Early Treatment Discontinuation Research Articles

Genome-wide association studies of toxicity to oxaliplatin and fluoropyrimidine chemotherapy with or without cetuximab in 1800 patients with advanced colorectal cancer.

Chemotherapies administered at normal therapeutic dosages can cause significant side-effects and may result in early treatment discontinuation. Inter-individual variation in toxicity highlights the need for biomarkers to personalise treatment. We sought to identify such biomarkers by conducting 40 genome-wide association studies, together with gene and gene set analyses, for any toxicity and 10 individual toxicities in 1800 patients with advanced colorectal cancer treated with oxaliplatin and fluoropyrimidine chemotherapy ± cetuximab from the MRC COIN and COIN-B trials (385 patients received FOLFOX, 360 FOLFOX + cetuximab, 707 XELOX and 348 XELOX + cetuximab). Single nucleotide polymorphisms (SNPs), genes and gene sets that reached genome-wide or suggestive significance were validated in independent patient groups. We found that MROH5 was significantly associated with neutropenia in MAGMA gene analyses in patients treated with XELOX (P= 6.6 × 10-7 ) and was independently validated in those receiving XELOX + cetuximab; pooled P= 3.7 × 10-7 . rs13260246 at 8q21.13 was significantly associated with vomiting in patients treated with XELOX (odds ratio=5.0, 95% confidence interval=3.0-8.3, P= 9.8 × 10-10 ) but was not independently replicated. SNPs at 139 loci had suggestive associations for toxicities and lead SNPs at five of these were independently validated (rs6030266 with diarrhoea, rs1546161 with hand-foot syndrome, rs9601722 with neutropenia, rs13413764 with lethargy and rs4600090 with nausea; all with pooled P's < 5.0 × 10-6 ). In conclusion, the association of MROH5 with neutropenia and five other putative biomarkers warrant further investigation for their potential clinical utility. Despite our comprehensive genome-wide analyses of large, well-characterised, clinical trials, we found a lack of common variants with modest effect sizes associated with toxicities.

Addition of Polatuzumab Vedotin to Bendamustine and Rituximab (BR) Improves Outcomes in Transplant-Ineligible Patients with Relapsed/Refractory (R/R) Diffuse Large B-Cell Lymphoma (DLBCL) Versus BR Alone: Results from a Randomized Phase 2 Study

Addition of Polatuzumab Vedotin to Bendamustine and Rituximab (BR) Improves Outcomes in Transplant-Ineligible Patients with Relapsed/Refractory (R/R) Diffuse Large B-Cell Lymphoma (DLBCL) Versus BR Alone: Results from a Randomized Phase 2 Study

Phase 2 Study of Brentuximab Vedotin in Patients with Advanced Systemic Mastocytosis

Phase 2 Study of Brentuximab Vedotin in Patients with Advanced Systemic Mastocytosis

Improving Medication Tolerance: A Pilot Study in Disorders of Gut-brain Interaction Treated With Tricyclic Antidepressants.

Tricyclic antidepressants (TCAs) are commonly used to treat disorders of gut-brain interaction (DGBI). However, these medications are often associated with side effects that lead to early treatment discontinuation. Research in other chronic medical conditions suggests that many TCA side effects may be caused by nocebo (negative placebo) effects. The current study tests a brief, verbal intervention aimed at improving tolerance of TCAs in DGBI by providing education about nocebo effects. This pilot randomized controlled trial was performed in a tertiary care gastroenterology clinic. Participants with DGBI were randomized "standard information," describing the benefits and risks of TCAs, or "augmented information," which included an additional <30-second education about nocebo effects. Two weeks after their visit, participants were emailed a survey evaluating the number and bothersomeness of side effects, adequate relief, global improvement, and treatment satisfaction. Thirty-one patients were randomized and 22 responded to the survey. The average age was 40% and 59% were women. Although not statistically significant, the augmented group attributed nominally fewer symptoms to TCAs than the standard group, with a medium effect size (1.5 vs. 4.2, effect size d=0.56, P=0.212) and reported being significantly less bothered by those symptoms (13.4 vs. 38.1, P=0.037). A nominally larger percentage of the augmented group reported adequate relief of symptoms after 2 weeks of treatment compared with the standard group (55% vs. 27%, respectively). This pilot study demonstrates that a brief (≈30 s) clinical intervention addressing nocebo effects may improve tolerance of TCAs. These findings provide support for future, fully powered studies to evaluate the impact of framing on clinical outcomes, especially in chronic conditions.

Hepatitis C Treatment by Nonspecialist Providers in the Direct-acting Antiviral Era.

Hepatitis C virus (HCV) remains under-treated in the United States and treatment by nonspecialist providers can expand access. We compare HCV treatment provision and treatment completion between nonspecialist and specialist providers. This retrospective study used claims data from the Healthcare Cost Institute from 2013 to 2017. We identified providers who prescribed HCV therapy between 2013 and 2017, and patients enrolled in private insurance or Medicare Advantage who had pharmacy claims for HCV treatment. We measured HCV treatment completion, determined based on prescription fills for the minimum expected duration of the antiviral regimen. Using propensity score-weighted regression, we compared the likelihood of early treatment discontinuation by the type of treating provider. The number of providers prescribing HCV treatment peaked in 2015 and then declined. The majority were gastroenterologists, although the proportion of general medicine providers increased to 17% by 2017. Among the 23,463 patients analyzed, 1008 (4%) discontinued before the expected minimum duration. In the propensity score-weighted analysis, patients treated by general medicine physicians had similar odds of treatment discontinuation compared with those treated by gastroenterologists [odds ratio (OR)=1.00, 95% confidence interval (CI): 0.99-1.01, P=0.45]. Results were similar when comparing gastroenterologists to nonphysician providers (OR=1.00, 95% CI: 0.99-1.01, P=0.53) and infectious diseases specialists (OR=1.00, 95% CI: 0.99-1.01, P=0.71). HCV treatment providers remain primarily gastroenterologists, even in the current simplified treatment era. Patients receiving treatment from general medicine or nonphysician providers had a similar likelihood of treatment completion, suggesting that removing barriers to the scale-up of treatment by nonspecialists may help close treatment gaps for hepatitis C.

DOP54 Real-world effectiveness of thiopurine monotherapy in Crohn’s Disease: Is there still a place for thiopurines in the biological era?

Abstract Background In current guidelines, thiopurines are still recommended as first-line maintenance therapy for patients with Crohn’s disease (CD). Due to their lack of immunogenicity, oral administration route and low costs, thiopurines are an attractive first-line treatment option. However, in recent studies the position of thiopurine monotherapy in CD has been questioned as a result of relatively lower overall effectiveness rates compared to ulcerative colitis. Real-world long-term effectiveness data substantiating the use and position of thiopurines in CD management remain sparse. We assessed long-term effectiveness of thiopurine monotherapy in CD using the population-based IBD South-Limburg (IBDSL) cohort. Methods All CD patients in the IBDSL cohort starting thiopurine monotherapy as first-line maintenance therapy between 1991–2014 were included. Thiopurine monotherapy was defined effective if either: (1) no escalation to biological treatment, (2) no course of corticosteroids, (3) no resective surgery or, (4) no hospitalization for active disease was required whilst on thiopurine treatment. Patients with early treatment discontinuation (i.e. &amp;lt;3 months) were identified, including reason of discontinuation. Long-term effectiveness was assessed adjusting for differences in follow-up between patients using Kaplan-Meier analysis. Potential risk factors for therapy failure were identified using Cox regression. Results In total, 643/1162 (55.3%) CD patients (median follow-up: 8.5 years IQR 5.0–13.2) received first-line thiopurine monotherapy after a median of 9.7 months (IQR 3.2–31.3) after diagnosis. Therapy was discontinued within three months in 164 patients (25.5%), mainly due to adverse events [Figure 1]. Thiopurine monotherapy was effective for the duration of treatment in 229/479 (35.6%) patients, corresponding to estimated effectiveness rates of 62.9%, 43.9% and 31.2% after 1, 5 and 10 years, respectively [Figure 1–2]. No significant difference in effectiveness was observed after stratifying for era of thiopurine initiation (pre-biological (1991–1998) vs. biological (&amp;gt;1999) era, p=0.84). Factors associated with thiopurine failure were stricturing disease (aHR 1.41, 95%CI 1.01–1.96) and upper GI involvement (aHR 1.52, 95%CI 1.02–2.28) at diagnosis. During follow-up, 40/229 patients with a durable response discontinued treatment due to quiescent disease. Of these, 35 patients (87.5%) remained without treatment 24 months after discontinuation. Conclusion Real-world data from this population-based study demonstrate that thiopurine monotherapy remains an effective and durable first-line treatment option for CD, even in the biological era. These results should be considered in the ongoing discussion regarding the position of thiopurine therapy.

AMEERA-1: Phase 1/2 study of amcenestrant (SAR439859), an oral selective estrogen receptor (ER) degrader (SERD), with palbociclib (palbo) in postmenopausal women with ER+/ human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (mBC).

1058 Background: AMEERA-1 (NCT03284957) investigates amcenestrant, an oral SERD, as monotherapy and combined with targeted therapies in ER+/HER2– mBC. Here we report data from dose escalation (Part C) and dose expansion (Part D) of amcenestrant + palbo. Methods: Patients (pts) were postmenopausal women with ER+/HER2– mBC and ≥ 6 mos prior advanced endocrine therapy (ET) or adjuvant (adj) ET resistance (relapse on adj ET started ≥ 24 mos ago or &lt; 12 mos after completing adj ET). Prior chemotherapy (≤ 1) for advanced disease was allowed; targeted therapies were not except ≤ 1 CDK4/6i in Part C. Part C assessed dose-limiting toxicities (DLTs) and aimed to establish the recommended phase 2 dose (RP2D) for amcenestrant (200 or 400 mg once daily [QD], in 28-day cycles) in combination with palbo (125 mg QD for 21 days on/ 7 days off). Safety (treatment-emergent adverse events [TEAEs] and lab abnormalities per CTCAE v4.03) and pharmacokinetics (PK) were evaluated. Antitumor activity at the RP2D for amcenestrant + palbo was evaluated in a subset of Part C pts and Part D, according to RECIST v1.1, determined locally by investigators. Results: Feb 8, 2021 data cutoff. In Part C (n = 15; 200 mg: 9; 400 mg: 6), no DLTs occurred and amcenestrant 200 mg QD was selected as the RP2D with palbo, based on PK and safety data. In the pooled safety population at the RP2D (n = 39; Part C: 9; Part D: 30), median (range) age was 59 y (33–86) with ECOG PS 0 (74.4%) or 1 (25.6%) and 2 (1–6) organs involved. Immediate prior therapy was neo/adj (41.0%, all ET resistant) or advanced (59.0%, range 1–4 lines). Median (range) exposure was 32 wks (1–66) with 59.0% pts on ongoing therapy. No amcenestrant dose reductions occurred; 25.6% had ≥ 1 palbo dose reduction. Most common non-hematological TEAEs related to amcenestrant were Grade 1–2 nausea and fatigue (17.9% each), asthenia and hot flush (10.3% each); to palbo were fatigue (30.8%), nausea (25.6%), asthenia and dysgeusia (10.3% each). Two pts discontinued due to AEs. The majority (94.9%) had neutrophil count decrease (53.8% Grade ≥ 3). Preliminary antitumor activity after at least 6 cycles of therapy (unless early treatment discontinuation) is reported in the table below. Conclusions: In pts with ER+/HER2– mBC, safety at the RP2D of amcenestrant + palbo was favorable, with no safety signals of bradycardia or eye disorders. Preliminary antitumor activity was observed (ORR: 31.4% and CBR: 74.3%). Clinical trial information: NCT03284957 .[Table: see text]

Clinical significance of the cachexia index in patients with small cell lung cancer

BackgroundCancer cachexia worsens the treatment outcomes of patients with small-cell lung cancer (SCLC). However, no reliable biomarker of cancer cachexia is yet known.MethodsWe retrospectively evaluated male SCLC patients who received induction chemotherapy or concurrent chemoradiotherapy. The cachexia index (CXI) was calculated as skeletal muscle index × serum albumin level (g/dL)/neutrophil-to-lymphocyte ratio. The CXI cutoff according to tumor stage was determined based on a time-dependent receiver operating characteristic curve, and all patients were divided into low- and high-CXI groups.ResultsOf 267 patients, 83 and 24 patients with limited-stage disease (LD) and 123 and 37 patients with extensive-stage disease (ED) were assigned to the high- and low-CXI groups, respectively. Only one of 24 patients (4.2%) with LD in the low-CXI group achieved a complete response (CR), whereas 30 of 83 patients (36.1%) with LD in the high-CXI group achieved CRs (p = 0.004). More low-CXI patients required early discontinuation of treatment because of treatment-related toxicity compared to the high-CXI patients (37.5% vs. 16.9%, respectively, p = 0.030, for LD patients; 27.0% vs. 11.4%, respectively, p = 0.019, for ED patients). The median progression-free survival (PFS) and overall survival (OS) were significantly shorter in the low-CXI group than the high-CXI group (6.3 vs. 11.1 months and 7.5 vs. 20.6 months, respectively, both p < 0.001 for LD patients; 2.9 vs. 6.3 months and 5.8 vs. 12.8 months, respectively, both p < 0.001, for ED patients). On multivariate analysis, low-CXI status was an independent poor prognostic factor for both PFS and OS regardless of the tumor stage.ConclusionA low CXI was associated with treatment intolerance, poor treatment response rate, and poor prognosis in SCLC.

The impact of cachexia and sarcopenia in elderly pancreatic cancer patients receiving palliative chemotherapy.

Elderly pancreatic cancer (PC) patients are often considered vulnerable to treatment and standard treatment strategy for this subpopulation is uncertain. Cachexia and sarcopenia are reported to be associated with reduced physical performance, reduced anti-tumor response, increased chemotherapy toxicity, and poor prognosis in several malignancies. The aim of this study was to evaluate the impact of cachexia and sarcopenia on the clinical course of elderly PC patients receiving chemotherapy. We retrospectively investigated consecutive elderly metastatic PC patients (≥ 75years) treated with chemotherapy at our institution between January2015 and April2020. Skeletal muscle index was calculated at the third lumbar vertebra using pretreatment computed tomography. We evaluated time to treatment failure (TTF), progression-free survival (PFS), overall survival (OS), early treatment discontinuation, relative dose intensity (RDI), and severe adverse events (AEs). Among 80 patients included (gemcitabine plus nab-paclitaxel [GnP] 52; gemcitabine 21; S1 6; modified FOLFIRINOX 1), cachexia and sarcopenia were present in 48 (60%) and 61 (76%) patients, respectively. Cachexia was associated with older age, worse performance status, higher level of neutrophil to lymphocyte ratio, worse nutritional status, and shorter TTF and PFS. Furthermore, it was also associated with early treatment discontinuation, reduced RDI of nab-paclitaxel, and increased incidence of grade 4 neutropenia in patients receiving GnP. On the other hand, sarcopenia had less impact on the clinical course of elderly PC patients. In our experience, cachexia was considered an effective tool in the management of elderly PC patients receiving palliative chemotherapy.

Antipsychotic Treatment Duration in Children and Adolescents: A Register-Based Nationwide Study.

Objective: Despite the increasing use of antipsychotic drugs in children and adolescents in many countries, little is known about the treatment duration in this vulnerable population. The present nationwide study investigated the duration of antipsychotic treatment and factors associated with treatment discontinuation in Finnish children and adolescents. Methods: All subjects aged 1-17 years who had started a second-generation antipsychotic (SGA) drug (risperidone, quetiapine, aripiprazole, or olanzapine) between January 2008 and December 2016 (n = 20,932) were extracted from the Finnish Prescription Registry and followed up until December 31, 2017. Treatment duration was calculated as the time between the initial purchase of medication and treatment discontinuation. Treatment was considered discontinued if the treatment-free gap was more than 270 days. The associations between explanatory factors and treatment discontinuation were analyzed with the Cox proportional hazards models. Results: The mean and median treatment durations were 509 days (95% confidence interval [95% CI]: 500-517 days) and 317 days (95% CI: 306-325 days), respectively. The duration was shorter in girls than in boys (p < 0.001). Of all SGA users, 35.1% used antipsychotics less than 50 days and 16.0% used more than 600 days. Shorter treatment duration was associated with age groups of 7-12 and 13-15 years compared with 1-6 years (hazard ratio [HR]:1.23 [95% CI: 1.11-1.36]; HR: 1.35 [95% CI: 1.21-1.51], respectively) and initiating treatment with quetiapine or olanzapine compared with risperidone (HR: 1.18 [95% CI: 1.12-1.25]; HR: 1.66 [95% CI 1.46-1.88], respectively). Switching of SGA drug during treatment was associated with longer treatment duration (HR: 0.40 [95% CI: 0.38-0.43]). Conclusions: In children and adolescents, the mean treatment duration of SGAs was relatively long given that the majority of SGA use was off-label. Older age and initiating treatment with quetiapine were associated with earlier treatment discontinuation, whereas switching of antipsychotic drug during therapy increased the possibility of longer SGA use.

Does trastuzumab-related cardiotoxicity influence long-term outcome in patients with HER-2 positive breast cancer? A prospective study

IntroductionTrastuzumab is a monoclonal antibody directed against the HER-2 receptor that has led, in an adjuvant setting, to higher disease-free (DFS) and overall survival (OS) in HER-2 positive breast cancer (BC) compared with chemotherapy alone. Cardiotoxicity often results in early discontinuation of trastuzumab, which may elevate the risk of cancer recurrence or mortality. Our study aimed to assess how early interruption or early permanent termination of adjuvant trastuzumab treatment influences DFS and OS of patients with HER-2 positive BC.Material and methodsThis is a prospective observation of 253 women (55 ±10 years of age) with HER-2 positive unilateral, non-metastatic BC treated with trastuzumab in an adjuvant setting. To monitor the safety of the treatment echocardiography was performed at baseline and every 3 months up to 12 months after the end of therapy. If cardiotoxicity developed, trastuzumab was stopped early. Overall survival and DFS were assessed.ResultsTrastuzumab-associated cardiac complications resulting in treatment discontinuation developed in 52 (20.55%) patients. Median DFS time was 21.1 months in the group with interruption compared with 25.7 months in the group with full trastuzumab treatment, being significantly shorter (HR = 2.32, 95% CI: 1.15–4.71, p = 0.0106). Two year OS in the interruption and no-interruption groups were 80.8% and 88.5%, respectively, which were not statistically significantly different (p = 0.268). In a multivariate regression analysis the cumulative dose of anthracycline (OR = 1.01, 95% CI: 1.00–1.01, p = 0.002) and LVEF at baseline (OR = 0.83, 95% CI: 0.70–0.99, p = 0.0344) were independent predictors of a cardiotoxic effect.ConclusionsTrastuzumab-related cardiotoxicity resulting in early treatment discontinuation negatively influences DFS, but does not seem to influence OS.

Real-world retrospective observational study exploring the effectiveness and safety of antifibrotics in idiopathic pulmonary fibrosis

BackgroundPirfenidone and nintedanib are the only disease-modifying treatments available for idiopathic pulmonary fibrosis (IPF). Our aim was to test their effectiveness and safety in clinical practice.MethodsThis is a single-centre retrospective...

Safety and Efficacy of Checkpoint Inhibition in Patients With Melanoma and Preexisting Autoimmune Disease : A Cohort Study.

Because immune checkpoint inhibition (ICI) can cause immune-related adverse events (irAEs) mimicking immunologic diseases, patients with preexisting autoimmune disease (AID) have been excluded from clinical trials. To evaluate the safety and efficacy of ICI in patients with advanced melanoma with and without AID. Nationwide cohort study. The Netherlands. 4367 patients with advanced melanoma enrolled in the Dutch Melanoma Treatment Registry (DMTR) between July 2013 and July 2018 and followed through February 2019. Patient, clinical, and treatment characteristics; irAEs of grade 3 or higher; treatment response; and survival. A total of 415 patients (9.5%) had AID, categorized as rheumatologic AID (n = 227), endocrine AID (n = 143), inflammatory bowel disease (IBD) (n = 55), or "other" (n = 8). Of these, 228 patients (55%) were treated with ICI (vs. 2546 [58%] without AID); 87 were treated with anti-cytotoxic T lymphocyte-associated protein 4 (CTLA-4), 187 with anti-programmed cell death 1 (PD-1), and 34 with the combination. The incidences of irAEs of grade 3 or higher in patients with AID were 30% (95% CI, 21% to 41%) with anti-CTLA-4, 17% (CI, 12% to 23%) with anti-PD-1, and 44% (CI, 27% to 62%) with combination therapy; for patients without AID, the incidences were 30% (CI, 27% to 33%) (n = 916), 13% (CI, 12% to 15%) (n = 1540), and 48% (CI, 43% to 53%) (n = 388), respectively. Patients with AID more often discontinued anti-PD-1 treatment because of toxicity than patients without AID (17% [CI, 12% to 23%] vs. 9% [CI, 8% to 11%]). Patients with IBD were more prone to anti-PD-1-induced colitis (6/31 = 19% [CI, 7% to 37%]) than patients with other AIDs (3% [CI, 0% to 6%]) and patients without AID (2% [CI, 2% to 3%]).The objective response rate was similar in patients with versus without AID who were treated with anti-CTLA-4 (10% [CI, 5% to 19%] vs. 16% [CI, 14% to 19%]), anti-PD-1 (40% [CI, 33% to 47%] vs. 44% [CI, 41% to 46%]), or the combination (39% [CI, 20% to 59%] vs. 43% [CI, 38% to 49%]). Survival did not differ between patients with and those without AID (median, 13 months [CI, 10 to 16 months] vs. 14 months [CI, 13 to 15 months]). Information was limited on AID severity and immunosuppressive treatment. Response to ICI with anti-CTLA-4, anti-PD-1, or their combination for advanced melanoma and overall incidence of any irAEs of grade 3 or higher were similar in patients with and without preexisting AID. However, severe colitis and toxicity requiring early discontinuation of treatment occurred more frequently among patients with preexisting IBD, warranting close follow-up. The Netherlands Organization for Health Research and Development.

Safety profile of immune checkpoint inhibitors versus sorafenib as first-line treatment in advanced hepatocellular carcinoma: A meta-analysis of randomized controlled trials.

315 Background: Systemic treatment with tyrosine kinase inhibitors such as sorafenib represents the mainstay of advanced-stage hepatocellular carcinoma (HCC). However, survival outcomes remain disappointing, mostly because of the onset of acquired resistance and a suboptimal safety profile, which frequently requires treatment modifications and early discontinuation of treatment – thus, interfering with compliance and long-term outcomes of patients. With immune checkpoint inhibitors (ICIs) quickly expanding as a novel therapeutic option in advanced HCC, the toxicity profiles of these agents should be kept in mind. We performed a meta-analysis with the aim to compare all-grade (G) adverse drug events (ADEs) of ICIs (alone or in combination with other anticancer agents) versus sorafenib monotherapy across randomized controlled trials (RCTs) of first-line treatment for advanced HCC. Methods: Eligible studies included RCTs comparing ICIs versus sorafenib as first-line treatment in HCC. Safety profile from each selected study was investigated for all-G most common ADEs. Outcomes of interest were as follows: pruritus, diarrhea, hand-foot skin reaction (HFSR), fatigue, aspartate aminotransferase (AST) increase, rash, hypertension and decreased appetite. Results were compared by calculating odds ratios (ORs) with 95% confidence intervals (CIs); ORs were combined with Mantel-Haenszel method. All statistical analyses were performed using R studio software. Results: Two RCTs (CheckMate 459, IMbrave 150) involving 1,228 patients were included in the analysis. Patients treated with ICIs showed higher risk of pruritus (OR 1.99, 95% CI = 1.22-3.24) while sorafenib treatment was associated with higher risk of diarrhea (OR 0.26, 95% CI = 0.18-0.37) and HFSR (OR 0.01, 95% CI = 0-0.04). Conversely, no statistically significant differences were observed in terms of fatigue (OR 0.84, 95% CI = 0.45-1.58), AST increase (OR 1.21, 95% CI = 0.78-1.88), rash (OR 0.71, 95% CI = 0.46-1.11), hypertension (OR 0.28, 95% CI = 0.01-9.76) and decreased appetite (OR 0.41, 95% CI = 0.14-1.21) between the two groups. Conclusions: Although the substantial heterogeneities affecting our analyses, ICIs appear feasible in advanced HCC, being endowed with an acceptable safety profile. Beyond activity and efficacy, careful consideration should be given to toxicity while choosing the appropriate first-line treatment in advanced HCC.

Myosteatosis evaluation using erector spinae and psoas muscles to predict adverse events during adjuvant chemotherapy for breast cancer.

Myosteatosis (intramuscular adiposity) is predictive of chemotherapy toxicity in women undergoing adjuvant chemotherapy for breast cancer (BC). We evaluated a novel, user-friendly and cost-effective technique utilizing a Picture Archiving and Communication Systems (PACS) tool that is readily available in the electronic medical record (EMR), using skeletal muscle density (SMD) to detect myosteatosis and then compared PACS results with those derived from widely used body composition software (SliceOMatic, QC, Canada). Using retrospective data from a sample of women with early BC (Stage I-III) who had CT scan and received chemotherapy. Pearson correlation coefficients were used to compare SliceOMatic with PACS results. Associations of PACS results with chemotherapy-related adverse events were evaluated using multivariable (MV) log-binomial models adjusted for age, race, BMI, anthracycline-based therapy, and number of comorbidities. In 338 patients, mean age was 51, 32% were non-white, and 40% had obesity (BMI ≥ 30kg/m2). Correlation of SMD using SliceOMatic whole muscle measurements with PACS psoas muscle was 0.76 (p < .0001) and with PACS erector spinae muscle 0.91 (p < .0001). Using PACS psoas muscle, myosteatosis was associated with any adverse event [RR 1.66, CI 1.22-2.26 (p < .0001)], dose reduction [RR 1.63, CI 1.01-2.65 (p = .05)], and early treatment discontinuation [RR 2.14, CI 1.10-4.14 (p = 0.03)]. Using PACS erector spinae muscle, myosteatosis was associated any adverse event [RR 1.59, CI 1.11-2.27 (p = 0.01)] and dose reduction [RR 1.91, CI 1.07-3.42 (p = .03)]. Skeletal muscle density measures using PACS correlated strongly with SliceOMatic results and both are similarly predictive of chemotherapy-related adverse events.

Short Versus Extended Treatment with a Carbapenem in Haematology Patients with High Risk Fever of Unknown Origin During Neutropenia: An Open-Label Multicentre Randomised Clinical Trial

Background: Early antibiotic discontinuation in haematology patients with fever of unknown origin during chemotherapy-induced neutropenia has been advocated to reduce unnecessary antibiotic treatment, but the safety of this strategy is unknown. We aimed to assess if short treatment with carbapenems is non-inferior to extended treatment. Methods: In this randomised, multicentre, non-inferiority trial we assigned 292 haematology patients with fever of unknown origin during high-risk neutropenia (≥7 days) to short treatment, with carbapenem discontinuation after 72 hours (± 12 hours), or extended treatment, with carbapenem continuation for ≥ 9 days until being afebrile for 5 days or neutrophil recovery. The composite primary endpoint was treatment failure, defined as recurrent fever or a carbapenem-sensitive infection between day 4 and day 9 and septic shock/respiratory failure or death from day 4 until neutrophil recovery. Findings: Treatment failure in the intention-to-treat analysis (281 patients) was 19·4% (28/144) in the short treatment versus 15·3% (21/137) in the extended treatment arm (adjusted risk difference 4·0%, 90% confidence interval [CI] -1·7% to 9·7%, excluding the 10% non-inferiority threshold). Mortality until 30 days after neutrophil recovery occurred in five patients (3·5%) in the short treatment group and in one (0·7%) in the extended treatment group (adjusted risk difference 2·6%, 95% CI % 1·2 to 5·4%), of which none were related to infections with carbapenem-sensitive microorganisms. Interpretation: Early discontinuation of carbapenem treatment in neutropenic patients with fever was non-inferior to extended treatment with regard to treatment failure, but all-cause mortality before 30 days after neutrophil recovery was significantly higher in patients with persistent fever at day 3. Early discontinuation of carbapenem treatment is therefore possible in afebrile patients, but caregivers should be vigilant of other non-carbapenem susceptible infections in patients with persistent fever.: Clinical Trial Registration Details: This trial is registered with ClinicalTrials.gov (number NCT02149329). Funding Information: Dutch Research Council (ZonMw) and Fonds NutsOhra. Declaration of Interests: The authors 408 declare no competing interests. Ethics Approval Statement: The protocol was approved by the research ethics review committee of VU university medical centre (current name: Amsterdam University medical centres, location VUmc) and ethical bodies of each participating centre. An independent data and safety monitoring board oversaw study procedures and data quality during conduct of the study and performed a planned interim safety analysis. All participants provided written informed consent.

Flare phenomenon in prostate cancer: recent evidence on new drugs and next generation imaging.

Over the years, an increasing proportion of metastatic prostate cancer patients has been found to experience an initial bone flare phenomenon under both standard therapies (androgen deprivation therapy, chemotherapy, radiotherapy, abiraterone, enzalutamide) and novel agents (immunotherapy, bone-targeting radioisotopes). The underlying biological mechanisms of the flare phenomenon are still elusive and need further clarification, particularly in relation to different types of treatment and their treatment response assessment. Flare phenomenon is often underestimated and, in some cases, can negatively affect clinical outcome. In cases with suspected bone flare, the treatment should be continued for a minimum of 12 more weeks before further decisions about efficacy can be taken. Physicians and patients should be aware of this effect to avoid unwarranted anxiety and inadequate early discontinuation of treatment. This review aims at highlighting new evidence on flare phenomenon arising after the introduction of new drugs extending across the biochemical, radiographic and clinical spectrum of the disease.

Prediction of Therapeutic Outcome in a Naturalistic Setting Using Pretreatment Psychological Distress Indicators

Background: Outcome predictions allow to improve psychotherapy and to increase economic benefit. The efficient translation into practice requires simple prediction methods. The present study evaluates the prediction of treatment outcome based on initial distress level. Methods: Routine data of a university psychotherapy outpatient clinic were used (N = 3,145, M_age = 35.8, 67% female). Low versus high distress patients (classified by overall psychological distress, symptomatology, and previous treatment) were compared on total reduction in psychopathology, (early) response, remission, and premature treatment discontinuation using t tests and logistic regressions. Response and remission were assessed via relative (percentage improvement) and absolute measures (Reliable Change Index; RCI). Results: Distress level was inversely related to percentage improvement (OR = 0.62) and remission (OR = 0.34). It was positively related to total reduction in psychopathology (d = 0.63), RCI response (OR = 2.37), and treatment discontinuation (OR = 2.15). Early response and treatment discontinuation partially mediated the relationship between distress level and treatment outcome. Conclusions: Treatment success tends to be lower when initial distress is high, but this finding appears contingent on the operationalization of treatment outcome. The presented classification approach is easy to implement in practice and may be useful in order to counter an excessive workload in psychotherapy trainees.

Patient-reported symptom severity, interference with daily activities, and adverse events in older and younger women receiving chemotherapy for early breast cancer.

To the authors' knowledge, it is unknown whether patient-reported symptom severity and symptom interference with daily activities differ between younger (aged <65 years) and older (aged ≥65 years) women receiving similar chemotherapy regimens for early breast cancer (EBC). Study participants rated 17 side effects of chemotherapy regimens currently in use in clinical practice (2014-2019). Of 284 women with EBC (stage I-III), approximately 57% were aged <65 years and 43% were aged ≥65 years. For anthracycline-based regimens, a higher percentage of younger women reported moderate, severe, or very severe (MSVS) hot flashes (49% vs 18%) (P < .001). For nonanthracycline regimens, a higher percentage of younger women reported MSVS hot flashes (38% vs 19%) (P = .009) and a lower percentage reported MSVS arthralgia (28% vs 49%) (P = .005). With regard to symptom interference with daily activities, a higher percentage of younger women being treated with anthracycline-based regimens reported MSVS hot flashes (32% vs 7%) (P = .001) and myalgia (38% vs 18%) (P = .02). For nonanthracycline chemotherapy, a higher percentage of younger women reported MSVS interference for hot flashes (26% vs 9%) (P = .006) and lower percentages reported abdominal pain (13% vs 28%) (P = .02). Overall, there were no significant differences noted among younger versus older patients with regard to hospitalizations (19% vs 12%; P = .19), dose reductions (34% vs 31%; P = .50), dose delays (22% vs 25%; P = .59), or early treatment discontinuation (16% vs 16%; P = .9546). Older and younger women with EBC who were treated with identical chemotherapy regimens generally experienced similar levels of symptom severity, symptom-related interference with daily activities, and adverse events. In this study, women receiving chemotherapy for early breast cancer rated the severity of 17 symptoms and symptom interference with their activities of daily living. Older (aged ≥65 years) and younger (aged <65 years) women who received identical chemotherapy regimens generally experienced similar levels of symptom severity, symptom-related interference with daily activities, and adverse events.

PCSK9 inhibition in clinical practice: Treatment patterns and attainment of lipid goals in a large health maintenance organization

BackgroundProprotein convertase subtilisin/kexin type-9 inhibitors (PCSK9i) effectively reduce low-density lipoprotein cholesterol (LDL-C), improving cardiovascular outcomes in clinical trials when added to statin therapy. ObjectivesAs real-world evidence is lacking, we aimed to evaluate treatment and adherence patterns using PCSK9i in clinical practice. MethodsWe investigated 1600 patients initiating PCSK9i between January 2016 and December 2019 in a large health maintenance organization. Treatment discontinuation was defined as a gap ≥60 days between last days' supply of one prescription and the start of the next. Re-initiation rates as well as proportion of days covered (PDC) over 1-year period and attainment of lipid goals under PCSK9i, were analyzed. ResultsEvolocumab 140 mg was initiated by 50.7%, alirocumab 75 mg by 29.5% and 150 mg by 19.8%. Cumulative discontinuation rates were 28.1% after 6-months and 49.9% after 3-years. Overall, 58% of the patients that discontinued therapy have re-initiated PCSK9i (31% after 3-months from discontinuation). Mean PDC over 1-year of therapy was 56% ± 29, with PDC ≥80% evident in 29%. Of those with established cardiovascular disease (n = 991), 55% achieved LDL-C<70 mg/dL and 38% LDL-C<55 mg/dL. Attainment rates were lower in patients with PDC<80%, baseline LDL-C>190 mg/dL and in those not treated with concurrent statin therapy. ConclusionsIn real-world practice of patients treated by PCSK9i, high proportion of early treatment discontinuation was evident, with non-negligible re-initiation rates but overall low medication coverage over time. This have contributed to sub-optimal attainment of LDL-C treatment goals, particularly observed in patients with severe hypercholesterolemia, inadequate drug adherence, and those using PCSK9i as monotherapy.