Treatment Failure-free Survival Research Articles

Phase Ib/II study combining tosedostat with capecitabine in patients with advanced pancreatic adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with limited therapeutic options. We evaluated the safety and efficacy of the aminopeptidase inhibitor tosedostat with capecitabine in advanced PDAC. We conducted a phase Ib/II trial of tosedostat with capecitabine as second-line therapy for advanced PDAC. Planned enrollment was 36 patients. Eligible patients were treated with capecitabine 1,000 mg/m2 oral twice-daily days 1-14 and oral tosedostat in a dose de-escalation design on days 1-21 of each 21-day cycle. Primary endpoints were the recommended phase 2 dose (RP2D) and progression-free survival (PFS). Sixteen patients were enrolled. Tosedostat 120 mg oral twice daily with capecitabine 1,000 mg/m2 oral twice daily was the RP2D. There was one dose-limiting toxicity (DLT) (grade 3 acute coronary syndrome) during phase Ib. The most common treatment-related adverse events were gastrointestinal (nausea, diarrhea), cardiac [QTc prolongation, decreased ejection fraction (EF)], and fatigue. The median PFS was 7.1 months, and the median treatment failure free survival was 3 months. Eight patients experienced stable disease for greater than 3 months. The study was closed early due to lack of drug availability. Tosedostat with capecitabine displayed tolerable toxicity, and prolonged disease control in a subset of patients. These data encourage further exploration of aminopeptidase inhibitors in pancreatic cancer.

Hemigland Cryoablation of Localized Low, Intermediate and High Risk Prostate Cancer: Oncologic and Functional Outcomes at 5 Years.

We evaluated 5-year oncologic and functional outcomes of hemigland cryoablation of localized prostate cancer. We reviewed the records of 160 consecutive men who underwent hemigland cryoablation of localized prostate cancer. Recurrent and/or residual clinically significant prostate cancer was defined as Grade Group 2 or greater on followup biopsy. A prostate specific antigen nadir plus 2 ng/ml according to the Phoenix criteria was used to define biochemical failure. Radical treatment was defined as any whole gland therapy. Treatment failure was defined as any radical and/or whole gland treatment, systemic therapy initiation, metastasis or prostate cancer specific mortality. The study primary end point was treatment failure-free survival. The secondary end points were survival free of biochemical failure, clinically significant prostate cancer and radical treatment. Followup biopsy and functional outcomes were also evaluated. Statistical analysis included the Kaplan-Meier method, and univariate and multivariable Cox and logistic regression with significance considered at p <0.05. Median patient age was 67 years, baseline prostate specific antigen was 6.3 ng/ml and followup was 40 months. A total of 131 patients (82%) had D'Amico intermediate (66%) or high risk (16%) prostate cancer. At 5 years the treatment failure-free survival rate was 85%, the biochemical failure-free survival rate was 62% and the survival rate free of clinically significant prostate cancer was 89%. Higher baseline prostate specific antigen independently predicted treatment failure (p <0.001), biochemical failure (p=0.048), recurrence and radical treatment (p <0.01). Grade Group 3 or greater independently predicted treatment failure (p=0.04). The metastasis-free survival rate was 100% at 5 years. Pad-free continence and potency (erections sufficient for intercourse) were retained in 97% and 73% of patients, respectively. There was no rectal fistula or mortality. Hemigland cryoablation of localized prostate cancer provides effective midterm oncologic outcomes with good continence and potency. Patients with higher baseline prostate specific antigen are at increased risk for biochemical failure, recurrent cancer and treatment failure.

Salvage high-intensity focused ultrasound for locally recurrent prostate cancer after low-dose-rate brachytherapy: oncological and functional outcomes.

To evaluate the oncological and functional outcomes of salvage high-intensity focused ultrasound (S-HIFU) for locally recurrent prostate cancer after low-dose-rate (LDR) brachytherapy. Clinical phase II studies (2003-2015) included 50 consecutive patients with post-brachytherapy local recurrence treated by S-HIFU. S-HIFU was performed with post-external beam radiotherapy (EBRT) parameters and, since 2008, with specific post-brachytherapy parameters. Treatments were whole-gland ablation and, since 2009, hemi-ablation in cases of unilateral prostate cancer. The primary objective was to assess oncological outcomes: treatment failure-free survival, progression-free survival (PFS), overall survival (OS), cancer-specific survival (CSS), and metastasis-free survival (MFS) rates. The secondary objective was to evaluate adverse events, continence, and erectile function. Kaplan-Meier analysis estimated oncological outcomes. In all, 13 patients were treated with post-EBRT parameters, 37 with post-brachytherapy parameters, 35 with whole-gland treatment, and 15 with hemi-ablation. The median follow-up was 4.6years. After S-HIFU, the median prostate-specific antigen level was 0.3ng/mL. At 6years, treatment failure-free survival, PFS, OS, CSS, and MFS rates were 41%, 45%, 93%, 98%, and 80%, respectively. Post-brachytherapy compared with post-EBRT parameters reduced Grade 2-3 incontinence (34% vs 62%, P=0.015). Incontinence, bladder outlet obstruction and Grade ≥III complications were significantly reduced with hemi-ablation compared with whole-gland treatment (14% vs 54%, P<0.001; 13% vs 46%, P=0.03; 13% vs 63%, P=0.001; respectively). Before S-HIFU, 25 patients had a five-item version of the International Index of Erectile Function score of ≥17, which was maintained in 48% at 12months. S-HIFU for locally recurrent prostate cancer after LDR brachytherapy is associated with favourable survival rates at a price of significant morbidity. Dedicated post-brachytherapy parameters and hemi-ablation improve the safety of the treatment.

Association of Missense Polymorphism in HSD3B1 With Outcomes Among Men With Prostate Cancer Treated With Androgen-Deprivation Therapy or Abiraterone

Recently, genetic polymorphism in HSD3B1 encoding 3β-hydroxysteroid dehydrogenase-1 has been shown to be associated with oncological outcome when treated with androgen-deprivation therapy (ADT) for prostate cancer. Upfront abiraterone combined with ADT has proved survival benefit. However, its effect on oncological outcome among different ethnicities and in abiraterone treatment remain unclear. To investigate the significance of missense polymorphism in HSD3B1 gene among men treated with primary ADT or abiraterone. This prognostic study included Japanese patients with metastatic hormone-sensitive prostate cancer between June 1993 and July 2005 and with castration-resistant prostate cancer between September 2014 and February 2018. Genome DNA was obtained from patient whole blood samples, and genotyping on HSD3B1 (rs1047303, 1245C) was performed by Sanger sequencing. Primary ADT for metastatic hormone-sensitive prostate cancer and abiraterone for castration-resistant prostate cancer. The association of genotype in HSD3B1 with clinicopathological parameters and oncological outcome, including prostate-specific antigen response, progression-free survival, treatment failure-free survival, and overall survival was examined. Of 203 men, 104 were in the primary ADT cohort (median [interquartile range] age, 72 [67-76] years) and 99 men were in the abiraterone group (median [interquartile range] age, 74 [67-80] years). Most patients carried metastatic lesions in each cohort. Among the cohort of primary ADT, men carrying heterozygous and homozygous variant types in HSD3B1 gene showed higher progression risk (hazard ratio [HR], 2.34; 95% CI, 1.08-4.49; P = .03) but not any-caused death risk (HR, 1.36; 95% CI, 0.52-2.92; P = .50), compared with men carrying homozygous wild type. In contrast, among the abiraterone cohort, men carrying variant type in HSD3B1 gene showed lower progression risk (HR, 0.32; 95% CI, 0.12-0.69; P = .006) and lower all-cause mortality risk (HR, 0.40; 95% CI, 0.13-0.94; P = .04) compared with men carrying homozygous wild type. This study showed that HSD3B1 genetic variant is distinctly associated with oncological outcome between primary ADT and abiraterone in Japanese men, suggesting universal significance among different ethnicities in primary ADT, as well as promise as a predictive biomarker of ADT and abiraterone.

Spirit 2: Final 5 Year Analysis of the UK National Cancer Research Institute Randomized Study Comparing Imatinib with Dasatinib in Patients with Newly Diagnosed Chronic Phase CML

▪Objective. SPIRIT 2 is the largest phase 3 prospective randomized open-label trial comparing imatinib (I) 400mg with dasatinib (D) 100mg daily in newly diagnosed chronic phase CML. The primary endpoint was 5 year event-free survival. Methods. 812 (406 in each arm) of 814 patients recruited started study medication (median age 53.2, 275/812 (33.8%) were over 60 years old). Patients were recruited at 144 hospitals between August 2008 and March 2013 and randomized to receive either imatinib 400mg or dasatinib 100mg daily. Secondary endpoints included overall survival, rates of treatment failure, cytogenetic/molecular response - RT-PCR BCR-ABL/ABL ratio of <0.1%IS(major molecular response (MMR), 3 log reduction, MR3) and deeper. To address the potential confounding effect on the primary endpoint of patients switching from randomized treatment to an alternative TKI or other treatment, exploratory per-protocol analyses were performed using the inverse probability of censoring weighting (IPCW) method.Results. All patients have now completed 5 years of follow-up. 424/812 (52.2%) patients completed the study whilst still taking first line medication: 230/406 (56.7%) on dasatinib, 194/406 (47.8%) on imatinib. Of the patients who discontinued first line therapy, more patients on the imatinib arm switched due to suboptimal PCR response (as decided by the local investigator) than on dasatinib (D7/406, 1.7%; I71/406, 17.4%) but more patients on the dasatinib arm discontinued due to intolerance (D123/406, 30.3%; I68/406, 16.7%). More patients went on to transplant in the imatinib arm than in the dasatinib arm (D 6/406, 1.5%; I 30/406 7.6%) and in the imatinib patients undergoing transplant the reason for first line treatment failure was disease progression in 5/30 and suboptimal molecular response in 11/30. Using an intention to treat analysis cumulative incidence of MR3 and MR4 on first line therapy within 5 years was higher in the dasatinib arm than the imatinib arm (MR3: D 83.0%, I 63.0% - difference 20.0%, p<0.0001; MR4: D 77.5%, I 57.2% - difference 20.3%, p<0.0001).At 24 months the complete cytogenetic response rate was D 42.6%, I 31.8% - difference 10.8%, Chi-square test p=0.001.At 5 years the probability of treatment failure-free survival was higher with dasatinib than imatinib(D60.9%, I52.9% - HR: 0.73 (95%-CI:0.59-0.90), p=0.004) but there were no significant differences in event free survival (D91.0%, I89.0% - HR:0.80 (95%-CI:0.51-1.25), p=0.319) or overall survival (D91.9%, I91.2% - HR: 0.90 (95%-CI:0.56-1.47), p=0.690). IPCW modelling results will be presented at the meeting.The overall rate of pleural effusion over 5 years in the dasatinib arm was 36.0% with a higher incidence in older patients. 13 patients developed their first pleural effusion after 3 years on study. Conclusions. In SPIRIT 2 we observed a higher molecular and cytogenetic response rate and also a higher pleural effusion rate with dasatinib but a higher treatment failure rate with imatinib often because investigators were concerned about sub-optimal PCR responses. More imatinib-treated patients proceeded to transplant. There were no statistically significant differences in event free survival (the primary endpoint) or overall survival. Imatinib remains a highly effective first line therapy though subgroup analyses are planned to explore whether dasatinib may have advantages in particular clinical scenarios. DisclosuresO'Brien:Bristol Myers Squibb: Research Funding; CTI: Other: Chair of Independent Data Monitoring Committee; National Institute for Health and Care Excellence (NICE): Other: Chair of Technology Appraisal Committee. Osborne:Servier: Honoraria; Pfizer: Honoraria; Takeda: Honoraria; MSD: Honoraria; Roche: Honoraria; Novartis: Honoraria. Bell-Gorrod:Bristol-Myers Squibb: Consultancy; Merck EDM Serono: Consultancy; PharmaMar: Consultancy; Novartis: Consultancy; GlaxoSmithKline: Consultancy. Latimer:Pfizer: Consultancy; BMS: Consultancy; Merck: Consultancy; Astra Zeneca: Consultancy; Bluebirdbio: Consultancy; Janssen: Consultancy. Apperley:Incyte: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau. Byrne:Novartis: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau. Pocock:Kent & Canterbury Hospital: Employment. Copland:Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Clark:Ariad/Incyte: Consultancy; Pfizer: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy, Research Funding.

Focus on Internal Urethrotomy as Primary Treatment for Untreated Bulbar Urethral Strictures: Results from a Multivariable Analysis

BackgroundThe use of internal urethrotomy for treatment of urethral stricture remains a controversial topic in urology. ObjectiveTo investigate outcomes and predictors of failure for internal urethrotomy as primary treatment for untreated bulbar urethral strictures. Design, setting, and participantsWe performed a retrospective analysis of patients who underwent internal urethrotomy. Patients with bulbar urethral stricture who did not receive any previous treatment were included. Patients with traumatic, penile or posterior urethral strictures, lichen sclerosus, failed hypospadias repair, or stricture length >4cm were excluded. Outcome measurements and statistical analysisThe primary outcome was treatment failure. Kaplan-Meyer plots were used to depict treatment failure–free survival. Univariate and multivariable Cox regression analyses were used to test the association between predictors (age, body mass index, diabetes, history of smoking, etiology, stenosis type and length, preoperative maximum flow [pQmax]) and treatment failure. Results and limitationsOverall, 136 patients were included. The median stricture length was 2cm. Median follow-up was 55 mo. At 5-yr follow-up the failure-free survival rate was 57%. On univariate analysis, diabetes, nonidiopathic etiology, stricture length of 3–4cm, and pQmax were significantly associated with treatment failure. These predictors were included in a multivariable analysis, in which pQmax was the only significant predictor of treatment failure. ConclusionsFailure of internal urethrotomy for untreated bulbar urethral strictures greatly depends on pQmax flow at uroflowmetry. Patients with pQmax >8ml/s have a high probability of success, while patients with pQmax <5ml/s have a low probability of success. Patient summaryThe use of internal urethrotomy in patients with an untreated bulbar urethral stricture should only be considered in selected cases.

A randomized phase II study of pleurectomy/decortication preceded or followed by (neo-)adjuvant chemotherapy in patients with early stage malignant pleural mesothelioma (EORTC 1205).

Radical multimodality treatment for malignant pleural mesothelioma (MPM) is controversial, with intense debate (but lack of data) about which surgical procedure to perform [extrapleural pneumonectomy (EPP) or pleurectomy/decortication (PD)], if any. In order to perform a randomized comparison, the most optimal sequence of surgery and chemotherapy should be determined. EORTC 1205 is a clinical trial randomizing between upfront surgery, followed by chemotherapy (cisplatin plus pemetrexed) and deferred surgery, following neoadjuvant chemotherapy in early stage (T1-3 N0-2 M0) MPM (irrespective of histological subtype). The surgical procedure performed is (extended) pleurectomy/decortication (e-PD), which is promoted as an alternative for EPP, but lacks standardization. Primary outcome parameter is successful completion of multimodality treatment; secondary outcome parameters are surgical quality parameters (in order to standardize the procedure), progression free survival (PFS) and overall survival (OS), treatment-failure free survival, operative morbidity and mortality, toxicity and safety.

Ruxolitinib as Salvage Therapy for Chronic Graft-versus-Host Disease

Chronic graft-versus-host disease (cGVHD) continues to be a major complication after allogeneic hematopoietic cell transplantation, significantly affecting patients' quality of life. A regimen of systemic corticosteroids is considered first-line therapy but is often associated with inadequate responses and multiple side effects. In patients with refractory disease, an evidenced-based consensus is lacking as to the single best approach to managing symptoms. Ruxolitinib, a selective JAK1/2 inhibitor, has recently gained favor as a second-line approach in patients with steroid-refractory cGVHD. In this retrospective study, we evaluated the outcomes of 46 patients who received ruxolitinib for cGVHD between March 2016 and December 2017 at our institution, and evaluated ruxolitinib's impact at 6 and 12 months, based on the National Institutes of Health Severity Scale, including organ-specific responses, and mean prednisone dose. Furthermore, we present the first reported probability of ruxolitinib's treatment failure-free survival (FFS) in patients with cGVHD. After 12 months of ruxolitinib therapy, complete response, partial response, and stable disease was observed in 13% (n = 6), 30.4% (n = 14), and 10.9% (n = 5) of patients, respectively. The 1-year probability of FFS was 54.2% (95% confidence interval, .388 to .673), and ruxolitinib use was associated with a reduction in prednisone dose. In conclusion, our data, which represent the largest cohort of patients with cGVHD reported to date, support the use of ruxolitinib for cGVHD refractory to steroids and currently available salvage therapies, discontinued due to lack of response and high cost.

Validation of the ezrin, CK20, and Ki-67 as potential predictive markers for BCG instillation therapy of non–muscle-invasive bladder cancer

ObjectiveThe aim of our study was to try to validate 3 promising predictive biomarkers in a database based on prospective trials comparing bacillus Calmette-Guerin (BCG) with mitomycin-C and a combination of epirubicin and interferon, respectively. BackgroundThe most common form of bladder cancer is non–muscle-invasive tumors treated initially with transurethral resection. Unfortunately more than half recur and some also progress. Consequently, an attempt to prevent poor outcome is frequently made by intravesical instillations either by chemo- or immunotherapy. The response to such treatment is unpredictable, which is why markers predicting outcome would be valuable. Patients and methodsImmunohistochemical expression of ezrin, CK20, and Ki-67 was evaluated in a tumor tissue microarray based on 2 nordic multicenter trials comparing treatment with BCG vs. other intravesical adjuvant therapies. Kaplan-Meier analysis, log-rank test, and Cox regression were used to evaluate the effect of the biomarkers on recurrence-, progression-, and treatment failure-free survival. ResultsOf the 294 available patients immunoreactivity could be assessed in 285 patients for ezrin (97%), 285 patients for CK20 (97%), and 294 patient׳s for Ki-67 (100%). The 3 biomarkers did not predict time to any of the endpoints. Multifocality was the only predictive factor for time to recurrence (P = 0.029) and progression (P = 0.031). Ezrin was, however, predictive for treatment failure (P = 0.029) in a subgroup (BCG treated in one of the trials). In a multivariate analysis among BCG treated, none of the variables correlated to recurrence and only multifocality correlated to progression. Limitations in our study are the retrospective design and those inherent to immunohistochemistry. ConclusionsThe negative results from this validation study question the ability of the tested biomarkers to predict therapy effect.

PD60-04 PREDICTIVE FACTORS OF SUCCESS IN ADULT PATIENTS TREATED FOR URETHRAL STRICTURE AFTER PRIMARY HYPOSPADIAS REPAIR FAILURE: A MULTIVARIABLE ANALYSIS OF A SINGLE-SURGEON SERIES

You have accessJournal of UrologyTrauma/Reconstruction/Diversion: Urethral Reconstruction (including Stricture, Diverticulum) IV1 Apr 2017PD60-04 PREDICTIVE FACTORS OF SUCCESS IN ADULT PATIENTS TREATED FOR URETHRAL STRICTURE AFTER PRIMARY HYPOSPADIAS REPAIR FAILURE: A MULTIVARIABLE ANALYSIS OF A SINGLE-SURGEON SERIES Guido Barbagli, Nicola Fossati, Alessandro Larcher, Francesco Montorsi, Salvatore Sansalone, Denis Butnaru, and Massimo Lazzeri Guido BarbagliGuido Barbagli More articles by this author , Nicola FossatiNicola Fossati More articles by this author , Alessandro LarcherAlessandro Larcher More articles by this author , Francesco MontorsiFrancesco Montorsi More articles by this author , Salvatore SansaloneSalvatore Sansalone More articles by this author , Denis ButnaruDenis Butnaru More articles by this author , and Massimo LazzeriMassimo Lazzeri More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2017.02.2750AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES The repair of urethral strictures after hypospadias repair still represent a challenging problem. Although the number of surgeries for the correction of primary hypospadias may represent a risk factor for surgical failure, no evidence for this currently exists in the current literature. Therefore, we investigated the predictive factors of success in adult patients treated for urethral stricture after primary hypospadias repair failure. METHODS The study was an observational, retrospective, descriptive study of adults with urethral strictures following hypospadias surgery. We included only patients with complete clinical data regarding the type of primary hypospadias, the number of operations needed for repair and the surgeon who performed the repair. The primary outcome of the study was treatment failure, defined as the need for any post-operative instrumentation. Secondary outcomes consisted of the relationships between the site of hypospadias, the site of the stricture and patient demotivation, defined as patient refusal of further treatments. Statistical analyses were performed using Stata (StataCorp LP, College Station, TX, USA) version 12.0. Tests were two-sided with a significance level set at p<0.05. RESULTS Overall, 408 patients were included in the study. The most frequent type of primary hypospadias was penile (56%), whereas the most frequent site of secondary stricture was penile (49%). A concordance between the site of primary hypospadias and the site of the secondary stricture was observed. A Kaplan Meier analysis revealed that two-stage techniques were significantly associated with lower treatment failure-free survival compared to one-stage techniques (p=0.001). At multivariable analysis, the number of previous operations needed for initial hypospadias repair was not associated with the risk of treatment failure (hazard ratio 0.95; 95% Confidence Interval: 0.88 - 1.03; p=0.2). Conversely, length of stenosis, with a cut-off of 3 cm (HR 1.42; CI 1.09 - 1.74; p=0.003), and presence of lichen sclerosus (HR 1.92; CI 1.01 - 3.65; p=0.047) were associated with an increased risk of treatment failure. Age (HR 1.03; CI 1.01 - 1.05; p=0.003), diabetes (HR 6.68; CI 1.38 - 32.3; p=0.018), penile hypospadias (HR HR 0.40; CI 0.24 - 0.68; p<0.001) and presence of lichen sclerosus (HR 2.51; CI 1.24 - 5.09; p=0.011) were associated with increased risk of patient demotivation for further surgeries. CONCLUSIONS Stricture length, but not the number of previous operations needed for primary hypospadias repair, was associated with the risk of failure. © 2017FiguresReferencesRelatedDetails Volume 197Issue 4SApril 2017Page: e1184 Advertisement Copyright & Permissions© 2017MetricsAuthor Information Guido Barbagli More articles by this author Nicola Fossati More articles by this author Alessandro Larcher More articles by this author Francesco Montorsi More articles by this author Salvatore Sansalone More articles by this author Denis Butnaru More articles by this author Massimo Lazzeri More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Validation of the Kattan Nomogram for Prostate Cancer Recurrence After Radical Prostatectomy.

The Kattan postoperative radical prostatectomy (RP) nomogram is used to predict biochemical recurrence-free progression (BCRFP) after RP. However, external validation among contemporary patients using modern outcome definitions is limited. A total of 1,931 patients who underwent RP at Roswell Park Cancer Institute (RPCI) between 1993 and 2014 (median follow-up, 47 months; range, 0-244 months) were assessed for NCCN-defined biochemical failure (BF) and RPCI-defined treatment failure (TF). Actual rates of biochemical failure-free survival (BFS; defined as 1 - BF) and treatment failure-free survival (TFS; defined as 1 - TF) were compared with Kattan BCRFP nomogram predictions. The Kattan BCRFP nomogram predictions at 5 and 10 years were predictive of BFS (area under the receiver operating characteristic curve [AUC], 0.772) and TFS (AUC, 0.774). The Kattan BCRFP nomogram tended to underestimate BFS and TFS compared with actual outcomes. The Kattan 5-year BCRFP predictions consistently overestimated actual 5-year BFS outcomes among subgroups of high- and intermediate-risk patients with at least 5-year outcomes. The Kattan BCRFP nomogram is a robust predictor of NCCN-defined BF in a large sample of patients with RP with substantial follow-up and modern, standardized failure definitions.

Long-Term Outcome of Pyogenic Vertebral Osteomyelitis: A Cohort Study of 260 Patients

Background The long-term outcome of patients with pyogenic vertebral osteomyelitis (PVO) has not been fully assessed.Methods We conducted a retrospective cohort study to describe the long-term outcome of PVO and to assess risk factors for treatment failure in patients evaluated at our institution between 1994 and 2002. Patients were observed until July 1, 2013.Results Two hundred sixty patients with PVO were included in this study. Twenty-seven percent (70) of patients developed their infection after an invasive spinal procedure. Staphylococcus aureus accounted for 40% (103) of infections. Forty-nine percent (128) of patients underwent spinal surgery as part of their initial therapy. The median duration of parenteral antimicrobial therapy was 42 days (interquartile range, 38–53). The estimated 2-, 5-, and 10-year cumulative probability of treatment failure-free survival was 72%, 69%, and 69%, respectively. Seventy-five percent of patients who developed treatment failure did so within 4.7 months of diagnosis. Residual neurological defects and persistent back pain were seen in 16% and 32% of patients, respectively. In a multivariate analysis, longer duration of symptoms before diagnosis and having an infection with S. aureus were associated with increased risk of treatment failure.Conclusions Increasing duration of symptoms and infection with S. aureus were associated with treatment failure in patients with PVO. Most treatment failures occurred early after initiation of treatment. Pyogenic vertebral osteomyelitis is associated with a high 2-year failure rate. Persistent neurological deficits and back pain are common after therapy.

Role of Bcl-2 Immunohistochemical Expression As An Independent Biological Prognostic Marker At Diagnosis of Classical Hodgkin's Lymphoma

Abstract 4859 BACKGROUND:Most patients with classical Hodgkin's Lymphoma (CHL) are cured with primary treatment. However, a proportion of them fail to first line treatment needing to be rescued with subsequent lines of chemotherapy and/or autologous or allogeneic stem cell transplantation (auto-SCT and allo-SCT, respectively). The identification of clinical and biological characteristics of these patients at diagnosis is still a challenge and most prognostic systems fail to identify a proportion of patients with worse prognosis. In this context, different groups are currently analyzing several biological markers as determinants of clinical outcome. It has been reported that Bcl-2 immunohistochemical expression in Hodgkinxs Reed Sternberg cells (HRSC) might confer a worse prognosis. OBJETIVE:To analyze clinical outcomes following 1st line chemotherapy according to Bcl-2 expression at diagnosis of CHL. PATIENTS AND METHODS:CHL patients, older than 16 years old, receiving at least 1 line of treatment, were retrospectively studied for Bcl-2 expression in diagnostic samples. For this purpose, tissue sections were immunostained and semiquantitatively assessed for this marker. Cumulative incidence (CI) of treatment failure, treatment failure free survival (TfFS) and overall survival (OS) were defined as primary outcomes. Treatment failure was considered when a different treatment regimen was set up due to relapse after CR or failing to achieve CR following 1st line. RESULTS:103 patients (55 Bcl-2 positive patients and 48 Bcl-2 negative patients) were analyzed. Main patient and clinical features are shown in Table 1. Both cohorts were well balanced for the main prognostic factors. At a median follow up of 36m (2-221), 34m (2-140) for Bcl-2 negative patients and 38m (4.5-221) for Bcl-2 positive patients, CI of 3 years treatment failure was 19% and 50% for the negative and positive cohorts, respectively (p=0.02). 3 years TfFS after diagnosis was 75% for Bcl-2 negative patients vs 47% for Bcl-2 positive patients (p=0.1). Within the cohort of Bcl-2 negative patients, 9/48 (19%) underwent auto-SCT as part of rescue treatment while 18/55 (33%) of Bcl-2 positive patients received an SCT (13 auto-SCT and 5 allo-SCT) and 3 of them, a second SCT (allo) for the treatment of post-auto-SCT relapse. 3 years OS was 84.5% for negative and 86% for positive patients (p=NS). [Display omitted] CONCLUSIONS:According to these preliminary results, Bcl-2 expression in HRSC at diagnosis may constitute an independent biological prognostic marker in CHL patients, seemingly associated with worse outcome and need of second line chemotherapy. More studies and a longer follow up is needed in order to confirm that aggressive treatment strategies such as SCT may overcome the negative impact in survival of Bcl-2 expression in this population. Disclosures:No relevant conflicts of interest to declare.

Antibiotic Treatment Duration and Long‐Term Outcomes of Patients with Early Lyme Disease from a Lyme Disease–Hyperendemic Area

The length of antibiotic therapy and long-term outcomes in patients with early Lyme disease are incompletely described. We report the long-term clinical outcomes of patients with early localized and early disseminated Lyme disease based on the duration of antibiotic therapy prescribed. A retrospective cohort study and follow-up survey of patients diagnosed as having early localized and early disseminated Lyme disease from 1 January 2000 through 31 December 2004 was conducted in a Lyme disease-hyperendemic area. Six hundred seven patients met the study inclusion criteria. Most patients (93%) were treated with doxycycline for treatment durations of 10 days, 11-15 days, or 16 days in 17%, 33%, and 47% of doxycycline-treated patients, respectively. Treatment failure criteria, defined before performing the study, were met in only 6 patients (1%). Although these 6 patients met a priori treatment failure criteria, 4 of these patients' clinical details suggested reinfection, 1 was treated with an inappropriate antibiotic, and 1 developed facial palsy early in therapy. Reinfection developed in 4% of patients. The 2-year treatment failure-free survival rates of patients treated with antibiotics for 10 days, 11-15 days, or 16 days were 99.0%, 98.9%, and 99.2%, respectively. Patients treated with antibiotics for 16 days had lower 36-item Short-Form Health Survey social functioning scores on the follow-up survey. No other differences were found in follow-up clinical status or 36-item Short-Form Health Survey scores by duration of antibiotic treatment. Patients treated for 10 days with antibiotic therapy for early Lyme disease have long-term outcomes similar to those of patients treated with longer courses. Treatment failure after appropriately targeted short-course therapy, if it occurs, is exceedingly rare.

Survival after Hodgkin lymphoma

The objective of this study was to analyze cause-specific excess mortality in adult patients with Hodgkin lymphoma (HL) with respect to treatment modality. The study population consisted of 4401 Belgian, Dutch, and French patients aged 15 to 69, in all stages of disease, who were treated between 1964 and 2000. Excess mortality was expressed by using a standardized mortality ratio (SMR) and calculating the absolute excess risk (AER). Relative survival was calculated and analyzed using a previously described regression model. At a median follow-up of 7.8 years, 725 of 4401 patients (16.5%) had died, 51% of HL, 10% of treatment-related toxicity, 18% of second cancer, 5% of cardiovascular diseases, 2% of infections, 8% of other causes, and 6% of an unspecified cause. Overall, the SMR was 7.4 (95% confidence limits [CL], 6.9-8.0), and the AER was 182.8 (95% CL, 167.7-198.8). These indicators were 3.8 (95% CL, 3.2-4.5) and 27.9, respectively, for deaths from a second cancer and 4.0 (95% CL, 2.3-6.7) and 3.3, respectively for deaths from infection. After 15 years, the observed survival rate was 75%, and the relative survival rate was 80%. In patients with early-stage disease, the overall excess mortality was associated with age > or =40 years (P = .007), men (P < .001), unfavorable prognosis features (P < .001), and 2 treatments: combined nonstandard nonalkylating chemotherapy plus involved-field radiotherapy (P = .002) and mantle-field irradiation alone (P = .003). With follow-up censored at the first recurrence, no treatment modalities were associated with excess mortality. Progressive disease remained the primary cause of death in patients with HL in the first decades after treatment. Excess mortality in patients with early-stage disease was linked significantly to treatment modalities that were associated with poor treatment failure-free survival.

BEACOPP Chemotherapy Is Able to Induce Durable Complete Remission in Poor-Prognosis Hodgkin's Lymphoma Patients with a Positive Interim PET after 2 ABVD Cycles

Background: Early interim-PET (PET-2) is the most powerful factor able to predict treatment outcome in advanced-stage Hodgkin Lymphoma (HL) patients treated with ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine). The 2-y PFS of PET-2 positive patients is only 12%, but the optimal treatment for this patient subset is still unknown. For this reason in January 2006 a treatment policy was designed by GITIL (Gruppo Italiano Terapie Innovative nei Linfomi) to early intensify chemotherapy with BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) for HL patients with a PET-2 positive after 2 ABVD cycles.Patients and methods: 136 HL patients with advanced-stage or intermediate-stage with adverse prognostic factors (more than 3 nodal sites, ESR > 50 mm, sub diaphragmatic presentation, bulky lesion), consecutively admitted to nine GITIL Italian centers were treated with two ABVD courses and re-evaluated with interim-PET. Twenty-one of these 136 patients proved to be PET-2 positive, and 19/21 are the object of this analysis. The mean age was 31.7 years (16–64), 10 patients were in stage II, 9 in stage III–IV. Bulky disease was present in 11, and B-symptoms in 16. Fourteen patients showed an IPS score 0–2, 5 patients a score 3–7. The median interval between the end of second ABVD course and PET-2 was 11 days (5–14). BEACOPP (4 escalated and 4 standard cycles) was followed by consolidation radiotherapy in 3 patients for bulky mediastinal tumor. PET scan were centrally reviewed by two well-experienced nuclear medicine experts, using the blood pool mediastinal structures (BPMS) as reference for the residual uptake, as elsewhere published (Gallamini, JCO 2007).Results. Upon central review, 2 interim-PET scan were classified as minimally positive in 2 patients, with a single MRU (Minimal Residual Uptake) lesion showing a SUV (Standardized Uptake Value) lower than BPMS, and therefore only 19 cases were suitable for the BEACOPP salvage treatment. After a mean follow-up of 14.3 months (7.0–30.2), 15 patients remain in continuous CR and 4 had a treatment failure because of disease relapse (1) or progression (3). For the responding patients the mean duration of CR was 13.0 months (6.5–30.2). The IPS score for progressing patients was 2, 3, and 4; for the relapsing-one, 0. At time of this analysis, l8 patients are still alive and 1 died during BEACOPP treatment for disease progression. The 1-year second treatment failure-free survival (1-y 2TFFS) was 94.7 % (95% C.I. 84.7–100). The 1 y OS survival was 93.3 (95%C.I. 80.7–100). In univariate analysis the only clinical factor related to treatment failure was the presence of extra-nodal disease. (Log-rank=6.8 p=0.009).Conclusions. BEACOPP-escalated regimen was able to induce durable CR in most (15/19) HL patients with a positive interim-PET. These results, although requiring a longer follow-up and a higher number of patients, seem to suggest thatthe very-poor prognosis of PET-2 positive, ABVD-treated HL patients can be substantially improved by early chemotherapy intensification;escalated-BEACOPP is likely to represent a good treatment choice for this very poor prognosis patient subset.

10-Year-Outcome of Acquired Aplastic Anemia Children Treated with Antithymocyte Globulin, Cyclosporine with or without G-CSF.

BACGROUND: Acquired aplastic anemia (AA) is thought to be an immune-mediated disease. Immunosuppressive therapy (IST) has been the treatment of choice for patients who did not have suitable donors. Previously, we had published promising results of IST for children with acquired AA. In the study, overall survival rate (OS) at 4 years was 83% in patients with vSAA and 92% in those with SAA/nonSAA.OBJECTIVES: Here we report follow-up results focusing on pediatric patients with relapse and clonal diseases, MDS/AML and PNH.PATIENTS and TREATMENT: From 1992 to 1997, 119 newly diagnosed children with acquired AA (median age; 9) entered AA-92 study. 50 vSAA patients were treated with ATG+CyA+mPSL+danazole +G-CSF, 36 SAA and 28 nonSAA patients were treated with ATG+CyA+mPSL+danazole +/−G-CSF. Complete remission (CR) was defined as a neutrophil count >1.5x10^9/L, a platelet count >100xx10^9/L, and a hemoblobin level of >11 g/dl. Partial response (PR) was defined as a neutrophil count >0.5x10^9/L, a platelet count >20x10^9/L, and a hemoglobin level of >8.0 g/dl. Relapse was indicated by the return of the PB counts to levels meeting the definition of SAA and/or the requirement for blood transfusion. Response rate was 71% at 6 months in vSAA patients, 65% in SAA/nonSAA patients, respectively. There was no statistical difference in 6-month response rate between G-CSF +/− treatments. No patient responded after 6 months. Therefore, 75 responders and 29 non-responders at 6 months were analyzed their OS, relapse rate (RR), and treatment-failure-free survival (TFFS). The median observation time of surviving patients is 118 months, ranging from 75 to 168 months.RESULTS: Among 119 patients, 38 patients received BMT and 17 patients died during an observation period. The OS was 81.9+−3.8% at 10 years, but has not reached plateau. Of the 75 6mo-responders, 23 patients relapsed and the RR was 33.6+−6.0% at 10 years. TFFS of the 75 was 67.4+−5.5%. Fourteen patients received 2nd ATG therapy and 5 of them responded. Eleven of the 23 patients with relapse received alternative donor BMT and 8 are alive. 10y-OS of these relapsed patients was 73.4+−9.4%. Nineteen of the 29 6mo-non-responders received alternative donor BMT and 15 are alive. There is no statistically significant difference in 10y-OS between the responders and the non-responders (89.1+−3.7% vs. 75.0+−8.2%, p=0.09). New clonal abnormalities appeared in 9 of 119 patients (10.0+−3.2%KM probability): monosomy 7(3 patients), trisomy 8(3 patients), trisomy 9, trisomy11, del (13)(1 patient each). There is no statistically difference in 10y-OS, RR, and incidence of clonal abnormality between randomized G-CSF+/− treatments. Clinical PNH with symptomatic hemolysis developed in 3 of the responder patients, 96, 105 and 138 months after the AA diagnosis, respectively. Among 65 surviving responders, 33(51%) have CR and 26(40%) PR at last follow-up time.CONCLUSIONS: Our data demonstrate that IST is effective for children with acquired AA, but relapse are common. Effective 2nd line treatment should be developed. PNH developed even in pediatric AA patients during long-term observation.

Finasteride and flutamide therapy in patients with advanced prostate cancer: response to subsequent castration and long-term follow-up

Objectives To report the efficacy of castration after progression on finasteride and flutamide. Standard androgen deprivation strategies for prostate cancer typically lead to castrate levels of testosterone. One alternative is the use of finasteride and flutamide. Methods A Phase II trial evaluated the combination of finasteride (5 mg/day) and flutamide (250 mg three times daily) in patients with rising prostate-specific antigen levels after local treatment for prostate cancer or with newly discovered metastatic disease. Patients were followed up for subsequent events, including castration-free, androgen-independent prostate cancer (AIPC)-free, and overall survival. Results With a median follow-up of 88 months, 5 patients (25%) continued on finasteride and flutamide, and 12 had stopped this combination and subsequently underwent medical or surgical castration. No patients experienced a flutamide withdrawal effect. All patients experienced more than a 50% decline in prostate-specific antigen after castration (mean 89%). The median protocol treatment failure-free survival was 29.9 months, the median castration-free survival was 37 months, and the median AIPC-free survival was 48.6 months. At 5 years, the overall survival rate was 65% (95% confidence interval 47% to 90%); 29% were alive and have not required castration, and 35% were alive and free of AIPC. Conclusions Finasteride and flutamide have a durable effect in suppressing prostate-specific antigen progression in some men with advanced prostate cancer. Furthermore, castration induces secondary responses that may be of shorter duration than if started initially, although the overall period of hormonally responsive prostate cancer is more than 4 years.

High-Dose Platinum versus Standard Dose in Advanced Ovarian Carcinoma: A Randomized Trial from the Gynecologic Cooperative Group of the French Comprehensive Cancer Centers (FNCLCC)

Objective. The aim of this study was to evaluate the impact of platinum dose intensity on pathological response rate and overall survival in patients with advanced ovarian adenocarcinoma.Methods. Between February 1992 and December 1996, 195 previously untreated patients with FIGO stage IIb-c, IIIb-c, or IV with macroscopic residual disease after suboptimal debulking surgery were randomized to receive CCC (100 mg/m2 of cisplatin, 300 mg/m2 of cyclophosphamide, 300 mg/m2 of carboplatin, n = 96) or CC (100 mg/m2 of cisplatin, 600 mg/m2 of cyclophosphamide, n = 99) for six courses at 28-day intervals. A second-look laparotomy was planned at the end of chemotherapy.Results. In the CCC arm, the platinum compound received dose intensity and relative total dose were 85 and 76%; in the CC arm, they were 94 and 85%. Grade 3–4 toxicity was more frequent in the CCC arm than in the CC arm for leukopenia (56% vs 26%, P < 0.001), febrile neutropenia (18% vs 4%, P = 0.002), anemia (31% vs 5%, P < 0.001), thrombopenia (55% vs 4%, P < 0.001), and ototoxicity (8% vs 0%, P < 0.001). The pathologic complete response rate was 22 and 14% in the CCC and CC arms, respectively (P = 0.19). With a median follow-up of 53 months, the median time to failure and the 3-year treatment failure-free survival rate were 17.4 months and 22% vs 13 months and 11% in the two arms, respectively (P = 0.01). The median survival time and the 3-year overall survival rate were, respectively, 30 months and 42% vs 25 months and 33% (P < 0.20).Conclusion. The platinum dose intensification (1.6-fold increase) obtained with the CCC association improves the treatment failure-free survival without significant impact on overall survival when compared with the CC regimen in suboptimal debulked ovarian adenocarcinoma. However, because of its high rate of hematologic toxicity and ototoxicity, this association cannot be recommended for routine practice.

Is neuro-ectodermal differentiation of Ewing's sarcoma of bone associated with an unfavourable prognosis?

Among Ewing's sarcoma (ES) of bone and related entities are tumours with neuro-ectodermal features that could represent a biologically distinct type. In order to assess the prognostic significance of the various forms of ES, a retrospective joint study involving three cancer centres in Europe and the U.S.A. was initiated. The material from 315 primary ES was reviewed by a panel of five pathologists and classified as typical ES (220 cases), atypical ES (48 cases) or ES with neuro-ectodermal features (47 cases). Prognostic factor analysis on treatment failure-free survival was performed using the Cox model. It included histopathological classification, initial patient characteristics, clinical presentation and treatment type. After multivariate analysis, in addition to treatment type (P < 0.001), metastases (P = 0.003) and proximal tumour location (P = 0.006), two histopathological parameters correlated with poor treatment failure-free survival, the presence of filigree pattern (P = 0.044) and dark cells (P = 0.043). We conclude that ES with neuro-ectodermal features does not appear to have a different outcome to the other subtypes.