Prostate and testicular cancers

PSAD is useful for predicting reclassification of prostate cancer patients eligible for
active surveillance

Author(s)：: Takahiro Inoue¹, Naoki Terada¹, Takashi Kobayashi¹, Tomomi Kamba¹, Hidefumi Kinoshita², Tadashi Matsuda², Koji Yoshimura¹, Osamu Ogawa¹
Affiliation(s)：: 1 Department of Urology, Kyoto University Graduate School of Medicine
2 Department of Urology and Andrology, Kansai Medical University

Introduction and Background: Widespread prostate-specific antigen (PSA) testing has led to a dramatic increase in detecting very low-risk cancer in Western countries and as well as in Japan. Without detection, most men with these very low-risk diseases would likely remain asymptomatic and clinically unaffected during their lifetime. Active surveillance (AS) is an alternative way to immediate treatment for men with low-risk disease, reducing the risk of overtreatment. Although several criteria for selecting patients for AS have been described, there still remain unknown with appropriate characteristics of patients who should be managed by AS.
Our aim is to test the common criteria for AS eligibility and retrospectively review the pathological findings of prostatectomy specimens of patients who met the criteria. We also evaluates preoperative factors appropriate for predicting upstaged (pT≥3 )/ upgraded (Gleason score ≥7), defining as "reclassification disease.
Patients and Methods: A retrospective analysis of 293 and 521 consecutive radical prostatectomy procedures (Jan 2005 through Dec2011) performed without neoadjuvant hormonal therapy at two independent high volume centers (Kyoto University: KU, and Kansai Medical University: KMU) in Japan was performed. Seventy (KU) and 84 (KMU) patients fulfilled the following criteria: clinical T1 or T2 disease, PSA level of ≤10ng/ml, one or two positive biopsies, and Gleason score of <7 at diagnosis. Clinicopathological features at diagnosis were compared between patients with or without reclassification after radical prostatectomy. The Mann-Whitney U test or Student's t test were used for univariate analysis as appropriate. Logistic regression analysis was used for multivariate analysis. All tests were two-sided with p<0.05 considered statistically significant.
Results: The characteristics of 70 (KU) and 84 (KMU) patients fulfilled the criteria for AS was the following: the median age, pre-biopsy PSA level, and PSAD was 63 years, 5.48 ng/ml, and 0.17 ng/ml2 at KU and 66.3 years, 5.86 ng/ml, and 0.18 ng/ml2 at KMU, respectively. Twenty-eight of 70 patients (40%) (KU) and 40 of 84 patients (47.6%) (KMU) had a Gleason score of ≥7, and 5 (7%)and 8 (9.5%) had upstaged disease (≥pT3), respectively. Three (KU) and 7 (KMU) patients with upstaged disease also showed upgraded reclassification. No (KU) and two (KMU) patients with reclassification showed biochemical recurrence. The time of biochemical recurrence after surgery in these two patients at KMU was 59 and 89 months. Preoperative parameters evaluated included age, PSA level, PSA density (PSAD), clinical T stage, Gleason score at biopsy, and number and percentage of positive prostate cores. Univariate analysis showed that PSAD was significantly different between reclassification disease and the others (p=0.025 at KU and p=0.0006 at KMU, respectively). Among 64 (KU) and 82 (KMU) patients with complete data, multivariate analysis revealed that PSAD was the only independent variable to predict disease with reclassification (p=0.021 and p=0.006, respectively). The analysis for PSAD as a predictor of reclassification gave an AUC of 0.675 (KU) and 0.72 (KMU). A PSAD cut-off 0.147 yielded a sensitivity of 0.808 and a specificity of 0.500 at KU, and cut –off 0.151 yielded a sensitivity of 0.81 and a specificity of 0.56 at KMU, respectively.
Conclusion: Preoperative PSAD may be a good indicator for selecting patients with eligible for AS in the Japanese population.

Surveillance policy for patients with stage I testicular germ cell cancer in the
multi-detector computed tomography era

Author(s)：: Takeshi Yuasa,¹ Naoko Inoshita,² Hajime Tanaka,¹ Shinji Urakami,¹ Shinya Yamamoto,¹ Hitoshi Masuda,¹ Iwao Fukui,¹ Yuichi Ishikawa,² and Junji Yonese¹
Affiliation(s)：: Department of Urology¹ and Pathology², Cancer Institute Hospital, Japanese Foundation for Cancer Research, Ariake, Tokyo, 135-8550, Japan

Background and objectives: Testicular germ cell cancer (GCC) is a relatively rare cancer but the most common solid malignancy affecting young men in their twenties or thirties. Approximately 75–80% of seminoma patients and 55% of patients with non-seminomatous germ cell tumor (NSGCT) cancer have stage I disease at diagnosis. However, some patients with stage I testicular cancer have occult metastases, which are not visible radiologically. These patients experience a recurrence of their cancer and need to undergo induction chemotherapy. Recent improvements in radiological techniques mean that a wide range of imaging modalities is now available, including multi-detector computed tomography (MDCT). The risk of occult disease, which will result in relapse, should be decreased in the current era of MDCT.
In this study, we retrospectively investigated the outcome of patients with clinical stage I testicular GCC after MDCT surveillance. We also investigated the outcome of patients with stage I testicular GCC and risk factors for recurrence as determined by single-detector CT.
Patients and Methods: The medical records of 92 patients with previously untreated stage I GCC, who received treatment in our institution between March 1999 and February 2013, were reviewed.
Results: Among 225 GCC patients attending our institution during the study period, 92 (40.9%) patients were diagnosed with stage I testicular GCC. Data from a total 86 patients were analyzed, as six patients requested and received prophylactic chemotherapy and were therefore excluded from the study.
The median follow-up period from diagnosis was 5.0 years (inter-quartile range (IQR): 1.7–7.6 years). Of the 86 patients, eight (9.3%) experienced a recurrence in this observation period. Regarding histologic subtypes, the recurrence rates were five (9.3%) of the 54 patients with seminoma and three (9.4%) of the 32 patients with NSGCT. All eight patients who experienced a recurrence did so within 2 years; they all underwent induction chemotherapy and remain alive at the time of writing, with no evidence of disease. Consequently, the OS rate of this study is 100%. Among the patients with recurrence, one with NSGCT underwent retroperitoneal lymph-node dissection to remove residual nodal metastases, whereas the residual seven patients were cured without surgical management.
On current, patients with GCC are usually investigated for nodal and visceral metastases using 18fluorodeoxyglucose positron emission tomography (FDG-PET)-CT. None of the ten patients with retroperitoneal lymph-node lesion were observed to have increased tracer uptake on FDG-PET-CT and none had suffered a recurrence at the time of writing.
Among patients with stage I seminoma, the presence of a tumor more than 4 cm in size and rete testis invasion are considered to be risk factors for occult metastatic disease. Among the 54 patients with seminoma in this study, 31 patients were observed to have both these risk factors, whereas the remaining 21 patients had none. Among the 31 patients with risk factors, cancer recurred in three (9.7%) during the surveillance period, whereas it recurred in two of the 17 patients (11.8%) without risk factors; the difference in recurrence rate is not statistically different (P=0.78).
In patients with stage I NSGCT, vascular invasion is considered to indicate occult metastatic disease. Among the 32 patients in our study with NSGCT, six were not investigated for vascular invasion. Of the remaining 26 patients, 13 (50%) had this risk factor of vascular invasion, of whom three (25%) experienced a recurrence of their cancer during the surveillance period. None of the patients (0%) without vascular invasion experienced a recurrence of cancer, although the difference between them is not statistically different (P=0.10).
Conclusion: Fewer than 10% of patients with stage I testicular GCC suffered a recurrence in the 5-year observation period of this study in the MDCT era. We believe that surveillance is an important management option, even for high-risk patients. All patients must be fully informed of the anticipated recurrence rate and the potential risks of exposure to chemotherapy agents.

Reassessment of risk factors for biochemical recurrence in intermediate-risk prostate cancer treated with radical prostatectomy

Author(s)：: Shintaro Narita¹, Koji Mitsuzuka², Takahiro Yoneyama³, Norihiko Tsuchiya¹, Takuya Koie³, Narihiko Kakoi⁴, Sadafumi Kawamura⁴, Yasuhiro Kaiho², Chikara Ohyama³, Tatsuo Tochigi⁴, , Yoichi Arai²、Tomonori Habuchi¹
Affiliation(s)：: ¹Department of Urology, Akita University School of Medicine
²Department of Urology, Tohoku University School of Medicine
³Department of Urology, Hirosaki University School of Medicine
⁴Department of Urology, Miyagi Cancer Center
Michinoku Japan Urological Cancer Study Group (MJUCSG)

Purpose: D'Amico risk classification has been widely accepted as a tool in predicting biochemical recurrence in patients with localized prostate cancer. Here, we reassessed the risk factors for biochemical recurrence using the D'Amico's classification in patients with intermediate-risk prostate cancer treated with radical prostatectomy.
Materials and Methods: Medical records of 1268 men with prostate cancer treated with radical prostatectomy without neoadjuvant therapy between 2001 and 2009 at four medical institutes in the Tohoku district, Japan were retrospectively reviewed. Association of various risk factors with biochemical recurrence was statistically evaluated. Biochemical recurrence was defined as a prostate specific antigen (PSA) level > 0.2 ng/mL. The Kaplan–Meier method, log-rank test, and Cox proportional hazards model were used for statistical analysis. A P value of 0.05 was considered to be statistically significant.
Results: Of 1268 patients, 222 (17.5%), 664 (52.4%), and 382 (30.1%) were classified as low-, intermediate-, and high-risk groups, respectively, according to the D'Amico classification. In the intermediate-risk group, 96 (14.5%) patients experienced biochemical recurrence during the median follow-up of 41 months. The rate of biochemical recurrence was significantly lower in the intermediate-risk group than in the high-risk group (P = 0.001), although no significant difference was observed in the rate of biochemical recurrence between the low- and intermediate-risk groups (P = 0.122). In the intermediate-risk group, initial PSA and surgical era were independent risk factors for biochemical recurrence, whereas other factors including age, biopsy Gleason 4 + 3, clinical stage > T2, and percentage positive core were not independent factors for biochemical recurrence. The intermediate-risk patients with PSA level of ≥15 ng/mL had a significantly higher rate of biochemical recurrence than those with PSA of <15 ng/mL（P = 0.008), and biochemical recurrence-free survival in the intermediate-risk group with the PSA level of ≥15 ng/mL was comparable to those with the high-risk group (P = 0.632).
Conclusion: A PSA level of ≥15 ng/mL was an independent risk factor for biochemical recurrence in patients with intermediate-risk prostate cancer. In addition, the rate of biochemical recurrence in the intermediate-risk group with the PSA level of ≥15 ng/mL was comparable to that in the high-risk group. The surgical era may also influence the treatment outcome. Subclassification and reassessment of the risk factors for biochemical recurrence in patients with intermediate-risk prostate cancer may be required, because biological aggressiveness of prostate cancer in this group may be considerably heterogenous.

An analysis of PSA recurrence-free survival by therapy in localized prostate cancer

Author(s)：: Atsushi Takamoto, Ryuta Tanimoto, Yasuhiro Kobayashi, Shin Ebara, Toyohiko Watanabe, Yasutomo Nasu, Hiromi Kumon
Affiliation(s)：: Department of Urology , Okyama University Graduate School of Medicine, Dentistry and Pharmaceutical science

OBJECTIVE: It is important to estimate and assess the risks of not only complications and side effects of therapy but also recurrence after treatment in determining the best treatment for prostate cancer. Recurrence rates by therapy for localized prostate cancer in our hospital were examined retrospectively.
METHODS: This study included 916 patients with localized prostate cancer who underwent surgical therapy, radiation therapy, or hormone therapy at Okayama University Hospital from June 1999 to December 2009. PSA recurrence was defined as increases in PSA levels of 0.2 ng/mL or more after surgical therapy, increases in PSA levels of 2.0 ng/mL or more from the minimum PSA level after radiation therapy, and increases in PSA levels by 25% or more of the minimum level with increases of 2.0 ng/mL or more after hormone therapy. The time from the date of initial treatment was calculated using the Kaplan-Meier method and analyzed using a proportional hazard model.
RESULTS: The age of the 916 patients with localized prostate cancer ranged from 47 to 106 years (median, 69 years), and the Gleason scores were 6 in 472 patients, 7 in 321 patients, and 8 in 109 patients. The PSA levels ranged from 2.99 to 33 ng/mL (median, 7.96 ng/mL). Of the patients undergoing surgical therapy (n=295), radiation therapy (n=464), and hormone therapy (n=157), PSA recurrence was noted in 32, 29, and 23 patients, respectively, and 5-year PSA non-recurrence rates were 83.8%, 84.6%, and 77.2%, respectively. In a multivariate analysis including age, Gleason score, and PSA, PSA recurrence rate was significantly lower after radiation therapy than after hormone therapy (p=0.0176), but no significant difference was noted for surgical therapy (p=0.0842).
CONCLUSION: The PSA recurrence rate was higher after hormone therapy than after radiation therapy in the treatment of localized prostate cancer. A longer follow-up is required.

Long-term outcomes of prostate brachytherapy in Japan

Author(s)：: Yasuto Yagi¹, Ken Nakamura¹, Mitsuyashi Tamaki¹, Toru Nishiyama¹,
Kazuhito Toya², Atsunori Yorozu², Shiro Saito¹
Affiliation(s)：: The Department of Urology¹ and Radiation Oncology²
National Hospital Organization Tokyo Medical Center, Tokyo, Japan

Purpose: This study is to evaluate long-term outcomes of prostate brachytherapy (BT) with I-125 permanent seed implantation in Japan.
Material/Methods: Between September 2003 and April 2008, 1003 patients underwent BT for cT1-3N0M0 prostate cancer at single institution. Among those patients, 990 were able to be followed for more than 5 years. Kaplan-Meier analysis was performed to evaluate their overall survival rate (OS), disease-specific survival rate (DSS), clinical progression-free survival rate (CPFS) and biochemical progression-free survival rate (BPFS). Cases with initial PSA ≤10ng/ml and Gleason Score ≤6 / Gleason Score 3+4 with positive core rate <34% and ≤cT2c were treated with BT alone, and their prescription dose was 145-160 Gy. Cases with initial PSA ≥10ng/ml or Gleason Score 3+4 with positive core rate ≥34% / ≥ 4+3 or ≥ cT3a were treated with combination of BT and EBRT, and their prescription dose was 100-110 Gy for BT and 45 Gy (1.8Gy X 25) for EBRT. The Phoenix definition was used to determine biochemical failure after the treatment. However, clear prostate-specific antigen (PSA) bounce cases were excluded from failure for the analysis. Univariate and multivariate regression analysis were performed by log-rank test and Cox's proportional hazard regression model, respectively. Statistical significance was defined as a P-Value less than 0.05.
Results: The median follow-up period was 6.6 years.　The OS at 5-year and 9-year were 99.6% and 91.8%, respectively. The DSS at 5-year and 9-year were 99.8% and 99.4%, respectively. The CPFS at 5-year and 9-year were 96.2% and 92.4%, respectively. The BPFS at 5-year and 9-year were 95.4% and 91.0%, respectively. Of 990 patients, 332 (33.5%) were low risk cases, 561 (56.7%) were intermediate risk cases and 97 (9.8%) were high risk cases. BPFS of each risk classification was 98.8%, 94.9% and 86.5% at 5-year, and 98.0%, 89.2% and 76.7% at 9-year in the order of low, intermediate and high risk. The significant features of BPFS were initial PSA, Gleason score, clinical stage, positive core rate on biopsy, external beam radiotherapy and Biologically Effective Dose by the log-rank test. Initial PSA, Gleason Score and clinical stage were identified as independent predictors of PSA recurrence after BT by multivariate Cox proportional hazards survival analysis.
Conclusion: Analysis for long-term outcomes of BT for prostate cancer revealed excellent results. BT can be considered as treatment not only for low risk cases but also for intermediate and high risk cases.

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