Clinical validation of a targeted methylation-based multi-cancer early detection test using an independent validation set.

BACKGROUND: A multi-cancer early detection (MCED) test used to complement existing screening could increase the number of cancers detected through population screening, potentially improving clinical outcomes. The Circulating Cell-free Genome Atlas study (CCGA; NCT02889978) was a prospective, case-controlled, observational study and demonstrated that a blood-based MCED test utilizing cell-free DNA (cfDNA) sequencing in combination with machine learning could detect cancer signals across multiple cancer types and predict cancer signal origin (CSO) with high accuracy. The objective of this third and final CCGA substudy was to validate an MCED test version further refined for use as a screening tool. PATIENTS AND METHODS: This pre-specified substudy included 4077 participants in an independent validation set (cancer: n = 2823; non-cancer: n = 1254, non-cancer status confirmed at year-one follow-up). Specificity, sensitivity, and CSO prediction accuracy were measured. RESULTS: Specificity for cancer signal detection was 99.5% [95% confidence interval (CI): 99.0% to 99.8%]. Overall sensitivity for cancer signal detection was 51.5% (49.6% to 53.3%); sensitivity increased with stage [stage I: 16.8% (14.5% to 19.5%), stage II: 40.4% (36.8% to 44.1%), stage III: 77.0% (73.4% to 80.3%), stage IV: 90.1% (87.5% to 92.2%)]. Stage I-III sensitivity was 67.6% (64.4% to 70.6%) in 12 pre-specified cancers that account for approximately two-thirds of annual USA cancer deaths and was 40.7% (38.7% to 42.9%) in all cancers. Cancer signals were detected across >50 cancer types. Overall accuracy of CSO prediction in true positives was 88.7% (87.0% to 90.2%). CONCLUSION: In this pre-specified, large-scale, clinical validation substudy, the MCED test demonstrated high specificity and accuracy of CSO prediction and detected cancer signals across a wide diversity of cancers. These results support the feasibility of this blood-based MCED test as a complement to existing single-cancer screening tests. CLINICAL TRIAL NUMBER: NCT02889978.

Deep androgen receptor suppression in prostate cancer exploits sexually dimorphic renal expression for systemic glucocorticoid exposure.

BACKGROUND: Enzalutamide and apalutamide are potent next-generation androgen receptor (AR) antagonists used in metastatic and non-metastatic prostate cancer. Metabolic, hormonal and immunologic effects of deep AR suppression are unknown. We hypothesized that enzalutamide and apalutamide suppress 11ß-hydroxysteroid dehydrogenase-2 (11ß-HSD2), which normally converts cortisol to cortisone, leading to elevated cortisol concentrations, increased ratio of active to inactive glucocorticoids and possibly suboptimal response to immunotherapy. On-treatment glucocorticoid changes might serve as an indicator of active glucocorticoid exposure and resultant adverse consequences. PATIENTS AND METHODS: Human kidney tissues were stained for AR and 11ß-HSD2 expression. Patients in three trials [neoadjuvant apalutamide plus leuprolide, enzalutamide ± PROSTVAC (recombinant poxvirus prostate-specific antigen vaccine) for metastatic castration-resistant prostate cancer (CRPC) and enzalutamide ± PROSTVAC for non-metastatic castration-sensitive prostate cancer] were analyzed for cortisol and its metabolites using liquid chromatography-mass spectrometry (LC-MS/MS). Progression-free survival was determined in the metastatic CRPC study of enzalutamide ± PROSTVAC for those with glucocorticoid changes above and below the median. RESULTS: Concurrent AR and 11ß-HSD2 expression occurs only in the kidneys of men. A statistically significant rise in cortisol concentration, cortisol/cortisone ratio and tetrahydrocortisol/tetrahydrocortisone ratio with AR antagonist treatment occurred uniformly across all three trials. In the trial of enzalutamide ± PROSTVAC for metastatic CRPC, high cortisol/cortisone ratio in the enzalutamide arm was associated with significantly improved progression-free survival. However, in the enzalutamide + PROSTVAC arm, the opposite trend was observed. CONCLUSION: Enzalutamide and apalutamide treatment toggles renal 11ß-HSD2 and significantly increases indicators of and exposure to biologically active glucocorticoids, which is associated with clinical outcomes.

Sensitive and specific multi-cancer detection and localization using methylation signatures in cell-free DNA.

BACKGROUND: Early cancer detection could identify tumors at a time when outcomes are superior and treatment is less morbid. This prospective case-control sub-study (from NCT02889978 and NCT03085888) assessed the performance of targeted methylation analysis of circulating cell-free DNA (cfDNA) to detect and localize multiple cancer types across all stages at high specificity. PARTICIPANTS AND METHODS: The 6689 participants [2482 cancer (>50 cancer types), 4207 non-cancer] were divided into training and validation sets. Plasma cfDNA underwent bisulfite sequencing targeting a panel of >100 000 informative methylation regions. A classifier was developed and validated for cancer detection and tissue of origin (TOO) localization. RESULTS: Performance was consistent in training and validation sets. In validation, specificity was 99.3% [95% confidence interval (CI): 98.3% to 99.8%; 0.7% false-positive rate (FPR)]. Stage I-III sensitivity was 67.3% (CI: 60.7% to 73.3%) in a pre-specified set of 12 cancer types (anus, bladder, colon/rectum, esophagus, head and neck, liver/bile-duct, lung, lymphoma, ovary, pancreas, plasma cell neoplasm, stomach), which account for ∼63% of US cancer deaths annually, and was 43.9% (CI: 39.4% to 48.5%) in all cancer types. Detection increased with increasing stage: in the pre-specified cancer types sensitivity was 39% (CI: 27% to 52%) in stage I, 69% (CI: 56% to 80%) in stage II, 83% (CI: 75% to 90%) in stage III, and 92% (CI: 86% to 96%) in stage IV. In all cancer types sensitivity was 18% (CI: 13% to 25%) in stage I, 43% (CI: 35% to 51%) in stage II, 81% (CI: 73% to 87%) in stage III, and 93% (CI: 87% to 96%) in stage IV. TOO was predicted in 96% of samples with cancer-like signal; of those, the TOO localization was accurate in 93%. CONCLUSIONS: cfDNA sequencing leveraging informative methylation patterns detected more than 50 cancer types across stages. Considering the potential value of early detection in deadly malignancies, further evaluation of this test is justified in prospective population-level studies.

Efficacy of post-operative radiation in a prostatectomy cohort adjusted for clinical and genomic risk.

BACKGROUND: To date, there have been no published trials examining the impact of salvage radiation therapy (SRT) in the post-operative setting for prostate cancer (PCa). We conducted a retrospective, comparative study of post-operative radiation following radical prostatectomy (RP) for men with pT3 disease or positive margins (adverse pathological features, APF). METHODS: 422 PCa men treated at four institutions with RP and having APF were analyzed with a primary end point of metastasis. Adjuvant radiation treatment (ART, n=111), minimal residual disease (MRD) SRT (n=70) and SRT (n=83) were defined by PSA levels of <0.2, 0.2-0.49 and ⩾0.5 ng ml(-1), respectively, before radiation therapy (RT) initiation. Remaining 157 men who did not receive additional therapy before metastasis formed the no RT arm. Clinical-genomic risk was assessed by Cancer of the Prostate Risk Assessment Post-Surgical (CAPRA-S) and Decipher. Cox regression was used to evaluate the impact of treatment on outcome. RESULTS: During the study follow-up, 37 men developed metastasis with a median follow-up of 8 years. Both CAPRA-S and Decipher had independent predictive value on multivariable analysis for metastasis (P<0.05). Adjusting for clinical-genomic risk, SRT and no RT had hazard ratios of 4.31 (95% confidence interval, 1.20-15.47) and 5.42 (95% confidence interval, 1.59-18.44) for metastasis compared with ART, respectively. No significant difference was observed between MRD-SRT and ART (P=0.28). Men with low-to-intermediate CAPRA-S and low Decipher value have a low rate of metastatic events regardless of treatment selection. In contrast, men with high CAPRA-S and Decipher benefit from ART, however the cumulative incidence of metastasis remains high. CONCLUSIONS: The decision as to the timing and need for additional local therapy following RP is nuanced and requires providers and patients to balance risks of morbidity with improved oncological outcomes. Post-RP treatment can be safely avoided for men who are low risk by clinical-genomic risk, whereas those at high risk should favor enrollment in clinical trials.

Prostatectomy at high-volume centers improves outcomes and lowers the costs of care for prostate cancer.

BACKGROUND: High-volume surgeons with ⩾250 radical prostatectomies provide superior oncological outcomes as evidenced by a lower rate of PSA recurrence (PSAR). The financial benefits of performing prostatectomies at high-volume centers (HVC) are unexplored. METHODS: A base case--referent scenario--where the share of prostatectomies at high- and low-volume centers were evenly divided at 50% was defined. Additional scenarios with increasing shares of prostatectomies at HVC with 10% increments were also modeled. Using a lower probability of PSAR as the only advantage of more experienced surgeons, the savings that would result from fewer recurrences, avoidance of salvage radiation therapy (SRT) and management of fewer men with metastatic cancer were calculated. RESULTS: The savings associated with performing 80% of radical prostatectomy at HVC were $177, $357 and $559 per prostatectomy at 5, 10 and 20 years, respectively. These savings would offset referral costs of up to $1833 per prostatectomy referral at no additional total societal costs. Given the longer average biochemical failure-free survival with prostatectomies at HVC, referral costs of more than $1833 may be cost effective. CONCLUSIONS: Under the conservative assumption of accounting for lower rates of PSAR as the only benefit of surgery in an HVC, performing prostatectomies at an HVC was associated with savings that may offset part of the initial referral costs.

Novel biomarkers and genomic tests in prostate cancer: a critical analysis.

The aim of this review is to critically analyze the current state of research in selected biomarkers and genomic-based tests for prostate cancer (PCa) diagnosis, staging, prognostication, and monitoring. Although in Western societies, PCa is the most common solid malignancy and the second leading cause of cancer death in men, the vast majority of men with PCa are diagnosed with clinically localized disease. The widespread use of prostate-specific antigen (PSA) testing, on one hand, has resulted in earlier PCa detection at a potentially more curable stage, but on the other hand has led to an increase in the rate of negative biopsies, as well as overdetection and overtreatment of potentially indolent tumors that would not have become life-threatening to a patient. A multitude of molecular tests and algorithms has been developed to enhance diagnostic accuracy, improve pretreatment and post-treatment patient risk stratification, and identify aggressive versus indolent disease to facilitate therapeutic decision-making. PSA and derivatives (PSA kinetics, PSA density, percentage of free PSA) as well as algorithms based on PSA and PSA isoforms measurements (prostate health index, four-kallikrein score), urinary molecular biomarkers-based tests (Prostate Cancer Antigen 3, and the Michigan Health System Prostate Score) and selected genomic/proteomic tests now commercially available for disease prognostication (such as Confirm MDx, Prostate Core Mitomic Test, Oncotype DX, Prolaris, ProMark, and Decipher) are herein discussed to inform the readers about current and future clinical applications and their limitations. Finally, we briefly touch upon potential biomarkers predictive of response to therapy, such as androgen receptor splice variant AR-V7, and detection and quantification of circulating tumor cells in the blood stream.

High-throughput transcriptomic analysis nominates proteasomal genes as age-specific biomarkers and therapeutic targets in prostate cancer.

BACKGROUND: Although prostate cancer (PCa) is hypothesized to differ in nature between younger versus older patients, the underlying molecular distinctions are poorly understood. We hypothesized that high-throughput transcriptomic analysis would elucidate biological differences in PCas arising in younger versus older men, and would nominate potential age-specific biomarkers and therapeutic targets. METHODS: The high-density Affymetrix GeneChip platform, encompassing >1 million genomic loci, was utilized to assess gene expression in 1090 radical prostatectomy samples from patients with long-term follow-up. We identified genes associated with metastatic progression by 10 years post-treatment in younger (age<65) versus older (age⩾65) patients, and ranked these genes by their prognostic value. We performed Gene Set Enrichment Analysis (GSEA) to nominate biological concepts that demonstrated age-specific effects, and validated a target by treating with a clinically available drug in three PCa cell lines derived from younger men. RESULTS: Over 80% of the top 1000 prognostic genes in younger and older men were specific to that age group. GSEA nominated the proteasome pathway as the most differentially prognostic in younger versus older patients. High expression of proteasomal genes conferred worse prognosis in younger but not older men on univariate and multivariate analysis. Bortezomib, a Food and Drug Administration approved proteasome inhibitor, decreased proliferation in three PCa cell lines derived from younger patients. CONCLUSIONS: Our data show significant global differences in prognostic genes between older versus younger men. We nominate proteasomeal gene expression as an age-specific biomarker and potential therapeutic target specifically in younger men. Limitations of our study include clinical differences between cohorts, and increased comorbidities and lower survival in older patients. These intriguing findings suggest that current models of PCa biology do not adequately represent genetic heterogeneity of PCa related to age, and future clinical trials would benefit from stratification based on age.

A randomized controlled Alzheimer's disease prevention trial's evolution into an exposure trial: the PREADViSE Trial.

OBJECTIVES: To summarize the ongoing prevention of Alzheimer's disease (AD) by vitamin E and selenium (PREADViSE) trial as an ancillary study to SELECT (a large prostate cancer prevention trial) and to present the blinded results of the first year as an exposure study. DESIGN: PREADViSE was designed as a double blind randomized controlled trial (RCT). SETTING: SELECT terminated after median of 5.5 years of exposure to supplements due to a futility analysis. Both trials then converted into an exposure study. PARTICIPANTS: In the randomized component PREADViSE enrolled 7,547 men age 62 or older (60 if African American). Once the trial terminated 4,246 of these men volunteered for the exposure study. Demographics were similar for both groups with exposure volunteers having baseline mean age 67.3 ± 5.2 years, 15.3 ± 2.4 years of education, 9.8% African Americans, and 22.0% reporting a family history of dementia. INTERVENTION: In the RCT men were randomly assigned to either daily doses of 400 IU of vitamin E or placebo and 200 µg of selenium or placebo using a 2x2 factorial structure. MEASUREMENTS: In the RCT, participants completed the memory impairment screen (MIS), and if they failed, underwent a longer screening (based on an expanded Consortium to Establish a Registry in AD [CERAD] battery). CERAD failure resulted in visits to their clinician for medical examination with records of these examinations forwarded to the PREADViSE center for further review. In the exposure study, men are contacted by telephone and complete the telephone version of the memory impairment screen (MIS-T) screen. If they fail the MIS-T, a modified telephone interview of cognitive status (TICS-M) exam is given. A failed TICS-M exam also leads to a visit to their clinician for an in-depth examination and forwarding of records for a centralized consensus diagnosis by expert clinicians. A subgroup of the men who pass the MIS-T also take the TICS-M exam for validation purposes. RESULTS: While this ancillary trial was open to all 427 SELECT clinical sites, only 130 (30.0%) of the sites chose to participate in PREADViSE. Staff turnover at the sites presented challenges when training persons unfamiliar with cognitive testing procedures to conduct the memory screens. In the RCT few participants (1.6%) failed the MIS screen and among those who passed this screen a significant practice effect was encountered. In the exposure study 3,581 men were reached by phone in year 1, 15.7% could not be reached after 5 calls, and of those contacted 6.0% refused the screen even after consenting to the procedures at their clinical site. Most notable is that the failure rate for the MIS-T increased fourfold to 7.2%. Of the 257 men who took the TICS-M, 84.0% failed and were asked to contact their physicians for a more detailed memory assessment, and approximately half of these had some form of dementia or cognitive impairment. Several of these dementia cases are not AD. CONCLUSION: Partnering with SELECT led to an AD prevention trial conducted at a very reasonable cost by taking advantage of the experience and efficient clinical trial management found in a cancer cooperative group (Southwest Oncology Group or SWOG). Once unblinded, the RCT and exposure study data have the potential to yield new information on long term exposure to antioxidant supplements under controlled conditions.

A simple indentation device for measuring micrometer-scale tissue stiffness.

Mechanical properties of cells and extracellular matrices are critical determinants of function in contexts including oncogenic transformation, neuronal synapse formation, hepatic fibrosis and stem cell differentiation. The size and heterogeneity of biological specimens and the importance of measuring their mechanical properties under conditions that resemble their environments in vivo present a challenge for quantitative measurement. Centimeter-scale tissue samples can be measured by commercial instruments, whereas properties at the subcellular (nm) scale are accessible by atomic force microscopy, optical trapping, or magnetic bead microrheometry; however many tissues are heterogeneous on a length scale between micrometers and millimeters which is not accessible to most current instrumentation. The device described here combines two commercially available technologies, a micronewton resolution force probe and a micromanipulator for probing soft biological samples at sub-millimeter spatial resolution. Several applications of the device are described. These include the first measurement of the stiffness of an intact, isolated mouse glomerulus, quantification of the inner wall stiffness of healthy and diseased mouse aortas, and evaluation of the lateral heterogeneity in the stiffness of mouse mammary glands and rat livers with correlation of this heterogeneity with malignant or fibrotic pathology as evaluated by histology.

Phase II trial of neoadjuvant nab-paclitaxel in high risk patients with prostate cancer undergoing radical prostatectomy.

PURPOSE: Taxane based chemotherapy has activity in advanced prostate cancer but previous studies of neoadjuvant docetaxel demonstrated a prostate specific antigen response with no obvious antitumor activity. The efficacy and safety of neoadjuvant albumin-bound paclitaxel (nab-paclitaxel, Abraxane), a novel nanoparticle based formulation, were assessed in patients with high risk, locally advanced prostate cancer. MATERIALS AND METHODS: Eligible patients had locally advanced prostatic adenocarcinoma, clinical stage cT2b or greater, Gleason score 8 or greater, or serum prostate specific antigen 15 ng/ml or greater without metastatic disease. Patients received 2 cycles of 150 mg/m(2) nab-paclitaxel weekly for 3 weeks during each 4-week cycle, followed by radical prostatectomy with bilateral lymphadenectomy. Efficacy assessments included pathological and prostate specific antigen response. RESULTS: A total of 19 patients completed neoadjuvant therapy and 18 underwent radical prostatectomy. Median pretreatment prostate specific antigen was 8.5 ng/ml and median Gleason score was 8. Despite the lack of complete pathological responses 5 of 18 patients (28%) had organ confined disease and 9 of 18 (50%) had specimen confined disease. Post-chemotherapy prostate specific antigen was decreased in 18 of 19 (95%) patients and median decrease was 2.9 ng/ml (35%, p <0.001). An initial prostate specific antigen after radical prostatectomy of 0.02 ng/ml or less was achieved in 17 of 18 (94%) patients. There were no significant perioperative complications. Cytoplasmic vacuolization (focal in 10 and extensive in 7) was evident in all but 1 patient (94%). Ten patients (56%) had grade 3 and 1 had grade 4 neutropenia with no febrile neutropenia. CONCLUSIONS: Neoadjuvant nab-paclitaxel was well tolerated. Similar to our experience with neoadjuvant docetaxel there were no pathological complete responses, although a possible histological antitumor effect was observed.

Family caregiving in bipolar disorder: caregiver consequences, caregiver coping styles, and caregiver distress.

AIMS: This study investigated the consequences caregivers of outpatients with bipolar disorder are confronted with, the distress they experience and their coping styles. METHODS: Caregivers (n = 115) were asked to complete the Involvement Evaluation Questionnaire (IEQ) to measure caregivers' consequences, the Utrecht Coping List (UCL) to measure caregivers' coping styles, and the 12-item General Health Questionnaire (GHQ-12) to measure caregiver distress. Scale (sub)scores were calculated and relationships between the results were explored. RESULTS: Caregiver consequences were found to be limited, although approximately 30% reported distress. Male caregivers used a more avoiding coping style and undertook activities to provide diversion. Female caregivers used a less active approach and sought less social support. Correlations were found between the IEQ overall score and its subscales 'tension' and 'worrying' and the UCL subscales 'palliative reaction pattern' and 'passive reaction pattern'. Distress appears to occur more often in caregivers who report more consequences, tend to use a more avoiding coping style, and have a more passive reaction pattern. CONCLUSIONS: Clinicians should assess symptoms of caregiver distress. When caregiver distress is noticed, efforts should be undertaken to support the caregiver and teach them skills to cope effectively with the consequences they experience in order to stay well.

Self-reported care needs of outpatients with a bipolar disorder in the Netherlands.

The care needs of patients with a bipolar disorder have not been studied to date. In the present research, the care needs, care received and unmet care needs for a population of outpatients with a bipolar disorder in the Netherlands are described. The participants (n = 157) completed the Need for Care Questionnaire and a questionnaire addressing various demographic and clinical characteristics. The results show the care needs to mainly involve the domains of psychological help, psychiatric help and social functioning. Unmet needs are frequently reported for all domains and found to be particularly frequent for needs on social functioning. Some significant associations between source of income, number of hospitalizations and involvement of community psychiatric nurses, on the one hand, and reported care needs, on the other hand, are identified and discussed. Incorporation of needs assessment into the treatment process is recommended in the form of structured questionnaires which can also then be used to guide and evaluate the treatment process. Future research should focus on the identification of the specific risk factors for particular care needs and thereby work to minimize the occurrence of such risk factors and promote early intervention efforts to reduce the burden on patients and their relatives.

[Lamotrigine in the treatment of bipolar disorder, a review]. / Lamotrigine bij de behandeling van bipolaire stoornissen. Een overzicht.

BACKGROUND: Lamotrigine is being prescribed increasingly for the treatment of bipolar disorder. In this article we review the current literature on the subject. AIM: To review the literature in order to assess the present position of lamotrigine in the treatment of bipolar disorder. METHOD: We reviewed the literature from 1985 to 2005 by means of PubMed and we also consulted the bibliographic references for the articles we found. In addition, we studied a review article by Goldsmith e. a. (2003). RESULTS: Although a considerable amount of research has been done, evidence for the efficacy of lamotrigine is limited. Lamotrigine was not effective in the treatment of acute mania. In only one of three studies was lamotrigine effective in the treatment of acute depression. In two extensive maintenance studies lamotrigine was found to be effective in preventing new depression episodes; however, the latter studies have such serious methodological weaknesses that the results provide only very limited evidence that lamotrigine is beneficial. CONCLUSION: In the guideline for the treatment of bipolar depression published by the NVVP (the Dutch Psychiatric Association; 2001), lamotrigine was mentioned as a possible treatment option for bipolar disorder and rapid cycling. In view of the results of randomised controlled trials (RCTS) that have been published so far, there is at present no reason to alter the status of lamotrigine.

[Psychotherapeutic treatment options for bipolar disorders. A review of randomized controlled studies]. / Psychotherapeutische behandelmogelijkheden voor bipolaire stoornissen. Een overzicht van gerandomiseerde en gecontroleerde onderzoeken.

BACKGROUND: Until recently research into the efficacy of treatment of bipolar disorders focused mainly on the pharmacological treatment. Over the last few years more and more research has concentrated on the psychological treatments for bipolar disorders. aim To review published, controlled and randomised studies dealing with the efficacy of forms of psychotherapeutic treatment for bipolar disorders. METHOD: By searching Medline and Embase using the search terms, 'psychotherapy', 'cognitive (behavioural) therapy', 'family therapy' and 'psychoeducation' we found eight relevant reports of randomised, controlled trials, which described the interventions that were undertaken and recorded the relapse rates. RESULTS: The following forms of treatment were investigated: Relapse-Prevention Plan, Cognitive Behavioural Therapy, Interpersonal and Social Rhythm Therapy, Family-Focused Treatment and Group Psychoeducation. These forms of treatment were used in addition to standard pharmacological treatment. The addition of psychotherapeutic treatment was found to reduce lower the relapse rate, to lead to less hospitalisation and to improve functioning. CONCLUSION: The authors recommend that patients with bipolar disorders be offered psychotherapeutic treatment because it is likely to lower the risk of relapse.

[Bipolar disorder and pregnancy; experiences from the practice]. / Bipolaire stoornis en zwangerschap: ervaringen uit de praktijk.

Patients with bipolar disorder who become pregnant may develop an episode during their pregnancy, but an episode is much more likely to occur during the postpartum period. Three case histories show the kinds of problems that can arise. Risk factors are mentioned and advice is given about the best ways of preventing such problems.

Periprostatic local anesthesia eliminates pain of office-based transrectal prostate biopsy.

Up to 96% of patient who undergo prostate biopsy report pain. We performed periprostatic local anesthesia injection in an effort to improve patient acceptance of prostate biopsy. Sixty patients were randomized to receive either local injection of lidocaine in the periprostatic nerves or no anesthetic. Lidocaine was injected through a 7-inch spinal needle placed through a transrectal ultrasound biopsy guide. Ten-core biopsies were immediately performed. Following biopsy, all patients gave a Visual Analog Scale (VAS) assessment of their pain experienced during biopsy.A majority of patients reported Visual Analog Scale (VAS) scores in the moderate (28.6%) or severe (28.6%) ranges unless local anesthesia was given. Only one of 27 patients (3.7%) receiving local anesthetic reported moderate pain, and none reported severe pain. Mean VAS pain scores were 1.4 in the anesthetic group and 4.5 in the control group (P<0.0001). No difficulty was encountered from scarring in the five patients who underwent nerve spring radical retropubic prostatectomy following local anesthetic injection. Periprostatic injection of local anesthetic essentially eliminates pain from prostate biopsy. Nerve-sparing radical retropubic prostatectomy is not more difficult as a result.

Short-course intensity-modulated radiotherapy (70 GY at 2.5 GY per fraction) for localized prostate cancer: preliminary results on late toxicity and quality of life.

PURPOSE: To present our preliminary observations on the late toxicity and quality of life (QOL) of patients treated with short-course intensity-modulated radiotherapy (SCIM-RT). METHODS AND MATERIALS: Fifty-one patients were treated with SCIM-RT at the Cleveland Clinic Foundation between October 1998 and May 1999. The technique consisted of intensity-modulated radiotherapy using 5 static fields (anterior, 2 laterals, and 2 anterior obliques). Inverse plans were generated by the Corvus treatment-planning system. The treatment delivery was performed with a dynamic multileaf collimator. A total of 70.0 Gy was prescribed in all cases at 2.5 Gy per fraction to be delivered in 28 fractions over 5 and a half weeks. The location of the prostate gland was verified and adjusted daily with the BAT transabdominal ultrasound system. The median follow-up was 18 months (range: 11 to 26 months). The Radiation Therapy Oncology Group (RTOG) scales were used to evaluate late toxicity. The Expanded Prostate Cancer Index Composite (EPIC) was used to evaluate QOL. A total of 24 patients completed the EPIC questionnaire at approximately 2 years after therapy (median time from treatment to questionnaire administration: 24 months; range: 21 to 26 months). The results from the EPIC questionnaires were compared to scores from 46 patients treated during the same time period with conformal radiotherapy (CRT) to 78 Gy at 2 Gy per fraction. RESULTS: The dose was prescribed to an isodose line ranging from 82.0% to 90.0% (mean: 87.2%). The range of the individual prostate mean doses was 73.5 to 78.5 Gy (average: 75.3 Gy). To date, only 1 patient had Grade 1 late urinary toxicity. To date, only 4 patients had Grade 1 late rectal toxicity. No Grade 2 or 3 late urinary or rectal complications have occurred. The actuarial rectal bleeding rate observed at 18 months was 7%. There were no differences in scores from the urinary, bowel, hormonal, and overall QOL domains between SCIM-RT patients and patients treated with CRT. The overall physical and mental QOL scores were also nearly identical to scores reported for the general U.S. population. CONCLUSION: Preliminary late toxicity results up to 2 years after SCIM-RT are encouraging, with a median follow-up of 18 months (range 11 to 26 months). Late toxicity assessed by the physicians using RTOG late toxicity scores has been excellent. QOL reported by the patients using the EPIC questionnaire reveals no difference between patients treated with high-dose CRT at standard fractionation and patients treated with SCIM-RT. SCIM-RT is an alternative method of dose escalation in the treatment of localized prostate cancer. The proposed schedule significantly increases convenience to patients due to the decrease in overall treatment time.

Preliminary observations of single-agent docetaxel as neoadjuvant therapy for locally advanced prostate cancer.

Patients with locally advanced prostate cancer present a significant therapeutic dilemma. Despite aggressive local therapies, including radical prostatectomy (RP), these patients are at high risk for biochemical failure. Several research groups have recently demonstrated the feasibility of hormonal and chemohormonal therapy before RP, but limited published data are available regarding the usefulness of chemotherapy without hormonal therapy in the neoadjuvant setting. At Cleveland Clinic Foundation, a phase II trial was initiated to evaluate a 6-week course of docetaxel, 40 mg/m(2) intravenously every 7 days, followed by RP in patients with locally advanced prostate cancer. RP was to be performed within 3 weeks of completion of neoadjuvant chemotherapy. The primary endpoint of this study is pathologic complete response. Preliminary toxicity data suggest that weekly docetaxel is well tolerated and does not increase the risk of perioperative or post operative complications. Reductions in prostate-specific antigen levels were noted in seven of 10 patients who completed the 6-week course of neoadjuvant docetaxel. The neoadjuvant use of investigational cancer therapies may allow for relatively rapid assessment of their antitumor activity.

Molecular epidemiologic studies within the Selenium and Vitamin E Cancer Prevention Trial (SELECT).

OBJECTIVE: To conduct timely epidemiologic investigations of molecular/genetic markers that may contribute to the development of prostate, lung, colorectal, or other cancers within the Selenium and Vitamin E Cancer Prevention Trial (SELECT), and to evaluate interactions between these markers and the study interventions. METHODS: The epidemiologic studies within SELECT will be based on 32,400 men aged 55 years or older (age 50 or older for the African-American men) enrolled into an intergroup, randomized, placebo-controlled, double-blind, phase III prevention trial of supplemental selenium and vitamin E developed and funded by the National Cancer Institute, and coordinated by the Southwest Oncology Group. During the 12-year study period approximately 1500-2000 cases of prostate cancer, 800 lung cancers, and 500 colon cancers are estimated to be diagnosed, based on data from the ongoing Prostate Cancer Prevention Trial of finasteride. A modified fasting blood sample will be processed to collect plasma for analysis of micronutrients, hormones, cytokines, and other proteins. Buffy-coat derived white blood cells collected at baseline will be used for isolation of DNA and establishment of immortalized cell lines. Red blood cells will be stored for analysis of hemoglobin adducts and other components. RESULTS: Specific results anticipated from these molecular studies will provide information on factors hypothesized to contribute to prostate cancer risk and that may modify the efficacy of either trial supplement, including: steroid sex hormones and several polymorphic genes that encode proteins affecting androgenic stimulation of the prostate, including the androgen receptor, steroid 5alpha-reductase type II, CYP17, and beta-hydroxysteroid dehydrogenase; polymorphisms of DNA repair genes and carcinogen metabolism genes, including those involved in the activation of chemical carcinogens to reactive intermediates (e.g., CYP1A1) or the detoxification of reactive intermediates (e.g., glutathione S-transferase M1); DNA and protein adducts; and insulin-like growth factors and leptin. CONCLUSION: SELECT offers an excellent opportunity to conduct molecular epidemiologic investigations to assess gene-environment interactions and their role in prostate, lung, and colon carcinogenesis.