Japanese Journal of Clinical Oncology 33:73-77 (2003)
© 2003 Foundation for Promotion of Cancer Research
External Beam Radiation Monotherapy for Localized or Locally Advanced Prostate Cancer
1 Departments of Urology and 3 Radiology, Sapporo Medical University School of Medicine, Sapporo, 4 Department of Radiology, Hokkaido University School of Medicine, Sapporo, 2 Department of Urology, Sunagawa City Medical Center, Sunagawa, Hokkaido and 5 Department of Urology, Muroran City General Hospital, Muroran, Hokkaido, Japan
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Purpose: We report the treatment results and complications of external beam radiation monotherapy for localized or locally advanced prostate cancer patients.
Methods: Fifty-four patients with T1b–3aN0(pN0)M0 prostate cancer were treated with external beam radiation monotherapy between 1989 and 2001 at four institutes.
Results: During the 4–122 month follow-up period (median: 25 months), 11 (20%) patients experienced biochemical failure, including one with simultaneous local recurrence. The 2-year actuarial biochemical control rate was 85%. Univariate analysis showed that the clinical T classification (P = 0.01), Gleason score (P = 0.006), pretreatment PSA (P = 0.02) and PSA nadir value (P = 0.01) were associated with a higher probability of biochemical failure. Multivariate analysis using the Cox proportional hazards model demonstrated that only the PSA nadir value was a strong predictor of PSA recurrence (P < 0.01). Adverse events were mild and tolerable. No severe urinary or bowel complications were observed.
Conclusions: External beam radiation monotherapy is effective for clinically organ-confined prostate cancer with a low incidence of severe complications in a mean follow-up period of 2 years.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Definitive radiation therapy and radical prostatectomy have been considered the standard curative treatment for localized prostate cancer in the USA and Europe (1). In Japan, much attention has also recently been paid to radiation therapy as an alternative primary treatment. This may be due in part to the high success rate and limited adverse effects with recent innovations in radiation techniques. New strategies such as three-dimensional (3-D) conformal therapy and intensity modulated radiation therapy (IMRT) allow conformation to the shape of the prostate and minimize radiation exposure to normal tissue, resulting in a lower incidence of radiation-induced complications (2). In addition, these techniques are expected to permit radiation dose escalation in order to improve local control. Another reason for the attention may be the recent advances in and prevalence of transmission systems such as the Internet, which can allow patients easily to obtain information about the treatment of prostate cancer around the world. In Japan, there are few reports about radical radiotherapy for localized prostate cancer (3,4). In this paper, we report on the efficacy and adverse effects of external beam radiation therapy alone in localized or locally advanced prostate cancer patients.
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PATIENTS AND METHODS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Between 1989 and 2001, 54 patients with T1b–3a prostate cancer were treated with external beam radiation alone at Sapporo Medical University Hospital, Hokkaido University Hospital, Sunagawa City Medical Center and Muroran City General Hospital. No patients received neoadjuvant or adjuvant hormonal therapy before biochemical failure or clinical failure. In principle, patients selected this modality based as their preference.
The external beam radiotherapy was delivered to the prostate using the conventional four-field box (anterior, posterior and right and left laterals) technique in 24 patients. The total dose ranged from 60 to 70 Gy (median, 65 Gy) in 24–30 fractions within 6–7.5 weeks. Thirty patients (56%) were treated with conformal techniques. Of these patients, 26 received a total dose of 70 Gy within 7 weeks with 10 MV X-rays in daily fractions of 2 Gy. For four other patients, radiotherapy was performed with 2.5 daily fractions for 6.5 weeks to give a total dose of 65 Gy.
Serum PSA was measured by the Hybritech assay, with a lower limit of detection of 0.2 ng/ml. Biochemical failure was defined according to the American Society for Therapeutic Radiology and Oncology (ASTRO) Consensus Panel statement (5). Thus, three consecutive rises in PSA after reaching the PSA nadir were regarded as biochemical failure. The date of failure was the midpoint between the nadir and the first of the three rises in PSA. If hormonal therapy was given to patients prior to meeting the above criteria for failure, the patients were considered to suffer from biochemical failure at the time of initiation of hormonal therapy.
Late complications induced by radiation were scored using the Radiation Therapy Oncology Group (RTOG) toxicity scoring system, with grade 1 for minimal symptoms with no requirement of medication, grade 2 for slightly more severe symptoms with a need for medication, grade 3 for complications requiring minor surgical intervention such as transurethral resection, laser coagulation or blood transfusion and grade 4 for requirement of hospitalization and major intervention.
The time to biochemical failure was calculated from the date of completion of radiation to the date of PSA relapse. The biochemical progression-free rate was calculated by the Kaplan–Meier method. The statistical significance of differences was determined by the log rank test. A P-value of <0.05 was considered statistically significant. Multivariate analysis by Cox’s proportional hazards model was performed to determine whether any variables independently affected biochemical failure. The variables studied were (1) patient age, (2) clinical T classification (T1b–2b or T3), (3) biopsy Gleason score (3–6 or 7–9), (4) pretreatment PSA (
10 or >10), (5) total radiation dose, (6) PSA nadir value (1.0 or >1.0) and (7) PSA half-life. All analyses were performed using StatView 5.0 for Macintosh (SAS Institute, Cary, NC).
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RESULTS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Patients’ Characteristics
Patients’ characteristics are shown in Table 1. The mean age at diagnosis was 71.3 years (range, 41–81 years). Of the 54 patients, 45 (83%) were diagnosed as having clinically localized prostate cancer (T1b–2b). Of all patients, 32 (59%) received staging lymphadenectomy, by which they were proved to be pathologically free of lymph node metastasis. The median pretreatment PSA level was 14.9 ng/ml (range, 1.4–80.5 ng/ml). The median Gleason score was 5 (range, 2–9). The follow-up period ranged from 4 to 122 months with a median of 25 months.
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Outcome
During the follow-up period, 11 (20%) patients experienced biochemical failure. Of these, one had simultaneous local recurrence. The patient who experienced local recurrence had T3a with Gleason score 7. He received a total dose of 65 Gy in a conventional four-field box. Sixteen months after radiation, he had two consecutive PSA elevations and suffered from a weak urinary stream due to local recurrence. He received transurethral resection of the prostate and then hormonal therapy. No patients developed distant metastasis.
Of the 11 patients, seven met the criteria of ASTRO and the others underwent hormonal therapy before meeting the criteria because of rapid PSA elevation.
The 2-year actuarial biochemical control rate was 85% (Fig. 1). Of these patients with PSA failure, nine had biochemical failure within 25 months and the other two at 38 and 41 months, respectively. No death due to prostate cancer was observed during the follow-up period.
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Factors Affecting Biochemical Recurrence
By univariate analysis, the clinical T classification (P = 0.01), Gleason score (P = 0.006), pretreatment PSA (P = 0.02) and PSA nadir value (P = 0.01) were associated with a higher probability of biochemical failure (Table 2). Neither the total radiation dose nor PSA half-life predicted PSA failure in this study.
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First, to identify if parameters before radiation can predict PSA failure, multivariate analysis by the Cox proportional hazards model was performed using age, preoperative PSA, clinical T classification and biopsy Gleason score. However, no parameter could predict biochemical failure. Next, when PSA nadir and PSA half-life were included in the multivariate analysis, the PSA nadir value was independently a strong predictor of PSA recurrence (P < 0.01). The 2-year actuarial biochemical control rates in patients with PSA nadir values
1.0 and PSA nadir values >1.0 were 95.5 and 73.7%, respectively.
Adverse Events
Bowel and urinary toxicities were generally mild and tolerable (Table 3). There was a trend towards reduced toxicity with regard to gastrointestinal toxicity in the conformal radiation group when compared with the conventional radiation group. No grade 3 or higher toxicity was observed in either group.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Radiation therapy already occupies an important position as a curative treatment for organ-confined prostate cancer throughout the world (1), although there have been no prospective randomized trials that directly compared the clinical efficacy of radiation with radical surgery for the disease.
To date, retrospective studies have demonstrated that the 5-year biochemical progression-free rate in external beam radiotherapy alone ranges from 40 to 65% (6–9). A possible explanation for the wide variation in biochemical control may be the selection of different risk groups (i.e. pretreatment PSA, clinical T stage, Gleason score). Indeed, in a multi-institutional analysis of a total of 1765 patients with T1–2, the 5-year biochemical progression-free rate was as high as 65% (6). On the other hand, studies containing higher stage (T3) patients had lower biochemical control rates (7–9). In this study, 11 of the 54 patients (20%) experienced biochemical failure, with the 2-year biochemical control rate being 85%. Of the patients with PSA failure, nine (82%) failed within 25 months, suggesting that biochemical failure occurs relatively soon after treatment. Several studies with longer follow-up periods have also shown that most patients have an increasing risk of biochemical failure within 36 months, but few fail beyond 4 years (7,8). Therefore, despite the short follow-up in this study, our results are likely not to be overestimated. Of the 11 patients with PSA relapse, five had T3a (one with T3apN0M0 and four T3aN0M0). If T3 patients were excluded from analysis, the 2-year biochemical progression-free rate became higher (89%). This finding is consistent with other workers’ data (6–9), suggesting that radiation monotherapy for the treatment of clinical T3 prostate cancer does not represent a satisfactory modality. Since recent reports have demonstrated that the combination of androgen deprivation and radiation produced a significant benefit for locally advanced prostate cancer (10,11), combining the two modalities may seem to be the standard approach for clinical T3 prostate cancer patients. However, at present, when and how long hormonal therapy should be added to radiation therapy remains unclear.
Several studies have demonstrated that the pretreatment PSA level, Gleason score, clinical T stage and PSA nadir level are significantly associated with biochemical failure (12–16). Our study showed that only the PSA nadir level was an independent predictor for PSA recurrence among the several parameters examined. While the importance of the PSA nadir is clear, in the clinical setting it is inconvenient to predict the outcome by the PSA nadir, because it usually takes a long time to determine it (mean: 14 months in this study). Therefore, we tried to examine whether the PSA half-life was a good parameter for predicting PSA recurrence. However, we failed to obtain a positive association between the PSA half-life and biochemical failure. This finding is in agreement with those of Ritter et al. (17) and Zagars and Pollack (18). The latter reported that the PSA half-life was correlated with the pretreatment PSA level, but did not predict disease outcome.
Since the survival outcome and biochemical control for radiation therapy and radical surgery seem to be comparable in localized prostate cancer (19,20), complications have increasingly become an important factor for decision making for treatment selection. Our study showed that radiation-induced complications were generally mild and acceptable. Conformal radiotherapy, especially, had a trend towards less toxicity when compared with conventional therapy. Several other studies support this result (21,22). Recently, investigators at the Memorial Sloan-Kettering Cancer Center reported that high-dose radiotherapy (75 Gy or higher) by 3-D conformal therapy and IMRT could be administered effectively in localized prostate cancer patients without increasing complications (23). In particular, IMRT allowed dose escalation to 81 Gy or higher with a lower incidence of rectal toxicity (grade 2: 2%) than 3-D conformal therapy (grade 2: 14%). Moreover, such ultra-high-dose radiation produced excellent results. Taken together with these results, we expect that these conformal techniques may become the gold standard for treating localized prostate cancer.
In summary, external beam radiation monotherapy is an effective and safe modality for managing clinically localized prostate cancer in Japan. Accumulating data on this modality with regard to survival outcome, complications and assessment of quality of life will help Japanese patients to select appropriate treatment.
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Acknowledgement |
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This work was supported in part by a Grant-in Aid from the Japanese Ministry of Education, Science, Sports and Culture.
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FOOTNOTES |
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+ For reprints and all correspondence: Atsushi Takahashi, Department of Urology, Sapporo Medical University School of Medicine, S-1, W-16, Chuo-ku, Sapporo 060-8543, Japan. E-mail: atakahas@sapmed.ac.jp
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Received August 20, 2002; accepted November 12, 2002
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