Non-trial Cohorts Research Articles

Clinicopathological Analysis of a European Cohort of MYOD1 Mutant Rhabdomyosarcomas in Children and Young Adults.

Patients with PAX3/7-FOXO1 fusion-negative rhabdomyosarcomas (fnRMS) harbouring the rare L122R MYOD1 mutation have significantly poorer prognosis than other fnRMS. We undertook a detailed clinicopathological evaluation of a cohort of patients with MYOD1 mutated fnRMS in order to improve risk stratification and treatment options. Histological, mutational and clinical data from a cohort of patients with MYOD1 mutant RMS treated in Europe were analysed. Thirty-two cases with mutant MYOD1 RMS were identified from patients enrolled in sequential European rhabdomyosarcoma clinical trials from 1992 to 2022 (n = 22) and non-trial cohorts (n = 10). Thirty cases had the recurrent L122R missense mutation, one case harboured a K124E mutation and one case had a truncating mutation (S63X). Increased MyoD1 and reduced MYF4 immunostaining were consistent features of MYOD1L122R-mutated RMS. Applying the risk stratification of the European paediatric Soft tissue sarcoma Study Group (EpSSG) RMS2005 trial, among 20 localised RMS cases that could be assigned a risk category, one was Very High Risk, 13 were High Risk and six were Standard Risk. Eight patients had distant metastases at diagnosis. Of the 25 patients with adequate clinical follow-up data, 15/25 (60%) patients had an event at a median time of 9months (12/15 included failure of local control) and 13/25 (52%) died of disease. This MYOD1 mutant cohort demonstrates increased MYOD and reduced MYF4 immunostaining, high risk of local failure and poor survival in agreement with other studies. Increased treatment intensity and improved local control should be considered for these patients.

Engraftment Syndrome during Autologous Stem Cell Transplant in Hodgkin Lymphoma Patients Treated with Checkpoint Inhibitors: A Multi-Center Retrospective Analysis

Background: Engraftment Syndrome (ES) has traditionally been considered a rare complication of autologous stem cell transplant (ASCT) in patients (pts) with relapsed/refractory Hodgkin lymphoma (HL). There have been several attempts to define ES, but diagnostic criteria have not been unified. Diagnosis of ES is considered in pts developing non-infectious fever coinciding with neutrophil recovery, typically with at least one other inflammatory finding such as pulmonary infiltrates, diarrhea, rash, or transaminitis. The proposed pathogenesis of ES involves production of inflammatory cytokines by activated leukocytes, which may ultimately be suppressed by treatment with systemic corticosteroids. Recent clinical trials in HL have suggested that exposure to immune checkpoint inhibitors (ICI) before ASCT may increase the risk of developing ES. Methods: We conducted a retrospective study at several U.S. academic institutions to better characterize ES in HL pts undergoing ASCT in the era of ICIs. Eligibility criteria included age > 18, diagnosis with relapsed/refractory HL, treatment with an ICI as part of pre-transplant salvage therapy, and ASCT between January 1, 2015 and February 1, 2023. Inflammatory symptoms and timing of symptom onset were assessed by medical record review. ES was defined by Maiolino criteria (Maiolino et al. Bone Marrow Transpl, 2003) as at least two symptoms within 48 hours of engraftment not attributable to other causes, including fever in combination with diarrhea, rash, or pulmonary infiltrates. We assessed the incidence of inflammatory symptoms and ES, and evaluated potential risk factors associated with developing these symptoms. Results: A total of 53 pts with HL were identified. Pts had a median age of 33 (range 19-72), 49% were female, 75% White, and 11% Black. The majority (87%) had the nodular sclerosis subtype and were treated with ABVD (68%) or BV-AVD (23%) in the frontline setting, with a majority achieving CR (53%) or PR (15%). At relapse, 57% received BV-nivolumab and 13% received pembrolizumab-GVD. Overall, 70% received nivolumab prior to ASCT, and 30% received pembrolizumab. None of the pts in this reported cohort were treated on a clinical trial. On pre-ASCT PET, 77% achieved CR, after which all were mobilized with GCSF, with 42% also receiving plerixafor. An average of 9.57 million CD34+ cells/kg (median 7.28) were infused on day 0. Pts were hospitalized for an average of 20 days (range 2-99). All pts successfully engrafted, with a median time-to-engraftment (ANC 500) and time-to-platelet-recovery of 10 days. A majority of pts (70%) experienced at least one non-infectious inflammatory finding at engraftment, but only 21% met Maiolino criteria for ES. The frequency of non-infectious inflammatory findings is described in Figure 1. Of the 11 pts clinically diagnosed with ES by the treating physician, 7 received high-dose steroids for treatment, for a median of 8 days. There were no deaths attributed to ES. Following transplant, 91% achieved CR, with 5 pts experiencing progressive disease. Over a median follow-up of 15 months (range 1-57 months), 5 pts relapsed and 4 died. The outcomes of the entire cohort were excellent, with 2-year PFS of 78% (95% CI: 67-90%) and 2-year OS of 90% (95% CI 81-100%). There were no differences in survival based on ES status. We explored potential risk factors for developing ES, including number of cells infused, duration of ICI exposure/timing in relation to ASCT, and plerixafor use, but none achieved statistical significance. Conclusions: In this non-trial cohort of HL pts receiving ICI-based salvage before transplant, a minority of patients (21%) developed ES by traditional diagnostic criteria, but the majority of pts (70%) developed non-infectious inflammatory findings in the peri-engraftment period. Most pts experiencing ES were treated with steroids and had favorable outcomes similar to those without ES. With increasing use of ICI-based regimens in the pre-transplant setting, further studies with larger patient cohorts are needed to better characterize this entity, develop unified reporting and diagnostic criteria, identify pts at high risk for severe ES, and develop effective prophylactic and therapeutic strategies.

Comparison of survival outcomes of patients with newly diagnosed glioblastoma treated with standard chemoradiation in and outside of clinical trials.

2051 Background: Randomized clinical trials use stringent eligibility criteria to select patients which can raise concerns about generalizability of study results. Recent interest in external controls and new trial designs has increasingly focused on the possible use of real-world data sources. We examined potential differences of survival outcomes in clinical trial and real-world datasets in newly diagnosed glioblastoma. Methods: Patient-level data from 4 independent datasets were analyzed. Non-trial data were derived from an institutional dataset of 453 patients with newly diagnosed glioblastoma treated outside of a clinical trial with standard radiation therapy with concurrent and adjuvant temozolomide at a large academic center. Trial patients included patients on the control arm of several multi-institutional trials (NCT00689221, n = 273; NCT00813943, n = 89; NCT00943826; n = 459) and patients treated on trial at our institution (n = 210). Non-trial patients were compared with each of the 4 clinical trial datasets in pairwise comparisons with Cox regression with adjustments for age, sex, extent of resection, KPS and MGMT status. Results: Patient-level data from 1,484 patients were analyzed. Non-trial patients were older compared to patients in the multi-institutional trials (mean 58.6 vs. 56.1 years (NCT00943826), 53.9 years (NCT00813943), 55.7 years (NCT00689221); p < = 0.001). The non-trial cohort had fewer women (43.5% vs. 35.9%, p = 0.02), greater proportion of lower KPS patients (47% KPS <90 vs. 31% KPS <90, p < 0.001) and greater proportion of MGMT methylated patients (49% vs. 33%, p < 0.001) compared to NCT00943826 patients. There were no other significant differences between patient characteristics of non-trial patients and the 4 trial datasets. Trial participation was not associated with improved survival in multivariable analysis after adjustments for clinical covariates (non-trial patients vs. each trial dataset; Table, P > 0.05). Conclusions: Glioblastoma patients treated on multi-institutional clinical trials that were included in our analysis did not have statistically significant differences in survival compared to patients treated outside of a clinical trial at a large academic center after adjustment for relevant variables. Our findings support the possible use of real-world data in the development of external control arms for future trials in newly diagnosed glioblastoma. [Table: see text]

Translation of Prognostic and Pharmacodynamic Biomarkers from Trial to Non-trial Patients with Metastatic Castration-resistant Prostate Cancer Treated with Docetaxel

AimsWe conducted a pooled analysis of four randomised controlled trials and a non-trial retrospective dataset to study the changes in serum prostate-specific antigen (PSA) concentrations during treatment and its impact on survival in men treated with docetaxel for metastatic castration-resistant prostate cancer. We also compared the outcomes and pre-treatment prognostic factors between trial and non-trial patients. Materials and methodsData were obtained from four randomised controlled trials and a non-trial cohort from a tertiary cancer centre. The PSA kinetics covariates chosen were absolute value (PSAT), best percentage change (BPCH) and tumour growth rate (K). The association between the covariates collected and overall survival was assessed within a Cox proportional hazards model. How well a covariate captured the difference between trial and non-trial patients was assessed by reporting on models with or without trial status as a covariate. ResultsWe reviewed individual datasets of 2282 patients. The median overall survival for trial patients was 20.4 (95% confidence interval 19.6–22.2) months and for the non-trial cohort was 12.4 (10.7–14.7) months (P < 0.001). Of the pre-treatment factors, we found that only lactate dehydrogenase fully captured the difference in prognosis between the trial and non-trial cohorts. All PSA kinetic metrics appeared to be prognostic in both the trial and non-trial patients. However, the effect size was reduced in non-trial versus trial patients (interaction P < 0.001). Of the time-dependent covariates, we found that BPCH best captured the difference between trial and non-trial patient prognosis. ConclusionsThe analysis presented here highlights how data from open-source trial databases can be combined with emerging clinical practice databases to assess differences between trial versus non-trial patients for particular treatments. These results highlight the importance of developing prognostic models using both pre-treatment and time-dependent biomarkers of new treatments.

The Genetic Landscape in Elderly DLBCL Aged > 75 Years in the Australasian Leukaemia & Lymphoma Group NHL29 Iric Trial Identifies New Targetable Mutations

Background: Approximately 40% of patients with diffuse large B-cell lymphoma (DLBCL) are &amp;gt;70 years old and have poor clinical outcomes attributable to treatment-related factors or to disease biology. Genotyping data in elderly DLBCL patients is limited because of lack of representation in clinical trials. R-mini-CHOP is better tolerated than R-CHOP in elderly DLBCL but with reduced efficacy. The addition of ibrutinib to R-CHOP has been shown to be effective in younger pts aged &amp;lt; 60 years but is associated with poor tolerability and outcomes in older patients. The ALLG Ibrutinib with R-mini-CHOP (IRiC) study, a prospective multicentre single-arm phase II study in elderly (≥ 75 years) DLBCL patients provided an opportunity to genotype this uncommon cohort. We therefore aimed to map the genetic landscape of mutations in elderly DLBCL and compare them to a non-trial younger cohort. Methods: Mutations in genes commonly associated with DLBCL were assessed in 55 IRIC study patients with a median age of 81 years (75-91 years) and a gender ratio of 1.0 (27 M/28 F). A cohort of 51 non-trial patients withde novoDLBCL treated with anthracycline-based regimens was also genotyped. The median age of the control group was 65 years (29-91 years) with a gender ratio of 1.2:1 (28 M/23 F). The cell of origin (COO) measured using gene expression profiling on 39/55 trial patients (non-GC=13, GC= 22, unclassified= 4), and Hans algorithm on 45/51 non-trial patients (non-GC=14, GC=31) was comparable (p=0.571). Outcome data was available at a median follow-up of 18 and 40 months for the trial and non-trial cohorts respectively. We extracted genomic DNA from and performed next generation sequencing on diagnostic formalin-fixed paraffin-embedded or fresh frozen tissue samples using a customized capture library (SureSelectXT Target Enrichment System, Aqilent Technologies) covering genes involved in lymphomagenesis. The purified libraries were sequenced on the Illumina NextSeq500 platform at AGRF (Australian Genome Research Facility, Australia). Mutations in the following genes were compared across the two cohorts: ARID1A, BCL2, BTG1, BTG2, CARD11, CCND3, DTX1, EP300, ETS1, EZH2, FOXO1, GNA13, HIST1H1C, IKBKB, IRF8, KDM2B, KLHL6, MYC, MYD88, NOTCH1, NOTCH2, PIK3CD, PIM1, PRDM1, PTEN, PTPN21, SGK1, SPEN, STAT3, TET2, TNFAIP3, TNFRSF11A, TNFRSF14, TP53 and TRAF5. Statistical analysis for nominal data was done using the chi-square test and for ordinal data using the Kruskal-Wallis test (p &amp;lt; 0.05= significant). Kaplan-Meier curves were calculated for patients with and without each mutation and the curves compared using a log-rank approach. Results: Patients were divided into 2 groups, IRiC trial cohort aged &amp;gt;75 years (n=55) + non-trial elderly patients &amp;gt;75 years (n=9) =elderly cohort(n=64) and non-trialnon-elderly cohortof patients &amp;lt; 75 years (n=42). As expected, elderly patients were more likely to have high-risk disease with higher IPI of ≥ 3 (n=42, n=17, p=0.009). There was no significant difference in gender or COO. The frequency of mutations in the elderly (n=64) was compared to the non-elderly cohort (n=42). NOTCH2 was the most common mutation irrespective of age (34 [53%]; 16 [38%], p=0.129). Notably, we found that mutations in MYC (8 [12.5%]; 0, p= 0.021), PTEN (17 [26.5%]; 4 [9%], p=0.045) and TET2 (28 [43.7%]); 7 [16.6%], p=0.004) were more frequent in the elderly. As expected, MYD88 and CD79B mutations were more frequently associated with non-GC subtype (p=0.001). No other associations with COO were identified. No clear prognostic individual genes or gene clusters could be identified in the trial or the elderly cohort. Ibrutinib-responsive (MYD88 [L265P n=7] and CD79B [n=11]) and ibrutinib-resistant mutations (CARD11 [n=6] or PIM1 [n=12]) did not show clear associations with response rate, overall survival or progression-free survival. Conclusions: Our study found that the mutational profile of elderly DLBCL patients aged ≥ 75 years is enriched for targetable mutations in MYC, PTEN and TET2 compared to those &amp;lt; 75 years. PTEN and TET2 are tumour suppressors and MYC is an oncogene with an important regulatory role in cell growth and proliferation. We hypothesize that hypo-methylating agents targeting TET2, BET inhibitors in MYC mutated tumours and PI3K inhibitors to target PTEN deficient lymphoma may help improve clinical outcomes in elderly DLBCL. No clear prognostic markers were identified in this small cohort. Disclosures Trotman: Celgene:Research Funding;BeiGene:Research Funding;Takeda:Research Funding;PCYC:Research Funding;F. Hoffmann-La Roche:Research Funding.Verner:Janssen Cilag Pty Ltd.:Research Funding.Gandhi:Celgene:Research Funding;Bristol-Myers Squibb:Research Funding;Mater Research:Current Employment;Janssen-Cilag:Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding;Roche:Other: Travel, accommodation, expenses ;Genentech:Honoraria;Gilead Sciences:Honoraria;Amgen:Honoraria;Merck Sharp &amp; Dohme:Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.Gandhi:Integrated Sciences:Current Employment.Talaulikar:Takeda:Research Funding;Amgen:Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding;Janssen:Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau;Roche:Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

High-Risk Multiple Myeloma Patients Are Missed without Gene Expression Profiling

High-Risk Multiple Myeloma Patients Are Missed without Gene Expression Profiling

Another disappointment in treating relapsed, refractory high-risk aggressive B-cell lymphomas.

Another disappointment in treating relapsed, refractory high-risk aggressive B-cell lymphomas.

Adjuvant chemotherapy in stage II-III operated colon cancer patients from a nontrial cohort in a low colon cancer prevalence country with predominant use of modified CAPOX.

Background:Data regarding the practice of adjuvant chemotherapy, specifically with modified CAPOX, and survival outcomes in operated colon cancer patients from a nontrial cohort in a lower-middle income and low prevalence nation like India is scarce.Materials and Methods:Patients who underwent upfront curative resection for colon cancer from January 2013 to December 2016 were analyzed for baseline variables and outcomes.Results:A total of 491 patients underwent curative resection in the predefined time period. The median age of the patients was 53 years (range: 17–87). Patients with Stage I, Stage II, and Stage III disease comprised 7.9%, 44.8%, and 45.4% of the entire cohort, respectively. Patients with Stage I cancer were observed. Adjuvant chemotherapy was planned for 384 patients (78.2%), with the doublet regimens (capecitabine-oxaliplatin, or 5-fluorouracil-oxaliplatin) being used commonly (77.6%). Common toxicities were Hand-foot syndrome (Grade 2/3 - 21.4%) and peripheral neuropathy (Grade 2/3 - 20.1%). About 85% of patients receiving monotherapy (capecitabine or 5 fluorouracil) and 81.2% of patients receiving doublet chemotherapy (mCAPOX or modified FOLFOX-7) completed their planned adjuvant treatment. With a median follow-up of 22 months, estimated 3 years event-free survival was 86%, and overall survival (OS) was 93.6%. Stage, younger age (<50 years), underlying cardiovascular abnormalities, need for dose reductions and noncompletion of planned chemotherapy predicted for inferior estimated 3-year OS on multivariate analysis.Conclusions:Adjuvant chemotherapy especially with modified CAPOX appears well tolerated in the Indian population and early survival outcomes appear to be comparable to published literature.

External validation of the TIMI risk score for secondary cardiovascular events among patients with recent myocardial infarction

Background and aimsRisk stratification of patients with recent myocardial infarction (MI) for subsequent cardiovascular (CV) events helps identify patients most likely to benefit from secondary prevention therapies. This study externally validated a new risk score (TRS2˚P) for secondary events derived from the TRA2°P-TIMI 50 trial among post-MI patients from two large health care systems. MethodsThis retrospective cohort study included 9618 patients treated for acute MI at either the Cleveland Clinic (CC) or Geisinger Health System (GHS) between 2008 and 2013. Patients with a clinic visit within 2–52 weeks of MI were included and followed for CV death, repeat MI, and ischemic stroke through electronic medical records (EMR). The TRS2˚P is based on nine factors determined through EMR documentation. Discrimination and calibration of the TRS2˚P were quantified in both patient populations. ResultsMI patients at CC and GHS were older, had more comorbidities, received fewer medications, and had higher 3-year event rates compared to subjects in the TRA2°P trial: 31% (CC), 33% (GHS), and 10% (TRA2°P-TIMI 50). The proposed risk score had similar discrimination across the three cohorts with c-statistics of 0.66 (CC), 0.66 (GHS), and 0.67 (TRA2°P-TIMI 50). A strong graded relationship between the risk score and event rates was observed in all cohorts, though 3-year event rates were consistently higher within TRS2°P strata in the CC and GHS cohorts relative to TRA2˚P-TIMI 50. ConclusionsThe TRS2˚P demonstrated consistent risk discrimination across trial and non-trial patients with recent MI, but event rates were consistently higher in the non-trial cohorts.

Physician burnout: can we make a difference together?

Expanded abstractCitationWest CP, Dyrbye LN, Rabatin JT, Call TG, Davidson JH, Multari A, Romanski SA, Hellyer JMH, Sloan JA, Shanafelt TF. Intervention to promote physician well-being, job satisfaction, and professionalism: a randomized clinical trial. JAMA Intern Med. 2014;174:527–33.BackgroundDespite the documented prevalence and clinical ramifications of physician distress, few rigorous studies have tested interventions to address the problem.MethodsObjective: To test the hypothesis that an intervention involving a facilitated physician small-group curriculum would result in improvement in well-being.Design: A randomized clinical trial of practicing physicians. Additional data were collected on nontrial participants responding to annual surveys timed to coincide with the trial surveys.Setting: Department of Medicine at the Mayo Clinic in Rochester, Minnesota between September 2010 and June 2012.Participants: The study involved 74 practicing physicians in the Department of Medicine and 350 nontrial participants responding to annual surveys.Interventions: The intervention involved 19 biweekly facilitated physician discussion groups incorporating elements of mindfulness, reflection, shared experience, and small-group learning for 9 months. Protected time (1 hour of paid time every other week) for participants was provided by the institution.Outcomes: Meaning in work, empowerment and engagement in work, burnout, symptoms of depression, quality of life, and job satisfaction were assessed using validated metrics.ResultsEmpowerment and engagement at work increased by 5.3 points in the intervention arm vs. a 0.5-point decline in the control arm by 3 months after the study (P = .04), an improvement sustained at 12 months (+5.5 vs. +1.3 points; P = .03). Rates of high depersonalization at 3 months had decreased by 15.5 % in the intervention arm vs. a 0.8 % increase in the control arm (P = .004). This difference was also sustained at 12 months (9.6 % vs. 1.5 % decrease; P = .02). No statistically significant differences in stress, symptoms of depression, overall quality of life, or job satisfaction were seen. In additional comparisons including the nontrial physician cohort, the proportion of participants strongly agreeing that their work was meaningful increased 6.3 % in the study intervention arm but decreased 6.3 % in the study control arm and 13.4 % in the nonstudy cohort (P = .04). Rates of depersonalization, emotional exhaustion, and overall burnout decreased substantially in the trial intervention arm, decreased slightly in the trial control arm, and increased in the nontrial cohort (P = .03, P = .007, and P = .002 for each outcome, respectively).ConclusionsAn intervention for physicians based on a facilitated small-group curriculum improved meaning and engagement in work and reduced depersonalization, with sustained results 12 months after the study.

Intervention to Promote Physician Well-being, Job Satisfaction, and Professionalism

IMPORTANCE Despite the documented prevalence and clinical ramifications of physician distress, few rigorous studies have tested interventions to address the problem. OBJECTIVE To test the hypothesis that an intervention involving a facilitated physician small-group curriculum would result in improvement in well-being. DESIGN, SETTING, AND PARTICIPANTS Randomized clinical trial of 74 practicing physicians in the Department of Medicine at the Mayo Clinic in Rochester, Minnesota, conducted between September 2010 and June 2012. Additional data were collected on 350 nontrial participants responding to annual surveys timed to coincide with the trial surveys. INTERVENTIONS The intervention involved 19 biweekly facilitated physician discussion groups incorporating elements of mindfulness, reflection, shared experience, and small-group learning for 9 months. Protected time (1 hour of paid time every other week) for participants was provided by the institution. MAIN OUTCOMES AND MEASURES Meaning in work, empowerment and engagement in work, burnout, symptoms of depression, quality of life, and job satisfaction assessed using validated metrics. RESULTS Empowerment and engagement at work increased by 5.3 points in the intervention arm vs a 0.5-point decline in the control arm by 3 months after the study (P = .04), an improvement sustained at 12 months (+5.5 vs +1.3 points; P = .03). Rates of high depersonalization at 3 months had decreased by 15.5% in the intervention arm vs a 0.8% increase in the control arm (P = .004). This difference was also sustained at 12 months (9.6% vs 1.5% decrease; P = .02). No statistically significant differences in stress, symptoms of depression, overall quality of life, or job satisfaction were seen. In additional comparisons including the nontrial physician cohort, the proportion of participants strongly agreeing that their work was meaningful increased 6.3% in the study intervention arm but decreased 6.3% in the study control arm and 13.4% in the nonstudy cohort (P = .04). Rates of depersonalization, emotional exhaustion, and overall burnout decreased substantially in the trial intervention arm, decreased slightly in the trial control arm, and increased in the nontrial cohort (P = .03, .007, and .002 for each outcome, respectively). CONCLUSIONS AND RELEVANCE An intervention for physicians based on a facilitated small-group curriculum improved meaning and engagement in work and reduced depersonalization, with sustained results at 12 months after the study. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01159977.

Comparison of Phenotype and Outcome in Microscopic Polyangiitis Between Europe and Japan

There are differences between Europe and Japan in the incidence and antineutrophil cytoplasmic antibody (ANCA) serotype of patients with microscopic polyangiitis (MPA). However, differences in phenotype or outcome have not been explored. We aimed to identify differences in phenotype and outcome of MPA between Europe and Japan. Sequential cohorts of patients with MPA and renal limited vasculitis were collected from European and Japanese centers (n = 147 and n = 312, respectively). Trial databases from the European Vasculitis Society and the Japanese patients with Myeloperoxidase (MPO)-ANCA-Associated Vasculitis (JMAAV) trial were studied (n = 254 and n = 48, respectively). We evaluated baseline characteristics including ANCA status and organ involvement, treatment, survival, and renal survival. Differences in survival and renal survival were studied using multivariate analysis. The non-trial cohorts showed patients with MPA in Japan had a higher age at onset, more frequent MPO-ANCA positivity, lower serum creatinine, and more frequent interstitial pneumonitis than those in Europe (all p < 0.01). Comparisons between the trial databases demonstrated similar results. Cumulative patient survival and renal survival rates were not different between Europe and Japan (p = 0.71 and p = 0.38, respectively). Multivariate analysis identified age at onset, serum creatinine, gastrointestinal, and respiratory involvement as factors with higher risk of death. For endstage renal failure, serum creatinine and use of plasma exchange were identified as factors with higher risk, and immunosuppressant use as lower risk factors. Phenotypes in patients with MPA were different between Europe and Japan. However, the outcomes of patient survival and renal survival were similar.

Sequential TPF chemotherapy followed by concurrent chemoradiotherapy in locally advanced head and neck cancer – a retrospective analysis of toxicity and outcomes

Phase III trials have shown that the addition of a taxane to cisplatin/5FU-based induction chemotherapy (TPF) improves response rates and overall survival in unresectable stage III/IV head and neck cancer. We sought to assess the tolerability, compliance and clinical outcomes of this treatment regime. A retrospective study of patients treated within a single centre between September 2007 and November 2010. Toxicities were graded according to CTCAE version 3.0. Survival, distant metastasis and local control rates are expressed as percentages at two years using the Kaplan-Meier method. A total of 100 patients were identified (11% stage III, 86% stage IV) and 32% of patients were admitted as an emergency after TPF. The rate of neutropenic fever was 31%, this number fell to 9% when prophylactic G-CSF was used. In addition, 89% of patients underwent radical chemoradiation. Of these, 96% completed the full radiotherapy course. However, only 64% of patients received a minimum of two cycles of concurrent platinum chemotherapy. The two-year overall survival, metastasis free survival and local control rates were 62.6%, 88.5% and 73.3%, respectively. TPF chemotherapy can be delivered safely in a non-trial cohort of patients. There is, however, a significant reduction in concurrent chemotherapy dose intensity. The long-term impact of this remains unclear.

PROSTATE SPECIFIC ANTIGEN RESPONSE TO MITOXANTRONE AND PREDNISONE IN PATIENTS WITH REFRACTORY PROSTATE CANCER: PROGNOSTIC FACTORS AND GENERALIZABILITY OF A MULTICENTER TRIAL TO CLINICAL PRACTICE

We determine prostate specific antigen (PSA) response and durability, and prognostic factors associated with response and survival in patients with symptomatic hormone refractory prostate cancer treated with mitoxantrone and prednisone at a single institution. We then compare the results with those of a randomized phase III clinical trial. A retrospective review of all 133 patients treated with mitoxantrone and prednisone at Princess Margaret Hospital since 1994 was performed. PSA response and duration, and overall survival were determined as well as the influence of baseline factors on these outcome parameters. Results were compared to those for patients randomized to receive mitoxantrone and prednisone in the Canadian clinical trial which demonstrated palliative benefit of this regimen. Patients treated after trial closure had shorter survival (p = 0.003) but represented a poorer prognosis cohort. PSA response of the trial and post-trial cases was 34% and 28%, respectively (p = 0.36), and median duration of response was 118 and 175 days or greater, respectively. Factors predictive of PSA response in the non-trial cohort were longer time from diagnosis of prostate cancer (p = 0. 027) and higher baseline PSA (p = 0.013). Factors predictive of increased survival in both groups were younger age (p <0.04), better baseline Eastern Cooperative Oncology Group performance status (p <0. 02), and higher hemoglobin (p </=0.05) and PSA response (p <0.0001). Gleason score was not predictive of response or survival. Although patients treated outside of the trial had poorer prognostic features, rates of PSA response to mitoxantrone and prednisone were comparable. Factors predictive of survival were similar in the 2 cohorts. Results of the randomized trial are generalizable to clinical practice.