Chemotherapy-related Adverse Events Research Articles

Ivonescimab combined with chemotherapy in patients with EGFR-mutant non-squamous non-small cell lung cancer who progressed on EGFR tyrosine-kinase inhibitor treatment (HARMONi-A): A randomized, double-blind, multi-center, phase 3 trial.

8508 Background: Ivonescimab (AK112/SMT112) is a anti-PD-1/VEGF bispecific antibody. Previous phase I/II clinical studies have shown potential efficacy of ivonescimab in NSCLC patients with EGFR mutations who had failed prior EGFR-TKIs therapies. This phase 3 study aimed to evaluate and confirm the efficacy and safety of ivonescimab combined with chemotherapy versus chemotherapy alone in this population. Methods: Patients were randomized 1:1 to receive ivonescimab (20 mg/kg) plus pemetrexed (500 mg/m2) and carboplatin (AUC 5) or placebo plus chemotherapy once every 3 weeks for four cycles, with stratification according to the third-generation EGFR-TKI (received vs not received) and brain metastases (presence vs absence), followed by maintenance therapy of ivonescimab and pemetrexed or placebo and pemetrexed. The primary endpoint was progression-free survival (PFS) in intention-to-treat (ITT) population assessed by independent radiographic review committee (IRRC) per RECIST v1.1. Here we report the results of the first planned interim analysis. Results: Total 322 patients were randomized (161 to the ivonescimab plus chemotherapy arm, 161 to the placebo plus chemotherapy arm). 86.3% versus 85.1% of patients had received the third generation EGFR-TKIs treatment, 21.7% versus 23.0% of patients had brain metastases. As of March 10, 2023, median follow up time was 7.89 months. PFS was significantly improved in the ivonescimab plus chemotherapy arm (HR 0.46 [0.34, 0.62], P < 0.0001). Median PFS (95%CI) by IRRC were 7.06m (5.85, 8.74) in the ivonescimab arm versus 4.80m (4.21, 5.55) in chemotherapy arm. The prespecified subgroup analysis showed PFS benefit favoring patients receiving ivonescimab over placebo across almost all subgroups, including in patients who progressed on the third-generation EGFR-TKIs therapy (HR 0.48, 95% CI 0.35-0.66), those with brain metastases (HR 0.40, 0.22-0.73), those with EGFR mutation of deletion 19 (HR 0.48, 0.32-0.73), and individuals with T790M mutation positive (HR 0.22, 0.09-0.54). The ORR were 50.6% and 35.4%, respectively. Grade ≥3 TEAEs occurred in 99 (61.5%) patients versus 79 (49.1%) patients, the most common grade ≥3 TEAEs were chemotherapy related adverse events. Grade ≥3 immune-related adverse events occurred in 10 (6.2%) patients versus 4 (2.5%). Grade ≥3 VEGF blocking related adverse events occurred in 5 patients (3.1%) versus 4 patients (2.5%). Conclusions: Ivonescimab plus chemotherapy significantly improved PFS while maintaining a manageable safety profile in patients who had failed EGFR-TKIs treatments. Clinical trial information: NCT05184712 .

Safety and efficacy of PEG-rhG-CSF as primary prophylaxis against neutropenia induced by combination chemotherapy regimens involving oral chemotherapy agents in gastrointestinal cancer patients: A prospective, exploratory, non-randomized controlled study.

e24107 Background: The safety and efficacy of PEGylated recombinant human granulocyte colony-stimulating factor (PEG-rhG-CSF) for prevention of chemotherapy-induced neutropenia (CIN) in patients undergoing oral chemotherapy remain unclear. This study investigated the safety and efficacy of PEG-rhG-CSF as primary prophylaxis against CIN in gastrointestinal (GI) cancer patients receiving combination chemotherapy regimens involving oral chemotherapy agents. Methods: This is a prospective, single-center, open-label, exploratory, non-randomized controlled study. GI cancer patients receiving two consecutive cycles of IV oxaliplatin (150mg/m2 on day 1) combined with oral capecitabine 1000mg/m2 or tegafur gimeracil oteracil potassium capsule 40-60mg twice daily on days 1-14 every 3 weeks. PEG-rhG-CSF (6mg) was administered subcutaneously 24 hours post-oxaliplatin treatment in the PEG-rhG-CSF group, while the control group did not receive it. The primary endpoint was safety, and secondary endpoints included CIN incidence and neutropenic complications. The study was registered with the Chinese Clinical Trial Registry (registration number ChiCTR2100054854). Results: Between March 2022 and January 2023, a total of 49 patients was screened, and 43 patients completed the treatment (26 in PEG-rhG-CSF group and 17 in control group). The average age was 61.4 years, with 90.7% males and 83.7% having gastric cancer. Baseline characteristics were similar between the two groups. The overall adverse events (AE) did not differ statistically (88.5% vs. 88.2%, p = 1.000), with grade £2 fatigue and nausea being the most common AEs. Grade 3 platelet reduction showed no significant difference between the two groups (7.69% vs. 17.65%, p = 0.432). Four cases of bone pain (15.4%) and five cases of injection site reactions below grade 3 (19.2%) were observed in the PEG-rhG-CSF group. Grade ≥2 CIN was significantly lower in the PEG-rhG-CSF group (3.84% vs. 58.82%, p < 0.001). One case in the PEG-rhG-CSF group required antibiotic treatment due to febrile neutropenia. Regarding neutropenic complications, the PEG-rhG-CSF group exhibited lower proportion of chemotherapy delay (3.85% vs. 35.29%, p < 0.001) and dose reduction (1.92% vs. 23.53%, p = 0.002). Rescue treatment with rhG-CSF for grade 3/4 CIN was significantly less frequent in the PEG-rhG-CSF group (1.92% vs. 23.53%, p = 0.002). Conclusions: Primary prophylaxis with PEG-rhG-CSF in GI cancer patients undergoing oral capecitabine/tegafur gimeracil oteracil potassium may be safe, without an increased chemotherapy-related AEs, and is associated with a reduced grade ≥2 CIN. Clinical trial information: ChiCTR2100054854.

Abstract PO3-12-11: A phase-3 randomized controlled study to evaluate the role of hydroxyprogesterone in prevention of chemotherapy induced neurotoxicity in women with breast cancer

Abstract Introduction Chemotherapy induced peripheral neuropathy (CIPN) is seen in 60% breast cancer patients who receive paclitaxel-based chemotherapy with no conclusively known pathophysiology. Hydroxyprogesterone is known to have neuroprotective and neuro-regenerative potential. We conducted a randomized controlled trial assessing the role of hydroxyprogesterone in reducing the incidence and severity of CIPN. Methodology Histologically proven, post-menopausal, non-metastatic breast cancer patients without pre-existing neuropathy, planned to receive paclitaxel (with or without trastuzumab) in the adjuvant or neoadjuvant setting were screened and consented. They were randomized to receive depot hydroxyprogesterone injection 500 mg followed by 250 mg injection every 2 weekly (trial arm) versus 1 ampoule (2 ml) of vitamin-B complex (B1-100mg, B6-100mg and B12-1000µg) injection every 2 weekly (control arm) during the entire course of paclitaxel-based chemotherapy. The primary end point was cumulative incidence of grade II-IV CIPN, at the last cycle of chemotherapy as assessed by CTCAE-V4. Secondary end point was EORTC-QLQ-CIPN20 assessment 8 weeks after last cycle of chemotherapy. Patients were stratified for stage, diabetes mellitus, and frequency of paclitaxel administration. Sample size was calculated for a 20% reduction in CIPN from 60% with α-0.05 and power of 80%, for 2-sided significance of p-0.05, with a drop-out rate of 10%. Results A total of 240 patients were randomized between November 2015 and February 2023- 120 each on the trial and control arm. The median age was 54 (43-73) and 55 (43-74) years; 35% and 31.7% patients were early breast cancer (cT1-2, N0-1) in the trial and control arms respectively. The median pT size was 2.6 cm and 65% patients were node positive overall. The incidence of grade II-IV CIPN (motor and/or sensory) at the end of chemotherapy was 55.9% and 56.8% in the trial and control arms respectively (p=0.90, 95%CI-0.12-0.13). Overall, chemotherapy related adverse events (CTCAE-V4) were seen in 41.39 and 39.9% in trial and control arms respectively. The average EORTC-QLQ-CIPN20 score at 8 weeks after last cycle of chemotherapy for motor neuropathy was 11.18 (0-70) and 13.53 (0-74), for sensory neuropathy was 8.51 (0-76) and 9.27 (0-81) and that for autonomic neuropathy was 4.94 (0-67) and 4.65 (0-67) in the trial and control arms respectively (p=NS). Conclusion Hydroxyprogesterone did not reduce the incidence of paclitaxel related CIPN when assessed immediately post-chemotherapy. The absolute incidence of CIPN (any grade) was 61% in our study which is like that reported in literature. Long term follow-up of these patients will assess the recovery of CIPN and long-term impact of the study interventions on CIPN. The study was approved by Institutional Review Board and Drug Controller General of India (CTRI/2015/11/006381). Citation Format: Rajendra Badwe, Shalaka Joshi, Rohini Hawaldar, Tejal Panhale, Nita Nair, Sandesh Sawant, Vaibhav Vanmali, Mitchelle Engineer, Anuradha Daptardar, Vani Parmar, Seema Gulia, Sudeep Gupta. A phase-3 randomized controlled study to evaluate the role of hydroxyprogesterone in prevention of chemotherapy induced neurotoxicity in women with breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-12-11.

Abstract PS14-02: Real-world analysis comparing Black and White patients with triple-negative breast cancer receiving therapy per KEYNOTE-522

Abstract Abstract Title: Real-world analysis comparing Black and White patients with triple-negative breast cancer receiving therapy per KEYNOTE-522 Background: KEYNOTE-522 was a randomized, double-blind, placebo-controlled phase 3 trial which resulted in the FDA approval of pembrolizumab with neoadjuvant chemotherapy for patients with newly diagnosed, high-risk, early-stage triple-negative breast cancer (TNBC). Despite the significant improvement in pathological complete response (pCR) and event-free survival rates across all patients, the landmark trial included only 4.5% Black patients. It is essential to assess outcomes in representative treatment populations. We assessed real-world toxicity and treatment outcomes across Black and White patients who received standard-of-care treatment per KEYNOTE-522. Methods: In this retrospective, multicenter study, we examined patients with early-stage TNBC who received planned treatment per KEYNOTE-522 as standard-of-care (SOC) therapy. 16 sites were included in the analysis. IRB approval was obtained from each participating site. Number and length of treatment delays, treatment-related toxicities (both chemotherapy and immune-related) of all grades, and pCR rate were collected from the electronic medical record of each participating site, and deidentified data were shared for central analysis. Results: Of the 577 patients who initiated treatment with chemotherapy and immunotherapy, 534 patients were included in this analysis with 105 patients who self-identified as Black (19.7%) and 429 who self-identified as White (80.3%). There were no statistically significant differences in clinical and pathological characteristics between the two groups. White women were more likely to have grade 3+ immune-related adverse events (irAEs) compared to Black women (33.8% vs 20.9%, P=0.011). There was no significant difference across Black and White patients with respect to grade 3+ chemotherapy-related adverse events. Out of the 444 patients who have completed surgery, no difference in pCR rate was observed between Black and White women (45/86 52.3% vs 200/358 55.9%) (p = 0.6). The authors also saw no difference in the rates of hospitalizations between Black and White women (39% vs 36% p = 0.5), and rates of acute care utilization (38% vs 38% p = 0.9). Conclusions: We report safety and efficacy across Black and White women in a real-world analysis of patients who received treatment per KEYNOTE-522. Notably, White patients had a significantly higher frequency of grade 3+ irAEs, although the reason for this finding is unclear based on this analysis. Black patients had similar pCR rates and rates of treatment-related hospitalizations compared to White patients. Assessment of outcomes and toxicity by race in clinical trials and real-world analyses are critical in drug development. Citation Format: Mara Hofherr, Andrew Davis, Spenser January, Emily Owen, Farah Raheem, Lida A. Mina, Suganya Arunachalam Karikalan, Lauren Lyons, Meredith Watson Rose, Katherine Madden, Jerline Hsin, Aimee Keegan, Wai Yu, Shawna Kraft, Allison Schepers, Emily Armgardt, Douglas Mazewski, Alison Svoboda, Kayla Harwood, Jodi Taraba, Yonatan Resnick, Shelly Hummert, Lisa Grate, Sidney Keisner, Jacob Hobbs, Todd Davis, Kristin Bastian, Dawn Minikel, Wiliam Adler, Traci White, Avneek Singh Sandu, Fouad Boulbol, Kelsey Finch, Katherine Clifton. Real-world analysis comparing Black and White patients with triple-negative breast cancer receiving therapy per KEYNOTE-522 [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS14-02.

The efficacy of combining ondansetron with dexamethasone in delayed chemotherapy-induced nausea and vomiting

Background: Chemotherapy is the primary recourse for patients with cancer that cannot be treated using local surgery or radiotherapy. Its practical application often leads to adverse effects, including nausea and vomiting. Objective: This study determined the efficacy of oral ondansetron and oral dexamethasone as an antiemetic regimen among patients covered by the National Health Insurance. Methods: This cross-sectional study, conducted at one of the largest hospitals in South Kalimantan, Indonesia, involved 114 chemotherapy patients who received a combination antiemetic regimen of ondansetron and dexamethasone. Data on the incidence of delayed nausea and vomiting after chemotherapy were collected using the Index Nausea Vomiting and Retching (INVR) questionnaire from March to May 2023. Results: A cohort of 114 individuals were enrolled in the present investigation, with 57.02% and 42.98% of the participants receiving non-anthracycline and anthracycline-based treatment protocols, respectively. The results showed that only 1.84% of patients did not experience chemotherapy-related adverse events, 13.16% experienced mild symptoms, 21.84% had moderate symptoms, 55.26% faced severe symptoms, and 7.89% suffered from intense symptoms of nausea and vomiting. Conclusion: The antiemetic regimen covered by Badan Penyelenggara Jaminan Sosial (BPJS) (Social Insurance Administration Organization), consisting of a combination of ondansetron and dexamethasone, is moderately effective in preventing chemotherapy-induced delayed nausea and vomiting.

Роль полиморфных вариантов генов цитохромов Р450, а также генов GSTP1 и MDR1 в развитии токсических осложнений при проведении программной противоопухолевой лекарственной терапии у пациентов с классической лимфомой Ходжкина

Background. Although considerable progress has been achieved in the treatment of classical Hodgkin lymphoma (cHL), toxic complications of program drug chemotherapy remain an issue. Standard cytostatic agents used in cHL therapy are metabolized in liver by the enzymes with Р450 cytochrome and GSTP1 gene-controlled synthesis. At the same time, the excretion of active metabolites of antitumor drugs is mediated by MDR1 coded P-glycoprotein. Polymorphisms[1] of these genes may change the processes of antitumor drug biotransformation and their metabolite excretion. Additionally, they may result in organo-toxic complications, disablement of patients, and even death.
 Aim. To assess the role of polymorphisms in cytochrome genes Р450 as well as genes GSTP1 and MDR1 in organ toxicity dynamics during program chemotherapy (CT) in cHL patients.
 Materials & Methods. The study enrolled 122 cHL patients treated with first-line regimens (ABVD, BEACOPP) of program drug chemotherapy. The patients were aged 18–78 years (median 35 years); there were 67 (54.9 %) women and 55 (45.1 %) men. In compliance with the NCCN CTC (2003) criteria of hepatotoxicity and practical recommendations for correcting cardiovascular toxicity of chemotherapy (2021), the signs of toxic liver and heart damage were assessed in all patients. PCR was used to analyze polymorphisms in cytochrome genes Р450 as well as genes GSTP1 and MDR1, their association with toxic complications of CT was analyzed.
 Results. Drug-induced liver damage on program CT was identified in 80 % of cHL patients. The toxicity was increasing from CT cycle 1 to cycle 6 both on ABVD and BEACOPP. Complications grade 3/4 were observed only in BEACOPP recipients. Significant (p < 0.05) associations were found between hepatotoxic complications with increased cytolytic (AST, ALT) and cholestatic (ALP) values and polymorphic variants of MDR1. Significant (p < 0.05) reduction of left ventricle myocardium contractility in cHL patients was associated with Т-allele presence in genotypes CYP2D6*10 (rs1065852), CYP2C9*2 (rs1799853) and A-allele deletion in genotype CYP2D6_3 (rs4986774).
 Conclusion. The identification of genetic predictors for toxic effects of program CT in cHL patients at the baseline examination can minimize the risks of drug chemotherapy-related adverse events and allow these patients to maintain a satisfactory quality of life.
 
 [1] Gene polymorphism is a structural difference between alternative variants of a gene. Alternative variants of genes result from mutations.

Assessing Frailty in Gastrointestinal Cancer: Two Diseases in One?

This review examines the challenges of treating gastrointestinal cancer in the aging population, focusing on the importance of frailty assessment. Emphasized are the rise in gastrointestinal cancer incidence in older adults, advances in frailty assessments for patients with gastrointestinal cancer, the development of novel frailty markers, and a summary of recent trials. Increasing evidence suggests that the use of a Comprehensive Geriatric Assessment (CGA) to identify frail older adults and individualize cancer care leads to lower toxicity and improved quality of life outcomes. However, the adoption of a full CGA prior to chemotherapy initiation in older cancer patients remains low. Recently, new frailty screening tools have emerged, including assessments designed to specifically predict chemotherapy-related adverse events. Additionally, frailty biomarkers have been developed, such as blood tests like IL-6 and performance tracking through physical activity monitors. The relevance of nutrition and muscle mass is discussed. Highlights from recent trials suggest the feasibility of successfully identifying patients most at risk of serious adverse events. There have been promising developments in identifying novel frailty markers and methods to screen for frailty in the older adult population. Further prospective trials that focus on and address the needs of the geriatric population for early identification of frailty in cancer care, facilitating a more tailored treatment approach. Practicing oncologists should select a frailty assessment to implement into their routine practice and adjust treatment accordingly.

Veterinary oncologists and pet owners differ in their perceptions of chemotherapy-related adverse events in cancer-bearing dogs.

Chemotherapy is widely used in veterinary oncology but carries real and perceived risks of adverse events (AEs). Human cancer patients perceive AEs from chemotherapy as more severe than do their attending physicians. It is currently unknown whether this discrepancy exists in veterinary oncology. This survey study's aim was to assess differences in the ways that pet owners and veterinary oncologists perceive chemotherapy-related AEs. We hypothesized that veterinary oncologists would accept higher grade AEs and tolerate a greater risk of AEs of any grade than pet owners. 152 pet owners and 111 veterinary oncologists. Separate surveys were derived for pet owners and veterinary oncologists. Respondents were asked to define maximally acceptable AE scores and risks of AEs given 3 hypothetical outcomes of treatment: (1) cure, (2) extension of life, and (3) improved quality of life. Statistical tests were used to compare responses between groups. Veterinary oncologists accepted higher grade AEs if the hypothetical goal of chemotherapy was cancer cure (P = .003) or extension of life (P = .026), but owners accepted higher grade AEs if the goal of chemotherapy was to improve quality of life (P = .002). Owners accepted greater risk of moderate (P < .0001) or serious (P < .0001) AEs across the 3 treatment outcomes. This was the first study to assess how pet owners and veterinary oncologists differ in their perception of chemotherapy-related AEs. These initial results may help to frame discussions with pet owners on the expectations of chemotherapy.

Osimertinib with or without Chemotherapy in EGFR-Mutated Advanced NSCLC

BackgroundOsimertinib is a third-generation epidermal growth factor receptor–tyrosine kinase inhibitor (EGFR-TKI) that is selective for EGFR-TKI–sensitizing and EGFR T790M resistance mutations. Evidence suggests that the addition of chemotherapy may extend the benefits of EGFR-TKI therapy.MethodsIn this phase 3, international, open-label trial, we randomly assigned in a 1:1 ratio patients with EGFR-mutated (exon 19 deletion or L858R mutation) advanced non–small-cell lung cancer (NSCLC) who had not previously received treatment for advanced disease to receive osimertinib (80 mg once daily) with chemotherapy (pemetrexed [500 mg per square meter of body-surface area] plus either cisplatin [75 mg per square meter] or carboplatin [pharmacologically guided dose]) or to receive osimertinib monotherapy (80 mg once daily). The primary end point was investigator-assessed progression-free survival. Response and safety were also assessed.ResultsA total of 557 patients underwent randomization. Investigator-assessed progression-free survival was significantly longer in the osimertinib–chemotherapy group than in the osimertinib group (hazard ratio for disease progression or death, 0.62; 95% confidence interval [CI], 0.49 to 0.79; P<0.001). At 24 months, 57% (95% CI, 50 to 63) of the patients in the osimertinib–chemotherapy group and 41% (95% CI, 35 to 47) of those in the osimertinib group were alive and progression-free. Progression-free survival as assessed according to blinded independent central review was consistent with the primary analysis (hazard ratio, 0.62; 95% CI, 0.48 to 0.80). An objective (complete or partial) response was observed in 83% of the patients in the osimertinib–chemotherapy group and in 76% of those in the osimertinib group; the median response duration was 24.0 months (95% CI, 20.9 to 27.8) and 15.3 months (95% CI, 12.7 to 19.4), respectively. The incidence of grade 3 or higher adverse events from any cause was higher with the combination than with monotherapy — a finding driven by known chemotherapy-related adverse events. The safety profile of osimertinib plus pemetrexed and a platinum-based agent was consistent with the established profiles of the individual agents.ConclusionsFirst-line treatment with osimertinib–chemotherapy led to significantly longer progression-free survival than osimertinib monotherapy among patients with EGFR-mutated advanced NSCLC. (Funded by AstraZeneca; FLAURA2 ClinicalTrials.gov number, NCT04035486.)

Effects of Early Short-Course Corticosteroids on Immune-Related Adverse Events in Non-Small Cell Lung Cancer Patients Receiving Immune Checkpoint Inhibitors

Introduction: In real-world practice, most non-small cell lung cancer (NSCLC) patients receiving combined immunochemotherapy are exposed to short-course corticosteroids following immune checkpoint inhibitor (ICI) infusion to prevent chemotherapy-related adverse events. However, whether this early short-course corticosteroid use prevents immune-related adverse events (irAEs) remains unknown. Methods: Between January 1st, 2015, and December 31st, 2020, NSCLC patients who received at least one cycle of ICI with or without chemotherapy were enrolled. Early short-course corticosteroids were defined as corticosteroids administered following ICI injection and before chemotherapy on the same day and no longer than 3 days afterward. The patients were categorized as either “corticosteroid group” or “non-corticosteroid group” depending on their exposure to early short-course corticosteroid. The frequencies of irAEs requiring systemic corticosteroid use and irAEs leading to ICI discontinuation were compared between the two groups, and exploratory survival analyses were performed. Results: Among 252 eligible patients, 137 patients were categorized as “corticosteroid group” and 115 patients as “non-corticosteroid group.” The corticosteroid group enriched patients in the first-line setting (n = 75, 54.7%), compared to the non-corticosteroid group (n = 28, 24.3%). Thirty patients (21.9%) in the corticosteroid group and 35 patients (30.4%) in the non-corticosteroid group developed irAEs requiring systemic corticosteroid use (odds ratio [OR], 0.64; 95% confidence interval [CI], 0.35–1.18; p = 0.15). Eight patients (5.8%) in the corticosteroid group, as compared with 18 patients (15.7%) in the non-corticosteroid group, permanently discontinued ICI due to irAEs (OR, 0.34; 95% CI, 0.12–0.85; p = 0.013). Conclusion: Early short-course corticosteroids following each ICI injection may reduce the rate of irAEs that lead to ICIs discontinuation, warranting further investigation of its prophylactic use to mitigate clinically significant irAEs.

Neo-train: study protocol and feasibility results for a two-arm randomized controlled trial investigating the effect of supervised exercise during neoadjuvant chemotherapy on tumour response in patients with breast cancer

BackgroundPrehabilitation with exercise interventions during neoadjuvant chemotherapy (NACT) is effective in reducing physical and psychosocial chemotherapy-related adverse events in patients with cancer. In preclinical studies, data also support a growth inhibitory effect of aerobic exercise on the tumour microenvironment with possible improved chemotherapy delivery but evidence in human patients is limited. The aim of the study here described is to investigate if supervised exercise with high-intensity aerobic and resistance training during NACT can improve tumour reduction in patients with breast cancer.MethodsThis parallel two-armed randomized controlled trial is planned to include 120 women aged ≥ 18 years with newly diagnosed breast cancer starting standard NACT at a university hospital in Denmark (a total of 90 participants needed according to the power calculation and allowing 25% (n = 30) dropout). The participants will be randomized to usual care or supervised exercise consisting of high-intensity interval training on a stationary exercise bike and machine-based progressive resistance training offered three times a week for 24 weeks during NACT, and screening-based advice to seek counselling in case of moderate-severe psychological distress (Neo-Train program). The primary outcome is tumour size change (maximum diameter of the largest lesion in millimetre) measured by magnetic resonance imaging prior to surgery. Secondary outcomes include clinical/pathological, physical and patient-reported measures such as relative dose intensity of NACT, hospital admissions, body composition, physical fitness, muscle strength, health-related quality of life, general anxiety, depression, and biological measures such as intratumoural vascularity, tumour infiltrating lymphocytes, circulating tumour DNA and blood chemistry. Outcomes will be measured at baseline (one week before to 1–2 weeks after starting NACT), during NACT (approximately week 7, 13 and 19), pre-surgery (approximately week 21–29), at surgery (approximately week 21–30) and 3 months post-surgery (approximately 33–42 weeks from baseline).DiscussionThis study will provide novel and important data on the potential benefits of supervised aerobic and resistance exercise concomitant to NACT on tumour response and the tumour microenvironment in patients with breast cancer, with potential importance for survival and risk of recurrence. If effective, our study may help increase focus of exercise as an active part of the neoadjuvant treatment strategy.Trial registrationThe trial was registered at ClinicalTrials.gov (NCT04623554) on November 10, 2020.

The preventive effects of early short-course corticosteroids on immune-related adverse events in non-small cell lung cancer patients receiving immune checkpoint inhibitors.

144 Background: Corticosteroid is effective in treating immune checkpoint inhibitor (ICI)-induced immune-related adverse events (irAEs). However, whether its earlier use prevents irAEs remains unknown. In real-world practice, non-small cell lung cancer (NSCLC) patients receiving combined immunochemotherapy are often given corticosteroids right after ICI injection to reduce subsequent chemotherapy-related adverse events. It is thus an ideal model to examine whether this earlier use of corticosteroid also reduce irAEs following immunotherapy. Methods: NSCLC patients receiving at least one cycle of ICI with or without chemotherapy were enrolled. Patients receiving ICI with corticosteroid corticosteroid premedication exposure were categorized as “corticosteroid group (CS)”, whereas patients receiving ICI without corticosteroids premedication exposure were categorized as “non-corticosteroid group (non-CS)”. Frequency of irAEs prompting systemic corticosteroid or leading to ICI discontinuation were compared between the two groups. Exploratory survival analysis was performed. Results: Among 252 eligible patients, 137 patients were categorized as CS group, and 115 patients as non-CS group. 21.9% of patients in the CS group and 30.4% of patients in the non-CS group developed irAEs prompting systemic corticosteroid use (Odds ratio [OR], 0.64; 95% confidence interval [CI], 0.35 to 1.18; p=0.15). 5.8% of patients in the CS group and 15.7% of patients in the non-CS group developed irAEs leading to ICI discontinuation (OR, 0.34; 95% CI, 0.12 to 0.85; p=0.013). In the exploratory survival analysis, early short-course corticosteroids was not associated with a higher risk for death in first-line patients (hazard ratio [HR], 1.06; 95% CI, 0.56–2) or patients receiving immunochemotherapy (HR, 0.72; 95% CI, 0.37–1.45). Conclusions: Early short-course corticosteroids following each ICI injection may reduce the rate of irAEs that leads to ICIs discontinuation. The use of prophylactic corticosteroids on irAEs in cancer patients receiving ICIs should be evaluated in future prospective studies. [Table: see text]

Feasibility and Safety of Adjuvant Chemotherapy for Resected Colorectal Cancer in Patients With Renal Insufficiency: A Pooled Analysis of Individual Patient Data from Five Japanese Large-scale Clinical Trials.

The incidence of chemotherapy-related adverse events in colorectal cancer patients with renal insufficiency has been compared to patients with normal renal function in only a few studies. The purpose of this analysis was to verify the feasibility and safety of adjuvant chemotherapy for postoperative colorectal cancer patients with renal insufficiency. Adverse events and discontinuation of adjuvant chemotherapy for patients with curatively resected locally advanced colorectal cancer were examined using a combined database of individual patient data obtained from five large-scale clinical trials (n=4,106). The renal function of patients was classified into Level (L) 1-2: ≥60 ml/min and L3-4: <60 ml/min. As Grade 3 adverse events, hematological toxicities, such as neutropenia and anemia, and gastrointestinal disorders, such as diarrhea and vomiting, were significantly more frequent in the L3-4 group. Moreover, the time-to-treatment discontinuation in the L3-4 group was higher (hazard ratio=1.21, p=0.0012). T factor, N factor, and creatinine clearance level were found to be independent risk factors for the discontinuation of adjuvant chemotherapy. In the subgroup analysis of FOLFOX, neutropenia and diarrhea were significantly common in the L3-4 group, but neurotoxicities were not different. There was no significant difference in the discontinuation of adjuvant FOLFOX. Adverse events of adjuvant chemotherapy in patients with resected colorectal cancer were associated with renal insufficiencies. Since adverse events have the potential to shorten the duration of treatment, especially when using chemotherapy without oxaliplatin, careful management, including dose reduction, may be important in patients with renal insufficiency.

Adjuvant systemic chemotherapy with or without hepatic arterial infusion of floxuridine in patients following colorectal cancer liver metastases resection (HARVEST): A prospective, randomized controlled trial.

3516 Background: Several retrospective studies have previously demonstrated that a combination of adjuvant systemic chemotherapy and hepatic arterial infusion (HAI) could benefit patients following colorectal cancer liver metastases (CRLM) resection. This prospective clinical study aimed to determine whether adding HAI to adjuvant systemic chemotherapy could reduce the risk of recurrence following CRLM resection. Methods: The HARVEST study is an investigator-initiated, prospective, randomized controlled trial investigating the efficacy and safety of adjuvant intravenous chemotherapy with or without HAI floxuridine (FUDR) in CRLM patients that underwent liver metastasectomy. Patients in the systemic chemotherapy plus HAIC arm (HAI group) received systemic FOLFOX (q2w) plus HAI (FUDR, d1-14, q4w) for up to 6 months, while the systemic chemotherapy group without HAI (non-HAI group) received intravenous FOLFOX only. The primary study endpoint is the relapse-free survival in the modified intention-to-treat (mITT) population. Blood samples at different time points were also collected and circulating tumor DNA (ctDNA) was tested for NPY and SEPT9 methylation. Results: The study was prematurely terminated due to FUDR production halt in China. Ninety-two patients were randomized and seventy-seven patients (38 in the HAI group and 39 in the non-HAI group) were eventually included in our mITT analysis. After a median follow-up of 35.8 months, there were 22 (57.9%) and 25 (64.1%) recurrences in the HAI and non-HAI groups, respectively. The median relapse-free survival was 20.0 months in the HAI group and 11.7 months in the non-HAI group (p = 0.14; HR 0.65; 95% confidence interval [CI] 0.37 to 1.16). No significant difference was found in terms of overall survival between the two groups (p = 0.461). Our subgroup analysis revealed that patients with multiple liver metastases (p &lt; 0.01) and RAS/BRAF mutation (p &lt; 0.01) could benefit from adjuvant HAI treatment. Based on ctDNA status, patients with positive postoperative ctDNA methylation benefited from adjuvant HAI treatment (p &lt; 0.01), while those with negative postoperative ctDNA methylation status (p = 0.95) did not. Chemotherapy-related adverse events were comparable between the two groups. Conclusions: Adjuvant chemotherapy intensification using HAI did not significantly reduce recurrence following CRLM resection. However, patients with multiple liver metastases, RAS/BRAF mutation and those with positive postoperative ctDNA might benefit from adjuvant HAI treatment. Clinical trial information: NCT03500874 .

Adverse events during first-line treatments for mCRC: The Toxicity over Time (ToxT) analysis of three randomised trials

BackgroundIn clinical trials, the assessment of safety is traditionally focused on the overall rate of high-grade and serious adverse events (AEs). A new approach to AEs evaluation, taking into account chronic low-grade AEs, single patient’s perspective, and time-related information, such as ToxT analysis, should be considered especially for less intense but potentially long-lasting treatments, such as maintenance strategies in metastatic colorectal cancer (mCRC). Patients and methodsWe applied ToxT (Toxicity over Time) evaluation to a large cohort of mCRC patients enroled in randomised TRIBE, TRIBE2, and VALENTINO studies, in order to longitudinally describe AEs throughout the whole treatment duration and to compare AEs evolution over cycles between induction and maintenance strategies, providing numerical and graphical results overall and per single patient. After 4–6 months of combination therapy, 5-fluorouracil/leucovorin (5-FU/LV) + bevacizumab or panitumumab was recommended in all studies except for the 50% of patients in the VALENTINO trial who received panitumumab alone. ResultsOut of 1400 patients included, 42% received FOLFOXIRI (5-FU/LV, oxaliplatin, and irinotecan)/bevacizumab, 18% FOLFIRI/bevacizumab, 24% FOLFOX/bevacizumab, 16% FOLFOX/panitumumab. Mean grade of general and haematological AEs was higher in the first cycles, then progressively decreasing after the end of induction (p < 0.001), and always remaining at the highest levels with FOLFOXIRI/bevacizumab (p < 0.001). Neurotoxicity became more frequent over the cycles with late high-grade episodes (p < 0.001), while the incidence but not the grade of hand-and-foot syndrome gradually increased (p = 0.91). Anti-VEGF-related AEs were more severe in the first cycles, then setting over at low levels (p = 0.03), while anti-EGFR-related AEs still affected patients during maintenance. ConclusionsMost of chemotherapy-related AEs (except for HFS and neuropathy) reach the highest level in the first cycles, then decrease, probably due to their active clinical management. Transition to maintenance allows relief from most AEs, especially with bevacizumab-based regimens, while anti-EGFR-related AEs may persist.

Predictors of three-month mortality and severe chemotherapy-related adverse events in patients aged 70 years and older with metastatic non-small-cell lung cancer: A secondary analysis of ESOGIA-GFPC-GECP 08–02 study

IntroductionPredictors for mortality and toxicity in older patients with cancer are mainly studied in cohorts with various cancers at different stages. This study aims to identify predictive geriatric factors (PGFs) for early death and severe chemotherapy related adverse events (CRAEs) in patients aged ≥70 years with metastatic non-small-cell lung cancer (mNSCLC). Material and MethodsThis is a secondary analysis of the multicenter, randomized, phase 3 ESOGIA trial that compared, for patients ≥70 years with mNSCLC, a treatment algorithm based on performance status and age to another algorithm based on geriatric assessment. To identify PGFs of three-month mortality and grade 3, 4, or 5 CRAEs, multivariate Cox models and logistic models, adjusted for treatment group and center, and stratified by randomization arm, were constructed. ResultsAmong 494 included patients, 145 (29.4%) had died at three months and 344 (69.6%) had severe chemotherapy toxicity. For three-month mortality, multivariate analyses retained mobility (Test Get up and Go), instrumental activity of daily living (IADL) dependence and weight loss as PGFs. The combined effect of IADL ≤2/4 and weight loss ≥3 kg was strongly associated with three-month mortality (adjusted hazard ratio: 5.71 [95% confidence interval [CI]: 2.64–12.32]). For chemotherapy toxicity, Charlson Comorbidity Index ≥2 was independently associated with grade3, 4, or 5 CRAEs (adjusted odds ratio [95% CI]: 1.94 [1.06–3.56]). DiscussionMobility, IADL dependence, and weight loss were predictive of three-month mortality in a population aged ≥70 years treated for mNSCLC, while comorbidities were independently associated with severe chemotherapy toxicity.

Exercise during CHemotherapy for Ovarian cancer (ECHO) trial: design and implementation of a randomised controlled trial

IntroductionEpidemiological evidence supports an association between higher levels of physical activity and improved cancer survival. Trial evidence is now needed to demonstrate the effect of exercise in a clinical setting....

Adjuvant Dose Dense Chemotherapy in Patients With Obesity: Short-Term Toxicities and Breast Cancer Outcome

BackgroundDose dense adjuvant chemotherapy is associated with improved outcomes in breast cancer compared to standard dosing. Despite current guidelines recommending that chemotherapy is dosed according to actual body weight, reviews have shown patients with obesity often receive a capped chemotherapy dose. The latter is commonly undertaken as clinicians have concerns that adverse events are more frequent if full doses are administered. This study assessed surgical, radiotherapy and chemotherapy related adverse events between patients with and without obesity receiving dose dense adjuvant chemotherapy for breast cancer. Materials and MethodsA retrospective review of prospective collected data for patients receiving adjuvant chemotherapy from 30 April 2018 from a single institution was analyzed. Data collected included demographic data, height, weight, pathological information, comorbidities, surgical, radiotherapy chemotherapy treatment, and toxicity. Primary outcomes were surgical complications at 30 days, radiotherapy skin toxicity at 30 days and chemotherapy side-effects. Secondary outcomes were rates of recurrence and time to recurrence. ResultsA total of 280 patients were included in the analysis: 55 obese and 225 nonobese. Obese status was associated with higher rates of grade >2 skin toxicity and this difference was significant after adjusting for age, comorbidity and radiotherapy field (P = .017). Obese status was not associated with higher rates of surgical or chemotherapy related adverse events. All patients regardless of obese status received adequate dose intensity with similar rates of recurrence and time to recurrence. ConclusionPatients with obesity who receive dose dense adjuvant chemotherapy do not experience higher rates of surgical or chemotherapy related adverse events although they do experience higher rates of grade >2 radiotherapy related skin toxicity. This supports the use of dose dense chemotherapy being based on actual body weight in patients with obesity.

Profiles of Symptom Suffering and Functioning in Children and Adolescents Receiving Chemotherapy.

Some children and adolescents receiving chemotherapy experience few symptom-related adverse events, whereas others experience multiple adverse events. If oncology nurses could identify patients likely to have pronounced chemotherapy-related adverse events, tailored supportive care could be matched to these patients' symptom burdens. The aim of this study was to identify symptom profiles in children and adolescents before and after chemotherapy, and the sociodemographic and psychological factors associated with profile classification and change. Participants ranging from 7 to 18 years (n = 436) completed 6 Patient-Reported Outcomes Measurement Information System pediatric symptom measures within 72 hours preceding (T1) and 1 to 2 weeks after (T2) chemotherapy. Profile membership and change were determined by latent profile/latent transition analyses. Associations with profiles and profile transitions were examined using multinomial logit models and logistic regression. Three symptom suffering profiles were identified at T1 and T2: high, medium, and low. The high symptom suffering profile included the fewest participants (T1, n = 70; T2, n = 55); the low symptom suffering profile included the most participants (T1, n = 200; T2, n = 207). Of the participants, 57% remained in the same profile from T1 to T2. Psychological stress was significantly associated with T1 and T2 profile classifications and profile transition; age was associated with profile classification at T1. Three symptom suffering profiles existed in a sample of pediatric patients undergoing chemotherapy, indicating that children and adolescents have differing cancer treatment experiences. Oncology nurses could screen pediatric oncology patients for their symptom suffering profile membership and subsequently prioritize care efforts for those with a high suffering profile.

OP09 Association of patient sex with chemotherapy-related adverse events: A multicenter retrospective cohort study

OP09 Association of patient sex with chemotherapy-related adverse events: A multicenter retrospective cohort study