Treatment Toxicity In Patients Research Articles

Prognostic nutritional index and neutrophil-lymphocyte ratio predict toxicities and prognosis in patients with cervical cancer treated with curative radiochemotherapy

BackgroundThis study aimed to investigate the influence of immunonutritional factors on treatment-related toxicities and survival outcomes in patients with cervical cancer undergoing definitive radiochemotherapy. MethodsPatients with cervical cancer who received curative radiochemotherapy between 2016 and 2021 were retrospectively investigated. Pretreatment prognostic nutritional index (PNI), neutrophil-lymphocyte ratio (NLR), monocyte-lymphocyte ratio (MLR), and platelet-lymphocyte ratio (PLR) were measured. Survival outcomes, acute and late toxicities were evaluated. ResultsAmong the 138 patients, those with larger tumor diameters had significantly lower pre-treatment PNI (p = 0.005). Pre-treatment immunonutritional factors were predictive of clinical survival, whereas post-treatment factors did not correlate with prognosis. Patients with low pre-treatment PNI (<49.5) or high NLR (>2.4) had shorter progression-free survival (PFS, HR: 1.86, p = 0.045 for PNI; HR: 3.15, p = 0.002 for NLR) and overall survival (OS, HR: 1.80, p = 0.048 for PNI; HR: 3.83, p = 0.015 for NLR). High pre-treatment NLR was associated with an increased risk of acute diarrhea (p = 0.049) and late severe toxicities (p = 0.046). Combined analysis revealed that pre-treatment good nutritional status and low systemic inflammation were linked to longer PFS (p = 0.007) and OS (p = 0.002), and poor nutritional status and substantial systemic inflammation were associated with higher rates of late severe toxicities (p = 0.036), with higher prognostic value in advanced stage patients. ConclusionPretreatment immunonutritional measures serve as quantitative biomarkers for predicting survivals and treatment toxicities in patients with cervical cancer treated with definitive radiochemotherapy.

Rectum and Bladder Toxicity in Postoperative Prostate Bed Irradiation: Dose-Volume Parameters Analysis.

Although prostate cancer treatment is increasingly effective, its toxicities pose a major concern. The aim of our study was to assess the rate of adverse events (AEs) and the prognostic value of dose-volume histogram (DVH) parameters for the occurrence of treatment toxicity in patients treated with post-prostatectomy prostate bed radiotherapy (RT). The AEs were scored according to the CTCAE v.5.0. The rectum and bladder were contoured according to the RTOG Guidelines. The DVH parameters were assessed using data exported from the ECLIPSE treatment-planning system. Genitourinary (GU) and gastrointestinal (GI) toxicity were analysed using consecutive dose thresholds for the percentage of an organ at risk (OAR) receiving a given dose and the QUANTEC dose constraints. A total of 213 patients were included in the final analysis. Acute grade 2 or higher (≥G2) GU AEs occurred in 18.7% and late in 21.3% of patients. Acute ≥G2 GI toxicity occurred in 11.7% and late ≥G2 in 11.2% of the patients. Five patients experienced grade 4 AEs. The most common adverse effects were diarrhoea, proctitis, cystitis, and dysuria. The most significant predictors of acute ≥G2 GI toxicity were rectum V47 and V46 (p < 0.001 and p < 0.001) and rectum wall V46 (p = 0.001), whereas the most significant predictors of late ≥G2 GI AEs were rectum wall V47 and V48 (p = 0.019 and p = 0.021). None of the bladder or bladder wall parameters was significantly associated with the risk of acute toxicity. The minimum doses to bladder wall (p = 0.004) and bladder (p = 0.005) were the most significant predictors of late ≥G2 GU toxicity. Postoperative radiotherapy is associated with a clinically relevant risk of AEs, which is associated with DVH parameters, and remains even in patients who fulfil commonly accepted dose constraints. Considering the lack of survival benefit of postoperative adjuvant RT, our results support delaying treatment through an early salvage approach to avoid or defer toxicity.

The role of chemotherapy toxicity scales in decision-making for acute leukemia and lymphoma: a scoping review

Acute leukemias and non-Hodgkin lymphomas together rank 4th among the most common neoplasms. With curative treatment options, even in adverse situations, however, the decision-making process is delicate and statistical models can help. To identify the chemotherapy toxicity scales and their role in decision-making for the treatment of patients with acute lymphomas and leukemias, we conducted a scoping review on the PUBMED, BIREME, COCHRANE, and CAPES journal data platforms. Thirty articles were selected using the PRISMA protocol approach. There is no ideal scale for assessing chemotherapy toxicity, but there are common variables, such as comorbidities, functionality, age, LDH, renal function, and disease staging. Predictive models of treatment toxicity in patients with acute leukemia and lymphoma require more robust and prospective studies that include the validation of these models for better applicability.

Determinants of Treatment Toxicity in Patients with Soft Tissue Sarcomas

Soft tissue sarcomas are rare malignant tumors. Traditionally, treatment is guided by patient and tumor characteristics. Data on the influence of patient characteristics, particularly nutritional status, on clinical outcomes are scarce. Body composition and its changes during treatment play an essential role in predicting toxicity, clinical outcomes, and mortality. This analysis aimed to investigate the relationship between treatment toxicity and body composition. Patients diagnosed with sarcoma who underwent first-line palliative chemotherapy between October 2017 and January 2020 were included. Baseline and follow-up computed tomographic scans at the third lumbar vertebra, available from diagnostic purposes, were analyzed using SliceOmatic software. Treatment toxicity was defined as a composite score of the Common Terminology Criteria for Adverse Events. Nutritional Risk Screening (NRS) 2002 score, psoas muscle thickness to height ratio, and comorbidity showed a significant association with overall toxicity, while skeletal muscle index and age showed a strong trend. In summary, the NRS 2002 tool must be routinely implemented in inpatient and outpatient settings for cancer patients, and nutritional therapy needs to become a fixed component of multimodal cancer treatment. Furthermore, validated standardized procedures for the quantification of muscle mass are needed to individualize and optimize cancer treatment.

Abstract 1564: Novel combination of TRIP13 and Aurora kinase A inhibition demonstrated extensive DNA damage and immunogenic cell death in RB-deficient cancers

Abstract Many lethal cancer types have inactivation of the retinoblastoma (Rb) tumor suppressor pathway including cancers caused by human papillomavirus (HPV), which causes &amp;gt;5% of all cancers worldwide. There are no therapies that uniquely target Rb-deficient cancers. Biomarker-selected, molecular targeted therapy for Rb-deficient cancers represents both an unmet need and a translational knowledge gap. To address this gap, we recently published data that support a model in which Rb-deficient cancers, having high levels of Mad2, survive owing to TRIP13-mediated inhibition of Mad2 and Aurora A-mediated mitotic progression. The combination of Aurora A inhibition (alisertib) plus TRIP13 depletion caused extensive apoptosis in Rb-deficient, but not in Rb-proficient, cancer cells. Both Aurora A and TRIP13 are involved in the cell’s response to DNA damage and apoptosis that can lead to immunogenic cell death (ICD), prompting us to investigate the mechanism underlying the synthetic lethality of TRIP13 and Aurora A in Rb-deficient cancer cells. We transfected two HPV+ cell lines with TRIP13 or control siRNA and incubated with 100nM alisertib. We also generated two stable HPV+ cell lines with TRIP13KO. In both these systems, TRIP13 KD or KO alone did not cause apoptosis. Incubation with alisertib resulted in significant cell death, that validated our previous findings. We then tested the effect of the combination on DNA damage. Alisertib caused robust increases in γH2AX, pTIF1β (KAP1, TRIM28), and DNA PKcs, measured using immunoblotting, in both TRIP13 KD and KO HPV+ cell lines. We also observed enhanced γH2AX staining using confocal microscopy. ICD leads to activation of immune cells by the dying cancer cells in the tumor microenvironment involving the release of antigenic fragments that are engulfed, processed and presented by antigen presenting cells for the induction of antigen-specific T-cell responses. Studies have shown DNA damage stimulates the cGAS/STING pathway leading to ICD. In our system, we saw that TRIP13KO and KD in HPV+ cells treated with alisertib, resulted in marked activation of the cGAS/STING pathway and release of cytochrome C and IL1α in the cell supernatant, which are markers of pyroptosis. Additionally, we also observed gasdermin-E cleavage. The combination further led to increased cancer cell secretion of GM-CSF, IL6, and IL18 that can activate macrophages, NK cells and T-cells. The selective effect of the combination in Rb-deficient cancer cells allowed us to significantly reduce the concentration of alisertib. By sparing normal cells that express Rb, this combination can potentially reduce treatment toxicity in patients with Rb-deficient cancers. The ICD induced by this combination may lead to host T-cell engagement, thereby further enhancing tumor elimination. This work can shape future clinical trials that can change current treatment regime. Citation Format: Soma Ghosh, Tuhina Mazumdar, Lacin Yapindi, Pragya Sinha, Jagannadha Sastry, Faye M. Johnson. Novel combination of TRIP13 and Aurora kinase A inhibition demonstrated extensive DNA damage and immunogenic cell death in RB-deficient cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1564.

Enteral nutrition support and treatment toxicities in patients with head and neck cancer receiving definitive or adjuvant helical intensity-modulated radiotherapy with concurrent chemotherapy.

Enteral nutrition (EN) is often required in patients with head and neck cancer (HNSCC); however, initiation criteria is limited or inconsistent. This study aimed to describe the relationship of treatment toxicities and requirement for EN and investigate toxicity and baseline characteristics association with EN duration. Acute toxicities and baseline characteristics were collected from patients with HNSCC (n=110) undergoing H-IMRT. Percentage EN contributing to estimated requirements and EN duration were measured. The threshold for patients needing ≥50% of estimated requirements via EN increased from week 3 to 4 for grade ≥2 oral/pharyngeal mucositis, dysgeusia, thick saliva and nausea, and for grade 3 dysphagia. Patients with grade 2-3 dysphagia had a reduced risk of ceasing EN compared to those with grade 0-1 dysphagia. Using acute toxicities in clinical practice may be a useful tool to inform prompt initiation of EN prior to decline in nutritional status and anticipate EN duration.

346P Influence of single nucleotide polymorphisms in genes involved in capecitabine activation pathway on treatment toxicity in patients with colorectal cancer

Capecitabine, an oral pro-drug of 5-fluorouracil, is part of the standard treatment of colorectal cancer (CRC). Severe adverse drug reactions that impair treatment safety remain a relevant concern. Hand-foot-syndrome (HFS) is the most frequently reported dose-limiting side effect of capecitabine. Genotyping of 4 variants of the DPYD gene is currently standard practice for capecitabine-related toxicity prediction. However, numerous studies have reported that single nucleotide polymorphisms (SNPs) in genes of capecitabine activation pathway (CES1, CES1P1, CES2, CDA, TYMP) may also contribute to individual variation in toxicity.

Impact of proactive symptom monitoring on quality of life (QoL) and treatment toxicity in patients with cancer receiving chemotherapy: A meta-analysis of randomized clinical trials.

1545 Background: Early recognition and management of symptoms can improve outcomes in cancer patients receiving treatment. A number of randomized trials have investigated the effects of adding proactive symptom monitoring to usual care (UC). These include web-based, application-based, or telephone-based assessments. Results have been variable, and the impact of proactive symptom monitoring on QoL, treatment toxicity and utilization of unscheduled acute care remains unclear. Methods: A systematic search of MEDLINE identified prospective, randomized trials that studied the effect of proactive monitoring and intervention versus UC in cancer patients receiving chemotherapy. The difference between proactive symptom monitoring and UC on the mean and SD for QoL using validated scales was collected for each study and pooled in a meta-analysis. Analysis was performed using the standardized mean difference (SMD) using random-effects modeling. The effect size was reported as the Hedges’ adjusted g. We also calculated the odds ratios (OR) for the occurrence of several common symptoms of any grade in the individual trials and pooled them in a meta-analysis. Statistical significance was defined as P &lt; 0.05. Quantitative significance was defined as a difference in QoL score exceeding the minimal clinically important difference (MCID) based on previous studies for each QoL framework. Results: Of the 17 trials which met eligibility criteria, FACT-G and EORTC QLQ C30 were the most consistently utilized QoL tools. The mean difference in score between intervention and control at the last evaluation visits was 2.82 (95% CI -0.57 to 6.21; P = 0.10) in FACT-G and 2.33 (95% CI -0.29 to 4.96; P = 0.08) in EORTC QLQ C30, neither of which met quantitative or statistical significance. There was a statistically significant reduction in fatigue (OR 0.67, 95% CI 0.46 to 0.97; P = 0.04), but no difference in constipation (OR 0.63, 95% CI 0.34 to 1.17; P = 0.15), nausea (OR 1.03, 95% CI 0.72 to 1.47; P = 0.89), pain (OR 0.83, 95% CI 0.62 to 1.10; P = 0.19), or diarrhea (OR 1.41, 95% CI 0.40 to 5.01; P = 0.60). SMD for symptom severity was calculated for fatigue, diarrhea, and nausea. Severity of fatigue was statistically lower with proactive symptom monitoring (SMD -0.45, 95% CI -0.69 to -0.22; I² = 0%, P &lt; 0.001), however, magnitude of effect was modest. Conclusions: Proactive symptom monitoring in cancer patients receiving treatment is not associated with significant or meaningful QoL improvement. Similarly, there is limited impact on individual toxicity.

The Role of SLC22A1 and Genomic Ancestry on Toxicity during Treatment in Children with Acute Lymphoblastic Leukemia of the Amazon Region.

In Brazil, Acute lymphoid leukemia (ALL) is the leading cause of cancer deaths in children and adolescents. Treatment toxicity is one of the reasons for stopping chemotherapy. Amerindian genomic ancestry is an important factor for this event due to fluctuations in frequencies of genetic variants, as in the NUDT15 and SLC22A1 genes, which make up the pharmacokinetic and pharmacodynamic pathways of chemotherapy. This study aimed to investigate possible associations between NUDT15 (rs1272632214) and SLC22A1 (rs202220802) gene polymorphism and genomic ancestry as a risk of treatment toxicities in patients with childhood ALL in the Amazon region of Brazil. The studied population consisted of 51 patients with a recent diagnosis of ALL when experiencing induction therapy relative to the BFM 2009 protocol. Our results evidenced a significant association of risk of severe infectious toxicity for the variant of the SLC22A1 gene (OR: 3.18, p = 0.031). Genetic ancestry analyses demonstrated that patients who had a high contribution of African ancestry had a significant protective effect for the development of toxicity (OR: 0.174; p = 0.010), possibly due to risk effects of the Amerindian contribution. Our results indicate that mixed populations with a high degree of African ancestry have a lower risk of developing general toxicity during induction therapy for ALL. In addition, individuals with the SLC22A1 variant have a higher risk of developing severe infectious toxicity while undergoing the same therapy.

Evaluating the Role of Baseline Geriatric Assessment in Predicting Quality of Life in Older Adults with Non-Hodgkin Lymphoma on Oral Targeted Therapies

Background:Oral targeted therapies (OTT) have transformed the care of patients with non-Hodgkin lymphoma (NHL) with significantly improved survival outcomes compared to chemo-immunotherapy. While data from clinical trials suggest improvement in global health and some symptom scores, there is limited data on health-related outcomes in older adults who are more vulnerable to treatment-related adverse effects. Geriatric assessments can predict chemotherapy-related toxicity in older adults and the presence of geriatric impairments is associated with inferior quality of life. The role of geriatric assessment (GA) in predicting health-related quality of life (HRQoL) and treatment toxicity in patients with NHL on OTT is unknown. In this prospective study, we describe the association between OTT and HRQoL in older adults with NHL. We further describe the relationship between baseline geriatric assessment and longitudinal HRQoL parameters.Methods:We included patients (pts) ≥70 years (yrs) of age with NHL, initiating or already receiving OTT. A GA, including assessment of function, depression, cognition, physical performance and comorbidities, was performed at baseline. Pts were followed monthly for the first 3 months (mos), then every 3 mos for 1 year. Quality of life (QoL) was measured at each visit using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaires Core 30 (EORTC QLQ-C30) and EORTC QLQ - chronic lymphocytic leukemia 16 (EORTC QLQ-CLL16). The log QoL scores were modeled as a function of visit and mean scores at 6 months were compared to baseline using a linear mixed model. A change in score of >10 was considered clinically significant based on previous work.Results:We enrolled 25 pts with a median age of 77 yrs (71-93 yrs). Median follow up was 6.3 mos (range, 2.7-8.8 mos). The most common diagnosis was chronic lymphocytic leukemia (n=21) followed by mantle cell lymphoma (n=3) and marginal zone lymphoma (n=1). Most pts (72%) were on OTT at study entry and the most frequently used OTTs were ibrutinib (n=17) and venetoclax (n=5). GA revealed the presence of a geriatric syndrome (GS) in more than 90% of pts, including cognitive impairment (28%), depression (24%), polypharmacy (92%) and recent falls (12%); 48% of pts had ≥2 GS. Nine pts (36%) had impaired 4-meter gait speed and/or timed-up-and-go (TUG); 20 pts (80%) had an adjusted CIRS-G score of ≥6. At baseline, dependence in independent activities of daily living (IADL) was associated with inferior global health status scores (69.1 vs 86.1, p=0.023) and physical functioning scores (66.7 vs 88.1, p=0.008). Similarly, an abnormal TUG (>10 seconds) was associated with a lower global health score (71.3 vs 86.1, p=0.037). Dependence in 2 or more activities of daily living (ADL) was also associated with lower baseline physical functioning scores (57.8 vs 88.0, p=0.003) and role functioning scores (61.1 vs 90.8, p=0.030). During the 6-month follow up, there was significant worsening of global health status (mean difference -5.4, p=0.024) and cognitive functioning scores (mean difference -9.6, p<0.001) in the entire cohort. There were no changes in other functional scales (physical, role, emotional and social functioning, fatigue scale, infection scale, social problems and future health) over time (Figure 1). Trends in symptom scores were mixed with improvement in some scores (pain, fatigue) and worsening of others (dyspnea, diarrhea, constipation), none of which met the predefined criteria for clinical relevance (absolute difference of >10). Presence of various geriatric impairments at baseline did not impact changes noted in global health, physical, emotional, social and role functioning over time. Interestingly, we found a greater improvement in symptom scores in patients with baseline impairments in IADL (fatigue, pain), ADL (pain) and a CIRS-G score of ≥6 (insomnia).Conclusion:The presence of geriatric syndromes is common in older adults with NHL with almost half of the patients in our cohort with ≥2 GS. Older adults with GS had lower baseline global health status and physical functioning scores but experienced greater improvement in symptoms scores and maintenance of longitudinal HRQoL than those without GS at baseline. Chronological age had no impact on baseline or longitudinal HRQoL, underscoring the need to incorporate GA into clinical practice rather than relying on age alone. [Display omitted] DisclosuresWildes: Janssen: Consultancy; Carevive: Consultancy; Seattle Genetics: Consultancy; Sanofi: Consultancy. Torka: TG Therapeutics: Membership on an entity's Board of Directors or advisory committees.

Sarcopenia and anthracycline cardiotoxicity in patients with cancer

BackgroundSeveral studies have suggested that sarcopenia is associated with an increased treatment toxicity in patients with cancer. The aim of this study is to evaluate the relationship between sarcopenia and...

Clinical utility of identification and return of research germline mutation results to gynecologic cancer patients enrolled in total cancer care

<h3>Objectives:</h3> Approximately 18% of ovarian cancer and 5% of uterine cancer patients have underlying genetic predispositions. All women with ovarian cancer and young women with uterine cancer should receive germline genetic testing and counseling; however, fewer than 20% of ovarian cancer patients complete this process. Patients with germline alterations may respond differently to cancer therapies, and pharmacogene mutations may alter the efficacy and toxicity of cancer treatments. The objectives of our study were to identify associations between germline pharmacogene mutations in gynecologic cancers and to determine the clinical utility of returning research whole exome sequencing germline mutation results to gynecologic cancer patients enrolled in Total Cancer Care (TCC). <h3>Methods:</h3> At our institution, 229 patients enrolled in TCC underwent research germline whole exome sequencing and consented to return of these results. BAM files were processed in a Clinical Laboratory Improvement Amendments-compliant bioinformatics pipeline to identify clinically actionable and selected pharmacogene mutations. To date, our multidisciplinary Molecular Tumor Board has reviewed 112 sequencing reports; 25 of these patients have gynecologic malignancies. Patients with identified American College of Medical Genetics (ACMG)-reportable mutations are recommended to follow up with genetic counseling and confirmatory clinical testing. We compared mutation frequencies and genetic counseling practices with a cohort of 176 patients without malignancy who underwent similar sequencing. <h3>Results:</h3> We identified ACMG-reportable gene mutations, including <i>BRCA</i>2, MUTYH, and TP53, in 4/25 (16%) of gynecologic cancer patients. Two patients had previously completed genetic counseling and clinical testing. Two patients were recommended for follow-up genetic counseling and confirmatory clinical testing based on their research germline results; one followed up, and one did not. Clinical and research genetic testing were congruent in all cases. Patients with any cancer were more likely to carry any germline pharmacogene mutation (102/112, 91.1%) than patients without malignancy (115/176, 65.3%; p<0.001). In gynecologic cancer patients, mutations in UGT1A1, CYP4F2, TPMT, and CYP2C9 were seen with higher than expected population frequencies. <h3>Conclusions:</h3> Clinical genetic sequencing may only test for a small subset of pathogenic alterations; research whole exome sequencing may identify additional germline mutations that may carry clinical significance. Our experience reviewing and returning research sequencing results indicates this process can identify patients and families at risk and may identify additional treatment options. Further research on the risk of malignancy and treatment toxicities in patients with pharmacogenetic variants is warranted. Identifying women with germline mutations and follow-up genetic counseling is imperative for personalized cancer treatment.

P20.05 Oesophageal Dose Predicts on Treatment Toxicity in Patients Receiving Concurrent Chemo-Radiotherapy for Non-Small Cell Lung Cancer

P20.05 Oesophageal Dose Predicts on Treatment Toxicity in Patients Receiving Concurrent Chemo-Radiotherapy for Non-Small Cell Lung Cancer

50 Years Ago in TheJournalofPediatrics: From Toxicity to Specificity, an Overview on Acute Lymphocytic Leukemia Treatment

Pinkel D. Treatment of childhood acute lymphocytic leukemia. J Pediatr 1970;77:1089-91. Acute lymphoblastic leukemia (ALL) is the most common malignancy in childhood and the most curable disease in pediatric oncology. In the 1960s, ALL was an almost uniformly fatal disease, but due to new therapies and breakthroughs in the last 50 years, the current 5-year survival rate has improved to 89% in children and 61% in young adults.1Brown P. Inaba H. Annesley C. Beck J. Colace S. Dallas M. et al.Pediatric Acute Lymphoblastic Leukemia, Version 2.2020, NCCN Clinical Practice Guidelines in Oncology.J Natl Compr Canc Netw. 2020; 18: 81-112Crossref PubMed Scopus (19) Google Scholar The essence of ALL treatment remains the same and continues to be grouped in the following phases: induction, consolidation, and a prolonged maintenance. One of the most significant changes is the individualization of each patient, classifying them according to risk stratification, predictive biomarkers, molecular prognosis, and monitoring of minimal residual disease, aiming to reduce complications and mortality of chemotherapy itself. Another major shift includes central nervous system prophylaxis, an essential part of ALL management and a prerequisite for successful treatment.2Rafei H. Kantarjian H.M. Jabbour E.J. Recent advances in the treatment of acute lymphoblastic leukemia.Leuk Lymphoma. 2019; 60: 2606-2621Crossref Scopus (15) Google Scholar Fifty years ago, “complete remission” was based on Bisel morphologic criteria, which Pinkel considered insufficient, as it excluded central nervous system involvement. Today, analytic minimal residual disease testing using flow cytometry is a strong prognostic indicator in all leukemia subtypes.3Kaplan J.A. Leukemia in children.Pediatr Rev. 2019; 40: 319-331Crossref Scopus (11) Google Scholar The last decade has seen significant advances in treatment; thanks to molecular biology, Paul Ehrlich's “magic bullet” concept is reaching its full realization. Today, we are in the era of monoclonal antibody therapy with new drugs such as blinatumomab, inotuzumab, and chimeric antigen receptor T cells, which target specific abnormal molecules and pathways of cancer cells.2Rafei H. Kantarjian H.M. Jabbour E.J. Recent advances in the treatment of acute lymphoblastic leukemia.Leuk Lymphoma. 2019; 60: 2606-2621Crossref Scopus (15) Google Scholar These new therapies came with new complications and adverse effects, so the imperative to improve supportive care, comfort, and quality of life remains. However, they pave the way to a future in which treatment toxicity for patients is minimized. The challenges of 50 years ago are being today addressed with the goal to completely phase out conventional chemotherapy.

1504O Relationship between sarcopenia and anthracycline related cardiotoxicity in patients with cancer

sarcopenia is associated with poor prognosis and increased treatment toxicity in patients with cancer. However, there is limited data about sarcopenia and cardiotoxicity of chemotherapy. The aim of this study is to evaluate relationship between sarcopenia and anthracycline (AC) related cardiotoxicity. Patients who received AC-based chemotherapy between 2014-2018, and had baseline abdominal CT containing both L3-L4 levels for measuring skeletal muscle index (L3-L4 SMI) and psoas muscle index (PMI), and baseline and follow-up echocardiography after AC treatment were included. Sex-specific cutoffs for L3 SMI, L4 SMI and PMI were used for diagnosis of sarcopenia. Cardiotoxicity was defined as development of either systolic dysfunction according to European society of Cardiology (ESC) ejection fraction (EF) criteria, or diastolic dysfunction according to American Society of Echocardiography (ASE) diastolic dysfunction criteria. Multivariate analysis was performed to determine potential predictors of cardiotoxicity. A total of 166 patients (75 male, 91 female) were included; 50 (30.1 %) with breast cancer, 82 (49.4 %) with lymphoma, 11 (6.6 %) with sarcoma and 23 (13.9%) with other cancers. Median age was 48 years and median doxorubicin dose was 238 mg/m2. Sarcopenia was determined in 33 (19.9 %) according to L3 SMI, in 17 (10.2 %) according to L4 SMI and in 45 (27.1 %) according to PMI. After AC treatment, 27 patients (16.3 %) developed cardiotoxicity; 17 (10.2 %) had systolic dysfunction, 9 (5.4%) had diastolic dysfunction and 1 (0.6 %) had both. After adjustment for age, gender, doxorubicin dose, body mass index, and presence of cardiovascular disease; sarcopenia at any of the three levels was significantly associated with increased risk of cardiotoxicity. (L3 SMI Hazard ratio [HR]= 4.14, 95% confidence interval [CI] 1.66-10.31, p=0.002; L4 SMI HR= 3.65, 95% CI 1.21-11.0, p=0.022; PMI HR= 4.39, 95% CI 1.81-10.65, p=0.001). This is the first study demonstrating a significant association between CT-based diagnosis of sarcopenia and anthracycline-related cardiotoxicity. Routine CT scans may help clinicians identify high risk patients in whom closer follow-up or cardioprotective measures should be considered.

Metastatic melanoma patient outcomes since introduction of immune checkpoint inhibitors in England between 2014 and 2018.

e19310 Background: Population-based research provides real world information about prescribing trends, as well as benefits and harms associated with new interventions first evaluated in randomized clinical trials (RCTs). The national health service in England collects data on systemic anti-cancer therapy (SACT) prescribed to patients. We retrospectively examined outcomes including overall survival (OS) and treatment toxicity for patients (pts) prescribed checkpoint inhibitors (CPIs) approved for 1st line use in metastatic melanoma. Methods: National Cancer Registration and Analysis Service (NCRAS) datasets were used to identify metastatic melanoma pts prescribed 1st line CPIs and calculate survival outcomes. The Hospital Episode Statistics database was used to identify emergency department attendances and emergency hospital admissions. Results: Between April 2014 and March 2018, 5,465 melanoma pts were prescribed SACT. Of these, 2,322 pts received 1st line CPIs for metastatic disease at 56 different hospitals in England: 1,174 were prescribed pembrolizumab (pembro), 724 ipilimumab (ipi), 52 nivolumab (nivo), 372 ipinivo. Prescribing reflected national access, starting with ipi in July 2014, replaced by pembro in Nov 2015 and ipinivo prescriptions started in July 2016. By 2018, 1 in 3 pts were receiving ipinivo as treatment of choice. There was high concordance for 3yr OS with RCT outcomes for ipi (32%) and ipinivo (58%), but pembro outcomes were poorer (40%). Pts prescribed pembro were significantly older (51% vs. 12% &gt;70 years) and frailer (38% vs. 61% ECOG PS 0) than pts prescribed ipinivo (p&lt;0.0001). 30-day rates of emergency hospital attendances/admissions from the earliest SACT and last SACT treatment dates were significantly higher for ipinivo (16%/37% and 19%/55%) compared with pembro (8%/17% and 14%/29%). Colitis was the most common IrAE associated with hospitalization: 25% with ipinivo and 4% with pembro. 30-day mortality from last SACT was 3.8% with ipinivo and 9.1% with pembro (p&lt;0.0001). Conclusions: Linked real world datasets demonstrated OS outcomes remarkably similar to RCTs associated with ipi and ipinivo, while poorer outcomes associated with pembro may reflect patient selection bias. Ipinivo generated the highest rates of emergency hospital visits and admissions, but 30-day mortality was not compromised, potentially reflecting efficient and effective management of complications. Hospital-level outcomes and 30-day mortality causes are now being assessed to explore variations in care.

Skeletal muscle loss under chemotherapy and its association with survival and systemic treatment toxicity in metastatic colorectal cancer: An AGEO prospective multicenter study.

4025 Background: We showed in a previous work that “Patient Generated-Subjective Global Assessment” (PG-SGA) was independently associated with survival and treatment toxicities in non-pretreated metastatic colorectal cancer (mCRC) patients. We have evaluated here if muscle mass in these patients can provide useful additional information for clinical practice. The objective of the present work was to evaluate the association between baseline sarcopenia, and the variation of the Skeletal Muscle Index (SMI) under treatment with survival and chemotherapy-related toxicities in our population of non-pretreated mCRC patients. Methods: This prospective multicenter observational study enrolled non-pretreated mCRC patients. Measurement of SMI was performed on routine CT scan at day 0 (D0) and day 60 (D60). PG-SGA score and other nutritional factors were collected at D0. Progression-free survival (PFS) and overall survival (OS) were calculated from treatment start. Treatment related toxicities were registered according to the NCI CTCAE v4.0. Results: 149 patients were included in eight French centers from 7/2013 to 11/2016. Sarcopenia at baseline was not significantly associated with survival outcomes or chemotherapy-related toxicities. The best cut-point value of SMI variation (between D0 and D60) for OS prediction obtained with a log-rank maximisation method was -14%. The decrease in SMI &gt; 14%, with a median follow-up of 23 months, was significantly associated with shorter PFS (6 vs 9 mo; HR 1.8, 95%CI 1.1-3.1, p = 0.02) and OS (8.5 vs 26 mo; HR 2.4, 95%CI 1.3-4.4, p = 0.004), independently of hypoalbuminemia and malnutrition defined by PG-SGA, in multivariate analysis. 40% of patients with a SMI decrease &gt; 14%, and 22% of patients with a SMI increase or stable or decrease &lt; 14% developed grade ≥ 2 clinical toxicities (OR 3.0, 95%CI 1.2-7.7, p = 0.02), but the difference was not statistically significant in multivariate analysis (OR 2.3. 95%CI 0.8-6.7, p = 0.1). Conclusions: To our knowledge, this study is the first study assessing the association of skeletal muscle loss with survival and treatment toxicities in patients with mCRC prospectively. In our population of non pre-treated mCRC patients, baseline sarcopenia was not associated with poor survival outcomes, but the decrease in SMI &gt; 14% during the first two months of treatment was significantly associated with decreased PFS and OS, independently of other prognostic and nutritional factors.

DNA repair gene polymorphisms, tumor control, and treatment toxicity in prostate cancer patients treated with permanent implant prostate brachytherapy.

Radiotherapy and brachytherapy are common treatments for localized prostate cancer (PCa). However, very few studies evaluated the association of variations in DNA damage response genes and treatment outcomes and toxicity in brachytherapy-treated patients. To evaluate the association of inherited germline variations in DNA repair-associated genes with tumor control and treatment toxicity in patients treated with low-dose-rate prostate brachytherapy (LDRB). The cohort consists of 475 I-125 LDRB patients with a median follow-up of 51 months after seed implantation. Patients were genotyped for 215 haplotype tagging single nucleotide variations (htSNPs) in 29 candidate genes of DNA damage response and repair pathways. Their association with biochemical recurrence (BCR) was assessed using Cox regression models and Kaplan-Meier survival curves. Linear regressions and analysis of covariance (ANCOVA) between early and late International Prostate Symptom Score (IPSS) with htSNPs were used to evaluate the association with urinary toxicity. After adjustment for the established risk factors, six htSNPs in five genes were found to be significantly associated with an altered risk of BCR, with adjusted hazard ratios (HRadj. ) ranging between 3.6 and 11.1 (P < .05). Compared to carriers of the ERCC3 rs4150499C allele, patients homozygous for the T allele (n = 22) had a significant higher risk of BCR with a HR of 11.13 (IC95 = 3.9-32.0; P < .0001; q < 0.001). The Kaplan-Meier survival curve revealed a mean BCR-free survival time reduced from 213 ± 7 to 99 ± 12 months (log-rank P < .0001) for homozygous T carriers compare to noncarriers. For late IPSS (>6 months after treatment), htSNP rs6544990 from MSH2 showed a statistically significant b-coefficient of 1.85 ± 0.52 (P < .001; q < 0.1). Homozygous carriers of the MSH2 rs6544990C allele (n = 62) had a mean late IPSS 3.6 points higher than patients homozygous for the A allele (n = 132). This difference was significant when tested by ANCOVA using pretreatment IPSS as a covariate (P < .01). This study suggests an association of the intronic variants of the DNA nucleotide excision repair ERCC3 and DNA mismatch repair MSH2 genes with elevated risk of BCR and late urinary toxicity respectively after LDRB. Further validation is required before translational clinical advances.

First Line Treatment with Venetoclax and Ibrutinib Induction Followed By Obinutuzumab Intensification Exclusively in CLL/SLL Patients Not in Complete Remission and/or with Detectable Bone Marrow Minimal Residual Disease (NEXT STEP trial)

First Line Treatment with Venetoclax and Ibrutinib Induction Followed By Obinutuzumab Intensification Exclusively in CLL/SLL Patients Not in Complete Remission and/or with Detectable Bone Marrow Minimal Residual Disease (NEXT STEP trial)

PO-1095: Tolerance and toxicity of treatment in patients undergoing radiotherapy associated with hyperthermia

PO-1095: Tolerance and toxicity of treatment in patients undergoing radiotherapy associated with hyperthermia