Japanese Journal of Clinical Oncology 30:126-130 (2000)
© 2000 Foundation for Promotion of Cancer Research
Infrequent Involvement of the Anterior Base in Low-risk Patients with Clinically Localized Prostate Cancer and Its Possible Significance in Definitive Radiation Therapy
Departments of 1Urology and 2Pathology, Kitasato University School of Medicine, 1–15–1 Kitasato, Sagamihara, Kanagawa, Japan
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAcknowledgmentsREFERENCES |
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Background: The zonal distribution and location of tumors in different subgroups of Japanese patients with clinically localized prostate cancer have not been fully described. The appropriate radiation treatment volume thus remains unclear.
Methods: Radical prostatectomy specimens of 141 consecutive patients with clinically localized prostate cancer were examined by the whole organ step-section technique. The zonal distribution and location of tumors at different levels of the gland were investigated after stratification into patient subgroups based on preoperative clinicopathological findings and risk group assessment.
Results: The median tumor volume was 2.8 cm3; 72 patients (51.1%) had pathologically organ-confined disease (pT2). Higher risk groups showed a statistically significant increase in tumor volume and a decrease in the rate of pathologically confirmed organ confinement. Involvement of the anterior base was found infrequently in certain patient subgroups: in only one of 20 patients (5%) with preoperative PSA <4.0 ng/ml, in three of 19 patients (15.8%) with specimen Gleason scores of 2–4 and in two of 32 patients (6.3%) identified as low-risk.
Conclusions: Infrequent involvement of the anterior base in low-risk patients may be an intrinsic feature of clinically localized prostate cancer. Treatment volume modifications in these patients that reduce the radiation dose to the anterior base may be justified to avoid acute and late genitourinary toxicities.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAcknowledgmentsREFERENCES |
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Recent reports have suggested that advanced technology-assisted radiation therapy may provide results comparable to those of radical prostatectomy, with significantly lower morbidity (1–10). Determination of the appropriate treatment volume has been difficult, however, owing to the paucity of available information regarding precise tumor distribution. It is thus generally believed that uniform irradiation or dose distribution is essential to eliminate ‘hot and cold’ areas. One result is that genitourinary complications are not uncommon and sometimes serious (10–12).
D’Amico et al. recently found that tumors rarely involved the anterior base in low-risk prostate cancer patients [prostate-specific antigen (PSA) <10 ng/ml, biopsy Gleason score <6 and T1c-2a] (6,13). These investigators proposed redefining the treatment volume for this patient subgroup to exclude the anterior base and thus reduce morbidity. However, this finding needs further validation owing to their use of biopsy Gleason score, which may not necessarily reflect specimen tumor grade owing to random sampling (14). Tumor localization may be related to the actual tumor aggressiveness, that is, specimen rather than biopsy Gleason score. Whether their findings apply to Japanese patients is likewise unknown.
The purpose of this study was to clarify the zonal distribution and tumor locations in various subgroups of Japanese patients with clinically localized prostate cancer and to provide a basis for appropriately scheduling the treatment volume for radiation therapy. Specimen Gleason score was used to investigate the validity of stratifying patients based on risk group assessment.
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PATIENTS AND METHODS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAcknowledgmentsREFERENCES |
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Patient Characteristics and PSA Assay
Between April 1992 and March 1999, 141 consecutive men with clinically localized prostate cancer (T1c-T2c) underwent radical retropubic prostatectomy and bilateral pelvic lymph node dissection at Kitasato University Hospital. None of these underwent preoperative endocrine therapy. Preoperative serum PSA was quantitated by Eiken polyclonal radioimmunoassay (Eiken, Tokyo) up to March 1993, by Dainapack IMx PSA assay (Dinabot, Tokyo) between then and June 1997 and by AxSYM PSA assay (Dinabot, Tokyo) thereafter. For uniformity, data were converted to AxSYM assay values as previously described (15).
Preoperative Staging
Patients with prostate cancer were examined for staging by digital rectal examination, prostatic acid phosphatase, intravenous urography, computed tomography, magnetic resonance imaging and bone scanning, supplemented with radiographs of abnormal areas. Digital rectal examination was performed by one of the authors (S.E.), who recorded any abnormal findings. The 1992 TNM staging system was used for clinical stage assignment (13).
Pathological Processing
Radical prostatectomy specimens were examined by the whole organ step-section technique. All histology slides were examined and reviewed by a single pathologist (S.K.) and tumor grade was assigned based on the Gleason grading system. The specimens were fixed in 10% formalin and sectioned at 5 mm intervals in a plane perpendicular to the long axis of the gland, from the prostatic apex to tip of the seminal vesicles, followed by staining with hematoxylin and eosin. Tumor maps were drawn by directly tracing the outline of the tumor in each section, from which the tumor area was measured using a planimeter. Allowance was made for prostate section thickness by multiplying the measured area by 5 mm, the actual thickness of a cut section. Tissue shrinkage in 10% formalin is ~10% in one dimension and thus the volume of each tumor was determined by multiplying the measured volume by a shrinkage factor of 1.33.
Zonal Anatomy Definitions and Illustrations
To facilitate direct comparison, the definitions of D’Amico et al. (6) were adopted. Briefly, the apex was defined as being the most inferior 5 mm of the prostate gland and the base was defined as the most superior 1 cm. The anterior base was that region at least 5 mm anterior to the anterior border of the prostatic urethra and within 1 cm of the most superior aspect of the prostate gland. The mid-gland was defined as the region at a radius of at least 5 mm from the urethra and at least 1 cm inferior to the most superior aspect of the prostate gland, while also being more than 5 mm superior to the prostatic apex.
To illustrate tumor locations according to risk groups, tumor maps of each group were superimposed at three different levels (apex, mid-gland, base) using the Adobe Photoshop 4.01 J graphic software program (Adobe Systems, San Jose, CA, USA). Only the perpendicular scales of these maps were matched and the contour was left unadjusted. Denser areas are those in which tumors were more frequently located.
Statistical Analysis
Risk-group stratification similar to D’Amico et al. (5,6) was adopted; the only difference was the use of specimen rather than biopsy Gleason score. Patients with clinical stage T1c or 2a, PSA <10 ng/ml and specimen Gleason score <6 were defined as low-risk and patients with T2c, PSA >20 ng/ml or specimen Gleason score 
8 were defined as high-risk. The remaining patients, with PSA >10 ng/ml and <20 ng/ml, specimen Gleason score 7 or stage T2b, were defined as the intermediate-risk group.
A Kruskal–Wallis test was performed to assess differences between patients, with p < 0.05 considered significant.
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RESULTS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAcknowledgmentsREFERENCES |
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Clinicopathological Findings
The median age of the 141 patients was 64.0 years (range 49–74, mean 64.1 years) and median serum PSA was 8.5 ng/ml (range 1.8–95.0, mean 12.8 ng/ml). Clinicopathological findings in these cases are shown in Table 1. The median tumor volume was 2.8 cm3 (range 0.01–33.5, mean 5.2 cm3). Seventy-two patients (51.1%) had pathologically organ-confined disease (pT2). As risk group increased there was a statistically significant increase in tumor volume and decrease in the rate of pathologically confirmed organ confinement. The median tumor volume and confinement rates were 1.64, 2.73 and 6.33 cm3 and 81.3, 57.7 and 13.2% for patients in the low-, intermediate- and high-risk groups, respectively (p < 0.0001). There was also a statistically significant increase in tumor volume with increasing clinical stage (p = 0.003), increasing PSA level (p < 0.0001) and specimen Gleason score (p < 0.0001).
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Tumor Location
The most common tumor sites for all patients were the mid-gland (91.5%), apex (88.7%) and base (48.2%) (Figs 1–3). Tumors were found in the transition zone in 57.4% of the patients and in the peripheral zone in 98.6%. Statistically significant differences in tumor incidence within the anterior base were found with advancing stage (p < 0.0001), increasing PSA (p = 0.03), increasing specimen Gleason score (p = 0.04) and increasing risk group (p < 0.0001). Similarly, statistically significant differences in tumor incidence within the transition zone were noted with increasing PSA (p = 0.01) and increasing risk group (p = 0.007) and within the posterior base with increasing specimen Gleason score (p = 0.01). There was no significant difference in the percentage of tumors as a function of other parameters. Tumor was found within the anterior base in only one of 20 patients (5%) with preoperative PSA < 4.0 ng/ml, three of 19 patients (15.8%) with specimen Gleason score 2–4 and two of 32 patients (6.3%) in the low-risk group.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAcknowledgmentsREFERENCES |
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Renewed emphasis has been given to use of radiotherapy as treatment for clinically organ-confined prostate cancer (1–10). Conformal therapy with higher doses to the prostate and better sparing of organs at risk may be a promising approach to improve local control without increasing late morbidity (8,9,11). Interstitial radiotherapy (that is, brachytherapy) is another conformal approach (1–7).
However, these treatment modalities are not without morbidity. With conventional radiation techniques, severe sequelae increase if doses >70 Gy are given to the prostate (11). In the brachytherapy series of Blasko et al. (10), 19% of the treated patients developed genitourinary complications. These consisted of superficial urethral necrosis (3%), incontinence (6%), cystitis/urethritis (7%), stricture/contracture (2%) and hematuria (1%). These figures were even higher in a randomized dose–response study comparing 70 Gy (conventional) and 78 Gy (conformal) radiotherapy and assessing complications through a patient self-assessment questionnaire (12). The overall rate of persistent incontinence was 29% (with 2% requiring a protective device) and the rate of hematuria was 13%. Most patients had some degree of short-term bladder and bowel irritation. Complication rates were still higher in patients with previous transurethral resection of the prostate gland. The high central dose generally tolerated by the intact prostate is less condoned when the gland has been resected.
Many variations in radiation technique and other factors potentially affect the outcome of radiation therapy (2,16). Accurate and uniform delivery of the prescribed dose per unit volume, as required for tumor sterilization, is considered critical for achieving cure. The entire gland is usually selected for treatment, since the frequently multilocular nature of prostate tumors renders pretreatment assessment of their exact distribution difficult. The best localization of prostatic tumors is always the identification of the prostatic margins. In our study, tumor involvement of the gland’s anterior base was found infrequently in certain patient subgroups. Specifically, it was seen in only one of 20 patients (5%) with PSA <4.0 ng/ml, in three of 19 patients (15.8%) with specimen Gleason score 2–4 and in just two of 32 patients (6.3%) in the low-risk group. These findings are concordant with the study of D’Amico et al. (6), in which only one of 37 (2.7%) patients in the low-risk group had tumor at the anterior base.
The utility of pretreatment PSA, biopsy Gleason score and T stage in predicting post-treatment outcome has been reported previously (5–7). Biopsy Gleason score, however, is known to be inaccurate owing to sampling error in the biopsy cores (14). In our low-risk patients, use of biopsy cores led to over-grading (compared with surgical specimens) more frequently than under-grading (31.3 vs 6.3%). By definition, this trend makes patient assignment to the low-risk group even stricter. Had the biopsy Gleason score been used in this study, the two low-risk patients with anterior base involvement would have been excluded without any additional patients being assigned to the low-risk group. Hence the use of biopsy Gleason score rather than specimen Gleason score may be more practical and justified for selecting low-risk group patients. The rates of over- and under-grading in high-risk and intermediate-risk groups in this study were 8.3 and 12.5% and 18.6 and 32.6%, respectively.
Preservation of the bladder neck in radical retropubic prostatectomy is technically feasible in select patients and may be expected to shorten the interval of incontinence (17,18). Theoretically, careful and meticulous dissection can preserve circular fibers of the bladder neck, minimizing injury to the sphincteric mechanism. However, there is always a possibility of compromising surgical margins at the bladder neck. The high incidence of the posterior-base involvement in any patient subgroups makes the selection of candidates for this technique based solely on risk-group assessment inappropriate (Table 1). Submitting frozen section specimens from the bladder neck may be a reasonable option to avoid positive margins.
Our patient population differs from that of D’Amico et al. (6), since the median tumor volume was larger (2.8 vs 1.2 cm3), almost certainly reflecting the difference in the prevalence of PSA-based screening programs between the two countries. Interestingly, however, the incidence of anterior base involvement was similar in the low-risk patients. This characteristic localization of tumors may be an intrinsic feature of prostate cancer in this patient subgroup. Thus, modifying treatment volume to exclude the anterior base in these patients, as suggested by D’Amico et al. (6), may be justified to avoid acute and late genitourinary toxicities. Although the small number of patients in this study does not allow definitive conclusions to be drawn, physicians should at least be aware of the possibility that tumor foci may be absent from this particular location in a subgroup of patients with clinically localized prostate cancer. Further investigation is warranted.
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Acknowledgments |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAcknowledgmentsREFERENCES |
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This work was supported in part by a Grant from the Ministry of Health and Welfare of Japan (11–10) and the Foundation for Promotion of Cancer Research in Japan. Dr W.A. Thomasson is thanked for expert editorial assistance.
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FOOTNOTES |
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+ For reprints and all correspondence: Shin Egawa, Department of Urology, Kitasato University School of Medicine, 1–15–1 Kitasato, Sagamihara, Kanagawa 228–8555, Japan. E-mail: s-egpro@sa2.so-net.ne.jp
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REFERENCES |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAcknowledgmentsREFERENCES |
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Received September 17, 1999; accepted December 6, 1999.
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