ANTICANCER RESEARCH 27: 1847-1852 (2007)
Definitive Conformal Radiotherapy for Localized High-risk Prostate Cancer: A Long-term Follow-up Study with PSA Course FRANK BRUNS1, CORDULA FRANZKI1, GERD WEGENER2 and JOHANN H. KARSTENS1 1Department
of Radiotherapy and 2Clinical Cancer Registry, Hannover Medical School, Hannover, Germany
Abstract. Background: The present study investigated the long-term outcome of patients with localized high-risk prostate cancer after definitive conformal radiotherapy. Patients and Methods: Ninety-one consecutive patients with stage T1-T4 prostatic carcinoma were treated from 1996 through 2000. Each patient had at least one of the following risk factors: stage >T2b (UICC 1997; 55 patients), Gleason score >7 (24 patients), or pre-treatment PSA >20 ng/mL (40 patients). All patients received a conformal radiotherapy of the prostate (median dose, 70 Gy), eighty-three patients (91%) combined with temporary androgen deprivation (median duration, 4 months). All patients were followed continuously during a median of 5.2 years (range, 0.9 to 8.8 years). Biochemical failure after irradiation was defined as a PSA greater than 0.4 ng/mL and three consecutive serum PSA elevations. Results: The 5- and 7-year overall survival rates were 86% and 74%, respectively. The 5- and 7-year biochemical disease-free survival (bDFS) rates were 78% and 66% respectively. The most important predictors of bDFS were Gleason score and central axis dose of 70 Gy or higher. PSA nadir (median, 0.1 ng/mL) was not predictive of subsequent biochemical diseasefree survival. Conclusion: Our study confirms the findings of others and encourages us to proceed with this treatment policy for T1-T4 high-risk prostate cancer modified by using higher doses and long-term androgen deprivation. Prostate-specific antigen (PSA) is a glycoprotein that is almost exclusively produced in the prostate and the most important and clinically useful biochemical tumour marker for the screening and monitoring of prostate cancer at present (1, 2). In particular, it has affected the management of prostate cancer by allowing better case selection.
Correspondence to: Frank Bruns, MD, Department of Radiotherapy, Hannover Medical School (MHH), Carl-Neuberg-Straße 1, 30625 Hannover, Germany. Tel: +49 511 5322731, Fax: +49 511 5323796, e-mail:
[email protected] Key Words: PSA, prostate cancer, high-risk, radiotherapy, short-term, androgen deprivation.
0250-7005/2007 $2.00+.40
conformal
Moreover, the comparison between the two definitive treatment modalities, radiotherapy and radical prostatectomy, can now be made accurately with respect to case selection and treatment outcome. Prior to the routine use of PSA, Gleason score, T-stage, and pathological lymph node status have been described as major independent predictors of survival of prostate cancer patients who were treated with external beam radiotherapy (EBRT). A particularly poor prognostic group was found to be comprised of those with pretreatment prostate-specific antigen (PSA) levels above 30 ng/mL with any tumour grade, or PSA levels between 10 and 30 ng/mL and tumour grade 3 or 4. Patients with these high-risk features have an actuarial risk of biochemical failure over 80%, three years after definitive EBRT (3). In a recent meta-analysis of early Radiation Therapy Oncology Group (RTOG) prostate cancer trials, the factors T-stage, Gleason score and PSA level were combined to define prognostic subgroups that correlate with disease-specific survival from prostate cancer (4). The American Society for Therapeutic Radiology and Oncology (ASTRO) has thus established three levels of risk in localized prostate cancer based on the prognostic variables, T-stage, Gleason score, and PSA level. Low, intermediate and high risk values were defined for each pre-treatment variable (except for T-stage, which was limited to low and high risk); a patient’s risk group was then defined by the single highest factor present. According to this consensus definition, high-risk disease comprises at least one of the following features: pretreatment PSA level >20 ng/mL, Gleason score >7, or stage >T2b (5, 6). It is quite evident that better strategies are needed to treat patients of this poor prognostic group more effectively, but the best strategy has yet to be described. During the last ten years, the policy to treat such high-risk patients with radiotherapy and androgen deprivation was instituted. In the study presented here, the long-term treatment results of definitive conformal EBRT alone, or in combination with temporary androgen deprivation, for T1-T4 high-risk prostate cancer patients were evaluated.
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ANTICANCER RESEARCH 27: 1847-1852 (2007) Table I. Clinical characteristics of the patients with localized high-risk prostate cancer. Clinical factor
Number of patients Number of patients without with biochemical relapse (n=57) relapse (n=26)
Patient age (years) 20 ng/mL, Gleason score >7 or stage >T2b according to the fifth edition of the TNM classification (7). Patients were aged from 54 to 80 years (median, 69 years). The pre-treatment PSA level ranged from 3.2 to 94.5 ng/mL, with a median of 20.0 ng/mL. A summary of the pre-treatment clinical parameters for the patients is listed in Table I. All patients were treated definitively with three-dimensional conformal radiotherapy of the prostate with a median total dose of 70.2 Gy (range, 64.8 to 75.6 Gy). Linac-based radiotherapy was delivered by a conformal shaped four-field technique using 23 MV or 10 MV photons in daily fractions of 1.8 Gy, five times a week. Eighty-three patients (91%) received an additional temporary androgen deprivation for a median duration of four months (range, 1 to 100 months).
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All patients were followed up continuously, at least every three months for the first two years and at 6-month intervals thereafter. The follow-up procedure included disease-specific history, treatment-related toxicity, digital rectal examination and PSA monitoring. In case of suspected relapse, specific diagnostic procedures, such as bone scintigraphy, were performed. Measurement of PSA levels was performed with commercial test kits, whereas PSA during follow-up was determined by the same laboratory for each patient. Biochemical relapse (PSA failure) after irradiation was defined as a PSA of 0.4 ng/mL or more and three consecutive elevations of serum PSA, according to the ASTRO consensus statement (8). Outcome was measured from the date of diagnosis (date of prostate biopsy) to the date of biochemical disease-free failure. Patients alive without evidence of disease were censored at the date of their last follow-up. Biochemical disease-free survival (bDFS) rates and overall survival (OS) rates were estimated with the Kaplan-Meier method using the statistical software package of our clinical cancer registry. The log-rank test was used to evaluate differences in bDFS with a p=0.05 significance level. P-values >0.1 were not considered as significant.
Results Twenty-six patients (29%) experienced biochemical failure during the median follow-up period of 5.17 years (mean, 5.21 years; range, 0.94 to 8.75 years). Three of these patients developed hematogenous metastases shortly after the diagnosis of biochemical failure, upon which they passed away; a further two patients developed histologically proven local relapse. Nineteen patients (21%) died disease-free to date. According to the Kaplan-Meier analysis, the estimated 5and 7-year OS rates were 86.0%±7.6% and 73.5%±12.6% respectively. The actuarial rate of bDFS for all 91 patients is shown in Figure 1. At 5 and 7 years, the estimated bDFS rates were 77.7%±9.2% and 66.1%±13.3% respectively. Figure 2 shows the PSA course after treatment. The median PSA nadir after irradiation was 0.1 ng/mL (range, 0 to 2.89 ng/mL); median PSA at last follow-up 0.4 ng/mL (range, 0 to 308 ng/mL). The most important predictors of bDFS were Gleason score (p=0.043; significant value) and central axis dose of 70 Gy or higher (p=0.0986; trend towards significance). No significant differences were found in bDFS rates between patients with a PSA nadir below and above the median of 0.1 ng/mL (p=0.693) or between patients with a PSA nadir below and above the serum level of 0.5 ng/mL (p=0.499).
Discussion Measurement of serum PSA has become the standard for determining treatment efficacy in men after definitive therapy for localized prostate cancer for more than ten years (9, 10). After radical prostatectomy, it is clear that serum PSA should decrease and remain within the
Bruns et al: Definitive Radiotherapy for Localized High-risk Prostate Cancer
Figure 1. Biochemical disease-free survival (bDFS) of the 91 patients.
undetectable range according to standard assays if a patient is to be considered cured (11). The absolute serum PSA level associated with cure in patients treated with EBRT is much less clear. It is evident that serum PSA decreases immediately after EBRT in the majority of patients, but many patients will have an increasing PSA profile after radiation therapy, which indicates recurrent or persistent disease (10). Some early reports have focused on the relationship between the PSA nadir after treatment and the subsequent disease course in individual patients. For example, a level of 1.5 ng/mL was chosen as the upper limit of normal by Hanks et al. (12) based on long-term information obtained from patients treated with RTOG protocols. Other investigators demonstrated that particularly patients with a PSA nadir of less than 1 ng/mL following EBRT experienced favourable bDFS rates within the first five years of observation. Moreover, multivariate analysis demonstrated that patients who had a PSA nadir of less than 1 ng/mL experienced improved bDFS independent of clinical stage, pre-treatment PSA and Gleason score (13). However, it should be noted that we did not find any significant difference in the bDFS rate with respect to PSA nadir after EBRT and temporary androgen deprivation at the levels of 0.1 ng/mL (median) and 0.5 ng/mL. This is not unexpected, because serum PSA does not always reflect the behaviour of the tumour if anti-androgen treatment has
Figure 2. Distribution of PSA levels (ng/mL) at time of nadir (n=73) and last follow-up (n=83); 86% of the patients reached a PSA nadir below 1.0 ng/mL.
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ANTICANCER RESEARCH 27: 1847-1852 (2007) been initiated (14). In particular, androgen suppression can lead to low serum PSA levels although prostate cancer is present, so that the PSA nadir after combined treatment possibly may not be able to serve as a predictive factor, as seen in our study. In the present study, the 5- and 7-year bDFS rates of 78% and 66% respectively seem to be favourable and the overall survival was above the expected survival for high-risk prostate cancer patients. This treatment strategy has also been shown by other investigators to be an effective mode of treatment for patients with high-risk prostate cancer (15, 16). Kupelian et al. (17) showed that patients who receive EBRT with short-term androgen deprivation had an improved outcome when radiation doses exceeded 72 Gy. The meta-analysis of five large RTOG trials confirmed that the required irradiation dose is a strong independent predictor of failure in definitive irradiated patients (4). However, in our study we only found a trend to significantly better local control for high-risk patients who received radiation doses exceeding 70 Gy in combination with a shortterm androgen deprivation over a median of four months. The appropriate timing and duration of hormonal manipulation remain controversial. The RTOG trial 85-31 (18) demonstrated that administration of maximum androgen blockage prior to and during EBRT with a target dose between 65 and 70 Gy (neoadjuvant arm; duration, 4 months) increased local control and disease-free survival in comparison with the administration of EBRT alone (control arm). But the long-term follow-up results revealed that this form of short-term androgen ablation did not significantly enhance either locoregional control or survival in patients with Gleason 7-10 tumours, 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 ≤6 (18). The large, randomized RTOG trial 86-10 (19) showed that adjuvant hormonal therapy improved the outcome at 5 years with respect to local control (84% vs. 71%) and distant metastatic spread (17% vs. 30%) in comparison with EBRT alone at doses between 65 and 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, this form of endocrinal therapy significantly improved the overall 5-year survival rate of patients with a Gleason score of 8-10 as high-risk factor (19). In 2000, Roach et al. (4) performed a meta-analysis of five prospective randomized RTOG prostate cancer trials assessing the efficacy of shortand long-term androgen suppression in terms of diseasespecific and overall survival of 2,200 men. They reported that patients with high-risk prostate cancer had an approximately 20% higher chance of survival at eight years with the addition of long-term hormonal therapy. Most of the patients in these
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trials were irradiated with doses between 65 and 70 Gy so that the benefit of dose escalation, particularly in patients treated with long-term hormonal therapy, requires further validation. Bolla et al. (20) studied 415 patients with poor risk clinical stage T1-T4 disease who were randomly assigned to EBRT alone or with gonadotropin-releasing hormone agonist for three years, starting on the first day of EBRT. After a median follow-up of 66 months, combined hormone ablation plus EBRT was associated with a significant improvement in both 5-year disease-free survival (74% vs. 40%) and overall survival (78% vs. 62%). Moreover, the benefit for adjuvant androgen suppression was reported in the prospective randomized RTOG trials 85-31 and 92-02, as well as in the prospective GICOR study 05/99 (18, 21, 22).
Conclusion Although the appropriate timing and duration of hormonal manipulation remain controversial in prostate cancer patients, a risk-adapted management with dose-escalation and long-term adjuvant androgen suppression in high-risk disease, tailoring the period of endocrinal treatment, as well as the radiation dose in terms of cost and risk on the basis of the prognostic factors, remains the best promising treatment strategy in this disease. Advances in the definitive use of various forms of radiotherapy, such as intensitymodulated radiotherapy, conformal proton beam therapy and brachytherapy alone or combined with EBRT may provide better results in the future.
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Received March 9, 2007 Revised May 2, 2007 Accepted May 4, 2007
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