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.

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.

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.

Multi-disciplinary proactive follow-up algorithm for patients with advanced NSCLC receiving afatinib.

PURPOSE: Afatinib is a standard first-line therapy for advanced EGFR-positive NSCLC. We implemented a pharmacist-led proactive follow-up algorithm to identify and manage early afatinib-related adverse events (AEs). METHODS: We conducted a retrospective chart review of all patients treated with afatinib after implementation of the algorithm at the Sunnybrook Odette Cancer Centre (Toronto, ON, Canada) from April 1, 2015 to July 31, 2016. Our in-house algorithm involved consultations in person and proactive pharmacist-led callbacks on days 5, 10, and 17. All AEs were graded and documented in real time and management based on toxicity grade was standardized. This study evaluated the impact of our algorithm on real-world AEs. RESULTS AND DISCUSSION: Thirty-three patients were identified and reviewed. Median follow-up was 248 days. All patients experienced at least one drug-related AE; 18.2% were grade 3/4. The most common AEs were diarrhea 87.9%, rash 81.8%, stomatitis 57.6%, and paronychia 45.5%. Median dose of afatinib was 40 mg daily; 51.5% of patients had ≥ 1 dose reduction and 6.3% discontinued afatinib due to AEs. Proactive calls by the pharmacist identified 36.5% of all drug-related AEs, 33.3% of grade 3/4 AEs, 58.1% of first drug-related AEs and identified two patients that were non-compliant. Only 3.2% of AEs were identified by an emergency room/urgent clinic visit. CONCLUSIONS: This proactive multi-disciplinary AE management algorithm resulted in a low rate of urgent assessments and discontinuation due to toxicity while maintaining afatinib at ideal dose, thus providing a useful tool for centers prescribing afatinib.

Management of anticoagulation in patients with metastatic castration-resistant prostate cancer receiving abiraterone + prednisone.

PURPOSE: Abiraterone has been proven to be an effective agent used in the management of metastatic castration-resistant prostate cancer, significantly improving overall and progression-free survival. Due to the pharmacodynamic and pharmacokinetic properties of abiraterone, concurrent use with anticoagulation may pose a challenge for clinicians. Thrombosis within the cancer setting continues to increase patient mortality; therefore, appropriate anticoagulation through the use of a management algorithm can reduce adverse events and increase quality of life. METHODS: A review of the literature was preformed by a medical oncologist, haematologist and pharmacists to identify relevant randomized controlled trials, meta-analyses and retrospective studies. Major society guidelines were reviewed to further aid in developing the anticoagulation protocol for non-valvular atrial fibrillation and venous thromboembolism within this patient population. After reviewing the literature, a clinical framework was designed to aid clinicians in the management of those patients receiving abiraterone concurrently with an anticoagulant. RESULTS: In this review, we describe the potential interactions between abiraterone and various anticoagulants and provide management strategies based on the most recent literature for atrial fibrillation, venous thromboembolism and mechanical heart valves to avoid potential drug-drug interactions. CONCLUSION: Abiraterone therapy has become a mainstay of the management of advanced prostate cancer and is often used over prolonged years. In this review, we have summarized a framework of how to use abiraterone in men with prostate cancer on anticoagulants. Evidence available to date suggests that patients with an indication for anticoagulation such as atrial fibrillation, venous thromboembolism and mechanical heart valves can be treated safely with abiraterone in the appropriate setting, with appropriate monitoring.

EGFR Targeting TKI-Related Skin Toxicities in a Patient with Darker Skin: A Case Report.

Epidermal growth factor receptor (EGFR) targeting tyrosine kinase inhibitors (TKIs) can result in significant skin toxicities that may impact patients' quality of life. While these skin reactions are well documented in patients with lighter skin, there is a paucity of literature and images to guide clinicians in their assessment in patients with darker skin tones. Given that dermatological reactions in patients with darker skin are not well represented, this can result in the undertreatment or mistreatment of these otherwise common toxicities. Herein, we present a case of a female patient with a darker skin tone with metastatic non-small cell lung carcinoma (NSCLC) with EGFR-TKI-related skin toxicity and her clinical course.

Use of Adjuvant Bisphosphonates and Other Bone-Modifying Agents in Breast Cancer: ASCO-OH (CCO) Guideline Update.

PURPOSE: To update recommendations of the American Society of Clinical Oncology (ASCO)-Ontario Health (Cancer Care Ontario [CCO]) adjuvant bone-modifying agents in breast cancer guideline. METHODS: An Expert Panel conducted a systematic review to identify new, potentially practice-changing data. RESULTS: Four articles met eligibility criteria and form the evidentiary basis for revision of the previous recommendations. RECOMMENDATIONS: Adjuvant bisphosphonate therapy should be discussed with all postmenopausal patients (natural or therapy-induced) with primary breast cancer, irrespective of hormone receptor status and human epidermal growth factor receptor 2 status, who are candidates to receive adjuvant systemic therapy. Adjuvant bisphosphonates, if used, are not substitutes for standard anticancer modalities. The benefit of adjuvant bisphosphonate therapy will vary depending on the underlying risk of recurrence and is associated with a modest improvement in overall survival. The NHS PREDICT tool provides estimates of the benefit of adjuvant bisphosphonate therapy and may aid in decision making. Factors influencing the decision to recommend adjuvant bisphosphonate use should include patients' risk of recurrence, risk of side effects, financial toxicity, drug availability, patient preferences, comorbidities, and life expectancy. When an adjuvant bisphosphonate is used to prevent breast cancer recurrence, the therapeutic options recommended by the Panel include oral clodronate, oral ibandronate, and intravenous zoledronic acid. The Panel supports starting bisphosphonate therapy early, consistent with the points outlined in the parent CCO-ASCO guideline; this is a consensus recommendation. The Panel does not recommend adjuvant denosumab to prevent breast cancer recurrence, because studies did not show a consistent reduction of breast cancer recurrence in any subset of those with early-stage breast cancer.Additional information can be found at www.asco.org/breast-cancer-guideline.

Management of Pyrexia Associated with the Combination of Dabrafenib and Trametinib: Canadian Consensus Statements.

The combination of dabrafenib and trametinib is a well-established treatment for BRAF-mutated melanoma. However, the effectiveness of this approach may be hindered by the development of treatment-related pyrexia syndrome, which occurs in at least 50% of treated patients. Without appropriate intervention, pyrexia syndrome has the potential to worsen and can result in hypotension secondary to dehydration and associated organ-related complications. Furthermore, premature treatment discontinuation may result in a reduction in progression-free and overall survival. Despite existing guidance, there is still a wide variety of therapeutic approaches suggested in the literature for both the definition and management of dabrafenib and trametinib-related pyrexia. This is reflected in the practice variation of its prevention and treatment within and between Canadian cancer centres. A Canadian working group was formed and consensus statements were constructed based on evidence and finalised through a two-round modified Delphi approach. The statements led to the development of a pyrexia treatment algorithm that can easily be applied in routine practice. The Canadian working group consensus statements serve to provide practical guidance for the management of dabrafenib and trametinib-related pyrexia, hopefully leading to reduced discontinuation rates, and ultimately improve patients' quality of life and cancer-related outcomes.

Cancer Treatment During COVID-19: A Qualitative Analysis of Patient-Perceived Risks and Experiences with Virtual Care.

During the COVID-19 pandemic, most cancer centers shifted from in-person to virtual cancer care to curb community spread and ensure care continuity. This qualitative descriptive study aimed to understand cancer patient-perceived risks related to COVID-19 and cancer treatment, as well as the patient-perceived and experienced value of virtual care. From June to August 2020, focus groups were conducted with patients under active management or observation for a diagnosed malignancy in Toronto, Canada. A thematic analysis of six focus groups found that most participants worried more about treatment delays than they did about COVID-19 infection. Despite some concern about COVID-19 exposure in the hospital, care delays contributed to increased anxiety among participants who already subscribed to strict safety measures in their everyday lives. Most participants accepted virtual care for some appointment types; however, preference for in-person care was found to sustain the humanistic and therapeutic aspects of cancer care that many participants valued. Nuances in the appropriateness and adequacy of virtual cancer care still need exploration. Preserving the humanistic aspects of care is of paramount importance.

SARS-CoV-2 Testing for Asymptomatic Patients with Cancer Prior and during Treatment: A Single Centre Experience.

Patients with cancer are more vulnerable to severe COVID-19. As a result, routine SARS-CoV-2 testing of asymptomatic patients with cancer is recommended prior to treatment. However, there is limited evidence of its clinical usefulness. The objective of this study is to evaluate the value of routine testing of asymptomatic patients with cancer. Asymptomatic patients with cancer attending Odette Cancer Centre (Toronto, ON, Canada) were tested for SARS-CoV-2 prior to and during treatment cycles. Results were compared to positivity rates of SARS-CoV-2 locally and provincially. All 890 asymptomatic patients tested negative. Positivity rates in the province were 1.5%, in hospital were 1.0%, and among OCC's symptomatic cancer patients were 0% over the study period. Given our findings and the low SARS-CoV-2 community positivity rates, we recommend a dynamic testing model of asymptomatic patients that triggers testing during increasing community positivity rates of SARS-CoV-2.

Delivery of Virtual Care in Oncology: Province-Wide Interprofessional Consensus Statements Using a Modified Delphi Process.

Virtual cancer care (i.e., teleoncology) was rapidly adopted during the COVID-19 pandemic to meet the needs of patients with cancer. However, there is a paucity of guidance for clinicians regarding virtual cancer care. We sought to develop consensus-based statements to guide the optimal provision of virtual care for clinicians caring for patients with cancer, using a modified Delphi consensus process with a 29-member panel consisting of an interprofessional group of clinicians caring for patients with cancer and patient representatives. The consensus process consisted of two rounds and one synchronous final consensus meeting. At the end of the modified Delphi process, 62 of 62 statements achieved consensus. Fifty-seven statements reached consensus in the first round of the process. Concerns regarding the ability to convey difficult news virtually and maintaining similar standards as in-person care without disproportionate strain on clinicians and patients were addressed in the consensus process. We achieved interprofessional consensus on virtual cancer care practices. Further research examining the impact of virtual cancer care on person-centred and clinical outcomes are needed to inform practices during the COVID-19 pandemic and beyond.

Practical recommendations for the management of patients with gastroenteropancreatic and thoracic (carcinoid) neuroendocrine neoplasms in the COVID-19 era.

Neuroendocrine neoplasms (NENs) are a heterogeneous family of uncommon tumours with challenging diagnosis, clinical management and unique needs that almost always requires a multidisciplinary approach. In the absence of guidance from the scientific literature, along with the rapidly changing data available on the effect of COVID-19, we report how 12 high-volume NEN centres of expertise in 10 countries at different stages of the evolving COVID-19 global pandemic along with members of international neuroendocrine cancer patient societies have suggested to preserve high standards of care for patients with NENs. We review the multidisciplinary management of neuroendocrine neoplasms during the COVID-19 pandemic, and we suggest potential strategies to reduce risk and aid multidisciplinary treatment decision-making. By sharing our joint experiences, we aim to generate recommendations for proceeding to other institutions facing the same challenges.

Commonwealth Neuroendocrine Tumour Research Collaboration and the North American Neuroendocrine Tumor Society Guidelines for the Diagnosis and Management of Patients With Lung Neuroendocrine Tumors: An International Collaborative Endorsement and Update of the 2015 European Neuroendocrine Tumor Society Expert Consensus Guidelines.

Lung neuroendocrine tumors (LNETs) are uncommon cancers, and there is a paucity of randomized evidence to guide practice. As a result, current guidelines from different neuroendocrine tumor societies vary considerably. There is a need to update and harmonize global consensus guidelines. This article reports the best practice guidelines produced by a collaboration between the Commonwealth Neuroendocrine Tumour Research Collaboration and the North American Neuroendocrine Tumor Society. We performed a formal endorsement and updating process of the 2015 European Neuroendocrine Tumor Society expert consensus article on LNET. A systematic review from January 2013 to October 2017 was conducted to procure the most recent evidence. The stepwise endorsement process involved experts from all major subspecialties, patients, and advocates. Guided by discussion of the most recent evidence, each statement from the European Neuroendocrine Tumor Society was either endorsed, modified, or removed. New consensus statements were added if appropriate. The search yielded 1109 new publications, of which 230 met the inclusion criteria. A total of 12 statements were endorsed, 22 statements were modified or updated, one was removed, and two were added. Critical answered questions for each topic in LNET were identified. Through the consensus process, guidelines for the management of patients with local and metastatic neuroendocrine tumors have been updated to include both recent evidence and practice changes relating to technological and definitional advances. The guidelines provide clear, evidence-based statements aimed at harmonizing the global approach to patients with LNETs, on the basis of the principles of person-centered and LNET-specific care. The importance of LNET-directed research and person-centered care throughout the diagnosis, treatment, and follow-up journey is emphasized along with directions for future collaborative research.

Sunitinib dose-escalation after disease progression in metastatic renal cell carcinoma.

PURPOSE: Previous pharmacologic studies demonstrated that higher sunitinib exposure is associated with improved clinical outcomes in patients with metastatic renal cell carcinoma (mRCC). We aimed to assess the efficacy and toxicity of sunitinib dose-escalation in mRCC patients progressing on the standard 50mg dose. METHODS: A single-institution retrospective review was conducted on mRCC patients, treated outside trials with a 50mg sunitinib dose given on an individualized schedule between October 2009 and January 2016, who subsequently progressed on imaging. All progressing patients who were dose-escalated to 62.5 and 75mg on an individualized schedule if toxicity permitted were eligible for this analysis. Median progression-free survival (PFS) and overall survival (OS) were analyzed using the Kaplan-Meier method. PFS1 and 2 were defined as the time between the start of sunitinib and first progression and the time between dose-escalation and second progression respectively. RESULTS: A total of 25 eligible patients were identified with a median follow-up of 40.3 months (Q1-Q3: 11.1-66.6) and a mean age of 54 years (standard deviation: 12.4). Most of the patients underwent cytoreductive surgery (92%) and were men (88%). In total 32%, 44%, and 24% had a good, intermediate, and poor prognostic Heng Score, respectively. At standard doses, 60% and 16% of patients had a partial response (PR) and a stable disease (SD) as best response respectively for a median duration of 11.4 months (95% CI: 3-20.7). A total of 6 patients (24%) had progressive disease as best response. After progression, 36% and 28% had PR and SD on higher doses of sunitinib respectively for a median duration of 7.8 months (95% CI: 6.3-12.4). The median PFS1, PFS2 and OS were 6.1 months (95% CI: 2.3-19.4), 6.7 months (95% CI: 3.1-8.4) and 63.7 months (95% CI: 26-NR) respectively. The most common adverse events after dose-escalation were fatigue (56%), diarrhea (40%) and skin toxicity (28%). CONCLUSION: Patients with mRCC who progress on 50mg sunitinib dose, may derive a clinical benefit and prolonged survival from dose-escalation with acceptable toxicity profiles. These results need to be confirmed in prospective studies with the aim to overcome drug resistance and delay the change in systemic therapy at progression.