Japanese Journal of Clinical Oncology 31:18-24 (2001)
© 2001 Foundation for Promotion of Cancer Research
Prospective and Randomized Comparison of Combined Androgen Blockade Versus Combination with Oral UFT as an Initial Treatment for Prostate Cancer
1Tsurumi Nishiguchi Hospital, Yokohama, Kanagawa, 2Department of Urology, Gifu University School of Medicine, Gifu, 3Department of Urology, Nagoya University School of Medicine, Nagoya, 4Department of Pathology, Kanazawa Medical University, Kanazawa, and 5Department of Public Health, Gifu University School of Medicine, Gifu, Japan
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAcknowledgmentsREFERENCES |
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Objective: This prospective and randomized clinical study was initiated to compare the efficacy and safety of combined androgen blockade with combination with UFT in patients with untreated prostate cancer.
Methods: A total of 142 patients were entered in this study between April 1990 and December 1992. All patients received bilateral orchiectomy and 200 mg/day of diethylstilbestrol diphosphate. Of these patients, 70 patients were administered an additional 400 mg/day of UFT after randomization. Either treatment was continued for at least 1 year or until objective progression occurred if the initial response was equal to or better than no change. The endpoints of this study were progression-free survival, cancer-specific survival and change of QOL scores.
Results: A total of 136 patients were evaluable and 131 patients (96.3%) could be followed up with a median follow-up period of 1469 days. Both groups showed similar initial treatment response at 12 weeks, adverse effect and change of quality of life score during the first year after initiation of the treatment. There was a significantly longer progression-free survival and better but not significant cancer-specific survival in the endocrine chemotherapy group. The patients with earlier stage and initial serum prostate-specific antigen values <40 ng/ml showed a good indication for this endocrine chemotherapy.
Conclusion: This endocrine chemotherapy was confirmed to be tolerable and significantly effective in the delay of disease progression, which leads to longer survival in patients with prostate cancer.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAcknowledgmentsREFERENCES |
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The treatment for patients with advanced stages of prostate cancer (CAP) has mainly been endocrine therapy such as ablation of androgen (1). Moreover, in cases resistant to the endocrine treatment or showing relapse after the initial therapy, palliative therapies against symptoms such as pain or voiding difficulty may be chosen owing to lack of confirmed and effective treatment for these conditions. Therefore, one of the aims of the initial therapy of advanced CAP is protection against disease progression. Although there have been several studies on the clinical utility of addition of chemotherapeutic agent(s) to endocrine therapy (2–6), Eisenberger et al. (7) found the overall objective response rate to be as low as 6.5% from a review of 3184 patients reported in the literature. On the other hand, Issacs et al., using a Dunning adenocarcinoma tumor model, studied the optimal timing for treatment with cytotoxic drugs (8). They demonstrated that the early use of combined endocrine chemotherapy was superior to treatment with either modality alone and to sequential administration of endocrine and anti-cancer drugs.
Here, we report the results of a prospective and randomized cooperative study on endocrine chemotherapy for CAP as an initial treatment.
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PATIENTS AND METHODS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAcknowledgmentsREFERENCES |
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A total of 142 cases of newly diagnosed CAP seen in 26 participating Institutes were enrolled in this study from April 1990 to December 1992. After obtaining informed consent from each patient or his family prior to treatment, all patients received bilateral orchiectomy and were then divided into two groups using a lottery within 7 days after the castration. Patients in the endocrine chemotherapy (EC) group (n = 70) were orally administered 200 mg/day of diethylstilbestrol diphosphate (DES-P) and 400 mg/day of UFT (uracil plus tegafur) and those in the endocrine (E) group (n = 72) were administered 200 mg/day of DES-P only. The pathological diagnosis from biopsy specimens was re-evaluated by a pathologist. The patients in the following categories were excluded: patients having an episode while on anti-cancer therapy or double cancer, those suffering from cardiovascular disease, severe renal or hepatic impairment and those whose performance status (PS) was 4.
Subjective and objective symptoms, laboratory examination, digital rectal examination and prostate-specific antigen (PSA) test were assessed at every 4 weeks until 12 weeks after initiation, then repeated every 3 months. The change in the quality of life (QOL) score proposed by Kurihara et al. (9) was also evaluated at 2 weeks after the start of treatment in addition to the above evaluation timing. Diagnostic imaging such as ultrasonography for the prostate, CT, radioisotope bone scan and excretory urography were performed every 3 months. The first treatment effect was evaluated at 12 weeks after initiation according to the Response Criteria of the Prostatic Cancer of the Japanese Urological Association (10). When the initial treatment was successful [equal to or greater than no change (NC) in evaluation], treatment was continued either at least for 1 year or until objective progression occurred (10,11).
The endpoints of this study were progression-free survival, cancer-specific survival and change of QOL scores. All statistical analyses were performed by SPSS (12). Categorical data were compared using the 
2 test or U-test for proportion. The evaluations of prognosis were calculated using the Kaplan–Meier technique and compared using the log-rank test. The contribution of addition of chemotherapy to prognosis was evaluated using the Cox proportional hazard model.
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RESULTS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAcknowledgmentsREFERENCES |
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Of the 142 cases enrolled in this study, 69 in the EC group and 67 in the E group were evaluable. The remaining six cases were judged as unevaluable because of double cancer (two cases in the E group), no cancer cell in biopsy specimen diagnosed by a central pathologist (three cases, one in the EC and two in the E group) or no visit after initiation of the therapy (one case in the E group). The first treatment effect could be evaluated in 68 cases because suspension of the treatment occurred in one case in the EC group before 4 weeks.
The patients and tumor characteristics in the 136 evaluable cases are shown in Table 1. The average age in both groups was 75 years and more than 80% of the patients showed good PS of 
1. The clinical stages in the EC group were stage A in 1, B in 7, C in 11 and D in 50 and in the E group 4, 6, 7 and 50, respectively. There was no significant difference in the background analysis such as age, PS, clinical stage or pathological grade of CAP, TNM distribution (13) or QOL score between the two groups at the time of entry.
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As an adverse effect, the laboratory data worsened in 12 patients (17%) in the EC group and 10 patients (15%) in the E group. There was no grade IV worsening in laboratory data according to WHO criteria (14). Subjectively, 40 patients (58%) in the EC group and 41 patients (61%) in the E group complained of adverse effects. Among them, grade IV side effects such as cerebrovascular disease or ischemic heart disease were observed in two in the EC and three in the E group. Overall, 36 patients (52%) in the EC group and 41 patients (61%) in the E group showed a side effect. There was no significant difference in either number of cases showing adverse effect or distribution of the contents between the two groups.
The initial treatment effect at 12 weeks after initiation of treatment was good in both groups (Table 2). According to the Response Criteria of the Japanese Urological Association (10), 45 out of 68 patients (66%) in the EC group and 42 out of 67 patients (63%) in the E group showed a partial response (PR). A response of equal to or more than stabilized disease (
NC) was observed in 66 cases (97%) in the EC group and 66 cases (99%) in the E group.
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The median follow-up period was 1469 (35–2999) days; 1767 and 1147 days for the EC and E group, respectively. Of 136 cases evaluable, 131 (96.3%) could be successfully followed up. When examination judicable disease progression was not performed and only the patients’ survival was clarified, these cases were excluded from the analysis of progression-free survival at the end of the follow-up period. Owing to adverse effects (22 patients in the EC group and 26 patients in the E group) or patients’ refusal, the compliance of these drugs after 1 year was 59% for DES-P and 67% for UFT in the EC group and 54% for DES-P in the E group. Administration was discontinued and the patients were followed up without any further treatment.
The progression-free survival in the evaluable patients is shown in Fig. 1. The 5- and 8-year progression-free survival rates were 53.9 and 51.2% in the EC group and 43.2 and 36.9% in the E group, respectively. The EC group showed better survival than the E group, but not significantly (p = 0.065).
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The factors affecting the patient’s prognosis were then evaluated (Table 3) by univariate analysis. The significant factors affecting recurrence were found to be T-factor, PS, serum PSA values being cut off at 10 ng/ml, M-factor, stages and age in rank. With the use of Cox’s proportional hazard model in the selected factors, PS and treatment methods such as with or without UFT showed significant differences for disease progression.
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Figure 2 shows the progression-free survival in the patients whose initial treatment effect was equal to or greater than NC and the treatment continued at least for 2 months. Fifty-nine patients in the EC group and 63 patients in the E group belonged to this category. The 5- and 8-year progression-free survival rates were 58.4 and 55.5% in the EC group, whereas those in the E group were 41.2 and 35.3%, respectively. There was a significant difference between the two groups (p = 0.0164 in the log-rank test). The time to 50% progression-free survival was more than 98.5 months in the EC group and 30.2 months in the E group. Figure 3 shows the prostate cancer-specific survival. The 5- and 8-year survival rates were 70.6 and 52.9% for the EC group and 53.1 and 43.7% for the E group, respectively. Moreover, the time to 50% survival was more than 98.5 months in the EC group and 68.4 months in the E group. The EC group showed better cancer-specific survival than the E group, but not significantly (p = 0.1320). With the use of Cox’s proportional hazard model, the PS, stage and treatment were found to have significant relation to cancer-specific survival. The PS showed a significant relation to the overall survival.
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The QOL scores could be evaluated in 62 patients in the EC group and 63 patients in the E group. The QOL sum points did not change during the first 1-year follow-up. No significant difference was observed in QOL sum points between the two groups (Fig. 4).
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Using the cases treated by the endocrine chemotherapy, a similar evaluation was performed (Table 4). There were significant differences observed between disease progression and PS, M-factor, stage or PSA being cut at 40 ng/ml in rank. Then the prognosis according to the treatment and clinical stages of CAP was evaluated. As shown in Fig. 5, the patients with stages A–C treated with endocrine chemotherapy (19 patients) showed good survival both in progression-free survival and cancer-specific survival. This group showed no cancer-specific death in 8 years of follow-up. As for progression-free survival, the group of patients with stage D receiving endocrine chemotherapy (50 patients) and the group of patients with stages A–C treated with endocrine therapy (17 patients) showed the same prognosis. Similarly, the stage D group receiving endocrine chemotherapy and the stages A–C group treated with endocrine therapy were observed with the same cancer-specific survival rates.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAcknowledgmentsREFERENCES |
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Although radical prostatectomy has been widely accepted as a curative therapy for the patients with early stages CAP (15), androgen deprivation therapy has remained the main therapeutic approach for patients with advanced CAP. This endocrine therapy resulted in an improvement in 60–80% of patients with untreated metastatic CAP, but hormone-refractory disease occurs in 35–40% within the first 1 year and patients die of the disease under some palliative therapies (1). To improve these survival statistics, the addition of some other agents was considered.
As for cytotoxic chemotherapeutic agents, cyclophosphamide, 5-fluorouracil and methotrexate have been evaluated by the National Prostatic Cancer Project, USA (5,6,16–18). However, an obvious statistical difference was not observed in either non-recurrence or survival rate. Pummer et al. speculated that the reason for these disappointing results was the timing of the initiation of chemotherapy (19). Pre-clinical data have suggested that early chemotherapy improves treatment outcome (8,20). Recently, there have been a few reports showing the superiority of endocrine chemotherapy over endocrine therapy when used as an initial treatment. Of these, Kubota et al. (21) reported that patients treated with addition of cisplatin with or without other chemotherapeutic agents showed a significantly better survival than those on endocrine therapy alone. They did not perform a randomized trial although the background was the same for the two groups. These data only suggested the improvement of survival in the endocrine chemotherapy group. On the other hand, Pummer et al. (19) studied the significance of weekly epirubicin injection against total androgen blockade (TAB) alone with a prospective and randomized trial. They found that the addition of epirubicin to TAB showed a better prognosis in both progression-free and overall survival. However, only progression-free survival showed a significant difference. Moreover, they studied the change of QOL and found that addition of epirubicin did not affect QOL scores.
In this study, we evaluated the efficacy and safety of endocrine chemotherapy using additional UFT and the selection of a suitable group for the endocrine chemotherapy. This study was a prospective and randomized trial and completed in a short-time entry and satisfactory follow-up rate of 96.3%. The selection of UFT as a cytotoxic agent was based upon our previous report in which 5-fluorouracil (5-FU) was found to be effective for elongation of time of disease stabilization in patients with advanced CAP (22). UFT is an oral antineoplastic drug consisting of uracil and tegafur in a 4:1 molar ratio (23). Tegafur is a prodrug of 5-FU and is slowly metabolized to 5-FU in vivo. Uracil competitively inhibits the metabolism of 5-FU, resulting in increased plasma and tumor 5-FU concentrations. The UFT will be approved by the FDA (USA) for colon cancer in the near future. The other reason why we selected an oral cytotoxic drug was continuation of in-home treatment for maintaining QOL. This is very important for patients with CAP because of the advanced age of patients at diagnosis and the time from diagnosis to death of CAP is longer than that of other malignancies.
In comparison with the combined androgen blockade using castration and DES-P, our endocrine chemotherapy showed almost an equal initial response, adverse effect and QOL change in spite of the administration of UFT. The compliance of drugs was not satisfactory owing to adverse effects and patients’ refusal. However, even in the group on endocrine therapy, the 5- and 8-year prognoses were better than those in maximum androgen blockade which was recently published by the EORTC group (24). The addition of UFT showed a significantly better progression-free survival than endocrine therapy. In spite of the low compliance of UFT, a significantly lower progression-free survival in the EC group suggested that the shorter duration of less than 1 year of UFT administration may work for prolongation of disease stabilization. The cancer-specific survival, however, did not show a significantly better result as reported by Pummer et al. We believe that the difference will be significant if the number of patients enrolled is increased. Moreover, patients with lower stage, good PS or serum PSA values <40 ng/ml were also good indications for endocrine chemotherapy. Therefore, endocrine chemotherapy may become one option for patients with early-stage CAP as well as radical prostatectomy. The patients with poorly differentiated adenocarcinoma did not show the benefit of endocrine chemotherapy; therefore, another strategy will be necessary for this group.
In conclusion, this endocrine chemotherapy was confirmed to be tolerable and significantly effective for delay of disease recurrence, which leads to longer survival in patients with CAP.
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Acknowledgments |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAcknowledgmentsREFERENCES |
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We express our sincere appreciation to all researchers in 26 Institutes participating in this clinical trial for their follow-up of the cases.
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FOOTNOTES |
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+ For reprints and all correspondence: Manabu Kuriyama, Tsurumi Nishiguchi Hospital, 1–12–31 Tsurumi, Tsurumi-ku, Yokohama 230-0063, Japan E-mail: mkuriyama@mtg.biglobe.ne.jp
Abbreviations: CAP, prostate cancer; EC, endocrine chemotherapy; E, endocrine; PS, performance status; PSA, prostate-specific antigen; QOL, quality of life; NC, no change
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REFERENCES |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAcknowledgmentsREFERENCES |
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Received August 17, 2000; accepted November 9, 2000.
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