Appetite Stimulant and Anti-Emetic Effect of Mirtazapine Transdermal Ointment in Cats Affected by Lymphoma Following Chemotherapy Administration: A Multi-Centre Retrospective Study

In humans, mirtazapine can prevent chemotherapy-induced nausea and vomiting (CINV) and improve cancer patients’ quality of life (QoL). This drug is being increasingly used as an appetite stimulant in cats. The hypothesis of this retrospective study was that mirtazapine could reduce the incidence of CINV and weight loss in feline patients affected by lymphoma. The objectives were to report the use of mirtazapine transdermal ointment and assess the incidence of gastrointestinal (GI) toxicity and weight loss in cats diagnosed with lymphoma and receiving chemotherapy. Transdermal mirtazapine was topically administered to the inner surface of the pinna (2 mg/cat/daily) for 14 days following chemotherapy administration. Data recorded from 20 patients were collected. Different grades of GI toxicity were shown in 8/20 (40%) patients. Body weight (BW), body condition score (BCS), and muscle condition score (MCS) improved in 12/20 (60%), 6/20 (30%), and 2/20 (10%) cats, respectively. Mirtazapine-induced adverse events (AEs) occurred in 4/20 (20%) cats and did not require mirtazapine discontinuation. Substantial weight loss was not encountered, suggesting that patients had an adequate food intake after chemotherapy administration. Transdermal mirtazapine ointment was considered safe and well tolerated.

Two-Weekly High-Dose-Rate Brachytherapy Boost After External Beam Radiotherapy for Localized Prostate Cancer: Long-Term Outcome and Toxicity Analysis

PurposeEvaluation of clinical outcome of two-weekly high-dose-rate brachytherapy boost after external beam radiotherapy (EBRT) for localized prostate cancer.Methods338 patients with localized prostate cancer receiving definitive EBRT followed by a two-weekly high-dose-rate brachytherapy boost (HDR-BT boost) in the period of 2002 to 2019 were analyzed. EBRT, delivered in 46 Gy (DMean) in conventional fractionation, was followed by two fractions HDR-BT boost with 9 Gy (D90%) two and four weeks after EBRT. Androgen deprivation therapy (ADT) was added in 176 (52.1%) patients. Genitourinary (GU)/gastrointestinal (GI) toxicity was evaluated utilizing the Common Toxicity Criteria for Adverse Events (version 5.0) and biochemical failure was defined according to the Phoenix definition.ResultsMedian follow-up was 101.8 months. 15 (4.4%)/115 (34.0%)/208 (61.5%) patients had low-/intermediate-/high-risk cancer according to the D`Amico risk classification. Estimated 5-year and 10-year biochemical relapse-free survival (bRFS) was 84.7% and 75.9% for all patients. The estimated 5-year bRFS was 93.3%, 93.4% and 79.5% for low-, intermediate- and high-risk disease, respectively. The estimated 10-year freedom from distant metastasis (FFM) and overall survival (OS) rates were 86.5% and 70.0%. Cumulative 5-year late GU toxicity and late GI toxicity grade ≥ 2 was observed in 19.3% and 5.0% of the patients, respectively. Cumulative 5-year late grade 3 GU/GI toxicity occurred in 3.6%/0.3%.ConclusionsTwo-weekly HDR-BT boost after EBRT for localized prostate cancer showed an excellent toxicity profile with low GU/GI toxicity rates and effective long-term biochemical control.

Methotrexate Toxicity: Molecular Mechanisms and Management

Methotrexate (MTX) is the most widely used drug in cancer chemotherapy and is considered to be the first-line drug for the treatment of a number of rheumatic and non-rheumatic disorders. The pulmonary toxicity, hepatotoxicity of MTX are two of its major side effects. Other toxicities such as endocrinological toxicity, GI toxicity, cutaneous toxicity, hematological toxicity, fatal malfunction or loss, and malignancy can also occur, but at a significantly lower rate of prevalence. This review aims to provide a comprehensive understanding of the molecular mechanisms of methotrexate toxic effects and Lastly, we discussed the management of this toxicity.

Pharmacogenomic Single Nucleotide Polymorphism (SNP) Variants As Predictors of Toxicity Phenotypes in the Treatment of Acute Childhood Leukemia

Introduction: Despite cure rates in acute lymphoblastic leukemia (ALL) exceeding 90% in clinical trials, morbidity due to drug toxicities is high. Genetic polymorphisms can influence gene expression and activity, impacting pharmacokinetics and causing inter-individual variation in drug levels, which contributes to toxicity if levels are high or relapse if levels are low. We hypothesize that pharmacogenomic testing will identify patient specific variations in genes involved in metabolism of cytotoxic agents. This knowledge will allow clinicians to optimize therapy by providing pharmacogenomics based biomarkers related to increased toxicities. Data has shown that treatment interruptions and omissions due to toxicities affect outcomes and morbidities in children with cancer. Objective : To correlate pharmacogenomic biomarkers with toxicity phenotypes in children receiving therapy for ALL. Methods: This cross-sectional study involved subjects at a tertiary academic center (Fig. 1A). Subjects aged 1 year to 26 years with ALL treated after May 2012 were eligible. A total of 75 patients treated between 2012 and 2020 were included. Pharmacogenomic testing was performed on peripheral blood. Genomic DNA was tested for 118 single-nucleotide polymorphisms (SNP) in 55 genes for transport and metabolism of cytarabine, vincristine, methotrexate, dauno/doxorubicin, and mercaptopurine/thioguanine were analyzed using the Sequenom-based genotyping that uses MALDI-TOF based chemistry. SNPs were tested using logistic regression models for association with toxicities in additive, dominant, and recessive modes of inheritance. CTCAE v4.0 was used for grading all toxicities during the first 100 days of therapy. For endocrine (endo) and neurological (neuro) toxicities, 25 patients exhibited between grade 1-3 toxicities. For gastrointestinal (GI) toxicities, 25 patients exhibited between grade 2-3 toxicities. For hematological (heme) toxicities, 11 patients exhibited between grade 2-4 toxicities. Odds ratio and 95% confidence interval were calculated for each test and SNPs with association P-value <0.05 were considered significant. To conduct multivariable SNP combinations analysis, SNPs with univariate association p-value <0.1 were selected for each toxicity, and then SNP combinations (up to 3 SNPs per model) were tested for association with each toxicity. The combination model with the 1000 permutation p-value <0.05 and lowest BIC value was selected to build a SNP score after considering the mode of inheritance and the direction of association with the toxicity for the individual genotypes. A SNP score was generated by summation of genotype scores for the individual SNPs passing the top model. Patients were further classified into either of the 3 following SNP score groups: >0, 0 or <0. Results: For a GI toxicity score derived from 3 SNPs (TYMS-rs151264360, FPGS-rs1544105, and GSTM5-rs3754446), patients with >0 score had 79% incidence of GI toxicity (N=67) as compared to 10% in patients with score of 0 and 8% in patients with score <0 (p=2.07E-05, Fig 1B). For the SNP score (AKR1C3-rs6621365, ABCB1-rs4148737, and CTPS1-rs12067645) generated for heme toxicity, higher SNP scores were associated with high toxicity (p=0.003, Figure 1C). For neurotoxicity, the 3 SNPs (DCTD-rs6829021, SCL28A3-rs17343066, and CTPS1-rs12067635) involved were all in cytarabine metabolic pathway and predicted greater neurotoxicity (56%) with a score of >0; no toxicity was observed in patients with neurotoxicity score of <0 (p=0.0005, Fig. 1D). For SNP endo toxicity score (AKR1C3-rs1937840, TYMS-rs2853539, and CTS-rs648743), we observed 91% incidence of endo toxicity in patients with toxicity score of >0 (p=4.7E-08, Fig. 1E). None of the patients with a score of <0 experienced endo toxicity. Discussion: We identified germline SNPs predictive of toxicity phenotypes in a cohort of 75 subjects with ALL. The results of our multivariable SNP combination analysis suggest susceptibility to chemotherapy-induced toxicities is likely multigenic in nature. Instead of a single SNP approach, identification of combinations of mutations in drug pathways increases the robustness of predicting a patient's response to chemotherapy. Our results provide promising SNP models that can help establish clinically relevant biomarkers allowing for individualization of cancer therapy to optimize treatment for each patient. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Mycobiome Supporting Diet to Reduce Gastrointestinal (GI)Toxicity Associated with Autologous Stem Cell Transplant (ASCT) for Patients with Multiple Myeloma (MM)

Emerging data suggest healthy microbiome helps to protect against mucosal injury and inflammation. Dysbiosis results in biofilm formation in the gut which has been shown to be pro-inflammatory. MM patients potentially have significant dysbiosis result of long term corticosteroid use. Our group, previously showed that composition of microbiome presents at the pre-transplant period correlates with rate and degree of post-ASCT GI toxicities, neutropenic fever and neutrophilic engraftment among MM patients. Also, our data suggested a link between microbial communities at the count nadir and GI toxicity after high dose melphalan and ASCT. Mycobiome Supporting Diet (MSD) proposed in this study is designed to restructure the gut microbiome (both bacterial and fungal communities) and support optimal GI tract health. It combines elements from several diets (e.g., Paleo, low-carbohydrate, vegetarian, and Mediterranean) and excludes elements of these diets that have been specifically proven to increase pathogenic fungi in the human gut. Our group examined application of MSD among healthy volunteers between the ages of 30 and 70 who agreed to follow the MSD for 28 days on a prospective trial. At the end of the study period, subjects had a 1.7-fold decrease in the abundance of Proteobacteria (considered a red flag for inflammation), with levels reduced from 38.6% to 23.3% with significantly increased of beneficial species such as Faeclibacterium prausnitzii (up 35.8%) , Bifidobacterium adolescentis (up 61.6%) , Roseburia (up 57.5%) , Lactobacillus (up 77.6%) , and Bacteroides. Furthermore, Pathogenic bacteria decreased significantly, including Escherichia coli (down 74%), Bacteroides fragilis (down 45.3%), and Clostridium (down 55.7%). After the study, all participants with GI symptoms reported moderate or dramatic improvements. Two thirds of the participants who chose to track their weight lost significant weight (between two and 10 pounds) over the testing period. Thirty percent of the participants reported moderate or dramatically improved fatigue and higher energy levels. Given the association between baseline gut dysbiosis and post-transplant GI toxicities and availability of a highly curated diet to optimize the richness and diversity of gut microbiome communities, in this trial (ClinicalTrials.gov Identifier: NCT04685525) we sought to examine the feasibility of MSD diet among MM patients undergoing transplant by assessing its potential effect on decreasing post-transplant GI toxicities. Methods: The primary objective of this study is to evaluate the feasibility of MSD diet using patient's adherence to the MSD diet. The adherence will be assessed 3 times before transplant on days -21, -14 and -7. The MSD diet will deem feasible if at least 80% of patients showed adherence defined by 2 out of 3 assessment marked "more than half a time". With sample size of 40 we will be able to estimate the adherence rate of 80% with 95% confidence interval of +/- 12%. To assess impact of MSD on micro- and mycobiome, a custom pipeline based on Greengenes V13_8 and Unite database V7.2 will be designed for the taxonomic classification of 16SrRNA and ITS sequences, respectively. Downstream data analysis will be performed using Qiime software. Statistical analysis will be performed using the statistical programming language R (version 3.3.0). Change across time in phyla and genus abundance at the community level will be assessed using the non-parametric multivariate distance-based analysis of variance using BC distance for dissimilarity metric along with its standardized binary form. Diversity will be analyzed in an unbiased manner using the Shannon diversity index, a measure of abundance taking into account microbial distribution. Richness will be also assessed, reflecting the microbial counts of the bacterial and fungal communities in each sample. Longitudinal analysis will be performed using all pair wise Multiple Comparison of Mean Ranks as implemented in the PMCMR plus R package version 1.2.0, employing Kruskal & Wallis test followed by Bonferroni-Dunn post-hoc adjustment. P <.05 will be considered statistically significant for all tests after correcting for multiple comparisons. Correction for multiple testing were performed using Benjamini-Hochberg adjustment method for multiple testing. Figure 1 Figure 1. Disclosures Malek: Sanofi: Other: Advisory Board; Bluespark Inc.: Research Funding; Amgen: Honoraria; Cumberland Inc.: Research Funding; Medpacto Inc.: Research Funding; Janssen: Other: Advisory board ; BMS: Honoraria, Research Funding; Takeda: Honoraria. Metheny: Pharmacosmos: Honoraria; Incyte: Speakers Bureau.

Clinical Outcomes from Dose-Reduced Radiotherapy to the Prostate in Elderly Patients with Localized Prostate Cancer

Radical treatment of localized prostate cancer in elderly patients may lead to unacceptable treatment-associated toxicities that adversely impact quality of life without improving survival outcomes. This study reports on a cohort of 54 elderly (>70 years) patients that received 4000–5000 cGy of palliative external beam radiotherapy (EBRT) as an alternative to androgen deprivation therapy (ADT). The primary outcome of interest was the period of ADT-free survival, and secondary outcomes included overall survival (OS) and metastases-free survival (MFS). Kaplan–Meier regression was used to estimate survival outcomes. Thirty-six (67%) patients achieved a break in ADT post-radiotherapy, with a median time to ADT reinitiation of 20 months. Common Terminology Criteria for Adverse Events (CTCAE) were limited to low-grade gastrointestinal (GI) or genitourinary (GU) toxicities, with no skin toxicities observed. Grade 1 GI toxicity was observed in 9 (17%) patients, and grades 1 and 2 GU toxicities were observed in 13 (24%) and 3 (6%) patients, respectively, with no higher-grade toxicities reported. Five-year MFS and OS were 56% and 78%, respectively. In summary, the treatment regimen was well-tolerated and achieved durable ADT-free survival in most patients. Dose-reduced EBRT appears to be a viable alternative to ADT in elderly patients with localized prostate cancer.

Late Toxicity After Adjuvant Conventional Radiation Versus Image-Guided Intensity-Modulated Radiotherapy for Cervical Cancer (PARCER): A Randomized Controlled Trial

PURPOSE Postoperative Adjuvant Radiation in Cervical Cancer (PARCER), a phase III randomized trial, compared late toxicity after image-guided intensity-modulated radiotherapy (IG-IMRT) with three-dimensional conformal radiation therapy (3D-CRT) in women with cervical cancer undergoing postoperative radiation. METHODS Patients were randomly assigned to receive either IG-IMRT or 3D-CRT after stratification for the type of hysterectomy and use of concurrent chemotherapy. The primary end point was 3-year grade ≥ 2 late GI toxicity assessed using Common Toxicity Criteria for Adverse Events v 3.0 and estimated using time-to-event, intention-to-treat analysis, with a study level type I error of 0.05 and a nominal α of .047 after accounting for one interim analysis. Secondary end points included acute toxicity, health-related quality of life, and pelvic relapse-free, disease-free, and overall survival. RESULTS Between 2011 and 2019, 300 patients were randomly assigned (IG-IMRT 151 and 3D-CRT 149). At a median follow-up of 46 (interquartile range 20-72) months, the 3-year cumulative incidence of grade ≥ 2 late GI toxicity in the IG-IMRT and 3D-CRT arms were 21.1% versus 42.4% (hazard ratio [HR] 0.46; 95% CI, 0.29 to 0.73; P < .001). The cumulative incidence of grade ≥ 2 any late toxicity was 28.1% versus 48.9% (HR 0.50; 95% CI, 0.33 to 0.76; P < .001), respectively. Patients reported reduced diarrhea ( P = .04), improved appetite ( P = .008), and lesser bowel symptoms ( P = .002) with IG-IMRT. However, no difference was observed in the time by treatment interaction. The 3-year pelvic relapse-free survival and disease-free survival in the IG-IMRT versus the 3D-CRT arm were 81.8% versus 84% (HR 1.17; 95% CI, 0.68 to 1.99; P = .55) and 76.9% versus 81.2% (HR 1.03; 95% CI, 0.62 to 1.71; P = .89), respectively. CONCLUSION IG-IMRT results in reduced toxicity with no difference in disease outcomes.

Salvage Reirradiation Options for Locally Recurrent Prostate Cancer: A Systematic Review

BackgroundReirradiation using brachytherapy (BT) and external beam radiation therapy (EBRT) are salvage strategies with locally radiorecurrent prostate cancer. This systematic review describes the oncologic and toxicity outcomes for salvage BT and EBRT [including Stereotactic Body Radiation Therapy (SBRT)].MethodsAn International Prospective Register of Systematic Reviews (PROSPERO) registered (#211875) study was conducted using Preferred Reporting Items for Systematic reviews and Meta-analyses (PRISMA) guidelines. EMBASE and MEDLINE databases were searched from inception to December 2020. For BT, both low dose rate (LDR) and high dose rate (HDR) BT techniques were included. Two authors independently assessed study quality using the 18-item Modified Delphi technique.ResultsA total of 39 eligible studies comprising 1967 patients were included (28 BT and 11 SBRT). In 35 studies (90%), the design was single centre and/or retrospective and no randomised prospective studies were found. Twelve BT studies used LDR only, 11 HDR only, 4 LDR or HDR and 1 pulsed-dose rate only. All EBRT studies used SBRT exclusively, four with Cyberknife alone and 7 using both Cyberknife and conventional linear accelerator treatments. Median (range) modified Delphi quality score was 15 (6-18). Median (range) follow-up was 47.5 months (13-108) (BT) and 25.4 months (21-44) (SBRT). For the LDR-BT studies, the median (range) 2-year and 5-year bRFS rates were 71% (48-89.5) and 52.5% (20-79). For the HDR-BT studies, the median (range) 2-year and 5-year bRFS rates were 74% (63-89) and 51% (45-65). For the SBRT studies, the median (range) 2-year bRFS for the SBRT group was 54.9% (40-80). Mean (range) acute and late grade≥3 GU toxicity rates for LDR-BT/HDR-BT/SBRT were 7.4%(0-14)/2%(0-14)/2.7%(0-8.7) and 13.6%(0-30)/7.9%(0-21.3%)/2.7%(0-8%). Mean (range) acute and late grade≥3 GI toxicity rates for LDR-BT/HDR-BT/SBRT were 6.5%(0-19)/0%/0.5%(0-4%) and 6.4%(0-20)/0.1%(0-0.9)/0.2%(0-1.5). One third of studies included Patient Reported Outcome Measures (PROMs).ConclusionsSalvage reirradiation of radiorecurrent prostate cancer using HDR-BT or SBRT provides similar biochemical control and acceptable late toxicity. Salvage LDR-BT is associated with higher late GU/GI toxicity. Challenges exist in comparing BT and SBRT from inconsistencies in reporting with missing data, and prospective randomised trials are needed.

Proton Therapy of Prostate and Pelvic Lymph Nodes for High Risk Prostate Cancer: Acute Toxicity

Purpose To assess acute gastrointestinal (GI) and genitourinary (GU) toxicities of intensity-modulated proton therapy (IMPT) targeting the prostate/seminal vesicles and pelvic lymph nodes for prostate cancer. Materials and Methods A prospective study (ClinicalTrials.gov: NCT02874014), evaluating moderately hypofractionated IMPT for high-risk or unfavorable intermediate-risk prostate cancer, accrued a target sample size of 56 patients. The prostate/seminal vesicles and pelvic lymph nodes were treated simultaneously with 6750 and 4500 centigray radiobiologic equivalent (cGyRBE), respectively, in 25 daily fractions. All received androgen-deprivation therapy. Acute GI and GU toxicities were prospectively assessed from 7 GI and 9 GU categories of the Common Terminology Criteria for Adverse Events (version 4), at baseline, weekly during radiotherapy, and 3-month after radiotherapy. Fisher exact tests were used for comparisons of categorical data. Results Median age was 75 years. Median follow-up was 25 months. Fifty-five patients were available for acute toxicity assessment. Sixty-two percent and 2%, respectively, experienced acute grade 1 and 2 GI toxicity. Grade 2 GI toxicity was proctitis. Sixty-five percent and 35%, respectively, had acute grade 1 and 2 GU toxicity. The 3 most frequent grade 2 GU toxicities were urinary frequency, urgency, and obstructive symptoms. None had acute grade ≥ 3 GI or GU toxicity. The presence of baseline GI and GU symptoms was associated with a greater likelihood of experiencing acute GI and GU toxicity, respectively. Of 45 patients with baseline GU symptoms, 44% experienced acute grade 2 GU toxicity, compared with only 10% among 10 with no baseline GU symptoms (P = 0.07). Although acute grade 1 and 2 GI and GU toxicities were common during radiotherapy, most resolved at 3 months after radiotherapy. Conclusion A moderately hypofractionated IMPT targeting the prostate/seminal vesicles and regional pelvic lymph nodes was well tolerated with no acute grade ≥ 3 GI or GU toxicity. Patients with baseline GU symptoms had a higher rate of acute grade 2 GU toxicity.