Phase 3 Trial of Selpercatinib in Advanced RET-Mutant Medullary Thyroid Cancer.

BACKGROUND: Selpercatinib, a highly selective, potent RET inhibitor, has shown efficacy in advanced RET-mutant medullary thyroid cancer in a phase 1-2 trial, but its efficacy as compared with approved multikinase inhibitors is unclear. METHODS: We conducted a phase 3, randomized trial comparing selpercatinib as first-line therapy with the physician's choice of cabozantinib or vandetanib (control group). Eligible patients had progressive disease documented within 14 months before enrollment. The primary end point in the protocol-specified interim efficacy analysis was progression-free survival, assessed by blinded independent central review. Crossover to selpercatinib was permitted among patients in the control group after disease progression. Treatment failure-free survival, assessed by blinded independent central review, was a secondary, alpha-controlled end point that was to be tested only if progression-free survival was significant. Among the other secondary end points were overall response and safety. RESULTS: A total of 291 patients underwent randomization. At a median follow-up of 12 months, median progression-free survival as assessed by blinded independent central review was not reached in the selpercatinib group and was 16.8 months (95% confidence interval [CI], 12.2 to 25.1) in the control group (hazard ratio for disease progression or death, 0.28; 95% CI, 0.16 to 0.48; P<0.001). Progression-free survival at 12 months was 86.8% (95% CI, 79.8 to 91.6) in the selpercatinib group and 65.7% (95% CI, 51.9 to 76.4) in the control group. Median treatment failure-free survival as assessed by blinded independent central review was not reached in the selpercatinib group and was 13.9 months in the control group (hazard ratio for disease progression, discontinuation due to treatment-related adverse events, or death, 0.25; 95% CI, 0.15 to 0.42; P<0.001). Treatment failure-free survival at 12 months was 86.2% (95% CI, 79.1 to 91.0) in the selpercatinib group and 62.1% (95% CI, 48.9 to 72.8) in the control group. The overall response was 69.4% (95% CI, 62.4 to 75.8) in the selpercatinib group and 38.8% (95% CI, 29.1 to 49.2) in the control group. Adverse events led to a dose reduction in 38.9% of the patients in the selpercatinib group, as compared with 77.3% in the control group, and to treatment discontinuation in 4.7% and 26.8%, respectively. CONCLUSIONS: Selpercatinib treatment resulted in superior progression-free survival and treatment failure-free survival as compared with cabozantinib or vandetanib in patients with RET-mutant medullary thyroid cancer. (Funded by Loxo Oncology, a subsidiary of Eli Lilly; LIBRETTO-531 ClinicalTrials.gov number, NCT04211337.).

Sunitinib for metastatic progressive phaeochromocytomas and paragangliomas: results from FIRSTMAPPP, an academic, multicentre, international, randomised, placebo-controlled, double-blind, phase 2 trial.

BACKGROUND: No randomised controlled trial has ever been done in patients with metastatic phaeochromocytomas and paragangliomas. Preclinical and first clinical evidence suggested beneficial effects of sunitinib. We aimed to evaluate the safety and efficacy of sunitinib in patients with metastatic phaeochromocytomas and paragangliomas. METHODS: FIRSTMAPPP is a multicentre, international, randomised, placebo-controlled, double-blind, phase 2 trial done at 14 academic centres across four European countries. Eligible participants were adults (aged ≥18 years) with sporadic or inherited progressive metastatic phaeochromocytomas and paragangliomas. Patients were randomly assigned (1:1) to receive either oral sunitinib (37·5 mg per day) or placebo. Randomisation was stratified according to SDHB status (mutation present vs wild type) and number of previous systemic therapies (0 vs ≥1). Primary endpoint was the rate of progression-free survival at 12 months according to real-time central review (Response Evaluation Criteria in Solid Tumours version 1.1). On the basis of a two-step Simon model, we aimed for the accrual of 78 patients, assuming a 20% improvement of the 12-month progression-free survival rate from 20% to 40%, to conclude that sunitinib is effective. Crossover from the placebo group was allowed. This trial is registered with ClinicalTrials.gov, number NCT01371201, and is closed for enrolment. FINDINGS: From Dec 1, 2011, to Jan 31, 2019, a total of 78 patients with progressive metastatic phaeochromocytomas and paragangliomas were enrolled (39 patients per group). 25 (32%) of 78 patients had germline SDHx variants and 54 (69%) had used previous therapies. The primary endpoint was met, with a 12-month progression-free survival in 14 of 39 patients (36% [90% CI 23-50]) in the sunitinib group. In the placebo group, the 12-month progression-free survival in seven of 39 patients was 19% (90% CI 11-31), validating the hypotheses of our study design. The most frequent grade 3 or 4 adverse events were asthenia (seven [18%] of 39 and one [3%] of 39), hypertension (five [13%] and four [10%]), and back or bone pain (one [3%] and three [8%]) in the sunitinib and placebo groups, respectively. Three deaths occurred in the sunitinib group: these deaths were due to respiratory insufficiency, amyotrophic lateral sclerosis, and rectal bleeding. Only the latter event was considered drug related. Two deaths occurred in the placebo group due to aspiration pneumonia and septic shock. INTERPRETATION: This first randomised trial supports the use of sunitinib as the medical option with the highest level of evidence for anti-tumour efficacy in progressive metastatic phaeochromocytomas and paragangliomas. FUNDING: French Ministry of Health, through the National Institute for Cancer, German Ministry of Education and Research, and the German Research Foundation within the CRC/Transregio 205/2, EU Seventh Framework Programme, and a private donator grant.

Novel prognostic nomogram for predicting recurrence-free survival in medullary thyroid carcinoma.

AIMS: Recently, there have been attempts to improve prognostication and therefore better guide treatment for patients with medullary thyroid carcinoma (MTC). In 2022, the International MTC Grading System (IMTCGS) was developed and validated using a multi-institutional cohort of 327 patients. The aim of the current study was to build upon the findings of the IMTCGS to develop and validate a prognostic nomogram to predict recurrence-free survival (RFS) in MTC. METHODS AND RESULTS: Data from 300 patients with MTC from five centres across the USA, Europe, and Australia were used to develop a prognostic nomogram that included the following variables: age, sex, AJCC stage, tumour size, mitotic count, necrosis, Ki67 index, lymphovascular invasion, microscopic extrathyroidal extension, and margin status. A process of 10-fold cross-validation was used to optimize the model's performance. To assess discrimination and calibration, the area-under-the-curve (AUC) of a receiver operating characteristic (ROC) curve, concordance-index (C-index), and dissimilarity index (D-index) were calculated. Finally, the model was externally validated using a separate cohort of 87 MTC patients. The model demonstrated very strong performance, with an AUC of 0.94, a C-index of 0.876, and a D-index of 19.06. When applied to the external validation cohort, the model had an AUC of 0.9. CONCLUSIONS: Using well-established clinicopathological prognostic variables, we developed and externally validated a robust multivariate prediction model for RFS in patients with resected MTC. The model demonstrates excellent predictive capability and may help guide decisions on patient management. The nomogram is freely available online at https://nomograms.shinyapps.io/MTC_ML_DFS/.

Efficacy and safety of pembrolizumab monotherapy in patients with advanced thyroid cancer in the phase 2 KEYNOTE-158 study.

BACKGROUND: The authors report results from the thyroid carcinoma cohort of the multicohort phase 2 KEYNOTE-158 study (NCT02628067), which evaluated pembrolizumab monotherapy in patients with previously treated cancers. METHODS: Eligible patients had histologically and/or cytologically confirmed papillary or follicular thyroid carcinoma, failure of or intolerance to prior therapy, and measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Patients received pembrolizumab (200 mg) every 3 weeks for up to 35 cycles. The primary end point was objective response rate (ORR) per RECIST v1.1 by independent central review. RESULTS: A total of 103 patients were enrolled and received pembrolizumab. Median duration from first dose to data cutoff (October 5, 2020) was 49.4 (range, 43.9-54.9) months. ORR was 6.8% (95% confidence interval [CI], 2.8%-13.5%), and median duration of response was 18.4 (range, 4.2-47.2+) months. ORR was 8.7% (95% CI, 2.4%-20.8%) among patients with programmed cell death ligand 1 (PD-L1) combined positive score (CPS) ≥1 (n = 46) and 5.7% (95% CI, 1.2%-15.7%) among patients with PD-L1 CPS <1 (n = 53). Median overall survival and progression-free survival were 34.5 (95% CI, 21.2 to not reached) and 4.2 (95% CI, 3.9-6.2) months, respectively. Treatment-related adverse events occurred in 69.9% of patients (grade 3-5, 14.6%). CONCLUSIONS: Pembrolizumab demonstrated manageable toxicity and durable antitumor activity in a small subset of patients with advanced thyroid cancer. These results provide evidence of modest antitumor activity in this setting regardless of tumor PD-L1 expression. Future studies evaluating immune checkpoint inhibitors in patients with differentiated thyroid cancer should focus on biomarker-driven patient selection or combination of immune checkpoint inhibitors with other agents, in order to achieve higher response rates than observed in this study.

Bone metastases from differentiated thyroid carcinoma: heterogenous tumor response to radioactive Iodine therapy and overall survival.

PURPOSE: Bone metastases (BM) from differentiated thyroid carcinoma (DTC) impact negatively the quality of life and the life expectancy of patients. The aim of the study was (a) to evaluate the overall survival (OS) and prognostic factors of OS and (b) to assess predictive factors of complete BM response (C-BM-R) using radioiodine treatment (RAI) either alone or in association with focal treatment modalities. METHODS: A total of 178 consecutive DTC patients harbouring BM, treated between 1989 and 2015, were enrolled in this retrospective study conducted in two tertiary referral centers. OS analysis was performed for the whole cohort, and only the 145 considered non-RAI refractory patients at BM diagnosis were evaluated for C-BM-R following RAI. RESULTS: The median OS from BM diagnosis was 57 months (IQR: 24-93). In multivariate analysis, OS was significantly reduced in the case of T4 stage, 18FDG uptake by the BM and RAI refractory status. Among the 145 DTC considered non-RAI refractory patients at BM diagnosis, 46 patients (31.7%) achieved a C-BM-R following RAI treatment, either alone in 32 (18%) patients or in association with focal BM treatment modalities in 14. The absence of extra-skeletal distant metastasis and of 18FDG uptake in BM were predictive for C-BM-R. CONCLUSIONS: In nearly one-third of DTC patients with RAI avid BM, RAI alone or in combination with BM focal treatment can induce C-BM-R. The presence of 18FDG uptake in BM is associated with an absence of C-BM-R and with a poor OS. 18FDG PET-CT should be performed when BM is suspected.

Oxaliplatin and 5-Fluorouracil in Advanced Well-Differentiated Digestive Neuroendocrine Tumors: A Multicenter National Retrospective Study from the French Group of Endocrine Tumors.

INTRODUCTION: Oxaliplatin-based regimens have shown promising antitumor activity in digestive neuroendocrine tumors (NETs); however, the available data are limited. Our aim was to assess the efficacy of FOLFOX (association of 5-fluorouracil with oxaliplatin) in a large series of patients with advanced digestive NETs. METHODS: All patients with advanced digestive well-differentiated NETs treated with at least 3 cycles of FOLFOX between January 2004 and December 2018 in 12 centers from the French Group of Endocrine Tumors were included. Tumor response rate according to Response Evaluation Criteria in Solid Tumors version 1.1 criteria, progression free survival (PFS), and overall survival, as well as prognostic factors, were analyzed retrospectively. RESULTS: One hundred fifty-five patients were included. Primary tumor locations were pancreas (n = 89), small intestine (n = 40), unknown with no evidence for lung primary (n = 13), stomach (n = 7), and rectum (n = 6). Median Ki-67 was 10%, and 65% of the tumors were grade 2. The partial response rate was 30% for pancreatic NETs, 12.5% for small intestine NETs, 38.5% for unknown primary NETs, 14% for gastric NETs, and 17% for rectal NETs. Significant prognostic factors for poor PFS after FOLFOX were progressive disease at the beginning of treatment (hazard ratio [HR] = 1.83, p = 0.007), hepatic involvement superior to 50% (HR = 2.67, p = 0.0001), and rectal primary tumor location (HR = 2.6, p = 0.0036). Among pancreatic NETs, insulinomas had a better median PFS (22 months) than other pancreatic NETs (9 months, p = 0.026) and showed a high rate (8/9) of serum glucose normalization. CONCLUSIONS: FOLFOX shows a promising antitumor activity in advanced digestive NETs. Rapid symptomatic response is observed in metastatic insulinomas.

Safety of direct oral anticoagulants in patients with advanced solid tumors receiving anti-VEGF agents: a retrospective study.

PURPOSE: Kinase inhibitors (KI) and antibodies targeting the VEGF pathway are approved in a broad spectrum of cancers and associated with an increased risk of bleeding and thromboembolic events (TE). The use of direct oral anticoagulants (DOACs) apixaban and rivaroxaban is increasing in cancer patients, but limited data are available for patients receiving anti-VEGF agents. METHODS: To assess safety of DOAC with concomitant anti-VEGF agents, a retrospective chart review of all patients receiving concomitantly DOAC and anti-VEGF agents was performed from 2013 to 2020 in our center. Data on demographics, safety, and time on treatment were collected. Main outcome was safety (bleeding and thromboembolic events). RESULTS: Of 92 patients (median age 66 years (IQR: 59-72)), 40 were treated with KI and 52 with bevacizumab. The most frequent primary tumor sites were colon/rectum (24%), kidney (21%), ovary (13%), lung (11%), soft tissue sarcoma (10%), and thyroid (9%); 2% had brain metastases. Apixaban 5 mg bid (n = 41) or rivaroxaban 20 mg daily (n = 51) were given for TE (65%), atrial fibrillation (32%), or other indications (3%). The median duration of concomitant treatment was 4.8 months (95%CI: 0.7-50.0) with bevacizumab and 11.7 months (95%CI: 0.1-53.8) with KI. Grade ≥ 3 bleeding events occurred in 5 patients (5%): 4 patients receiving bevacizumab (one grade 5 upper digestive tract bleeding and three grade 3 rectal or vaginal hemorrhages) and 1 patient under cabozantinib for kidney cancer with endobronchial metastasis (grade 3 hemoptysis). Grade ≥ 3 TE occurred in 8 patients (9%): 7 patients receiving bevacizumab (including one grade 5 pulmonary embolism), and one patient receiving sunitinib (grade 3 pulmonary embolism). Median time-to-event (bleeding or thrombotic event) was not reached (NR) (95%CI: 76.9-NR) for KI and 86.9 months (95%CI: 42.9-148.0) for bevacizumab. CONCLUSIONS AND RELEVANCE: In our experience, the use of DOAC was safe in selected patients treated with KI, but unclear with bevacizumab. More data are needed to endorse guidelines in this specific group of patients.

Long-Term Results after Surgical Resection of Peritoneal Metastasis from Neuroendocrine Tumors.

INTRODUCTION: Peritoneal metastases from neuroendocrine tumors are associated with a bad prognosis. The objective of our study was to evaluate whether surgical resection could lead to prolonged survival in selected patients. This survival was compared to that of patients operated for liver metastasis. METHODS: From our prospectively maintained database we included 88 patients who underwent the complete resection of peritoneal and/or liver metastasis between January 1995 and December 2016 in Gustave-Roussy. Three resection groups were compared: peritoneal metastasis alone, liver metastasis alone, and the combined resection of liver and peritoneal metastases. RESULTS: The median peritoneal cancer index was 10 in the peritoneal group and 11 in the peritoneal + liver group. The 5-year overall survival was 81% (60-100) in the peritoneal group compared to 78% (65.2-92.8) in the liver group, and 72% (58.7-89.7) in the peritoneal + liver group (p = 0.71). The 3-year disease-free survival reached 26.9% (16.1-45.1) in the liver group, 12.5% (2.3-68.2) in the peritoneal group, and 32.4% (19.9-52.6) in the combined liver + peritoneal group (p = 0.45). In the univariate analysis, the prognosis factors for a longer survival were: small bowel primary tumor origin, low preoperative chromogranin A level, and tumor grade ≤1. CONCLUSION: Despite a high recurrence rate, long-term overall survival can be achieved after the resection of peritoneal metastasis in selected patients. This survival is comparable to that of patients operated for liver metastasis only. Surgery should stand as a standard treatment for peritoneal metastases in patients with resectable disease.

Post-Radiation Grade 3 Neuroendocrine Carcinoma: A New Entity?

BACKGROUND: Cancer survivors have a 14% increased risk of developing a malignancy compared with the general population. Second radiation-induced malignancies with different histologies have been described in different organs. Based on individual observations, we hypothesized that neuroendocrine carcinoma (NEC) could arise in irradiated organs. METHODS: In a retrospective analysis of Gustave Roussy database of NEC patients (small cell lung cancer excluded) diagnosed as a second cancer, we looked for the frequency of grade 3 NEC that arose in patients who had received previous radiation therapy for a first cancer. Radiation therapy for the first cancer, dose, location of radiation therapy, pathological characteristics, overall survival, and response to treatment of secondary NEC were analyzed. RESULTS: From January 1995 to December 2017, 847 cases of NEC were seen at Gustave Roussy. Among them, 95 (11.2%) patients had a history of previous malignancy of which 36 (4%) had been treated with radiation therapy. Out of these 36 patients, 12 (1.4% of all NEC patients) developed a NEC within the previous irradiated organ (median dose of 50 Gy, range 36-67.5). Most frequent first cancers were breast cancer (n = 4) and Hodgkin lymphoma (n = 3). NEC arose within a median time of 21.7 years (range 5.1-36.4) from radiation in the thorax (n = 5), digestive tract (n = 3), and other sites. Five large cell NEC, 3 small cell NEC, 1 mixed neuroendocrine neoplasm and 3 not otherwise specified NEC were diagnosed. Ten patients had stage IV disease at diagnosis; median overall survival was 37.8 months (95% CI [17.6 to NA]). Three patients (25%) achieved complete response with multimodal treatment. CONCLUSIONS: NEC can arise from previously irradiated organs and may have a better outcome in this setting. Other risk factors should be investigated to explain the high rate of previous cancer in this population of neuroendocrine neoplasm.

Correction to: Adrenocortical carcinoma complicated by renal thrombotic microangiopathy, a case-series.

Following publication of the original article [1], we have been notified that the name of one author was spelled incorrectly as Julien Haddoux, when the correct spelling is Julien Hadoux.

Adrenocortical carcinoma complicated by renal thrombotic microangiopathy, a case-series.

BACKGROUND: Cancer-related thrombotic microangiopathy (CR-TMA) is a rare entity associated with a dismal prognosis. Usually, CR-TMA is associated with mucin-producing carcinomas among which stomach, breast, prostate, lung and pancreas tumours are the most frequent. CASES PRESENTATION: We describe for the first time three cases of CR-TMA due to adrenocortical carcinoma (ACC). All of them had mechanical hemolytic anemia and thrombocytopenia without any other identifiable cause. Bicytopenia was diagnosed either simultaneously with ACC or at the time of metastatic evolution. Two patients had acute kidney injury (AKI) with severe pathological findings on kidney biopsy. Despite total adrenalectomy, chemotherapy, and specific treatment of TMA with plasma-exchanges, renal failure and hemolytic anemia remained. The only manifestation of CR-TMA in the third patient was hemolytic anemia, which resolved after surgical removal of ACC. The evolutions in these patients suggests ACC-related TMA may be related to a circulating factor. CONCLUSIONS: CR-TMAs are rare. Here we describe the first case series of ACC-related TMA, among which two had renal involvement. This entity is associated with dismal renal prognosis despite specific treatment of TMA. According to patients' evolution, the persistence of TMA may reflect an uncontrolled malignancy.

Occult Contralateral Lateral Lymph Node Metastases in Unilateral N1b Papillary Thyroid Carcinoma.

OBJECTIVE: Therapeutic lateral neck dissection (ND) is recommended for N1b papillary thyroid carcinoma (PTC), while prophylactic contralateral lateral ND is not. Given the paucity of data, we investigated the frequency of and risk factors for occult lymph node metastases (LNM) in the contralateral lateral neck for N1b patients. PATIENTS AND METHODS: This is a retrospective study conducted at a cancer center. Inclusion criteria were: unilateral PTC and ipsilateral lateral LNM confirmed by fine-needle aspiration biopsy. Patients with contralateral lateral LNM or bilateral tumor on ultrasound were excluded. All patients were treated with total thyroidectomy, bilateral central ND, ipsilateral therapeutic lateral ND and prophylactic contralateral ND of levels III-IV, followed by radioactive iodine. RESULTS: Sixty-three patients met the inclusion criteria. Occult contralateral lateral LNM were found in 23/63 patients (36.5%) who had more LNM in ispilateral (p = .01) and contralateral level VI (p < .0001), more frequent microscopic tumor in the contralateral lobe (p = .017) and a trend toward being at high risk (p = .06). Using receiver operating characteristic analysis, a cutoff of >4 LNM in ipsilateral level VI optimized sensitivity and specificity for predicting contralateral lateral LNM, with a sensitivity of 74%, specificity of 65%, positive predictive value of 55% and negative predictive value of 81%. Neck recurrence occurred in 14%, with only 1 patient recurring only in the contralateral lateral neck (1.5%). CONCLUSION: Occult LNM in the contralateral lateral neck was found in 36.5% of patients. Five or more ipsilateral central LNM may aid in predicting contralateral lateral LNM, and high-risk patients may be more at risk. The clinical benefit of prophylactic contralateral lateral ND remains doubtful, however.

Challenging pre-surgical localization of hyperfunctioning parathyroid glands in primary hyperparathyroidism: the added value of 18F-Fluorocholine PET/CT.

PURPOSE: To evaluate the added value of 18F-Fluorocholine (18F-FCH) PET/CT in presurgical imaging of patients with primary hyperparathyroidism (HPT) and challenging localization of the hyper-functioning parathyroid glands. METHODS: We included 27 consecutive patients with primary HPT (19 F; median age: 58 years), with either (i) non-conclusive pre-surgical localization with 99mTc-sestaMIBI scintigraphy and neck ultrasonography (US), (ii) recurrence of previously operated HPT, or (iii) familiar HPT with a suspicion of multiple gland disease. Histological findings and resolution of HPT were considered as the gold standard. RESULTS: 18F-FCH PET/CT was positive in 24/27 patients. Twenty-one patients underwent surgery with 27 resected lesions (14 adenomas, 11 hyperplastic glands, two hyper-functioning histologically normal glands), with resolution of HPT in 19/21 patients (90%). 18F-FCH PET/CT localized 22 lesions in 17/21 patients (per patient: sensitivity 81%, positive predictive value (PPV) 94%; per gland: sensitivity 76%, PPV 85%, specificity 91%, negative predictive value (NPV) 86%). 18F-FCH PET/CT found eight lesions which were undetectable on both 99mTc-sestaMIBI scintigraphy and US. In patients with a familial HPT and/or a multiple gland disease, sensitivity was 100 and 79% on a per-patient and a per-gland analysis respectively, while NPV was 63%. In six patients with a persistence or recurrence of previously treated HPT, 18F-FCH PET/CT localized all lesions, both in sporadic and familiar disease. CONCLUSIONS: 18F-FCH PET/CT is a promising modality in challenging pre-surgical localization of hyper-functioning parathyroid glands, such as inconclusive standard imaging, recurrence after surgery, or suspected multiple gland disease.

Multimodal treatment with doxorubicin, cisplatin, and ifosfamide for the treatment of advanced or metastatic uterine leiomyosarcoma: a unicentric experience.

OBJECTIVE: Uterine leiomyosarcoma (ULMS) is a rare gynecologic malignancy characterized by a poor prognosis due to a high rate of local and metastatic recurrences. Chemotherapy with doxorubicin or ifosfamide or both is associated with a 10% to 30% objective response rate. We report a monocentric experience with doxorubicin, cisplatin, and ifosfamide (API) combination in the setting of multimodal treatment of advanced or metastatic ULMS. PATIENTS AND METHODS: This monocentric retrospective study included patients with metastatic or locally advanced ULMS with a physiological age younger than 65 years treated in first line with a multimodal aggressive approach with API chemotherapy. Treatment consisted of doxorubicin 50 mg/m2 d1, ifosfamide 3 g/m2 per day d1d2 plus mesna, cisplatin 75 mg/m2 d3, plus G-CSF; every 3 weeks up to 6 cycles. Surgery, radiation therapy, or radiofrequency ablation therapy of metastatic sites was associated whenever possible. RESULTS: Thirty-eight patients received API for metastatic or locally advanced ULMS. Median age was 51 years (40-64 years); 4 (11%) patients were treated for a locally advanced disease and 34 (89%) for metastatic disease. Sixteen patients responded (4 complete responses+12 partial responses) among 33 evaluable patients (objective response rate, 48%); 8 and 9 patients had, respectively, stable and progressive disease. Twelve patients had surgeries with 9 surgical complete responses and 3 surgical partial responses. Median progression-free and overall survival in the whole population were 9.8 and 27 months, respectively. Main grade 3-4 toxicities in 38 patients were neutropenia (74%), thrombocytopenia (60%), anemia (55%), fatigue (18%), and vomiting (13%). Febrile neutropenia was observed in 37% of patients. CONCLUSIONS: Despite the toxicity observed, API is an effective treatment which compares favorably with other first-line therapies for patients with metastatic or advanced ULMS.

SDHB mutations are associated with response to temozolomide in patients with metastatic pheochromocytoma or paraganglioma.

Cyclophosphamide-dacarbazine-vincristine regimen is recommended for the treatment of malignant pheochromocytoma and paraganglioma (MPP); however, dacarbazine is the only recognized active drug in neuroendocrine tumours. We investigated the therapeutic benefit of temozolomide (TMZ), an oral alternative to dacarbazine, in patients with MPP. This is a retrospective study of consecutive patients with documented progressive MPP. We examined the correlation between Succinate dehydrogenase B (SDHB) mutation and O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation and MGMT expression in the French nation-wide independent cohort of 190 pheochromocytomas or paragangliomas (PP). Progression-free survival (PFS) according to RECIST 1.1 and PERCIST 1.0 criteria was the primary end point. Fifteen consecutive patients with MPP were enrolled; ten (67%) carried a mutation in SDHB. The mean dose intensity of TMZ was 172 mg/m(2) /d for 5 days every 28 days. Median PFS was 13.3 months after a median follow-up of 35 months. There were five partial responses (33%), seven stable (47%) and three progressive diseases (20%). Grade 3 toxicities were lymphopenia in two patients and hypertension in one. Partial responses were observed only in patients with mutation in SDHB. MGMT immunohistochemistry was negative in tumour samples from four patients who responded to treatment. SDHB germline mutation was associated with hypermethylation of the MGMT promoter and low expression of MGMT in 190 samples of the French nation-wide independent cohort. This study demonstrates that TMZ is an effective antitumour agent in patients with SDHB-related MPP. The silencing of MGMT expression as a consequence of MGMT promoter hypermethylation in SDHB-mutated tumours may explain this finding.

Impact of lymphovascular invasion on otherwise low-risk papillary thyroid carcinomas: a retrospective and observational study.

PURPOSE: Presence of venous vascular invasion is a criterion of intermediate risk of recurrence in papillary thyroid carcinoma (PTC). However, the presence and type of vascular invasion (lymphatic or venous) is often underreported and its impact on PTCs without other risk features remains unknown. The aim of this study was to evaluate the impact of both lymphatic and venous invasion on the risk of recurrence/persistence on otherwise low-risk PTCs. METHODS: Retrospective study including patients with otherwise low-risk PTCs but with vascular invasion, diagnosed between 2013 and 2019. The persistence/recurrence during the follow-up was evaluated. Pathology was reviewed to confirm the presence of lymphovascular invasion and determine the type of invasion. RESULTS: A total of 141 patients were included. Lymphovascular invasion was confirmed in 20.6%. After surgery, 48.9% (N = 69) of the patients received radioactive iodine (RAI). The median follow-up time was 4 [3-6] years. Overall, 6 (4.2%) patients experienced persistent/recurrent disease in the neck, including 3 with lymphovascular invasion, confirmed as "only lymphatic". Overall, patients with tumors harboring lymphovascular invasion had sensibly more persistent/recurrence disease compared with those without lymphovascular invasion (10.3% vs 2.7%, p = 0.1), especially in the subgroup of patients not treated with RAI (20% vs 1.6%, p = 0.049) [OR 15.25, 95% CI 1.24-187.85, p = 0.033]. CONCLUSION: Lymphovascular invasion, including lymphatic invasion only, is associated with a sensibly higher risk of persistent/recurrent disease in otherwise low-risk PTCs, namely in patients not treated with RAI. Lymphatic invasion could have a role in risk-stratification systems for decision making.

Interference With VIP to Distinguish Between Real and False VIPoma: National Study From the French Endocrine Tumors Group.

Background: Vasoactive intestinal peptide (VIP)-secreting tumors (VIPomas) are digestive neuroendocrine tumors in which the hormonal secretion is life-threatening. Biological confirmation is obtained by demonstrating an elevation in plasma VIP, usually using radioimmunoassay (RIA). In some cases, analytical interference is suspected. We developed 3 different techniques to detect interference in VIP RIA. Methods: Three techniques were used: RIA after Sephadex column chromatography separation, RIA after polyethylene glycol precipitation, and 125I-labeled VIP binding test. We included patients with suspicion of false positive VIP (FPV) elevation. We then compared results with those of a group of "real," proven VIPoma (RV). Results: A total of 15 patients with FPV elevation and 9 RV patients were included. Interference was detected in all FPV patients vs none in RV. Clinical and biochemical parameters did not differ between FPV and RV patients, but VIP concentration in RIA was significantly higher in FPV patients than in RV patients (228 pmol/L vs 66 pmol/L, P = .038). Using a 125I-labeled VIP binding test, median proportion of radioactivity in the pellet was significantly higher in FPV than in RV patients (53% vs 13%, P < .0001). A 20.5% threshold presented excellent performances (sensitivity 100% [79.6-100], specificity 100% [70.1-100]). Conclusion: We developed 3 different laboratory techniques to reveal interference in RIA VIP assays. The diagnostic performance of all 3 was excellent. These techniques must be employed in cases of discordance between VIP elevation and clinical presentation.

Outcome on Mesenteric Mass Response of Small-Intestinal Neuroendocrine Tumors Treated by 177Lu-DOTATATE Peptide Receptor Radionuclide Therapy: The MesenLuth Study, a National Study from the French Group of Endocrine Tumors and Endocan-RENATEN Network.

A mesenteric mass (MM), characterized by fibrotic reaction, is present in most small-intestinal neuroendocrine tumors (SI-NETs). 177Lu-DOTATATE peptide receptor radionuclide therapy (PRRT) has shown its efficacy in patients with progressive SI-NETs. However, because of specific tissue characteristics of desmoplastic MMs, we hypothesize that these lesions may be refractory to 177Lu-DOTATATE PRRT. Methods: From the national French Groupe d'étude des Tumeurs Endocrines database, we identified patients with an advanced SI-NET and a MM (≥2 cm with a retractile aspect) of a SI-NET treated by at least 1 course of 177Lu-DOTATATE PRRT. The primary endpoint was a MM objective response rate (ORR) of less than 5%. Secondary endpoints were metabolic response, MM-related safety, and clinical response, as well as MM progression-free survival (PFS) and non-MM PFS. Results: In total, 52 patients were included. The MM ORR was 4% (n = 2), and the non-MM ORR was 8% (n = 4). No patient had a MM metabolic response, and the non-MM metabolic response rate was 12% (n = 6). Among the 26 patients with baseline MM-related symptoms, 46% had a clinical response. Four patients presented with gastrointestinal complications during PRRT. The median MM-related PFS was not reached, and the non-MM PFS was 50.3 mo (95% CI, 38.2-61.7 mo). Conclusion: This study confirms that 177Lu-DOTATATE PRRT does not lead to morphologic response on MMs (ORR < 5%). However, it allows MM stability, with few MM-related side effects, and has a relevant impact on MM-related symptoms.

Pralsetinib in Patients with Advanced/Metastatic Rearranged During Transfection (RET)-Altered Thyroid Cancer: Updated Efficacy and Safety Data from the ARROW Study.

Background: Rearranged during transfection (RET) alterations are targetable oncogenic drivers in thyroid cancer. Primary data from the open-label, phase 1/2 ARROW study demonstrated clinical activity and manageable safety with pralsetinib, a selective RET inhibitor, in patients with advanced/metastatic RET-altered thyroid cancer. We present an updated analysis with more patients and longer follow-up. Methods: Adult patients with advanced/metastatic RET-mutant medullary thyroid cancer (MTC) or RET fusion-positive thyroid cancer who initiated oral pralsetinib at 400 mg once daily were included. Primary endpoints were overall response rate (ORR) by blinded independent central review (per RECIST v1.1) and safety. Secondary endpoints included duration of response (DoR), progression-free survival (PFS), and overall survival. Responses were assessed in three cohorts of patients with baseline measurable disease: patients with RET-mutant MTC who had received prior cabozantinib and/or vandetanib (C/V), treatment-naïve patients with RET-mutant MTC, and patients with previously treated RET fusion-positive thyroid cancer. Patient-reported outcomes (PROs) were an exploratory endpoint. Results: As of October 18, 2021, the measurable disease population comprised of 61 patients with RET-mutant MTC and prior C/V, 62 treatment-naïve patients with RET-mutant MTC, and 22 patients with RET fusion-positive thyroid cancer who had received prior systemic therapy, including radioactive iodine. The ORR was 55.7% [confidence interval; 95% CI: 42.4-68.5] in patients with RET-mutant MTC and prior C/V, 77.4% [95% CI: 65.0-87.1] in treatment-naïve patients with RET-mutant MTC, and 90.9% [95% CI: 70.8-98.9] in patients with previously treated RET fusion-positive thyroid cancer. Median DoR and median PFS were both 25.8 months in patients with RET-mutant MTC and prior C/V, not reached in treatment-naïve patients with RET-mutant MTC, and 23.6 and 25.4 months, respectively, in patients with previously treated RET fusion-positive thyroid cancer. In the RET-altered thyroid cancer safety population (N = 175), 97.1% of patients reported a treatment-related adverse event (TRAE); these led to discontinuation in 5.7% and dose reduction in 52.6% of patients. There was one death (0.6%) due to a TRAE. PROs improved or remained stable after pralsetinib treatment. Conclusions: In this updated analysis of the ARROW study, pralsetinib continued to show deep and durable clinical activity and a manageable safety profile in patients with advanced/metastatic RET-altered thyroid cancer. Clinical Trial Registration: NCT03037385.