Toxicity-related Events Research Articles

Dual therapy based on co-formulated darunavir/ritonavir plus lamivudine for initial therapy of HIV infection: The ANDES randomized controlled trial

Tenofovir-containing antiretroviral therapy regimens may have long-term toxicity-related side effects. This study aimed to compare the virological efficacy of co-formulated darunavir/ritonavir plus lamivudine with darunavir/ritonavir plus tenofovir and emtricitabine or lamivudine. The ANDES study was a 48-week, phase 4, randomized, open-label, non-inferiority trial in treatment-naïve adults living with human immunodeficiency virus (HIV). Patients were randomized on a 1:1 basis to receive a daily oral regimen of either dual therapy based on a generic co-formulation of darunavir/ritonavir (800/100 mg) plus a generic lamivudine 300 mg pill, or triple therapy with darunavir/ritonavir plus tenofovir/emtricitabine (300/200 mg) or tenofovir/lamivudine (300/300 mg). The primary endpoint was the proportion of patients with a viral load of <50 copies/mL at week 48 in the intention-to-treat population. The US Food and Drug Administration snapshot algorithm and a non-inferiority margin of -12% were used. The secondary objective was to analyse safety in the per-protocol population. This study has been registered at ClinicalTrials.gov (NCT02770508). Between November 2015 and 31 October 2020, 336 participants were assigned at random to the triple therapy arm (n=165) or the dual therapy arm (n=171). After 48 weeks, 153 patients in the triple therapy group (93%) and 155 patients in the dual therapy group (91%) achieved virological suppression (difference -2.1%, 95% confidence interval -7.0 to 2.9). Drug-related adverse events were more common in the triple therapy group (P=0.04). Two toxicity-related events led to discontinuation in each group. Co-formulated darunavir/ritonavir plus lamivudine showed non-inferiority and a safer toxicity profile compared with the standard-of-care triple therapy regimen including tenofovir in treatment-naïve patients.

Toxicological effects and underlying mechanisms of chlorination-derived metformin byproducts in Escherichia coli

Chlorination-derived byproducts of the emerging contaminant metformin, such as (3E)-3-(chloroimino)-N,N-dimethyl-3H-1,2,4-triazol-5-amine (3,3-CDTA) and N-cyano-N,N-dimethylcarbaminmidic chloride (NCDC), occur in global waters and are toxic to organisms, from bacteria to mice. However, the mechanisms underlying their toxicity remain unknown. Here, we explored the toxicological effects and potential molecular mechanisms of 3,3-CDTA and NCDC at milligram concentrations, using Escherichia coli as a model organism. Compared with metformin (>300 mg/L), 3,3-CDTA and NCDC exerted stronger toxicity to E. coli, with a 4-h half maximal inhibitory concentration of 2.97 mg/L and 75.7 mg/L, respectively. Both byproducts disrupted E. coli cellular structures and components, decreased membrane potential and adenosine triphosphate (ATP) biosynthesis, and led to excessive reactive oxidative species (ROS), as well as the ROS-scavenging enzymes superoxide dismutase and catalase. Proteomic analysis and molecular docking supported these biomarker responses in the byproduct-treated E. coli, and indicated potential damage to DNA/RNA processes, while also provided novel insights into the toxicological and detoxified-byproduct effects at the proteome level. The toxicity-related events of NCDC and 3,3-CDTA included membrane disruption, oxidative stress, and abnormal protein expression. This study is the first to examine the toxicological effects of chlorination-derived metformin byproducts in E. coli and the associated pathways involved; thereby broadening our understanding regarding the toxicity and transformation risks of metformin throughout its entire life process.

Cost-effectiveness analysis of pembrolizumab versus standard of care in recurrent or metastatic squamous cell carcinoma of the head and neck

Abstract Increasing costs of cancer treatment and anticancer drugs can create a financial burden on society and the individual. Pembrolizumab is an anti-PD-1 inhibitor immunotherapy approved for use in recurrent or metastatic head and neck squamous cell carcinoma. Limited data exists on the cost-effectiveness of pembrolizumab in this setting. This study compares the costeffectiveness of pembrolizumab against traditional chemotherapy using data from KEYNOTE-040. Published data from KEYNOTE-040 were used to create a model estimating treatment costs and overall survival benefit of pembrolizumab and traditional chemotherapy. Costs of treatment of toxicity-related events were obtained from previous literature and were incorporated into the model. Derivation of survival benefit gained from treatment was measured in quality-adjusted life-years (QALYs). The incremental cost-effectiveness ratio (ICER) of pembrolizumab compared to the investigator's choice (IC) was $801,864/QALY. The average drug cost of pembrolizumab would have to approximately decrease by 63% in order to reach the cost-effective threshold of $100,000/ QALY. Pembrolizumab would have to confer a survival benefit of 0.88 QALYs per patient over the IC to reach the cost-effective threshold. Pembrolizumab is not considered cost effective at a threshold of $100,000/QALY based on survival data reported in KEYNOTE-040. Improved long-term outcomes of patients on this relatively new immunotherapy have yet to be reported. Inclusion of these data in the future would likely improve the cost-effectiveness calculations of pembrolizumab and other immunotherapies.

Economic Burden Associated with Adverse Events of Special Interest (AESI) in Patients with Relapsed Acute Lymphoblastic Leukemia (ALL) in the US

IntroductionAcute lymphoblastic leukemia (ALL) is a type of cancer in which body overproduces lymphoblasts in the bone marrow (National Cancer Institute, 2016). Relapsed Philadelphia chromosome-negative (Ph-) B-cell ALL patients are extremely ill, and further compromised by treatment; hence, complications due to either the disease or the treatment are very common and often managed with inpatient admission. Infections, cytopenia and gastrointestinal (GI) toxicity events are often mentioned as important adverse events of special interest (AESI) among ALL patients (Hummel et al., 2016; Offidani et al., 2004, Schmiegelow et al., 2017) with detrimental impact on patients' quality of life. However, the economic burden of these events is not well documented in the published literature.ObjectiveThe aim of this study is to quantify the rates and economic burden of infections, cytopenia, and GI toxicity events among adults with relapsed Ph- ALL in the US.MethodsThis was a retrospective cohort study using Truven Health MarketScan® Commercial and Medicare Supplemental Databases. Patients with ≥1 inpatient claims or ≥2 non-diagnostic outpatient claims at least 30 days apart for relapsed ALL diagnosis (ICD-9-CM 204.02, ICD-10-CM C91.02) during 4/1/2009 - 10/31/2016 were extracted. All patients were required to have ≥1 hospitalization with diagnosis-related group in 834-839 on or after the first relapsed ALL diagnosis (index date was the admission date for the first hospitalization), were ≥18 years old on index date, and had ≥6 months of continuous enrollment prior to index date. Patients with medications for Ph+ or T-Cell ALL anytime during the study period were excluded. Patients were followed until the earliest event of inpatient death, end of continuous enrollment, end of the study period (10/31/2016), or 100 days post-index. AESI was defined as infections (including bacteremia, febrile neutropenia, line infections, pneumonia and sepsis), cytopenia (including anemia, neutropenia, thrombocytopenia and other cytopenia), or GI toxicities (including nausea/vomiting, diarrhea, gastritis/duodenitis, GI bleeding and mucositis/stomatitis) during the follow-up period. Outcomes included proportion of patients with AESI and AESI-related healthcare costs for any AESI and specific AESI categories and events. The AESI-related costs were calculated among those with at least one AESI and were the total costs accumulated during the follow-up after index date at the patient level. Costs were sum of the plan paid amount and out-of-pocket amount in 2016 US dollars.ResultsA total of 400 relapsed Ph- ALL patients were identified and 92.5% of them (mean age: 41.9 years; male: 63.0%; mean Charlson comorbidity index: 3.0) experienced at least one AESI during a mean (median) follow-up period of 84 (100) days. Among all the relapsed Ph- ALL patients with AESI, 64.6% had infections, 94.6% had cytopenia, and 46.2% had GI toxicity events (Table 1). The most frequent infection event observed was sepsis (40.0%); the most frequent cytopenia events were neutropenia (68.4%) and anemia (63.0%); and nausea/vomiting (26.8%) was the most frequent GI toxicity event. The total average (SD; median) AESI-related healthcare costs during 100 days post index date was $197,213 ($308,551; $105,731) (Table 1). Across all patients with AESI, the mean (SD) number of AESI-related hospitalizations was 2.0 (1.3), with a total mean (SD; median) length of stay of 32.2 (26.0; 27.0) days during the follow-up. Mean (SD; median) healthcare costs were highest for infection-related events ($164,461 [$347,083; $64,528]), followed by cytopenia ($125,210 [$165,141; $67,475]) and GI toxicity-related events ($11,652 [$40,231; $1,349]). At the specific event level, average healthcare costs were highest for sepsis ($204,151 [$412,572; $79,853]) and other cytopenia-related events ($98,900 [$143,961; $39,777]).ConclusionsInfections, cytopenia, and GI toxicity events affect the vast majority of relapsed Ph- ALL patients. The economic burden associated with AESI is substantial, with infections the most expensive AESI, followed by cytopenia and GI toxicity. One limitation of this study is that we couldn't separate the AESI due to treatment from those due to the disease itself. Nonetheless, new therapies that can improve the outcomes of the relapsed Ph- ALL patients while offering a favorable safety profile are needed. [Display omitted] DisclosuresZhang:Amgen Inc.: Employment, Equity Ownership. Romanov:Amgen, Inc.: Employment, Equity Ownership. Cong:Amgen Inc.: Employment, Equity Ownership.

Toxic marine microalgae and noxious blooms in the Mediterranean Sea: A contribution to the Global HAB Status Report

We review the spatial distribution of toxic marine microalgal species and the impacts of all types of harmful algal events (Harmful Algal Blooms, HABs) in the Mediterranean Sea (MS), including the Black Sea, the Sea of Marmara, coastal lagoons and transitional waters, based on two databases compiled in the Ocean Biogeographic Information System (OBIS). Eighty-four potentially toxic species have been detected in the MS (2,350 records), of which 16 described from these waters between 1860 and 2014 and a few suspected to have been introduced. More than half of these species (46) produce toxins that may affect human health, the remainders ichthyotoxic substances (29) or other types of toxins (9). Nevertheless, toxicity-related events are not frequent in the MS (308 records in 31 years), and mainly consist of impacts on aquaculture, caused by the dinoflagellates Dinophysis and Alexandrium, along with a few actual shellfish poisoning cases. Pseudo-nitzschia blooms are widespread, but domoic acid in shellfish rarely exceeds regulatory levels. Fish kills are probably less sporadic than reported, representing a problem at a few places along the southern MS coasts and in the Ebro River Delta. Since the last decade of the 20th century, blooms of the benthic dinoflagellates Ostreopsis cf. ovata have regularly occurred all along rocky shores of the MS, at times with human health problems caused by toxic aerosol. New records of Gambierdiscus and Fukuyoa, until now reported for the westernmost and easternmost MS coasts, raise concerns about the risk of ciguatera, a syndrome so far known only for subtropical and tropical areas. Recent discoveries are the dinoflagellates Vulcanodinium rugosum, responsible for the presence of pinnatoxins in French lagoons’ shellfish, and the azaspiracid-producers Azadinium spp. Mucilages and discolorations have a major impact on tourism in summer. Reports of toxic species and HABs have apparently increased in the MS over the last half century, which is likely related to the increased awareness and monitoring operations rather than to an actual increase of these phenomena. Indeed, while the case of Ostreopsis appears as a sudden upsurge rather than a trend, no actual increase of toxic or noxious events has so far emerged in intensively studied areas, such as the French and Spanish coasts or the Adriatic Sea. Moreover, some cases of decrease are reported, e.g., for Alexandrium minutum blooms disappearing from the Harbour of Alexandria. Overall, main HAB risks derive from cases of massive development of microalgal biomass and consequent impacts of reduced coastal water quality on tourism, which represents the largest part of the marine economy along the MS coasts.

IMRT Reduces Acute Toxicity in Patients Treated With Preoperative Chemoradiation for Gastric Cancer

PurposePreoperative chemoradiation is being currently evaluated in 2 randomized international trials. However, chemoradiation for gastric cancer can be associated with relatively high rates of acute toxicity. We compared rates of toxicity, toxicity-related events, and oncologic outcomes in patients treated with intensity modulated radiation therapy (IMRT) and those treated with 3-dimensional conformal radiation therapy (3DCRT). Methods and MaterialsWe retrospectively reviewed records of 202 patients with consecutive gastric cancer treated with preoperative intent radiation therapy at our institution from 1998 to 2018. Patients with gastroesophageal junction involvement and those with metastatic disease were excluded. Eighty-two patients received 3DCRT, and 120 patients received IMRT. The median radiation dose was 45 Gy, and 99% received concurrent chemotherapy. ResultsThere were no significant differences between the 3DCRT and IMRT groups regarding sex, race, histology, tumor location, histology, or nodal stage. The rate of grade 3 to 4 acute toxicity was significantly lower in patients treated with IMRT compared with 3DCRT (49% vs 70%, P = .004). The composite rate of toxicity-related events (hospitalization, feeding tube use, intravenous rehydration, or radiation therapy breaks) was also significantly lower in patients treated with IMRT compared with 3DCRT (56% vs 85%, P <.001). In addition, 68% of patients who received IMRT and 73% of patients who received 3DCRT underwent subsequent surgical resection (P = .245). Among patients who underwent surgery, the 3-year overall survival rates were not significantly different between those treated with IMRT and 3DCRT (71% vs 69%, P = .786). Patients receiving IMRT had a significantly higher absolute nadir lymphocyte count compared with patients receiving 3DCRT (median, 0.21 vs 0.16 K/UL; P = .047). ConclusionsOur study suggests that IMRT might significantly reduce rates of grade 3 to 4 acute toxicity and toxicity-related events compared with 3DCRT, with no significant difference in oncologic outcomes. IMRT is an appropriate and possibly preferable radiation modality in patients treated with preoperative chemoradiation for gastric cancer.

IMRT Reduces Acute Toxicity in Patients Treated with Preoperative Chemoradiation for Gastric Cancer

Two large randomized trials are currently investigating preoperative chemoradiation for localized gastric adenocarcinoma. However, radiation therapy (RT) can be associated with relatively high rates of acute toxicity. Newer techniques, such as intensity modulated RT (IMRT), could reduce toxicity by reducing radiation dose to normal structures. Our goal was to compare rates of toxicity, toxicity-related events, and oncologic outcomes in patients treated with IMRT compared to 3D conformal RT (3DCRT). The records of 202 gastric cancer patients treated with preoperative intent RT at our institution from 1998-2018 were retrospectively reviewed. Demographic data, treatment details, acute and late toxicities (CTCAE 4.0), progression and survival data were recorded. Patients who had stage IV disease were excluded. Statistical analysis included descriptive statistics, Cox regression analysis, and Kaplan-Meier survival. 54% were male, and the median age was 63. 82 patients received 3DCRT and 120 patients received IMRT. The median radiation dose was 45Gy (IQR: 45-45 Gy). 78% of patients in the 3DCRT group and 95% of patients in the IMRT group received neoadjuvant chemotherapy prior to RT (p=0.001). 99% of patients in both groups received concurrent chemotherapy. There were no significant differences between the 3DCRT and IMRT groups with respect to gender, race, histology, tumor, or nodal stage. The rate of grade 3-4 acute toxicity was significantly lower in patients treated with IMRT compared to those treated with 3DCRT (53% vs. 73%, p=0.004). The composite rate of toxicity-related events (hospitalization, feeding tube, IV rehydration or RT breaks) was also significantly lower in patients treated with IMRT compared to 3DCRT (56% vs. 85%, p<0.001). 73% of patients who received 3DCRT and 68% of patients who received IMRT underwent subsequent surgical resection (p=0.245). Among patients who underwent surgical resection, there was no significant difference in the rate of positive margins between those who received 3DCRT and those who received IMRT (7% vs 15%, p=0.13). Among patients who underwent surgical resection, the 3-year OS and PFS rates were not significantly different in patients receiving 3DCRT compared to IMRT (OS 73% vs. 73%, p=0.93, PFS 65% vs. 64%, p=0.68). Among patients who did not undergo surgical resection, the 3-year OS and PFS rates were also not significantly different in patients receiving 3DCRT compared to IMRT (OS 27% vs. 28%, p=0.93; PFS 19% vs. 14%, p=0.69). Our study indicates a reduction in the rates of grade 3-4 acute toxicity and toxicity-associated events in patients treated with IMRT compared to 3DCRT, with no significant difference in oncologic outcomes. These findings suggest that IMRT should be considered as the preferred radiation modality in patients treated with preoperative chemoradiation for gastric cancer.

Clinical Monte Carlo versus Pencil Beam Treatment Planning in Nasopharyngeal Patients Receiving IMPT.

Pencil beam (PB) analytical algorithms have been the standard of care for proton therapy dose calculations. The introduction of Monte Carlo (MC) algorithms may provide more robust and accurate planning and can improve therapeutic benefit. We conducted a dosimetric analysis to quantify the differences between MC and PB algorithms in the clinical setting of dose-painted nasopharyngeal cancer intensity-modulated proton radiotherapy. Plans of 14 patients treated with PB analytical algorithm optimized and calculated (PBPB) were retrospectively analyzed. The PBPB plans were recalculated using MC to generate PBMC plans and, finally, reoptimized and recalculated with MC to generate MCMC plans. The plans were compared across several dosimetric endpoints and correlated with documented toxicity. Robustness of the planning scenarios (PBPB, PBMC, MCMC) in the presence of setup and range uncertainties was compared. A median decrease of up to 5 Gy (P < .05) was observed in coverage of planning target volume high-risk, intermediate-risk, and low-risk volumes when PB plans were recalculated using the MC algorithm. This loss in coverage was regained by reoptimizing with MC, albeit with a slightly higher dose to normal tissues but within the standard tolerance limits. The robustness of both PB and MC plans remained similar in the presence of setup and range uncertainties. The MC-calculated mean dose to the oral avoidance structure, along with changes in global maximum dose between PB and MC dosimetry, may be associated with acute toxicity-related events. Retrospective analyses of plan dosimetry quantified a loss of coverage with PB that could be recovered under MC optimization. MC optimization should be performed for the complex dosimetry in patients with nasopharyngeal carcinoma before plan acceptance and should also be used in correlative studies of proton dosimetry with clinical endpoints.

Statin use associated with improved overall and cancer specific survival in patients with head and neck cancer

ObjectivesStudies have shown the utility of lipid-lowering agents in improving outcomes in various cancers. We aim to explore how statins affect overall survival and cancer specific survival in head and neck cancer patients using population-based datasets. Patients and methodsUsing the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked dataset, we separated HNC patients into three groups: those with no hyperlipidemia (nH), those with hyperlipidemia and not taking a statin (HnS), and those with hyperlipidemia and taking a statin (H + S). Overall survival (OS) and cancer specific survival (CSS) were compared between the three groups based on disease subsite (oral cavity, oropharynx, and other) using Kaplan-Meier and multivariate Cox regression analysis (MVA), controlling for demographic, socioeconomic, staging, treatment, and comorbidity covariates. Using Pearson chi-square analysis, we also compared the incidence of cancer-related toxicity events. ResultsThere were 495 nH, 567 HnS, and 530 H + S patients. H + S patients had superior OS and CSS (73.0, 81.2%) relative to nH (58.6, 69.1%) and HnS groups (61.7, 69.2%) (p < 0.01). On MVA, H + S patients showed improved OS (p < 0.01) and CSS (p = 0.04) compared to nH (HR = 1.64, 1.56) and HnS (HR = 1.40, 1.37). MVA stratified by subsite yielded similar results for oral cavity and oropharyngeal disease. Toxicity-related events did not differ significantly between the groups. ConclusionHNC patients with hyperlipidemia and taking a statin demonstrated improved outcomes compared to nH and HnS patients, further supporting statins' role as a potential adjuvant anti-neoplastic agent in HNC. Further prospective studies to investigate the impact of statins on HNC outcomes are warranted.

The effect of IMRT on acute toxicity in patients with gastric cancer treated with preoperative chemoradiation.

153 Background: Two trials are currently investigating preoperative chemoradiation (CRT) for localized gastric adenocarcinoma. However, radiation therapy (RT) can be associated with relatively high rates of acute toxicity. Newer techniques, such as intensity modulated RT (IMRT), could reduce toxicity by reducing radiation dose to normal structures. Our goal was to compare rates of toxicity and toxicity-related events in patients treated with IMRT compared to 3D conformal RT (3DCRT). Methods: The records of 202 gastric cancer patients treated with preoperative intent RT at our institution from 1998-2018 were retrospectively reviewed. Demographic data, treatment details, acute and late toxicities (CTCAE 4.0 criteria), progression and survival data were recorded. Patients who had stage IV disease were excluded. Statistical analysis included descriptive statistics, Cox regression analysis, and Kaplan-Meier survival. Results: 54% were male and the median age was 63. 82 patients received 3DCRT and 120 patients received IMRT (median 45Gy, IQR, 45-45Gy in each group). 78% of patients in the 3DCRT group and 91% of patients in the IMRT group received neoadjuvant chemotherapy prior to RT. 99% of patients received concurrent chemotherapy. The rate of grade 3-4 acute toxicity was significantly lower in patients treated with IMRT compared to 3DCRT (53% vs. 73%, p = 0.004). The composite rate of toxicity-related events (hospitalization, feeding tube, IV rehydration, or RT break) was also significantly lower in patients treated with IMRT compared to 3DCRT (80% vs. 91%, p = 0.031). 72% of patients who received 3DCRT and 68% of patients who received IMRT underwent subsequent surgical resection. The 3-year OS rate was 58.1% for patients receiving IMRT and 60.2% for patients receiving 3DCRT (p = 0.649). The 3-year PFS rate was 47.5% for patients receiving IMRT and 52.7% for patients receiving 3DCRT (p = 0.486). Conclusions: Our study indicates a marked reduction in the rates of grade 3-4 acute toxicity and toxicity-associated events in patients treated with IMRT compared to 3DCRT. These findings suggest that IMRT should be considered as the radiation modality in patients treated with preoperative CRT for gastric cancer.

Adjuvant therapy confers no survival benefit following curative surgery for peri-ampullary adenocarcinoma: a Meta-Analysis

Background: Peri-ampullary cancers are uncommon malignancies, often amenable to surgery. The use of adjuvant chemo- and chemo-radiotherapy in improving survival for peri-ampullary cancers has had variable results. The aim of this meta-analysis was to determine the survival benefit from adjuvant therapy in these cancers. Methods: A systematic review of the literature was undertaken between the 1st January 2000 and 31st December 2015. The pooled overall survival associated with the use of either adjuvant chemo- and chemo-radiotherapy, as opposed to post-surgical surveillance for peri-ampullary cancers was elicited. Included articles were screened for tumour stage, prognostic factors and toxicity-related events. Results: Of the 14 full text articles included, 6 were randomised control trials. A total of 1671 patients (904 controls and 767 who underwent adjuvant therapy) were included. The median 5-year overall survival was 37.5% compared 40% in the control and adjuvant groups, respectively (HR 1.08, p=0.067). In 31.4% of adjuvant patients, one or more WHO grade 3 or 4 toxicity-related events was noted. High T-stage was associated worse survival (coefficient -0.14, P=0.04), whilst nodal status and grade of differentiation were not. Conclusion: No associated survival benefit of adjuvant therapy in the treatment of peri-ampullary cancers was found. Further studies should aim to investigate if patients with advanced disease would benefit from adjuvant strategies, to prevent exposing patients to significant toxicity.

Sirolimus for the treatment of progressive kaposiform hemangioendothelioma: A multicenter retrospective study.

Kaposiform hemangioendothelioma (KHE) is an aggressive disease with high morbidity and mortality. The aim of this study was to retrospectively evaluate the efficacy and safety of sirolimus for the treatment of progressive KHE. A multicenter, retrospective cohort study was conducted in patients with progressive KHE treated with sirolimus. A total of 52 patients were analyzed. Thirty-seven (71%) patients exhibited Kasabach-Merritt phenomenon (KMP) and were significantly younger than the patients without KMP [95% confidence interval (CI), 14.39-41.61; p < 0.001]. Patients without KMP were all treated with sirolimus alone, whereas 21 KMP patients with severe symptoms received short-term combination therapy with prednisolone. Overall, 96% and 98% of patients showed improved relief of notable symptoms and/or improved complications at 6 and 12 months after treatment, respectively. After sirolimus treatment, significant decreases in mean severity scores occurred at 6 months (95% CI, 2.23-2.54, p < 0.001) and 12 months (95% CI, 1.53-1.90, p < 0.001). Compared to KMP patients, patients without KMP showed a response that was similar to but less pronounced during the 12 months of treatment (95% CI, 40.87-53.80; p < 0.001). For subgroup analysis of KMP patients, there were no significant differences in tumor shrinkage between those treated with combination therapy and those receiving sirolimus alone (95% CI, 18.11-25.02; p > 0.05). No patients permanently discontinued treatment due to toxicity-related events, and no drug-related deaths occurred. Sirolimus was effective and safe for the treatment of progressive KHE. Sirolimus may be considered as a first-line therapy or as part of a multidisciplinary approach for the treatment of KHE.

Meta-analysis of adjuvant therapy following curative surgery for periampullary adenocarcinoma.

Periampullary cancers are uncommon malignancies, often amenable to surgery. Several studies have suggested a role for adjuvant chemotherapy and chemoradiotherapy in improving survival of patients with periampullary cancers, with variable results. The aim of this meta-analysis was to determine the survival benefit of adjuvant therapy for periampullary cancers. A systematic review was undertaken of literature published between 1 January 2000 and 31 December 2015 to elicit and analyse the pooled overall survival associated with the use of either adjuvant chemotherapy or chemoradiotherapy versus observation in the treatment of surgically resected periampullary cancer. Included articles were also screened for information regarding stage, prognostic factors and toxicity-related events. A total of 704 titles were screened, of which 93 full-text articles were retrieved. Fourteen full-text articles were included in the study, six of which were RCTs. A total of 1671 patients (904 in the control group and 767 who received adjuvant therapy) were included. The median 5-year overall survival rate was 37·5 per cent in the control group, compared with 40·0 per cent in the adjuvant group (hazard ratio 1·08, 95 per cent c.i. 0·91 to 1·28; P = 0·067). In 32·2 per cent of patients who had adjuvant therapy, one or more WHO grade 3 or 4 toxicity-related events were noted. Advanced T category was associated worse survival (regression coefficient -0·14, P = 0·040), whereas nodal status and grade of differentiation were not. This systematic review found no associated survival benefit for adjuvant chemotherapy or chemoradiotherapy in the treatment of periampullary cancer.

A new parameter computed with independent component analysis to predict rectal toxicity following prostate cancer radiotherapy.

The main challenge in prostate cancer radiotherapy is to deliver the prescribed dose to the clinical target while minimizing the dose to the neighboring organs at risk and thus avoiding subsequent toxicity-related events. With the aim of improving toxicity prediction following prostate cancer radiotherapy, the goal of our work is to propose a new predictive variable computed with independent component analysis to predict late rectal toxicity, and to compare its performance to other models (logistic regression, normal tissue complication probability model and recent principal component analysis approach). Clinical data and dose-volume histograms were collected from 216 patients having received 3D conformal radiation for prostate cancer with at least two years of follow-up. Independent component analysis was trained to predict the risk of 3-year rectal bleeding Grade ≥ 2. The performance of all the models was assessed by computing the area under the receiving operating characteristic curve. Clinical parameters combined with the new variable were found to be predictors of rectal bleeding. The mean area under the receiving operating curve for our proposed approach was 0:75. The AUC values for the logistic regression, the Lyman-Kutcher-Burman model and the recent principal component analysis approach were 0:62, 0:53 and 0:62, respectively. Our proposed new variable may be an useful new tool in predicting late rectal toxicity. It appears as a strong predictive variable to improve classical models.

Sirolimus and mycophenolate mofetil as GVHD prophylaxis in myeloablative, matched-related donor hematopoietic cell transplantation

We investigated sirolimus and mycophenolate mofetil (MMF) as graft-versus-host disease (GVHD) prophylaxis in patients with advanced hematologic malignancies receiving myeloablative hematopoietic cell transplantation (HCT) from HLA-identical sibling donors. Based on pre-study stopping rules, the trial was closed to accrual after enrollment of 11 adult patients. Seven of the 11 patients received busulfan-containing preparative regimens. Sirolimus was discontinued in 3 patients due to toxicity-related events of severe sinusoidal obstructive syndrome, portal vein thrombosis, altered mental status and in 1 patient due to risk of poor wound healing. Six of the 11 patients developed grade II-IV acute GVHD (AGVHD) a median of 15.5 days post-HCT. Two of 3 patients with grade IV AGVHD had sirolimus discontinued by 9 days post-HCT. All patients responded to AGVHD therapy without GVHD-related deaths. There were 2 nonrelapse- and 2 relapse-related deaths. At a median follow-up of 38 months (2–47 months), 7 of 11 patients were alive without disease. MMF and sirolimus GVHD prophylaxis did not reduce the risk of acute GVHD, however, there were no GVHD-related deaths. The severe toxicities in the patients receiving the busulfan-containing preparative regimens limited the continued use of sirolimus and MMF for the prevention of AGVHD.

Niveau de preuve du suivi thérapeutique pharmacologique du méthotrexate au décours de son administration à haute-dose

After HDMTX infusions, i.e. at a dose >1g/m(2), monitoring of serum MTX concentrations is a standard practice which helps reducing the incidence of toxicity in patients with decreased clearance by guiding dose adjustment of leucovorin. Therapeutic monitoring of methotrexate is based on iterative measurements of serum concentration until concentration is below a certain threshold. This practice is supported by numerous observations of exposure-related toxicity as well as some clinical studies comparing drug exposure between patients with and without toxicity. Despite no prospective clinical study has clearly demonstrated the usefulness of methotrexate TDM, historical comparison reveals a huge reduction of toxicity-related events over past decades. Systematic monitoring may also help identifying patients with abnormally high methotrexate concentrations, who require immediate treatment with carboxypeptidase.

Abstract 3602: Radiation pharmacogenomics: an integrative analysis approach to identify biomarkers using the human lymphoblastoid cell lines

Abstract Background Radiation therapy is used to treat half of the all cancer patients. Response to radiation therapy varies widely, in terms of both response and toxicity related events. Previous studies suggested almost 80% of the variation in normal tissue response to radiation treatment was likely to be due to genetic factors. Therefore, we performed a genome-wide association study (GWAS) to identify biomarkers that might help predict radiation response using a the “Human Variation Panel” lymphoblastoid cell lines (LCLs) that consists 287 ethnically defined cell lines. Method Basal gene expression level, 1.3 million genome-wide SNP data were obtained for 287 human LCLs using Affymetrix U133 plus 2.0 GeneChip, Illumina HumanHap 550K, 510S BeadChips and Affymetix SNP Array 6.0. Radiation cytotoxicity assay was also performed to obtain the area under radiation dose response curve (AUC), a summary measure for cytotoxicity for the same cell lines. Functional validation of candidate genes, selected based on the integrated analysis of SNP, expression and AUC data, was performed in multiple cancer cell lines using specific siRNAs followed by MTS and colony formation assays. Results 27 loci, containing at least 2 SNPs of p values &amp;lt;10−4 within 50kb were associated with radiation AUC. 270 expression probe sets were associated with radiation AUC (p&amp;lt; 10−3). The integrated analysis of 27 loci, 54,000 basal expression probe sets and radiation AUC identified 50 unique SNPs associated with AUC were also associated with gene expression of 39 unique annotated genes. In addition, these 39 genes were associated with radiation AUC with p values &amp;lt;10−3. Based on the GWAS and integrated analysis of SNP, expression array and radiation AUC data, 22 genes were selected for functional validation studies using siRNA knock down followed by MTS and colony formation assays in multiple tumor cell lines. C13orf34 (Bora), MAD2L1, PLK4, TPD52 significantly altered the radiation sensitivity in at least 2 cancer cell lines for both MTS and colony formation assays (p&amp;lt;0.05). Knock down of DEPDC1B, a gene containing 2 SNPs at the 3′-end that was significantly related with Bora gene expression level (p&amp;lt;10−4) significantly desensitized cancer cells to radiation treatment. Both microarray data and QRT-PCR analysis indicated that expression levels for those two genes were significantly correlated. Conclusion Our results using the lymphoblastoid cell lines might help identify novel biomarkers that contribute to variation in response to radiation therapy and help understand the mechanisms underlying the association. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3602.

Commentary on ‘‘Toxicity Testing in the 21st Century: A vision and a Strategy’’

Toxicity Testing in the 21st Century: A Vision and a Strategy (NRC, 2007) presents a bold plan for chemical toxicity testing that replaces whole-animal tests with cell-culture, genetic, other in-vitro techniques, computational methods, and human monitoring. Although the proposed vision is eloquently described, and recent advances in in-vitro and in-silico methods are impressive, it is difficult believe that replacing in-vitro testing is either practical or wise. It is not clear that the toxicity-related events that occur in whole animals can be adequately replicated using the proposed methods. Protecting public health is a serious endeavor that should not be limited by denying animal testing. Toxicologists and regulators are encouraged to read the report, carefully consider its implications, and share their thoughts. The vision is for too important to ignore.

Sirolimus and Mycophenolate Mofetil as Graft-Versus-Host Disease Prophylaxis in Myeloablative, Matched Related Donor Hematopoietic Cell Transplantation

We investigated a novel graft-versus-host disease (GVHD) prophylactic regimen, sirolimus and mycophenolate mofetil (MMF), in patients with advanced hematologic malignancies receiving myeloablative hematopoietic cell transplantation (HCT) from matched related donors (MRD). The sirolimus and MMF combination was chosen based on intriguing evidence of sirolimus, and less dramatically MMF, conserving the inhibition of T cell proliferation compared to cyclosporine (CSP) in an AGVHD murine model as well as multiple reports supporting sirolimus' preservative or augmentative effects on the T regulatory cell population (CD4+CD25+, FoxP3+) in animals and humans in comparison to cyclosporine (CSP) and a theoretical reduction in the incidence and severity of AGVHD. In addition, this regimen may cause less severe toxicities compared with standard methotrexate and/or calcineurin inhibitor (CI)-containing GVHD prophylactic regimens. Sirolimus was begun as an oral medication on day -3 with a 12 mg loading dose followed by 4 mgs daily, dose adjusted to maintain serum trough levels of 3–12 ng/ml. MMF was begun on D0 at 15 mg/kg IV every 12 hours. Mycophenolic acid (MPA) pharmacokinetics were conducted on days 2 and 21 post-HCT. Sirolimus and MMF were scheduled to be tapered simultaneously beginning 100 days post-HCT. FoxP3+ cell populations in the peripheral blood (PB) were analyzed before and after HCT in the patients receiving sirolimus and MMF GVHD prophylaxis as well as in 15 control patients with similar disease categories and preparative regimens receiving CI-containing GVHD prophylaxis. Based on pre-study stopping rules of expected grade II–IV AGVHD incidence, the trial was closed to accrual after enrollment of 11 patients. The median age of the 11 patients was 51 years (26–59). The diagnoses of the study patients included myelodysplasia (5), acute myelogenous leukemia (3) and nonhodgkin lymphoma (3). Seven patients received busulfan, etoposide and cyclophosphamide (CY); three patients received carmustine, etoposide and CY and one patient received total body irradiation, etoposide and CY as the preparative regimens. Sirolimus was discontinued in 4 patients due to concern for toxicity-related events including severe sinusoidal obstructive syndrome (1), altered mental status (1), portal vein thrombosis (1) and risk of poor wound healing after abdominal exploratory surgery (1) 9 days, 9 days, 61 days and 39 days post-HCT, respectively. Six of 11 patients developed grade II-IV AGVHD a median of 15.5 days post-HCT (range 11–25 days), 3 of the 6 with grade IV AGVHD. Two of the 3 patients with grade IV AGVHD required discontinuation of sirolimus 9 days post-HCT due to toxicity. Five of the 6 AGVHD patients had skin-only and one had liver, gut and skin involvement. All patients responded to AGVHD therapy and there were no AGVHD-related deaths. One patient died 54 days post-HCT due to complications of colonic ulceration believed related to oral MMF therapy. Two patients died of relapsed disease at 103 and 304 days post-HCT. At a median follow-up of 416 days (328–652 days), 8 of 11 patients were alive without disease, 5 with active chronic GVHD. The median MPA area under the curve (AUC) on day 2 was 12.8 mcg*hr/mL (6.4–17.4) and day 21 was 17.9 mcg*hr/mL (8–26.6). We measured a statistically significant increase in the percentage of CD4+FoxP3+ cells per total CD4+ cells in the sirolimus/MMF study group compared to the CI historical control group with a mean of the individual patient means over the first 100 days post-HCT of 16% versus 6%, respectively (p.0005). Despite the increased percentage of CD4+FoxP3+ cells per total CD4+ cells identified in the PB of the sirolimus/MMF cohort, the incidence of grade II-IV AGVHD was similar to the CI cohort (6 of 11 versus 7 of 15, respectively). However, all but one patient had skin-only AGVHD and there were no GVHD-related deaths in the sirolimus/MMF group. All patients requiring early withdrawal of sirolimus had received the busulfan-containing preparative regimen with two of these patients developing severe AGVHD. In a subsequent GVHD prophylaxis trial including sirolimus and MMF, the busulfan-containing preparative regimen will be eliminated to optimize sirolimus and MMF administration with the continued goal of reducing the incidence and severity of AGVHD.

Disparities in the Use of Chemotherapy and Monoclonal Antibody Therapy for Elderly Advanced Colorectal Cancer Patients in the Community Oncology Setting

The clinical trials on which the treatment of advanced colorectal (CRC) is based enroll few elderly patients. Furthermore, few investigations have determined the use and outcomes of the treatment of advanced CRC in practice. This study evaluated the treatment of advanced CRC in community oncology practices, focusing on age-related differences in treatment and outcome. A national, retrospective chart review was conducted to evaluate the management of advanced CRC in 10 community practices across the U.S. All medical records of patients diagnosed with advanced CRC initiating chemotherapy treatment after January 1, 2003 through 2006 were included. The primary aim was to compare the proportion receiving doublet chemotherapy (irinotecan or oxaliplatin with a fluoropyrimidine) as initial therapy in young (age <or=65 years) and elderly (age >65 years) patients. Additional aims included age-based comparisons of the addition of bevacizumab to chemotherapy, overall chemotherapy use, all-cause mortality, and toxicity-related events. Overall, 520 patients (56% elderly) received 6,253 cycles of chemotherapy. Of the younger patients, 84% received doublet chemotherapy first-line, compared with 58% of elderly patients (p < .001). The use of each of the medications--irinotecan, oxaliplatin, and bevacizumab--was lower in elderly patients (p < .001). Independent predictors of a higher risk for mortality were age >65 (adjusted hazards ratio [HR],1.19; 95% confidence interval [CI], 1.02-1.39) and performance status score >or=2 (HR, 1.65; 95% CI, 1.41-1.91). Elderly patients are less likely to receive first-line doublet chemotherapy than younger patients. Age and performance status are independent predictors of treatment and overall survival.