© 2004 Foundation for Promotion of Cancer Research
Efficacy of Modest Dose Irradiation in Combination with Long-term Endocrinal Treatment for High-risk Prostate Cancer: A Preliminary Report
1 Department of Clinical Radiology, Graduate School of Medical Sciences, Kyushu University, 2 Department of Radiation Technology, School of Health Sciences, Faculty of Medicine, Kyushu University, 3 Department of Urology, Graduate School of Medical Sciences, Kyushu University and 4 Department of Urology, Harasanshin Hospital, Fukuoka, Japan
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Background: Although radiotherapy in combination with endocrinal manipulation has been identified as an effective treatment for patients with high-risk prostate cancer, the optimal dose for locoregional control of prostate cancer in combination with hormonal therapy has not yet been determined.
Methods: The efficacy of modest doses of irradiation (60–62 Gy) combined with long-term endocrinal treatment for patients with high-risk prostate cancer (defined as a pretreatment prostate-specific antigen (PSA) level greater than 20 ng/ml or a Gleason’s score of 8–10 or T3-T4 disease) was analyzed in 60 Japanese patients. The patients included in this study had received radical radiotherapy with long-term endocrinal manipulation in the period between 1993 and 2000. The median age of the patients was 70 years (range, 56–83). Neoadjuvant hormonal therapy with a median duration of 3.9 months was performed prior to radiotherapy, and hormonal therapy was continued until recurrence. A median dose of 61.4 Gy (range, 44–71.4) was delivered to the prostate. Pelvic node irradiation was performed in 49 patients (81.6%).
Results: After a median follow-up period of 28.5 months, the overall survival, cause-specific survival and biochemical relapse-free survival at 3 years were 94.4%, 96% and 89.8%, respectively. Local failure was observed in one patient, distant metastases were observed in three patients and a late toxic effect greater than Grade 2 was not observed in any patients.
Conclusions: This study, though preliminary due to a short-term follow-up period, reveals the possibility that modest doses of irradiation combined with long-term endocrinal treatment could be an effective means of achieving excellent local control of high-risk prostate cancer.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Although the prostate is one of the leading cancer sites in men in the United States, both the incidence rate and mortality rate for prostate cancer are low in Asian countries (1). However, the number of patients with prostate cancer has been increasing in Japan, and a majority of the patients who had received radical radiotherapy also had high-risk disease (2). It has now become evident that fewer patients are cured with the standard dose of 65–70 Gy than was previously expected. However, recent analyses have revealed that escalation of the target dose to the prostate by conformal radiotherapy does improve the local control rate (3). Hormonal therapy, another mainstream mode of treatment for prostate cancer, is frequently combined with radiotherapy in Japan due to the risk of distant or pelvic lymph node metastases (2,4). According to recent analyses, a combination of hormonal therapy and radiotherapy for patients with high-risk prostate cancer has improved locoregional control as well as survival rates (5–8). Although long-term hormonal manipulation might be necessary in the treatment of high-risk prostate cancer (9,10), the optimal target doses for locoregional control have not yet been unequivocally determined. A target dose
65 Gy is commonly employed in combination with androgen suppression in Western countries (5–14), whereas the dose commonly used in Japan ranges from 60–65 Gy (2). With regard to this, the efficacy of modest doses of irradiation, which were administered in combination with long-term endocrinal treatment of patients with high-risk prostate cancer, was assessed in this study. |
SUBJECTS AND METHODS |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Sixty patients with high-risk prostate cancer (defined as a pretreatment prostate-specific antigen (PSA) level greater than 20 ng/ml or a Gleason’s score of 8–10 or stage T3-T4 disease), who had received radical radiotherapy in combination with long-term endocrinal manipulation in the period between 1993 and 2000 were analyzed in the present study. Patients who satisfied any of the definitions mentioned above were eligible to participate in this analysis. The patient characteristics are summarized in Table 1. The median age was 70 years (range, 56–83). The duration of the follow-up period was 6–62 months, with a median of 28.5 months. Patients were staged according to the Union Internationale Contre le Cancer tumor, node and metastasis classification (1997) using digital examination, computed tomography, magnetic resonance imaging and bone scintigram. The median pretreatment PSA level was 50.0 ng/ml. Prostate cancer was pathologically confirmed in all patients; however, the Gleason’s score was not available for 17 patients.
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Most of the patients were treated with neoadjuvant hormonal therapy for a period of 3–6 months in combination with irradiation to the pelvis and the prostate. This was followed by adjuvant hormonal therapy alone until recurrence. The median duration of neoadjuvant hormonal therapy was 3.9 months (range, 0–16.3). The total number of patients treated with luteinizing hormone-releasing hormone (LH-RH) analogues, anti-androgen drugs and estrogen agents were 51, 38 and 5, respectively. Maximum androgen blockage was performed in 33 patients, while 17 patients were given LH-RH agonist alone. After radiotherapy, adjuvant hormonal therapy was continued until recurrence with a median duration of 28.3 months (range, 4–60 months), except for eight patients who had undergone castration. Seven patients had undergone castration prior to radiotherapy, and five patients had received anti-androgen drugs. Total number of patients who received continuous long-tem adjuvant hormonal therapy including castration was 56 (93.3%).
All patients received treatment with linear accelerators generating 6 or 10 MV photons. The treatment consisted of irradiation of the prostate and pelvic lymph nodes, i.e., of the whole pelvis, followed by cone-down of the prostate and paraprostatic tissues. The whole pelvis was defined as follows: laterally, 2 cm beyond the maximal width of the bony pelvic wall; superiorly, at the intervertebral space between the 5th lumbar and the 1st sacral vertebral body; inferiorly, at the bottom of the ischial tuberosities. The internal pelvis was defined as follows: laterally, the maximal width of the bony pelvic wall; superiorly, the bottom of the sacroiliac joint; inferiorly, the measurements were the same as those used for the whole pelvis. Whole pelvic irradiation of 40–41.4 Gy was performed in 49 patients (81.7%), and internal pelvic irradiation of 38–41.4 Gy was performed in 10 patients (16.7%). The initial field size of irradiation for both the whole pelvis and the internal pelvis was decided by the physicians on the basis of the performance status and age of each patient. A 20 Gy boost to the prostate and/or the seminal vesicle was performed after pelvic irradiation. A 4-field box technique or rotation technique (not 3D conformal RT) was employed with a 2D simulator for the boost field simulation. The prostate and a part of the seminal vesicle were included, and the posterior wall of the rectum was avoided. Catheters were inserted into the rectum, and radiopaque contrast was instilled into the rectum to facilitate its identification on the simulation film. A 4-field box technique for boost irradiation was employed in 23 patients with fields shaped to protect the posterior rectal wall. One patient (1.7%) was given a dose of 60 Gy to the prostate alone by the 4-field box technique. The rotation technique was employed in the remaining 36 patients. The decision regarding the boost field, either box or rotation, was made by the physicians on the basis of the field size. The 4-field box technique was selected when the field size exceeded 8 x 8 cm2. Subsequently, the boost field was finally confirmed with a diagnostic CT. The daily fraction size to the pelvis and the prostate was 1.5–2 Gy and 2 Gy, respectively. The fraction size was also decided by the physicians on the basis of performance status and age of the patient. Table 2 shows the total dose and fraction size for the patients in this analysis. Total doses of 60–61.4 Gy were delivered to the prostate in 56 patients, and the remaining four patients received total doses of 44, 58, 70 and 71.4 Gy, respectively.
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Biochemical relapse was defined according to the consensus definition set by the American Society for Therapeutic Radiology and Oncology (15). Survival and time to biochemical failure curves were calculated from the time of initiation of radiotherapy, using the Kaplan–Meier product limit method. Late bladder and rectal side effects were graded according to the Radiation Therapy Oncology Group (RTOG) late radiation morbidity scoring scale.
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RESULTS |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Kaplan–Meier estimates of overall survival, cause-specific survival (CSS) and biochemical relapse-free (bRFS) survival at 3 years were 94.4%, 96% and 89.8%, respectively. Figure 1 shows the actuarial analysis of the survival rates of these patients. No statistically significant difference was observed when the patients were individually analyzed on the basis of their tumor stage (data not shown). However, as shown in Fig. 2, a significant difference was observed in the bRFS rate at 3 years between patients with and without pelvic lymph node metastases (53.5% vs 98%; P = 0.0005).
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Only one patient with N1 disease died of prostate cancer, while two patients died of intercurrent diseases that were not cardiovascular diseases. Local failure was observed in only one patient with N1 disease. Bone metastases were observed in three patients, and para-aortic lymph node metastasis was detected in one patient. Biochemical relapse was identified in six patients. Although only one patient suffered from Grade 2 rectal bleeding, late morbidity greater than Grade 2 on the RTOG scale was not observed in any patient.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Radiotherapy in combination with endocrinal treatment has been shown to be an effective mode of treatment for patients with high-risk prostate cancer (5–9). However, although the required irradiation dose is a strong independent predictor of failure, the optimal dose for the locoregional control of prostate cancer in combination with hormonal therapy has not been determined. Pilepich et al. demonstrated that administration of androgen deprivation therapy prior to and during radiation therapy (neoadjuvant arm) results in an increase in local control and disease-free survival in comparison with the administration of radiotherapy alone (control arm) (13). In their study, target doses to the prostate were 65–70 Gy, and maximum androgen blockage was performed for 2 months prior to radiotherapy and during the 2-month course of radiotherapy in the neoadjuvant arm. In the median follow-up period of 4.5 years, the estimated 5-year rate of local progression was reduced from 71% in the control arm to 46% in the neoadjuvant arm. The incidence of distant metastases was also reduced. However, the long-term follow up results revealed that a short course of androgen ablation administered prior to and during radiotherapy did not significantly enhance either locoregional control or survival in patients with Gleason 7–10 tumors, although a highly significant improvement was observed in local control, reduction in disease progression and overall survival in patients with prostate cancer with a Gleason score of 2–6 (11). Another large, randomized RTOG study showed that adjuvant hormonal therapy improved the outcomes at 5 years with respect to local control (84% vs 71%) and distant metastatic spread (17% vs 30%) in comparison with radiotherapy alone (14). The target doses in the analysis were 65–70 Gy. Although overall survival did not significantly differ between patients who were administered radiotherapy alone and patients who were administered radiotherapy and adjuvant hormonal therapy, adjuvant hormonal therapy improved the overall 5-year survival rate of patients with the high-risk factor of a Gleason score of 8–10. Roach et al. assessed the efficacy of short-term and long-term androgen suppression in terms of the disease-specific and overall survival of 2200 men in five prospective randomized trials; they reported that patients with high-risk prostate cancer had an approximately 20% higher chance of survival at 8 years with the addition of long-term hormonal therapy (10). Most of the patients in these trials were irradiated with doses of 65–70 Gy.
Meanwhile, Kupelian et al. suggested that radiation doses exceeding 72 Gy might improve outcomes of patients who also receive hormonal therapy (16). However, the median duration of androgen depletion in the study was 6 months. The benefit of dose escalation in patients treated with long-term hormonal therapy has not yet been confirmed.
According to the Patterns of Care Study for prostate cancer in Japan (2), modest doses (60–62 Gy) are most commonly used in combination with hormonal therapy for high-risk prostate cancer patients. It was reported that of the 162 surveyed patients who were treated with radical radiotherapy, local progression was observed in only five patients, while distant metastases were observed in 10 patients. Although the follow-up period was rather short, similar results were obtained in our study in which local failure was found in only one patient. In the European Organization for Research and Treatment of Cancer trial reported by Bolla et al., 415 men with high-risk prostate cancer without nodal involvement were randomly assigned to a protocol of radiotherapy alone or radiotherapy plus immediate androgen suppression, which continued for a period of 3 years (9). In the combined-treatment group, local failure was observed in only five patients, while distant metastases were observed in 24 patients. In contrast, local failure was observed in 34 patients who were administered radiotherapy alone. Although the target dose to the prostate was 65–70 Gy in the study by Bolla et al., the local failure rate was far lower than that of distant metastases in the combined-treatment group. Although the follow-up period was too short to evaluate the treatment outcome, these results may suggest that modest doses of irradiation are sufficient for locoregional control in combination with long-term hormonal manipulation in patients with high-risk prostate cancer. Long-term follow-up is required for confirming our preliminary results.
The combination of endocrinal treatment and radiation appears to exert an additive effect on local control by inducing apoptosis and destroying hormone-dependent micrometastases outside the planning target volume (17,18). However, the appropriate timing and duration of hormonal manipulation remain controversial (5–7). In the management of locally advanced prostate cancer, the period of adjuvant or neoadjuvant hormonal treatment as well as the optimal radiation dose should be tailored in terms of cost and risk on the basis of the prognostic factors.
Although many patients with prostate cancer in Japan are likely to be at a high risk, only a few studies have been conducted with respect to the use of radical radiotherapy in combination with endocrinal manipulation for Japanese patients with prostate cancer (19,20). A comparison of the histological differences between Japanese and American samples has revealed that the cribriform pattern is predominant among the clinically significant cancers in the Japanese population. On the other hand, the simple glandular pattern is predominant among the clinically significant cancers in the United States (4). The histological origin of prostatic adenocarcinoma may also differ between Caucasians and Asians; therefore, different clinical approaches to treatment might be required for the two races. Moreover, biological responses to irradiation and endocrinal manipulation may differ between the races. Therefore, optimal doses in combination with long-term hormonal therapy should be carefully defined by large randomized trials.
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FOOTNOTES |
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+ For reprints and all correspondence: Tomonari Sasaki, Department of Clinical Radiology, Graduate School of Medical Sciences, Kyushu University, Maidashi 3–1–1, Higashi-ku, Fukuoka 812-8582, Japan. E-mail: tomonari{at}radiol.med.kyushu-u.ac.jp
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Received October 19, 2003; accepted April 2, 2004
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