Dose Intensification Strategies Research Articles

Simulated cost-effectiveness of a novel precision-guided dosing strategy in adult patients with Crohn's disease initiating infliximab maintenance therapy.

Patients with Crohn's disease (CD) who lose response to biologics experience reduced quality of life (QoL) and costly hospitalizations. Precision-guided dosing (PGD) provides a comprehensive pharmacokinetic (PK) profile that allows for biologic dosing to be personalized. We analyzed the cost-effectiveness of infliximab (IFX) PGD relative to two other dose intensification strategies (DIS). We developed a hybrid (Markov and decision tree) model of patients with CD who had a clinical response to IFX induction. The analysis had a US payer perspective, a base case time horizon of 5 years, and a 4-week cycle length. There were three IFX dosing comparators: PGD; dose intensification based on symptoms, inflammatory markers, and trough IFX concentration (DIS1); and dose intensification based on symptoms alone (DIS2). Patients that failed IFX initiated ustekinumab, followed by vedolizumab, and conventional therapy. Transition probabilities for IFX were estimated from real-world clinical PK data and interventional clinical trial patient-level data. All other transition probabilities were derived from published randomized clinical trials and cost-effectiveness analyses. Utility values were sourced from previous health technology assessments. Direct costs included biologic acquisition and infusion, surgeries and procedures, conventional therapy, and lab testing. The primary outcomes were incremental cost-effectiveness ratios (ICERs). The robustness of results was assessed via one-way sensitivity, scenario, and probabilistic sensitivity analyses (PSA). PGD was the cost-effective IFX dosing strategy with an ICER of 122,932 $ per quality-adjusted life year (QALY) relative to DIS1 and dominating DIS2. PGD had the lowest percentage (1.1%) of patients requiring a new biologic through 5 years (8.9% and 74.4% for DIS1 and DIS2, respectively). One-way sensitivity analysis demonstrated that the cost-effectiveness of PGD was most sensitive to the time between IFX doses. PSA demonstrated that joint parameter uncertainty had moderate impact on some results. PGD provides clinical and QoL benefits by maintaining remission and avoiding IFX failure; it is the most cost-effective under conservative assumptions.

P684 Using a pharmacokinetic simulation model to determine the optimal infliximab intensification strategy to address loss of response in inflammatory bowel disease

Abstract Background The optimal dose intensification strategy to address loss of response associated with low infliximab levels remains uncertain. Favorable associations between higher infliximab levels and objective endpoints imply that post-intensification trough and treatment targets may have utility. This simulation study aimed to identify intensification strategies capable of achieving post-intensification trough thresholds associated with aspirational treatment targets in Crohn’s disease (CD) and ulcerative colitis (UC). Methods A previously published infliximab pharmacokinetic model, applied to 200 simulated patients, identified those with subtherapeutic(<3.00mg/L) trough levels after 30-weeks of standard dosing, and subsequently applied ten dose intensification strategies (Figure 1) over a further 32 weeks. The proportion of simulations achieving infliximab trough thresholds associated with endoscopic remission (CD >9.7mg/L; UC >7.5mg/L) was the primary outcome, with clinical improvement (CD >7.0mg/L; UC >3.7mg/L) and perianal fistula healing (CD >10.1mg/L) representing secondary outcomes. Outcomes were stratified by intensity of dose intensification, with five deemed intensive (>10mg/kg 8-weekly). The impact of pre-intensification antibodies to infliximab (ATI) on post-intensification trough levels was also evaluated. Results The median pre-intensification infliximab trough level was 0.91mg/L (IQR 1.31). Intensive intensification strategies were more likely to achieve infliximab trough concentrations associated with endoscopic remission (UC: 34.76 v 10.56%, CD: 25.80 v 4.92%), clinical improvement (UC: 61.40 v 34.52%, CD: 39.58 v 12.12%) and perianal fistula healing (24.70 v 4.50%, all p<0.01) than standard intensification strategies (Figure 2). When controlling for cumulative (mg/kg) infliximab dose over 32 weeks, strategies that concurrently dose increased and interval shortened achieved the highest trough levels (all p<0.01). Patients simulated to have ATI prior to dose intensification had lower median infliximab trough levels at weeks 30/32 (3.38 mg/L, IQR 5.52 mg/L) compared to those without ATI (3.89 mg/L IQR 6.14 mg/L) across all dose intensification strategies (p=0.015). Conclusion This simulation-based analysis highlights the potential of using post-intensification trough level targets to guide dosing strategy and intensity. Combined high-dose, interval-shortened strategies appear to achieve higher infliximab levels, which may be important in the pursuit of stringent endpoints such as endoscopic remission and fistula healing. These findings require validation across real-world cohorts.

Radiotherapy intensification for atypical and malignant meningiomas: A systematic review.

The outcomes of nonbenign (WHO Grades 2 and 3 [G2, G3]) meningiomas are suboptimal and radiotherapy (RT) dose intensification strategies have been investigated. The purpose of this review is to report on clinical practice and outcomes with particular attention to RT doses and techniques. The PICO criteria (Population, Intervention, Comparison, and Outcomes) were used to frame the research question, directed at outlining the clinical outcomes in patients with G2-3 meningiomas treated with RT. The same search strategy was run in Embase and MEDLINE and, after deduplication, returned 1 807 records. These were manually screened for relevance and 25 were included. Tumor outcomes and toxicities are not uniformly reported in the selected studies since different endpoints and time points have been used by different authors. Many risk factors for worse outcomes are described, the most common being suboptimal RT. This includes no or delayed RT, low doses, and older techniques. A positive association between RT dose and progression-free survival (PFS) has been highlighted by analyzing the studies in this review (10/25) that report the same endpoint (5y-PFS). This literature review has shown that standard practice RT leads to suboptimal tumor control rates in G2-3 meningiomas, with a significant proportion of disease recurring after a relatively short follow-up. Randomized controlled trials are needed in this setting to define the optimal RT approach. Given the increasing data to suggest a benefit of higher RT doses for high-risk meningiomas, novel RT technologies with highly conformal dose distributions are preferential to achieve optimal target coverage and organs at risk sparing.

S824 Cost-Effectiveness of Precision-Guided Dosing in Adult Crohn’s Disease Patients Initiating Infliximab Maintenance Therapy

Introduction: Crohn’s disease (CD) patients that lose response to biologics experience reduced quality of life (QoL) and costly hospitalizations. Precision-guided dosing provides clinicians with a comprehensive pharmacokinetic (PK) profile that allows for the next biologic dose to be personalized. We analyzed the cost-effectiveness of infliximab (IFX) Precision-guided dosing relative to two IFX dose intensification strategies (DIS). Methods: We developed a hybrid (Markov and decision tree) model of CD patients who had a clinical response to IFX induction and entered IFX maintenance in “remission” or “mild symptoms” health states. The analysis took a US payer perspective, a time horizon of 2 years in the base case, and a cycle length of 4 weeks. There were 3 comparators for IFX dosing: Precision-guided dosing, dose intensification based on symptoms, inflammatory markers, and trough IFX concentration (DIS1), and IFX dose intensification based on symptoms alone (DIS2). Patients that failed IFX initiated ustekinumab (UST), followed by vedolizumab, and conventional therapy. Transition probabilities for IFX were estimated from real-world clinical PK data and interventional clinical trial (PMID: 34978325; 29317275) patient-level data. All other transition probabilities were derived from published randomized clinical trials and cost-effectiveness analyses. Utility values were sourced from previous health technology assessments. Direct costs included biologic acquisition and infusion, surgeries and procedures, conventional therapy, and lab testing. The primary outcomes were total discounted costs, total quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs). The robustness of results was assessed via one-way sensitivity and scenario analyses. Results: Total costs and QALYs at 2 years are presented in Table. The ICERs of Precision-guided dosing relative to DIS1 and DIS2 were 171,810 and 127,990, respectively. One-way sensitivity analyses (Figure) demonstrated that the cost-effectiveness of Precision-guided dosing was most sensitive to the time between IFX doses. Precision-guided dosing had the lowest proportion of patients requiring a new biologic through 2 years (0.5% vs 2.4% and 27.7% for DIS1 and DIS2, respectively). Conclusion: Precision-guided dosing provides substantial clinical and QoL benefits for adult CD patients by maintaining clinical remission and avoiding IFX failure; it is cost-effective relative to other DISs at a WTP of $175,000/QALY.Figure 1.: Precision-guided Dosing ICER Relative to DIS2 † Varied by ±10% * Varied by ±5% CD: Crohn's disease, DIS: dose intensification strategy, ICER: incremental cost-effectiveness ratio, IFX: infliximab, M-S: moderate-severe, PMPM: per member per month, Rem: remission Table 1. - Base Case Results (2-year Horizon Discounted) DIS Total QALYs Total Costs ICER Relative to Precision-guided Dosing ICER Relative to DIS1 ICER Relative to DIS2 Incremental NMB vs DIS1 (WTP $150,000/QALY) Incremental NMB vs DIS1 (WTP $50,000/QALY) Incremental NMB vs DIS2 (WTP $150,000/QALY) Incremental NMB vs DIS2 (WTP $50,000/QALY) Precision-guided Dosing* 1.572 $50,753 - 171,810 127,990 -$765 -$4,274 $1,816 -$6,436 DIS1† 1.537 $44,725 171,810 - 95,581 - - $2,581 -$2,162 DIS2 ‡ 1.489 $40,191 127,990 95,581 - -$2,581 $2,162 - - DIS: dose intensification strategy, ICER: incremental cost-effectiveness ratio, NMB: net monetary benefit, QALY: quality-adjusted life year, WTP: willingness to pay.*Model informed precision dosing with homogenous mobility shift assay (Prometheus Laboratories).†Dose intensification based on a combination of symptoms, inflammatory markers and proactive therapeutic drug monitoring. Corresponds to cohorts 1 and 2 of the TAILORIX clinical trial.‡Dose intensification reactive on symptoms only. Corresponds to cohort 3 of the TAILORIX clinical trial.

P462 Upfront infliximab dose intensification for secondary loss of response in IBD: similar efficacy to dose interval shortening with the added advantage of early clinical and pharmacokinetic predictors of response

Abstract Background The efficacy and pharmacokinetic profile of upfront dose intensification strategies such as re-induction (RI) have not been well described, nor directly compared with more prevalent intensification strategies to address secondary loss of response (LOR) in inflammatory bowel disease (IBD). Hence this study aimed to prospectively compare infliximab RI and 6-weekly dose interval shortening (DIS) with reference to clinical and pharmacokinetic effectiveness, and to identify early predictors of response. Methods A prospective multicentre parallel cohort study of consecutive patients with IBD who underwent dose intensification to address secondary LOR using (1) infliximab RI (i.e. repeat week 0,2,6 dosing) followed by 8-weekly maintenance, or (2) 6-weekly DIS, over 30 weeks (6 doses) was undertaken. Primary outcomes were: (1) Clinical response, defined as a decrease in Harvey Bradshaw Index ≥3 or partial Mayo score ≥2 from pre-intensification baseline, assessed at weeks 12 and 32, and (2) Clinical and pharmacokinetic predictors of week 32 response, with serum infliximab samples collected at predefined timepoints (Figure 1). Patients who were dose intensified in the absence of clinical symptoms, were excluded from the primary analysis. Results Of 104 patients, 54 underwent RI and 50 underwent 6-weekly DIS (Table 1), including 43 patients from each cohort who were dose intensified to address clinically active disease. Baseline infliximab trough levels prior to RI and DIS (2.03 v 2.02ug/ml, p=0.83) were comparable. Clinical response was similar across both RI and DIS cohorts at weeks 12 (70 v 65%, p=0.89) and 32 (53 v 63%, p=0.51). Multivariate logistic analyses demonstrated that objectively verified active disease at baseline (OR 20.43[2.53–64.94]; p=0.005) and clinical response at week 12 (OR 15.44[1.20–19.97]; p=0.036) were associated with week 32 response, as were week 2 infliximab levels within the RI cohort only (OR 1.34[1.02–1.47]; p=0.036). Following RI, week 2 infliximab levels below 15.6ug/ml (sensitivity 100.0%; specificity 42.9%; AUROC 0.76; p<0.05) were predictive of not achieving clinical response at week 32; potentially indicating that amongst this patient subset, week 12 clinical response may be useful in differentiating between early clinical responders who may benefit from sequential DIS following RI to prevent subsequent non-response, and early clinical non-responders who may benefit from early biologic switching. Conclusion Despite similar clinical outcomes across both dose intensification strategies, only upfront dose intensification using infliximab RI was associated with early clinical and pharmacokinetic predictors of response capable of facilitating early dose optimisation and biologic switching.

Systematic review and meta-analysis: evaluating response to empiric anti-TNF dose intensification for secondary loss of response in Crohn's disease.

Introduction:Anti-tumor necrosis factor (TNF) dose intensification represents an effective method of overcoming secondary loss of response (LOR); however, a subset of patients may not respond (tertiary non-response), or fail to demonstrate durable response (tertiary LOR) to intensified dosing. This systematic review and meta-analysis aimed to evaluate these outcomes to determine the clinical effectiveness of empiric dose intensification in Crohn’s disease.Methods:Multiple databases including MEDLINE and EMBASE were interrogated to identify studies that reported outcomes following anti-TNF dose intensification to address secondary LOR in Crohn’s disease. Studies that used anti-TNF levels as the primary basis for dose intensification were excluded. Studies that reported (1) tertiary response and tertiary non-response within 6 months or (2) tertiary response and tertiary LOR beyond 6 months, were pooled using a random effects model with risk ratio (RR) derived, quantifying the effect of each comparison.Results:Twenty-six studies reported outcomes following anti-TNF dose intensification to address secondary LOR. Short-term response within 12 weeks of any dose-intensification strategy was 33–90%, while sustained response (⩾48 weeks) was achieved in 25–85%. Tertiary non-response occurred in up to 45% of intensified patients within 6 months of anti-TNF dose intensification, while tertiary LOR beyond 6 months occurred in up to 64% of patients. Tertiary response was more likely than tertiary non-response within 6 months (RR 2.58, 95% CI (1.76, 3.79), I2 = 82%, 12 studies), while sustained response beyond 6 months compared to tertiary LOR (RR 1.10 (0.75, 1.61) I2 = 85%, 7 studies) was less convincing.Conclusion:Although anti-TNF dose intensification is clinically effective in patients with Crohn’s disease, particularly within the first 6 months, a proportion of patients will fail to demonstrate short-term and/or sustained clinical response. Hence, clinical reassessment following anti-TNF dose intensification, particularly beyond 6 months, remains important to differentiate between effective and ineffective dose-intensification strategies.

CCG 1953: Acute Lymphoblastic Leukemia in Infants: Analysis of Prognostic Factors: A Report from the Children's Oncology Group.

Background: Infant ALL has a poor therapeutic outcome. In contrast to other subtypes of ALL, infants have not benefited from risk-adapted therapy and intensification of therapy. This is the first cooperative group trial characterizing all infants at the molecular level for MLL/11q23 rearrangements for better stratification in future trials.Procedure: All infants enrolled on CCG 1953 were tested for MLL rearrangement by Southern Blot, and the 11q23 translocation partner was identified (4;11, 9;11, 11;19, or “other”) by reverse-transcriptase PCR.Results: 115 infants were enrolled (July 1996 to August 2000). Treatment for patients consisted of 4 courses of induction-consolidation-intensification followed by 3 cycles of intensified maintenance and 4 cycles of routine maintenance. Infants with 11q23/MLL abnormalities and a protocol-defined 5-6/6 related or unrelated donor identified within 4 months were assigned to BMT. Central nervous system prophylaxis consisted of triple intrathecal therapy during the first 10 weeks of therapy. Infants not undergoing BMT received additional CNS prophylaxis with very high dose methotrexate. Patients then received one year of intensified maintenance, followed by a year of standard maintenance. Overall event-free survival (EFS) was 41.7% (SD = 9.2%) and overall survival (OS) was 44.8% at 5 years. Five-year EFS for MLL rearranged cases was 33.6%, and for MLL non-rearranged cases was 60.3% (p=.006). 5-year EFS for MLL/11q23 subgroups was as follows: t(4;11): 29.0%; t(11;19): 30.0%; t(9;11): 22.2%; and “other 11q23” 53.5% (p=.122). Multivariate Cox regression analyses showed a rank order of significance for negative impact on prognosis for CD10 negativity, age less than 6 months, and MLL rearrangement, in that order. We did not observe a statistically significant difference in outcome between different MLL translocation partners, though we did observe a non-significant trend toward improved outcome in patients with “other” MLL translocation partners as compared to those with t(4;11), t(9;11) or t(11;19). Toxicity was the most frequent cause of death. Relapse as a first event in 1953 was later (median 295 days) compared to the predecessor1883 infant ALL trial (median 207 days).Conclusions: MLL/11q23 rearrangement, CD10 expression, and age are important prognostic factors in infant ALL, but individual molecular 11q23 translocation partners do not predict outcome. These results indicate that certain subgroups have an unusually poor outcome and are therefore candidates for novel therapeutic approaches in first remission. Given the high mortality, further dose intensification strategies are unlikely to result in better long-term survival.

Systematic review: efficacy of escalated maintenance anti-tumour necrosis factor therapy in Crohn's disease.

Loss of response to anti-TNF agents is a common clinical problem. Dose escalation may be effective for reestablishing clinical response in Crohn's disease (CD). To perform a systematic review assessing the efficacy of escalated maintenance anti-TNF therapy in CD. EMBASE, MEDLINE, Web of Science, and CENTRAL databases were searched for English language publications through to April 25, 2021. Full-text articles evaluating escalated maintenance treatment (infliximab or adalimumab) in adult CD patients were included. A total of 4733 records were identified, and 68 articles met eligibility criteria. Rates of clinical response (33%-100%) and remission (15%-83%) after empiric dose escalation for loss of response to standard anti-TNF therapy were high but varied across studies. Dose intensification strategies (doubling the dose versus shortening the therapeutic interval) were similarly efficacious. Dose-escalated patients tended to have higher serum drug levels compared to those on standard dosing. An exposure-response relationship following dose escalation was found in a number of observational studies. Randomised controlled trials comparing therapeutic drug monitoring (TDM) to empiric treatment intensification have failed to reach their primary end-points. Strategies including Bayesian dashboard-dosing and early treatment escalation targeting biomarker normalisation were found to be associated with improved long-term outcomes. Empiric escalation of maintenance anti-TNF therapy can recapture clinical response in a majority of patients with secondary loss of response to standard maintenance doses. Proactive optimisation of maintenance dosing might prolong time to loss of response in some patients.

Expression and significance of CD47, PD1 and PDL1 in T-cell acute lymphoblastic lymphoma/leukemia

Although dose intensification strategies achieve a favorable prognosis for pediatric patients of T-lmphoblastic lymphoma/leukemia (T-LBL/ALL), numerous side effects have been followed. Molecular targeted therapies will be needed to optimize the current treatment strategy for T-LBL/ALL. The aim of this study was to analyse expression and significance of CD47, PD1 and PDL1 in. T-LBL/ALL. We performed immunohistochemistry staining and real time fluorescence quantitative PCR (qRT-PCR) on FFPE tissues. Immunohistochemistry results showed that the high expression rate of CD47 protein was 46.4% (26/56) and the positive expression rate of PDL1 protein was 37.5% (21/56). PD1 expression was observed in tumor infiltrating lymphocytes in approximately 20% of T-LBL/ALL patients, but not expressed on tumor cells of T-LBL/ALL. And the results of qRT-PCR showed that the relative expression levels of CD47, PDL1 and PD1 mRNA in 56 cases of T LBL/ALL were significantly higher than those in control group (6.915 vs 4.050, 12.255 vs 2.575, 37.990 vs 3.615), and the differences were all statistically significant (p all <0.05). Univariate analysis showed that age, CD47 protein, CD47 mRNA,PDL1 protein and PDL1 mRNA expression were closely correlated with prognosis (P all <0.05). We found that the overall one-year survival rates of patients with a high expression (≥M) of CD47 and PDL1 mRNA were higher than in patients with low expression (<M). However, the overall one-year survival rate of patients with a high expression (≥M) of CD47 and PDL1 protein were lower than in patients with low expression (<M). And patients with ≤25 years old had a worse prognosis than with >25 years old. Multivariate Cox regression analysis showed that the high expression of CD47 and PDL1 protein were independent prognostic factors (both p < 0.05). In a word, PD1/PDL1 and CD47 may be involved in the disease progression and prognosis of T-LBL/ALL, and detection and targeting of CD47 and PD1/PDL1 may provide a rational basis to for treatment of T-LBL/ALL.

The Negative Impact of Longer Delays to Starting Radiation after Surgery for Head and Neck Cancer Patients in the United States

For patients with head and neck cancer, the National Comprehensive Cancer Network recommends keeping the time from surgery to radiation (TS-RT) under 6 weeks when adjuvant therapy is given. However, an associated survival benefit remains controversial. We set out to explore the effect of a delayed TS-RT for patients in the US. Patients with squamous cell carcinoma of the oropharynx, oral cavity, hypopharynx, and larynx treated with definitive surgery followed by adjuvant radiation between 2004-2013 were identified from the National Cancer Database. Overall survival (OS) was compared according to a 6-week TS-RT cutoff. The effect of ≤42 day, 43-49 day, or ≥50 day TS-RT was tested using multivariate Cox regressions controlling for socioeconomic variables, comorbidity, clinicopathologic risk factors, type of facility, distance travelled, time from diagnosis to surgery, length of hospital stay, unplanned hospital readmissions, chemotherapy, radiation dose, and use of IMRT. The effect of accelerated fractionation (≥5.2 fractions/week) was tested according to length of TS-RT. We identified 42,740 patients. Median OS was greater for the 19,859 (46%) patients with a ≤6 week TS-RT (10.0 years vs 7.7 years, P < .0001). Compared to a ≤42 day TS-RT, there was no significant increase in mortality with a 43-49 day TS-RT (HR 1.03, P = .19), although there was for a ≥50 day TS-RT (HR 1.11, P <.0001). Compared to patients who had both surgery and radiation at an academic center, those who transferred care after surgery at an academic hospital (HR 1.12, P =.0001), or had all care at a Comprehensive Community Cancer Program (HR 1.06, P = .01) or all care at a community center (HR 1.08, P = .03) had inferior OS. For patients with a >6 week TS-RT, accelerated fractionation was associated with improved OS (HR 0.92, P = .02), and for those with a ≤6 week TS-RT there was a trend for improved OS (HR 0.93, P = .08). A TS-RT delayed >7 weeks is associated with worse overall survival. Treatment at academic centers may be associated with improved outcomes, and the benefit to care at specialized centers should continue to be explored. Treating teams should focus on shortening TS-RT, and unavoidable delays may warrant consideration of accelerated fractionation or other dose intensification strategies.

Association of Survival With Shorter Time to Radiation Therapy After Surgery for US Patients With Head and Neck Cancer

Shortening the time from surgery to the start of radiation (TS-RT) is a consideration for physicians and patients. Although the National Comprehensive Cancer Network recommends radiation to start within 6 weeks, a survival benefit with this metric remains controversial. To determine the association of delayed TS-RT with overall survival (OS) using a large cancer registry. In this observational cohort study, 25 216 patients with nonmetastatic stages III to IV head and neck cancer were identified from the National Cancer Database (NCDB). Patients received definitive surgery followed by adjuvant radiation therapy, with an interval duration defined as TS-RT. Overall survival as a function of TS-RT and the effect of clinicopathologic risk factors and accelerated fractionation. We identified 25 216 patients with nonmetastatic squamous cell carcinoma of the head and neck. There were 18 968 (75%) men and 6248 (25%) women and the mean (SD) age of the cohort was 59 (10.9) years. Of the 25 216 patients, 9765 (39%) had a 42-days or less TS-RT and 4735 (19%) had a 43- to 49-day TS-RT. Median OS was 10.5 years (95% CI, 10.0-11.1 years) for patients with a 42-days or less TS-RT, 8.2 years (95% CI, 7.4-8.6 years; absolute difference, -2.4 years, 95% CI, -1.5 to -3.2 years) for patients with a 43- to 49-day TS-RT, and 6.5 years (95% CI, 6.1-6.8 years; absolute difference, -4.1 years, 95% CI, -3.4 to -4.7 years) for those with a 50-days or more TS-RT. Multivariable analysis found that compared with a 42-days or less TS-RT, there was not a significant increase in mortality with a 43- to 49-day TS-RT (HR, 0.98; 95% CI, 0.93-1.04), although there was for a TS-RT of 50 days or more (HR, 1.07; 95% CI, 1.02-1.12). A significant interaction was identified between TS-RT and disease site. Subgroup effect modeling found that a delayed TS-RT of 7 days resulted in significantly worse OS for patients with tonsil tumors (HR, 1.22; 95% CI, 1.05-1.43) though not other tumor subtypes. Accelerated fractionation of 5.2 fractions or more per week was associated with improved survival (HR, 0.93; 95% CI, 0.87-0.99) compared with standard fractionation. Delayed TS-RT of 50 days or more was associated with worse overall survival. The multidisciplinary care team should focus on shortening TS-RT to improve survival. Unavoidable delays may be an indication for accelerated fractionation or other dose intensification strategies.

Review article: dose optimisation of infliximab for acute severe ulcerative colitis.

Although optimal medical management of acute severe ulcerative colitis (UC) is ill-defined, infliximab has become a standard of care. Accumulating evidence suggests an increased rate of infliximab clearance in patients with acute severe UC and a reduced colectomy rate with an intensified infliximab induction regimen. To assess the strength of the current evidence for the relationship between infliximab pharmacokinetics, dosing strategies and disease behaviour in patients with acute severe UC. We systematically searched MEDLINE and conference proceedings from 2000 to 2016 for relevant articles describing the pharmacokinetics of infliximab in acute severe UC and/or infliximab dose intensification strategies in acute severe UC. Eligible articles described randomised controlled trials, and cohort, cross-sectional, and case-controlled studies. Of 400 citations identified, 76 studies were eligible. Increased infliximab clearance occurs in patients with acute severe UC, and is driven by the total inflammatory burden and leakage of drug into the colonic lumen. Several cohort studies suggest that infliximab dose intensification is beneficial to at least 50% of acute severe UC patients and the results of case-controlled studies indicate that an intensified infliximab dosing regimen with 1-2 additional infusions in the first 3 weeks of treatment could reduce the early (3-month) colectomy rate by up to 80%, although these data require prospective validation. Uncontrolled studies suggest a benefit for infliximab dose optimisation in patients with acute severe UC. A randomised controlled trial in acute severe UC patients comparing a personalised infliximab dose-optimisation strategy with conventional dosing is a research priority.

Cancers bronchiques à petites cellules étendus Traitement standard et nouvelles approches thérapeutiques

Extensive-stage small-cell lung cancer (ES-SCLC) represents 70% of SCLC. Firstline treatment is based on chemotherapy. Cisplatin or carboplatin-etoposide combination is the standard chemotherapy. Objective response is around 60 to 75%. Maintenance chemotherapy or dose-intensification strategies did not improve survival. In asian population, cisplatine-irinotecan combination gives better results in terms of survival than cisplatine-etoposide. Topotecan is the only approved drug in second-line treatment. Reintroduction of the first-line chemotherapy regimen is a good option for chemo-sensitive patients. Use of anti-angiogenic agents is not recommanded. Currently, no targeted therapy can be use in SCLC. Molecular characterization of SCLC is at the beginning. The development of immunotherapy and check-points blockade could be a future direction for ES-SCLC treatment. Studies are ongoing. Finally, prophylactic cranial irradiation is recommanded for good responder patients to chemotherapy.

Local control after fractionated stereotactic radiation therapy for brain metastases.

Stereotactic radiosurgery (SRS) is frequently used in the management of brain metastases, but concerns over potential toxicity limit applications for larger lesions or those in eloquent areas. Fractionated stereotactic radiation therapy (SRT) is often substituted for SRS in these cases. We retrospectively analyzed the efficacy and toxicity outcomes of patients who received SRT at our institution. Seventy patients with brain metastases treated with SRT from 2006-2012 were analyzed. The rates of local and distant intracranial progression, overall survival, acute toxicity, and radionecrosis were determined. The SRT regimen was 25 Gy in 5 fractions among 87 % of patients. The most common tumor histologies were non-small cell lung cancer (37 %), breast cancer (20 %) and melanoma (20 %), and the median tumor diameter was 1.7 cm (range 0.4-6.4 cm). Median survival after SRT was 10.7 months. Median time to local progression was 17 months, with a local control rate of 68 % at 6 months and 56 % at 1 year. Acute toxicity was seen in 11 patients (16 %), mostly grade 1 or 2 with the most common symptom being mild headache. Symptomatic radiation-induced treatment change was seen on follow-up MRIs in three patients (4.3 %). SRT appears to be a safe and reasonably effective technique to treat brain metastases deemed less suitable for SRS, though dose intensification strategies may further improve local control.

Prostate brachytherapy: the impact of smoking on recurrence and overall survival of localized prostate cancer

Brachytherapy has been shown to be an efficacious and cost-effective treatment among patients with localized prostate cancer. In this study, we examined the effects of smoking on prostate cancer recurrence and mortality in patients undergoing brachytherapy for locally advanced prostate cancer. The study population consisted of 405 patients with an average age of 73.4 years. Smoking history included 88 (21.7%) patients with no history of smoking, 108(26.6%) patients with one to twenty pack-years, and 209 (51.7%) patients with twenty-one or more pack-years. The impact of smoking history on OS relative to nonsmokers was hazards ratio 1.39 (CI: 0.81-2.64; P&lt;0.05). In conclusion, the era of brachytherapy dose and treatment intensification strategies to improve upon prostate cancer outcomes, our study showed that smoking increases the risk of cancer recurrence and mortality. Patients who have smoked a higher number of pack-years are at increased risk of recurrence and mortality compared to those who smoked less.

Dose-Limiting Toxicity After Hypofractionated Dose-Escalated Radiotherapy in Non–Small-Cell Lung Cancer

Local failure rates after radiation therapy (RT) for locally advanced non-small-cell lung cancer (NSCLC) remain high. Consequently, RT dose intensification strategies continue to be explored, including hypofractionation, which allows for RT acceleration that could potentially improve outcomes. The maximum-tolerated dose (MTD) with dose-escalated hypofractionation has not been adequately defined. Seventy-nine patients with NSCLC were enrolled on a prospective single-institution phase I trial of dose-escalated hypofractionated RT without concurrent chemotherapy. Escalation of dose per fraction was performed according to patients' stratified risk for radiation pneumonitis with total RT doses ranging from 57 to 85.5 Gy in 25 daily fractions over 5 weeks using intensity-modulated radiotherapy. The MTD was defined as the maximum dose with ≤ 20% risk of severe toxicity. No grade 3 pneumonitis was observed and an MTD for acute toxicity was not identified during patient accrual. However, with a longer follow-up period, grade 4 to 5 toxicity occurred in six patients and was correlated with total dose (P = .004). An MTD was identified at 63.25 Gy in 25 fractions. Late grade 4 to 5 toxicities were attributable to damage to central and perihilar structures and correlated with dose to the proximal bronchial tree. Although this dose-escalation model limited the rates of clinically significant pneumonitis, dose-limiting toxicity occurred and was dominated by late radiation toxicity involving central and perihilar structures. The identified dose-response for damage to the proximal bronchial tree warrants caution in future dose-intensification protocols, especially when using hypofractionation.

Prognostic and Predictive Impact of Expression of the Angiogenic Markers CD105 and CD31 Expression in Patients with High Risk Breast Cancer (HRBC).

Abstract Purpose: Several angiogenic factors have been reported to influence prognosis of breast cancer and spread to regional lymph nodes. CD105 (Endoglin) is expressed by human vascular endothelial cells and plays a major role in angiogenesis. Similarly, CD31 is a platelet endothelial cell adhesion molecule involved in normal and pathologic vessel function. In the prospective randomized WSG-AM-01 trial HRBC patients with more than 9 positive lymph nodes derived particular benefit from tandem high-dose (HD) rather than dose-dense (DD) chemotherapy with regard to both event-free (EFS) and overall survival (OS), particularly among tumors carrying a basal-like or HER2 molecular phenotype. The goal of the present study was to examine the interaction between angiogenic factors and efficacy of different dose intensification strategies in the WSG-AM-01 trial among both unselected patients as well as among distinct molecular disease subtypes.Methods: Immunohistochemical staining for CD31 (n=128) and CD105 (n=130) was performed to assess vascular surface area (VSA) separately for both factors using the Chalkley count method.Expression of estrogen (ER) and progesterone receptor (PR), HER2, Ki67, and epidermal growth factor receptor (EGFR) was analyzed immunohistochemically using tissue microarrays, allowing for stratification into molecular breast cancer subclasses (k-clustering k=5 by expression of 24 proteins). Correlation analysis between CD31 and CD105 expression and molecular subtypes was carried out using Pearson correlations. Univariate survival estimates were determined by Kaplan-Meier analysis and tested for significance by log rank statistics. Multivariate survival modeling was performed by a generalized Cox model, with linear proportional hazards terms in the first block and time-varying interactions in the second block.Results: Both VSA/CD 31 and VSA/CD105 showed significantly higher expression among HER-2 and basal-like breast cancer subtypes (p=0.007), as well as among cases wit increased Ki67 (p=0.005).Increased VSA/CD105 (above a median of 1.295) was associated with significantly decreases in both EFS (p=0.01) and OS (p=0.02). In multivariate analysis (including therapy, tumor size, age and grade as well as expression of ER, PR, HER-2 and Ki-67) increased VSA/CD 105 was an independent prognostic factor for decreased EFS (HR=1.68, p=0.05). Dose intensification showed significantly increased efficacy (for OS and EFS) only among patients with low VSA/CD105 tumors.Discussion: Expression of angiogenic markers may mirror/confer resistance to chemotherapy among patients with breast cancer, particularly in the context of dose intensified chemotherapy and may explain differences observed among distinct molecular breast cancer phenotypes. The correlation observed between angiogenic markers and distinct molecular subtypes may serve as a rationale for exploring antiangiogenic treatment options in patients carrying these tumors. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2154.

Lipid nanocapsules: Ready-to-use nanovectors for the aerosol delivery of paclitaxel

Aerosol drug delivery permits the development of dose-intensification strategies in severe, malignant lung diseases. The aim of the study was to demonstrate that the encapsulation of paclitaxel in lipid nanocapsules (LNCs), a novel drug nanocarrier for lipophilic components, allows one to provide pulmonary drug delivery of paclitaxel by nebulisation, thereby allowing preclinical and clinical studies. LNC dispersions are made into aerosols with commercial nebulisers. The structure, drug payload and cytotoxicity of nebulised LNCs were compared to fresh LNCs. The results demonstrated that LNC dispersions could be made into aerosols by using mesh nebulisers without altering the LNC structure. Only eFlow rapid-produced aerosols are compatible with human use: the mean duration to nebulise 3 ml of LNC dispersion is less than 9 min, with an aerosol mass median aerodynamic diameter equal to 2.7+/-0.1 microm and a fine-particle fraction (between 1.0 and 5.0 microm) of 81.5+/-3.1%. No modifications of drug payload or cytotoxicity effects of paclitaxel-loaded LNC (PTX-LNC) were observed. In order to carry out preclinical studies, a scaled-up LNC formulation protocol was used. Chemical parameters, such as acidity and osmolarity, were optimised, and a storage procedure for PTX-LNC batches was set-up. Animal studies are now needed to determine the tolerance and therapeutic potential of LNC dispersion aerosols.

Triple-negative high-risk breast cancer derives particular benefit from dose intensification of adjuvant chemotherapy: results of WSG AM-01 trial

BackgroundThis paper evaluates the prognostic and predictive impact of protein expression of various molecular markers in high-risk breast cancer (HRBC) patients with >9 involved lymph nodes, who received different chemotherapy dose-intensification strategies within a prospective randomized WSG AM-01 trial. Materials and methodsParaffin-embedded tumors from 236 patients, who were randomly assigned to dose-dense conventional chemotherapy with four cycles of E90C600 followed by three cycles of C600M40F600 every 2 weeks (DD) or a rapidly cycled tandem high-dose regimen with two cycles of E90C600 every 2 weeks followed by two cycles of E90C3000Thiotepa400 every 3 weeks (HD), were available for retrospective central pathological review (116 HD/120 DD). Expression of estrogen receptor (ER), progesterone receptor (PR), MIB-1, epidermal growth factor receptor, and Her-2/neu was evaluated immunohistochemically using tissue microarrays. Results were correlated with follow-up data and treatment effects by proportional hazard Cox regression models (including interaction analysis). ResultsAfter a median follow-up of 61.7 months, 5-year event-free survival (EFS) as well as overall survival (OS) rates for the 236 patients were significantly better in the HD arm: EFS: 62% versus 41% [hazard ratio (HR) = 0.60, 95% CI 0.43–0.85, P = 0.004]; OS: 76% versus 61% (HR = 0.58, 95% CI 0.39–0.87, P = 0.007). In multivariate analysis, HD, tumor size <3 cm, positive PR, negative MIB-1 staining, and grade 1/2 were associated with favorable outcome. Interaction analysis showed that regarding predictive effects, triple negative (ER/PR/Her-2/neu) and G3 tumors derived most benefit from HD. ConclusionTandem HD improves both EFS and OS in HRBC. This therapy effect may be partly attributable to superior efficacy in the subgroup of triple-negative tumors and/or G3 with their poor prognostic marker profile.

YB-1 expression and effectiveness of different dose-intensification strategies in high-risk breast cancer: Five-year follow-up results of prospective randomized WSG-AM-01 trial

563 Background: Y-box binding protein (YB-1), known as oncogenic transcription factor, is associated with up-regulation of MDR1, alters p53 function, and induces growth of an aggressive phenotype. In high-risk breast cancer, the prospective randomized WSG-AM-01 trial has reported significantly better event-free (EFS) and overall survival (OS) for tandem high-dose (HD) vs. dose-dense (DD) chemotherapy, especially in basal-like und HER2 subgroups. The present study examines the interaction of a drug resistant phenotype induced by YB-1 within the WSG-AM-01 collective at 5-year follow-up. Methods: 236 tumors (116 HD/120 DD) of 403 randomized patients (60%) were available for construction of tissue microarrays and determination of molecular classification by k-clustering of expression of 34 protein markers. Immunostaining of YB-1 by specific peptide antibody was scored semiquatitatively by intensity. Associations of YB-1 staining with other protein expression factors were studied by Pearson correlations. Univariate survival was estimated by Kaplan-Meier analysis and tested by log rank statistics. Multivariate survival modeling was performed by a generalized Cox model, with linear proportional hazards terms in the first block and time-varying interactions in the second block. Results: At a median follow-up of 61.7 months, the WSG-AM-01 confirms a significant EFS and OS benefit for HD in HRBC. In 60% of tumors, there was strong YB-1 expression. YB-1 was significantly associated with several proliferation and drug resistance markers, such as p53, EGFR, S6 and with basal-like/Her2 subtypes.YB-1 expression was highly predictive for response to HD: both EFS (HR=0.29, p=0.001) and OS (HR=0.16, p=0.0001) were significantly improved by HD compared to DD for YB-1 positive tumors; these favorable time-varying hazard ratios signify decreases in early (≤3 years) relapses and deaths, respectively. Conclusions: Among all investigated markers, only YB-1 expression was significantly associated by time- varying interaction analysis with efficacy of HD. The results suggest YB-1 as a potential stratification criterion for future trials as well as a target for treatment of drug resistant HRBC. No significant financial relationships to disclose.