activity in this neoplasm [10-14]. Interestingly, fluoropyrimidines have shown synergistic antitumor activity in combination with interferons, with the two exerting different clinical dose-limiting toxic effects [15-19]. The interactions between interferons and fluoropyrimidines which might explain their enhanced cytotoxicity are not yet completely understood, but they may include effects on thymidine kinase and thymidylate synthetase enzyme activities, thymidine transport, the induction of DNA strand breaks and fluoropyrimidines clearance [16, 17, 26-30], The combination of recombinant a-IFN and fluoropyrimidine has been extensively evaluated in metastatic colorectal cancer, but clinical results have been contradictory and recent randomised trials have not supported the clinical use of this association in this disease [31-33]. However, in renal cell carcinoma, where recombinant ainterferon is active also as a single agent, its combination with fluoropyrimidines could more explicitly show therapeutic improvement. We therefore evaluated FUDR plus a2b-IFN in metastatic renal cell carcinoma and our preliminary results in 16 patients demonstrated promising activity for this drug combination and the feasibility of its use [20]. Thus, we have extended this study to 42 metastatic renal cell carcinoma patients, and our results demonstrate and confirm that this combination has interesting activity (response rate 33%; 95% CI 19%-50%) in metastatic renal-cell carcinoma. Of note is the fact that responses were observed also in patients with unfavourable prognostic characteristics such as the presence of liver metastasis, ECOG performance status >1, multiple metastatic sites or previous systemic therapy; in fact, the response rate among the patients, which fell in the Palmer's high- and veryhigh-risk groups, was still relatively high (32%). Nevertheless, toxicity was also significant, with 32% of patients experiencing grade ni-IV diarrhea and 27% severe fatigue. However, moderate reductions in the a2b-IFN doses or the administration of relatively low FUDR dosages did not seem to impair the activity of this combination. This may suggest that a similar association, using lower a2b-IFN doses and without escalating the initial FUDR dose of 0.1 mg/kg/day, could be equally active and less toxic; furthermore, the chronomudulated infusion of FUDR should also significantly reduce gastrointestinal toxicity. Thus far this is the largest study which has evaluated the combination of a-IFN and FUDR and the only one in which moderately high a-IFN doses were used. Two
other studies which administered significantly lower aIFN doses (daily doses between 1 and 3 x 1061.U.) and including 13 and 11 evaluable patients have been reported: their results are contradictory and while in the first study by Dimopoulos et al. [34] 4 (31%) patients responded, in the other, by Soori et al. [35], no activity was observed. Stadler et al. [36] have combined highdose a-IFN with FUDR and leucovorin, but among 20 evaluable patients no activity was observed. Other phase II studies have evaluated the combination of aIFN with another fluoropyrimidine, 5-fluorouracil, which can be intracellularly activated to 5-FdUMP like FUDR, and responses have ranged between 0% and 30% [37-39]. Although any definitive conclusion cannot be drawn from these studies, it is interesting that a recent overview of chemotherapy trials in advanced renal-cell carcinoma, conducted from 1983 to 1993, showed that the combination of a-IFN + fluoropyrimidine has obtained, overall, the highest response rate (18.6%) [3]. Finally, recent phase II studies where interleukin-2 has been combined with a fluoropyrimidine and a-interferon have also reported very promising activity, with objective responses documented in almost 50% of the patients [40,41]. In conclusion, our study suggests that the combination of FUDR and a-IFN which we used has promising activity in metastatic renal cell carcinoma and supports the hypothesis that the combination of a fluoropyrimidine with a-IFN might be more active than either agent used alone. In particular, the antitumor activity of FUDR and a-IFN seems to be cumulative, but toxicity is also increased, and ways to reduce if, such as by the chronomodulated infusion of FUDR or the administration of lower a-IFN doses, should be evaluated. Of course, these results will require confirmation in randomised trials which will also have to determine the effect of this combination on survival.
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Received 2 April 1996; accepted 7 June 1996. Correspondence to: Alfredo Falcone, MD U.O. Oncologia Medica Osp. S. Chiara Via Roma, 67 56126 Pisa Italy
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Original article Treatment of metastatic renal cell carcinoma with constant-rate floxuridine infusion plus recombinant a2b-interferon A. Falcone,1 C. Cianci,1 E. Pfanner,1 S. Ricci,1 M. Lencioni,1 I. Brunetti,1 P. C. Giulianotti,2 L. Vannucci,2 F. Mosca2 & P. F. Conte 1 'U.O. Oncologia Medica, Ospedale S. Chiara; 7Istituto Chirurgia Generate e Sperimentale Universitd, Pisa, Italy
increase the initial FUDR does in 21 (50%) patients; the median FUDR dose intensity was 0.35 mg/kg/week (range Background: Floxuridine (FUDR) and a-interferon (IFN) are 0.18-0.54). Among 39 evaluable patients, 3 (7.5%) complete active agents in advanced renal cell carcinoma, with different and 10 (25.5%) partial responses were observed (response dose-limiting toxic effects and antitumor synergism in experi- rate 33%, 95% confidence interval (CI) 19%-50%) which mental models. The main purpose of this phase II study was lasted a median of 13 months (5.5-40+). Responses also to assess the activity and toxic effects of a combination of occurred in liver (2), in patients pretreated with systemic therapy (5) and in patients who had other unfavourable progFUDR and a2b-IFN in metastatic renal cell carcinoma. Patients and methods: Metastatic renal cell carcinoma nostic characteristics (7). Median progression-free and surpatients with measurable disease entered the study. FUDR vival times were 9 and 16 months, respectively. was administered as a constant-rate continuous infusion for Conclusions: In this study FUDR + a2b-IFN demonstrat14 days every 28 days at a starting daily dose of 0.1 mg/kg ed interesting activity in metastatic renal cell carcinoma, and with dose escalations of 0.025 mg/kg/day at each sub- showing promise also in patients with unfavourable prognossequent cycle if WHO >2 toxicity had not occurred. EFN- tic characteristics. The antitumor activity of FUDR and a2ba2b 10 x 1061.U. was administered intramuscularly 3 times IFN seems to be cumulative, but cumulative toxicity is also per week. observed. These results require confirmation in randomised Results: Forty-two patients entered the study and a total trials. of 272 cycles of FUDR + a2b-IFN were administered. In 41 evaluable patients WHO grade LQ-IV toxic effects included nausea and vomiting (22%), diarrhea (32%), stomatitis Key words: floxuridine, interferon, metastatic, renal carci(12%), fatigue (27%) and anorexia (12%). It was possible to noma, phase II Summary
Metastatic renal cell carcinoma (MRCC) is a poorprognosis disease with a median survival of approximately 8 months and a 5-year survival of less than 10% [1, 2]. There is no standard treatment for this neoplasm - one of the most chemo-resistant of all malignancies [3-5]. However, human cytokines such as a-interferon (a-IFN) and interleukin-2 (IL-2) have shown modest but reproducible results: response rates of approximately 10%-20% have been reported and some improvement in survival, in retrospective analyses, has been observed [6, 7|. Many different combinations of a-IFN and chemotherapy have been clinically evaluated, but no relevant benefits for combined regimens have been demonstrated [4, 5, 8, 9]. More recently, interest has been focused on the use of 5-fluoro-2deoxyuridine (FUDR), an S-phase fluoropyrimidine antimetabolite which is directly activated to 5-fluorodeoxyuridine-monophosphate (5-FdUMP). In fact, when administered as a continuous or circadian infu-
sion, responses have been observed in approximately 15%-20% of MRCC patients. The circadian infusion of FUDR has rendered it possible to significantly reduce toxicity and consequently to increase the maximum tolerable FUDR dose and dose-intensity when compared to a flat continuous infusion [10-13]; this observation was recently confirmed in a randomised study in advanced renal cancer patients [14]; however, preliminary results do not indicate a significantly improved activity in the circadian infusion arm [14]. Because of the demonstrated synergism between fluoropyrimidines and IFN [15-19] and their different dose-limiting toxicities, we previously conducted a preliminary evaluation of the combination of a2b-IFN, administered at 10 x 106 I.U. 3 times a week, and FUDR, administered as a 14-day flat continuous infusion every 28 days, in 16 metastatic renal carcinoma patients [20]. The study demonstrated that the combination was feasible, that the maximum tolerable dose of FUDR ranged between 0.1 and 0.175 mg/kg/d and that this treatment was active (33% response rate), with
Downloaded from http://annonc.oxfordjournals.org/ by guest on June 6, 2016
Introduction
602 responses observed also in patients pretreated with a-IFN + vinblastine. In the present study we extended these preliminary studies in 42 metastatic renal cancer patients to better define the clinical activity and toxicity of this new drug combination. Patients and methods Patient eligibility
Treatment and study design Eligible patients received recombinant a2b-IFN 10 x 106 l.U. intramuscularly 3 times a week, and FUDR at a starting daily dose of 0.100 mg/kg (in a minority of patients the starting FUDR daily dose was 0.075 or 0.125 mg/kg) administered as a constant-rate continuous infusion for 14 days every 28 days, through an implantable central venous catheter and an external volumetric pump (Pharmacia CADD-1, Pharmacia Deltec Inc., St. Paul, MN, USA). To improve IFN tolerability, most patients received concomitant therapy with acetaminophen and prednisolone (8 mg/day), which has been demonstrated to reduce LFN-induced toxic effects but not its efficacy [21, 22]. IFN therapy was temporarily interrupted and doses were subsequently reduced to 5 x 106 l.U. (and if not tolerated, to 3 x 106 l.U.) if intolerable IFN-related toxic effects (fever, fatigue and anorexia) had occurred. The FUDR dose was escalated at each subsequent cycle up to 0.025 mg/kg/day if FUDR-related World Health Organisation (WHO) gastrointestinal toxicity > grade 2 had occurred. After recovery from toxicity, FUDR therapy was resumed and continued at the dose immediately preceding the one which had caused > grade 2 toxicity. FUDR therapy was administered for a maximum of 12 cycles or until the onset of progressive disease. IFN therapy, if well tolerated, was continued until progressive disease was documented.
Assessability, toxicity and response criteria Pretreatment evaluation included history and physical examination, performance status assessment, complete blood cell with differential and platelet counts, complete blood profile, urine analysis, electrocardiogram, chest X-ray or computed tomography (CT) scan, abdominal CT scan and/or sonogram and any other examination necessary for evaluating metastatic sites. During treatment, physical examination and complete blood cell counts were repeated every two weeks, blood profile and urine analysis every 4 weeks, and sites of metastatic disease were evaluated every 8 weeks with radiographs or CT scan. Toxicity and responses were scored according to standard WHO criteria [23]. Duration of objective responses (CR and PR) as well as of minor responses and stable disease were calculated from the first day of treatment to the date of first observation of progressive disease or last examination.
This study was an open, non-randomised phase II trial and its main purpose was to assess the activity of a combination of FUDR and a2b-IFN in metastatic renal cell carcinoma. The optimal two-stage sequential sampling design described by Simon [24] was used to determine the number of patients to be included. The design parameters p0 (response rate in null hypothesis), pj (response rate in alternative hypothesis) and a and p" errors considered were 0.20, 0.40, 0.10 and 0.10, respectively. Therefore the first stage of the study required 17 patients and, if at least 3 objective responses were observed, the second stage required a total of 37 evaluable patients. If at least 10 patients responded after the second accrual stage the treatment was considered promising unless other factors indicated otherwise. Objective response rates between different subgroups of patients were compared using the standard x2 test. Tune to progression and survival distributions were calculated by using the KaplanMeier method and measured from the date of treatment start
Results A total of 42 consecutive patients with progressive metastatic renal cell carcinoma entered the study; their characteristics are summarised in Table 1. Classifying the patients into four risk subgroups as previously described by Palmer et al. [25] where ECOG PS, time from diagnosis to treatment and number of metastatic Table 1. Patient characteristics. No. of patients Median age (years) Range Female/male ECOG PS 0 1 2 3 Prior nephrectomy Prior systemic therapy Hormonotherapy a-IFN Chemotherapy Multiple pretreatment Sites of disease Lung/pleura Retro peritoneum Bone Liver Soft tissues Others Number of metastatic sites Single Multiple Median time from diagnosis to metastases (months) Range Median time from diagnosis to study entry (months) Range Risk group (Palmer) Very low Low Medium High
42 63 38-77 13/29 18 21 2 1 41 18 6 12 8 7 27 16 13 7 5 3 21 21 10 0-182 12 1-219 3 15 12 12
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Eligibility criteria included: histologicaUy proven diagnosis of renal cell carcinoma with recurrent or metastatic disease, Eastern Cooperative Oncology Group (ECOG) performance status < 3, measurable or evaluable disease, serum creatinine <3 mg/dl, serum bilirubin <1.5 mg/dl, transaminase <2.5 times normal values, leukocytes >3500 mm3 and platelets > 100,000 mm3. Prior nephrectomy in patients with synchronous metastatic disease was not considered an eligibility criteria; however, it was a standard treatment practice at our institution in all patients with an ECOG PS <2, a life expectancy >3 months and no major contraindications to surgery. Approval for the study was obtained from the local Ethics Committee, patients were informed of the nature of the study, gave their informed consent and were pre-registered before entry into the study.
Statistical considerations
603 among 6 patients in whom single interferon doses were reduced to 3 x 106 I.U. (P = 0.2). Of the remaining 26 patients 3 (7.5%) obtained minor responses, 15 (38.5%) had stable disease and 8 (21%) progressed (Table 3). Minor responses lasted a median of 13 months (range 4.5-13) and stable diseases lasted a median of 7 months (range 2-39+). Median progression-free and survival times estimated by the Kaplan-Meier method from the first day of treatment in all 42 of the study patients were 9 and 16 months, respectively; progression-free and overall survival distributions are shown in Figure 1. Table 2. Worst overall toxic effects (41 evaluable patients). Adverse effect
WHO grade ('%)
Nausea/vomiting Diarrhea Stomatitis Fever Leukopenia Fatigue* Anorexia*
I
n
ra
rv
20 17 27 7 22 7 5
37 20 19 27 15 30 17
15 22 10 0 0 27 12
7 10 2 0 0 -
* Grade t mild; grade II: moderate; grade HI: severe. Table 3. Responses to FUDR + a2b-IFN. Evaluable1 No. of patients 39 Proportion 100% Median duration Months Range
PR
CR 3 7.5%
MR 3 7.5%
10 25.5%
12.5 11-15.5
13 5.5-40+
13 4.5-13
SD
PD
15 38.5%
8 21%
7 2-39+
-
• Three patients were not evaluable because: 1 had radical surgery after 1st cycle, 1 refused therapy after 1 st cycle, 1 was lost to follow-up.
100 Entered 42
Progressed 35
Died 29
Figure I. Actuarial progression free and overall survival curves.
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sites are considered, 18 fell into the very low- or lowrisk groups and 24 into the medium- and high-risk groups. A total of 272 cycles of FUDR + a2b-IFN were administered, with a median of 6 cycles per patient. Forty-one patients are evaluable for toxicity (1 patient who died of the disease before toxicity could be assessed is not evaluable) and most frequent side effects included nausea, vomiting, diarrhea and stomatitis which developed during the second week of FUDR infusion or immediately after its end, flu-like symptoms which appeared in all patients mostly during the first 2 weeks of IFN therapy, and finally, fatigue and anorexia which were more common and severe in patients who received IFN for several months. No toxic deaths occurred, but 4 patients required hospitalisation because of severe diarrhea with dehydration. One of these patients, who experienced grade 4 diarrhea at the end of the first cycle with FUDR at 0.1 mg/kg/day, continued, after recovery, FUDR + IFN therapy with FUDR 0.075-0.100 mg/kg/day administered in circadian chronomodulated infusion (67% of total daily dose administered between 4 p.m. and midnight) this time without severe side effects. Because of fatigue and anorexia 20 (47%) patients required IFN dose reductions during the first 4 months of treatment and 4 (10%) after that period. In 21 (50%) patients the initial FUDR dose could be increased in the subsequent cycles, with the maximum FUDR dose ranging from 0.100 to 0.200 mg/kg/day (median 0.125 mg/kg/day). FUDR dose intensity during the entire treatment period was also calculated and ranged between 0.18 and 0.54 mg/kg/week (median 0.35 mg/kg/week). Thirty-nine patients are evaluable for response. Three patients are not evaluable because one underwent surgery after the first cycle of FUDR and was rendered disease-free, another refused further therapy after the first cycle and the last was lost to follow-up before first re-evaluation. Overall, 13 objective responses have been observed (response rate 33%, 95% CI 19%-50%) and of these 3 (7.5%) were complete and 10 (25.5%) partial (Table 3). Responses occurred in lung (9), liver (2), lymph nodes (3) and soft tissues (1); the median time to response was 3 months (range 1-9) and responses lasted a median of 13 months (range 5.5-40+). Two of the 3 complete responses occurred in lung and one in liver , and lasted 11 to 15.5 months. No significant correlation was found between FUDR dose-intensity and response (<0.35 mg/kg/ week: 7/19 (37%) vs. >0.35 mg/kg/week: 6/20 (30%); P- 0.90), between IFN dose and response '10 x 106 I.U.: 5/15 (33%) vs. <10 x 106 I.U.: 8/24 (33%)', between previous systemic therapy and response (previous therapy: 5/17 (29%) vs. no previous therapy: 8/22 (36%); P " 0.9) nor between the risk subgroups previously described by Palmer and response (very low + low risk: 6/17 (35%) vs. medium + high risk 7/22: (32%); P= 0.81). However, only 1 partial remission, 2 stable diseases and 3 progressions were observed
604 Discussion
Acknowledgements
The work was partially supported by a grant from the Associazione Italiana Ricerca Cancro. The authors thank the nurses and staff of the Division of Medical Oncology (S. Chiara Hospital, Pisa, Italy) for their assistance in conducting the study. References 1. De Forges A, Rey A, Klink M et al. Prognostic factors of adult renal carcinoma: Multivariate analyses. Semin Surg Oncol 1988; 4: 149-54. 2. Giuliani L, Giberti C, Martorana G et al. Radical extensive surgery for renal cell carcinoma; Long term results and prognostic factors. J Urol 1990; 143:468-74. 3. Yagoda A, Abi-Rached B, Petrylak D. Chemotherapy for advanced renal-cell carcinoma: 1983-1993. Semin Oncol 1995; 22: 42-60. 4. WM Linehan WM, Shipley WV, Parkinson DR. Cancer of the
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Despite the accumulation of knowledge about cancer biology results in the therapy of metastatic renal carcinoma are still discouraging [3-5]. Interferon-a and IL-2 are the most widely used treatments, but objective responses are obtained in only 10%-20% of the patients and the impact of these compounds on the natural history of the disease is limited [3-7]. Of the chemotherapeutic agents, FUDR has recently demonstrated modest, but definitive activity in this neoplasm [10-14]. Interestingly, fluoropyrimidines have shown synergistic antitumor activity in combination with interferons, with the two exerting different clinical dose-limiting toxic effects [15-19]. The interactions between interferons and fluoropyrimidines which might explain their enhanced cytotoxicity are not yet completely understood, but they may include effects on thymidine kinase and thymidylate synthetase enzyme activities, thymidine transport, the induction of DNA strand breaks and fluoropyrimidines clearance [16, 17, 26-30], The combination of recombinant a-IFN and fluoropyrimidine has been extensively evaluated in metastatic colorectal cancer, but clinical results have been contradictory and recent randomised trials have not supported the clinical use of this association in this disease [31-33]. However, in renal cell carcinoma, where recombinant ainterferon is active also as a single agent, its combination with fluoropyrimidines could more explicitly show therapeutic improvement. We therefore evaluated FUDR plus a2b-IFN in metastatic renal cell carcinoma and our preliminary results in 16 patients demonstrated promising activity for this drug combination and the feasibility of its use [20]. Thus, we have extended this study to 42 metastatic renal cell carcinoma patients, and our results demonstrate and confirm that this combination has interesting activity (response rate 33%; 95% CI 19%-50%) in metastatic renal-cell carcinoma. Of note is the fact that responses were observed also in patients with unfavourable prognostic characteristics such as the presence of liver metastasis, ECOG performance status >1, multiple metastatic sites or previous systemic therapy; in fact, the response rate among the patients, which fell in the Palmer's high- and veryhigh-risk groups, was still relatively high (32%). Nevertheless, toxicity was also significant, with 32% of patients experiencing grade ni-IV diarrhea and 27% severe fatigue. However, moderate reductions in the a2b-IFN doses or the administration of relatively low FUDR dosages did not seem to impair the activity of this combination. This may suggest that a similar association, using lower a2b-IFN doses and without escalating the initial FUDR dose of 0.1 mg/kg/day, could be equally active and less toxic; furthermore, the chronomudulated infusion of FUDR should also significantly reduce gastrointestinal toxicity. Thus far this is the largest study which has evaluated the combination of a-IFN and FUDR and the only one in which moderately high a-IFN doses were used. Two
other studies which administered significantly lower aIFN doses (daily doses between 1 and 3 x 1061.U.) and including 13 and 11 evaluable patients have been reported: their results are contradictory and while in the first study by Dimopoulos et al. [34] 4 (31%) patients responded, in the other, by Soori et al. [35], no activity was observed. Stadler et al. [36] have combined highdose a-IFN with FUDR and leucovorin, but among 20 evaluable patients no activity was observed. Other phase II studies have evaluated the combination of aIFN with another fluoropyrimidine, 5-fluorouracil, which can be intracellularly activated to 5-FdUMP like FUDR, and responses have ranged between 0% and 30% [37-39]. Although any definitive conclusion cannot be drawn from these studies, it is interesting that a recent overview of chemotherapy trials in advanced renal-cell carcinoma, conducted from 1983 to 1993, showed that the combination of a-IFN + fluoropyrimidine has obtained, overall, the highest response rate (18.6%) [3]. Finally, recent phase II studies where interleukin-2 has been combined with a fluoropyrimidine and a-interferon have also reported very promising activity, with objective responses documented in almost 50% of the patients [40,41]. In conclusion, our study suggests that the combination of FUDR and a-IFN which we used has promising activity in metastatic renal cell carcinoma and supports the hypothesis that the combination of a fluoropyrimidine with a-IFN might be more active than either agent used alone. In particular, the antitumor activity of FUDR and a-IFN seems to be cumulative, but toxicity is also increased, and ways to reduce if, such as by the chronomodulated infusion of FUDR or the administration of lower a-IFN doses, should be evaluated. Of course, these results will require confirmation in randomised trials which will also have to determine the effect of this combination on survival.
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Received 2 April 1996; accepted 7 June 1996. Correspondence to: Alfredo Falcone, MD U.O. Oncologia Medica Osp. S. Chiara Via Roma, 67 56126 Pisa Italy
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