Use Of Multiagent Chemotherapy Research Articles

The impact of a bloodless medicine program on pancreatic resections: A single-institution experience incorporating patients with borderline-resectable and locally advanced pancreatic cancer

BackgroundPatients undergoing pancreatic resection who decline blood transfusion represent a clinical challenge. While bloodless medicine programs are valuable, their impact remains unclear, especially for those with borderline-resectable and locally advanced pancreatic ductal adenocarcinoma (PDAC). MethodsRetrospective review of institutional databases identified patients who did not accept blood transfusion and underwent pancreatic resection from 2013–2022. We collated hemoglobin values, interventions to minimize symptomatic anemia, and patient outcomes. ResultsThirteen patients were identified. Median age was 63 years (range: 52–75 years) and eight (61.5 %) were female. All procedures were performed electively for invasive malignancy with PDAC as the most common diagnosis (11/13; 84.6 %) and pancreaticoduodenectomy as the most common procedure (11/13; 84.6 %). Vascular involvement was common in the 11 patients with PDAC (borderline-resectable: 7/11; 63.6 % and locally advanced: 3/11; 27.3 %), as was the use of multi-agent chemotherapy (n = 10) and preoperative radiotherapy (n = 8) prior to surgery. Median blood loss was 400 mL (range: 100–2200 mL). Intraoperative measures included acute normovolemic hemodilution in one patient and red blood cell salvage in three patients. Median preoperative hemoglobin was 12.3 g/dL (range: 10.3–14.2 g/dL) and median nadir hemoglobin was 9.2 g/dL (range: 5.2–11.8 g/dL). Median hospital stay was 10 days (range: 6–42 days). Thirty-day mortality was 0 % and one-year overall survival was 69.2 % with median follow-up of 26.4 months. ConclusionPancreatic resections can be performed safely in patients who decline blood transfusion, even with borderline-resectable and locally advanced PDAC. Avoiding transfusions and employing blood-conservation techniques does not appear to detrimentally impact survival.

Effect of Age and Socioeconomic Factors in the Utilization of Chemotherapy in Acute Lymphoblastic Leukemia (ALL): A SEER Database Study of 16,196 Patients.

The use of multiagent chemotherapy in acute lymphoblastic leukemia (ALL) has resulted in improvement in overall survival (OS), albeit to a different extent across various age groups. This large database study aims to assess the disparity in the utilization of chemotherapy in ALL in the real-world setting. Using the Surveillance, Epidemiology, and End Results database, patients with ALL diagnosis from 2006 to 2016 were identified. Baseline characteristics were compared between the groups who did vs. did not receive chemotherapy using χ2 test. Multivariable logistic regression was used to evaluate the association between various sociodemographic factors and the receipt of chemotherapy in the entire cohort and in different age groups. Out of 16,196 patients, 1258 patients (8%) did not receive chemotherapy. There was a steady increase in the number of patients who did not receive chemotherapy with advancing age: 2.5% (0-18 years), 5.2% (19-40 years), 9.3% (41-65 years), and 36.2% (>65 years). There was an upward trend in the receipt of chemotherapy in patients >65 years over the last decade. In multivariate analysis, the likelihood of receiving chemotherapy decreased with advancing age, single or widowed status, low income and educational status, and lack of insurance. Insurance status was an independent predictor of receipt of chemotherapy across each age category. A significant proportion of patients >65 years do not receive chemotherapy in the United States. Age, marital status, income, education, and insurance status contribute to the disparity in utilization of chemotherapy.

Determinants of ten-year overall survival of acute myeloid leukemia: a large national cancer database analysis

Clinical trials do not routinely capture long-term overall survival (OS) in acute myeloid leukemia (AML). We utilized a large National Cancer Database (NCDB) to determine different factors affecting 10-year OS in AML. For patients, 18–59 years who were treated with chemotherapy only without upfront hematopoietic cell transplant (HCT), younger age, female, CBF AML, higher income, and private insurance conferred higher 10-year OS. Among patients, 18–59 years treated with chemotherapy and upfront HCT, younger age and private insurance conferred higher 10-year OS. In a Cox proportional hazard model, the likelihood of death decreased with younger age, fewer comorbidities, treatment at an academic center, private insurance, and use of multiagent chemotherapy. Our results demonstrate poor long-term OS even among younger patients and highlights disparities in leukemia care based on insurance type.

Safety and Effectiveness of a Pharmacist-Driven High-Dose Methotrexate Monitoring Protocol at an Academic Medical Center

Introduction: High-dose methotrexate (HD-MTX) requires extensive monitoring and implementation of supportive care strategies to prevent associated toxicities. Although monitoring protocols for MTX vary across institutions, standardized supportive care measures can improve treatment outcomes. The purpose of this study was to evaluate the impact of a pharmacist-driven monitoring protocol on management of patients with delayed MTX elimination.Methods: This was a single-center, retrospective analysis that included hospitalized adult cancer patients receiving HD-MTX therapy (≥ 1 g/m 2). The study consisted of a pre-protocol group (August 2014 to July 2017) and a post-protocol group (August 2017 to August 2020). Patients were included in the analysis more than once if they had a repeat but separate hospital encounter. The primary outcome measure was to compare the rate of appropriate leucovorin dosage adjustments, defined by adherence to institution-specific HD-MTX monitoring guidelines, before and after protocol implementation (Table 1). Secondary outcomes included MTX concentrations at 24, 48, and 72 hours; time to MTX elimination; evidence of delayed MTX clearance; urine pH; length of stay; drug-drug interactions; and incidence of toxicities. Group comparisons for continuous data were made using Mann-Whitney U test and Chi-square or Fisher's exact test was used for categorical data. A p-value of < 0.05 was used to indicate significance.Results: Of 272 hospital encounters initially identified, 82 pre-protocol encounters and 59 post-protocol encounters were included in the analysis. Thirty-five percent of patient encounters in the pre-protocol group were excluded as a result of inappropriately timed methotrexate levels compared to only 9% in the post-protocol group, indicating improved MTX monitoring after protocol implementation. Baseline characteristics are summarized in Table 2. The most common malignancy was primary CNS lymphoma (53.8%) followed by non-Hodgkin lymphoma (28.8%). HD-MTX monotherapy was the most common regimen used in the pre-protocol group (57.1%) whereas combination therapy with rituximab +/- procarbazine was the most common regimen used in the post-protocol group (62.5%). Twenty-one encounters in the pre-protocol group and 22 encounters in the post-protocol group required leucovorin dose escalations at 24, 48, or 72 hours (Table 3). Following the implementation of the pharmacist-driven protocol, the rate of appropriate leucovorin dose adjustments increased significantly from 61.9% to 90.9% (p = 0.034). The median methotrexate concentration at 48 and 72 hours was higher in the post-protocol group when compared to the pre-protocol group. [0.22 µM/L vs.0.18 µM/L (p = 0.019) and 0.1 µM/L vs. 0.07 µM/L (p < 0.001), respectively]. Median time to methotrexate elimination was slightly longer in patients managed according to the MTX protocol [73 hours vs. 72.4 hours, p = 0.022] with higher rates of delayed clearance noted in these patients [18 (30.5%) vs. 16 (19.5%), p < 0.001]. There were no statistically significant differences in length of stay, urine pH, or drug-drug interactions between the two groups during methotrexate therapy (Table 4). However, a lower percentage of concomitant drug interactions with methotrexate were identified after protocol implementation, suggesting improved drug interaction screening [29 (49.2%) vs. 53 (64.9%), p = 0.857]. Rates of toxicities are shown in Table 5. The post-protocol group experienced a higher incidence of any-grade hyperbilirubinemia [20 (33.9%) vs. 18 (22%), p = 0.019], encephalopathy [10 (17%) vs. 5 (6.1%), p = 0.043], and grade ≥ 3 neutropenia [4 (6.8%) vs. 4 (4.9%), p = 0.009]. These differences in toxicity rates may in part be due to more frequent use of multi-agent chemotherapy in the post-protocol group and greater number of MTX cycles administered to these patients. The incidence of nephrotoxicity was similar in both groups (6 (7.3%) vs. 5 (8.5%), p= 0.493) and in line with previous reports.Conclusion:The implementation of a pharmacist-driven HD-MTX monitoring protocol improved optimal timing of MTX serum concentrations, resulted in a statistically significant improvement in the rate of appropriate leucovorin dose escalations, and led to enhanced detection of drug interactions. These findings demonstrate the important role pharmacists can play in dosing and monitoring high-risk regimens. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

The perplexing role of immuno-oncology drugs in osteosarcoma

Osteosarcoma is a rare, primary tumour of bone. Curative treatment consists of multi-agent chemotherapy and complete surgical resection. Despite the use of multi-agent chemotherapy, the risk of recurrence is high. Survival outcomes for patients with osteosarcoma have not changed since the 1980′s. Based on biologic rationale, there has been interest in adding immunotherapies to upfront curative intent chemotherapy, including mifamurtide (a macrophage activator) and interferon. However, results to date have been disappointing. In the metastatic setting, checkpoint inhibitors alone have not proven effective. Ongoing translational work is needed to further understand which patients may benefit from immune-oncology approaches with standard cytotoxic chemotherapy.

Hyper-CVAD in 2021: Lessons Learned and New Approaches

AbstractThe hallmark of acute lymphoblastic leukemia (ALL) treatment is the use of multi-agent chemotherapy based on a backbone including vincristine, anthracyclines, and corticosteroids. Hyper-fractionated cyclophosphamide, vincristine, adriamycin, and dexamethasone (hyper-CVAD) alternating with high-dose methotrexate (MTX) and cytarabine for a total of an 8-intensive-course regimen, developed at MD Anderson Cancer Center in 1992,1,2 was inspired by a Burkitt lymphoma regimen developed in the 1980s by the pediatric oncology group at St. Jude Children’s Research Hospital and incorporated basic therapeutic principles of pediatric regimens, with reduced reliance on asparaginase during remission induction.3 The initial regimen, limited by infectious complications, induction mortality, and high rates of relapse in select populations have since been modified to improve outcomes and safely incorporate the newest agents in the anti-leukemic armamentarium. These changes, which include modifying maintenance and intensification therapy, incorporating novel monoclonal antibodies, BCR-ABL1 tyrosine kinase inhibitors (TKIs), and the use of growth factors, have resulted in improved complete remission rates, overall survival, and decreased induction mortality.4–9

Personalized Medicine for Neuroblastoma: Moving from Static Genotypes to Dynamic Simulations of Drug Response.

High-risk neuroblastoma is an aggressive childhood cancer that is characterized by high rates of chemoresistance and frequent metastatic relapse. A number of studies have characterized the genetic and epigenetic landscape of neuroblastoma, but due to a generally low mutational burden and paucity of actionable mutations, there are few options for applying a comprehensive personalized medicine approach through the use of targeted therapies. Therefore, the use of multi-agent chemotherapy remains the current standard of care for neuroblastoma, which also conceptually limits the opportunities for developing an effective and widely applicable personalized medicine approach for this disease. However, in this review we outline potential approaches for tailoring the use of chemotherapy agents to the specific molecular characteristics of individual tumours by performing patient-specific simulations of drug-induced apoptotic signalling. By incorporating multiple layers of information about tumour-specific aberrations, including expression as well as mutation data, these models have the potential to rationalize the selection of chemotherapeutics contained within multi-agent treatment regimens and ensure the optimum response is achieved for each individual patient.

Outcomes for relapsed versus resistant low risk gestational trophoblastic neoplasia following single-agent chemotherapy

ObjectiveTo compare outcomes for relapsed versus resistant low risk gestational trophoblastic neoplasia (GTN) following single-agent chemotherapy. MethodsThis was a single center retrospective study of low risk GTN. Cases failing to achieve a normal hCG with first-line therapy were defined as chemotherapy resistance. Cases achieving hCG remission, but recurring, were defined as relapse. Primary endpoints were remission rate with second-line therapy and time to remission. Univariate and multivariate analyses were performed to define prognostic factors. ResultsAmong 877 low risk GTN patients there were 124 (14.8%) chemotherapy resistant and 22 (2.6%) relapse cases. Complete remission rates with second-line therapy were similar between relapse (77.3%) and resistant (76.6%) cases (p = 0.95), but resistance was associated with a longer time to reach complete remission with second-line therapy (median 8.3 vs 4.9 weeks; p = 0.024). In multivariate analysis, the significant prognostic factors for second-line therapy remission and time to second-line therapy remission were use of multi-agent chemotherapy (OR of 9.45; 95%CI, 2.13–41.97; p = 0.003) and primary chemo-resistance (HR of 0.27; 95%CI, 0.12–0.59; p = 0.001), respectively. With additional therapies, sustained remission rates rose to 90% (18/20) for relapse and 99.2% (120/121) for chemo-resistance (p = 0.053). ConclusionsAlthough second-line therapy for resistant or relapsed low risk GTN is able to achieve complete remission in most cases, time to complete remission for relapsed disease was shorter than for resistant disease. Further studies on the biologic differences between resistant and relapsed disease may clarify the optimal treatment for these clinical situations.

Chemotherapy and Survival in Patients with Primary High-Grade Extremity and Trunk Soft Tissue Sarcoma.

The use of upfront chemotherapy for primary localized soft tissue sarcoma (STS) of the extremity and trunk is debated. It remains unclear if chemotherapy adds clinical benefit, which patients are likely to benefit, and whether the timing of therapy affects outcomes. We used the National Cancer Database (NCDB) to examine the association between overall survival (OS) and chemotherapy in 5436 patients with the five most common subtypes of STS with primary disease localized to the extremity or trunk, mirroring the patient population of a modern phase 3 clinical trial of neoadjuvant chemotherapy. We then examined associations between timing of multi-agent chemotherapy (neoadjuvant or adjuvant) and OS. We used a Cox proportional hazards model and propensity score matching (PSM) to account for covariates including demographic, patient, clinical, treatment, and facility factors. In the overall cohort, we observed no association between multi-agent chemotherapy or its timing and improved OS. Multi-agent chemotherapy was associated with improved OS in several subgroups, including patients with larger tumors (>5 cm), those treated at high-volume centers, or those who received radiation. We also identified an OS benefit to multi-agent chemotherapy among the elderly (>70 years) and African American patients. Multi-agent chemotherapy was associated with improved survival for patients with tumors >5 cm, who receive radiation, or who receive care at high-volume centers. Neither younger age nor chemotherapy timing was associated with better outcomes. These ‘real-world’ findings align with recent randomized trial data supporting the use of multi-agent chemotherapy in high-risk patients with localized STS.

Low Rates of Chemotherapy Use for Primary, High-Grade Soft Tissue Sarcoma: A National Cancer Database Analysis.

There is conflicting evidence regarding the role of chemotherapy for high-grade soft tissue sarcoma (STS) in adults. We sought to characterize patterns of chemotherapy use, including multiagent and neoadjuvant chemotherapy, in the United States. Using the National Cancer Database, we identified 19,969 adult patients who underwent surgical resection for primary high-grade STS from 2004 to 2016. Using logistic regression, we examined factors associated with overall, multiagent, and neoadjuvant chemotherapy use. Chemotherapy was administered to 22% (n=4,377) of the study population. Among patients treated using chemotherapy, 85% received multiagent treatment and 47% received neoadjuvant treatment. On multivariate analysis, factors associated with chemotherapy use included tumor size, depth, histology, and primary site; receipt of radiation treatment; younger age; higher patient income; and academic treatment facility. Factors associated with multiagent chemotherapy use included tumor histology, tumor primary site, and younger age. Factors associated with neoadjuvant chemotherapy use included tumor size, depth, margin status, and primary site; receipt of radiation treatment; higher patient income; academic treatment facility type; and distance to treatment facility. Treatment at a high-volume facility was the only factor associated with overall, multiagent, and neoadjuvant chemotherapy use. No significant temporal trend was seen in overall, multiagent, or neoadjuvant chemotherapy use. Overall chemotherapy use was low (22%). The variability in chemotherapy use was driven by clinical, patient, demographic, and facility factors. Among patients treated with chemotherapy, the use of multiagent chemotherapy was high (85%), and nearly half received neoadjuvant therapy. There was a discrepancy in the use of chemotherapy-including neoadjuvant and multiagent chemotherapy-between high- and low-volume treatment centers.

Outcome of elderly patients with classical Hodgkin lymphoma (HL) in British Columbia.

8031 Background: Outcomes in elderly patients (pts) with Hodgkin lymphoma (HL) have traditionally been poor. We evaluated the survival of elderly pts (&gt;60 years [y]) with classical HL in British Columbia (BC). Methods: All pts aged &gt;60 y newly diagnosed with classical HL from 1961 to 2019 were identified in the BC Cancer Lymphoid Cancer Database. Limited stage was defined as non-bulky (&lt;10 cm) stage 1A/IB or 2A (before 2000 1B = advanced stage), with the remainder considered advanced stage. Results: Following exclusions (HIV positive n=4, incomplete data n=21, prior or concurrent other lymphoproliferative disease n=67), 713 pts were identified. With a median follow up of 6.0 y (0.1 - 24.0 y) in living pts, there has been an improvement in 5 y DSS/OS (both p&lt;.001) by decade comparison: 1960s (n=52) 25%/17%; 1970s (n=75) 38%/31%; 1980s (n=90) 51%/43%; 1990s (n=115) 53%/42%; 2000s (n=180) 66%/57%; 2010s (n=201) 63%/53%. To account for advances in diagnosis, staging, supportive care, and therapy in the modern era, we evaluated the outcome of pts diagnosed since 01/1995. A total of 368 pts were treated with curative intent (Table). Most pts received multi-agent chemotherapy (n=359, 98%: ABVD[like] n=351, alkylator-based n=7, CHOP n=1), 8 pts had radiotherapy (RT) alone, and 1 pt had surgery (primary CNS HL). The 5 y DSS, PFS, and OS were 74%, 57%, and 62%, respectively. Increasing age was associated with inferior outcomes (5 y DSS/PFS/OS): 61-70 y (81%/70%/74%), 71-80 y (69%/47%/52%), and &gt;80 y (59%/27%/31%) (DSS p=.011; PFS p&lt;.0001; OS p&lt;.0001). Of 318 pts that received bleomycin, 60 (19%) developed pulmonary toxicity, including 22 cases that occurred after cycles 1 and 2. Overall, 24/368 pts (7%) died of acute treatment toxicity (pulmonary [bleomycin n=10, radiation n=1], infection n=10, cardiac n=3). There was no association between age and developing bleomycin (p=.80) or lethal treatment toxicities (p=.74). Conclusions: The outcome of elderly pts with HL has improved in recent decades. However, treatment related toxicity remains a concern and use of multi-agent chemotherapy, particularly bleomycin-containing regimens, should be undertaken with caution. [Table: see text]

Survival of Older Adults With Newly Diagnosed Acute Myeloid Leukemia: Effect of Using Multiagent Versus Single-agent Chemotherapy

BackgroundControversy exists regarding the optimal chemotherapy regimen for older adults with acute myeloid leukemia (AML). Patients and MethodsWe analyzed data from the US National Cancer Data Base of 25,621 patients aged 60 to 79 years, with a diagnosis of AML from 2004 to 2014, who had received single-agent versus multiagent chemotherapy. A Cox proportional hazard model was used for overall survival (OS) analysis for the entire study cohort and separately for patients who had received single-agent (n = 6743) versus multiagent (n = 6743) chemotherapy, matched for age, Charlson comorbidity index, and AML subtype. ResultsThe use of multiagent chemotherapy was high overall (70%) but declined with factors, such as increasing age, Charlson comorbidity index, AML subtype other than good risk, academic center, lower rate of high school graduation, and more recent year of diagnosis. Patients treated with multiagent chemotherapy had greater 1-year OS (43% vs. 28%), especially for patients aged 60 to 69 years and those with good-risk AML or Charlson comorbidity index of 0 to 1. OS (hazard ratio, 1.32; 95% confidence interval, 1.28-1.36) remained more favorable for the multiagent chemotherapy group on multivariable analysis. This was confirmed in a matched cohort analysis. ConclusionsTo the best of our knowledge, this is the largest real-world study that has demonstrated an association between factors such as age, comorbidity, and AML subtype and the use of multiagent chemotherapy. The use of multiagent chemotherapy was associated with improved OS, especially for patients aged <70 years, those with good-risk AML, and those with a low Charlson comorbidity index.

Effect of Using Multiagent Versus Single Agent Chemotherapy on Overall Survival (OS) of Older Adults with Acute Myeloid Leukemia (AML)

Introduction: Whether adults aged ≥60 years with AML benefit from multiagent (or intensive) chemotherapy is a matter of controversy. Prior studies have demonstrated conflicting results. We performed analysis of a large National Cancer Data Base (NCDB) to determine the value of multiagent vs. single agent chemotherapy. Methods: NCDB captures approximately 70% of all cancer diagnoses in US, and undergoes rigorous quality monitoring. We utilized NCDB to identify patients aged 60-79 years, who were newly diagnosed with AML (other than APL) between the years 2004-2014. Logistic regression model was used to determine factors associated with the use of multiagent chemotherapy. Kaplan-Meier curves were generated and compared using the log rank test. Logistic regression model and Cox Proportional Hazard model were used for one-month mortality and OS analyses, respectively. In a separate analysis, patients who received single agent (n=6743) vs. multiagent chemotherapy (n=6743) were matched based on the variables age, Charlson comorbidity score, and AML subtypes (good-risk AML, therapy-related AML/AML with myelodysplasia related changes, and other intermediate/high-risk AML). A Cox Proportional Hazard model was used for OS analysis of the matched cohort. Results: Of a total of 25,621 patients, 70% received multiagent chemotherapy. The receipt of multiagent chemotherapy declined with increasing age, Charlson comorbidity score, AML subtypes other than good-risk, female, non-academic center, shorter distance traveled to receive care, lower rate of high school graduation, and more recent year of diagnosis. Patients treated with multiagent chemotherapy had higher likelihood of receiving hematopoietic cell transplant (HCT) (9% vs. 1%); lower one-month mortality (11% vs. 19%); and greater 1-year OS (43% vs. 28%) (Figure 1). The use of multiagent chemotherapy had particularly higher 1-year OS in patients aged 60-64 and 65-69 years, in good-risk AML, patients with Charlson comorbidity score of 0-1 and those who did not receive upfront HCT consolidation (Table 1). One-month mortality (odds ratio 1.64, 95% confidence interval, CI 1.51-1.78) and OS (hazard ratio, HR 1.32, 95% CI 1.28-1.36) remained more favorable for multiagent chemotherapy group in multivariable analyses. Other factors that affected OS included age, comorbidity, AML subtypes, median household income, insurance, use of HCT, academic status of facility, distance traveled to receive care, sex and year of diagnosis. In a matched analysis of 13,486 patients, the use of single agent vs. multiagent chemotherapy resulted in a higher risk of mortality (HR 1.28, 95% CI 1.23-1.32). Conclusions: In one of the largest real-world studies, we demonstrate an association between factors such as age, comorbidity and AML subtypes and the use of multiagent chemotherapy. After adjusting for covariates, the use of multiagent chemotherapy among older adults was associated with higher receipt of HCT, and improved one-month mortality and OS. Improved OS was confirmed in a matched analysis. Certain groups such as patients younger than 70 years, good-risk AML and those with low Charlson comorbidity score had the greater OS benefit with the use of multiagent chemotherapy. Further studies to determine the role of multiagent or intensive chemotherapy are particularly important with approvals of several new drugs in the recent years and integration of many novel drugs in both low-intensity and intensive chemotherapy regimens. Disclosures Bhatt: Tolero Pharmaceuticals: Research Funding; Incyte: Consultancy, Research Funding; Partner therapeutics: Consultancy; Abbvie: Consultancy; Agios: Consultancy; CSL Behring: Consultancy; National Marrow Donor Program: Consultancy; Pfizer: Consultancy. Holstein:Celgene: Consultancy; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy; Genentech: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Sorrento: Consultancy. Al-Kadhimi:Celldex Biotech: Other: Stocks; Seattle Genetics: Other: Stocks. Armitage:Union Pacific: Consultancy; Tesaro bio: Membership on an entity's Board of Directors or advisory committees; Ascentage: Consultancy; Samus Therapeutics: Consultancy; Oncology Analytics: Consultancy; Partner Therapeutics: Consultancy. Gundabolu:Pfizer: Consultancy; Novartis: Consultancy; Jazz pharmaceuticals: Consultancy; Samus Therapeutics: Research Funding.

Adjuvant systemic therapy after resection of node positive gallbladder cancer: Time for a well-designed trial? (Results of a US-national retrospective cohort study)

BackgroundIdeal oncologic management of gallbladder carcinoma (GBCA) after complete surgical resection is unclear. We sought to define benefit of post-resection adjuvant systemic chemotherapy alone in T2 or greater gallbladder carcinoma utilising a large national dataset. Study DesignThe National Cancer Data Base (NCDB) 2004–2012 cohort was retrospectively reviewed for patients with GBCA (T2+) undergoing curative-intent resection and surviving at least 6 weeks. Univariate group comparisons, unadjusted Kaplan-Meier and adjusted Cox proportional hazards analyzed overall survival. Results4373 patients were included (N = 2479 T2, N = 1894 T3/4). Overall, 22.1% of patients received adjuvant chemotherapy. Use of multi-agent chemotherapy increased during the study period. Patients receiving adjuvant therapy were younger, had fewer comorbidities, more often node-positive and more likely R1-margins than those receiving surgery alone. Unadjusted overall survival was improved in all patients with node-positive disease as well as for those with inadequate nodal staging. The benefit of chemotherapy persisted after adjustment for patient and tumor factors. ConclusionAdjuvant systemic chemotherapy is associated with survival benefit in patients with T2 or greater GBCA with node positive disease. We recommend a multidisciplinary approach in these patients as less than 1-in-4 of them currently receive adjuvant chemotherapy. Future clinical trials should address adjuvant chemotherapy in node positive GBCA.

Practice patterns and clinical outcomes of therapy-related acute myeloid leukemia (TAML) in the US.

e18139 Background: tAML, compared to de novo AML, has higher adverse features and a shorter overall survival (OS). The use of chemotherapy and hematopoietic cell transplant (HCT), and OS of tAML outside of clinical trials has not been studied well. Current study was designed to identify the treatment patterns and OS of tAML based on a national database. Methods: A total of 1,611 cases of tAML were identified between 2001-2011 using the National Cancer Database (NCDB). Data on age, race, gender, income, insurance and educational status, Charlson comorbidity index (CCI), receipt of chemotherapy and HCT were abstracted. Log-rank test was used to test equality of survivor function among the variables. Factors that attained statistical significance during bivariate analysis were factored into multivariate analysis using Cox Regression model. Results: Median age at diagnosis was 63 years (range 18-90), with 54% &lt; 65 years, 59% females and 80% Caucasians. 67% underwent chemotherapy (20% single agent, 45% multiple agents and 2% unknown). 19% received HCT. Median OS was 6.7 months (m) with 1-year OS of 33%. Median OS was lower among patients ≥65 versus &lt; 65 years (4.1 vs. 9.5 m; p &lt; 0.001), those with higher comorbidity burden (7.8 m for CCI of 0, 6.0 m for CCI of 1, and 3.8 m for CCI of 2; p &lt; 0.001), and diagnosed before versus during/after 2008 (5.6 vs. 7.7 m, p = 0.05). Median OS was higher among patients who received chemotherapy (8.4 vs. 3.7 m; p &lt; 0.001) and HCT (22.6 vs. 4.9 m, p &lt; 0.001), as compared to those who did not. Cox regression model showed the predictors of OS to be: receipt of HCT (hazard ratio, HR 0.36); use of multiagent chemotherapy (HR 0.80); age≥65 years (HR 1.25), higher comorbidities (HR of 1.21 for CCI of 1, and 1.45 for CCI of 2) and diagnosis on or after 2008 (HR of 0.81). Conclusions: Over half of patients with tAML are younger adults ( &lt; 65 years), however, the receipt of chemotherapy and HCT is relatively low. OS is poor in general but improves with the use of multiagent chemotherapy and HCT. OS is worse in older patients and those with comorbidities. Given a dismal prognosis, older patients may be managed by leukemia team with expertise in geriatric oncology and should be encouraged to participate in clinical trials of novel therapies.

Inotuzumab ozogamicin in relapsed B-cell acute lymphoblastic leukemia.

Despite an improved understanding of disease biology and the use of multi-agent chemotherapy, the long-term survival of adults with B-cell acute lymphoblastic leukemia (B-ALL) ranges from 35% to 50%. Management of patients with relapsed B-ALL, a group characterized by dismal outcomes, poses a clinical challenge. To address this unmet need, novel therapeutics are being investigated in the setting of relapsed B-ALL with encouraging results. CD22 is an important B-cell antigen expressed in 80-90% of B-ALL cases. CD22 undergoes constitutive endocytosis with antibody ligation, making it an attractive biologic target for immunoconjugates. Inotuzumab ozogamicin (IO), a CD22-targeted antibody-drug conjugate demonstrated impressive single agent activity even among heavily pretreated relapsed B-ALL patients. A recent randomized phase III clinical trial demonstrates superiority of IO over standard of care chemotherapy as first- or second-line salvage therapy for relapsed B-ALL. In this review, we summarize the preclinical and clinical data available to date using IO in relapsed B-ALL.

Recent advances in the management of Hodgkin lymphoma.

Hodgkin lymphoma (HL) is a rare cancer of the immune system that typically affects lymph nodes and sometimes other organs. Although the majority of patients can be potentially cured with the use of multi-agent chemotherapy and radiotherapy, a proportion of them will relapse or develop resistant disease for which treatment options are limited. In recent years, new agents have been developed and tested in HL with encouraging results. Two classes of drugs stand out as highly active in advanced HL based on recent study results: antibody-drug conjugates and programmed death 1 inhibitors. Clinical trials in HL with these agents have been completed in the past several years and the results have recently become available. In this review, we discuss the recent advances in the management of HL with a focus on strategies to decrease toxicity and a review of the two drug classes that have the potential to change the landscape of treatment of this disease.

A 30-year experience in using oral methotrexate as initial treatment for gestational trophoblastic neoplasia regardless of risk group

Background. Treatment of postmolar gestational trophoblastic neoplasia (GTN) is often stratified according to FIGO score using methotrexate (MTX) for low-risk patients and first-line multi-agent chemotherapy (e.g. EMA-CO) for high-risk patients. In contrast, oral MTX may be given as first-line therapy to all GTN patients regardless of risk group. The aim was to examine the efficacy of oral MTX and a response-adapted treatment policy, which has been used for three decades at Aarhus University Hospital (AUH).Material and methods. Seventy-one consecutive postmolar GTN patients treated 1981–2011 were included. Data were obtained from medical records, using histopathology and human choriogonadotropin (hCG) to verify the diagnosis. All patients received oral MTX as first-line chemotherapy. Second- and third-line chemotherapy was given according to response.Results. Sixty-four (90%) patients were retrospectively categorized as FIGO low-risk disease, whereas seven patients (10%) had high-risk disease. Complete response to first-line oral MTX chemotherapy was observed in 35/71 (49%) patients, while 62/71 (87%) had complete remission on MTX (first-line) and/or MTX plus dactinomycin (second-line), without the use of multi-agent therapy. Nine patients (13%) received third-line multi-agent chemotherapy, six low-risk (67%) and three high-risk (33%) patients. There were no recurrences and no patients died as a consequence of toxicity or disease.Conclusion. Fifty percent of all patients can be cured on oral MTX alone. By adding dactinomycin, about 90% are cured without use of multi-agent chemotherapy. The use of oral MTX as initial treatment can minimize the number of patients receiving multi-agent chemotherapy.

Prognostic factors associated with time to hCG remission in patients with low-risk postmolar gestational trophoblastic neoplasia

ObjectiveThe purpose of this study was to identify the clinical factors associated with time to hCG remission among women with low-risk postmolar GTN. MethodsThis study included a non-concurrent cohort of 328 patients diagnosed with low-risk postmolar GTN according to FIGO 2002 criteria. Associations of time to hCG remission with history of prior mole, molar histology, time to persistence, use of D&C at persistence, presence of metastatic disease, FIGO score, hCG values at persistence, type of first line therapy and use of multiagent chemotherapy were investigated with both univariate and multivariate analyses. ResultsOverall median time to remission was 46days. Ten percent of the patients required multi-agent chemotherapy to achieve hCG remission. Multivariate analysis incorporating the variables significant on univariate analysis confirmed that complete molar histology (HR 1.45), metastatic disease (HR 1.66), use of multi-agent therapy (HR 2.00) and FIGO score (HR 1.82) were associated with longer time to remission. There was a linear relationship between FIGO score and time to hCG remission. Each 1-point increment in FIGO score was associated with an average 17-day increase in hCG remission time (95% CI: 12.5–21.6). ConclusionsComplete mole histology prior to GTN, presence of metastatic disease, use of multi-agent therapy and higher FIGO score were independent factors associated with longer time to hCG remission in low-risk GTN. Identifying the prognostic factors associated with time to remission and effective counseling may help improve treatment planning and reduce anxiety in patients and their families.

CYP3A inhibitors and adverse outcomes in patients treated with docetaxel chemotherapy.

2596 Background: Docetaxel (D) is an anti-mitotic drug metabolized by the cytochrome P450 (CYP) 3A4 enzyme. While case reports have demonstrated a potential association of CYP3A inhibitor use with severe toxicity in D treated patients (pts), there are no data whether co-administration of CYP3A inhibitors with D increases the rate of hospitalization and/or death. Methods: A retrospective cohort of pts treated with D at the Mayo Clinic Rochester from 1/1/09-10/1/11 was identified. Information regarding D and concomitant chemotherapy (starting dose and dose reductions), type of CYP3A inhibitor, growth factor use, hospitalizations and deaths was abstracted. Time to event analyses (either hospitalization or death) were conducted using Kaplan-Meier estimates and proportional hazards modeling. Results: 384 pts (median age 63, range 20-93) received D as monotherapy (48%) or as multi-agent chemotherapy (52%) for a median of 4 cycles. 56 pts were co-administered CYP3A inhibitors (45 moderate, 11 strong). 90 pts were hospitalized during D chemotherapy and 15 died. The mean time to hospitalization was significantly shorter in pts treated with a mod/strong CYP3A inhibitor (186 days) vs not treated (408 days) (p=0.02) . While time to death was not significantly different based on inhibitor use (111 vs. 177 days, p=0.49), time to first event (hospitalization or death) varied significantly according to those on inhibitors (187 days) versus not (397 days) (HR: 1.78, p=0.02). Time dependent analyses indicated that use of multiage chemotherapy (combination vs D monotherapy; HR 1.96, p= 0.002) and chemotherapy dose reduction of either D (HR 0.54, p&lt;0.01) or other chemotherapy (HR 0.61, p=0.02) were significantly associated with the risk of an event. In a multivariate analysis, moderate/strong CYP3A inhibitor use was associated with a higher risk of any event (HR 1.79, p&lt;0.02), independent of the use or dose of either multi-agent chemotherapy or D dose. Conclusions: These are the first data to demonstrate that co-administration of CYP3A inhibitors with D increases the risk of hospitalization and/or death. Oncologists should reconcile medications prior to D administration and mod/strong CYP3A inhibitors should be avoided or used with caution.