Japanese Journal of Clinical Oncology 32:466-471 (2002)
© 2002 Foundation for Promotion of Cancer Research
Salvage External Beam Radiotherapy for Local Recurrence without Systemic Progression or Prostate Specific Antigen Recurrence of Prostate Cancer after Initial Hormonal Therapy: Is It Possible to Identify Patients Likely to Have Good Treatment Outcomes?
Department of Urology and Radiology, Gunma University School of Medicine, Maebashi, Japan
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Background: We attempted to identify factors that predict the outcomes of salvage external beam radiotherapy (sEBRT) in patients who showed local recurrence without systemic progression or isolated prostate specific antigen (PSA) recurrence after initial hormonal therapy.
Methods: The subjects were 33 patients who were diagnosed as having local recurrence without systemic progression (30 cases) or isolated PSA recurrence (three cases). Of these patients, those with continuously decreasing PSA levels, which were 1.0 ng/ml or less 1–1.5 years after sEBRT, were regarded as good responders (GR) whereas the remaining patients were regarded as poor responders (nGR). Survival rates in these patients and factors that distinguish GR from nGR were evaluated retrospectively.
Results: The cancer-specific 10-year survival rate was 82.4% in the 33 patients, 100% in the 21 GR patients and 55% in the 12 nGR patients (P < 0.0001). Stepwise variable selection to discriminate between GR and nGR revealed that the time from sEBRT initiation to the nadir PSA was the most significant factor (P = 0.000097). Before sEBRT, GR can be predicted in patients with pre-sEBRT PSA <30.0 ng/ml and PSA doubling time (PSADT) >7.0 months, with a sensitivity of 95.2% (20/21), a specificity of 100% and an accuracy of 97.0%.
Conclusion: Good responses to sEBRT can be expected in patients with local recurrence without systemic progression or isolated PSA recurrence after initial hormonal therapy when the patients show both pre-sEBRT PSA <30.0 ng/ml and PSADT >7.0 months.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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In Japan, the widespread use of prostate specific antigen (PSA) screening has increased the detection of early prostate cancer, but the incidence of detection in the advanced stages is still high. Our previous study showed that the incidence of advanced prostate cancer is >60% even in the PSA era and the mean age at the time of diagnosis is 74.1 years (1). In our department, radical prostatectomy is only performed on patients <70 years old and external beam radiotherapy (EBRT) for stage C was established as a standard treatment only after 1998. Consequently, hormonal therapy has been used as initial therapy in many patients and therefore many patients with hormone refractory prostate cancer have been treated. Since 1995, patients with local recurrence without systemic progression or isolated PSA recurrence have been actively treated by salvage EBRT (sEBRT) in our department.
The clarification of the type of prostate cancer recurrence after initial therapy is useful for selecting subsequent treatment methods. However, digital rectal examination (DRE) and the diagnosis of local recurrence by diagnostic imaging do not allow a distinction between local recurrence with and without systemic progression. In addition, recently, treatment is often initiated at the time of isolated PSA recurrence before clinical failure is observed. Therefore, there have been many studies to clarify whether PSA kinetics are useful for the determination of the recurrence type. Following radical prostatectomy and definite EBRT, the time to nadir PSA, PSA doubling time (PSADT) (2) and PSA velocity (PSAV) (3) are considered to be useful for identifying local recurrence without systemic progression. On the other hand, there have been few studies about factors, including PSA kinetics, that determine the type of recurrence after initial hormonal therapy (4), because PSA production is androgen dependent and is therefore inhibited by hormonal therapy.
We retrospectively evaluated the outcomes of sEBRT and other factors, including PSA kinetics, as predictors of the treatment outcome in patients with hormone refractory prostate cancer with local recurrence without systemic progression or isolated PSA recurrence.
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PATIENTS AND METHODS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Between January 1987 and December 1999, 368 patients with stage B–D prostate cancer underwent hormonal therapy as initial therapy in the Department of Urology, Gunma University Hospital. After May 1994, 42 of the 368 patients were diagnosed as having local recurrence without systemic progression and three were diagnosed with isolated PSA recurrence, as revealed using only one PSA kit (ng/ml, E test TOSOH II PA, Tosoh, Tokyo, Japan). Thirty-three patients who had not received any other treatment and had their PSA levels assessed regularly for at least 12 months after sEBRT were selected for this study. Of these patients, those in whom a continuously decreasing PSA level that was <1.0 ng/ml 1–1.5 years after sEBRT was observed were regarded as good responders (GR) to sEBRT, whereas the remaining patients were considered poor responders (nGR).
Definitions of local recurrence without systemic progression and isolated PSA recurrence were as follows. The frequency of PSA measurement was once every 4 weeks in patients treated by LHRH agonist and once within 3 months in castrated patients. If PSA increased consecutively, PSA was measured once every 4 weeks, DRE was performed once every 3 months and imaging diagnosis such as TRUS, CT scanning, MRI or bone scintigraphy was performed once every 3–6 months. If imaging or DRE revealed local recurrence without any findings suggesting systemic recurrence, we diagnosed the patient with local recurrence without systemic progression. Patients with a PSA increase without clinical recurrence were diagnosed with isolated PSA recurrence.
In sEBRT, radiation was limited to the prostate gland and was administered using a linear accelerator with FOUR oblique irradiating fields, at a dose of 3 Gy three times per week (total dose, 69 Gy).
sEBRT treatment was considered unsuccessful if PSA increased in three consecutive samples. Second-line hormonal therapy was prescribed when continuously increasing PSA after treatment failure or clinical re-recurrence was evident.
The discriminant factors between the GR and nGR groups were age, initial stage, Gleason score, PSADT (months), the period from the first visit to local recurrence, PSA before sEBRT (pre-sEBRT PSA), nadir PSA after sEBRT, the period from the initiation of sEBRT to nadir PSA and the PSA half-lives after sEBRT (Fig. 1). PSA was logarithmically expressed and plotted and the PSADT and PSA half-lives after sEBRT were calculated from the slope of the regression line. Four or more points were plotted and the correlation coefficient of the regression line was r > 0.800 in all cases.
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The cause-specific survival rate and the rate of patients not receiving second-line hormonal therapy in the GR and nGR groups were analyzed. In addition, factors that may discriminate between GR and nGR group were retrospectively evaluated.
For statistical analysis, the survival rate was analyzed using the log rank test and discrimination was performed using discriminant analysis. P values were determined using multiple regression analysis, with P < 0.05 considered significant.
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RESULTS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Patients’ Characteristics
Of the 42 patients with local recurrence without systemic progression and three isolated PSA recurrences, four patients underwent additional fosfestrol infusion at the time of sEBRT, six patients had incomplete PSA follow-ups, one patient died of an unrelated cause within 1 year after sEBRT and one patient underwent transurethral resection of the prostate immediately before sEBRT. All of these patients were excluded from the study. The characteristics and pre-sEBRT parameters of the other 33 patients (21 in the GR group and 12 in the nGR group) are shown in Table 1.
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Survival Rates, Responses to sEBRT and Adverse Effects
Fig. 2a and b show the cause-specific survival rates for the initial hormonal therapy and the rate of patients not receiving second-line hormonal therapy in the GR and nGR groups, obtained using the Kaplan–Meier method. The mean follow-up period after initial hormonal therapy was 99.0 ± 50.6 months and that after sEBRT was 23.0 ± 16.4 months.
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The 10-year cancer-specific survival rate after initial hormonal therapy was 82.4% in the 33 patients, 100% in the GR group and 55% in the nGR group (P < 0.0001). The rate of patients not receiving second-line hormonal therapy was 8% (1/12) in the nGR group, but 85.7% (18/21) in the GR group (P < 0.0001). Three patients in the GR group underwent second-line hormonal therapy after 35.1 months (PSA at the initiation of this therapy, 1.7 ng/ml), 36 months (3.1 ng/ml) and 46 months (3.2 ng/ml).
Regarding adverse effects, NCI-CTC grade 1 bloody stool was observed in one patient and grade 3 urinary retention was observed in two patients.
Discriminant Factor Analysis for GR and nGR
Tables 1 and 2 show the discriminant coefficients and P values for various factors. The significant discriminant factors were the initial stage (P = 0.014) and the time from the initiation of sEBRT until nadir PSA. Stepwise variable selection revealed that the time from the initiation of sEBRT until nadir PSA was the most significant factor (P = 0.000097).
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Discrimination Between GR and nGR by PSADT and Pre-sEBRT PSA
The increasing slope of PSA (PSADT) and/or pre-sEBRT PSA differed markedly between the GR and nGR groups (Fig. 3), therefore pre-sEBRT PSA was plotted versus PSADT for GR and nGR patients (Fig. 4). It was revealed that the GR patients can be identified if PSADT is >7 months and pre-sEBRT PSA is <30.0 ng/ml, with a sensitivity of 95.2% (20/21), a specificity of 100% and an accuracy of 97.0%.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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There have been only a few studies on radiotherapy for local recurrence without systemic progression after initial hormonal therapy (5,6). Kawakami et al. (5) reported that palliative EBRT at 27–30 Gy for symptomatic stage D2 hormone refractory prostate cancer is useful for controlling symptoms but does not prolong survival. Furuya et al. (6), who only included patients with local recurrence after initial hormonal therapy, observed significant prolongation of survival in the group treated using sEBRT compared with the non-irradiated group. This study was limited to patients with local recurrence without systemic progression in whom PSA was measured regularly using the same type of PSA kit. Twelve stage D2 patients participated in this study, as we hypothesized that if sEBRT can postpone second-line hormonal therapy, then the QOL decrease caused by second-line hormonal therapy can also be delayed. Patients who showed a continuous decrease in PSA after sEBRT and a PSA level of 1.0 ng/ml or less after 1–1.5 years were considered GR. In this GR group, second-line hormonal therapy was performed in only 14.3% (3/21) of patients during a mean observation period of 23.0 months after sEBRT. The cause-specific 10-year survival rate in this group was 100% with a mean observation period of 99.0 months after initial hormonal therapy. GR can be predicted if pre-sEBRT PSA is <30.0 ng/ml and PSADT is >7 months, with a sensitivity of 95.2%, a specificity of 100% and an accuracy of 97.0%. These results demonstrate that the outcome of sEBRT can be predicted by PSA kinetics despite the fact that androgen-dependent PSA production is inhibited by hormonal therapy.
The criteria for GR used in this study were the opposite of the criteria for definite EBRT treatment failure that were reported by Zeitman et al. (7) and Wallner et al. (8). In this study, the time from sEBRT to nadir PSA significantly predicted GR. This was similar to the findings reported by Kestin et al. (9) and Aref et al. (10), even though our study group was treated using initial hormonal therapy (Tables 1 and 2).
Currently, physical examination and imaging techniques are used to examine sites for recurrence, but it has been demonstrated that detection rates are low (11). A previous study reported that 50% of patients with normal DRE findings exhibit positive biopsy findings (12). Another study also suggested that TRUS is inappropriate for the detection of recurrence sites (13). On the other hand, previous studies demonstrated that the positive rate of detection by biopsy for isolated PSA recurrence is 39% (14) or 50% (13) and one-third of those biopsies were found to be positive after repeated biopsies (13). In systemic progression, it has been reported that the sensitivity of CT diagnosis of pelvic lymph node metastasis is 30–80% (15). Bone scintigraphy is not useful unless PSA levels reach 30–40 ng/ml (16). In particular, in isolated PSA recurrence, these diagnostic imaging techniques may not be useful unless the PSA level is higher than 20 ng/ml/yr (11,17).
A good response to salvage therapy indicates that recurrence is locally isolated and some factors associated with a good response to salvage therapy have been reported. Local recurrence after radical prostatectomy is often treated using sEBRT and the factors associated with a good response to sEBRT include time to PSA failure >2 years, Gleason score 
7, PSADT 
10 months (2), PSA velocity (PSAV) 0.75 ng/ml/yr (3) and pre-sEBRT PSA 1.0 ng/ml (18). The factors associated with a good response to salvage brachytherapy for local recurrence after definite EBRT are PSA nadir <0.5 ng/ml after therapy (19) and pre-brachytherapy PSA <2.0 ng/ml (20). Factors associated with a good response to salvage cryotherapy for local recurrence after definite EBRT were initial clinical stage T1–2 and pre-cryotherapy PSA <10.0 ng/ml (21).
As indicated by the above discussion, the accurate diagnosis of local recurrence without systemic progression by conventional diagnostic imaging techniques can be difficult. However, in addition to the diagnosis of local recurrence by conventional imaging techniques, the use of PSA kinetics such as PSADT, PSAV and PSA before salvage therapy can identify the patients who are likely to respond to salvage therapy. If different types of PSA kits are used, considerable biases of PSA values are expected (22).
In conclusion, in patients with recurrence after initial hormonal therapy, those who are suitable candidates for sEBRT can be identified based on PSADT and pre-sEBRT PSA, even though PSA production is inhibited by hormonal therapy. In patients selected according to these factors, good outcomes can be expected.
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Acknowledgement |
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We thank Professor Shigenobu Aoki of the Faculty of Social and Information Studies, Gunma University, for statistical assistance.
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FOOTNOTES |
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+ For reprints and all correspondence: Kohei Kurokawa, Department of Urology, Gunma University School of Medicine, 3–39–22, Showa-machi, Maebashi, Gunma 371-8511, Japan. E-mail: kohei@showa.gunma-u.ac.jp
Abbreviations: sEBRT, salvage external beam radiotherapy; PSA, prostate specific antigen; GR, good responders to sEBRT; nGR, poor responders to sEBRT; PSADT, PSA doubling time; DRE, digital rectal examination; PSAV, PSA velocity; pre-sEBRT PSA, PSA before sEBRT
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REFERENCES |
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Received April 15, 2002; accepted July 31, 2002
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