Bone Scanning Who Needs it Among Patients with Newly Diagnosed Prostate Cancer?

Bone Scanning Who Needs it Among Patients with Newly Diagnosed Prostate Cancer? Megumi Hirobe 1, Atsushi Takahashi 1, Shin-ichi Hisasue 1, Hiroshi Kitamura 1, Yasuharu Kunishima 1, Naoya Masumori 1, Akihiko Iwasawa 2, Kenji Fujimori 3, Tadashi Hasegawa 4 and Taiji Tsukamoto 1 1 Department of Urology, Sapporo Medical University School of Medicine, Sapporo, 2 Iwasawa Clinic, Sapporo, 3 Department of Radiology, Sapporo Medical University School of Medicine, Sapporo and 4 Department of Surgical Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan Received March 8, 2007; accepted June 11, 2007; published online October 2, 2007 Jpn J Clin Oncol 2007;37(10)788 792 doi:10.1093/jjco/hym097 Background: We evaluated the relationship between serum PSA and clinical variables to eliminate bone scanning in patients with prostate cancer having a low probability of bone metastasis. Methods: The study included 366 patients with newly diagnosed prostate cancer between 1999 and 2005. Bone metastasis was studied for its correlation with various clinical and pathological variables in these patients. Results: Bone metastasis was found in 28 (7.7%) of 366 patients. Fourteen patients had skeletal symptoms related to bone metastasis. The risk for bone metastases increased considerably with increases of PSA level, clinical T stage and Gleason score. The metastasis was not found in 161 patients with serum PSA concentration of 10 ng/ml or lower. In 95 patients with the concentration between 10 and 20 ng/ml only two had the metastasis. These two patients had T2 disease and Gleason scores of 7 or greater. In 204 patients with clinical stage T1 disease, one (0.5%) had the metastasis. In 117 patients with Gleason scores of 6 or less, the metastasis was found in two (1.7%). Conclusions: For patients with serum PSA levels of 10 ng/ml or lower, bone scanning may be eliminated because of the negligible risk of bone metastases. In addition, scanning may not be necessary for those with PSA levels between 10 and 20 ng/ml, when they have T1 disease and Gleason scores of 6 or lower. Key words: bone scan prostatic-specific antigen prostate cancer INTRODUCTION Bone scanning has been routinely used to detect bone metastasis for patients with newly diagnosed prostate cancer. However, it is an expensive and time-consuming staging modality. In the era of prostate-specific antigen (PSA), the number of patients who have bone metastasis or local extension of the disease at diagnosis has been decreasing, and most patients with the disease tend to have a low risk for bone metastasis. Today, the American Urological Association guideline states that routine use of bone scanning may not be required for staging asymptomatic patients who have clinically localized disease that is newly diagnosed, when their PSA is equal to For reprints and all correspondence: Taiji Tsukamoto, Department of Urology, Sapporo Medical University School of Medicine, S-1, W-16, Chuo-Ku, Sapporo 060-8543, Japan. E-mail: taijit@sapmed.ac.jp or less than 20.0 ng/ml (1). The European Association of Urology guideline for prostate cancer suggests that bone scintigraphy may not be indicated in asymptomatic patients, if the serum PSA level is less than 20 ng/ml in the presence of well or moderately differentiated tumors (2). These guidelines were followed by the publication of a clinical guideline for prostate cancer by the Japanese Urological Association in 2006 (3). The guideline indicates that bone scanning can be eliminated for patients with PSA of 10 ng/ml or less who have well or moderately differentiated carcinoma. However, the guideline also suggests that it does not necessarily exclude the use of bone scanning even for such patients. In addition, a recent review article recommended the use of bone scanning for patients with PSA concentrations greater than 10 ng/ml (4). Thus, the controversy still exists. Unfortunately, because there are only a few Japanese studies on the # 2007 Foundation for Promotion of Cancer Research

Jpn J Clin Oncol 2007;37(10) 789 issue, the situation does not allow us to draw a concrete conclusion (5, 6). In this study, we evaluated the relationship between bone metastasis and clinical or pathological variables, including the serum PSA concentration, in patients with newly diagnosed prostate cancer. With the evaluation, we tried to determine the clinical profiles of patients for whom bone scanning could be eliminated due to a low probability of bone metastasis. PATIENTS AND METHODS PATIENT POPULATION This retrospective study included 366 consecutive patients with newly diagnosed adenocarcinoma of the prostate ( prostate cancer), who visited Sapporo Medical University Hospital or the Iwasawa Clinic between January 1999 and September 2005. All needle biopsy specimens of the prostate were evaluated by surgical pathologists in the university hospital. Bone scans were done in the Diagnostic Radiology department of the hospital according to the procedures described below. The study did not include patients who had a past history of antiandrogen treatment for benign prostatic hyperplasia or that of other malignant diseases with possible development of bone metastasis. CLINICAL DATA We thoroughly reviewed the local clinical stage, histological grade, serum PSA concentration and skeletal symptoms. The local clinical T stage was determined with digital rectal examination and transrectal ultrasonography before prostate biopsy, and was categorized according to the TNM classification of malignant tumors (7). All but eight patients underwent transrectal systematic biopsies for diagnosis of the disease. In the biopsy, three to seven cores from each prostatic lobe with a total of six to 14 cores were taken and served for diagnosis. In the other eight patients, prostate cancer was diagnosed by pathological examination of specimens from transurethral resection of the prostate done for relief of bladder outlet obstruction. Histological grading of all specimens was evaluated according to the Gleason grading system. The rate of positive biopsy cores was determined by the following formula: the number of positive cores/the number of total biopsy cores. The serum concentration of PSA was determined by the Tandem-R PSA, monoclonal immunoradiometric assay with the normal range set between 0 and 4.0 ng/ml. BONE SCANS Bone scans and computed tomography (CT) of the pelvis were done in all patients for the initial evaluation of bone or lymph node metastasis. All bone scans were performed with standard procedures. Patients were intravenously given 555 MBq Technetium-99m ( 99m Tc) methylene diphosphonate (MDP). One of the authors (K.F.), who specialized in nuclear medicine, evaluated the findings of bone scans and made a tentative diagnosis as positive, negative or equivocal. In the latter diagnosis, plain X-rays, CT or magnetic resonance imaging (MRI) was additionally used to establish the final diagnosis. Thus, a positive bone scan was prudently interpreted as bone metastasis. STATISTICAL ANALYSIS Statistical significance between serum PSA and other clinical variables was determined with the Mann Whitney U-test and P, 0.05 was considered to be statistically significant. RESULTS The patients characteristics at the time of diagnosis are summarized in Table 1. More than 75% of the patients were examined between 2002 and 2005. The median age of patients was 71 years (range, 43 92 years). The median serum concentration of PSA was 11.7 ng/ml, which reflected the recent trend of stage migration of the disease to an earlier one. More than 80% of the patients were diagnosed as having clinically localized disease. However, 10% of patients had either lymph node metastasis or distant metastasis. Bone scan findings were tentatively classified into three categories, positive in 16 patients, negative in 300 patients and equivocal in 50 patients. Further work-up finally revealed that 28 patients (7.7%) had bone metastasis of the disease. The relationship between bone metastasis and clinical variables is shown in Table 2. Of the 28 patients with bone metastasis, 14 (50%) had skeletal symptoms such as lumbago and leg pain relating to the metastasis. The prevalence of metastasis increased apparently with the elevation of the serum PSA level and progression of the clinical T stage. Bone metastasis was not found in patients with serum PSA equal to or less than 10 ng/ml. However, 42.3% of Table 1. Patients characteristics and clinical stage at diagnosis Clinical variables Number of patients 366 Median age (years) 71 (43 79) Median PSA (ng/ml) 11.7 (2.4 5100) Clinical T stage T1N0M0 203 (55.5%) T2N0M0 96 (26.2%) T3-4N0M0 30 (8.2%) Any T, Nþ, M0 5 (1.4%) Any T, any N, Mþ 32 (8.7%) PSA, prostate-specific antigen.

790 Bone scan for newly diagnosed prostate cancer Table 2. Relationship between bone metastasis and clinical variables Variables Total Bone metastasis P value Negative Positive (%) Number of patients 366 338 28 (7.7) Bone symptoms without 343 329 14 (4.1),0.001 with 22 8 14 (63.6) Serum PSA (ng/ml) 10 161 161 0 (0) 10.1 20.0 95 93 2 (2.1),0.001 20.1 50.0 58 54 4 (6.9) 50.1 52 30 22 (42.3) Clinical T stage T1a/b 8 8 0 (0) T1c 196 195 1 (0.5),0.001 T2 103 97 6 (5.8) T3 or T4 59 38 21 (35.6) Table 3. Relationship between bone metastasis and pathological variables Variables Total Bone Scan P value Negative Positive (%) Number of patients 366 338 28 (7.7) Gleason score 5 30 30 0 (0) 6 87 85 2 (2.3) 7 187 176 11 (5.9),0.001 8 18 16 2 (11.1) 9 10 35 27 8 (22.9) unknown 9 4 5 Rate of positive biopsy cores (%) 25 143 143 0 (0) 25.1 50.0 107 103 4 (3.7),0.001 50.1 75.0 40 39 1 (2.5) 75.1 100.0 68 50 18 (26.5) Uknown 8 3 5 patients had the metastasis when their serum PSA was higher than 50.0 ng/ml. If we used a PSA level of 10 ng/ml or lower as the cutoff value, the negative predictive value was 100%. Since patients with this category of PSA comprised only less than 50% of all patients, the category was extended to those with a level of PSA 20 ng/ml. Based on the result of bone metastasis in 256 patients who had serum PSA with 20 ng/ml or less, only two patients had the metastasis. Their serum PSA concentrations were 14.5 and 15.8 ng/ml, and had T2 disease and Gleason score 7 or greater. Thus, the negative predictive value was determined to be 99.2%, when the serum PSA concentration of 20 ng/ml or less was used as a cut-off point. As for the correlation of bone metastasis with clinical T stage, the metastasis was found in only one patient with clinical T1 disease. However, for stages T2 and T3/4 there was significant prevalence of metastasis. Among the 307 patients with T1 T2 disease, only seven patients (2.3%) had positive bone scans. Their PSA concentrations were distributed from 14.5 to 93 ng/ml, and their Gleason scores were 6 in one patient, 7 in four patients and 9 in two patients. There were no significant differences in the pathological grade or level of PSA among the patients with T1 T2 disease. In the seven patients bone metastasis was confirmed with additional CT scans or MR imaging, while two patients had obvious hot spots that undoubtedly indicated bone metastasis. Gleason grading of prostate cancer was not available for 9 patients, leaving 357 to be evaluated for the grading. Gleason score 7 was the most common grade, accounting for 51% of patients (Table 3). The risk of bone metastasis increased considerably with an increase of the Gleason score. Of 117 patients with Gleason scores of 6 or less, only two (1.7%) patients had the metastasis. Although the rate of positive biopsy core did not linearly increase as the prevalence of bone metastasis increased, it was clear that onequarter of the patients had bone metastasis when the rate of positive biopsy core exceeded 75%. DISCUSSION PSA is the most valuable tumor marker for prostate cancer and most accurately reflects the tumor status in patients with the disease. In our study, significant correlations exist between the incidence of bone metastasis and clinical variables such as the PSA level, clinical T stage, Gleason score and the rate of positive biopsy cores. Because of these correlations, bone scanning may not be necessary for patients who are at low risk for bone metastasis. Indeed, bone metastasis is significantly correlated with the PSA level. Chybowski et al. (8). documented that the PSA level was correlated with the risk of bone metastasis in 521 patients randomly selected. They suggested that the PSA concentration was the best predictor for bone metastases among other clinical and pathological parameters when the receiver operating curve was used. In that study, only one patient had bone metastases among 307 with PSA concentration of 20 ng/ml or less, indicating that the negative predictive value was 99.7%. Also, Oesterling et al. (9). evaluated 852 patients with newly diagnosed prostate cancer having PSA concentrations equal to or less than 20 ng/ml. In their large series, only seven patients (0.8%) had abnormal findings on bone scans. The result of our study is consistent with that reported by Oesterling et al. In our study, none of the 161 patients with PSA concentration of 10 ng/ml or less had bone metastases and only two of the 256 (0.8%) patients whose PSA concentrations were equal to

Jpn J Clin Oncol 2007;37(10) 791 or less than 20.0 ng/ml had bone metastases, with a 99.2% negative predictive value. Several studies, however, raised the question of whether a staging bone scan could be omitted for patients with PSA concentrations of 20 ng/ml or less. Wolff et al. (10) retrospectively studied 359 patients, and they found that, of 40 patients with bone metastases, seven (17.5%) patients had PSA concentrations of 10 ng/ml or less. Their results gave an estimated negative predictive value of 96%. A multicenter study done in Japan reported that positive bone scans were found in four (1.3%) of 300 patients whose PSA concentrations were equal to or less than 10 ng/ml. (5). However, it must be noted that these studies had lower proportions of patients with clinically localized disease than our study. In contrast, recent patients are diagnosed at an earlier stage and with lower PSA levels than before. Thus, it may be valid for bone scans to be eliminated for patients with low PSA levels in the current practice. The risk for bone metastasis increases with higher clinical stage and higher tumor grade. Gleave et al. (11) reported that the rates of positive bone scan were 19% in T3 disease, 1% in T2 and 4% in T1 among 490 patients who were eligible for evaluation. They also mentioned that the negative predictive value of clinical T stage and tumor grade were insufficient to identify the patients with a low risk for bone metastases. Consequently, they recommended that bone scans be indicated in patients with PSA concentrations of 10 ng/ml or greater, clinical T3 or poorly differentiated disease. In our series, bone metastasis was found in only two patients with PSA concentrations of 20 ng/ml or less and no skeletal symptoms. Since they had T2 disease and Gleason scores of 7 or greater, incorporation of the clinical T stage and Gleason score into prediction of bone metastasis may have avoided making a misdiagnosis of not having metastasis in patients with PSA concentrations between 10 and 20 ng/ml. Based on our results, bone scanning may be safely eliminated for patients with PSA concentrations of 10 ng/ml or less. In addition, scanning may not be necessary for patients with serum PSA between 10 and 20 ng/ml, when they have T1 disease and Gleason scores of 6 or lower. However, in those with serum PSA between 10 and 20 ng/ml, the scanning may be offered, when they have T2 or more advanced disease, or Gleason scores of 7 or greater. In our study, these criteria allow 52% of the total patients to avoid bone scanning. In this study, because the rate of positive biopsy cores was strongly correlated with tumor volume, the rate was incorporated with the PSA cutoff point in addition to the Gleason score and tumor grade. However, nonlinear correlation of the rate with the incidence of bone metastasis did not support the use of predictive factors for eliminating bone scan. An important limitation of the present study is its relatively small study population and the few patients with bone metastases. Only 28 of 366 patients (7.7%) had bone metastases at diagnosis. On the other hand, the cancer registration committee of the Japanese Urological Association reported the clinical data of 4529 prostate cancer patients in Japan (12). The report indicated that almost 20% of patients had bone metastases. This result indicates that the patients in the present study may not necessarily reflect the entire population having prostate cancer in Japan. This discrepancy may be partly explained by the fact that more than 75% of the patients in the study visited us between 2002 and 2005, indicating that they might have had earlier-stage disease than those before 2000. The current results should be validated prospectively in a larger number of patients. The second issue for the limitation may be the diagnosis basedongleasonscore.overthe years, there has been a controversy about diagnosis for a low grade adenocarcinoma based on needle biopsy. Epstein (13) noted that low-grade prostate cancers with Gleason scores of 2 4 should not be diagnosed on needle biopsy because of the possible underestimation of a high-grade tumor and the poor reproducibility in the diagnosis. Recently an international conference was held to establish a consensus on the controversy related to the Gleason grading system (14). In this context, low-grade Gleason scores in previous studies should be re-evaluated with the contemporary definition. In our study, the majority of patients (92%) had Gleason scores of 6 or more, which fits with the current trend for the distribution of Gleason scores. CONCLUSIONS For patients with serum PSA levels of 10 ng/ml or lower, bone scanning may be eliminated because of the negligible risk of bone metastases. Scanning may not be necessary for those with PSA levels between 10 and 20 ng/ml, when they have T1 disease and Gleason scores of 6 or lower. Conflict of interest statement None declared. References 1. PSA Best Practice Policy Task Force from the American Urological Association. Prostate-Specific Antigen (PSA) Best Practice Policy. http://www.cancernetwork.com/journals/oncology/o0002e.htm 2. Aus G, Abbou CC, Bolla M, Heidenreich A, van Poppel H, Schmid H-P, et al. EAU guidelines on prostate cancer. Eur Urol 2005;48:546 51. 3. The Japanese Urological Association. Prostate Cancer: Clinical Practice Guideline. Tokyo: Kanehara Shuppan Kabushikikaisha, 2006; 59 60 (in Japanese). 4. Hricak H, Choyke PL, Eberhardt SC, Leibel SA, Scardino PT. Imaging prostate cancer: a multidisciplinary perspective. Radiology 2007;243:28 53. 5. Kosuda S, Yoshimura I, Aizawa T, Koizumi K, Akaza K, Kuyama J, et al. Can initial prostate specific antigen determinations eliminate the need for bone scans in patients with newly diagnosed prostate carcinoma? Cancer 2002;94:964 72. 6. Ishizuka O, Tanabe T, Nakayama T, Kawakami M, Kinebuchi Y, Nishizawa O. Prostate-specific antigen, Gleason sum and clinical T stage for predicting the need for radionuclide bone scan for prostate cancer patients in Japan. Int J Urol 2005;12:728 32.

792 Bone scan for newly diagnosed prostate cancer 7. Sobin LH, Wittekind CH. TNM Classification of Malignant Tumors, 5th edn. New York: Wiley-Liss, 1997. 8. Chybowski FM, Larson Keller JJ, Bergstralh EJ, Oestering JE. Predicting radionuclide bone scan finding in patients with newly diagnosed, untreated prostate cancer: prostate specific antigen is superior to all other clinical parameters. JUrol1991;145:313 18. 9. Oesterling JE, Martin SK, Bergstralh EJ, Lowe FC. The use of prostatespecific antigen in staging patients with newly diagnosed prostate cancer. JAMA 1993;269:57 60. 10. Wolff JM, Zimny M, Borchers H, Wildberger J, Buell U, Jakse G. Is prostate-specific antigen a reliable marker of bone metastasis in patients with newly diagnosed cancer of the prostate? Eur Urol 1998;33: 376 81. 11. Gleave ME, Coupland D, Drachenberg D, Cohen L, Kwong S, et al. Ability of serum prostate-specific antigen levels to predict normal bone scan in patients with newly diagnosed prostate cancer. Urology 1996;47:708 12. 12. Cancer Registration Committee of the Japanese Urological Association. Clinicopathological statistics on registered prostate cancer patients in Japan: 2000 report from the Japanese Urological Association. Int J Urol 2005;12:46 61. 13. Epstein JI. Gleason score 2 4 adenocarcinoma of the prostate on needle biopsy; a diagnosis that should be made. Am J Surg Pathol 2000;24:477 8. 14. Epstein JI, Allsbrook WC, Amin MB, Egevad LL, the ISUP Grading Committee. The 2005 International Society of Urological Pathology (ISUP) consensus conference on Gleason grading of prostatic carcinoma. Am J Surg Pathol 2005;29:1228 42.