[177Lu]Lu-DOTA-TATE plus long-acting octreotide versus high­dose long-acting octreotide for the treatment of newly diagnosed, advanced grade 2-3, well-differentiated, gastroenteropancreatic neuroendocrine tumours (NETTER-2): an open-label, randomised, phase 3 study.

BACKGROUND: There are currently no standard first-line treatment options for patients with higher grade 2-3, well-differentiated, advanced, gastroenteropancreatic neuroendocrine tumours. We aimed to investigate the efficacy and safety of first-line [177Lu]Lu-DOTA-TATE (177Lu-Dotatate) treatment. METHODS: NETTER-2 was an open-label, randomised, parallel-group, superiority, phase 3 trial. We enrolled patients (aged ≥15 years) with newly diagnosed higher grade 2 (Ki67 ≥10% and ≤20%) and grade 3 (Ki67 >20% and ≤55%), somatostatin receptor-positive (in all target lesions), advanced gastroenteropancreatic neuroendocrine tumours from 45 centres across nine countries in North America, Europe, and Asia. We used interactive response technologies to randomly assign (2:1) patients to receive four cycles (cycle interval was 8 weeks ± 1 week) of intravenous 177Lu-Dotatate plus intramuscular octreotide 30 mg long-acting repeatable (LAR) then octreotide 30 mg LAR every 4 weeks (177Lu-Dotatate group) or high-dose octreotide 60 mg LAR every 4 weeks (control group), stratified by neuroendocrine tumour grade (2 vs 3) and origin (pancreas vs other). Tumour assessments were done at baseline, week 16, and week 24, and then every 12 weeks until disease progression or death. The primary endpoint was progression-free survival by blinded, independent, central radiology assessment. We did the primary analysis at 101 progression-free survival events as the final progression-free survival analysis. NETTER-2 is registered with ClinicalTrials.gov, NCT03972488, and is active and not recruiting. FINDINGS: Between Jan 22, 2020, and Oct 13, 2022, we screened 261 patients, 35 (13%) of whom were excluded. We randomly assigned 226 (87%) patients (121 [54%] male and 105 [46%] female) to the 177Lu-Dotatate group (n=151 [67%]) and control group (n=75 [33%]). Median progression-free survival was 8·5 months (95% CI 7·7-13·8) in the control group and 22·8 months (19·4-not estimated) in the 177Lu-Dotatate group (stratified hazard ratio 0·276 [0·182-0·418]; p<0·0001). During the treatment period, adverse events (of any grade) occurred in 136 (93%) of 147 treated patients in the 177Lu-Dotatate group and 69 (95%) of 73 treated patients in the control group. There were no study drug-related deaths during the treatment period. INTERPRETATION: First-line 177Lu-Dotatate plus octreotide LAR significantly extended median progression-free survival (by 14 months) in patients with grade 2 or 3 advanced gastroenteropancreatic neuroendocrine tumours. 177Lu-Dotatate should be considered a new standard of care in first-line therapy in this population. FUNDING: Advanced Accelerator Applications, a Novartis Company.

Indolent lymphoma care delivery and outcomes during the COVID-19 pandemic in Ontario, Canada.

The treatment pattern and outcomes in patients with indolent B-cell lymphoma treated during the coronavirus disease 2019 (COVID-19) pandemic period compared to the prepandemic period are unclear. This was a retrospective population-based study using administrative databases in Ontario, Canada (follow-up to 31 March 2022). The primary outcome was treatment pattern; secondary outcomes were death, toxicities, healthcare utilization (emergency department [ED] visit, hospitalization) and SARS-CoV-2 outcomes. Adjusted hazard ratios (aHR) from Cox proportional hazards models were used to estimate associations. We identified 4143 patients (1079 pandemic, 3064 prepandemic), with a median age of 69 years. In both time periods, bendamustine (B) + rituximab (BR) was the most frequently prescribed regimen. During the pandemic, fewer patients received R maintenance or completed the full 2-year course (aHR 0.81, 95% CI 0.71-0.92, p = 0.001). Patients treated during the pandemic had less healthcare utilization (ED visit aHR 0.77, 95% CI 0.68, 0.88, p < 0.0001; hospitalization aHR 0.81, 95% CI 0.70-0.94, p = 0.0067) and complications (infection aHR 0.69, 95% CI 0.57-0.82, p < 0.0001; febrile neutropenia aHR 0.66, 95% CI 0.47-0.94, p = 0.020), with no difference in death. Independent of vaccination, active rituximab use was associated with a higher risk of COVID-19 complications. Despite similar front-line regimen use, healthcare utilization and admissions for infection were less in the pandemic cohort.

Patient Priorities Concerning Treatment Decisions for Advanced Neuroendocrine Tumors Identified by Discrete Choice Experiments.

BACKGROUND: Patients with advanced neuroendocrine tumors (NETs) have multiple treatment options. Ideally, treatment decisions are shared between physician and patient; however, previous studies suggest that oncologists and patients place different value on treatment attributes such as adverse event (AE) rates. High-quality information on NET patient treatment preferences may facilitate patient-centered decision making by helping clinicians understand patient priorities. METHODS: This study used 2 discrete choice experiments (DCE) to elicit preferences of NET patients regarding advanced midgut and pancreatic NET (pNET) treatments. The DCEs used the "potentially all pairwise rankings of all possible alternatives" (PAPRIKA) method. The primary objective was to determine relative utility rankings for treatment attributes, including progression-free survival (PFS), treatment modality, and AE rates. Ranking of attribute profiles matching specific treatments was also determined. Levels for treatment attributes were obtained from randomized clinical trial data of NET treatments. RESULTS: One hundred and 10 participants completed the midgut NET DCE, and 132 completed the pNET DCE. Longer PFS was the highest ranked treatment attribute in 64.5% of participants in the midgut NET DCE, and in 59% in the pNET DCE. Approximately, 40% of participants in both scenarios prioritized lower AE rates or less invasive treatment modalities over PFS. Ranking of treatment profiles in the midgut NET scenario identified 60.9% of participants favoring peptide receptor radionuclide therapy (PRRT), and 30.0% somatostatin analogue dose escalation. CONCLUSION: NET patients have heterogeneous priorities when choosing between treatment options based on the results of 2 independent DCEs. These results highlight the importance of shared decision making for NET patients.

Optimizing a mentorship program from the perspective of academic medicine leadership - a qualitative study.

BACKGROUND: Effective mentorship is an important contributor to academic success. Given the critical role of leadership in fostering mentorship, this study sought to explore the perspectives of departmental leadership regarding 1) current departmental mentorship processes; and 2) crucial components of a mentorship program that would enhance the effectiveness of mentorship. METHODS: Department Division Directors (DDDs), Vice-Chairs, and Mentorship Facilitators from the Department of Medicine at the University of Toronto Temerty Faculty of Medicine were interviewed between April and December 2021 using a semi-structured guide. Interviews were audio-recorded and transcribed verbatim, then coded. Analysis occurred in 2 steps: 1) codes were organized to identify emergent themes; then 2) the Social Ecological Model (SEM) was applied to interpret the findings. RESULTS: Nineteen interviews (14 DDDs, 3 Vice-Chairs, and 2 Mentorship Facilitator) were completed. Analysis revealed three themes: (1) a culture of mentorship permeated the department as evidenced by rigorous mentorship processes, divisional mentorship innovations, and faculty that were keen to mentor; (2) barriers to the establishment of effective mentoring relationships existed at 3 levels: departmental, interpersonal (mentee-mentor relationships), and mentee; and (3) strengthening the culture of mentorship could entail scaling up pre-existing mentorship processes and promoting faculty engagement. Application of SEM highlighted critical program features and determined that two components of interventions (creating tools to measure mentorship outcomes and systems for mentor recognition) were potential enablers of success. CONCLUSIONS: Establishing 'mentorship outcome measures' can incentivize and maintain relationships. By tangibly delineating departmental expectations for mentorship and creating systems that recognize mentors, these measures can contribute to a culture of mentorship.

Upfront Small Bowel Resection for Small Bowel Neuroendocrine Tumors With Synchronous Metastases: A Propensity-score Matched Comparative Population-based Analysis.

OBJECTIVE: We examined the impact of upfront small bowel resection (USBR) for metastatic small bowel neuroendocrine (SB-NET) compared to nonoperative management (NOM) on long-term healthcare utilization and survival outcomes. SUMMARY OF BACKGROUND DATA: The role of early resection of the primary tumor in metastatic SB-NET remains controversial. Conflicting data exist regarding its clinical and survival benefits. METHODS: This is a population-based retrospective matched comparative cohort study of adults diagnosed with synchronous metastatic SB-NET between 2001 and 2017 in Ontario. USBR was defined as resection within 6 months of diagnosis. Primary outcomes were subsequent unplanned acute care admissions and small bowel-related surgery. Secondary outcome was overall survival. USBR and NOM patients were matched 2:1 using a propensity-score. We used time-to-event analyses with cumulative incidencefunctions and univariate Andersen-Gill regression for primary outcomes. E value methods assessed the potential for residual confounding. RESULTS: Of 1000 patients identified, 785 had USBR. The matched cohort included 348 patients with USBR and 174 with NOM. Patients with USBR had lower 3-year risk of subsequent admissions (72.6% vs 86.4%, P < 0.001) than those with NOM, with hazard ratio 0.72 (95% confidence interval 0.570.91). USBR was associated with lower risk of subsequent small bowel-related surgery (15.4% vs 40.3%, P < 0.001), with hazard ratio 0.44 (95% confidence interval 0.29-0.67). E -values indicated it was unlikely that the observed risk estimates could be explained by an unmeasured confounder. Sensitivity analysis excluding emergent resections to define USBR did not alter the results. CONCLUSIONS: USBR for SB-NETs in the presence of metastatic disease was associated with better patient-oriented outcomes of decreased subsequent admissions and interventions, compared to NOM. USBR should be considered for metastatic SB-NETs.

Effect of Chronic Comorbidities on Follow-up Colonoscopy After Positive Colorectal Cancer Screening Results: A Population-Based Cohort Study.

INTRODUCTION: Fecal occult blood tests (FOBTs) are colorectal cancer screening tests used to identify individuals requiring further investigation with colonoscopy. Delayed colonoscopy after positive FOBT (FOBT+) is associated with poorer cancer outcomes. We assessed the effect of comorbidity on colonoscopy receipt within 12 months after FOBT+. METHODS: Population-based healthcare databases from Ontario, Canada, were linked to assemble a cohort of 50-74-year-old individuals with FOBT+ results between 2008 and 2017. The associations between comorbidities and colonoscopy receipt within 12 months after FOBT+ were examined using multivariable cause-specific hazard regression models. RESULTS: Of 168,701 individuals with FOBT+, 80.5% received colonoscopy within 12 months. In multivariable models, renal failure (hazard ratio [HR] 0.71, 95% confidence interval [CI] 0.62-0.82), heart failure (HR 0.77, CI 0.75-0.80), and serious mental illness (HR 0.88, CI 0.85-0.92) were associated with the lowest colonoscopy rates, compared with not having each condition. The number of medical conditions was inversely associated with colonoscopy uptake (≥4 vs 0: HR 0.64, CI 0.58-0.69; 3 vs 0: HR 0.75, CI 0.72-0.78; and 2 vs 0: HR 0.87, CI 0.85-0.89). Having both medical and mental health conditions was associated with a lower colonoscopy uptake relative to no comorbidity (HR 0.88, CI 0.87-0.90). DISCUSSION: Persons with medical and mental health conditions had lower colonoscopy rates after FOBT+ than those without these conditions. Better strategies are needed to optimize colorectal cancer screening and follow-up in individuals with comorbidities.

Primary care utilization for patients with newly diagnosed cancer during the COVID-19 pandemic: a population-based study.

BACKGROUND: The COVID-19 pandemic greatly impacted primary care and cancer care. We studied how primary care utilization in Ontario, Canada changed for patients who were newly diagnosed with cancer just prior to the COVID-19 pandemic compared to those diagnosed in non-pandemic years. METHODS: This population-based, retrospective cohort study used linked healthcare databases to compare outcomes for patients with a new malignancy diagnosed within the year prior to the COVID-19 pandemic, between July 1 and September 30, 2019 (COVID-19 cohort) to those diagnosed in the same months in 2018 and 2017 (pre-pandemic cohort). We used Poisson regression models to compare rates of in-person and virtual visits to patients' usual primary care physician (PCP), emergency department (ED) visits, and hospitalizations, all reported per person-year of follow-up. RESULTS: In-person visits to usual PCPs decreased from 4.07/person-year in the pre-pandemic cohort to 2.58 in the COVID-19 cohort (p < 0.0001). Virtual visits to usual PCPs increased from 0.00 to 1.53 (p < 0.0001). Combined in-person and virtual visits to patients' usual PCPs was unchanged from 4.07 to 4.12 (p = 0.89). The rate of ED visits decreased from 0.99/person-year to 0.88 (p < 0.0001). Non-elective hospitalizations remained unchanged, from 0.49/person-year to 0.47 (p = 0.1675). CONCLUSION: There was a sizeable shift in primary care visits for cancer patients from in-person to virtual during the pandemic, although there was no resultant increase in hospitalizations. This suggests that early in the pandemic, virtual care allowed for continuity in utilization of primary care, though further studies are required to confirm this persisted later in the pandemic.

Stereotactic Ablative Radiotherapy for the Management of Liver Metastases from Neuroendocrine Neoplasms: A Preliminary Study.

INTRODUCTION: Liver metastases are common in patients with neuroendocrine neoplasms. The role of stereotactic ablative radiotherapy (SABR) is not well understood in this population. OBJECTIVE: The objective of this study was to evaluate the safety and efficacy of SABR in treating well-differentiated neuroendocrine liver metastases (WD-NELM). METHODS: A retrospective review of patients with WD-NELM treated with SABR was conducted between January 2015 and July 2019. Demographic, treatment, and clinical/radiographic follow-up data were abstracted. RECIST 1.1 criteria were applied to each individual target to evaluate the response to treatment. Local control (LC) and progression-free survival (PFS) were determined using the Kaplan-Meier methodology. Toxicity was reported according to the CTCAE v5.0. RESULTS: Twenty-five patients with a total of 53 liver metastases treated with SABR were identified. Most patients (68%) had midgut tumors, were grade 2 (80%), and had high-volume intrahepatic and/or extrahepatic disease (76%). The median number of liver metastases treated was 2, with a median size of 2.5 cm. The median radiation dose delivered was 50 Gy/5 fractions. The median follow-up was 14 months; 24 of the 25 patients were alive at the time of analysis. The objective response rate was 32%, with improvement or stability in 96% of lesions treated. The median time to best response was 9 months. The 1-year LC and PFS were 92 and 44%, respectively. No grade 3/4 acute or late toxicity was identified. CONCLUSIONS: Liver SABR is a safe and promising means of providing LC for WD-NELM. This treatment modality should be evaluated in selected patients in concert with strategies to manage systemic disease.

Incident Cancer Detection During the COVID-19 Pandemic.

BACKGROUND: Resource restrictions were established in many jurisdictions to maintain health system capacity during the COVID-19 pandemic. Disrupted healthcare access likely impacted early cancer detection. The objective of this study was to assess the impact of the pandemic on weekly reported cancer incidence. PATIENTS AND METHODS: This was a population-based study involving individuals diagnosed with cancer from September 25, 2016, to September 26, 2020, in Ontario, Canada. Weekly cancer incidence counts were examined using segmented negative binomial regression models. The weekly estimated backlog during the pandemic was calculated by subtracting the observed volume from the projected/expected volume in that week. RESULTS: The cohort consisted of 358,487 adult patients with cancer. At the start of the pandemic, there was an immediate 34.3% decline in the estimated mean cancer incidence volume (relative rate, 0.66; 95% CI, 0.57-0.75), followed by a 1% increase in cancer incidence volume in each subsequent week (relative rate, 1.009; 95% CI, 1.001-1.017). Similar trends were found for both screening and nonscreening cancers. The largest immediate declines were seen for melanoma and cervical, endocrinologic, and prostate cancers. For hepatobiliary and lung cancers, there continued to be a weekly decline in incidence during the COVID-19 period. Between March 15 and September 26, 2020, 12,601 fewer individuals were diagnosed with cancer, with an estimated weekly backlog of 450. CONCLUSIONS: We estimate that there is a large volume of undetected cancer cases related to the COVID-19 pandemic. Incidence rates have not yet returned to prepandemic levels.

Incident Cancer Detection During Multiple Waves of COVID-19: The Tsunami After the Earthquake.

No population-based study exists to demonstrate the full-spectrum impact of COVID-19 on hindering incident cancer detection in a large cancer system. Building upon our previous publication in JNCCN, we conducted an updated analysis using 12 months of new data accrued in the pandemic era (extending the study period from September 26, 2020, to October 2, 2021) to demonstrate how multiple COVID-19 waves affected the weekly cancer incidence volume in Ontario, Canada, and if we have fully cleared the backlog at the end of each wave.

Incidence of psychiatric illness in patients with neuroendocrine tumors: a comparative population-based analysis.

PURPOSE: Diversion of tryptophan to tumoral hormonal production has been suggested to result in psychiatric illnesses in neuroendocrine tumors (NET). We measured the occurrence of psychiatric illness after NET diagnosis and compare it to colon cancer (CC). METHODS: We conducted a population-based retrospective cohort study. Adults with NET were matched 1:1 to CC (2000-2019). Psychiatric illness was defined by mental health diagnoses and mental health care use after a cancer diagnosis, categorized as severe, other, and none. Cumulative incidence functions accounted for death as a competing risk. RESULTS: A total of 11,223 NETs were matched to CC controls. Five-year cumulative incidences of severe psychiatric illness for NETs vs. CC was 7.7% (95%CI 7.2-8.2%) vs 7.6% (95%CI 7.2-8.2%) (p = 0.50), and that of other psychiatric illness was 32.9% (95%CI 32.0-33.9%) vs 31.6% (95%CI 30.8-32.6%) (p = 0.005). In small bowel and lung NETs, 5-year cumulative incidences of severe (8.1% [95%CI 7.3-8.9%] vs. 7.0% [95%CI 6.3-7.8%]; p = 0.01) and other psychiatric illness (34.7% [95%CI 33.3-36.1%] vs. 31.1% [95%CI 29.7-32.5%]; p < 0.01) were higher than for matched CC. The same was observed for serotonin-producing NETs for both severe (7.9% [95%CI 6.5-9.4%] vs. 6.8% [95%CI 5.5-8.2%]; p = 0.02) and other psychiatric illness (35.4% [95%CI 32.8-38.1%] vs. 31.9% [95%CI 29.3-34.4%]; p = 0.02). CONCLUSIONS: In all NETs, there was no difference observed in the incidence of psychiatric illness compared to CC. For sub-groups of small bowel and lung NETs and of serotonin-producing NETs, the incidence of psychiatric illness was higher than for CC. These data suggest a signal towards a relationship between those sub-groups of NETs and psychiatric illness.

Transitions in oral and gut microbiome of HPV+ oropharyngeal squamous cell carcinoma following definitive chemoradiotherapy (ROMA LA-OPSCC study).

BACKGROUND: Oral and gut microbiomes have emerged as potential biomarkers in cancer. We characterised the oral and gut microbiomes in a prospective observational cohort of HPV+ oropharyngeal squamous cell carcinoma (OPSCC) patients and evaluated the impact of chemoradiotherapy (CRT). METHODS: Saliva, oropharyngeal swabs over the tumour site and stool were collected at baseline and post-CRT. 16S RNA and shotgun metagenomic sequencing were used to generate taxonomic profiles, including relative abundance (RA), bacterial density, α-diversity and ß-diversity. RESULTS: A total of 132 samples from 22 patients were analysed. Baseline saliva and swabs had similar taxonomic composition (R2 = 0.006; p = 0.827). Oropharyngeal swabs and stool taxonomic composition varied significantly by stage, with increased oral RA of Fusobacterium nucleatum observed in stage III disease (p < 0.05). CRT significantly reduced the species richness and increased the RA of gut-associated taxa in oropharyngeal swabs (p < 0.05), while it had no effect in stool samples. These findings remained significant when adjusted by stage, smoking status and antibiotic use. CONCLUSIONS: Baseline oral and gut microbiomes differ by stage in this HPV+ cohort. CRT caused a shift towards a gut-like microbiome composition in oropharyngeal swabs. Stage-specific features and the transitions in oral microbiome might have prognostic and therapeutic implications.

Temozolomide in Grade 3 Gastroenteropancreatic Neuroendocrine Neoplasms: A Multicenter Retrospective Review.

BACKGROUND: Grade 3 gastroenteropancreatic neuroendocrine neoplasms (G3 GEPNENs) are often aggressive, and the optimal treatment is unclear for this subgroup of neuroendocrine neoplasms (NENs). Temozolomide (TEM)-based regimens have been increasingly used to treat grade 1-2 NENs, but their efficacy in G3 NENs remains undetermined. We aimed to assess the clinical efficacy of TEM-containing regimens in advanced grade 3 GEPNENs. MATERIALS AND METHODS: A multicenter retrospective review (2008-2018) of patients with metastatic/unresectable G3 GEPNENs who received a TEM-containing regimen was undertaken within a North American partnership to pool data. The primary endpoint was time to treatment failure (TTF). Radiologic response was extracted from local reports. RESULTS: One hundred and thirty patients in six high-volume NEN centers were included (median age 55, 64% male, 18% functional, 67% pancreatic NEN). Forty-nine percent were well-differentiated, 35% poorly differentiated, and 15% unknown based on local pathology reports. The regimen used was capecitabine and temozolomide (CAPTEM) in 92% and TEM alone in 8%. Radiological response by local assessment was seen in 36% of patients. Median TTF was 3.6 months and median overall survival (OS) 19.2 months. Six percent of patients required discontinuation of therapy due to adverse events. TTF was longer in first-line treatment (7.8 months vs. 2.9 months; hazard ratio, 1.62; 95% confidence interval, 1.11-2.36; p = .015) and in patients with pancreatic NENs (panNENs) compared with gastrointestinal NENs (5.8 months vs 1.8 months; p = .04). The overall response rate was higher in the first-line setting (51% vs 29%; p = .02) and in panNEN (41% vs 23%; p = .04). CONCLUSION: This is the largest TEM treatment series in G3 NEN, involving collaboration of several major North American NEN centers as a partnership. Thirty-six percent of patients showed some degree of radiographic response, and treatment was generally well tolerated, although the median duration of response was short. Response rates and time to treatment failure were superior in the first-line setting. CAPTEM should be considered a viable treatment option in this setting. Further randomized trials are warranted. IMPLICATIONS FOR PRACTICE: Neuroendocrine neoplasms (NENs) are heterogeneous, and optimal treatment for aggressive grade 3 (G3) NENs remains undetermined. The capecitabine and temozolomide (CAPTEM) regimen has been used in low-grade pancreas NENs but there are few data for its safety and efficacy in the G3 setting. This article reports on the efficacy of temozolomide-containing regimens, particularly CAPTEM, in management of G3 NENs. The good tolerance and response rate show that CAPTEM should be considered a viable regimen in treatment of G3 NENs pending confirmatory prospective studies.

Carcinoid Heart Disease: Prognostic Value of 5-Hydroxyindoleacetic Acid Levels and Impact on Survival: A Systematic Literature Review.

BACKGROUND: Carcinoid heart disease (CHD) can develop in patients with carcinoid syndrome (CS), itself caused by overproduction of hormones and other products from some neuroendocrine tumours. The most common hormone is serotonin, detected as high 5-hydroxyindoleacetic acid (5-HIAA). This systematic literature review summarises current literature on the impact of CHD on survival, and the relationship between 5-HIAA levels and CHD development, progression, and mortality. METHODS: MEDLINE, Embase, Cochrane databases, and grey literature were searched using terms for CHD, 5-HIAA, disease progression, and mortality/survival. Eligible articles were non-interventional and included patients with CS and predefined CHD and 5-HIAA outcomes. RESULTS: Publications reporting on 31 studies were included. The number and disease states of patients varied between studies. Estimates of CHD prevalence and incidence among patients with a diagnosis/symptoms indicative of CS were 3-65% and 3-42%, respectively. Most studies evaluating survival found significantly higher mortality rates among patients with versus without CHD. Patients with CHD reportedly had higher 5-HIAA levels; median urinary levels in patients with versus without CHD were 266-1,381 versus 67.5-575 µmol/24 h. Higher 5-HIAA levels were also found to correlate with disease progression (median progression/worsening-associated levels: 791-2,247 µmol/24 h) and increased odds of death (7% with every 100 nmol/L increase). CONCLUSIONS: Despite the heterogeneity of studies, the data indicate that CHD reduces survival, and higher 5-HIAA levels are associated with CHD development, disease progression, and increased risk of mortality; 5-HIAA levels should be carefully managed in these patients.

Development of the Functional Assessment of Cancer Therapy-Carcinoid Syndrome Symptom Index.

OBJECTIVE: To develop a symptom-focused index to evaluate representative symptoms, treatment side effects, and emotional and functional well-being of patients with carcinoid syndrome (CS). METHODS: The development of the Functional Assessment of Cancer Therapy-Carcinoid Syndrome Symptom Index (FACT-CSI) followed US Food and Drug Administration guidelines for the development of patient-reported outcome (PRO) measures and involved the following: (a) literature review; (b) interviews with 14 CS patients; (c) interviews with 9 clinicians; and (d) instrument development involving input from a range of PRO measure development and CS experts. The resulting draft instrument underwent cognitive interviews with 7 CS patients. RESULTS: Forty-six CS sources were reviewed. Analysis of patient interviews produced 23 patient-reported symptoms. The most frequently endorsed physical symptoms were flushing, diarrhea, abdominal pain, fatigue, and food sensitivity/triggers. Seven priority CS emotional and functional themes were also identified by patients. Expert interviews revealed 12 unique priority symptoms - the most common being diarrhea, flushing, wheezing, edema, abdominal pain/cramping, fatigue, and 8 emotional and functional concerns. Through an iterative process of team and clinical collaborator meetings, data review, item reduction and measure revision, 24 items were selected for the draft symptom index representing symptoms, emotional concerns, global assessment of treatment side effects, and functional well-being. Cognitive interview results demonstrated strong content validity, including positive endorsement of item clarity (>86% across items), symptom relevance (>70% for most items), and overall measure content (86%). CONCLUSIONS: The FACT-CSI is a content-relevant, symptom-focused index reflecting the highest priority and clinically relevant symptoms and concerns of people with CS.

Risk of Cancer-Specific Death for Patients Diagnosed With Neuroendocrine Tumors: A Population-Based Analysis.

BACKGROUND: Although patients with neuroendocrine tumors (NETs) are known to have prolonged overall survival, the contribution of cancer-specific and noncancer deaths is undefined. This study examined cancer-specific and noncancer death after NET diagnosis. METHODS: We conducted a population-based retrospective cohort study of adult patients with NETs from 2001 through 2015. Using competing risks methods, we estimated the cumulative incidence of cancer-specific and noncancer death and stratified by primary NET site and metastatic status. Subdistribution hazard models examined prognostic factors. RESULTS: Among 8,607 included patients, median follow-up was 42 months (interquartile range, 17-82). Risk of cancer-specific death was higher than that of noncancer death, at 27.3% (95% CI, 26.3%-28.4%) and 5.6% (95% CI, 5.1%-6.1%), respectively, at 5 years. Cancer-specific deaths largely exceeded noncancer deaths in synchronous and metachronous metastatic NETs. Patterns varied by primary tumor site, with highest risks of cancer-specific death in bronchopulmonary and pancreatic NETs. For nonmetastatic gastric, small intestine, colonic, and rectal NETs, the risk of noncancer death exceeded that of cancer-specific deaths. Advancing age, higher material deprivation, and metastases were independently associated with higher hazards, and female sex and high comorbidity burden with lower hazards of cancer-specific death. CONCLUSIONS: Among all NETs, the risk of dying of cancer was higher than that of dying of other causes. Heterogeneity exists by primary NET site. Some patients with nonmetastatic NETs are more likely to die of noncancer causes than of cancer causes. This information is important for counseling, decision-making, and design of future trials. Cancer-specific mortality should be included in outcomes when assessing treatment strategies.

Influence of chronic comorbidities on periodic colorectal cancer screening participation: A population-based cohort study.

Guidelines recommend regular screening for colorectal cancer (CRC). We examined the effects of chronic comorbidities on periodic CRC testing. Using linked healthcare databases from Ontario, Canada, we assembled a population-based cohort of 50-74-year olds overdue for guideline-recommended CRC screening between April 1, 2004 and March 31, 2016. We implemented multivariable recurrent events models to determine the association between comorbidities and the rate of becoming up-to-date with periodic CRC tests. The cohort included 4,642,422 individuals. CRC testing rates were significantly lower in persons with renal disease on dialysis (hazard ratio, HR 0.66, 95% confidence interval, CI 0.63 to 0.68), heart failure (HR 0.75, CI 0.75 to 0.76), respiratory disease (HR 0.84, CI 0.83 to 0.84), cardiovascular disease (HR 0.85, CI 0.84 to 0.85), diabetes (HR 0.86, 95% CI 0.86 to 0.87) and mental illness (HR 0.88, CI 0.87 to 0.88). There was an inverse association between the number of medical conditions and the rate of CRC testing (5 vs. none: HR 0.30, CI 0.25 to 0.36; 4 vs. none: HR 0.48, CI 0.47 to 0.50; 3 vs. none: HR 0.59, CI 0.58 to 0.60; 2 vs. none: HR 0.72, CI 0.71 to 0.72; 1 vs. none: HR 0.85, CI 0.84 to 0.85). Having both medical and mental comorbidities was associated with lower testing rates than either type of comorbidity alone (HR 0.72, CI 0.71 to 0.72). In summary, chronic comorbidities present a barrier to periodic guideline-recommended CRC testing. Exploration of cancer prevention gaps in these populations is warranted.

Advanced Pancreatic Neuroendocrine Neoplasms: Which Systemic Treatment Should I Start With?

PURPOSE OF REVIEW: Pancreatic neuroendocrine neoplasms (panNENs) often present as advanced disease and there is little data to guide treatment sequencing in the advance disease setting. Therefore, we aim to provide a comprehensive summary of the current evidence supporting the use of systemic treatment for patients with diagnosis of advanced and metastatic panNENs, as well as to provide strategies for treatment selection and address challenges for treatment selection and sequencing of therapy. RECENT FINDINGS: Substantial advances have been made and many clinical trials have been performed over the past two decades expanding therapeutic options available for patients with advanced panNETs. Available systemic treatments for patients with well-differentiated pancreatic neuroendocrine tumors include somatostatin receptors ligands (SRLs), traditional cytotoxic chemotherapy regimens, peptide receptor radiotherapy (PRRT), and biologically targeted therapies, whereas patients with poorly differentiated neurodocrine carcinomas have more limited treatment options. Despite these advances, no clear guidelines exist to support the best sequence of treatments, not only the first-line, but also subsequent lines of therapy in patients with panNENs. Advances in molecular research and discovery of biomarkers for response allowing a more personalized approach to the multimodality therapy of panNENs are still limited. Understanding the impact of previous therapies on subsequent treatment efficacy and toxicity is also an ongoing research question. In the absence of definite predictive markers and paucity of comparative randomized trials, along with the heterogeneity of this patient population, systemic therapy selection in advanced non-resectable disease should be patient centered and often require evaluation within a multidisciplinary setting. The specific clinical context of the patient, with assessment of individual patient clinical and pathological features, somatostatin receptors imaging, and goals of treatment must all be considered when deciding on systemic therapy in the patient. Additional research is needed to address the gap in knowledge regarding optimal sequencing and timing of therapies and to provide individual care.

Impact of the early phase of the COVID pandemic on cancer treatment delivery and the quality of cancer care: a scoping review and conceptual model.

BACKGROUND: The disruption of health services due to coronavirus disease (COVID) is expected to dramatically alter cancer care; however, the implications for care quality and outcomes remain poorly understood. OBJECTIVE: We undertook a scoping review to evaluate what is known in the literature about how cancer treatment has been modified as a result of the COVID pandemic in patients receiving treatment for solid tumours, and what domains of quality of care are most impacted. METHODS: Citations were retrieved from MEDLINE and EMBASE (from 1 January 2019 to 28 October 2020), utilizing search terms grouped by the key concept (oncology, treatment, treatment modifications and COVID). Articles were excluded if they dealt exclusively with management of COVID-positive patients, modifications to cancer screening, diagnosis or supportive care or were not in English. Articles reporting on guidelines, consensus statements, recommendations, literature reviews, simulations or predictive models, or opinions in the absence of accompanying information on experience with treatment modifications in practice were excluded. Treatment modifications derived from the literature were stratified by modality (surgery, systemic therapy (ST) and radiotherapy) and thematically grouped. To understand what areas of quality were most impacted, modifications were mapped against the Institute of Medicine's quality domains. Where reported, barriers and facilitators were abstracted and thematically grouped to understand drivers of treatment modifications. Findings were synthesized into a logic model to conceptualize the inter-relationships between different modifications, as well as their downstream impacts on outcomes. RESULTS: In the 87 retained articles, reductions in outpatients visits (26.4%) and delays/deferrals were commonly reported across all treatment modalities (surgery: 50%; ST: 55.8% and radiotherapy: 56.7%), as were reductions in surgical capacity (57.1%), alternate systemic regimens with longer treatment intervals or use of oral agents (19.2%) and the use of hypofractionated radiotherapy regimens (40.0%). Delivery of effective, timely and equitable care was the quality domains found to be the most impacted. The most commonly reported facilitator of maintaining cancer care delivery levels was the shift to virtual models of care (62.1%), while patient-initiated deferrals and cancellations (34.8%), often due to fear of contracting COVID (60.9%), was a commonly reported barrier. CONCLUSIONS: As it will take a considerable amount of time for the cancer system to resume capacity and adjust models of care in response to the pandemic, these treatment delays and modifications will likely be prolonged and will negatively impact the quality of care and patient outcomes.

Impact of diabetes on colorectal cancer stage and mortality risk: a population-based cohort study.

AIMS/HYPOTHESIS: Diabetes is associated with an increased incidence of colorectal cancer (CRC). There exists conflicting evidence regarding the impact of diabetes on CRC-specific mortality (herein also referred to as cancer-specific mortality). The objectives of this study were to determine whether diabetes is associated with a more advanced CRC stage at diagnosis and with higher all-cause and cancer-specific mortality. METHODS: This retrospective cohort study used linked, population-based health databases from Ontario, Canada. Among individuals diagnosed with CRC from 2007 to 2015, we compared the likelihood of presenting with later- (III or IV) vs early- (I or II) stage CRC between patients with and without diabetes adjusting for relevant covariates. We then determined the association between diabetes and all-cause and CRC-specific mortality, after adjusting for CRC stage at diagnosis and other covariates. RESULTS: Of the 44,178 individuals with CRC, 11,822 (26.7%) had diabetes. After adjustment for CRC screening and other covariates, individuals with diabetes were not more likely to present with later-stage CRC (adjusted OR 0.97, 95% CI 0.93, 1.01). Over a median follow-up of 2.63 (interquartile range [IQR] 0.97-5.10) years, diabetes was associated with higher all-cause mortality (adjusted HR 1.08, 95% CI 1.04, 1.12) but similar cancer-specific survival (adjusted HR 1.0, 95% CI 0.95, 1.06). CONCLUSIONS/INTERPRETATION: Individuals with diabetes who develop CRC are not more likely to present with a later stage of CRC and have similar cancer-specific mortality compared with those without diabetes. Diabetes was associated with higher all-cause mortality in CRC patients, indicating that greater attention to non-cancer care is needed for CRC survivors with diabetes.