Toxicity Of Regimen Research Articles

SWOG S1826: A Phase III, Randomized Study of Nivolumab Plus AVD or Brentuximab Vedotin Plus AVD in Patients with Newly Diagnosed Advanced Stage Classical Hodgkin Lymphoma

SWOG S1826: A Phase III, Randomized Study of Nivolumab Plus AVD or Brentuximab Vedotin Plus AVD in Patients with Newly Diagnosed Advanced Stage Classical Hodgkin Lymphoma

Challenges in the Treatment of Newly Diagnosed and Recurrent Primary Central Nervous System Lymphoma.

Primary central nervous system lymphomas (PCNSLs) are rare cancers of the central nervous system (CNS) and are predominantly diffuse large B-cell lymphomas of the activated B-cell (ABC) subtype. They typically present in the sixth and seventh decade of life, with the highest incidence among patients aged >75 years. Although many different regimens have demonstrated efficacy in newly diagnosed and relapsed or refractory PCNSL, there have been few randomized prospective trials, and most recommendations and treatment decisions are based on single-arm phase II trials or even retrospective studies. High-dose methotrexate (HD-MTX; 3-8 g/m2) is the backbone of preferred standard induction regimens. Various effective regimens with different toxicity profiles can be considered that combine other chemotherapies and/or rituximab with HD-MTX, but there is currently no consensus for a single preferred regimen. There is controversy about the role of various consolidation therapies for patients who respond to HD-MTX-based induction therapy. For patients with relapsed or refractory PCNSL who previously experienced response to HD-MTX, repeat treatment with HD-MTX-based therapy can be considered depending on the timing of recurrence. Other more novel and less toxic regimens have been developed that show efficacy in recurrent disease, including ibrutinib, or lenalidomide ± rituximab. There is uniform agreement to delay or avoid whole-brain radiation therapy due to concerns for significant neurotoxicity if a reasonable systemic treatment option exists. This article aims to provide a clinically practical approach to PCNSL, including special considerations for older patients and those with impaired renal function. The benefits and risks of HD-MTX or high-dose chemotherapy with autologous stem cell transplantation versus other, better tolerated strategies are also discussed. In all settings, the preferred treatment is always enrollment in a clinical trial if one is available.

Less Toxic Chemotherapy in Locally Advanced Breast Cancer

Preoperative chemotherapy produces tumor shrinkage in most patients with locally advanced breast cancer, including some pathological complete responses (pCRs). We attempted this using a much less toxic sequential regimen, given with concurrent bevacizumab. Patients with locally advanced breast cancer received 3 intravenous doses each of preoperative sequential liposome encapsulated doxorubicin 25 mg/m2, paclitaxel 175 mg/m2, and cyclophosphamide 600 mg/m2, with concurrent bevacizumab every 2 weeks without growth factor support. Between March 2008 and December 2009, 32 patients received treatment. There was no cardiotoxicity, and other toxicity was mild (no grade 4 or 5 toxicity). No long-term toxicity, including cardiotoxicity, has been observed. Every patient had ≥30% reduction in tumor size; 9 of 31 patients who completed chemotherapy had pCR at operation. Seven years later, 22 of 32 patients remain free of recurrence and 27 of 32 are alive. The preoperative chemotherapy used appears to be comparably effective, but much less toxic than that used in most conventional regimens and should be studied further. Concurrent treatment with bevacizumab (reported separately) did not provide any additional benefit.

Augmented immunosuppression and PTCY-based haploidentical hematopoietic stem cell transplantation for thalassemia major.

Alternate donor HSCT for thalassemia major from a matched unrelated donor or haploidentical family donor is a feasible therapeutic option in children with no matched family donor. Aggressive pretransplant immunosuppression, reduced toxicity conditioning, and PTCY result in excellent thalassemia-free survival. We describe here our experience in this cohort. We performed a retrospective analysis of the data on children who underwent a haploidentical HSCT for thalassemia major with PTCY at our center from August 2017 to August 2019. All children received pretransplant immune suppression for 6weeks with fludarabine and dexamethasone, hypertransfusion and chelation with intravenous desferrioxamine. Conditioning included thiotepa, fludarabine, rabbit ATG, and cyclophosphamide, and GvHD prophylaxis included PTCY with tacrolimus. Twenty children were included and nineteen children engrafted. Acute hypertension occurred in five children, bacterial infection in eight children and viral respiratory infection in three children. Three children suffered from graft rejection. Reactivation of viruses namely CMV, adenovirus, and BK virus was seen in 60% of children. Grades 1-2 acute GvHD of the skin in four children (20%) and limited chronic GvHD of the skin in four children (20%). Immune cytopenia was documented in three children (15%). Haploidentical HSCT offers a therapeutic option for children with thalassemia major with no suitably matched family or unrelated donors. Our reduced toxicity regimen with PTCY offers a DFS of 75% and OS of 95% with low transplant-related mortality of 5%.

Randomized Phase II Study with Cetuximab in Combination with 5-FU and Cisplatin or Carboplatin vs. Cetuximab in Combination with Paclitaxel and Carboplatin for Treatment of Patients with Relapsed or Metastatic Squamous Cell Carcinoma of the Head and Neck (CETMET Trial).

Simple SummaryThe purpose of the CET-MET trial was to find a new platinum- based chemotherapy regimen in combination with cetuximab for relapsed or metastatic squamous cell carcinoma of the head and neck (RM- SCCHN), that would achieve an equivalent PFS with standard cetuximab and 5-FU/platinum-based chemotherapy (EXTREME regimen), albeit with less toxicity. RM-SCCHN is a disease which affects patients with severe comorbidity and unhealthy life styles, rendering it difficult to treat with toxic regimens such as the EXTREME trial regimen. Immune checkpoint inhibition (ICI) with/or without the addition of chemotherapy has recently been introduced as a first- line treatment option for RM-SCCHN. However, these new treatment options will not be suitable for all patients. The experimental arm of this trial with Cetuximab and paclitaxel/carboplatin is easier to administer and perhaps more beneficial to combine with ICIs due to its favorable toxicity profile and the potential immunomodulatory effects of taxanes.Background: Platinum-based chemotherapy with cetuximab is the standard of care for relapsed or metastatic squamous cell carcinoma of the head and neck (SCCHN). The aim of this trial was to investigate whether cetuximab and paclitaxel/carboplatin can achieve similar progression-free survival (PFS) with standard cetuximab and 5-FU/platinum-based chemotherapy. Standard chemotherapy treatment for SCCHN is related to severe toxicity and new, less toxic regimens are needed. Methods: In this multicentre, randomized, controlled, phase 2 trial, 85 patients with relapsed or metastatic SCCHN were randomized in a 1:1 ratio to cetuximab and 5-FU/cisplatin or carboplatin (arm A) vs. cetuximab and paclitaxel/carboplatin (arm B). Eligibility criteria included age ≥18 years, Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0–1, and adequate organ functions. The primary endpoint was to investigate whether PFS in arm B is significantly worse than PFS in arm A. Results: Median PFS in arm A was 4.37 months (95% CI: 2.9–5.9 m) and 6.5 months (95% CI: 4.8–8.2 m) in arm B, (p = 0.064). Median overall survival (OS) was 8.4 months (95% CI: 5.3–11.5 m) in arm A and 10.2 months (95% CI: 5.4–15 m) in arm B, (HR = 0.71; 95% CI: 0.43–1.16). PFS HR for arm B was not significantly worse than arm A (HR = 0.65; 95% CI: 0.41–1.03). Adverse events ≥ grade 3 were more frequent in arm A than arm B (60% vs. 40%; p = 0.034). Conclusion: Cetuximab and paclitaxel/carboplatin was found to have similar efficacy and less toxicity compared to cetuximab and 5-FU/cisplatin or carboplatin. The experimental arm is easier to administer rendering it a favorable alternative to standard therapy.

Treosulfan-Based Conditioning Regimen for Second Allograft in Patients with Myelofibrosis.

Simple SummaryCurrently, the only curative therapy in myelofibrosis is allogeneic hematopoietic stem cell transplantation. Donor lymphocyte infusion and second stem cell transplantation are the two main treatment options for myelofibrosis patients who relapse after the first transplantation. The optimal conditioning regimen for the second transplantation in myelofibrosis patients is not well defined. Our study aimed to address this question and showed that treosulfan-based conditioning for second allograft in relapsed myelofibrosis patients resulted in longtime freedom from disease in about 50% of the patients. This data supports the second allogeneic hematopoietic stem cell transplantation with a less toxic treosulfan-based conditioning regimen that is effective in relapsed, donor lymphocyte infusion resistant myelofibrosis patients with long term low transplant-related mortality and relapse rates.Relapse after allogeneic hematopoietic stem cell transplantation (AHSCT) in myelofibrosis (MF) patients remains as a significant issue despite advances in transplantation procedures and significant prolongation in survival. Second AHSCT is a potential treatment option but associated with high treatment-related mortality and novel less toxic conditioning regimens are needed. In 33 MF patients with relapse after AHSCT and failure to donor lymphocyte infusion (DLI) we investigated treosulfan (36–42 g/m2) in combination with fludarabine and anti-thymocyte globulin (ATG) as conditioning regimen for a second AHSCT with matched related (n = 2), unrelated (n = 23), or mismatched unrelated (n = 8) donors. All patients achieved leukocyte engraftment after a median of 11 days, and 56 ± 13% experienced acute GVHD grade II–IV at day 100. The therapy-related mortality at day 100 and at 3 years was 16% and 31%, respectively. The cumulative incidence of relapse at 5 years was 16%, resulting in a 5-year disease-free and overall survival of 45% and 47%, respectively. Treosulfan-based conditioning for second allograft in relapsed MF patients resulted in about 50% of the patients in long-term freedom from disease.

Adjuvant hypofractionated radiotherapy with simultaneous integrated boost after breast-conserving surgery: results of a\xa0prospective trial

PurposeWe report results of a multicenter prospective single-arm phase II trial (ARO-2013-04, NCT01948726) of moderately accelerated hypofractionated radiotherapy with a simultaneous integrated boost (SIB) in patients with breast cancer receiving adjuvant radiotherapy after breast-conserving surgery.MethodsThe eligibility criteria included unifocal breast cancer with an indication for adjuvant radiotherapy to the whole breast and boost radiotherapy to the tumor bed. The whole breast received a dose of 40 Gy and the tumor bed a total dose of 48 Gy in 16 fractions of 2.5 and 3 Gy, respectively. Radiotherapy could be given either as 3D conformal RT (3D-CRT) or as intensity-modulated radiotherapy (IMRT). The study was designed as a prospective single-arm trial to evaluate the acute toxicity of the treatment regimen. The study hypothesis was that the frequency of acute skin reaction grade ≥2 would be 20% or less.ResultsFrom November 2013 through July 2014, 149 patients were recruited from 12 participating centers. Six patients were excluded, leaving 143 patients for analysis. Eighty-four patients (58.7%) were treated with 3D-CRT and 59 (41.3%) with IMRT. Adherence to the treatment protocol was high. The rate of grade ≥2 skin toxicity was 14.7% (95% confidence interval 9.8–21.4%). The most frequent grade 3 toxicity (11%) was hot flashes.ConclusionThis study demonstrated low toxicity of and high treatment adherence to hypofractionated adjuvant radiotherapy with SIB in a multicenter prospective trial, although the primary hypothesis was not met.

Phase I/II trial of sequential treatment of nab-paclitaxel in combination with gemcitabine followed by modified FOLFOX chemotherapy in patients with untreated metastatic exocrine pancreatic cancer: Phase I results

BackgroundAlthough occasioned through different mechanisms, the potential neurotoxicity and also haematological toxicity of nab-paclitaxel and oxaliplatin-based chemotherapy regimen were studied in this trial, which aimed to determine the maximum-tolerated dose (MTD) and to evaluate safety and efficacy of the combination in a sequential regimen of nab-paclitaxel, gemcitabine (GEM) and modified FOLFOX (mFOLFOX) in untreated patients with metastatic pancreatic ductal adenocarcinoma (PDAC). Materials and methodsTreatment consisted of nab-paclitaxel (125/100 mg/m2) plus GEM (1000/800 mg/m2) on days 1, 8 and 15, followed by mFOLFOX (oxaliplatin [85/75/65 mg/m2], 5-FU bolus [400/300/200 mg/m2], 5-FU infusion [2400/2000/1600 mg/m2]) on day 28, of a 42-day cycle. Patients were enrolled at the highest dose level with a subsequent 3 + 3 dose de-escalation plan. ResultsEleven patients (median age = 61, 64% with performance status [PS] = 1) were eligible. All patients received the highest dose level. No de-escalation was needed. A dose-limiting toxicity was reported, an upper gastrointestinal haemorrhage. The MTD was nab-paclitaxel 125 mg/m2, GEM 1000 mg/m2, oxaliplatin 85 mg/m2, 5-FU bolus 400 mg/m2 and 5-FU infusion 2400 mg/m2. Common all-grade toxicities were neutropenia (73%), anaemia (55%), thrombocytopenia (55%) and asthenia (55%). Other relevant toxicities were paraesthesia (46%), nausea (36%), dysesthesia (27%) and pyrexia (27%). Objective response rate was 50% and disease control rate was 80%. ConclusionsThe regimen of nab-paclitaxel plus GEM followed by mFOLFOX showed favourable safety and tolerability profiles with significant anti-tumor activity. More data are being achieved in a randomised phase II trial, to confirm efficacy rates and dismiss long-term neurotoxicity concerns regarding the sequencing of nab-paclitaxel and oxaliplatin.

Acute toxicity and tolerability of anthracycline-based chemotherapy regimens in older versus younger patients with breast cancer: real-world data.

To compare the non-cardiac acute toxicity and tolerability profile of anthracycline-based regimens between older versus younger women diagnosed with breast cancer in a real-world setting. Retrospective cohort of female patients diagnosed with breast cancer and treated with neoadjuvant or adjuvant anthracycline-based regimens between 2017 and 2019. Patients were grouped in young versus older, using an age of 65 as cut-off. Differences in non-cardiac acute toxicity and change in treatment plan were examined. Among the 559 patients, 19.5% were aged ≥ 65 years. Regimens used were fluorouracil, epirubicin, and cyclophosphamide in 56.2% of patients, doxorubicin and cyclophosphamide in 33.3%, and epirubicin and cyclophosphamide in 10.5%; there were no differences in incidence of grade 3 or 4 toxicities between regimens (p = 0.184). Acute grade 3 or 4 toxicities occurred more frequently in the older group (33.9% versus 10.7%, p < 0.0001, OR 4.304, 95%-CI [2.619-7.073]). Delay of at least one chemotherapy cycle due to toxicity occurred more frequently in the older group (24.8% versus 9.3%, p < 0.0001, OR 3.199, 95%-CI [1.867-5.481]). Early termination of treatment also occurred more frequently in the older group (11.9% versus 1.6%, p < 0.0001, OR 8.571, 95%-CI [3.331-22.048]). Although acute grade 3 or 4 toxicities were more frequent in older patients, which resulted in increased cycle delay and/or premature termination of treatment, overall treatment was still reasonably well-tolerated, with 88.1% of older patients completing the planed anthracycline regimen.

Cardiac arrest and drug-related cardiac toxicity in the Covid-19 era. Epidemiology, pathophysiology and management

SARS-CoV-2 (Covid-19) infection has recently become a worldwide challenge with dramatic global economic and health consequences. As the pandemic is still spreading, new data concerning Covid-19 complications and related mechanisms become increasingly available. Accumulating data suggest that the incidence of cardiac arrest and its outcome are adversely affected during the Covid-19 period. This may be further exacerbated by drug-related cardiac toxicity of Covid-19 treatment regimens. Elucidating the underlying mechanisms that lead to Covid-19 associated cardiac arrest is imperative, not only in order to improve its effective management but also to maximize preventive measures. Herein we discuss available epidemiological data on cardiac arrest during the Covid-19 pandemic as well as possible associated causes and pathophysiological mechanisms and highlight gaps in evidence warranting further investigation. The risk of transmission during cardiopulmonary resuscitation (CPR) is also discussed in this review. Finally, we summarize currently recommended guidelines on CPR for Covid-19 patients including CPR in patients with cardiac arrest due to suspected drug-related cardiac toxicity in an effort to underscore the most important common points and discuss discrepancies proposed by established international societies.

Preliminary Results Of Treatment Extranodal NK/T-Cell Lymphoma, Nasal Type Stage I-II AT K Hospital

Background: Extranodal NK/T-cell lymphoma, nasal type, is a rare subtype of non-Hodgkin lymphoma, origin from natural killer (NK) cells and T cells. This is a rare, fast-growing and poor prognosis disease. Currently there have been not many studies in Vietnam on this issue. We conduct this research with two objects: to describe characteristics of patients and evaluate premininary results of treatment extranodal NK/T cell lymphoma, nasal type, stage I to II at K hospital. Methods: Retrospective study. From January 2017 to June 2020, we enrolled 26 patients with extranodal NK/T cell lymphoma, nasal type, stage I to II. Patients were treated concurrent chemoradiotherapy with cisplatin, followed by 3 cycles of VIPD adjuvant regimen. Results: Patient characteristics: The average age was 43.2. Male/female ratio was 1.36. The most common symptoms were stuffy of nose 84.6%; runny nose 65.4%. Peripheral lymph nodes observed in 19.2%; 50% with B symptom. Staged I was dominated with 73.1%. Treatment results: Concurrent chemoradiotherapy phase: completed response was 26.9%, partial response 53.8% and progression disease 19.2%. At the end of treatment course, the overall response rate was 73% (including 61.5% completed response and 11.5% partial response), 26.9% cases with disease progression. Toxicity: Leukopenia was the most common toxicity (61.1%). Grade III and IV leukopenia were observed in 18.4%. Conclusions: Concurrent chemoradiotherapy followed by adjuvant VIPD regimen with stage I, II is effective regimen and acceptable toxicity.

Prevalence and Predictors of Virological Failure Among Adults Living with HIV in South Wollo Zone, Northeast Ethiopia: A Retrospective Cohort Study.

BackgroundHighly active antiretroviral therapy has dramatically altered progression of HIV infection and significantly improved patients’ quality of life. However, drug resistance with consequent treatment failure raises the need for much more expensive and toxic second-line regimens. Thus, this study aimed at investigating the predictors of virologic failure among adults in Northeast Ethiopia.MethodsA retrospective cohort study was carried out among adults who started first-line antiretroviral treatment from September 2005 to January 2018. Data were collected from patients’ medical records, entered and validated using EpiData version 3.1 and then exported to SPSS version 20 for analysis. Binary logistic regression was carried out; odds ratio with 95% CI was used to identify covariates associated with virologic failure. Statistical significance was considered at p-value <0.05.ResultsA total of 384 patients with mean age of 35.73±9.44 years were consecutively enrolled; of which, 213 (55.5%) were females, 255 (66.4%) had WHO clinical stage III/IV, and 130 (33.9%) had baseline CD4 count <100 cells/mm3. Mean baseline CD4 count was 179 cells/mm3 (range: 2–853 cells), and 158 (41.1%) participants were on AZT/3TC/NVP. Virological failure was diagnosed among 61 (15.9%) patients. The mean time to virologic failure after initiation of ART was 63.80 months (range: 17–150 months). After adjusting for other confounders, risk of experiencing virologic failure was significantly associated with being divorced (AOR 3.40, 95% CI 1.20–9.59), being naïve to ART (AOR 2.55, 95% CI 1.23–5.28), low (<100) baseline CD4 count (AOR 2.39, 95% CI 1.03–5.54) and nonadherence (AOR 6.73, 95% CI 3.29–13.76).ConclusionIn this study, the prevalence of antiretroviral treatment failure was 15.9%. Being divorced, being naïve to antiretroviral therapy, low (<100 cells/mm3) baseline CD4 count and nonadherence were found to be significant predictors of virologic failure. ART programs should focus on early HIV diagnosis and ART initiation as well as enhanced adherence support.

ABCL-261: Interim Results of a Study of Comparative Efficiency of the NHL-BFM-90 and CHOEP Programs in Primary Adult Patients of ALK-Positive Anaplastic Large Cell Lymphoma

Background: Anaplastic large cell ALK-positive lymphoma (ALCL ALK+) is a lymphoproliferative disease of the “young” age. ALCL ALK+ has a favourable prognosis. A failure in therapy (relapse) is diagnosed within the first 1.5-2 years of the follow up period. Aim: The aim of the present study was to compare the effectiveness of the NHL BFM-90 and CHOEP protocols intended for the treatment of adult patients presenting with the ALCL ALK+. Materials and methods: This prospective comparative randomized study was carried out based at the National Medical Research Centre of Hematology, Moscow, during the period from June 2014 to December 2019. It involved 23 patients with the ALCL ALK+ disease randomly allocated to two groups. One of them included 11 patients given a CHOEP, the other consisted of 12 patients treated using a high-dose CT in accordance with the NHL BFM-90 protocol (age medians 33 and 40 years respectively). Results: The 3-year OS and EFS rates among the patients receiving CHOEP was 91%, with all the members of this study group having completed the treatment regimen. All patients comprising the latter (NHL BFM-90) group achieved complete remission. However, only 9 of the 12 patients fully complied with the treatment protocol because of its toxic effects. It can be inferred that the two study groups are comparable in terms of the 3-year OS and EFS rates among the patients treated in accordance with the CHOEP and NHL BFM-90 programs, the differences between them being insignificant. Conclusion: High-dose CT based on the NHL BFM-90 protocol has no advantages over the less toxic CHOEP regimen as far as the treatment of the ALCL ALK+ is concerned (if the efficacy of both modalities is estimated in terms of the 3-year OS and EFS rates). However, additional studies with larger patient samples are needed to obtain statistically significant results before a definitive conclusion can be made as regards clinical feasibility of the use of high-dose therapeutic regimens for the treatment of adult patients presenting with the ALCL ALK+ disease.

A Comparative Study of High-Dose Colistin Administration for the Management of Multidrug-Resistant Gram-Negative Infections in the ICU

The aim of this study was to assess the clinical and microbiological efficacy and toxicity of different high-dose regimens of colistin in the ICU patients with colistin-sensitive MDR Gram-negative infections. In this prospective, open label, randomized clinical trial, patients with clinical features of infection and positive culture for MDR colistin-sensitive Gram-negative bacteria were randomly allocated to receive colistin, 3 or 9 million units every 8 and 24 hours, (groups A and B), respectively. For each dose regimen, clinical and microbiological response, the rates of nephrotoxicity, and its risk factors were analyzed. Forty-three patients were enrolled, and 35 completed the study protocol, of whom 30 (88.2%) had ventilator-associated pneumonia (VAP) and 5 (14%) had bacteremia. Although there were no statistically significant differences in the clinical or microbiological response between the study groups, the microbiological response favored the divided dose group numerically ( p = 0.40 ). Clinical response was achieved in 27 of 35 (77.1%) patients ( p = 0.999 ). Twelve (34.28%) patients developed AKI during colistin treatment, 4 and 8 in groups A and B, respectively ( p value =0.193). Significant risk factors for nephrotoxicity related to colistin were age, hyperbilirubinemia, and coadministration of other nephrotoxic agents. In multivariate regression analysis, the only independent risk factor for CMS-associated AKI was hyperbilirubinemia ( p value =0.008). Although the clinical and microbiological responses to colistin administration were not statistically different in two groups, the microbiological response favored the divided dose regimen group numerically. We did not observe any significant safety concerns with high-dose colistin administration in this population.

Pilot study of the combination of sorafenib and fractionated irinotecan in pediatric relapse/refractory hepatic cancer (FINEX pilot study).

Preclinical observations suggested a synergistic effect of sorafenib (SFN) and irinotecan (CPT-11) in hepatoblastoma (HB). Thus, we conducted a feasibility study of fractionated CPT-11 combined with SFN to develop a new therapy against relapsed/refractory pediatric hepatic cancer (HC). The study was originally designed as a phase I, standard 3+3 dose-finding study to evaluate dose-limiting toxicities (DLTs) for the regimen and the optimal CPT-11 dose in combination with SFN against relapsed/refractory pediatric HC, including HB and hepatocellular carcinoma (HCC). The enrolled patients received SFN at 200mg/m2 every 12hours or 400mg/m2 every 24hours daily combined with CPT-11 at 20mg/m2 /day on days 1 to 5 as an initial level 1 dose. Six patients with HB (n=4) or HCC (n=2) were enrolled and treated with CPT-11 dose level 1. The median age at enrollment was 8.7 (6.2-16.3) years. All patients received platinum-containing chemotherapy, and five or two patients received CPT-11 or SFN before enrollment, respectively. Regimen toxicities were evaluable in all patients. One of six patients experienced a grade 4 transaminase levels increase, which was defined as a DLT per protocol. Grade 3/4 neutropenia and a grade 3 transaminase level increase occurred in three patients and one patient, respectively. All patients reported grade 1/2 toxicities such as anemia, skin toxicity, gastrointestinal symptoms, and hypoalbuminemia. Although the study was terminated before determining the maximum-tolerated CPT-11 dose, SFN and CPT-11 at the level 1 dose were concluded to be tolerable in pediatric patients with HC.

Abstract 1789: Repurposing the anti-depressant sertraline to target serine/glycine synthesis addicted cancer

Abstract Metabolic reprogramming is a well-established hallmark of cancer cells, which supports tumor growth, survival, and chemotherapy resistance. In this respect, a subset of cancers gets addicted to intracellular serine/glycine synthesis via overexpression of the enzymes PHGDH, PSAT1, PSPH or SHMT1/2. This cancer-specific dependency highlights a novel therapeutic opportunity, as normal cells solely rely on serine and glycine uptake from their environment. Well established examples of serine/glycine-synthesis addicted tumors are triple-negative breast cancer and T-cell leukemia (1, 2), which are both currently treated with toxic intensive chemotherapy regimens. In the past decade, researchers have attempted to repurpose approved drugs for cancer treatment, with the aim to develop less toxic low cost therapies that can rapidly enter the clinical practice. In this work, we made use of Candida albicans biofilms as a lower eukaryotic screening system that specifically upregulates expression of serine/glycine synthesis enzymes in response to sub-lethal stress. Using this platform, we discovered two repurposed compounds, sertraline and thimerosal, that show selective toxicity to serine/glycine synthesis dependent cancer cell lines, while they had no effect on cancer and normal lymphoid cell lines that take up serine and glycine from their environment. By using a combination of a PHGDH enzymatic activity assay, molecular docking and labeled serine tracing experiments, we discovered that sertraline and thimerosal inhibit serine/glycine synthesis enzymes SHMT and PHGDH respectively. In contrast to thimerosal, for which clinical applications are limited because of a toxic mercury group in its structure, sertraline is a widely used anti-depressant for which synergy with established anticancer drugs in breast cancer had already been described. Most notably, combining sertraline with a mitochondrial inhibitor, such as the clinically used antimalarial drug artemether, resulted in an even more pronounced inhibition of serine/glycine synthesis dependent proliferation, both in cultured cells and in an in vivo breast cancer xenograft model. Collectively, our study provides molecular insights into the repurposed mode-of-action of sertraline and allows to delineate a hitherto unidentified group of cancers that are particularly sensitive to treatment with sertraline, including breast cancers and leukemias.

The effect of chemotherapy on olfactory function and mucociliary clearance.

Olfactory sensory neurons and the olfactory mucosa are both important for optimal olfactory function. The potential nasal mucosal toxicity of chemotherapy regimens has not been assessed yet. The aim of this study was to objectively investigate the effect of chemotherapy on mucociliary clearance and olfactory function and to evaluate whether this effect differs between different chemotherapy regimens and age groups. The study included consecutive patients admitted for the treatment of a variety of primary tumors (except head and neck and brain malignancies). Patients were evaluated for olfaction and mucociliary clearance before and immediately after completing the last session of chemotherapy cycles, according to the therapeutic protocol. For objective evaluation, the saccharine test was used for mucociliary clearance and the Sniffin' Sticks test for olfactory function. Of the 46 initial patients, 30 completed the study. Groups were formed according to the chemotherapy regimen (four groups: CA (doxorubicin + cyclophosphamide), Folfox (oxaliplatin +5-FU + folinic acid), DCF (docetaxel + cisplatin +5-FU), and GC (gemcitabine + cisplatin)) and according to age (two groups: < 55 years and > 55 years). In the overall analyses, significant deterioration was noted in both mucociliary clearance time and smell scores (olfactory threshold (OT), olfactory discrimination (OD), olfactory identification (OI), and the composite threshold-discrimination-identification (TDI) score). The changes in these scores showed no significant differences between chemotherapy groups. The decrease in OT and global TDI scores was more severe in the younger age group. Chemotherapy impairs both the mucociliary clearance and olfactory function in cancer patients. This might reflect the collective negative effect of chemotherapy on olfactory function, not only through the neurocytotoxic effect but also the cytotoxic effect on the nasal mucosa. In addition, the reduction in olfactory threshold and total olfactory function scores was seen to be more profound in younger patients, which could have been due to higher initial scores.

The changing face of paracetamol toxicity and new regimens for an old antidote acetylcysteine.

The changing face of paracetamol toxicity and new regimens for an old antidote acetylcysteine.

Clinical aspects of the use of ribociclib

Luminal metastatic HER2-negative breast cancer remains one of the most common cancers in oncological practice. This disease still remains incurable. Endocrine therapy remained the standard therapy of choice for disseminated patients for a long time. The search for new effective drugs, development of strategies that can overcome primary and secondary resistance to endocrinotherapy has shown that the CDK4/6-inhibitors group can improve not only the short-term treatment outcomes, but also affect the overall survival of patients, which has been demonstrated in a number of phase III studies. Along with that, the use of CDK4/6 inhibitors maintains a good quality of life, allows patients to maintain professional and social activities, which is of great importance for long-term prospects. Given that the endocrine therapy combined with CDK4/6-inhibitors today is the new standard of therapy in patients with luminal HER2- negative breast cancer, knowing how to use this therapy in daily clinical practice is crucial. Know and apply innovative drugs in clinical practice and the management of regimen toxicity always my work demands close application. This article provides an overview of the data on the efficacy of ribociclib based on phase III registration studies. It also presents its own clinical experience demonstrating the feasibility of using a new group of drugs in patients both in pre- and postmenopausal women. The authors discussed the issues related to the modification of the regimen due to the toxicity of therapy, in particular, neutropenia and hepatotoxicity. They also showed the possibility of managing adverse events with the preservation of a long-term effect with no loss in quality of life.

Metro-SMHOP 01: Metronomics combination with cyclophosphamide-etoposide and valproic acid for refractory and relapsing pediatric malignancies.

In low- and middle-income countries, therapeutic options for advanced, refractory, or relapsing malignancies are limited due to local constraints such as cost of drugs, distance from oncology centers, and lack of availability of new anticancer drugs. Metronomics, which combines metronomic chemotherapy (MC) and drug repositioning, allows for the provision of new therapeutic options for patients in this setting. To evaluate the activity and toxicity of a metronomic regimen in Moroccan pediatric patients with refractory or relapsing malignancies. From July 2014 to January 2018, patients with refractory/relapsing solid tumors treated in five pediatric oncology centers were consecutively enrolled. The metronomic regimen consisted of 28-day cycles with daily oral administration of cyclophosphamide (30mg/m2 ) from days 1 to 21, together with oral etoposide (25mg/m2 ) from days 1 to 21 followed by break of one week and daily valproic acid (20mg/kg) from days 1 to 28. Ninety-eight children (median age, 8 years) were included. Underlying malignancies were neuroblastoma (24 patients), Ewing sarcoma (18), osteosarcoma (14), rhabdomyosarcoma (14), and miscellaneous tumors (28). A total of 557 cycles were given (median: 6; range, 1-18 cycles). One-year progression-free survival of our patients was 19%, and one-year overall survival was 22%. Complete response was obtained in three cases (3%), partial response in 11 cases (11%), and tumor stabilization for more than six months in 28 cases (28%). This three-drug metronomic combination was well tolerated and associated with tumor response and disease stabilization in 42 patients even for a long period.