An Australian mainstream genetic testing program: Clinicians views about current and future practices.

PURPOSE: Germline genetic testing results can guide treatment decisions for oncology patients and are now offered to many cancer patients. Mainstream testing refers to genetic testing arranged by a non-genetics specialist. This repeated cross-sectional study aimed: (1) to capture clinician views on the existing mainstreaming genetic testing program for ovarian, breast, prostate, and endometrial cancer patients, and (2) to ascertain the interest of clinicians to consider changing practice to adopt mainstream testing. METHODS: Mainstreaming has occurred since 2015 for patients with ovarian and some breast cancer patients, expanding to include prostate cancer patients in 2019, and endometrial cancer patients in 2020. Two web-based surveys were administered within two health districts, covering seven hospitals in NSW. RESULTS: Fifty-four clinicians (70% response rate) participated. Clinicians who had arranged mainstream genetic testing (n = 30) were overall satisfied (76%), viewed the process as time-efficient and accessible for patients, and desired continuation of the program. Of those clinicians yet to engage in the program (n = 24), 88% expressed an interest in learning about mainstream testing. These clinicians identified time constraints, maintenance of current genetic knowledge, and completing the consenting and counseling process as barriers to mainstreaming. Future mainstreaming models are discussed. CONCLUSION: From the clinician's perspective, the mainstreaming program is considered a desirable pathway for germline testing of oncology patients. Access to ongoing education and resources is needed for the ongoing success of the program.

Comparison of capecitabine concentrations determined by microsampling versus plasma concentrations for therapeutic drug monitoring: a pilot study.

OBJECTIVES: Therapeutic drug monitoring allows personalized dosing of chemotherapy, but is not well established for capecitabine. The aim of this study was to compare the concentrations of capecitabine and its metabolites obtained simultaneously by microsampling with plasma sampling and their acceptability to patients. METHODS: Adults taking capecitabine for cancer had paired (duplicate) microsampling at steady state (hour 2 post dose) using Mitra® devices and venous blood samples for analysis. Capecitabine and metabolites were measured using a validated mass spectrometry assay. Correlation between the sampling methods was determined. Patients' preferences were elicited using a Likert numeric rating scale and pain by a Visual Analog Scale (range, 0-10). KEY FINDINGS: Capecitabine concentrations from 10 patients (60 paired samples) by microsampling and plasma sampling were highly correlated (Pearson correlation: 0.97, Coefficients of determination: 0.94, P < 0.0001). Capecitabine concentrations in capillary sampling were consistently lower than the paired plasma concentration (median capecitabine capillary/plasma concentration ratio = 2851/3846 µg/l 75%). The agreement between sampling matrices showed a 28% bias (95% Cl, 4.02-52.00). Participant ratings showed microsampling was the preferred method by all 10 patients. Most participants reported no pain with microsampling (median 0, range 0-1). CONCLUSION: Capecitabine concentration measured by microsampling and plasma sampling were highly correlated, but consistently lower in microsampling. Microsampling was the preferred method with minimal pain.

Stakeholder perspectives on the impact of COVID-19 on oncology services: a qualitative study.

BACKGROUND: As COVID-19 spread across the globe, cancer services were required to rapidly pivot to minimise risks without compromising outcomes for patients or staff. The aim of this study was to document changes to oncology services as a result of COVID-19 from the perspectives of both providers and receivers of care during the initial phase of the pandemic. METHODS: Participants were recruited between June and December 2020 through an email invitation via professional or consumer organisations, two hospital-based oncology services and snowballing. Semi-structured interviews focused on health service changes and their impacts, which were then analysed by thematic analysis. RESULTS: Thirty-two patients, 16 carers and 29 health professionals were recruited. Fifteen patients (n = 47%) had localised disease, and 19 (n = 59%) were currently receiving treatment. Oncology staff included oncologists, palliative care physicians, nurses, allied health and psychosocial practitioners. Four themes arose from the data: safety, increased stress and burnout, communication challenges and quality of cancer care. CONCLUSIONS: There is an ongoing need for cancer-specific information from a single, trusted source to inform medical practitioners and patients/carers. More data are required to inform evidence-based guidelines for cancer care during future pandemics. All stakeholders require ongoing support to avoid stress and burnout.

Influence of age on pharmacokinetics of capecitabine and its metabolites in older adults with cancer: a pilot study.

BACKGROUND: Capecitabine is an oral chemotherapy prodrug of 5-fluorouracil (5-FU) with unpredictable toxicity, especially in older adults. The aim of this study was to evaluate the pharmacokinetics (PK) of capecitabine and its metabolites in younger adults (< 70 years) and older adults (≥ 70 years) receiving capecitabine for solid cancer. METHODS: Eligible participants receiving capecitabine had 2 venous samples collected on day 14 of cycle 1 and cycle 2 of their treatment. Capecitabine and metabolite concentrations were determined using liquid chromatography with tandem mass spectrometry. A Bayesian estimation approach was used to generate individual estimates of PK parameters for 5-FU. A linear mixed-effect analysis of variance (ANOVA) model was used to compare dose-normalised log-transformed PK parameters between age groups. Correlations were determined by linear regression and logistic regression analyses. RESULTS: Of the total 26 participants, 58% were male with a median age of 67 years (range, 37-85) with 54% aged < 70 years and 46% aged ≥ 70 years. Participants aged ≥ 70 years, compared to those aged < 70 years, had a greater 5-FU exposure based on area under the concentration-time curve (AUC) of 17% (90% CI 103-134%; 0.893 vs. 0.762 mg h/L) and 14% increase in maximal concentration, Cmax (90% CI 82.1-159%; 0.343 vs. 0.300 mg/L). The 5-FU Cmax was positively associated with time up and go (TUG) (Pearson's correlation 0.77, p = 0.01), but not other geriatric assessment domains or severe toxicity. CONCLUSION: 5-FU exposure was significantly increased in older adults compared to younger adults receiving equivalent doses of capecitabine, and is a possible cause for increased toxicity in older adults.

Effect of core versus enhanced implementation strategies on adherence to a clinical pathway for managing anxiety and depression in cancer patients in routine care: a cluster randomised controlled trial.

BACKGROUND: Optimal strategies to facilitate implementation of evidence-based clinical pathways are unclear. We evaluated two implementation strategies (Core versus Enhanced) to facilitate implementation of a clinical pathway for the management of anxiety and depression in cancer patients (the ADAPT CP). METHODS: Twelve cancer services in NSW Australia were cluster randomised, stratified by service size, to the Core versus Enhanced implementation strategy. Each strategy was in place for 12 months, facilitating uptake of the ADAPT CP (the intervention being implemented). The Core strategy included a lead team with champions, staff training and awareness campaigns prior to implementation, plus access to feedback reports and telephone or online support during implementation. The Enhanced strategy included all Core supports plus monthly lead team meetings, and proactive, ongoing advice on managing barriers, staff training and awareness campaigns throughout implementation. All patients at participating sites were offered the ADAPT CP as part of routine care, and if agreeable, completed screening measures. They were allocated a severity step for anxiety/depression from one (minimal) to five (severe) and recommended management appropriate to their severity step. Multi-level mixed-effect regression analyses examined the effect of Core versus Enhanced implementation strategy on adherence to the ADAPT CP (binary primary outcome: adherent ≥ 70% of key ADAPT CP components achieved versus non-adherent < 70%), with continuous adherence as a secondary outcome. Interaction between study arm and anxiety/depression severity step was also explored. RESULTS: Of 1280 registered patients, 696 (54%) completed at least one screening. As patients were encouraged to re-screen, there were in total 1323 screening events (883 in Core and 440 in Enhanced services). The main effect of implementation strategy on adherence was non-significant in both binary and continuous analyses. Anxiety/depression step was significant, with adherence being higher for step 1 than for other steps (p = 0.001, OR = 0.05, 95% CI 0.02-0.10). The interaction between study arm and anxiety/depression step was significant (p = 0.02) in the continuous adherence analysis only: adherence was significantly higher (by 7.6% points (95% CI 0.08-15.1%) for step 3 in the Enhanced arm (p = .048) and trending to significance for step 4. DISCUSSION: These results support ongoing implementation effort for the first year of implementation to ensure successful uptake of new clinical pathways in over-burdened clinical services. TRIAL REGISTRATION: ANZCTR Registration: ACTRN12617000411347 (Trial registered 22/03/2017; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=372486&isReview=true ).

Dried Blood Spot Sampling in the Monitoring of Anticancer Therapy for Solid Tumors: A Systematic Review.

BACKGROUND: Dried blood spot (DBS) sampling is a convenient alternative to whole-blood sampling for therapeutic drug monitoring (TDM) in clinical practice. The aim of this study was to systematically review studies that have examined and used DBS sampling for the TDM of chemotherapy and targeted therapy agents for the treatment of patients with solid cancers. METHODS: Using the PRISMA guidelines, a systematic literature search of EMBASE and PUBMED was performed to identify eligible clinical studies that used DBS sampling to monitor chemotherapy or targeted therapy for the treatment of solid cancers. RESULTS: Of the 23 eligible studies, 3 measured concordance between drug concentrations determined by DBS and whole-blood, 7 developed analytical methods of DBS, and 13 performed both. DBS was employed for the TDM of everolimus (3 studies), vemurafenib (2 studies), pazopanib (2 studies), abiraterone (2 studies), mitotane, imatinib, adavosertib, capecitabine, 5-fluorouracil, gemcitabine, cyclophosphamide, ifosfamide, etoposide, irinotecan, docetaxel, gefitinib, palbociclib/ribociclib, and paclitaxel (one study each). The studies included a median of 14 participants (range: 6-34), with 10-50 µL of blood dispensed on DBS cards (20) and Mitra devices (3). Seventeen of the 20 studies that used DBS found no significant impact of the hematocrit on the accuracy and precision of the developed method in the normal hematocrit ranges (eg, 29.0%-59.0%). DBS and plasma or venous concentrations were highly correlated (correlation coefficient, 0.872-0.999) for all drugs, except mitotane, which did not meet a predefined level of significance (r > 0.872; correlation coefficient, r = 0.87, P < 0.0001). CONCLUSIONS: DBS provides an alternative sampling strategy for the TDM of many anticancer drugs. Further research is required to establish a standardized approach for sampling and processing DBS samples to allow future implementation.

Older age should not be a barrier to testing for somatic variants in homologous recombination DNA repair-related genes in patients with high-grade serous ovarian carcinoma.

BACKGROUND: Somatic pathogenic variants (PVs) in homologous recombination DNA repair (HR)-related genes found in high-grade serous ovarian carcinomas (HGSC) are not well-characterised in older patients (≥70 years). This may reflect low testing rates in older patients. METHODS: Data from 1210 HGSC patients in AACR Project GENIE and 324 patients in an independent dataset INOVATe were analysed. Cases where somatic variants could be distinguished from germline variants were included, and analysis was restricted to those with a somatic TP53 variant, to ensure cases were HGSC. RESULTS: Of 1210 patients in GENIE, 27% (n = 325) were aged ≥70 years at testing. Patients with somatic-only PVs in BRCA2 were older compared with BRCA1 (median 71 vs 60 years, p = 0.002). Median age for 21 patients with somatic-only PVs in 11 other HR-related genes ranged from 40 to 67 years. In older patients, 7% (n = 22) had somatic BRCA1/2 PVs, and 1% (n = 2) had PVs other HR-related genes; this rate was not significantly different to younger patients (<70 years), 7% (n = 62) BRCA1/2 and 2% (n = 19) other HR-related genes (p = 0.36). The overall frequency of somatic BRCA1/2 PVs was similar in INOVATe (n = 25; 7.7%) and somatic-only BRCA2 PVs were again found in older patients compared with BRCA1 (median age: at testing, 70 vs 63 years; at diagnosis, 68 vs 60 years). CONCLUSIONS: The overall frequency of somatic-only PVs in HR-related genes was similar in older and younger patients with HGSC, highlighting the importance of somatic testing irrespective of age. Limiting somatic testing by age may exclude patients who could benefit from maintenance poly(ADP-ribose) polymerase (PARP) inhibitors.

Implementation and evaluation of a smoking cessation checklist implemented within Australian cancer services.

INTRODUCTION: The detrimental impact of smoking tobacco can be mitigated when cancer patients quit smoking. Smoking cessation clinical pathways are inconsistently implemented within Australian cancer services. The aim of this study was to pilot test and evaluate the reach, adoption, and implementation of a smoking cessation checklist within oncology services. METHODS: The checklist was implemented over a 6-month period in medical and radiation oncology services at two metropolitan and one rural hospital. The RE-AIM framework guided the evaluation process. Implementation strategies included training, process mapping, and identifying champions. Evaluation measures included a clinical data audit, surveys, and semi-structured interviews with healthcare professionals (HCPs). RESULTS: Healthcare professionals (HCPs; N = 63; 41% oncologists, 32% nurses, 27% others) completed 1276 checklists with cancer patients between November 2019 and December 2020. Of the 126 (10%) identified current smokers, 34 (27%) accepted a referral to either Quitline, Nicotine Replacement Therapy, to a general practitioner or dedicated HCP for follow-up telephone support. There was variation in screening adoption by HCPs across the three hospitals, with 16%, 92% and 89.5% of patients screened respectively. Contextual factors, such as perceived commitment, role identity, and communication processes appeared to influence the outcomes. CONCLUSION: A checklist is a simple, effective, and versatile intervention used to standardise smoking cessation practices in medical and radiation oncology services. The checklist supports standardisation of referral practices to smoking cessation services for cancer patients by either oncologist and/or nurses.

Evaluation of a mainstream genetic testing program for women with ovarian or breast cancer.

INTRODUCTION: Mainstream genetic testing refers to genetic testing arranged by a patient's treating specialist. The aim of this study was to retrospectively review a Sydney-based ovarian cancer mainstream genetic testing program. METHODS: A Cancer Genetics Service (CGS)-supported mainstream genetic testing program was commenced in 2015. The CGS provided training, paperwork and ongoing and adaptable advice regarding appropriate genes for testing and interpretation of results. Written and electronic medical records were reviewed until August 2019 to assess patient and family history characteristics, genetic testing eligibility, results and posttest management for women who had testing coordinated via mainstreaming or by the CGS. RESULTS: Genetic testing was arranged for 289 women with ovarian cancer. Prior to 2017, 44% of genetic tests were mainstreamed, compared with 76% of tests from 2017 onwards. CGS was more likely to arrange testing for women with a strong family history of cancer and nonserous pathology. Germline pathogenic variants were detected in 13.7% (19/138) of women who had mainstream testing and 20.3% (14/69) of women tested by the CGS. Referral for posttest counseling occurred for pathogenic variant carriers identified through mainstreaming. CONCLUSION: This study demonstrated successful uptake of a mainstream ovarian cancer genetic testing program by medical oncologists, as evidenced by higher proportion and absolute numbers of eligible ovarian cancer patients accessing genetic testing through this pathway over time. The genetic testing criteria were appropriately assessed by oncologists and posttest referral occurred where required.

Getting the MOST out of follow-up: a randomized controlled trial comparing 3 monthly nurse led follow-up via telehealth, including monitoring CA125 and patient reported outcomes using the MOST (Measure of Ovarian Symptoms and Treatment concerns) with routine clinic based or telehealth follow-up, after completion of first line chemotherapy in patients with epithelial ovarian cancer.

BACKGROUND: Physical symptoms, anxiety, depression, fear of recurrence, sexual dysfunction, and social withdrawal are common in women after treatment for ovarian cancer. Most patients would like and need help dealing with these symptoms. The traditional model of follow-up care is unstructured and largely focused on diagnosing recurrent disease, and most oncologists lack skills to identify and manage psychosocial issues. No high quality prospective clinical trials have been conducted to determine the optimal follow-up regimen or the cost effectiveness of ovarian cancer surveillance strategies. PRIMARY OBJECTIVES: To assess emotional wellbeing, acceptability, safety, and cost effectiveness of nurse led follow-up via telehealth for women with ovarian cancer following completion of primary treatment. STUDY HYPOTHESIS: We hypothesize that compared with routine clinic based follow-up, nurse led follow-up via telehealth, including serum CA125 monitoring and completion of a patient reported outcome instrument, the Measure of Ovarian Symptoms and Treatment concerns-Surveillance (MOST-S26), will improve emotional wellbeing in women with ovarian cancer; be feasible, safe, acceptable, and not delay the time to diagnosis of recurrent disease; will result in greater patient satisfaction; will identify more patients with psychological distress, lead to better care, and improved psychological outcomes; and be cost-effective. TRIAL DESIGN: Phase II multicenter randomized trial comparing 3 monthly nurse led telehealth consultations that include serum CA125 monitoring and completion of the MOST-S26, with routine clinic based follow-up. The allocation ratio will be 1:1. MAJOR INCLUSION/EXCLUSION CRITERIA: Eligible patients will be women with high grade epithelial ovarian cancer who have normalized serum CA125 (to <35 kU/L) at completion of first line chemotherapy. PRIMARY ENDPOINTS: Emotional wellbeing at 12 months. SAMPLE SIZE: 150 patients. ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: July 2023. Results expected in 2025, 24 months after the last participant is enrolled. TRIAL REGISTRATION: ACTRN12620000332921.

Results of PD-L1 Analysis of Women Treated with Durvalumab in Advanced Endometrial Carcinoma (PHAEDRA).

Women with advanced endometrial carcinoma (EC) with mismatch repair (MMR) deficiency have improved outcomes when treated with immune checkpoint inhibitors; however, additional biomarkers are needed to identify women most likely to respond. Scores for programmed death ligand 1 (PD-L1), immunohistochemical staining of tumor (TC+), immune cells (IC+) and presence of tumor-associated immune cells (ICP) on MMR deficient (n = 34) and proficient (n = 33) EC from women treated with durvalumab in the PHAEDRA trial (ANZGOG1601/CTC0144) (trial registration number ACTRN12617000106336, prospectively registered 19 January 2017) are reported and correlated with outcome. Receiver operating characteristic (ROC) analyses and area under the ROC curve were used to determine optimal cutpoints. Performance was compared with median cutpoints and two algorithms; a novel algorithm derived from optimal cutpoints (TC+ ≥ 1 or ICP ≥ 10 or IC+ ≥ 35) and the Ventana urothelial carcinoma (UC) algorithm (either TC+ ≥ 25, ICP > 1 and IC+ ≥ 25 or ICP = 1 and IC+ = 100). The cutpoint ICP ≥ 10 had highest sensitivity (53%) and specificity (82%), being prognostic for progression-free survival (PFS) (p = 0.01), while the optimal cutpoints algorithm was associated with overall survival (p = 0.02); these results were not significant after adjusting for MMR status. The optimal cutpoints algorithm identified non-responders (p = 0.02) with high sensitivity (88%) and negative predictive value (92%), remaining significant after adjustment for MMR. Although MMR status had the strongest association with response, further work to determine the significance of ICP ≥ 10 and the novel optimal cutpoint algorithm is needed.

Acceptability and appropriateness of a clinical pathway for managing anxiety and depression in cancer patients: a mixed methods study of staff perspectives.

BACKGROUND: Clinical pathways (CPs) can improve health outcomes, but to be sustainable, must be deemed acceptable and appropriate by staff. A CP for screening and management of anxiety and depression in cancer patients (the ADAPT CP) was implemented in 12 Australian oncology services for 12 months, within a cluster randomised controlled trial of core versus enhanced implementation strategies. This paper compares staff-perceived acceptability and appropriateness of the ADAPT CP across study arms. METHODS: Multi-disciplinary lead teams at each service tailored, planned, championed and implemented the CP. Staff at participating services, purposively selected for diversity, completed a survey and participated in an interview prior to implementation (T0), and at midpoint (6 months: T1) and end (12 months: T2) of implementation. Interviews were recorded, transcribed and thematically analysed. RESULTS: Seven metropolitan and 5 regional services participated. Questionnaires were completed by 106, 58 and 57 staff at T0, T1 and T2 respectively. Eighty-eight staff consented to be interviewed at T0, with 89 and 76 at T1 and T2 (response rates 70%, 66% and 57%, respectively). Acceptability/appropriateness, on the quantitative measure, was high at T0 (mean of 31/35) and remained at that level throughout the study, with no differences between staff from core versus enhanced services. Perceived burden was relatively low (mean of 11/20) with no change over time. Lowest scores and greatest variability pertained to perceived impact on workload, time and cost. Four major themes were identified: 1) Mental health is an important issue which ADAPT addresses; 2) ADAPT helps staff deliver best care, and reduces staff stress; 3) ADAPT is fit for purpose, for both cancer care services and patients; 4) ADAPT: a catalyst for change. Opposing viewpoints are outlined. CONCLUSIONS: This study demonstrated high staff-perceived acceptability and appropriateness of the ADAPT CP with regards to its focus, evidence-base, utility to staff and patients, and ability to create change. However, concerns remained regarding burden on staff and time commitment. Strategies from a policy and managerial level will likely be required to overcome the latter issues. TRIAL REGISTRATION: The study was registered prospectively with the ANZCTR on 22/3/2017. Trial ID ACTRN12617000411347. https://www.anzctr.org.au/ .

Insights into ovarian cancer care: report from the ANZGOG Ovarian Cancer Webinar Series 2020.

Epithelial ovarian cancer (EOC) is among the top ten causes of cancer deaths worldwide, and is one of the most lethal gynecological malignancies in high income countries, with incidence and death rates expected to rise particularly in Asian countries where ovarian cancer is among the 5 most common cancers. Despite the plethora of randomised clinical trials investigating various systemic treatment options in EOC over the last few decades, both progression-free and overall survival have remained at approximately 16 and 40 months respectively. To date the greatest impact on treatment has been made by the use of poly (ADP-ribose) polymerase (PARP) inhibitors in women with advanced EOC and a BRCA1/2 mutation. Inhibition of PARP, the key enzyme in base excision repair, is based on synthetic lethality whereby alternative DNA repair pathways in tumor cells that are deficient in homologous recombination is blocked, rendering them unviable and leading to cell death. The Australia New Zealand Gynaecological Oncology Group (ANZGOG) is the national gynecological cancer clinical trials organization for Australia and New Zealand. ANZGOG's purpose is to improve outcomes and quality of life for women with gynecological cancer through cooperative clinical trials and undertaking multidisciplinary research into the causes, prevention and treatments of gynecological cancer. This review summarizes current ovarian cancer research and treatment approaches presented by Australian and New Zealand experts in the field at the 2020 ANZGOG webinar series entitled "Ovarian Cancer systems of Care".

Physician-patient communication of costs and financial burden of cancer and its treatment: a systematic review of clinical guidelines.

BACKGROUND: Optimising the care of individuals with cancer without imposing significant financial burden related to their anticancer treatment is becoming increasingly difficult. The American Society of Clinical Oncology (ASCO) has recommended clinicians discuss costs of cancer care with patients to enhance shared decision-making. We sought information to guide oncologists' discussions with patients about these costs. METHODS: We searched Medline, EMBASE and clinical practice guideline databases from January 2009 to 1 June 2019 for recommendations about discussing the costs of care and financial burden. Guideline quality was assessed with the AGREE-II instrument. RESULTS: Twenty-seven guidelines met our eligibility criteria, including 16 from ASCO (59%). 21 of 27 (78%) guidelines included recommendations about discussion or consideration of treatment costs when prescribing, with information about actual costs in four (15%). Recognition of the risk of financial burden or financial toxicity was described in 81% (22/27) of guidelines. However, only nine guidelines (33%) included information about managing the financial burden. CONCLUSIONS: Current clinical practice guidelines have little information to guide physician-patient discussions about costs of anticancer treatment and management of financial burden. This limits patients' ability to control costs of treatment, and for the healthcare team to reduce the incidence and severity of financial burden. Current guidelines recommend clinician awareness of price variability and high costs of treatment. Clinicians are recommended to explore cost concerns and address financial worries, especially in high risk groups. Future guidelines should include advice on facilitating cost transparency discussions, with provision of cost information and resources.

Computer-Based Decision Tools for Shared Therapeutic Decision-making in Oncology: Systematic Review.

BACKGROUND: Therapeutic decision-making in oncology is a complex process because physicians must consider many forms of medical data and protocols. Another challenge for physicians is to clearly communicate their decision-making process to patients to ensure informed consent. Computer-based decision tools have the potential to play a valuable role in supporting this process. OBJECTIVE: This systematic review aims to investigate the extent to which computer-based decision tools have been successfully adopted in oncology consultations to improve patient-physician joint therapeutic decision-making. METHODS: This review was conducted in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) 2020 checklist and guidelines. A literature search was conducted on February 4, 2021, across the Cochrane Database of Systematic Reviews (from 2005 to January 28, 2021), the Cochrane Central Register of Controlled Trials (December 2020), MEDLINE (from 1946 to February 4, 2021), Embase (from 1947 to February 4, 2021), Web of Science (from 1900 to 2021), Scopus (from 1969 to 2021), and PubMed (from 1991 to 2021). We used a snowball approach to identify additional studies by searching the reference lists of the studies included for full-text review. Additional supplementary searches of relevant journals and gray literature websites were conducted. The reviewers screened the articles eligible for review for quality and inclusion before data extraction. RESULTS: There are relatively few studies looking at the use of computer-based decision tools in oncology consultations. Of the 4431 unique articles obtained from the searches, only 10 (0.22%) satisfied the selection criteria. From the 10 selected studies, 8 computer-based decision tools were identified. Of the 10 studies, 6 (60%) were conducted in the United States. Communication and information-sharing were improved between physicians and patients. However, physicians did not change their habits to take advantage of computer-assisted decision-making tools or the information they provide. On average, the use of these computer-based decision tools added approximately 5 minutes to the total length of consultations. In addition, some physicians felt that the technology increased patients' anxiety. CONCLUSIONS: Of the 10 selected studies, 6 (60%) demonstrated positive outcomes, 1 (10%) showed negative results, and 3 (30%) were neutral. Adoption of computer-based decision tools during oncology consultations continues to be low. This review shows that information-sharing and communication between physicians and patients can be improved with the assistance of technology. However, the lack of integration with electronic health records is a barrier. This review provides key requirements for enhancing the chance of success of future computer-based decision tools. However, it does not show the effects of health care policies, regulations, or business administration on physicians' propensity to adopt the technology. Nevertheless, it is important that future research address the influence of these higher-level factors as well. TRIAL REGISTRATION: PROSPERO International Prospective Register of Systematic Reviews CRD42021226087; https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021226087.

Promising Anticancer Activity of [Bis(1,8-quinolato)palladium (II)] Alone and in Combination.

Due to similar coordination chemistry of palladium and platinum, a large number of palladium compounds as well have been investigated for their anticancer activity. In the present study, we describe synthesis, characterization, and anticancer activity of palladium complex [Bis(1,8-quinolato)palladium (II)], coded as NH3 against seven different cancer cell lines. NH3 is found to have higher antitumor activity than cisplatin against both parent ovarian A2780 cell line and cisplatin-resistant cell lines. Also, NH3 has the lower IC50 value in HT-29 colorectal cancer cell line. The higher antitumor activity of NH3 is due to the presence of bulky 8-Hydroxyquinoline ligand, thus reducing its reactivity. Proteomic study has identified significantly expressed proteins which have been validated through bioinformatics. NH3 has been found to be less toxic than cisplatin at 2.5 mg/kg and 5 mg/kg dosages on mice models. Binary combinations of NH3 with curcumin and epigallocatechin gallate (EGCG) have demonstrated dose and sequence-dependent synergism in ovarian and colorectal cancer models. All of the preclinical studies indicate promising therapeutic potential of NH3 [Bis(1,8-quinolato)palladium (II)] as an anticancer drug.

Clinical activity of durvalumab for patients with advanced mismatch repair-deficient and repair-proficient endometrial cancer. A nonrandomized phase 2 clinical trial.

BACKGROUND: In this study, we assessed the activity of durvalumab, an antibody to programmed death ligand-1, in two cohorts of women with advanced endometrial cancers (AEC)-mismatch repair proficient (pMMR) and mismatch repair deficient (dMMR). METHODS: A multicenter phase two study was performed in women with AEC with pMMR tumor progressing after one to three lines of chemotherapy and women with AEC with dMMR tumor progressing after zero to three lines of chemotherapy. Mismatch repair status was based on immunohistochemistry expression. All women received durvalumab 1500 mg given every 4 weeks until progression or unacceptable toxicity. The primary endpoint was objective tumor response by RECIST V.1.1 modified for immune-based therapeutics. RESULTS: Seventy-one women were recruited: 35 dMMR and 36 pMMR. Median follow-up was 19 vs 21 months in dMMR versus pMMR, respectively. Median age was 67 years. Histology in dMMR versus pMMR included endometrioid (94% vs 57%) and serous (0% vs 31%) and was high grade in 26% vs 74%. The objective tumor response rate (OTRR) in the dMMR cohort was 47% (17/36, 95% CI 32 to 63), including 6 complete responses and 11 partial responses (PRs)) vs 3% in the pMMR cohort (1/35, 95% CI 1 to 15, PR). In the dMMR cohort, durvalumab was the first-line therapy in 58% (OTRR 57%) and the second-line therapy in 39% (OTRR 38%). Median progression-free survival was 8.3 months in the dMMR cohort vs 1.8 months in the pMMR cohort. The 12-month overall survival (OS) rate was 71% in dMMR vs 51% in pMMR, with median OS not reached for dMMR vs 12 months for pMMR. Immune-related adverse events occurred in 14 women, mostly grades 1-2. CONCLUSION: Durvalumab monotherapy showed promising activity and acceptable safety in AEC with dMMR regardless of prior lines of chemotherapy, but activity was limited in AEC with pMMR. TRIAL REGISTRATION NUMBERS: ANZGOG1601, ACTRN12617000106336, and NCT03015129.

Sequenced Combinations of Cisplatin and Selected Phytochemicals towards Overcoming Drug Resistance in Ovarian Tumour Models.

In the present study, cisplatin, artemisinin, and oleanolic acid were evaluated alone, and in combination, on human ovarian A2780, A2780ZD0473R, and A2780cisR cancer cell lines, with the aim of overcoming cisplatin resistance and side effects. Cytotoxicity was assessed by MTT reduction assay. Combination index (CI) values were used as a measure of combined drug effect. MALDI TOF/TOF MS/MS and 2-DE gel electrophoresis were used to identify protein biomarkers in ovarian cancer and to evaluate combination effects. Synergism from combinations was dependent on concentration and sequence of administration. Generally, bolus was most synergistic. Moreover, 49 proteins differently expressed by 2 ≥ fold were: CYPA, EIF5A1, Op18, p18, LDHB, P4HB, HSP7C, GRP94, ERp57, mortalin, IMMT, CLIC1, NM23, PSA3,1433Z, and HSP90B were down-regulated, whereas hnRNPA1, hnRNPA2/B1, EF2, GOT1, EF1A1, VIME, BIP, ATP5H, APG2, VINC, KPYM, RAN, PSA7, TPI, PGK1, ACTG and VDAC1 were up-regulated, while TCPA, TCPH, TCPB, PRDX6, EF1G, ATPA, ENOA, PRDX1, MCM7, GBLP, PSAT, Hop, EFTU, PGAM1, SERA and CAH2 were not-expressed in A2780cisR cells. The proteins were found to play critical roles in cell cycle regulation, metabolism, and biosynthetic processes and drug resistance and detoxification. Results indicate that appropriately sequenced combinations of cisplatin with artemisinin (ART) and oleanolic acid (OA) may provide a means to reduce side effects and circumvent platinum resistance.