Treatment Recommendations for Urological Symptoms in Cancer Patients: Clinical Guidelines from the Japanese Society for Palliative Medicine.

BACKGROUND: Urological symptoms such as gross hematuria, lower and upper urinary tract symptoms, and bladder pain are common in and distressing for patients with advanced cancer. Although palliation of urological symptoms is important to improve the quality of life of cancer patients and their families and caregivers, clinical guidelines for managing urological symptoms in patients with cancer have not been published. METHODS: Following the formal guideline development process, the Japanese Society for Palliative Medicine (JSPM) developed comprehensive clinical guidelines for the management of urological symptoms in patients with cancer. RESULTS: This article summarizes the recommendations and their rationales and provides a short summary of the development process of the JSPM urological symptom management guidelines. We established five recommendations, all of which were based on the best available evidence and expert consensus. CONCLUSION: JSPM released the first edition of the "Clinical Guidelines for Urological Symptoms in Cancer Patients." Future clinical research and continuous guideline updates are required to improve the quality of managing urological symptoms in patients with cancer.

Silodosin versus naftopidil for the treatment of benign prostatic hyperplasia: a multicenter randomized trial.

This was a multicenter randomized trial to investigate the clinical efficacy and the impact on sexual function of alpha-1A selective silodosin and alpha-1D selective naftopidil for treatment of benign prostatic hyperplasia. A total of 97 patients with lower urinary tract symptoms/benign prostatic hyperplasia who had an International Prostate Symptom Score of 8 or more were randomly assigned to receive silodosin (8 mg/day, n = 53) or naftopidil (75 mg/day, n = 44). Before and 4, 8 and 12 weeks after treatment, International Prostate Symptom Score and its quality of life score were used to assess lower urinary tract symptoms. Also, International Index of Erectile Function-5, and an original questionnaire were used to evaluate erectile function and ejaculation for sexually active patients, respectively. The silodosin group showed advantages in terms of voiding symptoms and quality of life of International Prostate Symptom Score when compared with the naftopidil group. Both silodosin and naftopidil showed no significant effect on International Index of Erectile Function-5. A total of 23 sexually active patients in the silodosin group experienced more ejaculatory impairment than 21 patients in the naftopidil group, with a decrease of ejaculation volume (87% vs 40%, P = 0.003), prolonged time to ejaculation (56% vs 33%, P = 0.027) and decrease of orgasm (50% vs 39%, P = 0.027). These results suggest that alpha-1A selective blockers are more effective for voiding symptoms, whereas alpha-1D selective blockers offer a minor degree of ejaculatory dysfunction.

Implications of circulating chromogranin A in prostate cancer.

OBJECTIVE: To evaluate whether measurement of circulating chromogranin A (CgA) levels provides clinicopathological and prognostic information in prostate cancer. MATERIAL AND METHODS: Plasma CgA levels were measured in 57 patients with histologically confirmed prostate cancer (stage B or less, n=22; stage C, n=10; stage D1, n=2; hormone-naive D2, n=12; hormone-refractory D2, n=11) and in 22 with undetected prostate cancer using an enzyme-linked immunoabsorbent assay. RESULTS: Median plasma CgA levels were significantly higher in patients with prostate cancer than in those with undetected cancer (p=0.0271). Higher stage (p<0.0001) and higher grade (p=0.0412) tumours were also significantly associated with higher plasma CgA levels. Above-normal CgA levels were also detected in 4/27 patients (15%) who underwent radical prostatectomy. Postoperative clinical failure was not reported in the prostatectomy patients; however, prostate-specific antigen (PSA) failure was reported in 44% of patients after a median follow-up period of 20.3 months. Multivariate analysis revealed that the pathological stage of the tumour was the only independent predictive variable for postoperative PSA failure (p=0.0494). Preoperative plasma CgA levels had no impact on postoperative PSA failure in the subgroup (prostatectomy patients). Elevated plasma CgA levels were associated with a poor survival prognosis in patients with stage D2 prostate cancer after a median follow-up period of 22.5 months (p=0.0416). CONCLUSIONS: It was demonstrated in this study that plasma CgA levels in prostate cancer increase with the severity of the disease, especially for progressive hormone-refractory prostate cancer (HRPC), after hormone therapy. Although this cross-sectional study involved only a small number of patients, we believe that plasma CgA levels may effectively predict HRPC status and prognosis in metastatic cases.

Long-term outcome from a study on the prevention of postoperative recurrence in patients with renal cell carcinoma: could PBL be a predictor of postoperative recurrence in patients postoperatively treated with IFN-gamma?

This study examined the outcome of postoperative recurrence therapy on renal cell carcinoma (RCC) prevention involving treatment with single doses of interferon-gamma (IFN-gamma). From 1990-2000, 37 patients with no distant metastasis at the time they underwent a nephrectomy were enrolled in this investigation. Subcutaneous IFN-gamma was administered once a week. Total and differential white blood cells were counted before the pre-administration of IFN-gamma and then monthly thereafter for all patients. Blood lymphocyte subsets were analyzed phenotypically by direct immunofluorescence. Disease-free survival rates (DFSR) at 5 and 10 years were 81.7% and 75.9%, respectively. To clarify the effects of preoperative peripheral blood lymphocyte (PBL) and NK activity on DFSR, we categorized the patients into two groups according to the median number of PBL before the administration of IFN-gamma. Except for CD11b, PBL level had no effect on DFSR. Multiple logistic regression analysis showed that CD11b levels greater than 16.5% were associated with 25.35 odds ratio increase in the risk of postoperative recurrence. A multivariate analysis found that CD11b may be an independent factor for postoperative recurrence. In terms of preventing postoperative recurrence, our results showed that an elevated CD11b level may indicate patients who can benefit from further combination therapy.

Strong significant correlation between MMP-9 and systemic symptoms in patients with localized renal cell carcinoma.

OBJECTIVES: To identify a relationship between clinical symptoms and matrix metalloproteinase (MMP)-2 and MMP-9, tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2, and membrane type MMP-1. METHODS: Tumor samples from 232 patients with renal cell carcinoma with no distant metastasis were immunohistochemically stained for MMP-2 and MMP-9, TIMP-1 and TIMP-2, and membrane type MMP-1. The immunoreactivity of these factors was analyzed by semiquantitative multivariate analysis for correlation with clinical symptoms. RESULTS: Patard's criteria were used to classify symptoms at initial tumor clinical presentation, with three groups defined: S1, S2, and S3. The cancer-specific 5-year survival rate was 88.7%, 74.7%, and 67.6% for S1 (145 patients), S2 (69 patients), and S3 (18 patients), respectively (P = 0.0015). Multiple logistic regression analysis of preference was used to determine whether differences in the contribution of the symptoms were statistically significant. A maximal tumor diameter of 40 mm or greater and positive venous invasion were associated with a 262% and 281% increase in the odds of local symptoms, respectively. MMP-9 positive cases were associated with a 2979% increase in the odds of systemic symptoms with significance. CONCLUSIONS: This study found a strong significant correlation between the histopathologic expression of MMP-9 and the systemic symptoms of renal cell carcinoma. We propose the histopathologic measurement of MMP-9 as a useful tool for assessing the prognosis of patients with renal cell carcinoma with systemic symptoms.

Fluorescence in situ hybridization analysis of c-myc amplification in stage TNM prostate cancer in Japanese patients.

OBJECTIVE: Genetic aberration such as the amplification of c-myc has been commonly found in advanced prostate cancer. The aim of this study was to elucidate chromosome 8 alteration, including a gain and amplification of 8q24 (c-myc gene), related to the progression and survival in advanced (Stage C) prostate cancer. MATERIALS AND METHODS: We used dual-probe fluorescence in situ hybridization with a centromere-specific probe for chromosome 8 (8cen), and with a region-specific probe for c-myc (8q24) to evaluate genetic changes in tumor samples from 50 patients who had undergone radical retropubic prostatectomy from 1986 to 2001. RESULTS: We classified the 8cen and c-myc copy numbers as normal, gain and amplification. The carcinoma foci with extra copies of c-myc, which was defined in 35 cases (70%), were divided into two groups: (a) a simple gain of the whole chromosome 8 (no increase in the c-myc copy number relative to the chromosome 8 centromere), which was identified in 15 cases (30%); and (b) a substantial amplification of c-myc (additional increases [AI] in the c-myc copy number relative to the chromosome 8 centromere), which was detected in 20 cases (40%). AI-c-myc was strongly associated with higher histopathological grades and Gleason's scores (P = 0.0330, 0.0190, respectively). Patients with the AI-c-myc had earlier disease progression (P = 0.0029) and earlier cancer death (P = 0.0087) than did patients with normal patterns. CONCLUSION: Identification of an AI-c-myc may serve as a potential marker of prostate cancer progression.

Prostate-specific antigen failure within 2 years of radical prostatectomy predicts overall survival.

OBJECTIVE: This study attempts to determine whether prostate-specific antigen (PSA) failure following radical retropubic prostatectomy (RRP) affects patients' long-term overall survival. METHODS: This study examined 155 men diagnosed as clinical stages T1b-T3a who received RRP as primary therapy. To evaluate whether PSA failure following RRP affects overall survival, the patients were grouped into those who experienced PSA failure within 2 years and those who did not. Clinical failure-free survival, prostate cancer-specific survival and overall survival were used as endpoints. Comparisons of survival curves were performed using the log-rank test. Logistic regression analysis was performed to determine the variable most predictive of PSA failure within 2 years of surgery. RESULTS: At 10 years, the PSA failure-free survival rate, clinical failure-free survival rate, prostate cancer specific survival rate and overall survival rate of the 155 patients were 40.1%, 83.1%, 94.9% and 84.2%, respectively. The overall survival curve for patients with PSA failure within 2 years of surgery was significantly lower than for patients with no PSA failure within 2 years of surgery (P = 0.042). The multivariate logistic regression analysis demonstrated that PSA greater than 20 ng/mL and poor differentiation of the tumor were significant independent predictors of PSA failure within 2 years of surgery. CONCLUSION: These results imply that prospective studies should be conducted to detect patients at high risk for PSA recurrence in whom metastasis may occur early and to investigate postoperative treatments for these high-risk patients to improve overall survival.

Usefulness of contrast-enhanced ultrasound for the diagnosis of recurrent renal cell carcinoma in contralateral kidney.

We studied contrast-enhanced ultrasound (CEU) for recurrence of renal cell carcinoma (RCC) at the contralateral kidney during postoperative follow up of localized renal cell carcinoma. CEU successfully detected all recurring cases, despite the fact that 5/6 cases were observed using conventional ultrasound; the remaining one case was not detected using conventional ultrasound. CEU using Levovisto successfully revealed renal tumors as RCC. Lesions were diagnosed as cystic renal tumors by Bosniac classification, and pathological findings demonstrated RCC, in accordance with the prior tumor.

Immunohistochemical and ultrastructural features of neuroendocrine differentiated carcinomas of the prostate: an immunoelectron microscopic study.

The purpose of this study was to further define the immunohistochemical and ultrastructural characteristics of neuroendocrine (NE) differentiated prostatic carcinomas. Seventy-seven specimens were obtained from prostatic carcinoma tumors during prostatectomy, transurethral resection of prostate or biopsy in 77 prostate cancer patients, and analyzed by immunohistochemical staining for chromogranin A (CgA). Nine of these tumors were also studied by elctron microscopy and 4 were examined by pre-embedding immunoelectron microscopy. CgA-stained cells were detected in 36 tumors (47%). Clinically advanced tumors or tumors with higher histological grades were associated with increased NE differentiation. Three of the tumors studied by electron microscopy contained cells showing unequivocal NE differentiation revealed by the presence of neurosecretory granules, while the poorly NE-differentiated malignant cells contained pleomorphic granules, which were lysosomal-like rather than NE-type granules. Immunoelectron microscopy demonstrated the presence of CgA immunoreactivity on the pleomorphic granules in the poorly differentiated malignant glands. This study suggests that NE-differentiated malignant cells in prostate cancer tissues may induce aggressive behavior in adjacent proliferating neoplastic cells via a paracrine mechanism.

Immunosuppressive acidic protein detects high nuclear grade localized renal cell carcinoma.

OBJECTIVES: To identify a potentially useful preoperative predictor of high nuclear grade renal cell carcinoma (RCC). METHODS: Our investigation consisted of 181 patients with histologically confirmed clear cell RCC. The positive predictive value, sensitivity, and specificity for detecting nuclear grade RCC were calculated individually for the largest tumor diameter. Hemoglobin, alkaline phosphatase, C-reactive protein, ferritin, and immunosuppressive acidic protein (IAP) levels were also determined in all patients preoperatively. RESULTS: The distribution of patients by nuclear grade was 74 patients (41%) with grade 1, 75 (41%) with grade 2, and 32 (18%) with grades 3 and 4. With respect to sensitivity, tumor diameter detected 28 (87.5%) of 32 high nuclear grade RCC specimens, and hemoglobin, C-reactive protein, alkaline phosphatase, ferritin, and IAP detected 10 (31.2%), 25 (78.1%), 8 (25.0%), 16 (50%), and 27 (84.3%) of 32, respectively. Multiple logistic regression analysis showed that a higher than normal C-reactive protein and IAP was associated with a 252% and 405% increase in the odds of a high nuclear grade, respectively. In the Stage T1 cases, elevated IAP was also associated with a 989% increase in the odds of a high nuclear grade. CONCLUSIONS: IAP level may be a useful predictor for detecting high nuclear grade localized RCC preoperatively.

Retroperitoneoscopic adrenalectomy for adrenal tumors via a single large port.

BACKGROUND AND PURPOSE: Laparoscopic adrenalectomy is generally performed with carbon dioxide insufflation of the cavity and requires multiple trocars. This study reports the outcomes of retroperitoneoscopic adrenalectomy (RA) for adrenal tumors via a single port using a large cylinder without carbon dioxide insufflation. PATIENTS AND METHODS: Fifty-four patients with adrenal tumors were treated using RA via a single large port. The average tumor size was 2.6 cm. For surgery, patients were placed in the lateral decubitus position with slight flexion, and a 4.5-cm skin incision was performed below the 12th rib in the midaxillary line. The retroperitoneal space was dissected using index fingers and a balloon dilator. A rectoscope tube with a 4-cm diameter was inserted, and the adrenal glands were removed endoscopically via the single large port without carbon dioxide insufflation. RESULTS: This procedure was completed in 53 patients (98.1%). The average duration of surgery was 203 minutes, and the mean estimated blood loss was 252 mL. Four patients (7.4%) required blood transfusion. Postoperative major complications, including fulminant hepatitis and pulmonary thrombosis, were observed in two patients (3.7%), and the patient with hepatic disease died on the 14th postoperative day. The mortality rate after surgery thus was 1.9%. However, no local tumor recurrence or hormonal relapse has occurred at a median follow-up of 34 months. CONCLUSIONS: This procedure appears to be effective and relatively minimally invasive. However, it is limited by the narrow working space and restriction of the manipulation of instruments.

Prospective study of estramustine phosphate for hormone refractory prostate cancer patients following androgen deprivation therapy.

INTRODUCTION: Estramustine phosphate (EMP) in combination with other cytotoxic agents has been widely used in clinical trials as an anti-tumor agent for the treatment of hormone-refractory prostate cancer (HRPC). However, few prospective studies have considered the efficacy of EMP monotherapy for HRPC patients following androgen-deprivation therapy (ADT), given the availability of methods to measure prostate-specific antigen (PSA) levels in the serum. We therefore initiated a prospective study to determine whether EMP is efficient for HRPC following ADT using changes in PSA levels as the major endpoint. METHODS: After a diagnosis of anti-androgen withdrawal syndrome had been excluded, 34 patients with HRPC who showed an elevated serum PSA level in 3 or more sequential tests following ADT were treated orally with 560 mg/day of EMP. The clinical stage and the median PSA value for inclusion in the study were D2 and 25.9 (range 6.5-540.8) ng/ml, respectively. Treatment was continued until evidence of disease progression reappeared or until severe adverse effects appeared. RESULTS: Of the 34 patients enrolled, 29 were evaluated, while the other 5 (15%) patients were discontinued due to severe gastrointestinal side effects. Seven of the 29 patients (24%) showed a decrease of 50% or greater in serum PSA levels from the initially elevated values, with the median duration of PSA response being 8.0 (range 2.2-18.8) months. Baseline PSA, hemoglobin, alkaline phosphatase, lactate dehydrogenase, performance status, and length of time of initial hormonal treatment did not correlate with the PSA response. With a median follow-up time of 20.0 (range 3.2-45.6) months, the cancer-specific survival rate at 2 years was 83% in the PSA responders and 44% in the non-responders. The PSA response was correlated with cancer-specific survival (p = 0.029). CONCLUSIONS: Following ADT one quarter of HRPC patients responded to EMP, with more than 50% of patients showing a decrease in PSA levels and an enhanced survival rate.

A retrospective study of the treatment of locally advanced prostate cancer by six institutions in eastern and north-eastern Japan.

OBJECTIVE: To investigate patients with locally advanced prostate cancer treated at six academic institutions in eastern and north-eastern Japan from 1988 to 2000, to facilitate the establishment of Japanese guidelines for the diagnosis and treatment of locally advanced prostate cancer. PATIENTS AND METHODS: The study included 391 eligible patients with locally advanced prostate cancer who were treated by radical prostatectomy (RP), radiotherapy and/or primary hormone therapy. Disease-specific survival rates for these patients were assessed in relation to their clinicopathological characteristics and the types of treatment they received. The Mann-Whitney U-test, Kruskal-Wallis, chi-square and log-rank test were used for statistical analysis, as appropriate. RESULTS: In all, 128 patient with lower prostate-specific antigen levels (P = 0.023) and/or better performance status (P = 0.001) had RP. Neoadjuvant hormone therapy before RP was the treatment in 68 (53%) of these 128 patients; 66 (52%) received immediate adjuvant hormone therapy. Of 87 patients treated with radiotherapy, 75 (86%) had external beam radiotherapy (EBRT) as the primary treatment with no brachytherapy, and 12 (14%) had brachytherapy as the primary method. Neoadjuvant hormone therapy was given to 56 of the 87 patients (64%); 48 (55%) received immediate adjuvant hormone therapy. Of the 176 patients treated with primary hormone therapy alone, combined androgen blockade and surgical or medical castration was the treatment in 76 (43%) and 85 (48%), respectively. Disease-specific survival rates at 5 years for patients treated with RP, EBRT and primary hormone therapy were 90%, 98%, and 89%, respectively. CONCLUSION: The treatments provided by the participating institutions did not differ significantly from those set out in European and American guidelines, and short-term disease-specific survival rates for each treatment did not differ significantly from those of historical controls. Further investigation may facilitate the establishment of Japanese guidelines for the diagnosis and treatment of locally advanced prostate cancer.

Long-term survival following radical prostatectomy in Japanese men with clinically localized prostate cancer: a single institutional study.

BACKGROUND: We evaluated the outcome of radical prostatectomy to provide information about long-term survival following this procedure. METHODS: One hundred and twenty-three otherwise healthy Japanese patients with clinically localized tumors underwent radical prostatectomy. Treatment outcomes were measured in terms of clinical progression-free survival, prostate cancer-specific survival and overall survival. Overall survival was compared with expected survival of age-matched Japanese men. RESULTS: For these 123 patients, clinical progression-free survival and prostate cancer-specific survival at 10 years were 72.5% and 86.4%, respectively. Results of Cox multivariate analysis showed that only pathological stage (P = 0.047) and tumor grade (P = 0.009) were independent predictors of clinical progression. Only tumor grade was a statistically significant independent predictor (P = 0.048) in terms of prostate cancer death. Both the 10 and 15-year overall survival rates for these 123 patients were 58.6%, whereas the expected survival of age-matched Japanese men was 65.0% at the 10-year follow up, and 43.8% at the 15-year follow up. CONCLUSIONS: The long-term overall survival in this surgically treated group is comparable to the expected survival rate of age-matched Japanese men. These results might be useful in counselling patients with clinically localized prostate cancer.

[Adjuvant hormone therapy in patients with positive surgical margins after radical prostatectomy].

BACKGROUND: We carried out a retrospective study comparing radical prostatectomy plus adjuvant hormone therapy with radical prostatectomy plus surveillance in patients with positive surgical margins to evaluate whether adjuvant hormone therapy is beneficial for disease free survival. PATIENTS AND METHODS: Sixty-five patients with positive surgical margins after radical prostatectomy were included in this study. Twenty-six patients received adjuvant hormone therapy. Thirty-nine patients underwent surveillance with salvage hormone therapy at PSA failure. None of these 65 received androgen deprivation prior to surgery. Treatment outcomes were measured in terms of progression free survival. RESULTS: Five year clinical progression free survival rates for the patients with positive surgical margins in the adjuvant therapy group and surveillance group were 85.9% and 80.0% respectively (p = 0.85). Clinical progression free survival between the groups was not statistically different in terms of seminal vesicle involvement and tumor grade. The difference of clinical progression free survival between the two groups approached statistical significance in poorly differentiated tumor (p = 0.08). CONCLUSIONS: We conclude that adjuvant hormone therapy is not beneficial in terms of progression free survival in patients with positive surgical margins. Nevertheless, adjuvant hormone therapy could be beneficial in patients with poorly differentiated prostate cancer.