Comparative Effectiveness of Adalimumab vs Tofacitinib in Patients With Rheumatoid Arthritis in Australia

Importance: There is a need for observational studies to supplement evidence from clinical trials, and the target trial emulation (TTE) framework can help avoid biases that can be introduced when treatments are compared crudely using observational data by applying design principles for randomized clinical trials. Adalimumab (ADA) and tofacitinib (TOF) were shown to be equivalent in patients with rheumatoid arthritis (RA) in a randomized clinical trial, but to our knowledge, these drugs have not been compared head-to-head using routinely collected clinical data and the TTE framework. Objective: To emulate a randomized clinical trial comparing ADA vs TOF in patients with RA who were new users of a biologic or targeted synthetic disease-modifying antirheumatic drug (b/tsDMARD). Design, Setting, and Participants: This comparative effectiveness study emulating a randomized clinical trial of ADA vs TOF included Australian adults aged 18 years or older with RA in the Optimising Patient Outcomes in Australian Rheumatology (OPAL) data set. Patients were included if they initiated ADA or TOF between October 1, 2015, and April 1, 2021; were new b/tsDMARD users; and had at least 1 component of the disease activity score in 28 joints using C-reactive protein (DAS28-CRP) recorded at baseline or during follow-up. Intervention: Treatment with either ADA (40 mg every 14 days) or TOF (10 mg daily). Main Outcomes and Measures: The main outcome was the estimated average treatment effect, defined as the difference in mean DAS28-CRP among patients receiving TOF compared with those receiving ADA at 3 and 9 months after initiating treatment. Missing DAS28-CRP data were multiply imputed. Stable balancing weights were used to account for nonrandomized treatment assignment. Results: A total of 842 patients were identified, including 569 treated with ADA (387 [68.0%] female; median age, 56 years [IQR, 47-66 years]) and 273 treated with TOF (201 [73.6%] female; median age, 59 years [IQR, 51-68 years]). After applying stable balancing weights, mean DAS28-CRP in the ADA group was 5.3 (95% CI, 5.2-5.4) at baseline, 2.6 (95% CI, 2.5-2.7) at 3 months, and 2.3 (95% CI, 2.2-2.4) at 9 months; in the TOF group, it was 5.3 (95% CI, 5.2-5.4) at baseline, 2.4 (95% CI, 2.2-2.5) at 3 months, and 2.3 (95% CI, 2.1-2.4) at 9 months. The estimated average treatment effect was -0.2 (95% CI, -0.4 to -0.03; P = .02) at 3 months and -0.03 (95% CI, -0.2 to 0.1; P = .60) at 9 months. Conclusions and Relevance: In this study, there was a modest but statistically significant reduction in DAS28-CRP at 3 months for patients receiving TOF compared with those receiving ADA and no difference between treatment groups at 9 months. Three months of treatment with either drug led to clinically relevant average reductions in mean DAS28-CRP, consistent with remission

Physical activity and fitness in women with metastatic breast cancer.

PURPOSE: This study aimed to explore differences in physical activity and fitness between women with metastatic breast cancer compared to healthy controls and factors associated with their physical activity levels. METHODS: Seventy-one women with metastatic breast cancer, aged (mean (SD)) 57.7 (9.5) and 2.9 (3.1) years after the onset of metastatic disease, and 71 healthy controls aged 55.0 (9.4) years participated. Of those with metastatic disease, 27% had bone-only metastases, 35% visceral-only metastases and 38% bone and visceral metastases. Patient-reported outcomes and physical measures of muscle strength and aerobic fitness assessments were obtained. Participants wore a SenseWear® physical activity monitor over 7 days, and the average steps/day and the time spent in moderate-to-vigorous intensity physical activity were determined. RESULTS: Women with metastases were significantly (i) less aerobically fit than the control group (25.3 (5.4) vs. 31.9 (6.1) mL • kg(-1) • min(-1); P < 0.001); (ii) weaker (e.g. lower limb strength for the metastatic and control groups was 53.5 (23.7) vs. 76.0 (27.4) kg, respectively; P < 0.001); (iii) less active, with the metastatic group attaining only 56% of the mean daily step counts of the healthy women; and (iv) more symptomatic, reporting higher levels of fatigue and dyspnoea (P < 0.001). CONCLUSION: Women living in the community with metastatic breast cancer possessed lower aerobic fitness, reduced muscular strength and less daily physical activity compared to healthy counterparts. They also experienced poorer functioning and higher symptom burden. IMPLICATIONS FOR CANCER SURVIVORS: Women living with metastatic breast cancer may benefit from a physical activity programme to address their physical impairments

Strategies for the delay of surgery in the management of resectable hepatobiliary malignancies during the COVID-19 pandemic

Objective: We aimed to review data about delaying strategies for the management of hepatobiliary cancers requiring surgery during the covid-19 pandemic. Background: Given the covid-19 pandemic, many jurisdictions, to spare resources, have limited access to operating rooms for elective surgical activity, including cancer, thus forcing deferral or cancellation of cancer surgeries. Surgery for hepatobiliary cancer is high-risk and particularly resource-intensive. Surgeons must critically appraise which patients will benefit most from surgery and which ones have other therapeutic options to delay surgery. Little guidance is currently available about potential delaying strategies for hepatobiliary cancers when surgery is not possible. Methods: An international multidisciplinary panel reviewed the available literature to summarize data relating to standard-of-care surgical management and possible mitigating strategies to be used as a bridge to surgery for colorectal liver metastases, hepatocellular carcinoma, gallbladder cancer, intrahepatic cholangiocarcinoma, and hilar cholangiocarcinoma. Results: Outcomes of surgery during the covid-19 pandemic are reviewed. Resource requirements are summarized, including logistics and adverse effects profiles for hepatectomy and delaying strategies using systemic, percutaneous and radiation ablative, and liver embolic therapies. For each cancer type, the long-term oncologic outcomes of hepatectomy and the clinical tools that can be used to prognosticate for individual patients are detailed. Conclusions: There are a variety of delaying strategies to consider if availability of operating rooms decreases. This review summarizes available data to provide guidance about possible delaying strategies depending on patient, resource, institution, and systems factors. Multidisciplinary team discussions should be leveraged to consider patient- and tumour-specific information for each individual case.publishedVersio

Does the chemotherapy backbone impact on the efficacy of targeted agents in metastatic colorectal cancer? A systematic review and meta-analysis of the literature

IMPORTANCE The EGFR inhibitors (EGFR-I) cetuximab and panitumumab and the angiogenesis inhibitors (AIs) bevacizumab and aflibercept have demonstrated varying efficacy in mCRC. OBJECTIVE To document the overall impact of specific chemotherapy regimens on the efficacy of targeted agents in treating patients with mCRC. Data sources: MEDLINE, EMBASE and Cochrane databases were searched to 2014, supplemented by hand-searching ASCO/ESMO conference abstracts. STUDY SELECTION Published RCTs of patients with histologically confirmed mCRC were included if they investigated either 1) chemotherapy with or without a biological agent or 2) different chemotherapy regimens with the same biological agent. EGFR-I trials were restricted to KRAS exon 2 wild-type (WT) populations. DATA EXTRACTION AND SYNTHESIS Data were independently abstracted by two authors and trial quality assessed according to Cochrane criteria. The primary outcome was overall survival with secondary endpoints progression free survival (PFS), overall response rate (ORR) and toxicity. RESULTS EGFR-I added to irinotecan-based chemotherapy modestly improved OS with HR 0.90 (95% CI 0.81–1.00, p = 0.04), but more so PFS with HR 0.77 (95% CI 0.69–0.86, p<0.00001). No benefit was evident for EGFR-I added to oxaliplatin-based chemotherapy (OS HR 0.97 (95% CI 0.87–1.09) and PFS HR 0.92 (95% CI 0.83–1.02)). Significant oxaliplatin-irinotecan subgroup interactions were present for PFS with I2 = 82%, p = 0.02. Further analyses of oxaliplatin+EGFR-I trials showed greater efficacy with infusional 5FU regimens (PFS HR 0.82, 95% CI 0.72–0.94) compared to capecitabine (HR 1.09; 95% CI 0.91–1.30) and bolus 5FU (HR 1.07; 95% CI 0.79–1.45); subgroup interaction was present with I2 = 72%, p = 0.03. The oxaliplatin-irinotecan interaction was not evident for infusional 5FU regimens. For AIs, OS benefit was observed with both oxaliplatin-based (HR 0.83) and irinotecan-based (HR 0.77) regimens without significant subgroup interactions. Oxaliplatin+AI trials showed no subgroup interactions by type of FP, whilst an interaction was present for irinotecan+AI trials although aflibercept was only used with infusional FP (I2 = 89.7%, p = 0.002). CONCLUSION AND RELEVANCE The addition of EGFR-I to irinotecan-based chemotherapy has consistent efficacy, regardless of FP regimen, whereas EGFR-I and oxaliplatin-based regimens were most active with infusional 5FU. No such differential activity was observed with the varying chemotherapy schedules when combined with AIs.David L. Chan, Nick Pavlakis, Jeremy Shapiro, Timothy J. Price, Christos S. Karapetis, Niall C. Tebbutt, Eva Segelo

Off-trial evaluation of bisphosphonates in patients with metastatic breast cancer

BACKGROUND: Bisphosphonate therapy has been readily accepted as standard of care for individuals with bone metastases from breast cancer. In this study we determined whether the proportion of patients experiencing a skeletal related event (SRE) in a clinical practice population was similar to that observed in phase III randomized controlled studies. METHODS: A retrospective chart review was conducted of 110 patients receiving intravenous bisphosphonates for advanced breast cancer. The proportion of patients experiencing at least one SRE after 12 months of therapy was determined. SRE included vertebral or non-vertebral fracture, cord compression, surgery and/or radiotherapy to bone. RESULTS: The proportion of patients who had an SRE was 30% (28 individuals) and the median time to first event was greater than 350 days. Non-vertebral events and radiotherapy were the most frequent type of SRE, while cord compression and hypercalcaemia were rare (1%). Most patients in the study had bone-only disease (58.2%) and most had multiple bone lesions. In the first 12 months the mean duration of exposure to intravenous bisphosphonates was 261 days and most patients remained on treatment until just before death (median 27 days). CONCLUSION: This study suggests that the rate of clinically relevant SREs is substantially lower than the event rate observed in phase III clinical trials. We attribute this lower rate to observational bias. In the clinical trial setting it is possible that over-detection of skeletal events occurs due to the utilisation of regular skeletal survey or radionucleotide bone scan, whereas these procedures are not routine in clinical practice. Phase IV observational studies need to be conducted to determine the true benefits of bisphosphonate therapy in order to implement rationale use of bisphosphonates

A Machine-Learning-Based Bibliometric Analysis of the Scientific Literature on Anal Cancer

Squamous-cell carcinoma of the anus (ASCC) is a rare disease. Barriers have been encountered to conduct clinical and translational research in this setting. Despite this, ASCC has been a prime example of collaboration amongst researchers. We performed a bibliometric analysis of ASCC-related literature of the last 20 years, exploring common patterns in research, tracking collaboration and identifying gaps. The electronic Scopus database was searched using the keywords “anal cancer”, to include manuscripts published in English, between 2000 and 2020. Data analysis was performed using R-Studio 0.98.1091 software. A machine-learning bibliometric method was applied. The bibliometrix R package was used. A total of 2322 scientific documents was found. The average annual growth rate in publication was around 40% during 2000–2020. The five most productive countries were United States of America (USA), United Kingdom (UK), France, Italy and Australia. The USA and UK had the greatest link strength of international collaboration (22.6% and 19.0%). Two main clusters of keywords for published research were identified: (a) prevention and screening and (b) overall management. Emerging topics included imaging, biomarkers and patient-reported outcomes. Further efforts are required to increase collaboration and funding to sustain future research in the setting of ASCC

International Rare Cancers Initiative Multicenter Randomized Phase II Trial of Cisplatin and Fluorouracil Versus Carboplatin and Paclitaxel in Advanced Anal Cancer: InterAAct

PURPOSE: To compare cisplatin plus fluorouracil (FU) versus carboplatin plus paclitaxel in chemotherapy-naïve advanced anal cancer to establish the optimal regimen. PATIENTS AND METHODS: Patients who had not received systemic therapy for advanced anal cancer were randomly assigned 1:1 to intravenous cisplatin 60 mg/m2 (day 1) plus FU 1,000 mg/m2 (days 1-4) every 21 days or carboplatin (area under the curve, 5; day 1) plus paclitaxel 80 mg/m2 (days 1, 8, and 15) every 28 days for 24 weeks, until disease progression, intolerable toxicity, or withdrawal of consent. Primary end point was objective response rate (ORR). Primary and secondary end points were assessed in a hierarchic model to compare the regimens and pick the winner. RESULTS: We conducted an international multicenter randomized phase II study in 60 centers between December 2013 and November 2017. Median follow-up was 28.6 months. A total of 91 patients were randomly assigned: 46 to cisplatin plus FU and 45 to carboplatin plus paclitaxel. ORR was 57% (95% CI, 39.4% to 73.7%) for cisplatin plus FU versus 59% (95% CI, 42.1% to 74.4%) for carboplatin plus paclitaxel. More serious adverse events were noted in the cisplatin plus FU arm (62%) compared with the carboplatin plus paclitaxel arm (36%; P = .016). Median progression-free survival was 5.7 months (95% CI, 3.3 to 9.0 months) for cisplatin plus FU compared with 8.1 months (95% CI, 6.6 to 8.8 months) for carboplatin plus paclitaxel. Median overall survival was 12.3 months for cisplatin plus FU (95% CI, 9.2 to 17.7 months) compared with 20 months (95% CI, 12.7 months to not reached) for carboplatin plus paclitaxel (hazard ratio, 2.00; 95% CI, 1.15 to 3.47; P = .014). CONCLUSION: This is the first international randomized trial to our knowledge conducted in chemotherapy-naïve advanced anal cancer. Although there was no difference in ORR, the association with clinically relevant reduced toxicity and a trend toward longer survival suggest that carboplatin plus paclitaxel should be considered as a new standard of care

Management of Asymptomatic Sporadic Nonfunctioning Pancreatic Neuroendocrine Neoplasms (ASPEN) ≤2 cm: Study Protocol for a Prospective Observational Study

Introduction: The optimal treatment for small, asymptomatic, nonfunctioning pancreatic neuroendocrine neoplasms (NF-PanNEN) is still controversial. European Neuroendocrine Tumor Society (ENETS) guidelines recommend a watchful strategy for asymptomatic NF-PanNEN 18 years, the presence of asymptomatic sporadic NF-PanNEN ≤2 cm proven by a positive fine-needle aspiration (FNA) or by the presence of a measurable nodule on high-quality imaging techniques that is positive at 68Gallium DOTATOC-PET scan. Conclusion: The ASPEN study is designed to investigate if an active surveillance of asymptomatic NF-PanNEN ≤2 cm is safe as compared to surgical approach.info:eu-repo/semantics/publishedVersio

Management of Asymptomatic Sporadic Non-Functioning Pancreatic Neuroendocrine Neoplasms No Larger Than 2 Cm: Interim Analysis of Prospective ASPEN Trial

info:eu-repo/semantics/publishedVersio