Frequency Of Dose Reductions Research Articles

Comparison of Weekly Paclitaxel Regimens in Recurrent Platinum-Resistant Ovarian Cancer: A Single Institution Retrospective Study.

Weekly paclitaxel (WP) is a chemotherapeutic cornerstone in the management of patients with platinum-resistant ovarian carcinoma. Multiple WP dosing regimens have been used clinically and studied individually. However, no formal comparison of these regimens is available to provide objective guidance in clinical decision making. The primary objective of this study was to compare the cumulative dose of paclitaxel delivered using 80 mg/m2/week, administered using either a 3 weeks out of 4 (WP3) or a 4 weeks out of 4 (WP4) regimen. The secondary objective was to evaluate the clinical outcomes associated with both regimens, including efficacy and toxicity parameters. Our retrospective cohort comprised 149 patients harboring platinum-resistant ovarian cancer treated at the CHU de Québec from January 2012 to January 2023. WP3 and WP4 reached a similar cumulative dose (1353.7 vs. 1404.2 mg/m2; p = 0.29). No significant differences in the clinical outcomes were observed. The frequency of dose reduction was significantly higher for WP4 than WP3 (44.7% vs. 4.9%; p < 0.01), mainly due to treatment intolerance from toxicity (34.0% vs. 3.9%; p < 0.01). Our data suggest that a WP3 regimen delivers a similar cumulative dose to WP4, hence offering a better tolerability profile without compromising efficacy.

Real world experience of trastuzumab deruxtecan for the treatment of metastatic breast cancer in the UK.

1024 Background: Trastuzumab deruxtecan (TDXd), an antibody drug conjugate, was first approved in the UK for the treatment of human epidermal growth factor receptor 2 positive (HER2+) metastatic breast cancer (mBC) in 2021. We aimed to review the efficacy and tolerability of TDXd in a real-world UK setting. Methods: We collected clinical and demographic data from medical records on HER2+ mBC patients treated with TDXd in the UK from Jan 2021 to Dec 2023 inclusive. This included: radiological response, the frequency of dose reductions and treatment delays, and reasons for discontinuation. Clinical trial patients were excluded. Descriptive statistical techniques were applied. Results: Data was collected from 26 UK cancer centres on 280 patients. The median age at TDXd initiation was 56 years (range 29-85). Median treatment duration was 9 cycles (range 1-40). 239 patients (85%) had visceral disease. 257 and 196 patients (92% and 70%, respectively) had received prior Trastuzumab and Pertuzumab, respectively. 233 patients (83%) had received prior TDM1. The median number of lines of treatment prior to TDXd was 3 (range 1 to 9). 20 patients (7%) were initiated on a reduced dose and 115 further patients (41%) required at least one dose reduction. 151 patients (54%) had at least one dose interruption due to: infection or neutropenia (n=61), other toxicity (n=85), interstitial lung disease (ILD) investigation (n=39), patient request (n=81), other concurrent illness (n=10), and cardiac investigation (n=6). Of these, 55 patients had more than one treatment break. 157 patients (56%) had discontinued TDXd treatment due to: disease progression or death (n=100), drug toxicity (n=39) of which 22 were due to ILD, and patient choice (n=8). 123 patients remained treatment at the time of analysis. The overall response rate of TDXd was 63% overall: stable disease 23%, partial response 56%, complete response 7%. Conclusions: The real-world data set is not directly comparable to either the DB02 or DB03 trials, as it included patients who had received TDXd in both the second line and later line settings. However, the majority (80%) of these patients were treated in the third line and beyond. The rates of drug interruption and reduction were higher in the real-world data set than in DB02, which may impact on efficacy in the real-world setting. Overall response rate is similar between trial data and our real-world data, although the latter was not measured by RECIST. Data collection is ongoing, including an analysis of real-world progression free survival. [Table: see text]

Primary Care Clinicians' Prescribing Patterns of Reduced-Dose Direct Oral Anticoagulants for Extended-Phase Venous Thromboembolism Treatment.

The direct anticoagulants (DOACs), apixaban and rivaroxaban, are used for extended-phase treatment of venous thromboembolism (VTE) and have labeling for dose reduction for this indication. The objective of this study was to better understand primary care clinician prescribing patterns of apixaban and rivaroxaban for extended-phase anticoagulation. We conducted a 21-question survey targeting members of the American College of Physicians and United States Veterans Administration anticoagulation management services. Survey questions covered prescribing behaviors for dose reduction of apixaban and rivaroxaban for extended VTE treatment, as well as questions related to the respondent's practice setting. We used logistic regression to assess associations between demographics and prescribing behaviors. We used k-means clustering to identify distinct groups of prescribing patterns. Among 227 respondents, most were attending physicians (60%) and one-third (34%) practiced in internal medicine or primary care. Most (59%) indicated they dose-reduced DOACs. Hospitalists (no outpatient care) were least likely to dose-reduce (OR 0.09 [95% CI 0.03-0.22]), as well as early-career clinicians (0.53 [0.30-0.91]). Pharmacists and clinicians who treat over 500 VTE patients annually were most likely to dose reduce (6.4 [2.9-16.3]), (2.9 [1.5-6.0]), respectively. We identified five clusters of dosing behaviors and characterized clinician makeup. Clusters were primarily differentiated by frequency of dose reduction, DOAC preference, and temporary re-escalation of doses. We identified clinician characteristics that are associated with dose-reduction prescribing behaviors; these analyses provide insight into where targeted interventions, such as protocolization and education, would be most beneficial.

Impact of cumulative dose of brentuximab vedotin on outcomes of frontline therapy for advanced-stage Hodgkin lymphoma

AbstractIn the pivotal study ECHELON-1, brentuximab vedotin (BV), doxorubicin, vinblastine, and dacarbazine (A + AVD) demonstrated superior efficacy compared with bleomycin + AVD for the treatment of advanced-stage classic Hodgkin lymphoma (cHL). However, there are minimal available data regarding the frequency of dose reductions or omission of BV during curative therapy and the potential impact on patient outcomes. In a real-world analysis, we retrospectively reviewed the characteristics and outcomes of 179 patients with stage III or IV cHL treated with frontline A + AVD from January 2010 to April 2022. Treatment consisted of up to 1.2 mg/kg of BV and standard dose AVD IV on days 1 and 15 of each 28-day cycle for up to 6 cycles. At the time of treatment, the median patient age was 37 years, and a high-risk International Prognostic Score was observed in 46% of patients. Overall, 91% of patients received 6 cycles of AVD; 55% of patients did not receive the intended cumulative dose of BV (CDB); 28% of patients received two-thirds or less than the planned CDB. At a median follow-up time of 27.4 months (95% confidence interval [CI], 24.8-29), the median progression-free survival (PFS) was not reached, and the 12-month PFS was 90.3% (95% CI, 85.9-95.0). The impact of CDB on PFS was not significant (P = .15), nor was high CDB significantly associated with increased adverse events. In real-world experience, A + AVD is a highly effective treatment for patients with advanced-stage cHL, including for patients with prominent dose reductions of BV.

Low pretherapy skeletal muscle mass index is associated with an increased risk of febrile neutropenia in patients with esophageal cancer receiving docetaxel + cisplatin + 5-fluorouracil (DCF) therapy

PurposeDocetaxel + cisplatin + 5-fluorouracil (DCF) therapy, a frequently prescribed regimen for esophageal cancer, is associated with a high risk of febrile neutropenia (FN). This study investigated whether a low skeletal muscle mass index (SMI) is an independent risk factor for FN.MethodsThis retrospective, observational study investigated the SMI of patients with esophageal cancer who received DCF therapy between March 2018 and July 2020. Based on the Asian sarcopenia criteria, patients were divided into two groups: high and low SMI (SMI of < 7.0 and 5.7 kg/m2 for males and females, respectively). The incidence of FN was then compared between the two groups.ResultsThirty-nine patients (20 and 19 in the high- and low-SMI groups, respectively) were included in this study. The incidence of FN was significantly higher in the low-SMI group (63.2% vs. 20.0%, P = 0.006). Univariable and multivariable logistic regression analyses revealed that a low SMI was an independent risk factor for FN (odds ratio, 7.178; 95% confidence interval, 1.272–40.507; P = 0.026). In addition, the frequency of dose reduction in DCF therapy was significantly higher in the low-SMI group (68.4% vs. 35.0%, P = 0.037).ConclusionLow SMI is an independent risk factor for FN in patients with esophageal cancer receiving DCF therapy.

A single institution real-world disease free survival analysis of adjuvant capecitabine in TNBC patients with residual disease following neoadjuvant chemotherapy.

e12502 Background: Adjuvant capecitabine (Cape) is standard of care for triple negative breast cancer (TNBC) cancer patients with residual disease following neoadjuvant chemotherapy. This is based on data from the CREATE-X study, which demonstrated an increase in disease-free survival (DFS) and overall survival in the intent-to-treat population, but this effect was most pronounced in the TNBC population. However, the generalizability of the study has been questioned due to previously negative studies, the homogenous nature of study participants, and the lack of differentiation for HER2 positive patients. We proposed a real-world DFS analysis of the efficacy of adjuvant Cape in TNBC patients (pts) with residual cancer burden (RCB) I though III versus a matched control group. Methods: This is a retrospective analysis to assess the DFS in a real world setting (primary endpoint) of patients with histologically confirmed TNBC with RCB-I through III post-surgery, who received neoadjuvant chemotherapy with anthracycline and/or taxane and adjuvant Cape. Secondary endpoints included: frequency of dose reductions, frequency of discontinuation, physician preferred dosing and adverse drug events. Survival curves were estimated via Kaplan-Meier method and hazard ratios with 95% confidence intervals determined using Cox proportional-hazards model. Results: A total of 401 pts were screened for TNBC with 101 pts meeting the inclusion criteria for study: 47 and 54 in the control group and capecitabine group, respectively. Demographics consisted of 38% Caucasian women and 62% African American women. In the control group, 12 pts (12.5%) experienced disease recurrence: nine at 12 months and three at 24 months. Three (6.4%) had local regional recurrence. In the Cape group, eight pts (14.8%) had disease recurrence: two at 12 months and six at 24 months. Six (11.1%) had a local regional recurrence. In Kaplan-Meier survival analysis, the control group had 72.9% DFS at 24 months, while the Cape group had 69.8% DFS at 24 months (p = 0.77). Twenty-nine patients had RCB-III: 11 in the control group and 18 in the Cape group. In subgroup analysis of the RCB III group, the control had 36.4% DFS at 24 months, while the Cape group had 88.9% DFS (p = 0.007). The preferred dosing was 1250 mg/m2 with 12 pts (22%) and 19 pts (35%) requiring dose reduction or discontinuation, respectively. Adverse events were reported in 46 pts (85%). Conclusions: In this single institution real-world data, adjuvant Cape does not appear to offer any additional survival benefit to triple negative patients with residual disease following neoadjuvant chemotherapy. However, this study showed an increase in DFS for RCB III when compared to the control group. Given the limited patient numbers, a larger sample size will be required to determine the validity of benefit seen in the patients with RCB class III.

Feasibility and efficacy of a supervised home-based physical exercise program for metastatic cancer patients receiving oral targeted therapy: study protocol for the phase II/III - UNICANCER SdS 01 QUALIOR trial

BackgroundCurrently, oral targeted therapies are known to be effective and are frequently used to treat metastatic cancer patients, but fatigue is a frequently reported early side effect of these treatments. This fatigue may impact the patient’s treatment adherence and result in a negative impact on quality of life. Physical exercise significantly improved the general well-being and quality of life of advanced cancer patients. However, there is no specific physical activity program adapted for patients with advanced disease.MethodsQUALIOR is a two-part, randomized, open-label, and multicenter with two arms phase II/III trial. Patients (phase II: n = 120; phase III: n = 312) with metastatic cancer (breast cancer, kidney cancer, lung cancer, and other cancers [including but not limited to colon cancer, melanoma, sarcoma, or hepatocarcinoma]) treated with a first- or second-line oral targeted therapy without chemotherapy will be included. Patients will be randomized (2:1) to a 3-month supervised home-based standardized physical activity program or to a recommended adapted physical activity (via a booklet). The primary objective of the phase II is to evaluate the feasibility of the supervised program. The primary objective of the phase III is the evaluation of the benefit of the supervised home-based program compare to the recommended program in terms of fatigue and quality of life at 3 months. The secondary objectives aim to evaluate the impact of the supervised program on fatigue over time, pain, physical capacities, psychosocial and cognitive functions, general quality of life, frequency of dose reduction and patients’ adherence to the targeted therapy, overall survival, and progression-free survival. This study will also evaluate the medico-economic impact of supervised program compared to the recommended adapted physical activity program.DiscussionThe aim of this study is to evaluate home-based physical exercise program for metastatic cancer patients treated with oral targeted therapies to help patients to cope with fatigue and improve quality of life.Trial registrationThis trial was registered in ClinicalTrials.gov since May 2017 (NCT03169075).

Sarcopenia as a predictor of survival and chemotoxicity in patients with epithelial ovarian cancer receiving platinum and taxane-based chemotherapy

ObjectivesSevere skeletal muscle loss (sarcopenia) is associated with poor cancer outcomes, including reduced survival and increased treatment toxicity. Our goal was to evaluate if sarcopenia was associated with worse survival outcomes and chemotoxicity in EOC patients undergoing primary platinum and taxane-based chemotherapy. MethodsEOC patients diagnosed between 06/2000 and 02/2017 who received treatment with platinum and taxane-based chemotherapy were included. CT abdominal images closest to the time of diagnosis were retrospectively evaluated for skeletal muscle area at the 3rd lumbar vertebrae. Measurements were obtained with use of TomoVision® radiological software (SliceOmatic – version 5.0, Quebec, Canada). Sarcopenia was defined as Skeletal Muscle Index (SMI) ≤ 41. Data analysis included Kaplan-Meier plots to assess survival, and unpaired t-tests were used to compare the means by groups. Results201 EOC patients were evaluated. Sixty-four percent (128/201) met criteria for sarcopenia (SMI ≤ 41) at time of diagnosis. The mean overall survival did not differ between patients with SMI > 41 and SMI ≤ 41 (36.5 vs 40.8 months, p = 0.4, respectively). No difference in frequency of dose reduction, dose delay, hospital admissions, changes in regimen, blood transfusion, or toxicity was noted. There was no difference in distribution of toxicity grade. ConclusionSarcopenia was not associated with worse survival outcomes or chemotoxcity in EOC patients receiving first-line platinum and taxane-based chemotherapy in this cohort.Future prospective studies should focus on interventions to prevent or reverse sarcopenia and possibly increase ovarian cancer survival, performance status, and quality of life.

Clinical analysis of EGFR-positive non-small cell lung cancer patients treated with first-line afatinib: A Nagano Lung Cancer Research Group.

BackgroundIn the LUX‐Lung 3 and LUX‐Lung 6 trials, afatinib improved overall survival in previously untreated patients with EGFR 19del mutated non‐small cell lung cancer (NSCLC) compared to chemotherapy. The appropriate management of adverse events and dose reduction of afatinib are important for EGFR‐positive NSCLC patients. We conducted a retrospective and observational study of patients treated with first‐line afatinib for EGFR‐positive NSCLC in Nagano prefecture, Japan, focusing on efficacy and toxicities.MethodsWe retrospectively collected the medical records of NSCLC patients initially treated with afatinib between May 2014 and March 2018.ResultsA total of 62 patients with a median age of 67 years and a median body surface area (BSA) of 1.57 m2 were included. The overall response rate was 87.7% and median progression‐free survival (PFS) was 15.7 months. The median PFS was similar between standard initial dose (40 mg) and reduced initial doses (30 and 20 mg) (15.7 vs. 14.2 months; P = 0.978). The frequency of dose reduction and the discontinuation rate in the 40 mg daily dose group was higher in patients with BSA < 1.58 m2 (100%) compared to BSA ≥ 1.58 m2 (68.2%) (P = 0.014). The frequency of diarrhea was higher in patients with BSA < 1.58 m2 (93.5%) compared to BSA ≥ 1.58 m2 (71.0%) (P = 0.02).ConclusionIn real‐world clinical practice, first‐line afatinib was well managed and was equally as effective as in previous clinical trials of EGFR‐positive NSCLC. BSA is considered a predictive marker for appropriate afatinib dose reduction.

A Method to Summarize Toxicity in Cancer Randomized Clinical Trials.

Purpose: Despite development of clinical "value frameworks" by national and international groups, there remains no generally accepted method to summarize toxicity in cancer clinical trials. We explored ways to simplify toxicity data of an arm of a cancer clinical trial to a single value, termed a "weighted toxicity score" (WTS).Experimental Design: We compiled 58 randomized clinical trials of FDA-approved kinase-directed inhibitors. We generated 5 models, each of which assigned different weights for each observed grade 1 to 4 toxicities. For each model, we calculated WTS values as different weighted averages of the sum of the toxicities. We correlated each WTS with the dose reduction rate in each trial, using the dose reduction rate as a clinically relevant surrogate of treatment that is too toxic. The WTS method yielding the strongest correlation with frequency of dose reduction was declared the best model.Results: Nineteen of 58 trials were placebo controlled and had complete data. Of the 5 models examined, differences in dose reduction rates correlated best with differences in WTS using a model with a clinician-weighted scale for toxicities (model M5). The WTS difference thus serves as a surrogate for a desired dose reduction rate difference and could be used to adjust dose/schedule as patients are accrued to a clinical trial.Conclusions: The WTS distills a tabular listing of toxicities of a treatment into a single value, and provides a simple method that can be incorporated into value frameworks, or used to guide discussion of the risks and benefits of systemic therapy. Clin Cancer Res; 24(20); 4968-75. ©2018 AACR See related commentary by Vaishampayan, p. 4918.

Impact of Gender on Outcome after Chemoimmunotherapy with Fludarabine, Cyclophosphamide and Rituximab (FCR) or Bendamustine Plus Rituximab (BR) in Patients with Chronic Lymphocytic Leukemia (CLL): A Meta-Analysis of Three Phase II/III Studies of the German CLL Study Group (GCLLSG)

Impact of Gender on Outcome after Chemoimmunotherapy with Fludarabine, Cyclophosphamide and Rituximab (FCR) or Bendamustine Plus Rituximab (BR) in Patients with Chronic Lymphocytic Leukemia (CLL): A Meta-Analysis of Three Phase II/III Studies of the German CLL Study Group (GCLLSG)

549P - Gender and chemotherapy-related toxicity in colon cancer: an analysis of the PETACC-3 trial conducted by the EORTC GI-group

Drug metabolism is genetically determined. Gender is one of the factors responsible for the large interpatient variability in the dose-effect relationship of cytotoxics. Comparative data on the effect of gender on chemotherapy (CT)-related toxicity are lacking in colon cancer. This is a retrospective analysis of data from the PETACC-3 trial: 2974 pts (55.7% men (m) and 44.3% women (f)) with stage II and III colon cancer were treated with adjuvant 5-fluorouracil/leucovorin alone (5FU/LV) or with irinotecan (FOLFIRI). Primary aim was to compare CT-related toxicity (according to NCIC-CTCG) in m and f. Clinical and hematologic adverse events (AEs) rates and frequency of dose reductions in m and f were compared by Fisher's exact test; survival outcomes by log-rank test. Subgroup analyses were performed according to age (<50, 50-65, ≥65) and treatment. P-values are 2-sided. No multiple testing adjustments were done. Higher rates of all grade nausea (61.8 vs 53.7%, p < .0001), vomiting (32.5 vs 24.5%, p < .0001), alopecia (41.7 vs 26.0%, p < .0001) and more all grade leucopenia, anemia and neutropenia (p < .0001) were observed in f compared with m. Differences in these AEs between f and m were found significant (p < 0.05) in both arms and in all age groups except for nausea and neutropenia in age <50. Additionally, in the FOLFIRI arm, f had greater risks of stomatitis (40.6 vs 30%, p < .0001), cramping (24.2 vs 16.4%, p = 0.0002), cholinergic syndrome (18.3 vs 12.9%, p = 0.0045) and lethargy (48.9 vs 38.2%, p < 0.0001) as well as more grade 3-4 neutropenia (37.3 vs 21.1%, p < .0001) than m. There was no significant difference in febrile neutropenia between m and f. Dose reductions were more frequent in f (25.9% vs 16.8%, p < .0001) but the mean cumulative doses of CT (mg/m2) were not significantly different between m and f. There were no significant differences in PFS or OS. In this trial, women demonstrated significantly greater rates of various hematological and non-hematological AEs, especially under treatment with FOLFIRI. Thus, AEs need to be reported according to gender in future clinical trials. Further data investigating the relationship between gender and CT efficacy and toxicity is required.

RESPECT: Response Evaluation of Cancer Therapeutics in Metastatic Breast Cancer to the Bone – a Whole Body MRI Study

mostly extrapolated for older populations, who are more likely to have comorbidities/impaired performance status, and not represent the clinical trial population. We reviewed our local practice to see how much chemotherapy our older patients actually receive. Methods: A retrospective, single-centre audit of patients over 60 years, treated with adjuvant chemotherapy for breast cancer from 2010 to 2015. Data were collected from clinical and pharmacy records. Primary outcomes were the type of intended chemotherapy, the percentage delivered and the frequency of dose reductions. Results: 84 patients received adjuvant chemotherapy: 32 were aged 60e64 years, 33 were 65e69 years and 19 were over 70 years. The majority had T2 tumours (50%; 73%; 63%), were node positive (56%; 67%; 74%) and HER2 positive (69%, 73% and 53%), whereas hormone positivity declined with age (88%; 73%; 42%) (60e64 years; 65e69 years; >70 years, respectively). Patients aged 60e64 years were most likely to receive FEC/FEC-T and on average completed 95.8% of their planned chemotherapy, with 25.3% of cycles dose reduced and 9.1% stopping chemotherapy early. 26.3% of patients >70 years stopped chemotherapy early, with 35.1% of cycles delivered at a reduced dose. Conclusion: There were differences in the baseline characteristics of patients over 65 years who were offered adjuvant chemotherapy compared with younger patients: patients over 65 years were more likely to be ER-ve and/or HER2þve. Patients over 65 years were also more likely to have multiple dose reductions, discontinue chemotherapy early and were least likely to receive third generation chemotherapy, even for node-positive disease. Patients who do not complete their adjuvant chemotherapy may not derive the benefi ti n 10 year survival proposed by nhs.predict. This should be taken into consideration when counselling elderly patients for adjuvant chemotherapy.

Abstract P1-13-01: Comparison of 12 weeks neoadjuvant Nab-paclitaxel combined with carboplatinum vs. gemcitabine in triple- negative breast cancer: WSG-ADAPT TN randomized phase II trial

Abstract Background: Pathological complete response (pCR) is associated with improved prognosis in TNBC, but optimal chemotherapy remains unclear. Use of weekly nab- paclitaxel (Nab-Pac) vs. conventional paclitaxel and also addition of carboplatinum(Carbo) to anthracycline-taxane(A/T) containing chemotherapy results in significantly higher pCR rates in TNBC with unclear impact on survival and increased toxicity. The ADAPT study seeks to compare Carbo vs. gemcitabine(Gem) added to nab- paclitaxel as a short 12-week A-free regimen. It also assesses efficacy in early responders vs. non-responders by 3-week proliferation and/or imaging response. Methods: ADAPT TN compares 12-week neoadjuvant regimens: Carbo vs. Gem combined with Nab-Pac and aims to identify early-response markers for pCR (yPN0 and ypT0/is). TNBC patients (centrally confirmed ER/PR &amp;lt;1%, HER2 neg.), cT1c- cT4c, cN0/+ were randomized to arm A (Nab-Pac 125/Gem 1000 d1,8 q3w) vs. B (Nab-Pac 125/Carbo AUC2 d1,8 q3w). Randomization was stratified by center and nodal status. The trial is powered for pCR comparison by therapy arm and by presence vs. absence of early response markers. Pre-planned interim analysis aimed to identify a dynamic biomarker, e.g. drop of 3-week Ki-67, and to validate trial assumptions. Results: 336 patients were enrolled from 47 centers between 06/13-02/15 (n=182 ArmA: Nab-Pac/Gem and n=154 ArmB: Nab-Pac/Carbo). 90% and 95% completed therapy according to protocol respectively (n.s.). Median age was 50y. At baseline: A/B: 73% and 74%% had G3 tumors, median Ki-67 of 70% and 75%; 62.6% and 62.9%% had cT2-4c tumors, pN0 status prior to chemotherapy was confirmed in 50.5% and 50%, respectively. pCR (ypT0/is/ypN0) was A: 28.7% and B: 45.9% (p&amp;lt;0.001). Total pCR (ypT0/ypN0) was A: 25.8% and B: 45.2% respectively (p &amp;lt;0.001). Nab/Gem arm was associated with significantly higher frequency of dose reductions (20.6% vs. 11.9% (p=0.03), treatment related SAE's (13% vs. 5%, p=0.02), grade 3-4 infections (6.1% vs. 1.3%, p=0.04) and ALAT elevations (11.7 vs. 3.3%, p=0.01) compared to the Nab-Carbo arm. Within the planned interim analysis (n=130: A/B: 69/61), baseline Ki-67 (Nab- Pac/Carbo arm), age&amp;gt;50 years, and low cellularity (&amp;lt;500 tumor cells and/or Ki-67≤10% in the 3-week biopsy) (Nab-Pac/Gem arm) were positively associated with pCR by logistic regression analysis (separately by therapy arm). In all patients, therapy arm itself was significant for pCR. Validation of responder definitions for the whole study will be presented at the meeting. Conclusions: This is the first large randomized study comparing two short 12-week anthracycline- free regimens in unselected TNBC. Our results suggest superior efficacy and excellent toxicity of Nab-Pac/Carbo vs. Gem. Longer A/T-Carbo containing regimens render quite comparable pCR rates, thus overtreatment by 4xEC in unselected TNBC may be present in some patients. Early response criteria seem to differ according to regimen; their assessment may be impaired by substantial tumor necrosis already after the first therapy cycle. Citation Format: Gluz O, Nitz U, Liedtke C, Christgen M, Sotlar K, Grischke EM, Forstbauer H, Braun M, Warm M, Hackmann J, Uleer C, Aktas B, Schumacher C, Bangemann N, Lindner C, Kuemmel S, Clemens M, Potenberg J, Staib P, Kohls A, Pelz E, Kates RE, Wuerstlein R, Kreipe HH, Harbeck N. Comparison of 12 weeks neoadjuvant Nab-paclitaxel combined with carboplatinum vs. gemcitabine in triple- negative breast cancer: WSG-ADAPT TN randomized phase II trial. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-13-01.

Outcome of Elderly Patients with Diffuse Large B-Cell Lymphoma Treated with R-CHOP: Subgroup Analysis from the UK NCRI R-CHOP 14 Vs 21 Trial

Background:Elderly patients with diffuse large B-cell lymphoma (DLBCL) have an inferior prognosis compared to younger patients. Dose intense administration of cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP14) is superior to 3-weekly CHOP in elderly DLBCL patients (Pfreundschuh, Blood 2004), but this benefit has not been demonstrated with addition of rituximab (Delarue, Lancet Oncol 2013). We have previously shown that R-CHOP14 did not improve outcome compared to standard R-CHOP21 in newly diagnosed DLBCL patients aged 19-88 years across all subgroups (Cunningham, Lancet 2013). Here, we provide a detailed subgroup analysis of elderly patients (over 60 years) from the UK NCRI R-CHOP14 vs 21 randomised phase 3 trial.Methods:Between 2005 and 2008, 1080 patients were randomly assigned to receive 8 cycles R-CHOP21 or 6 cycles R-CHOP14 (+ G-CSF) with two additional rituximab applications. Of these, 604 patients were over 60 years and included in the current analysis (301 in the R-CHOP21 arm, 303 in the R-CHOP14 arm), with a median follow-up of 45 months.Results:Baseline characteristics were well balanced between treatment arms. 36% of patients were over 70 years, 15% had a WHO performance status (PS) of 2, 65% stage III/IV disease, 44% bulky disease and 42% B symptoms. There was a trend towards a higher rate of BCL6 rearrangements (26% vs. 16%; P=0.10) and concurrent MYC - and BCL2 rearrangements (double hit lymphoma as determined by FISH, 8% vs. 2%; P=0.06) in the R-CHOP14 arm compared to the R-CHOP21 arm.85% (257/303) of patients received 8 cycles of R-CHOP14, whereas only 76% (230/301) completed all 8 cycles R-CHOP21. However, percentage of patients receiving at least 6 cycles of therapy was similar (88% and 89%, respectively). Dose delays of myelosuppressive drugs occurred more frequently in patients receiving R-CHOP21 vs. R-CHOP14 (51% vs. 39%; P=0.03) due to a higher incidence of haematological toxicities likely related to the reduced use of G-CSF. G-CSF was mandatory for patients on R-CHOP14 and was given to 57% of patients on R-CHOP21 as secondary prophylaxis. The frequency of dose reductions was similar in the R-CHOP21 and R-CHOP14 arms (15% vs. 16%; P=0.73). Toxicities of grade III+ were seen in 72% and 60% of patients in the R-CHOP14 and R-CHOP21 arms, respectively. There was evidence of a higher incidence of grade III+ neutropenia (62% vs. 36%) and a lower rate of thrombocytopenia (7% vs. 12%) in the R-CHOP21 arm compared to R-CHOP14. The incidence of fever and infections was similar in both arms.There was no evidence of a difference in response rates between the R-CHOP14 and R-CHOP21 arms [complete response (CR)/unconfirmed CR (CRu) rates: 62% vs. 67%, respectively; overall response rate both 91%]. CR/CRu rates after 4 cycles of therapy were 33% and 39% respectively (P=0.15). There was no difference regarding progression-free survival (PFS) and overall survival (OS) between arms, neither in the total cohort of elderly patients, nor in the subgroup of patients over 70 years [OS (all elderly): hazard ratio (HR) 0.91 (95% CI: 0.67-1.24); P=0.55; PFS (all elderly): HR 0.98 (95% CI: 0.74-1.29); P=0.86]. 3-year PFS was 71% (95% CI: 67-74) in all patients over 60 years and 64% (95% CI: 58-71) in patients over 70 years. 3-year OS was 75% (95% CI: 72-79) and 67% (95% CI: 61-74) in patients over 60 years and over 70 years, respectively. In multivariate analysis including individual factors of the International Prognostic Index (IPI), as well as age as continuous variable, gender, presence of B symptoms, bulky disease, b2-microglobulin higher than 3mg/l and albumin higher than 35 g/l, only age was of independent prognostic significance for OS (P=0.01).Besides the standard IPI and the NCCN-IPI, an elderly IPI (E-IPI; Advani, BJH 2010) and the ABE4 score (Prochazka, PLoS One 2014) have been proposed for better prognostication of elderly DLBCL patients. A detailed comparison of these different prognostic models in our dataset will be presented at the meeting.Conclusion:Outcome and toxicities in DLBCL patients over 60 years treated within the NCRI R-CHOP14 vs 21 trial are comparable to results from other randomised studies investigating R-CHOP14 or R-CHOP21 in elderly DLBCL patients. Our data further support the similar efficacy and tolerability of both R-CHOP variants for first-line treatment of this patient group. DisclosuresCunningham:Amgen: Research Funding; Medimmune: Research Funding; Astra Zeneca: Research Funding; Bayer HealthCare Pharmaceuticals: Research Funding; Merrimack: Research Funding; Merck Serono: Research Funding; Celgene: Research Funding; Sanofi: Research Funding. Pocock:Janssen: Honoraria. Ardeshna:Roche: Honoraria.

Abstract P3-12-07: A multicenter randomized double-blind phase III clinical trial to evaluate the efficacy and safety of GCPGC, a novel pegylated G-CSF in patients receiving DA or TAC chemotherapy for breast cancer compared to peg-filgrastim

Abstract Introduction Treatment with cytotoxic chemotherapy is known to be associated with a significant risk of febrile neutropenia. GCPGC(Green Cross Co., Korea) is a novel long acting recombinant human granulocyte colony-stimulating factor (G-CSF) analog that reduces the severity and duration of neutropenia. We conducted a phase III trial to evaluate the efficacy and safety of GCPGC compared to pegfilgrastim. Methods A total of 117 patients were enrolled in this multicenter, phase III, double-blind randomized trial between Feb 2012 and May 2013. They were randomly assigned to receive either GCPGC or pegfilgrastim during the maximal 6 cycles of chemotherapy which consisted of DA (docetaxel and doxorubicin) or TAC (docetaxel, doxorubicin, and cyclophosphamide). Based on the results of the phase II dose-finding study for GCPGC, the dose of 6 mg was selected. Both medications were administered 24 hours after the completion of each cycle of chemotherapy. The primary efficacy endpoint of this study was the duration of grade 4 neutropenia (Absolute Neutrophil Count (ANC) &amp;lt;500/mm3) during the first cycle of chemotherapy. Secondary endpoints included the time to ANC recovery during the first cycle of chemotherapy, which was defined as the number of days required for neutrophil counts to exceed 2,000/mm3, the rate of febrile neutropenia, the rate of severe neutropenia which persisted for more than three days during first cycle of chemotherapy, the depth of ANC nadir, the ANC level on day 7 after each cycle of chemotherapy, the frequency of dose reduction or delay, the number of hospitalization related to febrile neutropenia after the first cycle of chemotherapy, and the number of treatment with intravenous antibiotics. Results A total of 116 patients were evaluable for safety and 115 patients were evaluable for efficacy. The intention-to-treat analysis showed that there was no statistical difference between GCPGC and pegfilgrastim in terms of the duration (days) of grade 4 neutropenia in chemotherapy cycle 1 (1.64±1.18 vs 1.80±1.05; difference -0.15±1.11 [97.5% C.I. -, 0.26]; the pre-specified non-inferiority margin of 1.0). Notably, patients treated with GCPGC had a statistically significant reduction in the time to recovery from neutropenia (ANC &amp;gt;2,000/mm3), one of the secondary endpoints of the study, compared to those treated with pegfilgrastim (8.85 ± 1.45 vs. 9.83 ± 1.20 days; p &amp;lt;0.0001). There was no difference between groups regarding the other secondary endpoints. In addition, no significant differences were observed between the safety profiles of the two groups. Conclusion Collectively, GCPGC is not inferior to peg-filgrastim and represents an effective alternative for reducing the duration of neutropenia in breast cancer patients receiving TAC or DA chemotherapy. Citation Format: Joo Han Lim, Ki-Hyeong Lee, Keon-Uk Park, In-Hae Park, Eun Kyung Cho, Moon Hee Lee, So-Young Yoon, Jee-Hyun Kim, In-Sil Choi, Jae-Hoo Park, Young-Jin Choi, Hee-Jun Kim, Kyung Hae Jung, Si-Young Kim, Do-Youn Oh, Seock-Ah Im. A multicenter randomized double-blind phase III clinical trial to evaluate the efficacy and safety of GCPGC, a novel pegylated G-CSF in patients receiving DA or TAC chemotherapy for breast cancer compared to peg-filgrastim [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-12-07.

Sorafenib use in elderly patients with hepatocellular carcinoma: caution about use of platelet aggregation inhibitors.

Sorafenib is the standard of care for advanced hepatocellular carcinoma (HCC). The peak incidence of HCC is around 70 years. We aimed to evaluate safety and efficacy of sorafenib in the elderly population. We retrospectively reviewed data from patients treated with sorafenib for HCC at our institution. We compared safety and efficacy data across different age groups. Since 2005, 129 patients were treated, 78 (60.5 %) were <70 years old and 51 (39.5 %) were ≥70. The frequency of dose reduction was similar between the two groups (48.7 vs. 58.8 %), as was the occurrence of severe toxicities (41.0 vs. 51.0 %) and hospitalization due to toxicity (9.0 vs. 13.7 %). However, asthenia and bleeding were more frequent in the elderly. The higher frequency of bleeding was explained by concomitant antiplatelet treatments, and major asthenia was frequent in PS1 elderly patients. There was a trend toward less frequent interruption of treatment in the younger group (25.6 vs. 39.2 %) and significantly less frequent definitive discontinuation of treatment due to toxicity (24.4 vs. 45.1 %). Median progression-free survival was 5.6 months in both age groups, while median overall survival was 9.6 months in the younger age group and 12.6 months in the older age group. Sorafenib showed similar results in terms of safety and efficacy in the elderly and younger HCC populations. Careful baseline evaluation is needed for patient's selection in the elderly population, including discussion about antiplatelet therapy discontinuation and caution in PS1 patients, as well as active management of toxicity.

Long-term therapy with sunitinib and sorafenib in patients with metastasizing renal cell carcinoma.

407 Background: Multitargeted tyrosine kinase inhibitors (MTKIs) constitute the established therapy in patients with metastasizing renal cell carcinoma. There are only few data concerning efficiency and safety, the reasons for a longterm response with good tolerability under MTKIs is still unknown. Methods: We retrospectively analyzed the data of patients (pts.) under long-term therapy (&gt;1 year) with sorafenib or sunitinib. Localization of metastases, number of cycles, sequence of therapy, treatment-associated toxicities, and frequency of dose reductions were our main focus of interest. Results: 15 pts. (14 male, one female) with an mean age of 66,33 (44-81) years, were treated with 19,86 (12-35) cycles of sorafenib or sunitinib. 14/15 pts. underwent radical nephrectomy before the treatment. Localization of metastasis were as follows: pulmonary (9/15), hepatic (4/15), nodal (8/15), osseous (3/15), and pancreatic (2/15). In four pts. two or more organs were affected, in six pts. only one organ. As a first-line therapy nine pts. received sunitinib for 20.67 (12-35) cycles and one patient sorafenib for 44 cycles. For second line therapy two pts. were treated with sunitinib for 13 (12-14) cycles and three pts. with sorafenib for 23.33 (18-28) cycles. In five pts. a dose reduction of 25-50% was necessary due to significant treatment associated side effects, afterwards toxicities were tolerable under long term therapy (grade 1 in 10 pts.). Conclusions: The results show, that longterm therapy with sunitinib or sorafenib is tolerable and efficacious independent on previous treatment. Prognostic factors concerning longterm response and low toxicity profile at a molecular biological level are still unknown, further investigations are of importance and are currently performed at our institution. No significant financial relationships to disclose.

Comparison of adverse effects related to pegylated interferon-based therapy for patients with chronic hepatitis B and chronic hepatitis C in Taiwan

Pegylated interferon (Peg-IFN)-based therapy is effective in treating chronic hepatitis B (CHB) and C (CHC) but frequently induces adverse events (AEs). This study was conducted to compare the incidence of Peg-IFN-based therapy-associated AEs in Taiwanese patients with CHB and CHC. Fifty-six patients with CHB and 103 age-, sex- and treatment duration-matched patients with CHC were enrolled. Patients with CHB were treated with Peg-IFN-α-2a 180μg/week for 24weeks (HBeAg(+), n=31) or 48weeks (HBeAg(-), n=25); patients with CHC were treated with Peg-IFN-α-2a 180μg/week plus ribavirin 1,000-1,200mg/day for 24weeks (genotype 2/3, n=57) or 48weeks (genotype 1, n=46). Significantly higher incidences of Peg-IFN-related AEs, especially neuropsychiatric symptoms, and ribavirin-associated skin manifestations were observed in patients with CHC compared with those with CHB, with either the 24- or 48-week regimen. Frequencies of laboratory abnormalities, except for anemia, were comparable in both groups. Neither group showed overt hepatic decompensation. Frequency of dose reduction was similar between the groups. Substantially higher rates of early termination and severe AEs were observed in patients with CHC. Patients with CHB treated with Peg-IFN had fewer AEs than patients with CHC treated with Peg-IFN/ribavirin. All patients were treated safely.

Comparing carboplatin dose administered to the calculated dose using the Modification of Diet and Renal Disease (MDRD) equation

13003 Background: Renal function assessment is vital for dosing of chemotherapy drugs. GFR is usually estimated by creatinine clearance (CrCl). The MDRD equation is thought to provide a more accurate estimation of GFR than the Cockcroft-Gault or 24-hour CrCl measurement. Although this formula has been validated in kidney disease, it has not been extensively studied in cancer patients. Methods: We retrospectively reviewed records for patients who received carboplatin from the University of Illinois at Chicago for a 4-year study period. General demographic information, carboplatin dose for cycles one to three, and common laboratory parameters at baseline and following cycles one to three were collected. The MDRD derived value of GFR was then used in the Calvert equation to calculate carboplatin dose. This calculated dose was compared to the actual dose administered in the first cycle. From this comparison, the records were divided into two groups: (A) actual vs. calculated dose ≥ 20% and (B) actual vs. calculated dose &lt; 20%. We then assessed toxicity by determining the frequency in each group requiring dose reduction on the second cycle of carboplatin. Results: Data are available for 116 patient comparisons. 78 patient comparisons were in group B with agreement between actual vs. calculated MDRD dose. 38 were in group A with 36 having the actual dose being ≥ 20% less than the MDRD-calculated dose. Wilcoxin and Chi analysis reveals statistical significance for African American, women, lower serum creatinine, and older age for Group A. In Group A, cycle 2 dose reductions were made in 3 cases (8% and due to hematologic). In Group B, cycle 2 dose reductions were made in 12 cases. In 8 of these cases (10%), dose reductions were based on ANC, and in 4 cases dose reductions were made likely on the basis of changes in weight or creatinine. Conclusion: In the comparisons examined to date, differences in carboplatin doses due to different methods of calculation do not appear to significantly influence the frequency of dose reduction. Factors used in calculating MDRD such as age, sex, serum creatinine, and ethnicity were variables associated with ≥ 20% difference in actual vs. calculated MDRD dose. No significant financial relationships to disclose.