Chemotherapy-associated Adverse Events Research Articles

Abstract CT169: First-in-human, phase 1/2 study of GSK4524101, an oral DNA polymerase theta inhibitor (POLQi), alone or combined with the poly(ADP-ribose) polymerase (PARP) inhibitor (PARPi) niraparib in adults with solid tumors

Abstract Background: Double-stranded DNA breaks (DSBs) in human cells are typically repaired via nonhomologous end joining (NHEJ) or homologous recombination (HR). Deficiency of HR-mediated DNA repair plays a role in the initiation and progression of many tumor types. In tumors with HR deficiency, PARP inhibition leads to generation of DSBs that cannot be effectively repaired because of the HR defect, resulting in synthetic lethality. This finding has led to the clinical development and approval of several PARPi for the treatment of various tumors including certain ovarian, breast, prostate, and pancreatic cancers that are prone to display HR deficiency (HRd). DNA polymerase theta (encoded by POLQ) mediates an alternative DNA repair mechanism, microhomology-mediated end joining (MMEJ). DNA polymerase theta is generally not detectable in normal tissues but is upregulated in many tumor types. In preclinical studies, POLQi plus PARPi treatment demonstrated superior efficacy to PARPi alone in preventing the growth of HRd tumors. To evaluate the clinical potential of combining POLQi and PARPi, this first-in-human study investigates treatment with GSK4524101, an investigational POLQi, with or without the PARPi niraparib, in patients with solid tumors. Methods: This open-label, multicenter, phase 1/2 study (NCT06077877) opened in October 2023 and comprises dose-finding (part 1, including a food-effect cohort) and dose-expansion (part 2) parts. This trial aims to assess the maximum-tolerated dose, pharmacokinetics, safety, and preliminary antitumor activity of oral GSK4524101 with or without niraparib. The primary endpoints are safety (part 1) and confirmed objective response rate (part 2). Secondary endpoints include pharmacokinetics, safety, progression-free survival (part 2), and response duration (part 2). Up to 135 patients may be enrolled. To be eligible, patients must be aged ≥18 years; have an advanced or metastatic solid tumor, an Eastern Cooperative Oncology Group performance status score of 0-2, and a life expectancy of ≥3 months; and have exhausted all standard treatment options. Individuals are ineligible if they have not recovered from chemotherapy-associated adverse events or have symptomatic uncontrolled brain or leptomeningeal metastases, a history of myelodysplastic syndrome or acute myeloid leukemia, uncontrolled hypertension, or a second malignancy that has progressed or required active treatment in the previous 2 years. The study is actively recruiting in the US and Canada; as of January 1, 2024, 1 patient has been dosed. Patients enrolled in part 1 will receive GSK4524101 alone or GSK4524101 plus niraparib; patients enrolled in part 2 will be randomized to either GSK4524101 plus niraparib or niraparib alone. Part 1 of this study is expected to complete in 2025. Citation Format: Vivek Samnotra, Veronica Moroz, Luda Shtessel, Mita Kuchimanchi, Patrick Hanafin, Malar Pannirselvam, Aishwarya Bhaskar, Andrew Liu, Haluk Yuzugullu, Minal Barve, David Sommerhalder, Timothy Yap, Michele Sanicola-Nadel. First-in-human, phase 1/2 study of GSK4524101, an oral DNA polymerase theta inhibitor (POLQi), alone or combined with the poly(ADP-ribose) polymerase (PARP) inhibitor (PARPi) niraparib in adults with solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT169.

Impact of prophylactic dexamethasone on the efficacy of immune checkpoint inhibitors plus platinum-based chemotherapy in patients with advanced Non-Squamous Non-Small-Cell lung cancer

BackgroundBaseline corticosteroids exposure is associated with inferior clinical outcomes in patients with non-small-cell lung cancer (NSCLC) treated with programmed cell death-1 (PD-1) axis blockade. Dexamethasone is a potent corticosteroid used in the prevention of chemotherapy-associated adverse events (CAAEs). ObjectiveSince dexamethasone has immunosuppressive properties, this study attempted to elucidate its effects on the efficacy of immunotherapy plus chemotherapy in patients with non-squamous NSCLC. MethodsThe study retrospectively analyzed the medical records of 254 advanced non-squamous NSCLC patients who received front-line treatment with a PD-1 pathway inhibitor and platinum-based chemotherapy at three academic institutions. The average dosage of prophylactic dexamethasone per chemotherapy cycle was calculated. Patients were divided into three groups based on the dose of dexamethasone: High-d (≥24 mg), Moderate-d (12–24 mg), and Low-d (<12 mg). Spearman's rank correlation was used to assess the correlation between the dosage of dexamethasone and progression-free survival (PFS). Logistic regression was used to assess the correlation between dexamethasone dosage and the occurrence of immune related adverse effects (irAE). Univariate and multivariate Cox proportional hazards regression models were used to analyze the differences in survival among the different dexamethasone dosage groups. ResultThe dosage of prophylactic dexamethasone was not significantly correlated with PFS (Spearman’s rho = -0.103, P = 0.098). Results from the univariate [hazard ratio (HR)Low-d/High-d, 1.00; P = 0.997; HRModerate-d/High-d, 0.85; P = 0.438] and multivariate (HRLow-d/High-d, 0.71; P = 0.174; HRModerate-d/High-d, 0.87; P = 0.512) analyses showed no significant association between dexamethasone and PFS. Dexamethasone did not have significant effect on the objective response rate, disease control rate or overall survival. The toxicity profiles of irAE were similar across all three groups. ConclusionThe results of this study suggest that the use of prophylactic dexamethasone does not have an adverse effect on the clinical outcomes of non-squamous NSCLC patients treated with PD-1 blockade therapy and chemotherapy. Routine use of dexamethasone for preventing CAAEs should be recommended for patients undergoing combined immunotherapy and chemotherapy.

Сопроводительная терапия при множественной миеломе: практические рекомендации

Supportive therapy is becoming increasingly important for the state-of-the-art algorithm of multiple myeloma (MM) treatment. The introduction of innovative drugs and transplantation methods into clinical practice considerably improved the disease-free and overall survival rates. However, in the vast majority of cases, MM still remains an incurable malignant plasma cell tumor. It is often treated on a continuous basis with a succession of targeted drugs and integration of glucocorticosteroids and conventional cytostatic agents into the program therapy. All of these together with immunodeficiency, bone lesions, and myeloma nephropathy lead to a high risk of adverse events and cumulative toxicity of treatment. At the same time, one of the main goals at all MM therapy stages is to maintain quality of life. The characteristics of clinical symptoms, the nuances of targeted therapy and chemotherapy-associated adverse events justify the need for further development of supportive MM therapy algorithms which remain to be a matter of current concern. They should be mainly aimed at preventing the therapy complications, reducing the rate of adverse events and clinical manifestations of side effects as well as developing a treatment strategy for cumulative toxicity. In the state-of-the-art algorithm of program MM treatment, supportive therapy-related knowledge is of no less value than the information on antitumor drugs and their efficacy. This paper reports the personal experience and provides recommendations mostly based on the results of clinical studies or views of expert panels. It also offers practical recommendations for supportive therapy in symptomatic MM which include prevention of skeletal complications, thromboses, and infections, nausea and vomiting management, vaccination, pre-medication and the algorithm of monoclonal antibody administration, anesthesia, peripheral polyneuropathy treatment, correction of secondary immunodeficiency, nutritional support, fatigue assessment and countermeasures.

Mitigating long-term and delayed adverse events associated with cancer treatment: implications for survivorship.

Despite the importance of chemotherapy-associated adverse events in oncology practice and the broad range of interventions available to mitigate them, limited systematic efforts have been made to identify, critically appraise and summarize the totality of evidence on the effectiveness of these interventions. Herein, we review the most common long-term (continued beyond treatment) and lateor delayed (following treatment) adverse events associated with chemotherapy and other anticancer treatments that pose major threats in terms of survival, quality of life and continuation of optimal therapy. These adverse effects often emerge during and continue beyond the course of therapy or arise among survivors in the months and years following treatment. For each of these adverse effects, we discuss and critically evaluate their underlying biological mechanisms, the most commonly used pharmacological and non-pharmacological treatment strategies, and evidence-based clinical practice guidelines for their appropriate management. Furthermore, we discuss risk factors and validated risk-assessment tools for identifying patients most likely to be harmedby chemotherapy and potentially benefit from effective interventions. Finally, we highlight promising emerging supportive-care opportunities for the ever-increasing number of cancer survivors at continuing risk of adverse treatment effects.

MP50-14 A MULTICENTER EVALUATION OF THE PROGNOSTIC UTILITY OF CHANGES IN TREATMENT-ASSOCIATED BODY COMPOSITION IN MEN WITH GERM CELL TUMORS (GCT) OF THE TESTIS: IMPLICATIONS FOR ADVERSE EVENTS AND COMPLICATIONS

You have accessJournal of UrologyCME1 Apr 2023MP50-14 A MULTICENTER EVALUATION OF THE PROGNOSTIC UTILITY OF CHANGES IN TREATMENT-ASSOCIATED BODY COMPOSITION IN MEN WITH GERM CELL TUMORS (GCT) OF THE TESTIS: IMPLICATIONS FOR ADVERSE EVENTS AND COMPLICATIONS Claire Buxton, Benjamin N. Schmeusser, Sarah K. Holt, Datta Patil, Anthea Phuong, J. Peter Marquardt, Ryan O'malley, Grace Laidlaw, George R. Schade, Daniel W. Lin, Michael T. Schweizer, Todd Yezefski, Evan Y. Yu, Bruce Montgomery, Florian J. Fintelmann, Sophia Chahine, Viraj A. Master, and Sarah P. Psutka Claire BuxtonClaire Buxton More articles by this author , Benjamin N. SchmeusserBenjamin N. Schmeusser More articles by this author , Sarah K. HoltSarah K. Holt More articles by this author , Datta PatilDatta Patil More articles by this author , Anthea PhuongAnthea Phuong More articles by this author , J. Peter MarquardtJ. Peter Marquardt More articles by this author , Ryan O'malleyRyan O'malley More articles by this author , Grace LaidlawGrace Laidlaw More articles by this author , George R. SchadeGeorge R. Schade More articles by this author , Daniel W. LinDaniel W. Lin More articles by this author , Michael T. SchweizerMichael T. Schweizer More articles by this author , Todd YezefskiTodd Yezefski More articles by this author , Evan Y. YuEvan Y. Yu More articles by this author , Bruce MontgomeryBruce Montgomery More articles by this author , Florian J. FintelmannFlorian J. Fintelmann More articles by this author , Sophia ChahineSophia Chahine More articles by this author , Viraj A. MasterViraj A. Master More articles by this author , and Sarah P. PsutkaSarah P. Psutka More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003298.14AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Skeletal muscle mass is associated with oncologic outcomes and treatment-associated toxicity across malignancies. However, men with GCT are younger and less likely to suffer baseline age-related muscle loss. As such, the prognostic utility of body composition metrics in GCT is undefined. We aimed to quantify changes in body composition following cytotoxic chemotherapy (CC) for GCT and evaluate associations between these changes and rates of CC-associated adverse events (AEs) and post-retroperitoneal lymphadenectomy (RPLND) complications. METHODS: This retrospective study included 216 patients with GCT (N=152 from Fred Hutchinson Cancer Center/ University of Washington; N=64 from Emory University Hospital) treated with CC and/or RPLND, with CT scans within 75 days before initiation and after completion of treatment. We analyzed L3 axial CT scans for skeletal muscle index (SMI), subcutaneous adipose index (SAI), and visceral adipose index (VAI). Logistic regression was used to evaluate associations between body composition metrics and grade 3+ AEs and Clavien 3+ post-RPLND complications. RESULTS: Median age for the cohort was 30 years (IQR 25-39) of whom, 47% of men had nonseminomatous GCT (Stage IS, II, and III in 17%, 39%, and 42%, respectively). 182 men received CC including BEP (67%), EP (19%), and VIP (7%), with a median of 3 cycles while 34 men (33%) and 69 men underwent primary and post-CC RPLND, respectively. Median time between CTs was 114 days. Median change in SMI, VAI, and SAI was -6% (Figure 1), +13%, and +11%, respectively. Overall, 79 men (43%) experienced grade 3+ AEs, and 24 men (23%) experienced Clavien 3+ post-RPLND complications. On regression analysis, higher baseline VAI (p=0.048), lower post-CC SMI (p=0.008), and decreased SMI (p=0.047) were associated with increased risk of grade 3+ AE. No baseline body composition metrics or changes therein during CC predicted risk of post-RPLND complications. CONCLUSIONS: We observed a decline in skeletal muscle and an increase in adipose tissue following CC in men with GCT. Both skeletal muscle and adipose tissue metrics were associated with the incidence of chemotherapy-associated adverse events and may have the potential for use in risk evaluation. Source of Funding: None © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e690 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Claire Buxton More articles by this author Benjamin N. Schmeusser More articles by this author Sarah K. Holt More articles by this author Datta Patil More articles by this author Anthea Phuong More articles by this author J. Peter Marquardt More articles by this author Ryan O'malley More articles by this author Grace Laidlaw More articles by this author George R. Schade More articles by this author Daniel W. Lin More articles by this author Michael T. Schweizer More articles by this author Todd Yezefski More articles by this author Evan Y. Yu More articles by this author Bruce Montgomery More articles by this author Florian J. Fintelmann More articles by this author Sophia Chahine More articles by this author Viraj A. Master More articles by this author Sarah P. Psutka More articles by this author Expand All Advertisement PDF downloadLoading ...

Mitigating acute chemotherapy-associated adverse events in patients with cancer.

Despite the enthusiasm surrounding novel targeted agents and immunotherapies, chemotherapy remains the mainstay treatment for most human malignancies, either alone or in combination. Yet, the burden of chemotherapy-associated adverse events (CAAEs) remains high and, importantly, is associated with considerable morbidity, mortality and costs that affect patients across multiple dimensions, including physical, emotional and social functioning. CAAEs can directly affect patient outcomes and indirectly increase the risk of cancer recurrence by compromising treatment intensity and continuity. Systematic efforts to identify and critically summarize the evidence on management approaches for CAAEs remain limited. Herein, we review the most common acute CAAEs having a major effect on survival, quality of life, function and/or continuation of optimal therapy. We focus on selected acute toxicities that occur during treatment, summarizing their underlying pathophysiology, multifactorial aetiologies, evidenced-based treatments, prevention strategies and management recommendations. We also summarize the available evidence on risk factors, validated risk assessment tools and other efforts to optimize symptom control in patients most likely to benefit in order to personalize the prevention and treatment of acute CAAEs. Finally, we discuss innovative symptom monitoring and supportive care interventions that are under development to further improve the outcomes of patients with cancer.

Changes in skeletal muscle and adipose tissue during cytotoxic chemotherapy for testicular germ cell carcinoma and associations with adverse events.

To quantify changes in body composition during cytotoxic chemotherapy for germ cell carcinoma of the testis (GCT) and evaluate associations between change in skeletal muscle and adipose tissue and chemotherapy-associated adverse events. This retrospective single-institution study evaluated men with GCT treated with cytotoxic chemotherapy from 2005 to 2018. We measured skeletal muscle index (SMI [cm2/m2]), skeletal muscle density (SMD [Hounsfield Units (HU)]), skeletal muscle gauge (SMG [cm²*HU/m²]), fat mass index (FMI [kg/m2]), visceral adipose index (VAI [cm2/m2]), and subcutaneous adipose index (SAI [cm2/m2]) on axial computed tomography images at the level of the third lumbar vertebra within 75 days before and after chemotherapy. Chemotherapy-associated adverse events (AE) were graded based on the Common Terminology Criteria for Adverse Events (CTCAE v5.0.) Changes in body composition were quantified. Predictors of change in body composition were evaluated with multivariable linear regression. Associations between baseline or change in body composition and AEs were estimated with multivariable logistic regression adjusting for age, comorbidity, performance status, stage, and number/type of chemotherapy cycles. 141 patients (median age, 30 years [IQR 25-39]) including 86 patients (61%) with non-seminomatous GCT were included. Patients received a median of 3 cycles of cisplatin-based chemotherapy, and 124 patients (88%) completed planned chemotherapy. Median observed changes in SMI, SMD, and SMG were -6% (P<0.0001), -2% (P=0.07), and -7% (P<0.0001), respectively, while FMI increased 5.3% (P<0.0001). Overall, 120 patients (85%) experienced at least one AE including one or more ≥grade 3 AE in 57 patients (48%). Decrease in SMI (OR: 0.89, P=0.02), decrease in SMG (OR: 0.88, P=0.01,) and post-chemotherapy SMG (OR: 0.94, P=0.05) were independently associated with higher incidence of AEs, while pre-chemotherapy skeletal muscle parameters and post-chemotherapy SMI and SMD were not associated with AEs (P>0.05 for all). Preoperative adipose tissue or change in adiposity was not associated with incidence of AEs. In men with GCT receiving cytotoxic chemotherapy, a decrease in skeletal muscle mass and quality during chemotherapy were associated with a higher incidence of chemotherapy-associated AEs. Adipose tissue was not associated with the incidence of AEs.

Taxane monotherapy regimens for the treatment of recurrent epithelial ovarian cancer.

Taxane monotherapy regimens for the treatment of recurrent epithelial ovarian cancer.

MP46-12 DECLINES IN SKELETAL MUSCLE MASS AND QUALITY DURING CYTOTOXIC CHEMOTHERAPY PREDICT INCREASED RISK OF CHEMOTHERAPY-ASSOCIATED ADVERSE EVENTS IN MEN WITH TESTIS CANCER

You have accessJournal of UrologyCME1 May 2022MP46-12 DECLINES IN SKELETAL MUSCLE MASS AND QUALITY DURING CYTOTOXIC CHEMOTHERAPY PREDICT INCREASED RISK OF CHEMOTHERAPY-ASSOCIATED ADVERSE EVENTS IN MEN WITH TESTIS CANCER Anthea Phuong, J. Peter Marquardt, Florian J. Fintelmann, Ryan O'Malley, Grace Laidlaw, Zachary Eagle, Steven Ngo, Sarah Holt, Delaney Orcutt, George R. Schade, Daniel W. Lin, Michael T. Schweizer, Todd Yezefski, Evan Y. Yu, Bruce Montgomery, Petros Grivas, and Sarah Psutka Anthea PhuongAnthea Phuong More articles by this author , J. Peter MarquardtJ. Peter Marquardt More articles by this author , Florian J. FintelmannFlorian J. Fintelmann More articles by this author , Ryan O'MalleyRyan O'Malley More articles by this author , Grace LaidlawGrace Laidlaw More articles by this author , Zachary EagleZachary Eagle More articles by this author , Steven NgoSteven Ngo More articles by this author , Sarah HoltSarah Holt More articles by this author , Delaney OrcuttDelaney Orcutt More articles by this author , George R. SchadeGeorge R. Schade More articles by this author , Daniel W. LinDaniel W. Lin More articles by this author , Michael T. SchweizerMichael T. Schweizer More articles by this author , Todd YezefskiTodd Yezefski More articles by this author , Evan Y. YuEvan Y. Yu More articles by this author , Bruce MontgomeryBruce Montgomery More articles by this author , Petros GrivasPetros Grivas More articles by this author , and Sarah PsutkaSarah Psutka More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002612.12AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Baseline muscle mass (skeletal muscle index, SMI) is associated with outcomes across malignancies. The novel concept of skeletal muscle gauge (SMG=SMI*skeletal muscle density (SMD)) is proposed as a composite measure for muscle quality and quantity. To date, changes in SMI and SMI during cytotoxic chemotherapy (CC) in germ cell carcinoma of testis (GCT) remain undescribed. Herein, our objective was to quantify changes in SMI and SMG in men with GCT undergoing CC and evaluate associations between these measures and CC-associated adverse events (AE). METHODS: All consecutive men undergoing CC for GCT (2005-18) were retrospectively reviewed. Third lumbar SMI (cm2/m2) and SMD (HU) were obtained using validated methodology on axial computed tomography (CT) images within 75 days prior to the start (T1) and after the end (T2) of CC from which SMG was calculated. Changes in SMI, SMD, and SMG were quantified and associations with grade 1-5 AEs (CTCAE v.5) were estimated with multivariable logistic regression. RESULTS: This study of 141 men with median age of 30 years (IQR 25-39) included 61% with nonseminomatous GCT. Tumors were classified as Stage IS, II, and III GCT in 21%, 41%, and 38%, respectively. CC regimens included BEP (68%), EP (17%), VIP (8%), and other (6%) with median of 3-cycles; 90% of patients completed planned CC. Median time between CTs was 107 days. Median SMI-T1 and -T2 were 57.9 and 55.3 cm2/m2 (∆SMI -6%), median SMD-T1 and -T2 were 57 and 54 HU (∆SMD -2%), and median SMG-T1 and -T2 were 3256 and 3059 (∆SMG -6%, Figure). Overall, 120 men (85%) experienced at least one AE. On multivariable analysis adjusted for age, ECOG performance status, Charlson Comorbidity Index, CC type, and GCT stage, ∆SMI (OR 1.19; 95% CI 1.04-1.35, p=0.002) and ∆SMG (OR (/100-unit increments): 1.14; 95% CI 1.01-1.28, p=0.02) were independently associated with risk of AE. CONCLUSIONS: On average, men with GCT demonstrate declines in skeletal muscle mass and quality during CC, which are independently associated with risk of chemotherapy-associated AEs. Further work is needed to understand the risk factors for loss of muscle mass and quality during CC and to determine optimal interventions to mitigate these losses. Source of Funding: none © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e777 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Anthea Phuong More articles by this author J. Peter Marquardt More articles by this author Florian J. Fintelmann More articles by this author Ryan O'Malley More articles by this author Grace Laidlaw More articles by this author Zachary Eagle More articles by this author Steven Ngo More articles by this author Sarah Holt More articles by this author Delaney Orcutt More articles by this author George R. Schade More articles by this author Daniel W. Lin More articles by this author Michael T. Schweizer More articles by this author Todd Yezefski More articles by this author Evan Y. Yu More articles by this author Bruce Montgomery More articles by this author Petros Grivas More articles by this author Sarah Psutka More articles by this author Expand All Advertisement PDF DownloadLoading ...

187: EFFECT OF PERI-OPERATIVE CHEMOTHERAPY REGIMEN ON SURVIVAL IN THE TREATMENT OF LOCALLY ADVANCED GASTRO-OESOPHAGEAL ADENOCARCINOMA—FLOT VS ‘MAGIC’

Abstract Background and aim Peri-operative chemotherapy has been shown to improve survival in patients with locally advanced oesophago-gastric adenocarcinoma. Two commonly used regimens are epirubicin, cisplatin plus capecitabine or fluorouracil (MAGIC) and fluorouracil plus leucovorin, oxaliplatin, and docetaxel (FLOT). The primary aim of this study was to evaluate the effect of chemotherapy regimen (FLOT vs MAGIC) on survival. We also aimed to assess pathological response, surgical complications, chemotherapy associated adverse events and chemotherapy completion rates. Methods Cohort study including 946 patients treated with peri-operative FLOT or MAGIC chemotherapy who underwent oesophagectomy or gastrectomy for oesophageal or gastric adenocarcinoma between 2002–2021 at St Thomas’ Hospital, London, UK or The Royal Marsden Hospital, London, UK. Survival analysis was performed using Kaplan–Meier and Cox regression. Results Patients treated with MAGIC had worse overall and disease-free survival compared with FLOT on multivariable analysis (overall survival HR 1.353 95% CI 1.039–1.763, disease-free survival HR 1.335 95% CI 1.025–1.739). Stratified analysis by tumour location revealed similar results for both oesophageal and gastric tumours. Patients treated with FLOT were more likely to have a favourable pathological response (Mandard 1–2) (11.1% MAGIC vs 21.8% FLOT, P &amp;lt; 0.001). Patients treated with FLOT were less likely to have a positive resection margin (19.1% FLOT vs 32.2% MAGIC, P &amp;lt; 0.001). Surgical complications, chemotherapy associated adverse events and chemotherapy completion rates were comparable between groups. Conclusion Patients with oesophageal and gastric adenocarcinoma treated with peri-operative FLOT had improved survival compared with those treated with peri-operative MAGIC. Surgical complications, chemotherapy associated adverse events and chemotherapy completion rates were comparable between groups. Table https://secure.sem-2000.it/semUpload/OLC/file/9203828791100911681076702/94509_Table.jpg.

Changes in body composition during neoadjuvant platinum-based chemotherapy associations prior to radical cystectomy: Implications for chemotherapy-associated adverse events and oncologic outcomes.

476 Background: Low skeletal muscle index (SMI) is associated with an increased risk of mortality in muscle-invasive bladder cancer (MIBC) and chemotherapy-related adverse events (AE) across numerous other malignancies. Small case series suggest neoadjuvant chemotherapy (NAC) is associated with a significant decline in SMI in patients with MIBC. However, limited data exists regarding changes in fat mass during NAC. Herein, we examine changes in SMI, visceral fat index (VFI), and subcutaneous fat index (SFI) in patients receiving NAC for MIBC before radical cystectomy (RC). We describe associations between body composition changes and NAC-associated AE and all-cause mortality (ACM) in patients with MIBC. Methods: Retrospective review of patients with MIBC (≥pT2 N0/x/1 M0) who received NAC (2006-2019). Patients with digitized abdominal computed tomography scans (CT) within 75 days prior (T1) and 75 days following completion (T2) of NAC were included. We segmented and calculated the indices (cm2/m2) for SMI, VFI, and SFI at the third lumbar vertebra level at T1 and T2 using validated methodology. Associations with AE during NAC and ACM were evaluated with multivariate logistic regression and Cox proportional hazards models. Results: Included 170 patients, median age 63 years receiving a median of 4 (IQR 3-5) cycles of Gemcitabine/Cisplatin (52%), MVAC (28%), or other NAC (20%). Absolute and relative changes in SMI, VFI, and SFI over a median of 112 days (IQR 94-146) between measurements are presented in the Table. 117 (69%) patients experienced grade ≥3 chemotherapy-related AE. No associations between baseline body composition or change in body composition during NAC with chemotherapy-related AE. T1 SMI (HR: 0.98; 0.97-0.99, p = 0.008), as well as T2 SMI (HR: 0.98; 0.96-0.99, p = 0.003), T2 VFI (HR: 0.99; 0.99-1.0, p = 0.05) and T2 SFI (HR: 0.99; 0.98-1.0, P = 0.03) were associated with ACM after adjusting for age, clinical T and N stage, and performance status. Conclusions: Patients undergoing NAC prior to RC experienced a 6.4% decrease in SMI and a 5.2% decrease in VFI during an average of 112 days. Chemotherapy-related AE were not associated with a change in body composition. Baseline SMI and T2 SMI, SFI, and VFI were associated with ACM on multivariable analysis. Future work is needed to understand the mechanisms underpinning such changes and the extent to which potentially detrimental changes in body composition may be mitigated before surgery.[Table: see text]

Effect of peri-operative chemotherapy regimen on survival in the treatment of locally advanced oesophago-gastric adenocarcinoma – A comparison of the FLOT and ‘MAGIC’ regimens

BackgroundPeri-operative chemotherapy improves survival in patients with locally advanced oesophago-gastric adenocarcinoma. Two regimens with proven survival benefits are epirubicin, cisplatin plus capecitabine or fluorouracil (Medical Research Council Adjuvant Gastric Infusional Chemotherapy, MAGIC) and fluorouracil plus leucovorin, oxaliplatin, and docetaxel (FLOT). This study aimed to compare the effect of these regimens on survival (primary aim) and pathological response, surgical complications, adverse events and chemotherapy completion rates. MethodsCohort study including 946 patients treated with FLOT (n = 257) or MAGIC (n = 689) who underwent surgical resection for oesophageal (n = 743) or gastric (n = 203) adenocarcinoma between 2002 and 2021 at St Thomas’ Hospital or The Royal Marsden Hospital, London, UK. Survival analysis was performed using multivariable Cox regression, providing hazard ratios (HRs) with 95% confidence intervals (CIs) adjusted for age, sex, clinical T-stage, clinical N-stage, tumour grade and presence of signet ring cells. ResultsPatients treated with FLOT had better overall survival (HR = 0.69, 95% CI 0.50–0.94) and disease-free survival (HR = 0.75, 95% CI 0.58–0.98) than MAGIC. Patients treated with FLOT were more likely to have a complete pathological response (9.5% FLOT versus 5.5% MAGIC, p = 0.027) and were less likely to have a positive resection margin (19.1% FLOT versus 32.2% MAGIC, p < 0.001). The stratified analysis revealed similar results for oesophageal and gastric tumours. Rates of surgical complications, chemotherapy-associated adverse events and completion were similarly distributed between treatment groups. ConclusionsPatients with oesophageal or gastric adenocarcinoma treated with peri-operative FLOT had better survival and pathological response than those treated with peri-operative MAGIC. Rates of surgical complications, adverse events and chemotherapy completion were comparable.

Modulated TRPC1 Expression Predicts Sensitivity of Breast Cancer to Doxorubicin and Magnetic Field Therapy: Segue Towards a Precision Medicine Approach.

Chemotherapy is the mainstream treatment modality for invasive breast cancer. Unfortunately, chemotherapy-associated adverse events can result in early termination of treatment. Paradoxical effects of chemotherapy are also sometimes observed, whereby prolonged exposure to high doses of chemotherapeutic agents results in malignant states resistant to chemotherapy. In this study, potential synergism between doxorubicin (DOX) and pulsed electromagnetic field (PEMF) therapy was investigated in: 1) MCF-7 and MDA-MB-231 cells in vitro; 2) MCF-7 tumors implanted onto a chicken chorioallantoic membrane (CAM) and; 3) human patient-derived and MCF-7 and MDA-MB-231 breast cancer xenografts implanted into NOD-SCID gamma (NSG) mice. In vivo, synergism was observed in patient-derived and breast cancer cell line xenograft mouse models, wherein PEMF exposure and DOX administration individually reduced tumor size and increased apoptosis and could be augmented by combined treatments. In the CAM xenograft model, DOX and PEMF exposure also synergistically reduced tumor size as well as reduced Transient Receptor Potential Canonical 1 (TRPC1) channel expression. In vitro, PEMF exposure alone impaired the survival of MCF-7 and MDA-MB-231 cells, but not that of non-malignant MCF10A breast cells; the selective vulnerability of breast cancer cells to PEMF exposure was corroborated in human tumor biopsy samples. Stable overexpression of TRPC1 enhanced the vulnerability of MCF-7 cells to both DOX and PEMF exposure and promoted proliferation, whereas TRPC1 genetic silencing reduced sensitivity to both DOX and PEMF treatments and mitigated proliferation. Chronic exposure to DOX depressed TRPC1 expression, proliferation, and responses to both PEMF exposure and DOX in a manner that was reversible upon removal of DOX. TRPC1 channel overexpression and silencing positively correlated with markers of epithelial-mesenchymal transition (EMT), including SLUG, SNAIL, VIMENTIN, and E-CADHERIN, indicating increased and decreased EMT, respectively. Finally, PEMF exposure was shown to attenuate the invasiveness of MCF-7 cells in correlation with TRPC1 expression. We thus demonstrate that the expression levels of TRPC1 consistently predicted breast cancer sensitivity to DOX and PEMF interventions and positively correlated to EMT status, providing an initial rationale for the use of PEMF-based therapies as an adjuvant to DOX chemotherapy for the treatment of breast cancers characterized by elevated TRPC1 expression levels.

Comparative effectiveness of prophylactic hyperthermic intraperitoneal chemotherapy (HIPEC) for resected low-grade appendiceal mucinous neoplasm (LAMN): A protocol for systematic review and network meta-analysis.

Background:Whether prophylactic hyperthermic intraperitoneal chemotherapy (HIPEC) offers long-term survival benefit to patients with low-grade appendiceal mucinous neoplasms (LAMNs) after resection surgery is still under heated debate. The aim of the present meta-analysis is to investigate the comparative effectiveness and safety of prophylactic HIPEC regimens in LAMNsMethods:A systematic search of MEDLINE, EMBASE, PubMed, Web of Science, the Cochrane Central Register of Controlled Trials, International Clinical Trials Registry Platform (ICTRP), clinicaltrials.gov and controlledtrials.com will be performed. All published RCTs and quasi-RCTs through July 20, 2020 with language restricted in English will be included in this review study. Two reviewers will independently conduct the procedures of study identification, data collection, and methodological quality assessment. The primary outcomes are overall survival (OS) and disease-free survival (DFS). The secondary outcomes consist of peritonitis and sepsis, colonic fistula, chemotherapy-associated adverse events, and adhesive intestinal obstruction. The pooled odds ratios (ORs) or hazard ratios (HRs) and relative 95% confident intervals (CIs) of each outcome measurement will be calculated. EndNote X9 software will be applied to manage all citations. The Stata software version 14.0 and R x64 software version 3.5.1 will be employed for main statistical analyses.Discussion:This study will employ a network meta-analysis to summarize direct and indirect evidence in the specific area to provide detailed individualized guidance on surgical management for LAMNs.Registration:This protocol was registered with the International Platform of Registered Systematic Review and Meta-Analysis Protocols (INPLASY) on 25 July 2020 (registration number INPLASY202070112).

Efficacy of oral administration of cystine and theanine in colorectal cancer patients undergoing capecitabine-based adjuvant chemotherapy after surgery: a multi-institutional, randomized, double-blinded, placebo-controlled, phase II trial (JORTC-CAM03)

PurposeCapecitabine-based adjuvant chemotherapy for colorectal cancer patients often causes adverse events (AEs), such as diarrhea, stomatitis, anorexia, and hand-foot syndrome (HFS). Cystine and theanine were reported to attenuate some chemotherapy-associated AEs, and hence are also expected to attenuate capecitabine-induced AEs. Therefore, we aimed to investigate the safety and efficacy of cystine/theanine treatment in colorectal cancer patients undergoing capecitabine-based adjuvant chemotherapy after surgery.MethodsA total of 100 colorectal cancer patients treated with capecitabine as an adjuvant chemotherapy after surgery were randomly allocated into the cystine/theanine group (n = 52) or the placebo group (n = 48). The primary endpoint was incidence rate of diarrhea of grade 1 or higher in accordance with the Common Terminology Criteria for AEs (CTCAE) v.4.0, Japanese Clinical Oncology Group (JCOG) version. The secondary endpoints included incidence rates of other AEs (CTCAE v.4.0-JCOG), as well as the incidence rate of HFS according to the HFS grading scale.ResultsThere were no significant differences in capecitabine-induced AEs between the two groups. However, the incidence rate of diarrhea of grade 1 or higher tended to be lower in the cystine/theanine group than the placebo group (18.4% vs. 28.9%, p = 0.169) as well as the incidence rate of HFS of grade 1 or higher (CTCAE v.4.0-JCOG or HFS grading scale) (67.4% vs. 77.8%, p = 0.185, 67.3% vs. 80.0%, p = 0.124, respectively).ConclusionThis trial demonstrated that cystine/theanine treatment of colorectal cancer patients undergoing capecitabine-based adjuvant chemotherapy after surgery is safe and has the tendency to reduce the incidence rate of diarrhea or HFS.Trial registrationUMIN000024784

Adjuvant chemotherapy in resected bile duct cancer: A systematic review and meta-analysis of randomized trials.

The role of adjuvant chemotherapy (ACT) for resected biliary tract cancer (BTC) is still unclear and there is no specific recommendation by international guidelines. To perform a meta-analysis of randomized clinical trials (RCTs) to better define the clinical benefit and risks of ACT or observation in resected BTC. A systematic literature search of Pubmed, Embase, and the Cochrane Library was performed up to April 2019. A meta-analysis was carried out using the random effects model. ACT provided a mild improvement in recurrence free survival (RFS) (HR:0.83, 95%CI 0.69-0.99) and no effect on overall survival (OS) (HR:0.91, 95%CI 0.75-1.09). Similarly, ACT showed no effect on OS in lymph-node positive subgroup (HR:0.84, 95% CI 0.65-1.08) and surgical margin positive subgroup (HR:0.95, 95%CI 0.69-1.31). Moreover, ACT led to a substantial increase of chemotherapy-associated adverse events (RR:3.03, 95%CI 2.22-4.15). ACT for resected BTC patients modestly improved RFS with no effect on OS and a substantial increase in chemotherapy associated AEs.

Abstract OT1-01-01: IMpassion131: A phase III study comparing 1L atezolizumab with paclitaxel vs placebo with paclitaxel in treatment-naive patients with inoperable locally advanced or metastatic triple negative breast cancer (TNBC)

Abstract Background: Chemotherapy (including paclitaxel) remains the predominant treatment for metastatic TNBC but clinical outcomes remain poor. Therefore, new therapeutic approaches are needed. Atezolizumab blocks the binding of PD-L1 to its receptors PD-1 and B7.1, thus restoring tumor-specific T cell immunity. TNBC is a rational target for atezolizumab therapy due to high PD-L1 expression on tumor-infiltrating immune cells (IC) and elevated T cell tumor infiltration. Furthermore, combining chemotherapy with atezolizumab is hypothesized to enhance anti-tumor immune response via neoantigen release. Atezolizumab alone and in combination with nab-paclitaxel has demonstrated promising clinical benefit in metastatic TNBC and was well tolerated, with no exacerbation of chemotherapy-associated adverse events. Atezolizumab in combination with nab-paclitaxel is being further investigated as 1L TNBC treatment in IMpassion130. IMpassion131 is a global, multi-center, randomized, double-blind, placebo-controlled study comparing the efficacy and safety of 1L atezolizumab + paclitaxel vs placebo + paclitaxel in patients with untreated, inoperable, locally advanced or metastatic TNBC. (NCT03125902) Methods: Eligibility criteria include patients with inoperable, locally advanced or metastatic TNBC, histologically confirmed; de novo or recurrent disease after early breast cancer treated with chemotherapy ≥ 12 months prior; eligible for taxane monotherapy; no prior chemotherapy or targeted systemic therapy for inoperable locally advanced or metastatic disease; ECOG PS 0-1 and measurable disease by RECIST v1.1. Exclusion criteria include known symptomatic CNS disease, prior immunotherapy and a history of autoimmune disease. Approximately 495 patients will be randomized 2:1 to receive atezolizumab (840 mg) or placebo (q2w; days 1 and 15 of 28-day cycle) plus paclitaxel (90 mg/m2; days 1, 8, 15 of 28-day cycle) until disease progression. Stratification factors are PD-L1 expression on tumor-infiltrating IC (IC0 &amp;lt; 1% vs IC1/2/3 ≥ 1% with VENTANA SP142 IHC assay), prior taxane therapy, presence of liver metastases and geographical region. The primary endpoint is progression-free survival (PFS) measured by RECIST v1.1. Key secondary endpoints include overall survival (OS), 12- and 18-month OS rates, 12-month PFS rate, objective response rate, duration of response, and safety. Tumor biopsies will be collected at baseline, on treatment and at disease progression to assess for biomarkers of treatment response and immune escape. Citation Format: Miles D, André F, Gligorov J, Verma S, Xu B, Cameron D, Barrios CH, Schneeweiss A, Easton V, Ghazi Y, O'Shaughnessy J. IMpassion131: A phase III study comparing 1L atezolizumab with paclitaxel vs placebo with paclitaxel in treatment-naive patients with inoperable locally advanced or metastatic triple negative breast cancer (TNBC) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr OT1-01-01.

A developed model of cancer patients participation in intravenous chemotherapy safety

How to reduce intravenous chemotherapy-related adverse reactions of cancer patients is one focus of clinical work. Nowadays, patient for patient safety (PFPS) is an important component of hospital safety management and can contribute to a reduction in the rate of adverse events following intravenous chemotherapy of cancer patients. To guide and evaluate cancer patients participate in intravenous chemotherapy, we explored a scientific and practical model of cancer patients participation in intravenous chemotherapy safety. which can also guide nurse practitioners (NPs) practice. Based on a literature review and analysis of chemotherapy-associated adverse events from two large comprehensive hospitals, combined with the existing strategies for PFPS, the model of cancer patients participation in intravenous chemotherapy safety was drafted. Then we conducted two rounds of the Delphi-method questionnaire to revise the model. The two rounds Delphi questionnaire survey had a response rate of 82.36%. The authoritative coefficient was 0.87 and the coordination coefficients were 0.165 and 0.214, respectively. The proposed safety model included 3 first-order indicators, 8 second-order indicators, and 41 third-order indicators, including content of patients participation, responsibilities of medical personnel to assist cancer patients participation, and suggestions for guaranteeing implementation. Many NPs practice in a medical setting where cancer patients for patient safety behavior are blurred. The model of cancer patients participation in intravenous chemotherapy safety can guide NPs in their practice of promoting PFPS among cancer patients intravenous chemotherapy.

Microwave ablation in combination with chemotherapy versus chemotherapy in advanced non small cell lung cancer: A prospective, randomized, phase III clinical trial.

9048 Background: Previous studies showed that advanced non small cell lung cancer (NSCLC) benefited from microwave ablation in combination with platium-based doublet chemotherapy. This prospective, randomized, phase III clinical trial aimed to determining the survival benefit and safety of MWA combined with chemotherapy compared with chemotherapy alone, which was registered in Clinical Trials. gov (NCT02455843). Methods: Patients with untreated, stage IIIB or IV NSCLC and at least one additional measurable site other than the primary tumor site were recruited. They were divided into MWA/chemotherapy group and chemotherapy group, the former received MWA in the primary tumor sites, followed by chemotherapy and the latter treated with chemotherapy only. The primary endpoint was progression-free survival (PFS), the second endpoint included objective response rate (ORR), overall survival (OS) and adverse events (AE). Results: From Mar 1st, 2015 to Oct 31th, 2016, Two hundreds and eighty-six patients were enrolled, including 141 in MWA/chemotherapy group and 145 in chemotherapy group. Complete ablation was observed in 95.0 % patients. ORR were 38.3 % and 34.1 % in the MWA/chemotherapy group and chemotherapy group, respectively(p = 0.677). MWA prolonged PFS [MWA/chemotherapy group 7.3 (95 % CI,5.3–13.6) ms vs. chemotherapy group 5.2 (95 % CI, 4.0–12.4) ms, p = 0.003]. Multivariate analyses showed that MWA was an independent prognostic factor of PFS. OS was immature. AEs of MWA were observed in 67.4 % patients, mainly was pheumothorax, and only 15% needing chest tube insertion. No ablation associated death was observed. Chemotherapy-associated AEs were observed in 49.1 and 53.6 % of patients in the MWA/chemotherapy and chemotherapy group, respectively. Conclusions: MWA plus chemotherapy combination improved the PFS of advanced NSCLC compared to chemotherapy alone. Adverse events of MWA was tolerable. Clinical trial information: NCT02455843.

Gastrectomy plus chemotherapy versus chemotherapy alone for advanced gastric cancer with a single non-curable factor (REGATTA): a phase 3, randomised controlled trial

Chemotherapy is the standard of care for incurable advanced gastric cancer. Whether the addition of gastrectomy to chemotherapy improves survival for patients with advanced gastric cancer with a single non-curable factor remains controversial. We aimed to investigate the superiority of gastrectomy followed by chemotherapy versus chemotherapy alone with respect to overall survival in these patients. We did an open-label, randomised, phase 3 trial at 44 centres or hospitals in Japan, South Korea, and Singapore. Patients aged 20-75 years with advanced gastric cancer with a single non-curable factor confined to either the liver (H1), peritoneum (P1), or para-aortic lymph nodes (16a1/b2) were randomly assigned (1:1) in each country to chemotherapy alone or gastrectomy followed by chemotherapy by a minimisation method with biased-coin assignment to balance the groups according to institution, clinical nodal status, and non-curable factor. Patients, treating physicians, and individuals who assessed outcomes and analysed data were not masked to treatment assignment. Chemotherapy consisted of oral S-1 80 mg/m(2) per day on days 1-21 and cisplatin 60 mg/m(2) on day 8 of every 5-week cycle. Gastrectomy was restricted to D1 lymphadenectomy without any resection of metastatic lesions. The primary endpoint was overall survival, analysed by intention to treat. This study is registered with UMIN-CTR, number UMIN000001012. Between Feb 4, 2008, and Sept 17, 2013, 175 patients were randomly assigned to chemotherapy alone (86 patients) or gastrectomy followed by chemotherapy (89 patients). After the first interim analysis on Sept 14, 2013, the predictive probability of overall survival being significantly higher in the gastrectomy plus chemotherapy group than in the chemotherapy alone group at the final analysis was only 13·2%, so the study was closed on the basis of futility. Overall survival at 2 years for all randomly assigned patients was 31·7% (95% CI 21·7-42·2) for patients assigned to chemotherapy alone compared with 25·1% (16·2-34·9) for those assigned to gastrectomy plus chemotherapy. Median overall survival was 16·6 months (95% CI 13·7-19·8) for patients assigned to chemotherapy alone and 14·3 months (11·8-16·3) for those assigned to gastrectomy plus chemotherapy (hazard ratio 1·09, 95% CI 0·78-1·52; one-sided p=0·70). The incidence of the following grade 3 or 4 chemotherapy-associated adverse events was higher in patients assigned to gastrectomy plus chemotherapy than in those assigned to chemotherapy alone: leucopenia (14 patients [18%] vs two [3%]), anorexia (22 [29%] vs nine [12%]), nausea (11 [15%] vs four [5%]), and hyponatraemia (seven [9%] vs four [5%]). One treatment-related death occurred in a patient assigned to chemotherapy alone (sudden cardiopulmonary arrest of unknown cause during the second cycle of chemotherapy) and one occurred in a patient assigned to chemotherapy plus gastrectomy (rapid growth of peritoneal metastasis after discharge 12 days after surgery). Since gastrectomy followed by chemotherapy did not show any survival benefit compared with chemotherapy alone in advanced gastric cancer with a single non-curable factor, gastrectomy cannot be justified for treatment of patients with these tumours. The Ministry of Health, Labour and Welfare of Japan and the Korean Gastric Cancer Association.