Wolfgang Lilleby

Independent prognostic significance of HER-2 oncoprotein expression in pN0 prostate cancer undergoing curative radiotherapy.

Existing prognostic algorithms for localized prostate cancer (PC) are hampered by poor validation for endpoints other than biochemical relapse such as clinical disease progression or survival. Therefore, the prognostic relevance of Her‐2 (Her‐2/neu, c‐erbB2) protein expression in patients undergoing curative radiotherapy (RT) was compared to widely accepted prognostic factors such as pretreatment prostate‐specific antigen (PSA) levels, biopsy Gleason score and T category of the primary tumor. Biopsies from 112 homogeneously treated patients with T1‐4pN0M0 PC were examined by immunohistochemistry and 37% of cases showed membrane‐bound Her‐2 expression in more than 10% of cancer cells. No definite membrane staining was seen in normal prostate epithelium. With 25 patients dead of PC and a median follow‐up of surviving patients of 71 months (range 48–144), the prognostic relevance of Her‐2 expression was univariately associated with adverse outcome in terms of biochemical or clinical progression‐free survival (B/C‐PFS; p = 0.04), clinical progression‐free survival (C‐PFS; p = 0.02) and disease‐specific survival (DSS; p = 0.02). In multivariate analysis, Her‐2 expression, T category and Gleason score were independently associated with C‐PFS, whereas only Her‐2 expression and Gleason score were associated with DSS. Her‐2 expression and Gleason score together discriminated 2 groups of patients with 5‐year DSS of 95% and 79%, respectively (p < 0.001). Pretreatment PSA levels were associated only with B/C‐PFS but not with C‐PFS or DSS. Together the data show for the first time that expression of Her‐2 is of prognostic relevance in localized PC undergoing RT and suggest that analysis for Her‐2 may improve prognostic algorithms for clinically relevant endpoints other than biochemical relapse.

Impact of disseminated tumor cells in bone marrow at diagnosis in patients with nonmetastatic prostate cancer treated by definitive radiotherapy

The purpose of this study was to explore whether detection of disseminated tumor cells (DTCs) in bone marrow (BM) of nonmetastatic prostate cancer (PC) was associated with other clinical or histopathological factors at diagnoses or clinical outcome subsequent to definitive radiotherapy (RT). We evaluated BM aspirates from 272 cT1‐4pN0M0 PC patients by immunocytochemistry employing anticytokeratin antibodies (AE1/AE3). BM‐status was compared with clinical and histopathological parameters. Long‐term clinical outcome was assessed in 131 of the patients who all had completed definitive RT with or without androgen deprivation (AD), initiating treatment >5 years before cut‐off date June 1, 2005. They had at least 1 unfavorable prognostic feature defined as cT3‐4 or Gleason score (GS) ≥ 7B or PSA ≥ 10 μg/l. Overall death, cause‐specific death, distant metastases (DM) as first clinical relapse, local failure as first clinical relapse and biochemical failure were defined as end‐points. DTCs were detected in 18% of the patients and were associated with increasing GS (p = 0.04) and percentage of Gleason pattern 4/5 (p = 0.04). The 7‐year cumulative risk of DM was 21% for BM‐positive patients vs. 6% for BM‐negative patients (p = 0.07). In patients receiving RT without AD (n = 75), the 7‐year cumulative risk of DM for BM‐positive patients was 28% vs. 9% for BM‐negative patients (p = 0.03). BM‐status did not have impact on other end‐points. In conclusion our study shows that presence of DTCs in BM at diagnosis was associated with the histological differentiation of the primary tumor and an increased risk of developing distant metastases after RT.

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

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.

Chemotherapy in metastatic renal cell cancer.

Currently, there is no standard treatment for patients with advanced renal cell carcinoma (RCC) who do not respond to or progress after transient remission to first-line immunotherapy. At the end of the 1990s, no single chemotherapeutic drug, alone or in combination with interleukin-2 (IL-2) or interferon-alfa (IFN), had shown activity beyond the one expected by immunotherapy alone. New drugs on the market such as the pyrimidine analog gemcitabine or taxane-based chemotherapeutics may show promising tumor activity in combination with targeted therapy, but this has to be substantiated in upcoming trials. There is a great need to develop effective systemic therapy for advanced MRCC and to evaluate the efficacy of new drugs in clinical 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.

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.

Effects of strength training on body composition, physical functioning, and quality of life in prostate cancer patients during androgen deprivation therapy

Background. Androgen deprivation therapy (ADT) increases survival rates in prostate cancer (PCa) patients with locally advanced disease, but is associated with side effects that may impair daily function. Strength training may counteract several side effects of ADT, such as changes in body composition and physical functioning, which in turn may affect health-related quality of life (HRQOL). However, additional randomised controlled trials are needed to expand this knowledge. Material and methods. Fifty-eight PCa patients on ADT were randomised to either 16 weeks of high-load strength training (n = 28) or usual care (n = 30). The primary outcome was change in total lean body mass (LBM) assessed by dual x-ray absorptiometry (DXA). Secondary outcomes were changes in regional LBM, fat mass, and areal bone mineral density (aBMD) measured by DXA; physical functioning assessed by 1-repetition maximum (1RM) tests, sit-to-stand test, stair climbing test and Shuttle walk test; and HRQOL as measured by the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30. Results and Conclusion. No statistically significant effect of high-load strength training was demonstrated on total LBM (p = 0.16), but significant effects were found on LBM in the lower and upper extremities (0.49 kg, p < 0.01 and 0.15 kg, p < 0.05, respectively). Compared to usual care, high-load strength training showed no effect on fat mass, aBMD or HRQOL, but beneficial effects were observed in all 1RM tests, sit-to-stand test and stair climbing tests. Adherence to the training program was 88% for lower body exercises and 84% for upper body exercises. In summary, high-load strength training improved LBM in extremities and physical functioning, but had no effect on fat mass, aBMD, or HRQOL in PCa patients on ADT.

Disseminated tumor cells and their prognostic significance in nonmetastatic prostate cancer patients.

Detection of pretreatment disseminated cells (pre‐DTC) reflecting its homing to bone marrow (BM) in prostate cancer (PCa) might improve the current model to predict recurrence or survival in men with nonmetastatic disease despite of primary treatment. Thereby, pre‐DTC may serve as an early prognostic biomarker. Post‐treatment DTCs (post‐DTC) finding may supply the clinician with additional predictive information about the possible course of PCa. To assess the prognostic impact of DTCs in BM aspirates sampled before initiation of primary therapy (pre‐DTC) and at least 2 years after (post‐DTC) to established prognostic factors and survival in patients with PCa. Available BM of 129 long‐term follow‐up patients with T1‐3N0M0 PCa was assessed in addition to 100 BM of those in whom a pretreatment BM was sampled. Patients received either combined therapy [n = 81 (63%)], radiotherapy (RT) with different duration of hormone treatment (HT) or monotherapy with RT or HT alone [n = 48 (37%)] adapted to the criteria of the SPCG‐7 trial. Mononuclear cells were deposited on slides according to the cytospin methodology and DTCs were identified by immunocytochemistry using the pancytokeratin antibodies AE1/AE3. The median age of men at diagnosis was 64.5 years (range 49.5–73.4 years). The median long‐term follow‐up from first BM sampling to last observation was 11 years. Categorized clinically relevant factors in PCa showed only pre‐DTC status as the statistically independent parameter for survival in the multivariate analysis. Pre‐DTCs homing to BM are significantly associated with clinically relevant outcome independent to the patients treatment at diagnosis with nonmetastatic PCa.

Radical Prostatectomy, External Beam Radiotherapy, or External Beam Radiotherapy With Brachytherapy Boost and Disease Progression and Mortality in Patients With Gleason Score 9-10 Prostate Cancer

Importance The optimal treatment for Gleason score 9-10 prostate cancer is unknown. Objective To compare clinical outcomes of patients with Gleason score 9-10 prostate cancer after definitive treatment. Design, Setting, and Participants Retrospective cohort study in 12 tertiary centers (11 in the United States, 1 in Norway), with 1809 patients treated between 2000 and 2013. Exposures Radical prostatectomy (RP), external beam radiotherapy (EBRT) with androgen deprivation therapy, or EBRT plus brachytherapy boost (EBRT+BT) with androgen deprivation therapy. Main Outcomes and Measures The primary outcome was prostate cancer–specific mortality; distant metastasis-free survival and overall survival were secondary outcomes. Results Of 1809 men, 639 underwent RP, 734 EBRT, and 436 EBRT+BT. Median ages were 61, 67.7, and 67.5 years; median follow-up was 4.2, 5.1, and 6.3 years, respectively. By 10 years, 91 RP, 186 EBRT, and 90 EBRT+BT patients had died. Adjusted 5-year prostate cancer–specific mortality rates were RP, 12% (95% CI, 8%-17%); EBRT, 13% (95% CI, 8%-19%); and EBRT+BT, 3% (95% CI, 1%-5%). EBRT+BT was associated with significantly lower prostate cancer–specific mortality than either RP or EBRT (cause-specific HRs of 0.38 [95% CI, 0.21-0.68] and 0.41 [95% CI, 0.24-0.71]). Adjusted 5-year incidence rates of distant metastasis were RP, 24% (95% CI, 19%-30%); EBRT, 24% (95% CI, 20%-28%); and EBRT+BT, 8% (95% CI, 5%-11%). EBRT+BT was associated with a significantly lower rate of distant metastasis (propensity-score-adjusted cause-specific HRs of 0.27 [95% CI, 0.17-0.43] for RP and 0.30 [95% CI, 0.19-0.47] for EBRT). Adjusted 7.5-year all-cause mortality rates were RP, 17% (95% CI, 11%-23%); EBRT, 18% (95% CI, 14%-24%); and EBRT+BT, 10% (95% CI, 7%-13%). Within the first 7.5 years of follow-up, EBRT+BT was associated with significantly lower all-cause mortality (cause-specific HRs of 0.66 [95% CI, 0.46-0.96] for RP and 0.61 [95% CI, 0.45-0.84] for EBRT). After the first 7.5 years, the corresponding HRs were 1.16 (95% CI, 0.70-1.92) and 0.87 (95% CI, 0.57-1.32). No significant differences in prostate cancer–specific mortality, distant metastasis, or all-cause mortality (⩽7.5 and >7.5 years) were found between men treated with EBRT or RP (cause-specific HRs of 0.92 [95% CI, 0.67-1.26], 0.90 [95% CI, 0.70-1.14], 1.07 [95% CI, 0.80-1.44], and 1.34 [95% CI, 0.85-2.11]). Conclusions and Relevance Among patients with Gleason score 9-10 prostate cancer, treatment with EBRT+BT with androgen deprivation therapy was associated with significantly better prostate cancer–specific mortality and longer time to distant metastasis compared with EBRT with androgen deprivation therapy or with RP.

Differential expression of steroid receptors in prostate tissues before and after radiation therapy for prostatic adenocarcinoma

The expression, distribution and the role of steroid receptors in benign and malignant untreated prostate tissues is well recognized, however, the status of steroid receptors in prostate after radiotherapy (RT) for adenocarcinoma has not yet been studied fully. Immunohistochemical evaluation of androgen receptor (AR), estrogen receptor‐alpha (ER‐α), estrogen receptor‐beta (ER‐β), and progesterone receptor (PR) was carried out in prostate needle biopsies obtained before and after radiotherapy from 60 patients with adenocarcinoma. The ER‐β transcripts were also studied by RT‐PCR in LNCaP prostate carcinoma cell line before and 24 hr after γ‐irradiation at 0.5 Gy and 8.0 Gy. Significantly higher level of ER‐β expression was found in post‐radiation samples of prostate adenocarcinoma and benign epithelium. After RT, all steroid receptors were upregulated in prostatic stroma. Tumor AR expression did not change significantly. Although a positive association between AR and ER‐β expression was observed in pre‐treatment prostate adenocarcinoma, it was lost after RT suggesting that these 2 steroid receptors respond differently to RT. High levels of pretreatment tumor ER‐β were associated with local recurrence after RT and decreased biochemical recurrence‐free survival (p = 0.028). LNCaP cell line that expressed no ER‐β mRNA before γ‐irradiation, clearly expressed ER‐β mRNA 24 hr after 0.5 Gy and 8.0 Gy. Upregulation of all steroid receptors in the prostate stroma and upregulation of ER‐β in the tumor epithelium after RT, may represent a protective tissue response to radiation‐induced tissue injury. Although stromal AR was doubled after RT, the tumor and benign epithelium expression of AR seemed resistant to change by RT.