Doxorubicin-containing Regimens Research Articles

Evaluation of oral silymarin formulation efficacy in prevention of doxorubicin induced hepatotoxicity in patients with non-metastatic breast cancer.

Chemotherapy-induced hepatotoxicity is a common complication in breast cancer patients, especially with doxorubicin-containing regimens. Liver enzyme abnormality is reported in 34.8% of patients undergoing AC-T regimen and fatty liver is reported in 30% to 50% of cases. Antioxidant and anti-inflammatory properties of silymarin, a polyphenolic flavonoid extract derived from Silybum marianum, may be useful in preventing chemotherapy-induced hepatotoxicity. This study evaluated the effect of oral silymarin for preventing doxorubicin induced hepatotoxicity in non-metastatic breast cancer patients. In this triple-blind, placebo-controlled clinical trial, 50 patients with non-metastatic breast cancer were assigned to receive either 140 mg silymarin tablets or the placebo three times daily for 63 days and were evaluated for liver function test before the study and at the end of each chemotherapy cycle (every 3 weeks) for 4 cycles. In addition, an ultrasonography assessment was performed upon entry and the end of the study. Based on ultrasonography, the fatty liver grade was significantly higher in the placebo group at the end of the study. Moreover, the serum levels of aspartate aminotransferase (p = 0.015) and alkaline phosphatase (p = 0.004) at 6-week intervals, and the serum level of alkaline phosphatase (p = 0.002) at 9-week intervals were significantly lower in the silymarin group. Oral formulation of silymarin 420 mg/day for 63 days significantly prevented hepatotoxicity caused by doxorubicin in patients with non-metastatic breast cancer mostly based on liver ultrasonography but not laboratory parameters. Further investigations are suggested on different doses, durations and formulations of silymarin, particularly nano-formulations for increasing its oral bioavailability.

Retrospective evaluation of Penguin Cold Caps for chemotherapy-induced alopecia

BackgroundScalp cooling is an increasingly recognized non-pharmacologic approach to minimize chemotherapy-induced alopecia (CIA). Several commercially available machine-based and manual scalp cooling systems are available; however, literature reports of effectiveness are highly variable. The purpose of this study was to determine real-world tolerability and subjective effectiveness of a manual cold capping system in minimizing CIA across a variety of patient race and hair types. This study was a single-institution review of outcomes from manual cold capping.MethodsWe identified retrospective cohort of adult patients who presented to discuss cold capping between January 14, 2019, and March 31, 2022. Data collected from medical records included demographics, decision to pursue/continue cold capping, diagnoses, chemotherapy regimens, hair characteristics (length, thickness, coarseness, type), and subjective perception of percentage of hair retained. Those with successful vs. unsuccessful cold capping (≥ 50% vs. < 50% of hair retained) were compared based on the patient-level factors of interest.FindingsA total of 100 patients initiated cold capping during the study period, and 95% of them completed cold capping. The majority of patients who started cold capping completed it. The median-reported percentage of hair maintained was 75%, and 82/89 (92.1% of patients) had favorable results, defined as ≥ 50% of hair retained. The only patient-level factor associated with favorable response was chemotherapy regimen, with fewer patients receiving doxorubicin-containing regimens having successful hair retention compared to other chemotherapy types (71.4% successful results vs. 95.7% for those receiving paclitaxel-containing regimens and 96.6% for those receiving docetaxel-containing regimens (p = 0.018). There was no difference in success based on patient race/ethnicity or hair characteristics.InterpretationThe overall effectiveness (92.1%) in this study is consistent to higher than many literature reports. One possible reason for the high success in our cohort is compliance with cold capping protocols, meaning applying the cap in the appropriate manner and wearing the cap for the prescribed durations, which may impact effectiveness.

A Novel Nomogram Predicting Rituximab-Associated Interstitial Pneumonia in Patients with Diffuse Large B-Cell Lymphoma: A Retrospective Analysis of Single-Center

Background: The incidence rate of rituximab-induced interstitial lung disease (RILD) was reported to be 3.7%-16.7%. The onset of RILD was insidious, and the clinical symptoms were atypical. The course of the RILD progressed rapidly without timely treatment. However, there were no models reported to predict the risk of RILD. Herein, we investigated the incidence of RILD in consecutive patients with diffuse large B-cell lymphoma (DLBCL) and its correlation with clinicopathological features, and a novel nomogram was constructed to successfully predict the risk of RILD. Methods: The clinicopathological data of 110 consecutive patients with DLBCL who were treated in the Department of Hematology of Beijing Tongren Hospital from January 2020 to December 2022 were retrospectively collected, and all patients received first-line treatment regimens containing rituximab. The occurrence of interstitial pneumonia was assessed by chest CT or interim PET-CT. Efficacy was assessed according to Lugano criteria, and chi-square test was used to assess the difference in RILD in different characteristic groups. Results: The complete remission rate of 110 patients with DLBCL after treatment was 84.2%. Twenty-one patients (19.1%) developed RILD during treatment, and the median time of occurrence was the 4th cycle（range: 2~8). The median duration of treatment for RILD was 10 days (range: 5~60). Except for 5 patients with no obvious symptoms, all 16 patients received glucocorticoid-containing regimens, and all patients improved after treatment. The incidence of RILD was significantly higher in patients who received liposomal doxorubicin-containing regimens than those treated with adriamycin regimens (29.7% versus 13.7%, P=0.043). Smoking ( P=0.298) and advanced age ( P=0.156) were associated with a high incidence of RILD. Then we developed a RILD risk prediction model according to the risk factors, and the patients were divided into high-risk and low-risk groups, and the incidence of RILD was significantly different between the two groups ( P=0.027). Finally, a novel nomogram related to the occurrence of RILD in DLBCL patients was developed to scientifically and accurately predict the incidence of RILD. Conclusion: Patients with DLBCL should be alert to the occurrence of RILD after chemotherapy with rituximab-containing regimen, especially in smoking and elderly patients, and the prevention and monitoring of RILD should be strengthened after the application of liposomal doxorubicin.

Survival Patterns of Non-Randomized Patients in the IELSG37 Study: Deauville Score 4 Is Not Necessarily Associated with Poor Outcome in Primary Mediastinal Lymphoma

Background:Primary mediastinal B-cell lymphoma (PMBCL) is clinically and biologically distinct from other types of aggressive lymphoma, it is characterized by a bulky mediastinal mass and most commonly occurs in women between 30 and 40 years of age. Although consolidation radiotherapy (RT) has yielded extremely positive outcomes in PMBCL, it carries a higher risk of long-term complications. Consequently, there has been an ongoing debate regarding the necessity of RT in patients responding to frontline immunochemotherapy. Methods:In the IELSG37 study, PMBCL 530 patients were treated with rituximab- and doxorubicin-containing regimens; 98% had stage I-II. Their response was assessed by positron emission computed tomography (PET/CT); 268 achieved a complete metabolic remission (CMR) defined as Deauville score (DS) 1 to 3 according to the Lugano classification and were randomly allocated to observation or mediastinal RT. The primary analysis [Zucca et al. J Clin Oncol 2023; 41 (suppl 17): abs. LBA7505] has shown that patients in CMR can safely forgo RT. The 3-year overall survival (OS) rate was 99% irrespective of irradiation. RT provided only minimal benefit on progression-free survival (PFS), which was over 96% at 3 years in both arms. Here we present the outcome of the 262 patients who were not randomized and were managed according to the preference of their treating physician. Results:Median follow-up was 64 months (interquartile range [IQR], 49-69). Besides 230 patients failing frontline treatment (174 DS4 and 56 DS5), the non-randomized cohort also included 1 patient with DS2 (who refused randomization and received RT) and 31 patients with DS3 who were initially considered as partial responders before a protocol amendment that changed the definition of CMR from DS 1-2 to DS 1-3. Among these non-randomized patients with DS3, 27 had RT consolidation, 1 was only observed, 2 had salvage chemotherapy ± RT, and 1 had missing data due to consent withdrawal; their 3-year PFS was very close to the one of the randomized patients with DS3 (90 vs 92%, p=0.99). In the DS4 group, 12 patients were observed, 149 had only RT, and 13 had second-line chemotherapy, with (12) or without (1) autologous stem cell rescue, 8 of 13 also had RT. Among the patients with DS5, only 2 were observed, 32 had only RT, and 22 had second-line chemotherapy, with (15) or without (7) autologous stem cell rescue; 12 of them also had RT. The outcome of patients with DS4 was overlapping the one of the patients achieving a CMR, with 3-year PFS of 97.1% (95%CI 93-99) and 97.4% (95%CI 95-99), respectively, while patients with DS5 had a significantly poorer 3-year PFS (62.4%, 95%CI 48-74) [Figure1A]. The 3-year OS showed a similar trend (98% in patients with DS4, 99% in those randomized, and 78% in the DS5 group). Notably, compared to patients receiving consolidation RT alone or only observed, the residual lesions on post-immunochemotherapy PET/CT scans of patients with DS4 and DS5 who were treated more aggressively (with salvage chemotherapy ± autologous transplant and/or RT) displayed significantly higher tracer maximum standardized uptake value (SUVmax, median: 8.2, IQR 4.6-16.5 vs. 3.8, IQR 3.1-4.9; p&amp;lt;0.0001) and larger residual metabolic tumor volume (MTV, median: 18 ml, IQR 3-95 vs. 3.6, ml, IQR 1-10; p&amp;lt;0.0001). These patients had significantly worse outcomes compared to those who received consolidation RT or were observed only [Figure 1B]. Conclusions:Patients with DS4 had outcomes similar to those of patients achieving a CMR, indicating that this group may either include a significant number of “false-positive” cases with inflammatory uptake or that their residual disease is limited and can potentially be cured with consolidation RT. Patients with DS5 had a significantly poorer outcome, although nearly half of them did well with RT alone. It seems plausible that clinical condition of the patient and/or imaging features of the residual disease have influenced treatment choices in patients without CMR after frontline immunochemotherapy. Further studies are needed to investigate whether PET metrics and/or liquid biopsies can aid in personalizing treatment and identifying patients who could potentially avoid irradiation.

Study of usefulness of speckle-tracking echocardiography in detecting left ventricular dysfunction among adult cancer patients undergoing chemotherapy

Objective: Cancer treatment-related cardiac dysfunction (CTRCD) is a significant concern for patients undergoing chemotherapy. The aim of the present study was to study the accuracy and value of longitudinal strain in prediction of left ventricular dysfunction (LVD) in cancer patients undergoing cancer therapy. Methods: This was a prospective observational study conducted among 183 adult patients undergoing chemotherapy between 2018 and 2020. Patients with congenital or acquired valvular disease, prior myocardial infarction, coronary revascularization, or cardiac surgery were excluded. The patients were evaluated using a detailed history, clinical examination and echocardiography at baseline, 1 month, 3 months, and 6 months after chemotherapy. Speckle-tracking strain analysis was used to evaluate left ventricular (LV) global longitudinal strain (GLS), circumferential strain (GCS), and radial strain (GRS). LVD was defined as &amp;qt;15% decrease in GLS, GCS, or GRS from baseline to 6 months. Accuracy of longitudinal strain in prediction of LVD was studied using ROC analysis. Results: Of the 183 patients, 59% were male, and 54.1% were between 46-60 years of age. Breast cancer was the most common malignancy (10.9%). The most common chemotherapy regimen was doxorubicin + paclitaxel (9.9%). At baseline, the mean GLS, GCS, and GRS were -18.6 (1.03)%, -20.4 (1.11)%, and 39.9 (6.09)%, respectively. At the 6-month follow-up, 27 (14.8%) patients had LVD. The incidence of LVD was higher (51.48%) in patients who received doxorubicin-containing regimens compared to non-doxorubicin-containing regimens (P &amp;lt;0.0001). GLS has good accuracy in prediction of LVD at 6 months of follow-up (88.37%). Conclusions: The incidence of LV dysfunction was higher (51.48%) in patients who received doxorubicin-containing regimens. GLS is different in LVD vs non LVD and the accuracy of GLS is more in prediction of LVD development during 6-month follow-up (88.37%).

Cardiovascular diseases in elderly survivors of diffuse large B-cell lymphoma: a Danish population-based cohort study

Diffuse large B-cell lymphoma is an aggressive disease occurring primarily in elderly patients. Despite high curative rates with doxorubicin-containing treatment, some elderly patients receive less intensive treatments, mainly due to advanced age, comorbidities, and concerns of cardiotoxicity from doxorubicin-containing regimens. We analyzed 1009 patients aged 75 years or older and 10,090 age- and sex-matched comparisons. We aimed to evaluate long-term cardiovascular side effects in elderly patients treated with doxorubicin. Approximately, 64% of patients received doxorubicin-containing treatment. These patients had a persistently increased risk of new-onset heart failure with a hazard ratio of 1.5 and 1.7 when conditioning on survival without heart failure to 6 and 24 months, respectively. Moreover, we observed an increased risk of venous thromboembolism during the first six months following the lymphoma diagnosis. On the contrary, no difference in risk of developing ischemic heart disease or stroke following doxorubicin-containing treatment was observed.

POSA410 Cancer Subtypes and Systemic Antineoplastic Treatment Utilization Among Patients with Advanced Breast Cancer Across Large Community Health Systems in the US

Community health systems (CHSs) play a large role in the care of patients with cancer with these systems treating over 50% of patients with cancer across the US. The cancer subtypes observed and systemic treatments used among patients with advanced breast cancer seen in these CHSs are not widely published. This analysis describes the cancer subtypes and systemic treatment utilization of these patients treated across a sample of CHSs. A retrospective analysis was performed utilizing the Syapse Learning Health Network (SLHN), electronic medical record (EMR) derived database that collects data from multiple care settings that make up the US CHSs across 33 states, 450+ hospitals and 1,900+ community employed oncologists. Patients >18 yo at advanced breast cancer diagnosis (IIIB+) from January 1, 2017 through June 22, 2021 were identified from the SLHN using ICD-10 codes. Data utilized for this analysis included both structured (set EMR fields like sex, birth date) and unstructured EMR data (physician notes) validated by Syapse’s Certified Tumor Registrars and then descriptively summarized. 1,763 patients from the SLHN with advanced disease (stage IIIB+) were included in the analysis. 54% of these patients were HR+/HER2-, 24% HR-/HER2-,12% HR+/HER2+, 7% HR-/HER2+ and 3% were unknown. 1,445 patients received systemic treatment; in the 1L setting 31% received a cyclophosphamide containing regimen, 29% a doxorubicin containing regimen, 21% for paclitaxel, 17% for letrozole, 15% for anastrozole, 15% for trastuzumab, 15% for pertuzumab, 14% for docetaxel, 14% for carboplatin and 12% for a palbociclib containing regimen. HR+/HER2- patients were the most common breast cancer subtype within this sample of CHSs patients which roughly correlates to SEER statistics of breast cancer subtypes. Patients with advanced breast cancer treated in the SLHN were most likely to receive a cyclophosphamide or a doxorubicin-containing regimen. Further analysis is planned to understand treatment patterns by cancer subtype.

Activation of the PI3K-AKT-mTOR cascade in uterine leiomyosarcoma: a retrospective study of 31 patients

Background. Taking into account the literature data, the activation of the PI3K-AKT-mTOR cascade plays a role in the development of leiomyosarcoma (LMS), and the expression of markers of this signaling pathway in the tumor is associated with a more aggressive course of the disease. In addition, there is some data on the effective use of mTOR inhibitors in LMS.&#x0D; Aim. To study the frequency of expression of mTOR and phospho-mTOR markers in relapse of high-grade uterine LMS and to evaluate the effect of phospho-mTOR expression on the immediate and long-term results of the use of doxorubicin-containing chemotherapy regimens and the combination of gemcitabine + docetaxel.&#x0D; Materials and methods. The study included 31 patients with high-grade uterine LMS operated on for relapse. IHC was performed using mTOR and phospho-mTOR antibodies on ready-made histological preparations of the surgical material. The expression level of these markers was estimated as a percentage from 0 to 100%. The immediate and long-term results of the most commonly used drug treatment regimens (doxorubicin-containing regimens and gemcitabine + docetaxel combinations) were analyzed depending on the level of phospho-mTOR expression in the tumor.&#x0D; Results. The expression of mTOR in the tumor was detected in 4 patients with an expression level from 1 to 2%, and the expression of phospho-mTOR was detected in 20 patients with an expression level from 1 to 70%. Median OS in the group without phospho-mTOR expression was 135 months, in the group with expression 104 months, p=0.732. When using doxorubicin-containing regimens in the group with phospho-mTOR expression, 12% of patients had a partial response (PR), median PFS was 26.7 months, in the group without expression there was no PR, median PFS was 8.7 months, p=0.67. When using a combination of gemcitabine + docetaxel, in the group with phospho-mTOR expression, 24% of patients had PR, median PFS was 11.1 months, in the group without expression, 14% of patients had PR, median PFS was 12.4 months, p=0.372.&#x0D; Conclusion. Phospho-mTOR expression was detected in 2/3 of patients with high-grade uterine LMS. There was no effect of the expression of this marker on the OS of all included patients and on PFS in patients who received chemotherapy according to the gemcitabine + docetaxel regime. There was a tendency to an increase in PFS in the group with phospho-mTOR expression in patients who received doxorubicin-containing chemotherapy regimens.

Assessment of early cardiotoxic adverse effects of doxorubicin-containing regimens in breast cancer patients

Abstract Funding Acknowledgements Type of funding sources: Public hospital(s). Main funding source(s): 1. Tehran University of Medical Sciences 2. Iran University of Medical Sciences Assessment of early cardiotoxic adverse effects of Doxorubicin-containing regimens in breast cancer patients. Abstract: Introduction BC is the most prevalent cancer among women and comprises about 30% of cancers in this population group1. Numerous patients with breast cancer (BC) require cardiotoxic anthracycline-based chemotherapy. Purpose We intended to assess the early cardiotoxic effects of doxorubicin utilizing cardiac magnetic resonance (CMR) imaging. Methods Frothy-nine patients including 21 otherwise healthy females with BC at a mean age (±SD) of 47.62 ± 9.07 years and 28 normal controls at a mean age (±SD) of 45.18 ± 4.29 years were recruited. BC cases underwent both CMR and TTE at baseline and seven days after four biweekly cycles of Doxorubicin and Cyclophosphamide. Functional, volumetric, and strain parameters, including global longitudinal (GLS), circumferential (GCS), and radial strain (GRS), were analyzed. The findings compared with those of 28 controls. Results In post-chemotherapy CMR, four patients (19.04%) displayed evidence of drug cardiotoxicity. Ventricular ejection fraction, left ventricular end-systolic volume index, and strain values significantly changed after chemotherapy (all Ps &amp;lt; 0.05). One patient (4.76%) had myocardial edema in post-chemotherapy CMR, and three patients (14.28%) had evidence of myocardial fibrosis. In the follow-up time of 4 to 10 months (mean: seven months) after chemotherapy, eight patients (38.09%) complained of dyspnea on exertion and fatigue. None of the CMR parameters had any correlation with the evolution of symptoms. Conclusion We demonstrated a significant difference in ventricular ejection fraction and global strain values early after Doxorubicin chemotherapy. Exclusive CMR parameters can aid in the early initiation of preventive cardiac strategies.

Prognosis of follicular lymphoma: a predictive model based on a retrospective analysis of 987 cases

Patients (n-987) with a histologically confirmed diagnosis of follicular lymphoma were studied with the aim of developing a prognostic model specifically devised for this type of lymphoma. We collected information on age, sex, Ann Arbor stage, number of extranodal disease sites, bone marrow (BM) involvement, bulky disease, B symptom criteria (fever, night sweats, and weight loss), performance status (PS), serum lactate dehydrogenase (LDH) level, serum albumin level, hemoglobin level, and erythrocyte sedimentation rate (ESR). In the training sample of 429 patients with complete data, multivariate analysis showed that age, sex, number of extranodal sites, B symptoms, serum LDH level, and ESR were factors predictive for overall survival. Using these 6 variables, a prognostic model was devised to identify 3 groups at different risk. The 5- and 10-year survival rate was 90% and 65% for patients at low risk, respectively; 75% and 54% for patients at intermediate risk; and 38% and 11% for those at high risk (log-rank test, 86.62; P <. 0001). The model was also predictive (P =.0001) in the validation sample of 265 patients with complete data only for the 6 variables used in the development of the model and even in the group of 210 patients from the validation sample uniformly treated with doxorubicin-containing regimens (P =.0001). The prognostic model appears to be very useful in identifying patients with follicular lymphoma at low, intermediate, or high risk.

Chemotherapy with a Pegylated Liposomal Doxorubicin-Containing Regimen in Newly Diagnosed Hodgkin Lymphoma Patients.

Anthracycline-related cardiotoxicity is an important dose-limiting toxicity for Hodgkin lymphoma (HL) treatment. This study aimed to assess the efficacy and safety of pegylated liposomal doxorubicin (PLD) for HL treatment. Patients with newly diagnosed HL treated with at least two cycles of PLD-containing chemotherapy were retrospectively analyzed. The dosing and scheduling of the PLD-containing regimen (the PBVD regimen) were as follows: PLD 25mg/m2, vincristine 1.4mg/m2 (maximum dose of 2mg), bleomycin 10mg/m2, and dacarbazine 375mg/m2 at days l and 15, repeated every 28days. Forty-six HL patients were analyzed. The median age was 41.5years (range 12-77years), with a male/female ratio of 0.9:1. Fourteen (30%) patients had an Eastern Cooperative Oncology Group (ECOG) performance status score > 1, and 32 (70%) had a history of cardiovascular disease (CVD) or related risk factors. The median chemotherapy cycle number with the PBVD regimen was 6 (range, 2-8). The overall response rate (ORR) was 91% for the whole cohort; 35 (76%) patients achieved complete remission (CR), and 7 (15%) achieved partial remission. The efficacy of the PBVD regimen was similar in patients with or without CVD or related risk factors (ORR 93% vs. 91%, P = 1.00; CR 86% vs. 72%, P = 0.46). With a median follow-up of 28.5months, the 3-year progression-free survival (PFS) and overall survival (OS) rates were 70% and 82%, respectively, for the whole cohort. The differences in the PFS and OS rates between the groups with or without CVD or related risk factors were not significant. Cardiotoxicity was observed in 6 (13%) patients. All adverse events were grades 1-2. The PBVD regimen is an effective chemotherapy option with tolerable toxicity, and it could be a substitute in HL patients who cannot be treated with conventional doxorubicin, especially those with CVD or related risk factors.

Primary Cardioprotection Reduces Mortality in Lymphoma Patients with Increased Risk of Anthracycline Cardiotoxicity, Treated by R-CHOP Regimen

Background: Advances in anti-lymphoma therapy prolong overall survival, making late adverse effects, like doxorubicin-related cardiotoxicity, an even more important clinical issue. The effectiveness of cardioprotective strategies with close monitoring, angiotensin-converting enzyme inhibitors and/or β-blockers as well as liposomal doxorubicin are still unconfirmed in clinical practice. Methods: This study evaluated the role of a primary cardioprotection strategy in preventing cardiovascular mortality and heart failure occurrence in non-Hodgkin lymphoma (NHL) patients with a high risk of anthracycline cardiotoxicity. Thirty-five NHL patients were subjected prospectively to ramipril and/or bisoprolol at NHL diagnosis, before implementing doxorubicin-containing regimens. Additionally, patients with a diagnosis of asymptomatic/mild heart failure received the liposomal form of doxorubicin. The clinical outcome and frequency of all serious cardiac events were compared with the results in a historical cohort of 62 high-risk cases treated without primary cardioprotection. Results: NHL patients with a primary cardioprotection strategy did not experience cardiovascular deaths in contrast to the retrospective control group where cardiovascular mortality was 14.5% at 3 years (p < 0.05). Primary cardioprotection also decreased the frequency of new cardiotoxicity-related clinical symptoms (2.8 vs. 24.1%; p < 0.05) and prevented the occurrence of cardiac systolic dysfunction (0 vs. 8.5%, respectively; p < 0.05). Although the study was not planned to detect any survival benefit, it demonstrated a trend towards increased response rates (complete response 82 vs. 67%; p not significant) and prolonged survival (projected 5-year overall survival 74 vs. 60%; p < 0.05) for patients treated with primary cardioprotection. Conclusions: A primary personalized cardioprotection strategy decreases the number of cardiac deaths and may potentially prolong overall survival in NHL patients with increased risk of anthracycline cardiotoxicity.

A prospective cohort study of patients with peripheral T-cell lymphoma in the United States.

Long-term survival in patients with aggressive peripheral T-cell lymphoma (PTCL) is generally poor, and there currently is no clear consensus regarding the initial therapy used for these diseases. Herein, the authors analyzed treatment patterns and outcomes in a prospectively collected cohort of patients with a new diagnosis of nodal PTCL in the United States. Comprehensive Oncology Measures for Peripheral T-cell Lymphoma Treatment (COMPLETE) is a prospective multicenter cohort study designed to identify the most common prevailing treatment patterns used for patients newly diagnosed with PTCL in the United States. Patients with nodal PTCL and completed records regarding baseline characteristics and initial therapy were included in this analysis. All statistical tests were 2-sided. Of a total of 499 patients enrolled, 256 (51.3%) had nodal PTCL and completed treatment records. As initial therapy, patients received doxorubicin-containing regimens (41.8%), regimens containing doxorubicin plus etoposide (20.9%), other etoposide regimens (15.8%), other single-agent or combination regimens (19.2%), and gemcitabine-containing regimens (2.1%). Survival was found to be statistically significantly longer for patients who received doxorubicin (log-rank P = .03). After controlling for disease histology and International Prognostic Index, results demonstrated a trend toward significance in mortality reduction in patients who received doxorubicin compared with those who did not (hazard ratio, 0.71; 95% confidence interval, 0.48-1.05 [P = .09]). To the authors' knowledge, there is no clear standard of care in the treatment of patients with PTCL in the United States. Although efforts to improve frontline treatments are necessary, anthracyclines remain an important component of initial therapy for curative intent. Cancer 2017;123:1174-1183. © 2016 American Cancer Society.

Facteurs de risque et surveillance à long terme des complications cardiaques après traitement pour un cancer pendant l’enfance

Anthracycline-induced cardiotoxicity (ACT) is a severe complication in children and young adults that may lead to congestive heart failure. Some risk factors have been identified: high anthracycline cumulative dose, high radiation dose delivered on the cardiac area, or young age during the treatment. Primary prevention is not clearly defined in children. The dexrazoxane iron chelator seems to be interesting based on its short-term cardioprotective property in patients receiving doxorubicin-containing regimens. However, its long-term benefits remain to be determined, as well as the risk of secondary cancer. Childhood cancer survivors treated with anthracyclines are annually followed in the long-term. Trans-thoracic echocardiography is classically performed every 2 to 5 years for assessing the ventricular hemodynamics and function. Recent modern techniques including echocardiography with strain assessment and cardiac MRI seems to be promising for an early detection of myocardial impairment. Further studies are mandatory for validating their usefulness in the setting of anthracycline-induced cardiomyopathy. Recently, ACT predisposing variants in genes involved in oxydative stress and in metabolism and transport of anthracyclines have been identified. Their use in clinical practice could improve ACT risk stratification of children treated with anthracyclines-containing regimens. Predictive models combining replicated genetic variants and clinical factors need to be validated with the challenge to identify patients at high risk of cardiomyopathy. The objective is to personalize treatment strategy according to individual genetic background.

Liposomal doxorubicin in patients with breast cancer and concomitant cardiovascular diseases - interdisciplinary expert opinion

The use of liposomal doxorubicin in place of conventional form can significantly reduce the risk of clinically important cardiovascular complications of chemotherapy. The use of liposomal doxorubicin-containing regimen seems to be the most justified in treatment of breast cancer patients with coexisting cardiovascular diseases. The document defines the possible clinical scenarios for the use of chemotherapy with liposomal doxorubicin and presents the optimal cardiac monitoring of this therapy.

Retrospective analysis of the survival benefit of chemotherapy for recurrent or advanced epithelial ovarian carcinoma in patients previously treated with paclitaxel plus platinum-based chemotherapy.

The outcomes of treatment for women with recurrent or advanced epithelial ovarian carcinoma previously treated with pacli- taxel plus platinum-based chemotherapy were analyzed. Retrospective analysis was performed in a total of 65 series of treatments provided for 35 patients with a history of paclitaxel plus platinum-based chemotherapy. The chemotherapy regimens used were classified into the following four types for analysis: conventional paclitaxel plus carboplatin therapy (TC arm), pegylated liposomal doxorubicin-containing regimens (PLD arm), CPT-11-containing regimens (CPT-11 arm), and others. Disease-control rates (DCRs) were compared and subjected to univariate analysis. Progression-free survival (PFS) was determined from the date of the first cycle of each chemotherapy with the Kaplan-Meier method, and comparisons were performed using the log-rank test. DCR was 80%, 71%, and 26% for the TC, PLD, and CPT-l arms, respectively. The median PFS was 286, 372, and 76 days for the TC, PLD, and CPT-11 arms, respectively. There was no discernible difference in PFS between the TC and the PLD arm. In contrast, PFS of the CPT- 11 arm was significantly shorter than that of the TC and PLD arms. In addition, three of seven (42.9%) treatments in the PLD arm maintained a progression-free period for longer than one year, while only one of 25 (4%) treatments in the TC arm maintained a progression-free period for more than one year. The PFS of PLD is similar to that of TC. PLD-containing regimens might have a potential benefit with a higher PFS over one year than the TC regimen.

FOXO1 is a TXN- and p300-dependent sensor and effector of oxidative stress in diffuse large B-cell lymphomas characterized by increased oxidative metabolism.

Molecular profiling has led to identification of subtypes of diffuse large B-cell lymphomas (DLBCLs) differing in terms of oncogenic signaling and metabolic programs. The OxPhos-DLBCL subtype is characterized by enhanced mitochondrial oxidative phosphorylation. As increased oxidative metabolism leads to overproduction of potentially toxic reactive oxygen species (ROS), we sought to identify mechanisms responsible for adaptation of OxPhos cells to these conditions. Herein, we describe a mechanism involving the FOXO1-TXN-p300 redox-dependent circuit protecting OxPhos-DLBCL cells from ROS toxicity. We identify a BCL6-dependent transcriptional mechanism leading to relative TXN overexpression in OxPhos cells. We found that OxPhos cells lacking TXN were uniformly more sensitive to ROS and doxorubicin than control cells. Consistent with this, the overall survival of patients with high TXN mRNA expression, treated with doxorubicin-containing regimens, is significantly shorter than of those with low TXN mRNA expression. TXN overexpression curtails p300-mediated FOXO1 acetylation and its nuclear translocation in response to oxidative stress, thus attenuating FOXO1 transcriptional activity toward genes involved in apoptosis and cell cycle inhibition. We also demonstrate that FOXO1 knockdown in cells with silenced TXN expression markedly reduces ROS-induced apoptosis, indicating that FOXO1 is the major sensor and effector of oxidative stress in OxPhos-DLBCLs. These data highlight dynamic, context-dependent modulation of FOXO1 tumor-suppressor functions via acetylation and reveal potentially targetable vulnerabilities in these DLBCLs.

Pre-Clinical Investigation of Targeted Therapies for Double Hit Diffuse Large B-Cell Lymphoma (DH-DLBCL)

Background: Molecular studies divide DLBCL into three subtypes with distinct pathogenesis and clinical outcomes: activated B-cell (ABC), germinal center B-cell (GCB) and primary mediastinal lymphoma (PML). Florescence in situ hybridization (FISH) studies identified another subgroup of DLBCL, classified as DH-DLBCL, with a poor clinical outcome harboring concurrent gene rearrangements of the c-MYC, BCL2 and/or BCL6 proto-oncogenes, resulting in the over-expression of c-Myc, Bcl2 and Bcl6 proteins. DH-DLBCL has inferior response rates (RR) to rituximab-based chemotherapy, and a shorter progression-free survival (PFS)/overall survival (OS). DH-DLBCL is characterized by de-regulation of apoptosis and cell cycle progression, resulting in rapid cellular proliferation and resistance to apoptotic stimuli. In ABC-DLBCL, anti-apoptotic factor MCL-1 is implicated in poor prognosis leading to resistance to standard chemotherapy. C-MYC transcriptionally upregulates Mcl1. Translocation of c-MYC in DH-DLBCL may contribute to the aggressive phenotype and chemotherapy resistance via the MCL-1 pathway. We hypothesize that dual inhibition of both anti-apoptotic proteins BCL2 and MCL1 is an effective strategy in inducing lymphoma cell death in DH-DLBCL.Materials & Methods: At the pre-clinical level, we studied novel therapeutic strategies targeting key-regulatory pathways abnormally enhanced by the dual BCL2/BCL6 and c-MYC gene rearrangements or amplification using DH lymphoma cell lines (Val, DOHH-2, ROS-50). We evaluated the therapeutic value of three novel agents targeting BCL2 (ABT199), c-MYC (JQ-1), and cell cycle regulatory proteins (p21) and other BCL2 family members affecting ABT199 activity (carfilzomib (CFZ), an irreversible proteasome inhibitor) in a panel of DH-DLBCL cell lines. We retrospectively evaluated our single institution outcome experience over the last 15 years in DH-DLBCL patients. Using the lymphoma translational database that includes 611 DLBCL patients, we identified 30 patients (M=17/F=13) with aberrations in c-MYC and BCL2 or BCL6 by FISH. Demographic characteristics and clinical data were collected and analyzed.Results: In vitro, ABT199, JQ-1, and CFZ induced cell death in a dose- and time-dependent manner. Significant synergistic activity was observed by combining ABT199 with CFZ and to a lesser degree with JQ-1. Subsequently, we studied the outcome of DHL patients treated at our institute. Mean age at diagnosis was 63 years, mostly Caucasians (N=28). Using the Han's algorithm, 21 of the DH-DLBCL were GCB, 8 were non-GCB, and 1 unclassifiable. 22 patients had rearrangement of c-MYC and BCL2/ or BCL-6 by FISH and 8 had gain/amplification/aneuploidy at these loci. At diagnosis, 96% (n=29) patients presented with stage III/IV, 67% (n=20) with High-intermediate/High IPI score, and 77% (n=23) had extra nodal disease. Front-line chemo-immunotherapy included 1) standard doxorubicin-containing regimens: R-CHOP (N=11) or R-EPOCH (N=8), or 2) intensified regimens: R-DHAC (N=3) and R+HyperCVAD/R+HDMTXCytarabine (N=8). Prophylaxis IT chemotherapy was administered to 21 (70%) patients. The complete remission (CR) rate was 67% (n=20) and 37% (n=11) patients underwent HDC-ASCS (N=9)/allo-BMT (N=2) in first (N=9) or second-remission (N=2). The use of intensified regimens was associated with a non-statistically significant improvement is PFS and OS. Similarly, an improvement in OS was observed among patients receiving HDC-ASCT/allo-BMT as consolidation. As previously noted, CNS prophylaxis was associated with an improvement in OS. Mcl-1 and other Bcl-2 family members expression levels are been determined by IHC. These results highlight the poor clinical outcome of this patient population and the need for alternative therapeutic options.Conclusion: Our data suggests that ABT199 exhibited strong synergistic activity with CFZ. Dual targeting of BCL2 and c-MYC pathways results in synergistic activity in DHL cell lines. Of interest, this pharmacological interaction could be related to the effects of proteasome inhibition on MCL1 and p21 levels in lymphoma cells, further enhancing the activity of ABT199. Using combination therapy to inhibit c-MYC and the proteasome and in turn decreasing MCL1 will render ABT-199 more effective and be a more potent combination in causing apoptosis and lymphoma cell death. Further pre-clinical work is ongoing. DisclosuresNo relevant conflicts of interest to declare.

Intense Cytarabine-Based Chemo-Immunotherapy, Central Nervous System (CNS) Prophylaxis and Early High-Dose Chemotherapy and Autologous Stem Cell Support (HDC-ASCS) in First Remission Are Associated with an Improved Clinical Outcome in Double-Hit (DHL)/Triple-Hit (THL) Diffuse Large B-Cell Lymphoma (DLBCL)

Based on molecular studies, DLBCL is now further divided in three subtypes with distinct pathogenesis and clinical outcomes. Fluorescence in situ hybridization (FISH) studies identified a subgroup of DLBCL with a poor clinical outcome harboring concurrent gene rearrangements of the MYC, BCL2 and/or BCL6 proto-oncogenes leading to the over-expression of c-Myc, Bcl-2 and Bcl-6, inferior response rates to rituximab-based chemotherapy, and a shorter progression-free survival (PFS)/overall survival (OS). This group of patients is now categorized as double-hit (DHL) or triple-hit (THL) DLBCL. Immunohistochemistry (IHC) studies suggested that DLBCL patients with over-expression of Bcl-2 and c-Myc proteins exhibit a similar clinical course than those patients with DHL/THL. Alternative transcriptional (i.e. gene amplification or chromosomal gain) or post-translational regulatory mechanisms (yet to be defined) may be responsible for the over-expression of c-Myc, Bcl-2, or Bcl-6 in some patients with DHL/THL phenotype. The appropriate therapy for DHL/THL remains to be defined, but retrospective studies had demonstrated that at standard doses of R+CHOP are suboptimal. In order to study the impact of more aggressive therapeutic approaches in the management of DHL/THL, we retrospectively evaluated our single institution outcome experience over the last 14 years. Using the lymphoma translational database that includes 611 DLBCL patients, we identified 24 patients (M=13/F=11) (4%) with FISH-confirmed DHL/THL DLBCL. Demographic characteristics, clinical data, treatment history in the front line (including the use of CNS prophylaxis, high-dose chemotherapy and autologous stem cell support [HDC-ASCS] or allogeneic bone marrow transplant [allo-BMT]) were collected. In addition, response rate, PFS and OS were calculated. Since the first case-reports were published, we observed a steady increase in the number of DHL/THL patients at our Institution (7 vs. 18 cases before or after 2011) which represents an increasing medical awareness of this new clinical entity. The mean age at diagnosis was 62 years (25 to 85 years), most of them Caucasians (N=22). The median Ki67 proliferation index was 90%. Using the Han’s algorithm, 11 of the DHL/THL were categorized as germinal center B-cell like (GCB), 6 patients as non-GCB, and 7 patients could not be classified. By FISH studies, 58% were DHL (involvement of MYC and BCL2 [N=22] or BCL6 [N=10]) and 42% THL (involvement of MYC, BCL2 and BCL6, N=10). Gene rearrangements involving MYC, BCL2, or BCL6 were observed in 18 patients and MYC, BCL2 or BCL6 gain in 6. Clinically, 95% of the patients presented with stage III/IV, 67% with High-intermediate/High IPI score, and 79% of the patients had extranodal disease. Front-line chemo-immunotherapy included 1) standard doxorubicin-containing regimens: R+CHOP (N=10) or R-EPOCH (N=7), or 2) intensified regimens: R-DHAC (N=2) and R+HyperCVAD/R+HDMTXCytarabine (N=4). Prophylaxis IT chemotherapy was administered to 16 (67%) patients. The complete remission (CR) rate was 62.5% and 29% of the patients underwent HDC-ASCS (N=4)/allo-BMT (N=2) in first (N=2) or second-remission (N=4). In this group of patients, the use of intensified regimens was associated with a non-statistically significant improvement is OS when compared to R+CHOP/R+DA-EPOCH (OS at 3 years of 85.7% vs. 58%). Similarly, an improvement in OS was observed among patients receiving HDC-ASCT/allo-BMT as consolidation (71% vs. 60%, P=0.27). Of interest, CNS prophylaxis was associated with an improvement in OS at 3 years (81% vs. 37%, P=0.032). No differences in clinical outcomes were observed between DHL/THL harboring gene-rearrangements vs. gene gain. In summary, our single institution experience suggests that DHL/THL are increasingly being recognized as more aggressive sub-types of DLBCL with a dismal outcome with conventional therapeutic approaches. A high-index of suspicion should be raised and testing for DHL/THL in those DLBCL presenting with advance stage, multiple extra-nodal site of disease, and an elevated Ki67 index should be done. The accurate identification of DHL/THL patients is necessary, as they appear to benefit from rituximab-based intensified cytarabine-containing regimens, CNS prophylaxis and HDC-ASCT/allo-BMT consolidation. DisclosuresNo relevant conflicts of interest to declare.

P5-01-05: Activating Mutations in PIK3CA or AKT1 in the I-SPY 1 Trial (CALGB 150007/150012; ACRIN 6657).

Abstract Background Mutations in the catalytic domain of phosphatidylinositol 3-kinase (PIK3CA) are among the most frequently observed activating mutations in breast cancer. We used the I SPY 1 TRIAL, a group of biologically and clinically high risk patients molecularly profiled and treated with neoadjuvant chemotherapy, to determine the frequency of mutations and their relationship to pathologic complete response (pCR) and outcomes, within the entire cohort and within subtypes defined by growth and hormone receptor (HR) expression. Methods: Patients enrolled in the I-SPY 1 TRIAL had a tumor size ≥3.0cm and were administered a doxorubicin-containing regimen, followed by a taxane, prior to surgery. Sequenom single nucleotide polymorphism (SNP) profiling was performed on breast tumor genomic DNA isolated from a subset of patients (n=152). A total of 149 SNPs covering 16 genes (including PIK3CA and AKT1/2/3) were analyzed. Mutations were tested for association with estrogen receptor (ER), progesterone receptor (PgR), and HER2 status, as well as pCR, using Fisher's exact test; associations between mutations and recurrence-free survival (RFS) were measured by log-rank tests. pCR was defined as no invasive tumor present in either the breast or axillary lymph nodes following neoadjuvant treatment. Results: Of 149 mutations profiled in the cohort, 13 of the SNPs were observed. PIK3CA mutations were the most frequently observed in the panel (15.1%), followed by AKT1(E17K; 2.7%), CTNNB1 (D32; 1.4%), NRAS(Q61; 0.7%), and FGFR2(N549; 0.7%). Mutations in PIK3CA or AKT1 was associated with ER-positivity (p=0.0047) and PgR-positivity (p=0.044). Within receptor subtypes, the frequencies of PIK3CA/AKT1 mutations were also significantly different (HR+HER2−: 27%:(18/68); HER2+ 20% (8/40) [HR+HER2+: 26%, HR-HER2+: 14%]; HR-HER2−: 0% (0/36), p&amp;lt;0.0008). Unlike previous reports (Loi et al, PNAS 2010), no significant association between PIK3CA/AKT mutation status and RFS was observed when we restricted our analysis to the adjuvant endocrine treated subset of the HR+HER2− patients (n=49; log rank p = 0.369). In contrast, and similar to cell line reports (Junttila et al, Cancer Cell 2009), PIK3CA mutations appears to associate with worse RFS within the small subset of trastuzumab treated HER2+ patients (n=22, 13 HR-HER2+, 9 HR+HER2−; log rank p=0.001), suggesting mutations may influence response. Similar analyses of a larger cohort are planned to confirm these observations. Conclusions: Within the I-SPY 1 TRIAL cohort, PIK3CA and AKT1 mutations are much more frequent in the HR+ and HER2 subsets but are not predictive of response to therapy or outcome except potentially within the HER2+ subset. The potential link observed between activating PIK3CA/AKT mutations and trastuzumab resistance merits further investigation, as it may provide a clinical rationale for testing PIK3CA mutation status in HER2+ patients and investigating combinational therapies targeting this pathway, particularly in the HER2+HR+ subset which have an elevated risk for recurrence despite pCR and trastuzumab therapy. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-01-05.