Patient-reported outcomes associated with cancer screening: a systematic review.

BACKGROUND: Multi-cancer early detection tests have been developed to enable earlier detection of multiple cancer types through screening. As reflected by patient-reported outcomes (PROs), the psychosocial impact of cancer screening is not yet clear. Our aim is to evaluate the impact of cancer screening through PRO assessment. METHODS: A systematic review was conducted using MEDLINE, EMBASE, and reference lists of articles from January 2000 to August 2020 for relevant publications assessing the psychosocial impact of cancer screening before and within 1 year after screening in the general asymptomatic population, including following receipt of results. Studies focused on diagnostic evaluation or involving patients previously diagnosed with cancer were excluded. RESULTS: In total, 31 studies (12 randomized controlled trials; 19 observational studies) were included, reflecting PRO assessments associated with lung, breast, colorectal, anal, ovarian, cervical, and prostate cancer screening procedures. The most commonly assessed construct was symptoms of anxiety, using the State-Trait Anxiety Inventory. Cancer-specific distress and worry were also assessed using a broad range of measures. Overall, individuals tolerated screening procedures well with no major psychosocial effects. Of note, increases in symptoms of anxiety and levels of distress and worry were generally found prior to communication of screening results and following communication of indeterminate or positive results that required further testing. These negative psychosocial effects were, however, not long-lasting and returned to baseline relatively soon after screening. Furthermore, individuals with higher cancer risk, such as current smokers and those with a family history of cancer, tended to have higher levels of anxiety and distress throughout the screening process, including following negative or indeterminate results. CONCLUSIONS: The psychosocial impact of cancer screening is relatively low overall and short-lived, even following false-positive test results. Individuals with a higher risk of cancer tend to experience more symptoms of anxiety and distress during the screening process; thus, more attention to this group is recommended.

Encorafenib, Binimetinib, and Cetuximab in BRAF V600E-Mutated Colorectal Cancer.

BACKGROUND: Patients with metastatic colorectal cancer with the BRAF V600E mutation have a poor prognosis, with a median overall survival of 4 to 6 months after failure of initial therapy. Inhibition of BRAF alone has limited activity because of pathway reactivation through epidermal growth factor receptor signaling. METHODS: In this open-label, phase 3 trial, we enrolled 665 patients with BRAF V600E-mutated metastatic colorectal cancer who had had disease progression after one or two previous regimens. Patients were randomly assigned in a 1:1:1 ratio to receive encorafenib, binimetinib, and cetuximab (triplet-therapy group); encorafenib and cetuximab (doublet-therapy group); or the investigators' choice of either cetuximab and irinotecan or cetuximab and FOLFIRI (folinic acid, fluorouracil, and irinotecan) (control group). The primary end points were overall survival and objective response rate in the triplet-therapy group as compared with the control group. A secondary end point was overall survival in the doublet-therapy group as compared with the control group. We report here the results of a prespecified interim analysis. RESULTS: The median overall survival was 9.0 months in the triplet-therapy group and 5.4 months in the control group (hazard ratio for death, 0.52; 95% confidence interval [CI], 0.39 to 0.70; P<0.001). The confirmed response rate was 26% (95% CI, 18 to 35) in the triplet-therapy group and 2% (95% CI, 0 to 7) in the control group (P<0.001). The median overall survival in the doublet-therapy group was 8.4 months (hazard ratio for death vs. control, 0.60; 95% CI, 0.45 to 0.79; P<0.001). Adverse events of grade 3 or higher occurred in 58% of patients in the triplet-therapy group, in 50% in the doublet-therapy group, and in 61% in the control group. CONCLUSIONS: A combination of encorafenib, cetuximab, and binimetinib resulted in significantly longer overall survival and a higher response rate than standard therapy in patients with metastatic colorectal cancer with the BRAF V600E mutation. (Funded by Array BioPharma and others; BEACON CRC ClinicalTrials.gov number, NCT02928224; EudraCT number, 2015-005805-35.).

Survival after stem-cell transplant in pediatric and young-adult patients with relapsed and refractory B-cell acute lymphoblastic leukemia.

OBJECTIVE: Allogeneic stem-cell transplant (allo-SCT) is the standard of care for pediatric patients with acute lymphoblastic leukemia (ALL) who relapse after frontline chemotherapy; however, for patients who relapse after allo-SCT, outcomes are very poor. Few studies have examined overall survival in this patient population, particularly in patients who received a second allo-SCT. METHODS: This was a retrospective analysis using data from the Center for International Blood and Marrow Transplant Research (CIBMTR) registry. The study population included patients aged 3 to 21 years who were diagnosed with B-ALL and underwent their first allo-SCT between 2009 and 2013. The primary endpoint was the time from the date of posttransplant relapse to the date of death due to any reason. RESULTS: Outcomes in 1349 pediatric and young-adult patients were included in this analysis. The Kaplan-Meier estimated probability of survival at 3 years after first allo-SCT was 63.1% (95% CI, 60.2%-65.8%). Overall, 29.2% of patients relapsed after first allo-SCT and had a median survival of 7.4 months (95% CI, 6.0-9.6 months). Twenty-five patients in the analysis developed secondary malignancies, most of which were lymphoproliferative disorders. CONCLUSIONS: Survival rates are low in pediatric and young-adult patients who relapse after first and second allo-SCT, and new therapies are needed to improve outcomes in this population. This data can be used as a historical comparison for single-arm trials of novel therapies for this patient population, including chimeric antigen receptor T-cell therapy.

Building blocks for institutional preparation of CTL019 delivery.

Chimeric antigen receptor (CAR) T-cell therapy is an investigational immunocellular therapy that reprograms a patient's cytotoxic T cells to engage and eliminate malignant cells. CAR T-cell therapies targeting the CD19 antigen have demonstrated high efficacy in clinical trials for patients with B-cell malignancies and may potentially be available on a broader scale in the future. CAR T-cell therapy begins with the collection of a sufficient number of T cells from a patient's peripheral blood through leukapheresis. Several factors must be considered when patients undergo leukapheresis for CAR T-cell therapy, including age and prior therapies. The leukapheresis material is shipped to a manufacturing facility, followed by return of the CAR T cells to the treatment center. Careful coordination of a multidisciplinary team composed of physicians, nurses, pharmacists and other hospital personnel is critical for the proper care of the patient before, during and after CAR T-cell therapy. CAR T-cell therapy has been associated with adverse events (AEs) such as cytokine release syndrome, which requires rapid attention by the emergency department, intensive care unit and hospital pharmacy. In this review, we discuss several aspects of institutional preparation for leukapheresis, CAR T-cell infusion and AE management based on our experience with clinical trials of the CD19 CAR T-cell therapy CTL019.

Global Manufacturing of CAR T Cell Therapy.

Immunotherapy using chimeric antigen receptor-modified T cells has demonstrated high response rates in patients with B cell malignancies, and chimeric antigen receptor T cell therapy is now being investigated in several hematologic and solid tumor types. Chimeric antigen receptor T cells are generated by removing T cells from a patient's blood and engineering the cells to express the chimeric antigen receptor, which reprograms the T cells to target tumor cells. As chimeric antigen receptor T cell therapy moves into later-phase clinical trials and becomes an option for more patients, compliance of the chimeric antigen receptor T cell manufacturing process with global regulatory requirements becomes a topic for extensive discussion. Additionally, the challenges of taking a chimeric antigen receptor T cell manufacturing process from a single institution to a large-scale multi-site manufacturing center must be addressed. We have anticipated such concerns in our experience with the CD19 chimeric antigen receptor T cell therapy CTL019. In this review, we discuss steps involved in the cell processing of the technology, including the use of an optimal vector for consistent cell processing, along with addressing the challenges of expanding chimeric antigen receptor T cell therapy to a global patient population.

Long-Term Safety Follow-Up of Subjects Previously Treated with Non-Replicating Retroviral Vector-Based Gene Therapies.

OBJECTIVE: Our objective was to evaluate the life-long safety profile of gene therapy using retroviral (non-replicating) vectors (nRCR), or cell products in 127 subjects with hemophilia, human immunodeficiency virus (HIV), or cancer, previously treated with such gene therapy. METHODS: We assessed the occurrence of serious adverse events (SAEs), deaths and presence of replication competent retrovirus (RCR). RESULTS: A total of 23 subjects remained until the data cut-off date of 31 July 2013 and provided safety information of up to 18 years. Of the 104 subjects who discontinued, the primary reason was loss to follow-up (47.2 %; n = 60). The follow-up period for the 60 subjects lost to follow-up was 7-10 years. A total of 41 subjects experienced at least one SAE, and 15 subjects died. We reviewed SAEs and cause of death (none related to the active therapy), but no evidence was found for safety signals related to new malignancy or neurologic, rheumatological, autoimmune, or hematologic disorder. RCR results were negative, indicating no evidence for in vivo vector persistence. CONCLUSION: Despite the loss of follow-up, which is the limiting factor in this long-term safety trial, the findings from this long-term follow-up study are encouraging.

Evaluating the Impact of a Switch to Nilotinib on Imatinib-Related Chronic Low-Grade Adverse Events in Patients With CML-CP: The ENRICH Study.

BACKGROUND: Many patients with chronic myeloid leukemia in chronic phase experience chronic treatment-related adverse events (AEs) during imatinib therapy. These AEs can impair quality of life and lead to reduced treatment adherence, which is associated with poor clinical outcomes. PATIENTS AND METHODS: In the phase II ENRICH (Exploring Nilotinib to Reduce Imatinib Related Chronic Adverse Events) study (N = 52), the effect of switching patients with imatinib-related chronic low-grade nonhematologic AEs from imatinib to nilotinib was evaluated. RESULTS: Three months after switching to nilotinib, 84.6% of the patients had overall improvement in imatinib-related AEs (primary endpoint). Of 210 imatinib-related AEs identified at baseline, 62.9% had resolved within 3 months of switching to nilotinib. Of evaluable patients, most had improvements in overall quality of life after switching to nilotinib. At screening, 65.4% of evaluable patients had a major molecular response (BCR-ABL1 ≤ 0.1% on the International Scale). After switching to nilotinib, the rate of the major molecular response was 76.1% at 3 months and 87.8% at 12 months. Treatment-emergent AEs reported with nilotinib were typically grade 1 or 2; however, some patients developed more serious AEs, and 8 patients discontinued nilotinib because of new or worsening AEs. CONCLUSION: Overall, results from the ENRICH study demonstrated that switching to nilotinib can mitigate imatinib-related chronic low-grade nonhematologic AEs in patients with chronic myeloid leukemia in chronic phase, in conjunction with acceptable safety and achievement of molecular responses. This trial was registered at www.clinicaltrials.gov as NCT00980018.

Physician Underestimation of the Risk of Gastrointestinal Stromal Tumor Recurrence After Resection.

IMPORTANCE: Patients with resectable gastrointestinal stromal tumors (GISTs) might not receive the recommended duration of adjuvant therapy if their risk of recurrence is underestimated, which can have an impact on their recurrence-free survival (RFS). OBJECTIVE: To determine the extent of physician underestimation of risk of recurrence after complete primary GIST resection, the impact of underestimation on planned adjuvant treatment duration, and the association among high-risk patients of planned adjuvant treatment duration and RFS. DESIGN, SETTING, AND PARTICIPANTS: This was a retrospective observational medical record review reported by participating oncologists in 2013. US patients with complete primary GIST resection after 2010 were grouped as underestimated or not if their oncologists' charted risk assessments were lower than assessments based on the Revised National Institutes of Health Consensus Criteria or not. Patients were followed by general community oncologists until death or the end of follow-up. MAIN OUTCOMES AND MEASURES: Fisher exact tests compared planned adjuvant treatment duration between groups. Cox proportional-hazards models estimated the impact of planned adjuvant treatment duration on RFS. RESULTS: A total of 109 oncologists reported information on 506 patients with GIST after primary resection (65.8% were high-risk and 8.7% were intermediate-risk). Physicians underestimated risk for 190 patients (37.5%); 30.1% of tumors with an intermediate-level mitotic count (6-10 per 50 high-powered fields) and an intermediate tumor size (6-10 cm) were correctly recognized as high-risk, as were 7.5% of nongastric tumors with an intermediate-level mitotic count and a tumor size of 2 to 5 cm. A smaller proportion of high-risk patients in the underestimated vs not-underestimated groups had at least 3 years of planned adjuvant therapy (36.1% vs 65.9%; P < .001). Planned adjuvant treatment of at least 3 years vs less than 3 years among high-risk patients conferred a lower hazard of recurrence and/or death (adjusted hazard ratio, 0.29; P < .001; 95% CI, 0.14-0.59). CONCLUSIONS AND RELEVANCE: Overall, physicians tended to underestimate the risk of recurrence for many patients with GIST, especially for patients with tumors of intermediate size, intermediate-level mitotic count, and nongastric location, which had an impact on planned adjuvant therapy duration. Patients with at least 3 years of planned adjuvant treatment had longer RFS. Improved education on postresection risk assessment and risk reduction is needed.

The economic burden of gastrointestinal stromal tumor (GIST) recurrence in patients who have received adjuvant imatinib therapy.

OBJECTIVE: To estimate the economic burden of gastrointestinal stromal tumor (GIST) recurrence in patients who received imatinib adjuvant therapy. METHODS: Data from the MarketScan and PharmMetrics databases between January 2000 and March 2013 were extracted. Patients who had received at least one diagnosis of GIST, had undergone a primary surgery for GIST, and had received at least one prescription for imatinib were included in the analysis. An algorithm was applied to identify those who had a subsequent GIST recurrence. Patients who experienced a recurrence and those who did not have a recurrence were compared for differences in healthcare utilization measures and healthcare costs within 6 months after the recurrence, while adjusting for potential confounding factors. RESULTS: A total of 540 patients with primary resectable GIST who received imatinib adjuvant therapy were identified, including 444 (82.2%) patients who did not experience GIST recurrence and 96 (17.8%) patients who did experience recurrence. Patients who experienced GIST recurrence utilized significantly more healthcare resources in all categories than patients who did not have a recurrence, including the number of hospitalizations, days of hospitalization, emergency room visits, outpatient visits, and other medical services (all p-values <0.01). The total healthcare cost was significantly higher for patients with GIST recurrence, with a difference of $4464 per patient per month (p < 0.01). Both the medical and pharmacy costs were significantly higher with adjusted differences of $3488 and $1423 per patient per month, respectively (both p-values <0.01). CONCLUSIONS: Patients who had GIST recurrence after surgical resection incurred significantly more healthcare resource utilization and greater healthcare costs within 6 months after the recurrence than patients who did not have recurrence. These findings suggest that GIST recurrence is associated with a substantial economic burden.

Impact of low-grade adverse events on health-related quality of life in adult patients receiving imatinib or nilotinib for newly diagnosed Philadelphia chromosome positive chronic myelogenous leukemia in chronic phase.

OBJECTIVE: Chronic myeloid leukemia (CML) treatment relies on tyrosine kinase inhibitors (TKIs), but their use can be associated with low-grade adverse events (AEs). This analysis aimed to identify the low-grade AEs which significantly impact the Health Related Quality of Life (HRQoL) of CML patients in chronic phase (CP) and to compare the incidence of such AEs among nilotinib- and imatinib-treated patients. RESEARCH DESIGN AND METHODS: Data from the 48 month ENESTnd trial were used (N = 593 patients). HRQoL was assessed using generic (SF-36) and leukemia-specific (FACT-Leu) HRQoL surveys. AEs were categorized into 26 system organ classes. RESULTS: In the adjusted regression model, five low-grade AE categories - gastrointestinal disorders, blood and lymphatic system disorders, general disorders and administration site conditions, musculoskeletal disorders, and psychiatric disorders - significantly impaired at least one HRQoL score. The incidence rate of these five AE categories was either significantly lower for nilotinib than imatinib or not different between the two drugs. The AE categories with lower incidence for both nilotinib 300 mg BID and 400 mg BID versus imatinib 400 mg daily were gastrointestinal, blood and lymphatic system, and musculoskeletal; nilotinib 300 mg BID had lower incidence than imatinib for general disorders. LIMITATIONS: Low-grade AEs were grouped and analyzed by system organ class category, so the effect of some rare individual AEs on HRQoL may have been missed. CONCLUSIONS: The impact of low-grade AEs on HRQoL should be taken into account, along with other factors, when selecting the optimal treatment for patients newly diagnosed with CML-CP.

Treatment patterns, prescribing decision drivers, and predictors of complete response following disease recurrence in gastrointestinal stromal tumor patients-a chart extract-based approach.

PURPOSE: The aim of this study was to investigate tumor characteristics, treatment patterns, and outcomes in recurrent KIT + GIST patients treated in a community practice setting. METHODS: An online tool was used to retrieve data on 410 patients treated with adjuvant imatinib mesylate (IM) for primary resectable KIT + GIST, who discontinued, had a recurrence, and then restarted IM or initiated sunitinib. Tumor characteristics at recurrence, treatment patterns, and factors associated with post-recurrence complete response (CR) achievement were analyzed. RESULTS: About 72.7 % of patients did not have surgery post-recurrence as majority of them had unresectable (45 %), metastatic (40 %), or multifocal tumors (62.4 %). Following recurrence, 76.6 % of patients were re-started on IM and 23.4 % on sunitinib; patients were 7.37 times more likely to re-start IM if initial treatment duration was ≤18 months (p < 0.001). Patients were also more likely to re-start IM if recurrence occurred >12 months post-discontinuation, or they had a recurrence inside the GI system, lower or unknown Fletcher risk score at primary diagnosis, or lower mitotic rate, (odds ratio (OR) = 3.54, p < 0.001; OR = 2.64, p = 0.006; OR = 2.55, p = 0.007; and OR = 2.45, p = 0.002, respectively). About 22.4 % achieved CR; patients were more likely to achieve CR if they had unifocal tumor at recurrence, inside the GI system, of ≤2 cm, or had lower mitotic rate (OR = 2.61, p < 0.001; OR = 2.27, p = 0.036; OR = 2.16, p = 0.023, OR = 1.87, p = 0.017, respectively). CONCLUSIONS: IM treatment duration at primary diagnosis, time to develop recurrence after IM discontinuation, tumor location, and mitotic rate at recurrence were the main prescribing decision drivers. Tumor characteristics were the most important factor in achieving CR following c-KIT inhibitor retreatment.

Comparison of the long-term risk of recurrence and other clinical outcomes in GIST patients receiving imatinib as adjuvant therapy--a retrospective chart extract-based approach.

PURPOSE: To compare characteristics of patients, the risk of recurrence, and mortality among adult patients with primary resectable gastrointestinal stromal tumor (GIST) receiving short-term (6-12 months) versus long-term (≥ 24 months) imatinib therapy. METHODS: Detailed information on primary resectable KIT-positive GIST patients initiated on imatinib adjuvant therapy was retrospectively collected for short- and long-term imatinib patients from 318 US oncologists using an online data collection form. Patient characteristics were compared using Wilcoxon and Chi-square tests. Disease recurrence and mortality rates were compared using multivariate Cox proportional hazard models. RESULTS: Among the 406 short-term and 406 long-term imatinib patients, the median follow-up was 916 and 970 days, respectively. While patients generally had similar demographic characteristics, the short-term group had a higher prevalence of cardiovascular and ischemic heart diseases and patients in the long-term group had a higher pre-surgery risk profile. This finding was consistent with the main reason reported by oncologists for prescribing adjuvant imatinib over longer duration, i.e., patient risk profile. Disease recurrence [5.9 versus 1.2 %, (p < .001)] and mortality rates [7.1 % versus 2.0 %, (p < .001)] were higher in short- versus long-term patients. The adjusted risk of recurrence was 5.30 times (p < .001) higher, and mortality risk was 4.02 times (p < .001) higher in short- versus long-term patients. CONCLUSIONS: Patient risk profile is an important factor in oncologists' decisions to prescribe adjuvant imatinib. Despite the higher risk profile observed in long-term patients, the long-term use of imatinib was associated with a reduction in long-term risk of disease recurrence and mortality.

The use of an antibody drug conjugate, glembatumumab vedotin (CDX-011), for the treatment of breast cancer.

INTRODUCTION: Breast cancer (BC) is the most common malignancy in women in the USA. Despite the multi-modality treatments that are currently available, advanced BC has a persistent and unacceptable mortality rate. The need for new therapeutic strategies is extremely high. Experimental approaches with targeted therapies such as antibody drug conjugates provide hope for future treatment possibilities. AREAS COVERED: The development status and the possible role of antibody-mediated cytotoxic therapy are discussed in the setting of advanced BC. An overview of, mechanism of action, preclinical and Phase I/II results of glembatumumab vedotin (CDX-011) are discussed. EXPERT OPINION: The evidence that the glycoprotein NBM (GPNMB) target is a relevant target in BC, along with data showing that CDX-011 is safe and active in patients with advanced BC, provide a strong rationale to continue to explore this drug in patients with GPNMB-expressing breast tumors.

Hypoglycemia-induced anoxic brain injury possibly associated with levofloxacin.

Reports linking alterations in blood glucose concentrations with fluoroquinolones, mostly gatifloxacin and ciprofloxacin, have been published. We describe an elderly, non-diabetic patient with steroid-induced hyperglycemia prescribed glyburide who later developed severe hypoglycemia resulting in anoxic brain injury soon after initiating therapy with levofloxacin.