Reduced Dose Intensity Research Articles

The impact of nutritional intervention on quality of life and outcomes in patients with head and neck cancers undergoing chemoradiation.

Chemoradiotherapy in head and neck cancer patients has a curative intent but often deteriorates nutritional status leading to sarcopenia and cachexia. In this observational and single-centered study, a prospective evaluation of several biochemical and anthropometrical parameters, weight loss, handgrip strength, visual analogue scale of appetite, questionnaires associated with malnutrition & quality of life and body composition (obtained by Bioelectrical Impedance Vector Analysis) was performed before and after high-dose cisplatin chemotherapy combined with radiotherapy in 60 patients affected by head and neck cancer. Oral nutritional supplements were used to reach the correct number of daily calories and proteins. All patients completed radiotherapy as planned and the 96,4% of them did not interrupt chemotherapy for toxicity, reaching a total dose of at least 200mg/m2. Despite a rapid deterioration of body composition during treatment, nutritional support helped patients to maintain (or in some cases improve) anthropometric parameters from the end of chemoradiotherapy to the following 3 months. Low prealbumin and albumin pre-treatment led to higher risk of toxicities with consequent reduction of cisplatin dose intensity, whereas weight at the end of the treatment seems to be an interesting predicting factor for disease free and overall survival (p=0.007; p=0.015).

Vincristine Induced Adverse Effects in Lymphoma Bearing Dogs With Asymptomatic Neutropenia at the Time of Drug Administration.

Vincristine sulphate, a microtubule inhibitor, is used extensively in veterinary oncology for treating lymphoma. Neutropenia during multiagent protocols is a common reason for treatment delay and reduced dose intensity. This study evaluated toxicities associated with treating systemically well neutropenic lymphoma patients with vincristine. Lymphoma patients undergoing CHOP were evaluated retrospectively for instances of vincristine administration when absolute neutrophil counts (ANC) were 1.5 × 109/L or below. Instances of vincristine administration when ANC was equal to or less than 1.5 × 109/L were compared to vincristine administration where ANC was greater than 1.5 × 109/L in the same patient. Univariate and multivariate modelling compared VCOG-CTCAE v1.1 grading of vomiting, diarrhoea, anorexia and 7-day neutrophil nadir between groups. The median dose of vincristine administered was 0.7 mg/m2 for both study groups. A total of 112 doses of vincristine were administered to neutropenic patients (grade 2 n: 76, grade 3 n: 26, and grade 4 n: 10). These were compared to 223 doses of vincristine administered to the same patients when ANC was above 1.5 × 109/L. Neutropenic administration was most prevalent 7 days following cyclophosphamide administration. Day 7 post-administration neutropenia was more prevalent in patients with ANC greater than 1.5 × 109/L at the time of vincristine administration (neutropenic 9%; non-neutropenic 18%). Relative risk of 7-day neutropenia, vomiting, diarrhoea, and anorexia was similar between groups on multivariate analysis. Patients with lymphoma who receive vincristine when ANC is 1.5 × 109/L or below are at no greater risk of adverse effects than the same patient who receives vincristine when neutrophil counts are greater than 1.5 × 109/L.

Reduction in chemotherapy relative dose intensity decreases overall survival of neoadjuvant chemoradiotherapy in patients with locally advanced esophageal carcinoma

BackgroundMany patients undergo dose reduction or early termination of chemotherapy to reduce chemoradiotherapy-related toxicity, which may increase their risk of survival. However, this strategy may result in underdosing patients with locally advanced esophageal squamous cell carcinoma (LA-ESCC). This study aimed to analyze the relationship between the relative dose intensity (RDI) and survival outcomes in patients with LA-ESCC.MethodsThis retrospective study assessed patients with LA-ESCC (cT2N + M0, cT3-4NanyM0) receiving neoadjuvant chemoradiotherapy (NCRT) with curative-intent esophagectomy. The patients received 2 courses of paclitaxel plus carboplatin (TC) combination radiotherapy prior to undergoing surgery. During NCRT, RDI was computed, defined as the received dose as a percentage of the standard dose, and the incidence of dose delays was estimated (≥ 7 days in any course cycle). The best RDI cutoff value (0.7) was obtained using ROC curve. The Kaplan–Meier survival curves were compared using the log-rank test, the treatment effect was measured using hazard ratios (HR) and 95% confidence intervals (CI).ResultsWe included 132 patients in this study, divided into RDI < 0.7 and RDI ≥ 0.7 groups using cut-off value of 0.7. RDI grade was an independent prognostic factor for OS. Baseline demographic and clinical characteristics were well balanced between the groups. There was no evidence that patients with RDI < 0.7 experienced less toxicity or those with RDI ≥ 0.7 resulted in more toxicity. However, patients with RDI < 0.7 who were given reduced doses had a worse overall survival [HR 0.49, 95% CI 0.27–0.88, P = 0.015]. The risk of a lower RDI increased with a longer dose delay time (P < 0.001).ConclusionThe RDI below 0.7 for avoiding chemoradiotherapy toxicity administration led to a reduction in the dose intensity of treatment and decreased overall survival.

MDB-100. RETROSPECTIVE ANALYSIS OF CUMULATIVE DOSING OF CHEMOTHERAPY AGENTS AND THE EFFECT ON SURVIVAL IN PATIENTS WITH AVERAGE RISK MEDULLOBLASTOMA TREATED ON CHILDRENS ONCOLOGY GROUP STUDY ACNS0331

Abstract BACKGROUND Although survival outcomes for average risk (AR) medulloblastoma remain good, patients may experience significant acute and long-term toxicities from therapy. To evaluate the effect of dose modifications among children with AR medulloblastoma, we examined the effect of cumulative chemotherapy dose on overall and event-free survival. METHODS We retrospectively examined the association between the proportion of scheduled chemotherapy dose received on survival outcomes (OS and EFS) using Cox regression models and log-rank tests for patients treated on ACNS0331. We evaluated all chemotherapy agents for the group as a whole and within the four major subgroups. Dose intensity was analyzed continuously and categorically (&amp;gt;75% or &amp;lt;75% of planned dose) for each agent. RESULTS 274 evaluable children (medulloblastoma by methylation, received standard dose craniospinal radiation and chemotherapy) were followed for a median of 9.3 years (range, 7.0-10.4 years). Vincristine and cisplatin showed the most variable dose intensity (25.2% and 31.8% of patients received &amp;lt;75% of expected dosing, respectively). Cyclophosphamide and lomustine were not examined due to low dose variability (17.2% and 11.7%, respectively). The effect of dose intensity was evaluated in 235 patients who completed planned therapy. Molecular subgroup remained a significant predictor of outcome in AR medulloblastoma (EFS (p=0.012) and OS (p=0.008)). Although survival curves were lower for less dose intense treatments, no significant difference in EFS or OS was found due to reduced dose intensity for vincristine (p=0.36 EFS, p=0.35 OS) or cisplatin (p=0.49 EFS, p=0.52 OS). The hazard ratio [95% confidence interval] for chemotherapy proportion and EFS was 0.998[0.977-1.019] (vincristine) and 0.989[0.966-1.012] (cisplatin). There was no difference in the effect of dose reductions by molecular subgroup. CONCLUSIONS Moderate reductions in vincristine and cisplatin dose intensity do not significantly affect survival in AR medulloblastoma. It is unknown whether this reduction would reduce chemotherapy-related toxicity.

Neoadjuvant radiotherapy combined with fluorouracil-cisplatin plus cetuximab in operable, locally advanced esophageal carcinoma: Results of a phase I-II trial (FFCD-0505/PRODIGE-3)

BackgroundRadiotherapy combined with fluorouracil (5FU) and cisplatin for locally advanced esophageal cancer is associated with a 20–25% pathologic complete response (pCR) rate. Cetuximab increases the efficacy of radiotherapy in patients with head and neck carcinomas. The aim of this phase I/II trial was to determine the optimal doses and the pCR rate with chemoradiotherapy (C-RT) plus cetuximab. MethodsA 45-Gy radiotherapy regimen was delivered over 5 weeks. The phase I study determined the dose-limiting toxicity and the maximum tolerated dose of 5FU-cisplatin plus cetuximab. The phase II trial aimed to exhibit a pCR rate > 20 % (25 % expected), requiring 33 patients (6 from phase I part plus 27 in phase II part). pCR was defined as ypT0Nx. ResultsThe phase I study established the following recommended doses: weekly cetuximab (400 mg/m2 one week before, and 250 mg/m2 during radiotherapy); 5FU (500 mg/m2/day, d1-d4) plus cisplatin (40 mg/m2, d1) during week 1 and 5. In the phase II part, 32 patients received C-RT before surgery, 31 patients underwent surgery, and resection was achieved in 27 patients. A pCR was achieved in five patients (18.5 %) out of 27. After a median follow-up of 19 months, the median progression-free survival was 13.7 months, and the median overall survival was not reached. ConclusionsAdding cetuximab to preoperative C-RT was toxic and did not achieve a pCR > 20 % as required. The recommended doses, determined during the phase I part, could explain these disappointing results due to a reduction in chemotherapy dose-intensity. Trial registrationThis trial was registered with EudraCT number 2006-004770-27.

Efficacy and Safety of Less Frequent/Lower Intensity Dosing of Talquetamab in Patients with Relapsed/Refractory Multiple Myeloma: Results from the Phase 1/2 MonumenTAL-1 Study

Introduction: Talquetamab (tal) is an off-the-shelf, T-cell redirecting bispecific antibody targeting G protein-coupled receptor family C group 5 member D (GPRC5D) and CD3. Results from the phase 1/2 MonumenTAL-1 (NCT03399799/NCT04634552) trial showed overall response rates (ORRs) of &amp;gt;71% and a manageable safety profile with the recommended phase 2 doses (RP2Ds) of subcutaneous tal (0.4 mg/kg weekly [QW] or 0.8 mg/kg every other week [Q2W]) in patients (pts) with relapsed/refractory multiple myeloma (RRMM). The impact of reducing dose intensity with bispecifics on safety and efficacy is an area of clinical interest. We report safety and efficacy in pts from MonumenTAL-1 who switched to less frequent or reduced dosing with tal. Methods: In phase 1, pts were intolerant to or progressed on established therapies and had an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1. In phase 2, pts had received ≥3 prior lines of therapy, including ≥1 proteasome inhibitor, ≥1 immunomodulatory drug, and ≥1 anti-CD38 monoclonal antibody, and had an ECOG PS of 0-2. Phase 1 included 2 prospectively designed cohorts: (A) a reduced dosing cohort in which pts treated with tal 0.8 mg/kg Q2W were permitted to switch to 0.4 mg/kg Q2W at the next cycle following a confirmed partial response or better (≥PR), and (B) a less frequent dosing cohort in which pts treated with tal 0.8 mg/kg Q2W were permitted to switch to 0.8 mg/kg monthly (Q4W) at the next cycle following a confirmed ≥PR. Results for these phase 1 prospective cohorts are pooled. Supportive analyses were also performed based on pts in phases 1/2 who received the RP2Ds and switched to reduced dosing based on meeting response criteria or to mitigate treatment-emergent adverse events (TEAEs). Dose reduction could be achieved by reducing dose frequency or by reducing dose. ORRs were assessed per IMWG criteria. TEAEs were graded per CTCAE v4.03. Results: In total, 45 pts switched to reduced intensity dosing. As of June 20, 2023, 24 pts were included in the prospective cohorts, with a median follow-up of 9.7 months. In total, 9/12 pts achieved a ≥PR and switched from 0.8 mg/kg Q2W to 0.4 mg/kg Q2W dosing, and 10/12 pts achieved a ≥PR and switched from Q2W to 0.8 mg/kg Q4W dosing. Generally, pts switched to reduced intensity dosing during cycles 3-5. Following the change in dosing, responses deepened in 11/19 pts and were maintained in 5/19 pts; 3/19 pts had disease progression. At 6 months post switch, an estimated 88.9% of responders maintained a response. Oral-related TEAEs, reported in 16/19 (84.2%) pts, improved or resolved in 4 pts 1-6 months after switching to reduced intensity dosing. Nail-related TEAEs, reported in 7/19 (36.8%) pts, improved or resolved in 2 pts after 3-4 months. Skin-related TEAEs, reported in 8/19 (42.1%) pts, resolved in 3 pts after 1-3 months. Overall, improvement or resolution of oral-, nail-, and skin-related TEAEs was observed over time in some pts in the prospective reduced and less frequent dosing cohorts. No pts discontinued tal due to these TEAEs. As of January 17, 2023, supportive phase 1/2 analyses included 20 pts who switched from tal 0.4 mg/kg QW to a reduced dose (TEAE mitigation, n=16; response, n=3; both, n=1), and 6 pts who switched from tal 0.8 mg/kg Q2W to a reduced dose (TEAE mitigation, n=4; response, n=2). In pts who switched from tal 0.4 mg/kg to a reduced dose, an estimated 84.2% and 78.9% of responders maintained a response at 9 and 12 months, respectively. In pts who switched from tal 0.8 mg/kg Q2W to a reduced dose, an estimated 100% and 80.0% of responders maintained a response at 9 and 12 months, respectively. Conclusions: Most pts who switched to reduced intensity dosing in MonumenTAL-1 deepened or maintained responses to tal. GPRC5D-associated TEAEs generally improved over time in the prospectively design cohorts. Overall, reduced or less frequent tal dosing may help to mitigate these TEAEs while maintaining response. Further analyses on the impact of reduced or less frequent tal dosing on clinical outcomes are warranted.

Reducing chemotherapy dose intensity by 25% and adding rituximab improves survival in pediatric mature B-cell non-Hodgkin lymphoma in LMIC setting.

Pediatric B-cell non-Hodgkin lymphomas (NHL) in low- and middle-income countries (LMICs) have historically had inferior outcomes due to higher treatment-related mortality (TRM) and relapses. To address this issue, we evaluated the impact of reducing chemotherapy dose intensity by 25% and adding rituximab on outcomes in pediatric B-NHL. Patients, less than 18years of age with group B and C disease as per the Lymphome Malin de Burkitt (LMB) risk stratification were enrolled between September 2017 and October 2022. The LMB-89 protocol, with a 25% reduction in all chemotherapy doses and the addition of rituximab, was administered. The response was assessed using positron emission tomography with computed tomography (PET/CT) after four cycles of chemotherapy (interim) and at the end of treatment. The study included 25 patients with a median age of 6.9years, among whom 20 (80%) were males. Twenty patients had group B and five had group C disease. Complete metabolic response (CMR) was achieved by 22/25 (88%) patients, and three (12%) achieved partial metabolic response (PMR) in the interim PET/CT. At the end of treatment, 22/24 (92%) patients achieved CMR, one had PMR, and one had progressive disease. The median follow-up was 45months (range: 3-71months). The 4-year event-free survival and overall survival were 88% and 92%, respectively. There were two deaths, one due to disease progression and the other due to sepsis. Our study demonstrates a significant improvement in outcomes in pediatric B-NHL compared to previous reports from LMICs, achieved through a 25% reduction in chemotherapy dose intensity and the addition of rituximab.

Comparison of first-line treatment with CHOP versus ICED in patients with peripheral T-cell lymphoma eligible for upfront autologous stem cell transplantation.

Upfront autologous stem cell transplantation (ASCT) has been recommended for patients who are newly diagnosed with peripheral T-cell lymphoma (PTCL), and CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), an anthracycline-based chemotherapy has been the frontline chemotherapy for PTCL. However, it is not clear whether anthracycline-based chemotherapies such as CHOP could be standard induction therapy for PTCL. We conducted a randomized phase II study to compare CHOP with fractionated ifosfamide, carboplatin, etoposide, and dexamethasone (ICED) for patients eligible for ASCT. The primary endpoint was progression-free survival (PFS) and secondary endpoints included objective response rate, overall survival (OS), and safety profiles. Patients were randomized into either CHOP (n = 69) or ICED (n = 66), and the characteristics of both arms were not different. PTCL-not otherwise specified (NOS, n = 60) and angioimmunoblastic T-cell lymphoma (AITL, n = 53) were dominant. The objective response rate was not different between CHOP (59.4%) and ICED (56.1%), and the 3-year PFS was not different between CHOP (36.7%) and ICED (33.1%). In AITL patients, CHOP was favored over ICED whereas ICED was associated with more cytopenia and reduced dose intensity. Patients who received upfront ASCT after achieving complete response to CHOP or ICED showed 80% of 3-year OS. In summary, our study showed no therapeutic difference between CHOP and ICED in terms of response and PFS. Thus, CHOP might remain the reference regimen especially for AITL based on its better outcome in AITL, and upfront ASCT could be recommended as a consolidation of complete response in patients with PTCL.

Thrombopoietin Receptor Agonists for Thrombocytopenia Secondary to HER2-Targeted Antibody Drug Conjugates.

Trastuzumab emtansine and trastuzumab deruxtecan are widely used in breast cancer and other solid tumor malignancies. Thrombocytopenia is a common adverse event associated with the use of these agents that can lead to a treatment delay, reduction in dose intensity, and discontinuation. The role of thrombopoietin receptor agonists (TPO-RA) remains unknown in this setting. We report a case series of 6 individuals with breast cancer that experienced dose-reductions and therapy delays due to thrombocytopenia secondary to trastuzumab emtansine or trastuzumab deruxtecan therapy and received intervention with TPO-RA. All 6 were able to resume therapy with TPO-RA support.

A non-inferiority randomized phase III trial of standard immunotherapy by checkpoint inhibitors vs. reduced dose intensity in responding patients with metastatic cancer: the MOIO protocol study

BackgroundImmunotherapy (IO) has become a standard of care for treating various types of metastatic cancers and has significantly improved clinical outcome. With the exception of metastatic melanoma in complete response for which treatment can be stopped at 6 months, these treatments are currently administered until either disease progression for some IO, 2 years for others, or unacceptable toxicity. However, a growing number of studies are reporting maintenance of response despite discontinuation of therapy. There is currently no evidence of a dose effect of IO in pharmacokinetic studies. Maintaining efficacy despite a reduction in treatment intensity by decreasing the frequency of administration in patients with highly selected metastatic cancer, is the hypothesis evaluated in the MOIO study.Method/designThis non-inferiority, randomized phase III study aims to compare the standard regimen to a 3 monthly regimen of variousIO drugs in adult patients with metastatic cancer in partial (PR) or complete response (CR) after 6 months of standard IO dosing (except melanoma in CR). This is a French national study conducted in 36 centers. The main objective is to demonstrate that the efficacy of a three-monthly administration is not unacceptably less efficacious than a standard administration. Secondary objectives are cost-effectiveness, quality of life (QOL), anxiety, fear of relapse, response rate, overall survival and toxicity.After 6 months of standard IO, patients with partial or complete response will be randomized 1:1 between standard IO or a reduced intensity dose of IO, administered every 3 months. The randomization will be stratified on therapy line,, tumor type, IO type and response status. The primary endpoint is the hazard ratio of progression-free survival. With a planned study duration of 6 years, including 36 months enrolment time, 646 patients are planned to demonstrate with a statistical level of evidence of 5% that the reduced IO regimen is non-inferior to the standard IO regimen, with a relative non-inferiority margin set at 1.3.DiscussionShould the hypothesis of non-inferiority with an IO reduced dose intensity be validated, alternate scheduling could preserve efficacy while being cost-effective and allowing a reduction of the toxicity, with an increase in patient’s QOL.Trial registrationNCT05078047.

Abstract P4-06-01: Platinum-based chemotherapy for early triple-negative breast cancer: A Cochrane systematic review and meta-analysis

Abstract In early triple-negative breast cancer (eTNBC), platinum-based chemotherapy has been shown to improve pathological complete response, but recommendations to include platinum chemotherapy are not consistent in international guidelines. We performed a systematic review of published randomized control trials to assess to assess survival outcomes and quality of life for people with early TNBC. The results presented in this abstract have not yet been peer-reviewed by Cochrane. If the final version of the review meets the necessary standards, the review is expected to be published in the Cochrane Database of Systematic Reviews. Methods: Randomized controlled trials examining neoadjuvant or adjuvant platinum chemotherapy for eTNBC were included. We searched for published and unpublished data using standard Cochrane search strategies. The primary outcomes assessed were disease free survival (DFS) and overall survival (OS). Secondary outcomes included rate of pathological complete response (pCR), dose intensity and completion of regimens, grade III or IV toxicity related to chemotherapy, and quality of life. Prespecified subgroups included BRCA mutation status, HRD status, lymph node status, frequency of chemotherapy, type of platinum agent used, and the presence or absence of anthracycline chemotherapy. Results: From 3972 records, 19 published studies were eligible. Twenty six ongoing studies were identified. Risk of bias was judged low for most trials. There were 14 neoadjuvant chemotherapy trials, 4 adjuvant chemotherapy trials, and one trial of neoadjuvant and adjuvant therapy. Most trials used carboplatin (16 trials) followed by cisplatin (2), and lobaplatin (1). Eight trials had an anthracycline free intervention arm, 5 of which had a carboplatin-taxane intervention compared to an anthracycline-taxane control. All studies reporting DFS and OS used carboplatin. Twelve of 19 studies with a total of 3347 participants reported DFS data. Inclusion of platinum chemotherapy improved DFS in neoadjuvant and adjuvant setting (HR 0.63, 95% confidence interval (CI) 0.53-0.75; HR 0.69, 95% CI 0.54-0.88 respectively)). Eleven studies collected OS data, with a total of 3229 participants and 460 deaths reported. Inclusion of platinum chemotherapy in the regimen improved OS (neoadjuvant: HR 0.69, 95% CI 0.69, 0.55-0.86; adjuvant: 0.70, 95% CI 0.50 to 0.96). Median follow up for survival outcomes ranged from 36 – 97.6 months. Our analysis confirmed platinum chemotherapy increased pCR rates (RR 1.46 [1.33-1.61], p&amp;lt; 0.00001). Subgroup analysis revealed that survival outcome benefits were seen regardless of BRCA mutation status, HRD status, lymph node status, or whether the intervention arm contained anthracycline chemotherapy or not. Platinum chemotherapy was associated with reduced dose intensity, with participants more likely to require chemotherapy delays (RR 2.23 [1.70-2.94], 4 studies), dose reductions (RR 1.77 [1.56-2.02], 6 studies) and early cessation of treatment (RR 1.20 [1.04-1.38], 16 studies). Increased hematological toxicity occurred in the platinum group who were more likely to experience grade III/IV neutropenia (RR 1.55 [1.45-1.66]), anemia (RR 10.12 [6.61-15.50]) and thrombocytopenia (RR 7.59 [5.10-11.29]). There was no increase in febrile neutropenia (RR 1.16 [0.89-1.49]). Treatment-related death was very rare (7 events in 3094 patients) and similar across treatment groups (RR 0.58 [0.14-2.33]). Five studies collected quality of life data but did not report it. Conclusion: Platinum-based chemotherapy using carboplatin in the adjuvant or neoadjuvant setting improves long-term outcomes in eTNBC, regardless of the examined subgroups. This was at the cost of more frequent chemotherapy delays and dose reductions, and greater haematological toxicity. Benefit from platinum was seen both when platinum agents were added to anthracycline containing regimens, as well as in anthracycline-free regimens. Citation Format: Sofia Mason, Melina Willson, Annabel Goodwin, Jane Beith, Sam J. Egger, Rachel F. Dear. Platinum-based chemotherapy for early triple-negative breast cancer: A Cochrane systematic review and meta-analysis [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-06-01.

Real-Life Effectivity of Dose Intensity Reduction of First-Line mFOLFIRI-Based Treatment of Metastatic Colorectal Cancers: Sometimes Less Is More.

Aim: The key purposes of the treatment of metastatic malignancies are to extend survival and maintain the quality of life. Recently it has been emphasized in the scientific literature that the maintenance of maximal dose intensity is not always beneficial. Method: We examined the effectiveness of first-line mFOLFIRI-based treatments used in mCRC indication in 515 patients, treated between 1 January 2013 and 31 December 2018 at the Department of Oncotherapy of the University of Pécs, on a basis of real-world retrospective data analysis. We studied the effect of decreased dose intensity treatment modifications on patient survival. Results: 45% of all patients achieved the optimal relative dose intensity (RDI) of 85%, and the median progression-free and overall survival (mPFS, mOS) were 199 and 578 days, compared to 322 and 743 days, (mPFS p < 0.0002, 1 y (year) PFS OR (odds ratio) 0.39 (95% CI: 0.26−0.56) and mOS p = 0.0781, 2 yrs OS OR 0.58 (95% CI: 0.39−0.85), respectively) in the group of patients not achieving the RDI of 85%. Conclusions: Decreased dose intensity did not reduce the effectiveness of treatment; in fact, there was a significant improvement in most of the analyzed parameters. The option of reduced dose intensity, which shows the same or even better results with less toxicity, should definitely be considered in the future palliative treatment of mCRC patients.

Dose Delays, Dose Reductions, and Relative Total Dose Intensity in Patients With Advanced Cancer Who Exercised During Neoadjuvant Chemotherapy Treatment.

When it comes to chemotherapy, maintaining the dose and schedule of treatment are of vital importance, as clinical evidence suggests that dose intensity is associated with optimal treatment outcomes for various tumors. Yet, reduced dose intensity is a common method of mitigating the chemotherapy-induced side effects. Exercise has been shown to attenuate chemotherapy-related symptoms that frequently cluster together. Understanding this, we conducted a retrospective analysis in patients with advanced disease treated with adjuvant or neoadjuvant chemotherapy regimens and who completed exercise training during treatment. Data were collected retrospectively in a chart review of 184 patients, aged 18 years or older and treated for Stage IIIA-IV cancer. Data collection included baseline patient demographics and clinical characteristics, including age at diagnosis, cancer stage at initial diagnosis, chemotherapy regimen, and planned dose and schedule. Cancer types included brain (6.5%), breast (35.9%), colorectal (8.7%), non-Hodgkin's lymphoma (7.6%), Hodgkin's lymphoma (11.4%), non-small cell lung (16.8%), ovarian (10.9%), and pancreatic (2.2%). All patients completed at least 12 weeks of prescribed, individualized exercise. Each program included cardiovascular, resistance training, and flexibility components, under the supervision of a certified exercise oncology trainer once a week. RDI was measured for each myelosuppressive agent in a regimen over the entire chemotherapy course and then averaged across the myelosuppressive agents in a regimen. An RDI of less than 85% was designated as the clinically meaningful threshold for reduction in RDI based on previously published studies. A considerable proportion of patients across regimens had dose delays (18.3%-74.3%) and dose reductions (18.1%-84.6%). Between 12% and 83.9% of patients missed at least 1 dose of a myelosuppressive agent that was part of their standard regimen. Overall, 50.8% of patients received less than 85% of the RDI. In short, patients with advanced cancer and an exercise adherence above 84.3% saw fewer chemotherapy dose delays and dose reductions. These delays and reductions occurred significantly less frequently compared to the published norms in the sedentary population (P < .05).

Safety, tolerability, and effectiveness of anticoagulation and antiplatelet therapy in hereditary hemorrhagic telangiectasia

BackgroundAntithrombotic therapy (anticoagulation and antiplatelet therapy) is frequently needed in patients with hereditary hemorrhagic telangiectasia (HHT); however, data describing and guiding its use are very limited. ObjectivesTo investigate the safety, tolerability, and effectiveness of antithrombotic therapy in HHT in a cohort large enough to compare agents, evaluate for baseline predictors of premature discontinuation, and evaluate hematologic support requirements and healthcare utilization before and after antithrombitc therapy initiation. MethodsWe performed a multicenter observational cohort study characterizing the outcomes of antithrombic therapy in adults with HHT. ResultsA total of 119 patients with HHT with 187 discrete antithrombotic therapy episodes were included. Of these, 59 patients (50%) dose-reduced and/or prematurely discontinued therapy (including 52 patients [44%] who discontinued) due to worsened bleeding complications. Initiation at reduced dose intensity had a similar premature discontinuation rate (49%) as initiation at standard dose intensity (43%). In a multivariable logistic model, a history of gastrointestinal bleeding was associated with 3.25-fold odds of discontinuation (p = .001). Hemoglobin was significantly lower (10.8 g/dL vs 12.2 g/dL, p < .001), and the need for hematologic support (intravenous iron and/or red blood cell transfusion) was significantly higher (29 patients vs 12 patients, p = .004) in the 3 months after antithrombotic therapy initiation vs the 3 months before; emergency department visits and hospital admissions due to bleeding also increased. The rates of dose-reduction and/or premature discontinuation were similar regardless of the anticoagulant class (warfarin, 46%; heparin-based, 48%; direct oral anticoagulants, 44%) or with multiple simultaneous agents (44%) but were slightly lower with single-agent antiplatelet therapy (37%). Thromboembolism despite receiving antithrombotic therapy was common (18 patients, 15%) with varying outcomes. ConclusionAntithrombotic therapy is challenging in HHT, resulting in objectively higher morbidity and health care utilization from worsened bleeding. Discontinuation rates approached 50% regardless of the dose intensity at initiation or type of antithrombotic agent used and were higher in patients with a gastrointestinal bleeding history.

Thrombocytopenia As a Risk Factor for Developing Febrile Neutropenia in Patients with DLBCL Receiving R-CHOP Chemotherapy

Background: Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is currently the standard of care for diffuse large B-cell lymphoma (DLBCL). Although heterogeneous, approximately 60 % of patients are cured while 10% of patient's refractory to initial chemotherapy. These outcomes are highly dependent on the dose intensity of chemotherapy received with poor outcomes associated with reduced dose intensity. Febrile neutropenia is one of the most common adverse events experienced leading to dose delays and interruptions. Therefore, we planned to evaluate the incidence of febrile neutropenia, its influence on delaying chemotherapy doses, and the need for subsequent growth factor support. We also planned to identify risk factors for the development of febrile neutropenia after the initiation of chemotherapy. Methods: We conducted a single-center retrospective study including adults with newly diagnosed DLBCL initiating R-CHOP-21 chemotherapy without growth factor support between dates January 2016 to February 2021 at the University of Alabama at Birmingham. We extracted baseline clinical and demographic variables (age, sex, race, stage, bulky disease > 7.5 cm, number of extranodal sites, osseous or bone marrow involvement, presence of B-symptoms, ECOG score, height, weight) and laboratory variables (absolute lymphocyte count, absolute neutrophil count, absolute monocyte count, platelets, lactate dehydrogenase, albumin, and creatinine) within 7 days of initiating treatment. The outcome variable was the development of febrile neutropenia during treatment. We used a multivariate regression model to identify risk factors for the development of febrile neutropenia adjusted for demographic and laboratory covariates listed above. Collinearity amongst variables was evaluated and highly correlated variables were excluded. The hypothesis testing was two-sided, and the level of significance was chosen as 0.05. Results: Of the 257 patients with a diagnosis of DLBCL, 149 patients met the inclusion criteria and were included in our cohort. The median age at diagnosis was 60 yrs (IQR 50 - 68) with 61% male and 77% white. Stage I/II was present in 33% of patients with bulky disease in 32% pts and 17% with involvement of the bone or bone marrow at diagnosis. The ECOG PS was less than 2 in 82% of patients with only 17% of patients endorsing B symptoms prior to treatment. Delays in treatment by more than 3 days were seen in 49 pts (32%) and 32 pts(21%) had delays of more than 7 days. Treatment discontinuation due to toxicity or death was seen in 19 pts (13%). Febrile neutropenia was experienced by 17 pts (11%) requiring subsequent growth factor support in 8 pts and leading to subsequent delays in treatment in all but one patient. Increasing platelet count (Odds Ratio, OR 0.91; 95%CI 0.84 - 0.98; p value 0.02) was associated with a decreased risk of developing febrile neutropenia during treatment. Conclusions: R-CHOP chemotherapy is generally well-tolerated, however, febrile neutropenia remains the most-common toxicity occurring in approximately 11% of patients and leads to associated treatment delays. Lower platelet count prior to initiation of chemotherapy was identified as a risk factor for developing febrile neutropenia adjusted for other known variables of bone marrow function. Therefore, future predictive models of febrile neutropenia in DLBCL should include baseline platelet count as a feature. Affiliations: 1. The Joe R. and Teresa Lozano Long School of Medicine, San Antonio, TX 2. Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 3. Mays Cancer Center, UT San Antonio, San Antonio, TX 4. Division of Hematology and Oncology, Department of Medicine, O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

In Adults with Ph-Negative Acute Lymphoblastic Leukemia (ALL), Age-Adapted Chemotherapy Intensity and MRD-Driven Transplant Indication Significantly Reduces Treatment-Related Mortality (TRM) and Improves Overall Survival - Results from the Graall-2014 Trial

Background During the 2005-2014 period, the GRAALL conducted the GRAALL-2005 trial in patients (pts) with Philadelphia chromosome (Ph)-negative ALL aged 18-59y. In this trial, all pts received a pediatric-inspired chemotherapy, whatever their age. Post-hoc analysis revealed an unacceptable TRM in pts aged 45-59y (Huguet et al. J Clin Oncol 2018; 36:2514-23). Allogeneic hematopoietic stem cell transplantation (HSCT) was offered in first complete remission (CR) to most CR pts, defined at high-risk (HR) by at least one baseline clinical or biological HR factor (CNS involvement, complex karyotype [≥5 abns.], low hypodiploidy/near triploidy, poor early blast clearance, late CR, as well as WBC ≥ 30x109/L, lack of CD10 expression, KMT2A rearrangement or TCF3::PBX1 fusion for B-cell precursor [BCP] ALL). Minimal residual disease (MRD) response was not considered for HSCT indication at that time. In the next GRAALL-2014 trial conducted in a similar population, we introduced two major changes in the treatment strategy. First, chemotherapy intensity (steroids, anthracycline and L-asparaginase) was reduced in pts aged 45-59y to decrease excessive TRM. Secondly, the indication for HSCT was modified, relying on IG/TR MRD response only (post-induction MRD ≥10-3 and/or post-consolidation MRD ≥10-4) while not on any former baseline HR criterion. Here, we compare the outcomes of the two trials, focusing on the impact of these two major evolutions. Patients & Methods A total of 743 pts treated in the GRAALL-2014 trial between 2015 and 2020 were compared to the 787 pts from the historical GRAALL-2005 trial, in terms of CR and induction death rates, rate of HSCT in CR1, cumulative incidence of TRM (CITRM) and relapse (CIR), relapse-free (RFS) and overall (OS) survival. It should be noted that two nested Phase 2 trials were introduced by amendment during the GRAALL-2014 course (in 2017 and 2018, respectively), aiming to evaluate post-remission addition of nelarabine and blinatumomab in 87 T-ALL and 94 BCP-ALL selected pts, respectively. Results Main patient characteristics, including age, gender, BCP/T-ALL, WBC, and historical baseline HR features, did not significantly differ between the two trial cohorts, even if CNS disease at diagnosis was more frequent in the 2014 cohort (12 vs 7%, p= 0.001). Outcome comparisons are shown in Table 1. Overall, the induction death rate was significantly reduced in the GRAALL-2014 (3 vs 6%, p= 0.005). As expected, this was only observed in pts aged 44-59y (3 vs 11%, p= 0.001), in whom dose-intensity reduction also translated into a higher need for second induction course (9 vs 5%, p= 0.05) eventually resulting in a higher CR rate (92 vs 86%, p= 0.05). Due to the newly introduced MRD-based stratification, the rate of pts with HSCT indication was markedly reduced (30 vs 65%, p<0.001), especially in pts aged 18-44y (21 vs 40%, p<0001). Consequently, the rate of pts transplanted in CR1 dropped down from 38 to 23% (p<0.001). The GRAALL-2014 strategy also yielded a significant reduction in CITRM (5 vs 11% at 3 years; p<0.001; Figure 1B) after CR achievement. This reduction was more pronounced in pts aged 45-59y (7 vs 17%, p<0.001 compared to 4 vs 8%, p= 0.02 in 18-44y pts). This was associated with an increased CIR (35% vs 28% at 3 years; p= 0.01), with more late relapses as depicted in Figure 1A. Even if the resulting RFS was similar in both cohorts (59 vs 62% at 3 years; p= 0.77), OS was significantly longer in the GRAALL-2014 (71 vs 64%; p= 0.002) (Figure 1C) likely due to better post-relapse outcomes. When censoring those GRAALL-2014 pts who received nelarabine or blinatumomab in CR1, observations were basically unchanged, even if the difference in CIR was even more marked. Finally, using a 3-month RFS landmark in the 211 GRAALL-2014 pts eligible for HSCT in CR1 based on their poor early MRD response, HSCT significantly prolonged RFS (HR= 0.46 [95% CI, 0.27-0.78]; p= 0.004). Conclusions In adults with Ph-negative ALL enrolled in the GRAALL-2014, age-adapted chemotherapy intensity and MRD-driven indication for HSCT significantly reduced induction and post-remission TRM. This translated into a prolonged OS, indicating that this strategy was safe, despite a higher incidence of late relapses. Newly available salvage options along with HSCT in CR2 might also have played a role. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Reduced Toxicity FluBu3 Regimen Showed a Comparable Post-Transplant Outcomes to a Myeloablative BuCy Conditioing in Acute Myeloid Leukemia Patients Receiving First Allogeneic Hematopoietic Stem Cell Transplantation in MRD Negative CR1

Introduction: In a previous report, we found that post-transplant clinical outcomes were not significantly different between MAC (BuCy, CyTBI) and RIC (FluBu2TBI400) groups in AML CR1 with pre-transplant low WT1 expression. Based on this result, we expanded the use of conditioning regimen with reduced dose intensity for patients achieving deep response by minimal residual disease (MRD) assessment with available assays. FluBu3 regimen, consisting of fludarabine for 5 days (30mg/m2/day, D-6 to D-2) and busulfan for 3 days (3.2mg/kg/day, D-5 to D-3), was chosen and applied as reduced toxicity conditioning (RTC) in our institution since Jan 2017. Method: In this analysis, we compared MAC and RTC regimens; BuCy (busulfan 3.2 mg/kg/day for 4 days from D-7 to D-4 and cyclophosphamide 60 mg/kg/day for 2 days from D-3 to D-2) and FluBu3 protocols were used as MAC and RTC regimen, respectively. The inclusion criteria were set as follows: (1) adult (age ≥ 18 years) AML patients who were registered in a prospective cohort study; (2) receiving first allogeneic hematopoietic stem cell transplantation (HSCT) in CR1 between Aug 2017 and Nov 2021; (3) MRD negative at pre-transplant; (4) transplantation from either HLA-matched (8/8) sibling donor (MSD), matched unrelated donor (MUD) or 1-locus mismatched (7/8) unrelated donor (MMUD); (5) the use of either BuCy or FluBu3 conditioning. MRD negativity was defined by the absence of abnormalities in the following order; (i) <3 log reduction in RUNX1-RUNX1T1 and CBFB-MYH11, (ii) <4 log reduction of NPM1 level from diagnosis, and (iii) pre-transplant WT1 levels ≥ 250 copies for RUNX1-RUNX1T1, CBFB-MYH11, or NPM1 mutation negative AML. Peripheral blood was used as the source of stem cells in all patients, and the data was analyzed based on information available as of Jun 2022. Results: A total of 124 patients met the inclusion criteria, and 78 (62.9%) and 46 (37.1%) patients received BuCy and FluBu3 conditioning, respectively. The median age was 45 years and the patients with intermediate cytogenetics comprised the majority (71.8%). By the donor type, 64 (51.6%), 48 (38.7%) and 12 (9.7%) patients underwent MSD, MUD and MMUD transplantation. Between the two conditioning groups, patients receiving FluBu3 were older (median 39.5 vs 53 years, p<0.001) and significantly more patients in the FluBu3 group had received ATG (37.9% vs 93.5%, p<0.001). In each of the BuCy and FluBu3 groups, after median follow up of 39.5 and 53 months (p<0.001), the 2-year overall survival (OS) of 78.3% and 84.5% (p=0.358), relapse free survival (RFS) of 78.0% and 76.3% (p=0.806), cumulative incidence of relapse (CIR) of 7.7% and 21.5% (p=0.074) and non-relapse mortality (NRM) of 14.3% and 2.2% (p=0.0324) were observed. In addition, the probabilities of grade II-IV acute graft versus host disease (aGVHD) and cGVHD of moderated to severe at 2-year for BuCy and FluBu3 were 46.2% and 39.2% (p=0.306), and 59.5% and 36.0% (p=0.008), respectively. At the time of data cut-off, relapse was the main cause of HSCT failure in FluBu3 group (n=8) while NRM contributes most to HSCT failure in BuCy group (n=11). Six of 8 relapsed patients receiving FluBu3, compared to 1 out of 6 in BuCy group, had high-risk features of either poor cytogenetics or FLT3-ITD mutation. The majority of NRM in the BuCy group, 8 out of 11 cases, was due to GVHD and 4 of them received transplantation from MMUD. Conclusion: Among the AML patients in MRD negative CR1, the FluBu3 RTC regimen showed a comparable post-HSCT outcomes to a BuCy conditioing in terms of similar OS and RFS, while associated with significant reduced NRM that was offset by trend towards higher risk of relapse.

Neurofilament light as a predictive biomarker of unresolved chemotherapy-induced peripheral neuropathy in subjects receiving paclitaxel and carboplatin

Management of chemotherapy-induced peripheral neuropathy (CIPN) remains a significant challenge in the treatment of cancer. Risk mitigation for CIPN involves preemptive reduction of cumulative dose or reduction of dose intensity upon emergence of symptoms, despite the risk of reduced tumor efficacy. A predictive biomarker for dose-limiting CIPN could improve treatment outcomes by allowing providers to make informed decisions that balance both safety and efficacy. To identify a predictive biomarker of CIPN, markers of neurodegeneration neurofilament-light (NfL), glial fibrillary acidic protein (GFAP), tau and ubiquitin c-terminal hydrolase L1 (UCHL1) were assessed in serum of up to 88 subjects drawn 21 days following the first of 6 treatments with chemotherapeutics paclitaxel and carboplatin. Serum NfL and GFAP were increased with chemotherapy. Further, NfL change predicted subsequent onset of grade 2–3 CIPN during the remainder of the trial (mean treatment duration = 200 days) and trended toward stronger prediction of CIPN that remained unresolved at the end of the study. These results confirm previous reports that serum NfL is increased in CIPN and provide the first evidence that NfL can be used to identify subjects susceptible to dose-limiting paclitaxel and carboplatin induced CIPN prior to onset of symptoms.

The survival impact of palliative chemotherapy dose modifications on metastatic colon cancer

BackgroundAn uninterrupted dose of oxaliplatin-based cytotoxic therapy is an essential component in the standard treatment regimen of metastatic colon cancer (mCC). Data on the impacts of dose intensity reduction on the palliative treatment for patients with mCC remain scarce. Hence, this study aimed to investigate the impact of palliative chemotherapy dose modifications (DM) on the survival of patients with mCC.MethodsPatients with stage IV colon cancer who received first-line palliative FOLFOX regimen chemotherapy between 2014 until 2018 in the Oncology Department of the National Cancer Institute were conveniently sampled retrospectively to analyse the treatment efficacy. The cumulative dose and duration of chemotherapy received by the patients were summarised as relative dose intensity (RDI) and stratified as High RDI (RDI ≥ 70%) or Low RDI (RDI < 70%). Progression-free survival (PFS) and 2-year overall survival (OS) between the two groups were analysed using Kaplan-Meier survival analysis and Cox proportional hazards models.ResultsOut of the 414 patients identified, 95 patients with mCC were eligible and included in the final analysis. About half of the patients (n = 47) completed the 12-cycle chemotherapy regimen and one patient received the complete (100%) RDI. The overall median RDI was 68.7%. The Low RDI group (n = 49) had a 1.5 times higher mortality risk than the High RDI group [OS, Hazard Ratio (HR) = 1.5, 95% Cl: 1.19–1.82] with a significant median OS difference (9.1 vs. 16.0 months, p < 0.01). Furthermore, patients with lower dose intensity showed double the risk of disease progression (PFS, HR = 2.0, 95% CI: 1.23–3.13) with a significant difference of 4.5 months of median PFS (p < 0.01). Gender and RDI were the independent prognostic factors of both OS and PFS.ConclusionReduction in the dose intensity of palliative chemotherapy may adversely affect both disease progression and overall survival among mCC patients.

Risk Factor Analysis for the Occurrence of Severe Adverse Effects in Eribulin Treatment.

Eribulin is an effective chemotherapeutic agent for the treatment of metastatic breast cancer and advanced or metastatic soft-tissue sarcomas. However, severe adverse effects (SAEs) occur in 30-40% of the patients, and significantly reduce the patients' quality of life and disturb the recommended treatment schedules. Neutropenia is the main cause of treatment suspension, delay, and/or dose reductions, also leading to relative dose intensity reduction. This study aimed to examine the risk factors for SAE occurrence after eribulin treatment. Eighty patients with metastatic breast cancer or advanced or metastatic soft tissue sarcoma who received eribulin were retrospectively evaluated. Risk factors for SAE occurrence in the first cycle were primarily assessed. In addition, factors associated with SAE occurrence during all treatment cycles were evaluated. SAEs in the first cycle occurred in 45% of patients. The primary SAE was neutropenia (91.7%). The incidence of SAEs during all treatment cycles was 61.3%. Multivariate analyses suggested that lower baseline neutrophil and hemoglobin levels were risk factors for SAE occurrence and severe neutropenia incidence in the first cycle. An independent factor associated with SAE occurrence during all cycles was age ≥65 years and a tendency was confirmed for baseline anemia. Baseline neutropenia and anemia were risk factors for SAE occurrence during the first eribulin treatment cycle. Age ≥65 years was also associated with SAE occurrence during all treatment cycles. Patients with these risk factors should be carefully monitored for assessment and prophylaxis.