Effect Of Treatment Intensification Research Articles

The Effect of Treatment Intensification on Other-Cause Mortality in Clear-Cell Metastatic Renal Cell Carcinoma Patients

BackgroundThe effect of treatment intensification (systemic therapy [ST] + cytoreductive nephrectomy (CN) vs. ST alone) is unknown regarding rates of other-cause mortality (OCM) in clear-cell metastatic renal cell carcinoma (ccmRCC). We hypothesized that intensified treatment (ST + CN) may result in higher OCM, than when ST is used alone. MethodsWithin the Surveillance, Epidemiology, and End Results database, all ccmRCC patients treated 2010-2018 either with ST + CN or ST alone were identified. Propensity score matching (PSM), cumulative incidence plots, multivariable competing risks regression analyses and 6 months’ landmark analyses addressed OCM and cancer-specific mortality (CSM) according to treatment status. ResultsOf 2271 ccmRCC patients, 1233 (54%) were treated with ST + CN vs 1038 (46%) with ST alone. After 1:1 PSM, OCM was 5.3 vs. 4.6 % (P = .5) and CSM was 73.4 vs. 88.4% (P < .001) in ST + CN vs. ST alone patients. In multivariable competing risks regression, the combination of ST and CN was not associated with higher OCM (HR 1.3; 95% CI 0.8-2.1; P = .4), vs. ST alone. However, the combination of ST and CN was independently associated with lower CSM (HR 0.5; 95% CI 0.5-0.6; P < .001), vs. ST alone. After 6 months’ landmark analyses, these multivariable associations remained unchanged. ConclusionsThe current study indicates no OCM-disadvantage in ST + CN ccmRCC patients, relative to their ST alone counterparts. Conversely, a strong association with lower CSM was recorded in ST + CN patients, relative to their ST alone counterparts. These associations are robust and remained unchanged after strictest statistical adjustment including control for immortal time bias.

A comparative study of the treatment outcome of moderately accelerated radiation fractionation (with concurrent chemotherapy in daily dosing) to conventional chemo-radiotherapy in locally advanced head and neck cancers: Supportive in a resource constrained environment.

In our country, head and neck cancers account for about a third of all cancers. Moreover, the patients typically present in advanced stages, which entails intensive multimodality therapy; but there is not much scope for improved survival outcomes. In view of this, a study was conducted to know the effects of treatment intensification, wherein moderately accelerated fractionation radiotherapy was given to patients presenting with advanced cancer of head and neck. This treatment was further intensified by accompanying radiation with concurrent cisplatin chemotherapy in daily doses. The control arm received the current standard therapy of conventional fractionation radiotherapy with weekly cisplatin chemotherapy. The primary objective of the study was to determine the prospect of tumor control (TC), disease-free survival (DFS), and overall survival (OS). The secondary objective was to study acute toxicity and late toxicity of the highest grade in both treatment groups. The study was conducted on a total of 60 patients who presented with locally advanced squamous cell carcinoma of the head and neck. The 30 patients in the control group received conventional fractionated radiotherapy (five fractions per week) with weekly cisplatin chemotherapy (40 mg/m 2 ), whereas the remaining 30 in the study group received moderately accelerated radiotherapy (six fractions per week with same treatment field) along with daily cisplatin chemotherapy (6 mg/m 2 ) with a reduction in treatment time by 1 week. The overall response to therapy assessed as TC, DFS, and OS was compared, and no statistically significant difference between the two treatment arms was observed. However, the mean overall treatment time was reduced in the study group to 45 days as compared with 49 days in the control group ( P = 0.001). The acute toxicities of xerostomia ( P = 0.057) and skin ( P = 0.052) and late toxicity of aspiration/laryngeal toxicity ( P = 0.002) were higher in grade and number in the study group with accelerated fractionation. Hence, the study results suggest that it is a feasible option to combine the therapeutic benefits of accelerated fractionation radiotherapy with concurrent chemotherapy in patients with locally advanced head and neck carcinomas. There is a significant decrease in the overall treatment time and a considerable reduction in the load on the resource-constrained healthcare system. It would be equitable to point out that higher grade of few toxicities in the acceleration arm are likely due to doses to organs at risk being intensified with accelerated fractionation, which can now be delivered in a controlled manner with the latest high precision techniques, resulting in improved toxicity profile and quality of life which is the way forward for future studies.

Effect of treatment intensification on glycemic control in patients with subcontrolled type 2 diabetes who failed on two oral antidiabetic agents

AimsTreatment intensification (TI) may help patients with type 2 diabetes mellitus (T2DM) achieve target hemoglobin A1c (A1c) < 7.0%. This study aimed to measure the influence of TI on A1c outcome in patients who insufficiently responded to two classes of oral antidiabetic drugs (2OADs). Materials and methodsA retrospective observational study of patients with T2DM was performed using health plan claims and A1c records accrued between January 2010 and March 2017. The study population had an A1c ≥ 7.0% (baseline A1c) after treatment with 2OADs for one year. Patients who had TI with a third-class antidiabetic agent, including basal/biphasic insulin, glucagon-like peptide-1 receptor agonists (GLP-1RA), or OAD, within 365 days after baseline A1c were included. Patients who did not receive TI (NTI) within one year from the suboptimal A1c control were matched with TI patients using a propensity score approach. The odds ratio of achieving an A1c < 9.0% and < 7.0% for TI vs. NTI were calculated by logistic regressions. ResultsA1c values of 401 TI − NTI matched pairs were analyzed. TI patients achieved a significantly lower follow-up A1c than NTI patients (7.79% ± 1.45 vs. 8.02% ± 1.67, p = 0.03). The odds ratio [95% confidence interval] of achieving A1c < 9.0% and < 7.0% for TI was 1.50 [1.04−2.17] and 1.19 [0.87−1.63], respectively. ConclusionTI with a third-class agent further reduced A1c levels in patients whose A1c insufficiently responded with 2OADs; however, most patients failed to achieve an A1c < 7.0% on the intensified treatment.

Prognostic and predictive impact of consensus molecular subtypes and CRCAssigner classifications in metastatic colorectal cancer: a translational analysis of the TRIBE2 study

IntroductionThe consensus molecular subtypes (CMS) demonstrated prognostic value in metastatic colorectal cancer (mCRC). Similarly, a prognostic impact was suggested for the pre-consensus CRCAssigner (CRCA) classifier in early stages. The potential predictive role of these classifiers with regard to the choice of the first-line therapy has not been established. We investigated the prognostic and predictive impact of CMS and CRCA subtypes among mCRC patients treated in the TRIBE2 study.MethodsAmong 679 randomized patients, 426 and 428 (63%) samples were profiled according to CMS and CRCA classifications, respectively. The prognostic and predictive impact of both CMS and CRCA subtypes was investigated with univariate and multivariate analyses for progression-free survival (PFS), PFS 2 (PFS2), and overall survival (OS).ResultsSignificant associations of CMS and CRCA subtypes with PFS, PFS2, and OS were demonstrated; the CMS classifier confirmed its independent prognostic value in the multivariable model (P value for PFS/PFS2/OS = 0.01/0.07/0.08). The effect of treatment intensification was independent of CMS subtypes (P value for interaction for PFS/PFS2/OS = 0.88/0.75/0.55). A significant interaction effect between CRCA subtypes and treatment arm was demonstrated in PFS (P = 0.02), PFS2 (P = 0.01), and OS (P = 0.008). The benefit of FOLFOXIRI seemed more relevant in the stem-like (PFS, hazard ratio = 0.60; P = 0.03) and mixed subtypes (hazard ratio = 0.44; P = 0.002). These findings were confirmed in a subgroup of patients of the previous TRIBE study.ConclusionsWe confirmed the independent prognostic role of CMS classification in mCRC independently of RAS/BRAF status. CRCA classification may help identifying subgroups of patients who may derive more benefit from FOLFOXIRI/bevacizumab.

Consensus molecular subtypes and CRCassigner classifications in metastatic colorectal cancer (mCRC): Prognostic and predictive impact in the TRIBE2 study.

4016 Background: The TRIBE2 study (NCT02339116) recently demonstrated the superiority of upfront FOLFOXIRI/bevacizumab (bev) when compared to a pre-planned strategy of doublets/bev in molecularly unselected but mostly (74%) RAS/ BRAF mutant mCRC patients. The Consensus Molecular Subtypes (CMS) and CRCAssigner (CRCA) demonstrated prognostic value in multiple studies, but their predictive role has not been established so far. Given the poor prognosis associated with early stage mesenchymal/stem-like subtypes, we hypothesized that the CMS/CRCA classifiers could predict benefit from the upfront intensified strategy in patients included in the TRIBE2 study. Methods: Untreated formalin-fixed paraffin-embedded samples were classified into CMS/CRCA subtypes using a custom nCounter assay (NanoString Technologies). The impact of subtypes on progression free survival (PFS), progression free survival 2 (PFS2, defined as the time from randomization until the second evidence of disease progression) or overall survival (OS) was evaluated in the profiled population. Results: 426 and 428 (63%) patients enrolled in the TRIBE2 study were profiled according to CMS and CRCA classifications, respectively. The distribution of CMS/CRCA subtypes differed according to primary tumour site (both p &lt; 0.001 for CMS/CRCA) and RAS/ BRAF mutational status (both p &lt; 0.001 for CMS/CRCA). Significant associations of both CMS/CRCA classifiers with PFS, PFS2 and OS were demonstrated (Table). The effect of treatment intensification was independent of CMS subtypes (p for interaction for PFS/PFS2/OS: ns). Significant interaction effect between CRCA subtypes and treatment arm was reported in terms of PFS (p = 0.017), PFS2 (p = 0.010) and OS (p = 0.008). The benefit from the intensification of the upfront chemotherapy seemed more relevant in the stem-like (PFS, HR = 0.60; p = 0.03) and mixed subtypes (HR = 0.44; p = 0.002). Conclusions: CMS subtypes have a prognostic role in mCRC independently of RAS/ BRAF status. CRCA classification may help identifying subgroups of patients who may derive a more substantial benefit from upfront FOLFOXIRI/bev. [Table: see text]

Further Treatment Intensification in Undifferentiated and Rheumatoid Arthritis Patients Already in Low Disease Activity has Limited Benefit towards Physical Functioning

BackgroundIt is recommended to optimise treatment as long as a predefined treatment target is not met, but should the aim be remission if patients are in low disease activity (LDA)? The aim of this study was to assess if, in patients with rheumatoid arthritis (RA) or patients with undifferentiated arthritis (UA) with Disease Activity Score (DAS) ≤ 2.4 (LDA), treatment intensification results in better functional ability.MethodsIn the IMPROVED study 610 patients with early RA or UA were treated with methotrexate + tapered high-dose prednisone. After 4 months, patients with DAS ≥ 1.6 were randomised to either of two treatment strategies. Patients with DAS < 1.6 tapered treatment. Over 5 years, patients with DAS ≥ 1.6 required treatment intensification, but protocol violations occurred, which allowed us to test the effect of treatment intensification regardless of subsequent DAS. A linear mixed model was used to test, in patients in LDA, the relationship between treatment intensification and functional ability (Health Assessment Questionnaire [HAQ]) over time.ResultsThe number of patients in LDA per visit ranged from 88 to 146. Per visit, 27–74% of the patients in LDA had treatment intensification. We found a statistically significant effect of treatment intensification on ΔHAQ, corrected for baseline HAQ, age, sex and treatment strategy (β = −0.085, 95% CI −0.13 to −0.044). When ΔDAS was added, the effect of treatment intensification was partly explained by ΔDAS, and the association with HAQ was no longer statistically significant (β = −0.022, 95% CI −0.060 to 0.016). When the interaction between treatment intensification and time in follow-up was added, a statistically significant interaction was found (β = 0.0098, 95% CI 0.0010 to 0.019), indicating lesser improvement in HAQ after treatment intensification if follow-up time increased.ConclusionsFor patients with early RA and patients with UA already in LDA, further treatment intensification aimed at DAS remission does not result in meaningful functional improvement.Trial registrationISRCTN, 11916566. Registered on 28 December 2006. EudraCT, 2006-006186-16. Registered on 16 July 2007.

Efficacy of treatment intensification with adalimumab, etanercept and infliximab in rheumatoid arthritis: A systematic review of cohort studies with focus on dose

ObjectivesTo summarize the empirical evidence regarding the effect of treatment intensification on clinical outcomes in patients with rheumatoid arthritis treated with one of the TNF-α-inhibitors, adalimumab, etanercept or infliximab. MethodsA systematic search of the bibliographic databases Embase, Medline, Web of Science and Cochrane Central identifying articles concerning treatment with adalimumab, etanercept or infliximab in adult patients with rheumatoid arthritis exposed to dose increase or shortening of dosing intervals was performed. Longitudinal cohorts, both clinical trials and observational studies, were included. ACR and EULAR response criteria and DAS28 were the preferred outcome measures. ResultsOut of 1135 records, eleven studies were included in the final evidence synthesis. One article concerned all the three TNF-α-inhibitors, eight used infliximab, one adalimumab and one etanercept. According to GRADE, evidence was weakened in particular by the lack of control groups, and for treatment intensification with adalimumab and etanercept, no conclusions could be drawn. With infliximab, two trials of high quality revealed contradictory results, but six studies described an improved clinical outcome following intensified treatment strategies. Some studies (2/2) also indicated that for infliximab, frequency increase was superior to dose increase. ConclusionsAvailable studies indicate that intensifying treatment with infliximab in rheumatoid arthritis patients, preferably by increasing the frequency of drug administration, may lead to improved clinical outcome in some patients, but the evidence is weak. There is an urgent need for prospectively designed cohort studies to be able to draw a final conclusion.

Effects of Treatment Intensification on Acute Local Toxicity During Radiotherapy for Head and Neck Cancer: Prospective Observational Study Validating CTCAE, Version 3.0, Scoring System

To quantify the incidence and severity of acute local toxicity in head and neck cancer patients treated with radiotherapy (RT), with or without chemotherapy (CHT), using the Common Terminology Criteria for Adverse Events, version 3.0 (CTCAE v3.0), scoring system. Between 2004 and 2006, 149 patients with head and neck cancer treated with RT at our center were prospectively evaluated for local toxicity during treatment. On a weekly basis, patients were monitored and eight toxicity items were recorded according to the CTCAE v3.0 scoring system. Of the 149 patients, 48 (32%) were treated with RT alone (conventional fractionation), 82 (55%) with concomitant CHT and conventional fractionation RT, and 20 (13%) with accelerated-fractionation RT and CHT. Severe (Grade 3-4) adverse events were recorded in 28% (mucositis), 33% (dysphagia), 40% (pain), and 12% (skin) of patients. Multivariate analysis showed CHT to be the most relevant factor independently predicting for worse toxicity (mucositis, dysphagia, weight loss, salivary changes). In contrast, previous surgery, RT acceleration and older age, female gender, and younger age, respectively, predicted for a worse outcome of mucositis, weight loss, pain, and dermatitis. The T-score method confirmed that conventional RT alone is in the "low-burden" class (T-score = 0.6) and suggests that concurrent CHT and conventional fractionation RT is in the "high-burden" class (T-score = 1.15). Combined CHT and accelerated-fractionation RT had the highest T-score at 1.9. The CTCAE v3.0 proved to be a reliable tool to quantify acute toxicity in head and neck cancer patients treated with various treatment intensities. The effect of CHT and RT acceleration on the acute toxicity burden was clinically relevant.