Salvage prostate brachytherapy in radiorecurrent prostate cancer: An international Delphi consensus study.

BACKGROUND AND PURPOSE: Local recurrences after previous radiotherapy (RT) are increasingly being identified in biochemically recurrent prostate cancer. Salvage prostate brachytherapy (BT) is an effective and well tolerated treatment option. We sought to generate international consensus statements on the use and preferred technical considerations for salvage prostate BT. MATERIALS AND METHODS: International experts in salvage prostate BT were invited (n = 34) to participate. A three-round modified Delphi technique was utilized, with questions focused on patient- and cancer-specific criteria, type and technique of BT, and follow-up. An a priori threshold for consensus of ≥ 75% was set, with a majority opinion being ≥ 50%. RESULTS: Thirty international experts agreed to participate. Consensus was achieved for 56% (18/32) of statements. Consensus was achieved in several areas of patient selection: 1) A minimum of 2-3 years from initial RT to salvage BT; 2) MRI and PSMA PET should be obtained; and 3) Both targeted and systematic biopsies should be performed. Several areas did not reach consensus: 1) Maximum T stage/PSA at time of salvage; 2) Utilization/duration of ADT; 3) Appropriateness of combining local salvage with SABR for oligometastatic disease and 4) Repeating a second course of salvage BT. A majority opinion preferred High Dose-Rate salvage BT, and indicated that both focal and whole gland techniques could be appropriate. There was no single preferred dose/fractionation. CONCLUSION: Areas of consensus within our Delphi study may serve as practical advice for salvage prostate BT. Future research in salvage BT should address areas of controversy identified in our study.

Management of high-risk and post-operative non-metastatic prostate cancer in Catalonia: an expert Delphi consensus.

BACKGROUND: To reach a consensus on recommendations for the management of high-risk and post-operative non-metastatic prostate cancer by a group of Radiation Oncologists in Catalonia dedicated to prostate cancer. METHODS: A modified Delphi approach was employed to reach consensus on controversial topics in Radiation Oncology on high-risk non-metastatic (eight questions) and post-operative (eight questions) prostate cancer. An agreement of at least 75% was considered as consensus. The survey was electronically sent 6 weeks before an expert meeting where topics were reviewed and discussed. A second-round survey for the controversial questions only was sent and answered by participants after the meeting. RESULTS: After the first round of the survey, 19 experienced Radiation Oncologists attended the meeting and 74% fulfilled the second-round online questionnaire. An agreement of 9 of the 16 questions was accounted for the first round. After the meeting, an additional agreement was reached in 3 questions leading to a final consensus on 12 of the 16 questions. There are still controversial topics like the use of PET for staging of high-risk and post-operative non-metastatic prostate cancer and the optimal dose to the prostate bed in the salvage setting. CONCLUSION: This consensus contributes to establish recommendations and a framework to help in prostate cancer radiation therapy and pharmacological management in daily clinical practice of high-risk and post-operative non-metastatic prostate cancer.

Treatment of non-metastatic castration-resistant prostate cancer: facing age-related comorbidities and drug-drug interactions.

INTRODUCTION: Patients with non-metastatic castration-resistant prostate cancer (nmCRPC) are frequently poly-medicated due to age-related and androgen deprivation therapy (ADT)-derived comorbidities. In high-risk patients, androgen receptor inhibitors (ARIs) have shown to delay disease progression; however, drug-drug interactions (DDIs) with preexisting medications may impact the therapeutic effect and safety of these and of the ARIs themselves. AREAS COVERED: We review the potential comorbidity burden of nmCRPC patients on the basis of epidemiologic studies on age-related comorbidities, the impact of ADT and specific studies analyzing this topic. Using the DDIs compendia Lexicomp® and Drugs.com®, we provide a scenario of the potential DDIs between common mediations used to treat these comorbidities and the three currently available ARIs: apalutamide, enzalutamide and darolutamide. EXPERT OPINION: In high-risk nmCRPC patients to be treated with an ARI, careful multidisciplinary evaluation of potential DDIs is a fundamental component in the clinical-decision making. The lower potential for DDIs, the lower need for dose adjustment or change of current comedications and of patient monitoring, and safer introduction of new comedications. To optimize this step, an effort is still needed to determine the clinical relevance of DDIs and to harmonize their definition and classification among the different compendia.

Prostate cancer is one of the most common cancers in men. It is normally diagnosed at age 60 or above, so these men are usually taking medications to treat age-related conditions (e.g. hypertension, diabetes, high cholesterol, etc.).One of the main treatments for prostate cancer is 'androgen deprivation therapy' (ADT), a hormone treatment that reduces androgens level. This is because the growth of prostate cancer cells is dependent on male sex hormones called androgens. Despite ADT helping keep the cancer controlled for a time, it increases the risk for adverse events that may need new medications. Consequently, men with prostate cancer usually take multiple medications.After some years, ADT may not be enough to control the prostate cancer. A type of medication called 'androgen receptor inhibitors' (ARIs), which prevent the androgen entering the cell, are helpful at this stage, especially the second-generation ones: apalutamide, enzalutamide, and darolutamide. The problem is that these ARIs usually interact with other medications already taken by patients, an effect called 'drug­drug interaction.' When this happens, the ARI (the interaction 'perpetrator') may modify the effectiveness of other medications (the 'victims') and/or cause unexpected effects. Consequently, the conditions being treated by these medications may not be properly controlled, which may pose a risk to the patient's health. Thus, when starting treatment with a second-generation ARI, it is crucial to consider all possible interactions with the medications taken. The fewer potential interactions the ARI has, the easier it is to properly control other common conditions in prostate cancer patients.

Current and Emerging Therapies for Metastatic Castration-Resistant Prostate Cancer (mCRPC).

Metastatic castration-resistant prostate cancer (mCRPC) encompasses a heterogeneous wide range of molecular tumor behavior and a high risk of progression. Early detection and treatment are therefore crucial in these patients. Treatment has improved drastically in recent years and many novel therapeutic agents are currently under investigation. However, due to the rapidly changing therapeutic landscape in mCRPC, it is difficult for clinicians to keep up to date with the latest innovations in this area. In the present narrative review, we discuss the current and emerging therapies for mCRPC as well as the clinical and molecular factors that can help predict which patients are most likely to benefit from these novel agents.

Nonmetastatic castration-resistant prostate cancer: Novel agents to treat a lethal disease.

Nonmetastatic castration-resistant prostate cancer (nmCRPC) - defined as prostate-specific antigen (PSA) > 2 ng/mL, testosterone castration levels < 1.7 nm/L, and the absence of metastatic lesions on conventional imaging (computed tomography or bone scan) - has been defined as a lethal disease by the Prostate Cancer Work Group. One-third of patients with prostate cancer who receive androgen deprivation therapy for biochemical recurrence after local treatment will develop CRPC, with death occurring an average of 2.5 years after diagnosis of castration resistance. Most patients diagnosed with nmCRPC are asymptomatic or minimally symptomatic at diagnosis due to local treatment. In patients with short PSA doubling times (< 10 mo) and high baseline PSA levels, there is a high risk of bone metastases followed by prostate cancer-related mortality. These patients also present significant morbidity that negatively impacts quality of life (QoL). Recently, the results of three randomized trials (PROSPER, SPARTAN, and ARAMIS) were published. Those trials evaluated the efficacy of three different androgen receptor inhibitors - enzalutamide, apalutamide, and darolutamide - in patients with nmCRPC. In all three trials, the study drugs improved both metastasis-free survival and overall survival compared to placebo, plus on-going androgen deprivation therapy without a negative impact on QoL. In patients with nmCRPC, the most important clinical objective is early detection and treatment to maintain a low tumor burden and to prolong the symptom-free interval. For patients with nmCRPC, these novel drugs offer new hope for better QoL and survival outcomes.

Clinical Applications of Molecular Biomarkers in Prostate Cancer.

There is clinically relevant molecular heterogeneity in prostate cancer (PCa), but this biological diversity has had only a minimal impact on clinical practice. Treatment outcomes in patients with localised PCa are often highly variable, even among patients stratified to the same risk group or disease state based on standard clinical and pathological parameters. In recent years, the development of gene panels has provided valuable data on the differential expression of genes in patients with PCa. Nevertheless, there is an urgent need to identify and validate prognostic and predictive biomarkers that can be applied across clinical scenarios, ranging from localised disease to metastatic castration-resistant PCa. The availability of such tools would allow for precision medicine to finally reach PCa patients. In this review, we evaluate current data on molecular biomarkers for PCa, with an emphasis on the biomarkers and gene panels with the most robust evidence to support their application in routine clinical practice.

Bevacizumab and temozolomide versus temozolomide alone as neoadjuvant treatment in unresected glioblastoma: the GENOM 009 randomized phase II trial.

We sought to determine the impact of bevacizumab on reduction of tumor size prior to chemoradiotherapy in unresected glioblastoma patients. Patients were randomized 1:1 to receive temozolomide (TMZ arm) or temozolomide plus bevacizumab (TMZ + BEV arm). In both arms, neoadjuvant treatment was temozolomide (85 mg/m(2), days 1-21, two 28-day cycles), concurrent radiation plus temozolomide, and six cycles of adjuvant temozolomide. In the TMZ + BEV arm, bevacizumab (10 mg/kg) was added on days 1 and 15 of each neoadjuvant cycle and on days 1, 15 and 30 of concurrent treatment. The primary endpoint was investigator-assessed response to neoadjuvant treatment. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and the impact on outcome of MGMT methylation in tumor and serum. One hundred and two patients were included; 43 in the TMZ arm and 44 in the TMZ + BEV arm were evaluable for response. Results favored the TMZ + BEV arm in terms of objective response (3 [6.7 %] vs. 11 [22.9 %]; odds ratio 4.2; P = 0.04). PFS and OS were longer in the TMZ + BEV arm, though the difference did not reach statistical significance. MGMT methylation in tumor, but not in serum, was associated with outcome. More patients experienced toxicities in the TMZ + BEV than in the TMZ arm (P = 0.06). The combination of bevacizumab plus temozolomide is more active than temozolomide alone and may well confer benefit in terms of tumor shrinkage in unresected patients albeit at the expense of greater toxicity.

Hypofractionated high-dose-rate plesiotherapy in nonmelanoma skin cancer treatment.

PURPOSE: Nonmelanoma skin cancer (NMSC) is the commonest cancer in humans. NMSC treatment currently includes surgery, radiation therapy, and topical approaches. The objective was to analyze and compare the outcomes, toxicity, and cosmesis of NMSC treated by two hypofractionated high-dose-rate (HDR) plesiotherapy techniques. METHODS AND MATERIALS: A retrospective institutional clinical study of 134 basal cell or squamous cell skin carcinomas treated at Radiation Oncology Department. Lesions were treated from November 2006 to December 2011 with a moderate hypofractionated HDR plesiotherapy using a fixed applicator or a customized mold. RESULTS: After a median follow-up of 33 months, overall disease-free survival at 3 and 5 years was 95.12% and 93.36%, respectively. For Leipzig applicator, disease-free survival at 3 years was 94.9% and 94.9% at 5 years, for customized mold was 93.1% at 3 years and 88% at 5 years. Complete regression was achieved in 98% of lesions. Two lesions persisted after treatment; both had been treated by a Leipzig applicator. Six lesions suffered local recurrence (five Leipzig applicators and three molds, p = 0.404). Grade <2 acute toxicity noted in 57.3% of patients. Only 2.2% of lesions had Grade 4 acute toxicity. Borderline significant increase of toxicity was associated with customized molds (p = 0.067). Larger tumors were associated with higher acute skin toxicity. The cosmesis outcomes were excellent or good in 82% of patients, fair in 13%, and not available in 5%. CONCLUSIONS: Hypofractionated HDR plesiotherapy is an effective and well-tolerated treatment for NMSC with different toxicity levels depending on the plesiotherapy technique used.

Three linked nomograms for predicting biochemical failure in prostate cancer treated with radiotherapy plus androgen deprivation therapy.

BACKGROUND: Nomograms were established to predict biochemical recurrence (BCR) after radiotherapy (RT) with a low weight of the characteristic variables of RT and androgen deprivation therapy (ADT). Our aim is to provide a new stratified tool for predicting BCR at 4 and 7 years in patients treated using RT with radical intent. MATERIALS AND METHODS: A retrospective, nonrandomized analysis was performed on 5044 prostate cancer (PCa) patients with median age 70 years, who received RT-with or without ADT-between November 1992 and May 2007. Median follow-up was 5.5 years. BCR was defined as a rise in serum prostate-specific antigen (PSA) of 2 ng/ml over the post-treatment PSA nadir. Univariate association between predictor variables and BCR was assessed by the log-rank test, and three linked nomograms were created for multivariate prognosis of BCR-free survival. Each nomogram corresponds to a category of the Gleason score-either 6,7, or 8-10-and all of them were created from a single proportional hazards regression model stratified also by months of ADT (0, 1-6, 7-12, 13-24, 25-36, 36-60). The performance of this model was analyzed by calibration, discrimination, and clinical utility. RESULTS: Initial PSA, clinical stage, and RT dose were significant variables (p < 0.01). The model showed a good calibration. The concordance probability was 0.779, improving those obtained with other nomograms (0.587, 0.571, 0.554) in the database. Survival curves showed best clinical utility in a comparison with National Comprehensive Cancer Network (NCCN) risk groups. CONCLUSION: For each Gleason score category, the nomogram provides information on the benefit of adding ADT to a specific RT dose.

Quality assurance in radiotherapy: analysis of the causes of not starting or early radiotherapy withdrawal.

BACKGROUND: The aim of this study was to analyse the reasons for not starting or for early of radiotherapy at the Radiation Oncology Department. METHODS: All radiotherapy treatments from March 2010 to February 2012 were included. Early withdrawals from treatment those that never started recorded. Clinical, demographic and dosimetric variables were also noted. RESULTS: From a total of 3250 patients treated and reviewed, 121 (4%) did not start or complete the planned treatment. Of those, 63 (52%) did not receive any radiotherapy fraction and 58 (48%) did not complete the course, 74% were male and 26% were female. The mean age was 67 ± 13 years. The most common primary tumour was lung (28%), followed by rectum (16%). The aim of treatment was 62% radical and 38% palliative, 44% of patients had metastases; the most common metastatic site was bone, followed by brain. In 38% of cases (46 patients) radiotherapy was administered concomitantly with chemotherapy (10 cases (22%) were rectal cancers). The most common reason for not beginning or for early withdrawal of treatment was clinical progression (58/121, 48%). Of those, 43% died (52/121), 35 of them because of the progression of the disease and 17 from other causes. Incomplete treatment regimens were due to toxicity (12/121 (10%), of which 10 patients underwent concomitant chemotherapy for rectal cancer). CONCLUSIONS: The number of patients who did not complete their course of treatment is low, which shows good judgement in indications and patient selection. The most common reason for incomplete treatments was clinical progression. Rectal cancer treated with concomitant chemotherapy was the most frequent reason of the interruption of radiotherapy for toxicity.

Salvage brachytherapy in prostate local recurrence after radiation therapy: predicting factors for control and toxicity.

PURPOSE: To evaluate efficacy and toxicity after salvage brachytherapy (BT) in prostate local recurrence after radiation therapy. METHODS AND MATERIALS: Between 1993 and 2007, we retrospectively analyzed 56 consecutively patients (pts) undergoing salvage brachytherapy. After local biopsy-proven recurrence, pts received 145 Gy LDR-BT (37 pts, 66%) or HDR-BT (19 pts, 34%) in different dose levels according to biological equivalent doses (BED(2 Gy)). By the time of salvage BT, only 15 pts (27%) received ADT. Univariate and multivariate analyses were performed to identify predictors of biochemical control and toxicities. Acute and late genitourinary (GU) and gastrointestinal (GI) toxicities were graded using Common Terminology Criteria for Adverse Events (CTCv3.0). RESULTS: Median follow-up after salvage BT was 48 months. The 5-year FFbF was 77%. HDR and LDR late grade 3 GU toxicities were observed in 21% and 24%. Late grade 3 GI toxicities were observed in 2% (HDR) and 2.7% (LDR). On univariate analysis, pre-salvage prostate-specific antigen (PSA) > 10 ng/ml (p = 0.004), interval to relapse after initial treatment < 24 months (p = 0.004) and salvage HDR-BT doses BED(2 Gy) level < 227 Gy (p = 0.012) were significant in predicting biochemical failure. On Cox multivariate analysis, pre-salvage PSA, and time to relapse were significant in predicting biochemical failure. HDR-BT BED(2 Gy) (α/ß 1.5 Gy) levels ≥ 227 (p = 0.013), and ADT (p = 0.049) were significant in predicting grade ≥ 2 urinary toxicity. CONCLUSIONS: Prostate BT is an effective salvage modality in some selected prostate local recurrence patients after radiation therapy. Even, we provide some potential predictors of biochemical control and toxicity for prostate salvage BT, further investigation is recommended.

Patterns of care and outcome for patients with glioblastoma diagnosed during 2008-2010 in Spain.

BACKGROUND: To assess management patterns and outcome in patients with glioblastoma multiforme (GBM) treated during 2008-2010 in Spain. METHODS: Retrospective analysis of clinical, therapeutic, and survival data collected through filled questionnaires from patients with histologically confirmed GBM diagnosed in 19 Spanish hospitals. RESULTS: We identified 834 patients (23% aged >70 years). Surgical resection was achieved in 66% of patients, although the extent of surgery was confirmed by postoperative MRI in only 41%. There were major postoperative complications in 14% of patients, and age was the only independent predictor (Odds ratio [OR], 1.03; 95% confidence interval [CI],1.01-1.05; P = .006). After surgery, 57% received radiotherapy (RT) with concomitant and adjuvant temozolomide, 21% received other regimens, and 22% were not further treated. In patients treated with surgical resection, RT, and chemotherapy (n = 396), initiation of RT ≤42 days was associated with longer progression-free survival (hazard ratio [HR], 0.8; 95% CI, 0.64-0.99; P = .042) but not with overall survival (HR, 0.79; 95% CI, 0.62-1.00; P = .055). Only 32% of patients older than 70 years received RT with concomitant and adjuvant temozolomide. The median survival in this group was 10.8 months (95% CI, 6.8-14.9 months), compared with 17.0 months (95% CI, 15.5-18.4 months; P = .034) among younger patients with GBM treated with the same regimen. CONCLUSIONS: In a community setting, 57% of all patients with GBM and only 32% of older patients received RT with concomitant and adjuvant temozolomide. In patients with surgical resection who were eligible for chemoradiation, initiation of RT ≤42 days was associated with better progression-free survival.

Exeresis and brachytherapy as salvage treatment for local recurrence after conservative treatment for breast cancer: results of a ten-year pilot study.

PURPOSE: To analyze the long-term results of a pilot study assessing excision and brachytherapy as salvage treatment for local recurrence after conservative treatment of breast cancer. METHODS AND MATERIALS: Between December 1990 and March 2001, 36 patients with breast-only recurrence less than 3 cm in diameter after conservative treatment for Stage I or II breast carcinoma were treated with local excision followed by high-dose rate brachytherapy implants (30 Gy in 12 fractions over a period of 5 days). No patient was lost to follow-up. Special attention was paid to local, regional, or distant recurrences; survival; cosmesis; and early and late side effects. RESULTS: All patients completed treatment. During follow-up (range, 1-13 years), 8 patients presented metastases (2 regional and 6 distant) as their first site of failure, 1 had a differed local recurrence, and 1 died of the disease. Actuarial results at 10 years were as follows: local control, 89.4%; disease-free survival, 64.4%; and survival, 96.7%. Cosmetic results were satisfactory in 90.4%. No patient had Grade 3 or 4 early or late complications. Of the 11 patients followed up for at least 10 years, all but 1 still had their breast in place at the 10-year stage. CONCLUSIONS: High-dose rate brachytherapy is a safe, effective treatment for small-size, low-risk local recurrence after local excision in conservatively treated patients. The dose of 30 Gy of high-dose rate brachytherapy (12 fractions over a period of 5 days twice daily) was well tolerated. The excellent results support the use of breast preservation as salvage treatment in selected patients with local recurrence after conservative treatment for breast cancer.

Cosmetic outcome of breast conservative treatment for early stage breast cancer

Purpose. To evaluate the cosmetic outcome of breastconservative therapy and to examine the degree ofagreement between the patients’ and oncologists’ratings. We also analyze the influence of severalfactors on cosmesis.Methods and materials.We retrospectively evaluated145 patients with primary breast cancer treatedby local excision and radiotherapy between January2000 and May 2001. Cosmetic outcome wasevaluated by doctors and patients and was scoredas excellent, good, fair or poor.Results. 73% of patients rated cosmesis as excellentor good while the percentage was 71% when ratedby radiation oncologists. The degree of cosmesisconcordance evaluated by oncologists and patientswas low (kappa = 0.3). In our study the variableswhich significantly influence on the cosmetic outcomewere concomitant adjuvant chemotherapy(p = 0.04) and radiation therapy boost, either byelectron beam or brachytherapy (p = 0.013).Conclusion. The cosmetic outcome of breast conservingtherapy was good. There was a similar ratingby the patient and radiation oncologist, but thelevel of concordance between patients and doctorswas low. Factors that significantly influence thecosmesis appear to be concomitant adjuvant chemotherapyand radiation therapy boost

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