Applicability and dosimetric impact of ultrasound-based preplanning in high-dose-rate brachytherapy of prostate cancer

BACKGROUND AND PURPOSE: Analyses of permanent brachytherapy seed implants of the prostate have demonstrated that the use of a preplan may lead to a considerable decrease of dosimetric implant quality. The authors aimed to determine whether the same drawbacks of preplanning also apply to high-dose-rate (HDR) brachytherapy. PATIENTS AND METHODS: 15 patients who underwent two separate HDR brachytherapy implants in addition to external-beam radiation therapy for advanced prostate cancer were analyzed. A pretherapeutic transrectal ultrasound was performed in all patients to generate a preplan for the first brachytherapy implant. For the second brachytherapy, a subset of patients were treated by preplans based on the ultrasound from the first brachytherapy implant. Preplans were compared with the respective postplans assessing the following parameters: coverage index, minimum target dose, homogeneity index, and dose exposure of organs at risk. The prostate geometries (volume, width, height, length) were compared as well. RESULTS: At the first brachytherapy, the matching between the preplan and actual implant geometry was sufficient in 47% of the patients, and the preplan could be applied. The dosimetric implant quality decreased considerably: the mean coverage differed by -0.11, the mean minimum target dose by -0.15, the mean homogeneity index by -0.09. The exposure of organs at risk was not substantially altered. At the second brachytherapy, all patients could be treated by the preplan; the differences between the implant quality parameters were less pronounced. The changes of prostate geometry between preplans and postplans were considerable, the differences in volume ranging from -8.0 to 13.8 cm(3) and in dimensions (width, height, length) from -1.1 to 1.0 cm. CONCLUSION: Preplanning in HDR brachytherapy of the prostate is associated with a substantial decrease of dosimetric implant quality, when the preplan is based on a pretherapeutic ultrasound. The implant quality is less impaired in subsequent implants of fractionated brachytherapy.

[Malignant lymphoma of the prostate--diagnosis on the second biopsy]

BACKGROUND: Malignant lymphoma of the prostate is rare. In the literature, about 165 cases with either a primary lymphoma of the prostate or secondary infiltration of the prostate by a lymphoma are described. CASE REPORT: The case of a 59-year-old patient with an irregular tumor in the prostatic region, but normal prostate-specific antigen (PSA), a fracture in the vertebral column and a bilateral enlargement of the suprarenal glands is presented. Repetitive prostate biopsy revealed the diagnosis of a diffuse large B cell lymphoma. Further staging examinations gave hints to an epidural infiltration. A polychemotherapy including intrathecal drug applications was initiated. Staging after four therapeutic cycles already showed good partial remission of all lymphoma manifestations. After two further therapeutic cycles, a CT scan showed a small rest of prostatic bulk, but PET-CT did not detect vital lymphatic tissue (complete remission). CONCLUSION: In cases of irregular prostatic enlargements, carcinoma has to be considered as the most frequent diagnosis. Nevertheless, also a solitary lymphoma or infiltration of the prostate by a systemic lymphoma has to be taken into account, especially if the PSA value is in the normal range.

Distinct subcellular expression patterns of neutral endopeptidase (CD10) in prostate cancer predict diverging clinical courses in surgically treated patients

PURPOSE: Neutral endopeptidase (CD10), an ectopeptidase bound to the cell surface, is thought to be a potential prognostic marker for prostate cancer. EXPERIMENTAL DESIGN: Prostate cancer patients (N = 3,261) treated by radical prostatectomy at a single institution were evaluated by using tissue microarray. Follow-up data were available for 2,385 patients. The cellular domain (membranous, membranous-cytoplasmatic, and cytoplasmatic only) of CD10 expression was analyzed immunohistochemically and correlated with various clinical and histopathologic features of the tumors. RESULTS: CD10 expression was detected in 62.2% of cancer samples and occurred preferentially in higher Gleason pattern (P < 0.0001). CD10 expression positively correlated with adverse tumor features such as elevated preoperative prostate-specific antigen (PSA), higher Gleason score, and advanced stage (P < 0.0001 each). Survival analyses showed that PSA recurrence was significantly associated with the staining pattern of CD10 expression. Outcome significantly declined from negative over membranous, membranous-cytoplasmatic, to exclusively cytoplasmatic CD10 expression (P < 0.0001). In multivariate analysis, CD10 expression was an independent predictor for PSA failure (P = 0.0343). CONCLUSIONS: CD10 expression is an unfavorable independent risk factor in prostate cancer. The subcellular location of CD10 protein is associated with specific clinical courses, suggesting an effect on different important biological properties of prostate cancer cells. The frequent expression of CD10 in prostate cancer and the strong association of CD10 with unfavorable tumor features may qualify this biomarker for targeted therapies.

Acute and late toxicity in prostate cancer patients treated by dose escalated intensity modulated radiation therapy and organ tracking

BACKGROUND: To report acute and late toxicity in prostate cancer patients treated by dose escalated intensity-modulated radiation therapy (IMRT) and organ tracking. METHODS: From 06/2004 to 12/2005 39 men were treated by 80 Gy IMRT along with organ tracking. Median age was 69 years, risk of recurrence was low 18%, intermediate 21% and high in 61% patients. Hormone therapy (HT) was received by 74% of patients. Toxicity was scored according to the CTC scale version 3.0. Median follow-up (FU) was 29 months. RESULTS: Acute and maximal late grade 2 gastrointestinal (GI) toxicity was 3% and 8%, late grade 2 GI toxicity dropped to 0% at the end of FU. No acute or late grade 3 GI toxicity was observed. Grade 2 and 3 pre-treatment genitourinary (GU) morbidity (PGUM) was 20% and 5%. Acute and maximal late grade 2 GU toxicity was 56% and 28% and late grade 2 GU toxicity decreased to 15% of patients at the end of FU. Acute and maximal late grade 3 GU toxicity was 8% and 3%, respectively. Decreased late > or = grade 2 GU toxicity free survival was associated with higher age (P = .025), absence of HT (P = .016) and higher PGUM (P < .001). DISCUSSION: GI toxicity rates after IMRT and organ tracking are excellent, GU toxicity rates are strongly related to PGUM.

Androgen deprivation therapy for the treatment of prostate cancer: consider both benefits and risks

CONTEXT: Androgen deprivation therapy (ADT) is increasingly used for the treatment of prostate cancer (PCa), even in clinical settings in which there is no evidence-based proof of prolonged overall survival (OS). ADT, however, may be associated with numerous side effects, including an increased therapy-related cardiovascular mortality. OBJECTIVE: To discuss different clinical settings in which ADT is currently used and to critically weigh the benefits of ADT against its possible side effects. EVIDENCE ACQUISITION: A MEDLINE search was conducted to identify original articles and review articles addressing the efficacy and side effects of ADT for the treatment of PCa. Keywords consisted of prostate cancer, hormonal therapy, adverse effects, radical prostatectomy, and radiotherapy. The articles with the highest level of evidence for the various examined end points were identified with the consensus of all authors and were reviewed. EVIDENCE SYNTHESIS: Even short-term use of ADT may lead to numerous side effects, such as osteoporosis, obesity, sarcopenia, lipid alterations, insulin resistance, and increased risk for diabetes and cardiovascular morbidity. Despite these side effects, ADT is commonly used in various clinical settings in which a clear effect on improved OS has not been shown. CONCLUSIONS: ADT is associated with an increased risk of multiple side effects that may reduce quality of life and/or OS. Consequently, these issues should be discussed in detail with patients and their families before initiation of ADT. ADT should be used with knowledge of its potential long-term side effects and with possible lifestyle interventions, especially in settings with the highest risk-benefit ratio, to alleviate comorbidities.

The role of lymphadenectomy in high risk prostate cancer

Historically, patients with high risk prostate cancer were considered poor candidates for radical prostatectomy (RP) due to the likelihood of positive pelvic lymph nodes and decreased long term survival. Although there is still no consensus on the optimal therapy for this group of patients, there is increasing evidence that surgery could play a role. Cancer specific survival (CSS) rates after RP for locally advanced disease at 10 year follow up range from 29 to 72%, depending on tumor differentiation. The role of pelvic lymph node dissection (PLND) in prostate cancer remains a controversial topic. Nonetheless, in conjunction with RRP extended PLND (ePLND) should be performed as extended lymph node dissection in lieu of standard PLND may increase staging accuracy, influence decision making with respect to adjuvant therapy and possibly impact outcome. High risk patients with organ confined prostate cancer and low volume (micro)metastatic disease may be the ones to profit most from this approach.

Using PSA to guide timing of androgen deprivation in patients with T0-4 N0-2 M0 prostate cancer not suitable for local curative treatment (EORTC 30891)

OBJECTIVE: EORTC trial 30891 compared immediate versus deferred androgen-deprivation therapy (ADT) in T0-4 N0-2 M0 prostate cancer (PCa). Many patients randomly assigned to deferred ADT did not require ADT because they died before becoming symptomatic. The question arises whether serum prostate-specific antigen (PSA) levels may be used to decide when to initiate ADT in PCa not suitable for local curative treatment. METHODS: PSA data at baseline, PSA doubling time (PSADT) in patients receiving no ADT, and time to PSA relapse (>2 ng/ml) in patients whose PSA declined to <2 ng/ml within the first year after immediate ADT were analyzed in 939 eligible patients randomly assigned to immediate (n=468) or deferred ADT (n=471). RESULTS: In both arms, patients with a baseline PSA>50 ng/ml were at a>3.5-fold higher risk to die of PCa than patients with a baseline PSA12 mo. Time to PSA relapse after response to immediate ADT correlated significantly with baseline PSA, suggesting that baseline PSA may also reflect disease aggressiveness. CONCLUSIONS: Patients with a baseline PSA>50 ng/ml and/or a PSADT<12 mo were at increased risk to die from PCa and might have benefited from immediate ADT, whereas patients with a baseline PSA<50 ng/ml and a slow PSADT (>12 mo) were likely to die of causes unrelated to PCa, and thus could be spared the burden of immediate ADT.

The template of the primary lymphatic landing sites of the prostate should be revisited: results of a multimodality mapping study

OBJECTIVES: To map the primary prostatic lymphatic landing sites using a multimodality technique. METHODS: Thirty-four patients with organ-confined prostate cancer (cT1-cT2; cN0) underwent single-photon emission computed tomography fused with data from computed tomography (SPECT/CT) (n=33) or magnetic resonance imaging (SPECT/MRI) (n=1) 1h after ultrasound-guided intraprostatic injection of technecium (Tc-99m) nanocolloid. The presence of lymph nodes (LNs) containing Tc-99m was confirmed intraoperatively with a gamma probe. A backup extended pelvic lymphadenectomy (PLND) was performed to preclude missed primary lymphatic landing sites. The SPECT/CT/MRI data sets were used to generate a three-dimensional projection of each LN site. RESULTS: A total of 317 LNs (median, 10 per patient; range, 3-19) were detected by SPECT/CT/MRI, 314 of which were confirmed by gamma probe. With an "extended" PLND, two thirds of all primary prostatic lymphatic landing sites are resected compared with only one third with a "limited" PLND. CONCLUSIONS: The multimodality technique presented here enables precise mapping of the primary prostatic lymphatic landing sites. PLND for prostate cancer should include not only the external and obturator regions as well as the portions medial and lateral to the internal iliac vessels, but also the common iliac LNs at least up to the ureteric crossing, thus removing approximately 75% of all nodes potentially harbouring metastasis.

Extended lymph node dissection for prostate cancer

Lymph node status is an important determinant for the management of patients with newly diagnosed prostate cancer. Given the significant limitations of cross-sectional and functional preoperative imaging in the detection of small metastases, pelvic lymph node dissection remains the only reliable staging method in clinically localized prostate cancer. Although lymph node dissection is a well-established form of staging in prostate cancer, controversy remains about indications and the surgical extent of the procedure. Reported practices vary from omitting pelvic lymph node dissection in low-risk disease to routine pelvic lymph node dissection in all radical prostatectomy patients. This review highlights the recent literature concerning pelvic lymphadenectomy in prostate cancer with respect to anatomical extent and oncologic outcome.

Agents used for chemoprevention of prostate cancer may influence PSA secretion independently of cell growth in the LNCaP model of human prostate cancer progression

BACKGROUND: The aim of this study was to evaluate the inhibitory growth effects of different potential chemopreventive agents in vitro and to determine their influence on PSA mRNA and protein expression with an established screening platform. METHODS: LNCaP and C4-2 cells were incubated with genistein, seleno-L-methionine, lycopene, DL-alpha-tocopherol, and trans-beta-carotene at three different concentrations and cell growth was determined by the MTT assay. PSA mRNA expression was assessed by quantitative real-time RT-PCR and secreted PSA protein levels were quantified by the microparticle enzyme immunoassay. RESULTS: Genistein, seleno-l-methionine and lycopene inhibited LNCaP cell growth, and the proliferation of C4-2 cells was suppressed by seleno-L-methionine and lycopene. PSA mRNA expression was downregulated by genistein in LNCaP but not C4-2 cells. No other compound tested altered PSA mRNA expression. PSA protein expression was downregulated by genistein, seleno-L-methionine, DL-alpha-tocopherol in LNCaP cells. In C4-2 cells only genistein significantly reduced the secretion of PSA protein. CONCLUSIONS: In the LNCaP progression model PSA expression depends on the compound, its concentration and on the hormonal dependence of the cell line used and does not necessarily reflect cell growth or death. Before potential substances are evaluated in clinical trials using PSA as a surrogate end point marker, their effect on PSA mRNA and protein expression has to be considered to correctly assess treatment response by PSA.

Prostate carcinoma: diffusion-weighted imaging as potential alternative to conventional MR and 11C-choline PET/CT for detection of bone metastases

In a technical development study approved by the institutional ethics committee, the feasibility of fast diffusion-weighted imaging as a replacement for conventional magnetic resonance (MR) imaging sequences (short inversion time inversion recovery [STIR] and T1-weighted spin echo [SE]) and positron emission tomography (PET)/computed tomography (CT) in the detection of skeletal metastases from prostate cancer was evaluated. MR imaging and carbon 11 ((11)C) choline PET/CT data from 11 consecutive prostate cancer patients with bone metastases were analyzed. Diffusion-weighted imaging appears to be equal, if not superior, to STIR and T1-weighted SE sequences and equally as effective as (11)C-choline PET/CT in detection of bone metastases in these patients. Diffusion-weighted imaging should be considered for further evaluation and comparisons with PET/CT for comprehensive whole-body staging and restaging in prostate and other cancers.

[11C]Choline PET/CT for targeted salvage lymph node dissection in patients with biochemical recurrence after primary curative therapy for prostate cancer. Preliminary results of a prospective study

INTRODUCTION: In this prospective study we set out to investigate the diagnostic value of [(11)C]choline-PET/CT in patients with suspected lymph node metastases before salvage lymph node dissection. PATIENTS AND METHODS: 15 consecutive patients with rising PSA underwent [(11)C]choline-PET/CT and consecutive open salvage pelvic/retroperitoneal extended lymph node dissection due to uptake of [(11)C]choline in at least 1 lymph node. Mean age was 62.1 (range 53-73). RESULTS: [(11)C]choline-PET/CT results were compared with the histopathology reports and clinical follow-up (mean 13.7 months, range 6-24). Mean time to progression was 23.6 months (range 4-81). [(11)C]choline uptake was observed in nodes along the external and internal and common iliac arteries and in the paraaortic region. A positive histology was reported in 8/15 patients. Only one patient had a PSA nadir of <0.1 ng/ml after salvage surgery. Another patient had stable disease with a PSA of 0.5 ng/ml. Three patients developed bone metastases during follow-up. CONCLUSIONS: This interim analysis indicates that [(11)C]choline-PET/CT may be a useful technique in detection of lymph node metastases when rising PSA occurs after definite prostate cancer therapy. The presented cohort is limited in size, but there is still strong evidence that the patients benefit from [(11)C]choline-PET/CT and consecutive salvage lymph node dissection is rather small.

Immunological microenvironment in prostate cancer: high mast cell densities are associated with favorable tumor characteristics and good prognosis

BACKGROUND: Number of intratumoral mast cells predicts survival in various cancers. The prognostic significance of such mast cells in surgically treated prostate cancer is unknown. METHODS: Mast cell densities were determined in prostate cancer samples of more than 2,300 hormone-naïve patients using a tissue microarray format in correlation with clinical follow-up data. Mast cells were visualized immunohistochemically (c-kit). All patients were homogeneously treated by radical prostatectomy at a single institution. RESULTS: Mast cells were present in 95.9% of the tumor samples. Median mast cell number on the tissue spot was 9 (range: 0-90; median density: 31 mast cells/mm(2)). High mast cell densities were significantly associated with more favorable tumors having lower preoperative prostate-specific antigen (P = 0.0021), Gleason score (P < 0.0001) and tumor stage (P < 0.0001) than tumors with low mast cell densities. Prostate-specific antigen recurrence-free survival significantly (P = 0.0001) decreased with decline of mast cell density showing poorest outcome for patients without intratumoral mast cells. In multivariate analysis mast cell density narrowly missed to add independent prognostic information (P = 0.0815) for prostate-specific antigen recurrence. CONCLUSION: High intratumoral mast cell density is associated with favorable tumor characteristics and good prognosis in prostate cancer. This finding is consistent with a role of mast cells in the immunological host-defense reaction on prostate cancer. Triggering mast cell activity might expand immunotherapeutic strategies in prostate cancer.