SPCG-15: a prospective randomized study comparing primary radical prostatectomy and primary radiotherapy plus androgen deprivation therapy for locally advanced prostate cancer.

OBJECTIVE: To describe study design and procedures for a prospective randomized trial investigating whether radical prostatectomy (RP) ± radiation improves cause-specific survival in comparison with primary radiation treatment (RT) and androgen deprivation treatment (ADT) in patients with locally advanced prostate cancer (LAPC). MATERIALS AND METHODS: SPCG-15 is a prospective, multi-centre, open randomized phase III trial. Patients are randomized to either standard (RT + ADT) or experimental (RP with extended pelvic lymph-node dissection and with addition of adjuvant or salvage RT and/or ADT if deemed necessary) treatment. Each centre follows guidelines regarding the timing and dosing of postoperative RT and adjuvant treatment such as ADT The primary endpoint is cause-specific survival. Secondary endpoints include metastasis-free and overall survival, quality-of-life, functional outcomes and health-services requirements. Each subject will be followed up for a minimum of 10 years. RESULTS: Twenty-three centres in Denmark, Finland, Norway and Sweden, well established in performing RP and RT for prostate cancer participated. Each country's sites were coordinated by national coordinating investigators and sub-investigators for urology and oncology. Almost 400 men have been randomized of the stipulated 1200, with an increasing rate of accrual. CONCLUSIONS: The SPCG-15 trial aims to compare the two curatively intended techniques supplying new knowledge to support future decisions in treatment strategies for patients with LAPC The Scandinavian healthcare context is well suited for performing multi-centre long-term prospective randomized clinical trials. Similar care protocols and a history of entirely tax-funded healthcare facilitate joint trials.

Combined positron emission tomography/computed tomography in sunitinib therapy assessment of patients with metastatic renal cell carcinoma.

AIM: To assess the clinical benefit of combined functional imaging with [(18)F]2-fluoro-2-deoxy-d-glucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) in patients with metastatic renal cell carcinoma (mRCC) treated with the tyrosine kinase inhibitor sunitinib. MATERIALS AND METHODS: Fourteen patients with mRCC were prospectively enrolled in this study. All patients underwent PET/CT before receiving at least two cycles of sunitinib treatment. Three months after the onset of sunitinib treatment, a second PET/CT was carried out. The metabolic response evaluated from the PET (standard uptake value; SUV) was compared with the CT component of the PET/CT. The Response Evaluation Criteria in Solid Tumours criteria were used to assess the CT response and modified European Organization for Research and Treatment of Cancer criteria were used to assess the PET response. RESULTS: Three main results were obtained: (1) Patients with relatively low 18F-FDG uptake before treatment (SUV<5) had a longer progression-free survival than those with a relatively high 18F-FDG uptake (P=0.006). (2) Patients with a partial metabolic response or stable metabolic disease after two courses of sunitinib had improved prognosis as compared with those with progressive metabolic disease (P=0.031). (3) There was a clear discrepancy between PET and CT as a tool for the evaluation of treatment response after two courses of sunitinib. PET indicated progressive disease in three patients, a partial response in six patients and stable disease in four patients. In contrast, CT concluded with progression in only one patient and stable disease in all other patients. CONCLUSION: In patients with mRCC, a high baseline 18F-FDG uptake indicates aggressive disease, and the degree of reduction in 18F-FDG uptake after sunitinib treatment adds valuable prognostic information. Hence, the inclusion of PET results seems to improve the clinical counselling of patients with mRCC. Larger studies are needed to confirm these findings.

Prognostic significance of histologic grading in patients with prostate carcinoma who are assessed by the Gleason and World Health Organization grading systems in needle biopsies obtained prior to radiotherapy.

BACKGROUND: The current study was conducted to evaluate and compare the impact of two major histologic grading systems on failure-free survival in patients with prostate carcinoma who are treated with definitive radiation. METHODS: Eligible patients for the current study had localized adenocarcinoma of the prostate (T1-4pN0M0, T3/4: 67%, median observation time: 69 months) and were treated with intent-to-cure external radiotherapy between 1989 and 1995. The specimens from 178 patients, obtained by needle biopsies, were reviewed simultaneously by two pathologists assigning World Health Organization (WHO) and Gleason grades. Three-tiered Gleason grouping distributed patients into three groups (those with a score < 7, those with a score of 7, and those with a score of 8--10), whereas two-tiered Gleason categorization distributed patients into two groups (those with a Gleason score of 7A, major 3 + minor 4 patients were added to the group of patients with a Gleason score < 7 and patients with a Gleason score of 7B, major 4 + minor 3 were added to the group of patients with a Gleason score of 8--10). Univariate and multivariate analyses were performed. A P value < 0.05 was considered to be statistically significant. RESULTS: Three-tiered Gleason grouping resulted in a relatively even distribution of the patients (44 patients had a Gleason score < 7, 58 patients had a Gleason score of 7, and 76 patients had a Gleason score of 8--10) whereas 130 patients were determined to have Grade 2 tumors based on WHO criteria. Separating those patients with a Gleason score of 7 (score 3+4 vs. score 4+3) led to the two-tiered Gleason grouping (88 patients in the favorable group and 90 patients in the unfavorable group). The two-tiered Gleason grouping displayed differences with regard to failure-free survival with the lowest P values for all patients and separately for T1/2 versus T3/4 tumors. Together with T category and pretreatment prostate specific antigen, WHO grading, three-tiered Gleason grouping, and two-tiered Gleason grouping resulted in independent parameters in the Cox regression model. The proportional variance estimate confirmed the superior discrimination for survival of two-tiered Gleason grouping. CONCLUSIONS: The equal allocation of patients to subgroups based on the Gleason system helps the clinician to overcome the dilemma of overrepresentation of Grade 2 patients as occurs with WHO grading. The Gleason grading system and, most likely, the two-tiered Gleason grouping appear to result in better prognostic separation of patients referred to radiotherapy for relatively advanced primary tumors. Therefore the authors recommend the routine use of Gleason grading for these patients.

Prognostic value of neuroendocrine serum markers and PSA in irradiated patients with pN0 localized prostate cancer.

BACKGROUND: The prognosis of patients with localized prostate cancer depends on clinical stage, histological grade, and pretreatment prostate-specific antigen (PSA). We evaluated the additional prognostic impact of serum levels of neuron-specific enolase (NSE) and chromograninA (CgA) after curative radiotherapy and the importance of serum PSA, analyzed 3 months after irradiation. METHODS: From 1988 to 1995, 161 patients with localized T1-4, pN0M0, prostate adenocarcinoma were treated with external radiation (66Gy, 2Gy/5 fractions per week). Frozen serum samples were assessed for CgA, NSE, and PSA before and 3 months after radiotherapy. CgA was analyzed in only 100 patients. NSE and CgA were determined by a immunometric assay. Total PSA was measured by a time-resolved fluoro-immunometric assay. RESULTS: Prior to radiotherapy CgA was elevated in 16 of 100 patients, and NSE was elevated in 33 of the 161 patients. There was no association between grade, T category or pretreatment PSA and the levels of neuroendocrine markers. Pretreatment-elevated serum NSE, but not initial CgA, identified patients with an unfavorable prognosis. A < 50% reduction of PSA 3 months after radiotherapy was associated with decreased failure-free 10 years urvival. Multivariate analysis demonstrated an increased risk of failure for patients with elevated pretreatment NSE and PSA values, T3 category, and decline of PSA less than 50% 3 months after radiotherapy. The presence of none or several risk factors (1-4) defined clearly separable groups. CONCLUSIONS: Together with T category and pretreatment serum PSA values, serum NSE values before radiotherapy and decrease of serum PSA 3 months after radiotherapy represent easily assessable prognostic parameters in patients undergoing curative radiation treatment for prostate cancer.

Computed tomography/magnetic resonance based volume changes of the primary tumour in patients with prostate cancer with or without androgen deprivation.

BACKGROUND AND PURPOSE: To evaluate changes of the volume of the cancerous prostatic gland during androgen deprivation (AD) started immediately after diagnosis (IAD). Hypothetically, these data would assist the radiotherapist to determine the appropriate duration of pre-radiotherapy downsizing neoadjuvant luteinizing hormone releasing hormone (LHRH) treatment. A second aim was to assess any increase of the prostatic volume during the 1st year of diagnosis in patients who were allocated to a deferred treatment policy (DAD). METHODS AND MATERIALS Thirteen patients in the IAD cohort and 13 patients in the DAD group, all with T1-3pN1-2M0 prostate cancer, had regular computed tomography/magnetic resonance (CT/MR) examinations during the 1st year after randomization within the EORTC-GU trial 30846. Pre-treatment prostate specific antigen (PSA) values were available in only 12 patients. RESULTS: In the IAD group the prostate gland decreased with significant difference as compared with the DAD patients (P=0.033). As compared with the pre-treatment situation the prostate gland in the IAD group was reduced in size by 18, 35, and 46% at 1, 6, and 12 months, respectively. In four of six evaluable IAD patients the prostatic volume continued to shrink after achievement of the nadir PSA level (at 3 months). In three of the 13 DAD patients the prostate volume increased by >25% during the 1st 3 months after randomization. CONCLUSION: If neoadjuvant androgen deprivation is applied before local treatment to downsize the volume of the cancerous prostate gland, our limited data suggest that such treatment should last at least 6 months in order to achieve a maximal effect in the majority of patients. In about 1/4 of untreated patients an increase in the prostate volume by >25% may occur within 3 months of diagnosis. If no AD is given, radiotherapy should start within this period.

Long-term morbidity and quality of life in patients with localized prostate cancer undergoing definitive radiotherapy or radical prostatectomy.

PURPOSE: To assess morbidity, side effects, and quality of life (QoL) in patients treated for localized prostate cancer with curative aim. METHODS AND MATERIALS: This descriptive cross-sectional study comprises 154 patients who had undergone definitive radiotherapy (RAD) and 108 patients with radical prostatectomy (PRECT) at the Norwegian Radium Hospital during 1987-1995. At least 1 year after treatment the patients completed several questionnaires assessing quality of life (European Organization for Research and Treatment of Cancer QLQ-C30 instrument [EORTC QLQ-C30]), lower urinary tract symptoms (LUTS): International Prostate Symptom Score (IPSS), or sexuality (selected questions from the Psychosocial Adjustment to Illness Scale [PAIS]). Urinary incontinence and bowel distress were evaluated by ad hoc constructed questionnaires. A control group (OBS) consisted of 38 patients following the watch-and-wait policy. RESULTS: Twenty percent of the patients from the RAD Group had moderate (14%) or severe (6%) LUTS as compared to 12% in the PRECT group. However, 35% of men from the latter group reported moderate to severe urinary incontinence. "Overall" sexuality was moderately or severely impaired in 71% of the PRECT and 50% of the RAD patients. In the former group high age was correlated with erectile impotency (p < 0.001). In the RAD comorbidity was associated with erectile impotency (p < 0.001). Between 13-38% of the patients recorded moderate or severe bowel distress (blood per rectum: 13%; bowel cramps: 26%; flatulence: 38%), without significant differences comparing patients who had received conventional small 4-field box radiotherapy and patients who had undergone strictly conformal radiotherapy. Despite malignancy and/or treatment-related morbidity, QoL was comparable in both groups with respectively 9% and 6% RAD and PRECT patients, reporting moderately or severely impaired QoL. In the multivariate analysis physical function, emotional function and fatigue were significantly correlated with QoL, whereas sexuality, lower urinary symptoms, and urinary incontinence correlated with QoL only in the univariate analysis. CONCLUSION: In spite of considerable malignancy and/or treatment-related morbidity QoL was good or only slightly impaired in the majority of patients with localized prostate cancer who presented with stable disease > 1 year after definitive radiotherapy or radical prostatectomy with no difference as compared to the age-matched normal population. Clinicians should be aware of the fact that general QoL dimensions (physical function, emotional function, fatigue) are as a rule of greater significance for QoL than sexuality and lower urinary tract symptoms.