Ryder, Mabel

The aim of the NCCN Guidelines for Management of Immunotherapy-Related Toxicities is to provide guidance on the management of immune-related adverse events resulting from cancer immunotherapy. The NCCN Management of Immunotherapy-Related Toxicities Panel is an interdisciplinary group of representatives from NCCN Member Institutions, consisting of medical and hematologic oncologists with expertise across a wide range of disease sites, and experts from the areas of dermatology, gastroenterology, endocrinology, neurooncology, nephrology, cardio-oncology, ophthalmology, pulmonary medicine, and oncology nursing. The content featured in this issue is an excerpt of the recommendations for managing toxicities related to CAR T-cell therapies and a review of existing evidence. For the full version of the NCCN Guidelines, including recommendations for managing toxicities related to immune checkpoint inhibitors, visitNCCN.org.

Abstract Context Metastatic pheochromocytomas and paragangliomas (mPPGL) are rare vascular neuroendocrine tumors that highly express vascular growth factors. Systemic treatment options in cases of unresectable multisite disease are limited. Multikinase inhibitors that inhibit angiogenesis, such as lenvatinib, have proven effective in several other malignancies, and may be a viable option for mPPGL. Objective We aimed to evaluate the efficacy of lenvatinib as salvage therapy in mPPGLs. Methods This was a retrospective analysis of mPPGL patients ≥ 18 years of age who received lenvatinib from 2015 to 2020 at a tertiary referral center. Patients were started on lenvatinib 20 mg daily and dose was adjusted according to tolerance or disease progression. Results Eleven patients were included. Median treatment duration was 14.7 months (95% CI, 2.3-NE). Treatment was discontinued due to disease progression, adverse events, or death. Overall survival at 12 months was 80.8% (95% CI, 42.3-94.9%) but its median was not reached. Median progression-free survival was 14.7 months (95% CI, 1.7-NE). Among the 8 patients with measurable disease, overall response rate was 63%, as 5/8 experienced a partial response and 3/8 had stable disease. Worsening hypertension and anemia were the most common adverse events. Conclusion Lenvatinib may be a viable treatment option for mPPGL, although at the potential risk of worsening hypertension. Larger, multicenter studies are needed to better characterize treatment efficacy.

AbstractBackgroundThe development of systemic treatment options leveraging the molecular landscape of advanced thyroid cancer is a burgeoning field. This is a multidisciplinary evidence‐based statement on the definition of advanced thyroid cancer and its targeted systemic treatment.MethodsAn expert panel was assembled, a literature review was conducted, and best practice statements were developed. The modified Delphi method was applied to assess the degree of consensus for the statements developed by the author panel.ResultsA review of the current understanding of thyroid oncogenesis at a molecular level is presented and characteristics of advanced thyroid cancer are defined. Twenty statements in topics including the multidisciplinary management, molecular evaluation, and targeted systemic treatment of advanced thyroid cancer are provided.ConclusionsWith the growth in targeted treatment options for thyroid cancer, a consensus definition of advanced disease and statements regarding the utility of molecular testing and available targeted systemic therapy is warranted.

Immune checkpoint inhibitors (ICIs) can cause pituitary dysfunction due to hypophysitis. We aimed to characterize ICI-induced hypophysitis and examine its association with overall survival in this single-center retrospective cohort study of adult patients with cancer who received an ICI from January 1, 2012 through December 31, 2016. A total of 896 patients were identified who received ipilimumab alone (n=120); ipilimumab and nivolumab (n=50); ipilimumab before or after pembrolizumab (n=70); pembrolizumab alone (n=406); and nivolumab alone (n=250). Twenty-six patients (2.9%) developed hypophysitis after a median of 2.3 months. Median age at the start of ICI was 57.9 years and 54% were men. Hypophysitis occurred in 7.9% of patients receiving ipilimumab alone or in combination or sequence with a programmed cell death protein 1 inhibitor; 1.7% after pembrolizumab alone, never after nivolumab alone. Secondary adrenal insufficiency occurred in all hypophysitis cases. Use of ipilimumab alone or in combination was associated with pituitary enlargement on imaging and mass effects more frequently than pembrolizumab alone. Occurrence of hypophysitis was associated with improved overall survival by univariate analysis (median 50.7 vs 16.5 months; p=0.015) but this association was not observed in multivariable landmark survival analysis (HR for mortality 0.75; 95% CI 0.38 to 1.30; p=0.34) after adjusting for age, sex and malignancy type. To conclude, hypophysitis occurred most frequently after ipilimumab and manifested as anterior hypopituitarism affecting the corticotrophs more commonly than thyrotrophs and gonadotrophs. Mass effects and pituitary enlargement occurred more frequently in ipilimumab-induced hypophysitis. The association of hypophysitis with overall survival needs further investigation.

Purpose of review Our goal is to review pertinent data evaluating the association between immune checkpoint inhibitor (ICI)-induced endocrine dysfunction and survival in cancer patients as well as to understand the potential molecular links between these. Recent findings ICIs have revolutionized cancer therapy but have also led to multiple immune-related adverse events (irAEs). Studies have demonstrated a link between the development of irAEs and improved survival, suggesting that ICI-induced antitumor immunity and autoimmunity are coupled. Thyroid irAEs are most frequently and strongly associated with improved survival, particularly in the context of overt thyroid dysfunction. Other endocrine irAEs, such as hypophysitis and diabetes are quite rare wherein the treatment approach or the disease process itself may mitigate improvement in survival. Preclinical and translational data indicate a role for CD4+ T cells, regulatory T cells and/or cytokines mediating irAEs, including thyroiditis. Summary The development of irAEs is associated with improved tumor responses and survival in cancer patients. Thyroid irAEs, alone or in combination with other irAEs, are most strongly associated with improved outcomes. Biomarkers of response to ICIs are lacking, despite well-characterized pathologic and genomic susceptibilities predicting ICI efficacy. Early detection of thyroid irAEs may identify patients most likely to have durable antitumor response to ICIs. Although irAEs and antitumor immunity appear ‘coupled’, translational studies indicate the potential for their ‘uncoupling’, which could enable antitumor efficacy with greater safety margins.

Abstract This manuscript is the result of the North American Neuroendocrine Tumor Society consensus conference on the medical management and surveillance of metastatic and unresectable pheochromocytoma and paraganglioma held on October 2 and 3, 2019. The panelists consisted of endocrinologists, medical oncologists, surgeons, radiologists/nuclear medicine physicians, nephrologists, pathologists, and radiation oncologists. The panelists performed a literature review on a series of questions regarding the medical management of metastatic and unresectable pheochromocytoma and paraganglioma as well as questions regarding surveillance after resection. The panelists voted on controversial topics, and final recommendations were sent to all panel members for final approval.

AbstractObjectivesInhibitors to the checkpoint proteins cytotoxic T‐lymphocyte‐associated protein 4 (CTLA‐4) and programmed cell death protein 1 (PD‐1) are becoming widely used in cancer treatment. However, a lack of understanding of the patient response to treatment limits accurate identification of potential responders to immunotherapy.MethodsIn this study, we assessed the expression of PD‐1 and CTLA‐4 on 19 leucocyte populations in the peripheral blood of 74 cancer patients. A reference data set for PD‐1 and CTLA‐4 was established for 40 healthy volunteers to determine the normal expression patterns for these checkpoint proteins.ResultsUnsupervised hierarchical clustering found four immune profiles shared across the solid tumor types, while chronic lymphocytic leukaemia patients had an immune profile largely unique to them. Furthermore, we measured these leucocyte populations on an additional cohort of 16 cancer patients receiving the PD‐1 inhibitor pembrolizumab in order to identify differences between responders and non‐responders, as well as compared to healthy volunteers (n = 20). We observed that cancer patients had pre‐treatment PD‐1 and CTLA‐4 expression on their leucocyte populations at different levels compared to healthy volunteers and identified two leucocyte populations positive for CTLA‐4 that had not been previously described. We found higher levels of PD‐1+ CD3+ CD4− CD8− cells in patients with progressive disease and have identified it as a potential biomarker of response, as well as identifying other significant differences in phenotypes between responders and non‐responders.ConclusionThese results are suggestive that categorisation of patients based on immune profiles may differentiate responders from non‐responders to immunotherapy for solid tumors.

Abstract A previously published model (Atkins) allows for calculation of 131I maximum tolerated activity on the basis of 48-hour whole-body retention of 131I on a pretherapy diagnostic scan. Our practice uses iodine 123I for diagnostic imaging of metastatic thyroid cancer for staging before 131I therapy, with images typically acquired 24 hours after administration of the radiopharmaceutical. We explored the feasibility of an additional 123I whole-body scan and retention measurement at 48 hours, with application of the model to estimate maximum tolerated activity of radioiodine before 131I treatment of metastatic thyroid cancer.

ObjectivesThe spine is the most common site of bone metastases in differentiated thyroid cancer (DTC). The role of surgery in the management of cervical spine (C‐spine) metastases (CSpM) has not been adequately explored.MethodsThis is a retrospective cohort study at a tertiary referral center from 2002 to 2018. Inclusion criteria were pathologic diagnosis of DTC and imaging/pathologic diagnosis of CSpM. Statistical analysis utilized t tests for continuous variables and χ2 tests for categorical variables. Survival analysis was conducted using Kaplan–Meier curves with univariate and multivariate Cox regressions.ResultsFifty patients with DTC and CSpM were identified. Of those, 16 underwent surgical resection of the C‐spine, whereas 34 did not. The most common presenting symptom was neck pain (N = 37, 74%). Patients in the surgery group were more likely to report a subjective improvement of symptoms (P < .01) and to have local (P < .01) and systemic (P = .04) disease control. Five‐year overall survival was 44.7% for the surgery group (95% confidence interval [CI]: 17.1–69.3) and 11.1% (95% CI: 2.1–28.8) for the nonsurgery group (P = .01). The strongest risk factor for improved overall survival after C‐spine metastasis was local disease control at the C‐spine (multivariate hazard ratio [HR] = 0.32, 95% CI: 0.12–0.85, P = .02). Surgical intervention was significantly associated with improved survival on both univariate (HR = 0. 35, 95% CI: 0.15–0.82, P = .02) and multivariate (HR = 0.37, 95% CI: 0.14–0.98, P = .04) analysis.ConclusionSurgical management of CSpM in differentiated thyroid cancers is associated with significantly improved local disease control and overall survival. Referral to spine surgeons should be considered after diagnosis.Level of EvidenceIV. Laryngoscope, 131:E1741–E1747, 2021