Margaret Ottaviano

Phase II Study of Everolimus in Patients With Thymoma and Thymic Carcinoma Previously Treated With Cisplatin-Based Chemotherapy

Purpose No effective salvage treatments are available for patients with advanced/recurrent thymoma (T) or thymic carcinoma (TC) who have progressed after platinum-based chemotherapy. This study evaluated the activity of everolimus in patients with advanced/recurrent T or TC previously treated with cisplatin-containing chemotherapy. Patients and Methods This was a single-arm, single-stage, open-label, multicenter, phase II trial. Patients received oral everolimus 10 mg/d until disease progression, unacceptable toxicity, or patient refusal. A Fleming phase II trial was designed. The null hypothesis of a true disease control rate (DCR) of 40% was tested against a one-sided alternative of a true DCR of 60% (α = β = 0.10): If disease control were achieved in ≥ 21 of the first 41 evaluable patients, everolimus could be recommended for further evaluation. Progression-free survival, overall survival, and safety were also evaluated. Results From 2011 to 2013, 51 patients were enrolled (T, n = 32; TC, n = 19). Complete remission was observed in one patient with TC, partial response in five patients (T, n = 3; TC, n = 2), and stable disease in 38 patients (T, n = 27; TC, n= 11), with a DCR of 88% (T,: 93.8%; TC, 77.8%). With a median follow up of 25.7 months, median progression-free survival was 10.1 months (T,: 16.6 months; TC, 5.6 months), and median overall survival was 25.7 months (T, not reached; TC, 14.7 months). Fourteen patients had a serious drug-related adverse event; of these patients, nine permanently discontinued treatment. Three patients died of pneumonitis while in the study. Immunohistochemical positivity for p4E-BP1 or insulin-like growth factor-1 receptor was statistically significantly related to a shorter survival. Conclusion Everolimus may induce durable disease control in a high percentage of patients with T or TC, albeit with a potential high risk of fatal pneumonitis.

capecitabine plus gemcitabine in thymic epithelial tumors: final analysis of a Phase Ii trial

BACKGROUND A multi-institutional Phase II trial was initiated in 2005 to test the combination gemcitabine and capecitabine in patients with thymic epithelial malignancies (TETs). PATIENTS & METHODS Patients with histologic confirmation of TET diagnosis by central review who had received >1 systemic chemotherapy treatment were included. Patients received oral capecitabine (650 mg/mq twice daily on days 1-14) and intravenous gemcitabine (1000 mg/mq on days 1 and 8 every 3 weeks). RESULTS Of the 30 patients included (18 men, 12 women; median age: 57 years, range: 48-61 years), the majority (73%) had thymoma, and the remaining thymic carcinoma. Eight patients developed grade 3-4 neutropenia. A total of 12 patients had a response. Median progression-free survival was 11 months (range: 6.5-16.5). CONCLUSION Capecitabine and gemcitabine is highly active in TETs.

Tumor-to-tumor metastasis: Breast cancer metastatic to thymic epithelial tumor

Tumor-to-tumor metastasis is a rare phenomenon, with around 150 cases being reported in the literature. Breast cancer is the second most commonly reported donor tumor after lung cancer, but thymic epithelial tumors have never been reported as recipient tumors. Furthermore, the thymus is rarely affected by metastases. To our knowledge, the present report is the first case of breast cancer metastatic to thymic epithelial tumor.

Long term deficiency of vitamin D in germ cell testicular cancer survivors

Background Cisplatin-based chemotherapy significantly improved the survival of patients with germ cell testicular cancer. However, long term side effects of chemotherapy have non-negligible impact on the quality of life of these young patients, who have a long life expectancy after being successfully treated. Materials and Methods 25-OH vitamin D, testosterone, FSH and LH of patients with testicular cancer were retrospectively evaluated and for each patient clinical information were collected. The tissue of 52 patients with germ cell tumors was analyzed for VDR expression by immunohistochemistry. The serum 25-OH vitamin D and VDR expression were correlated to the patients ‘clinical characteristics. Results 25-OH vitamin D was analyzed in 82 patients. Insufficient (< 30 ng/ml) levels were detected in 65%–85%, mild deficient (< 20 ng/ml) in 25%–36% and severe deficient (< 10 ng/ml) in 6%–18% of the patients over a median follow-up of 48 months. No difference in serum 25-OH vitamin D was detected over the follow-up time points. No correlation with histology, stage and type of treatment was found. The 25-OH vitamin D levels were not correlated to testosterone, FSH and LH levels. Interestingly, the expression of VDR was much higher in non seminoma than in seminoma tissue. Conclusions Patients with testicular cancer have reduced vitamin D levels after the treatment of the primary cancer. Since long term hypovitaminosis D leads to high risk of fractures, infertility and cardiovascular diseases, we envision that vitamin D should be regularly checked in patients with testicular cancer and replaced if needed.

New options for neuroendocrine thymic tumors medical treatment

Neuroendocrine neoplasms (NENs) consist of a group of heterogenic malignancies, mainly arising from the gastroenteropancreatic (GEP) and the bronchopulmonary tract. Thymic neuroendocrine tumors (TNETs) are included in the thymic carcinoma group, due to the biological aggressiveness and the poor prognosis for the high incidence of local recurrences and distant metastases. The pathological classification of TNETs slightly differs from other NENs, considering in addition to Ki-67, also the grade of necrosis. Furthermore, almost 50% of these tumors can be complicated by endocrine diseases, either due to ectopic adrenocorticotropic hormone secretion (Cushing syndrome) or because of its association with other endocrine tumors, such as in multiple endocrine neoplasia type 1 syndrome (MEN1). Surgery remains the mainstay of therapy for resectable disease, whereas induction/adjuvant chemotherapy/radiotherapy play a role in case of incomplete resections or unresectable tumors. Somatostatin analogs (SSAs) play a fundamental role since the majority of well differentiated NETs expresses high levels of somatostatin receptors so that SSAs therapy is selected as first line treatment in functional and no functional NETs. In the complex scenario of treatment strategies, a pivotal role is acted by the inhibition of mTOR protein with everolimus. The angiogenesis is another important pathway in NETs. Pazopanib, a multi-targeted agent, has been recently evaluated in advanced NETs including patients who received mTOR inhibitors. Because comparative clinical trials are still lacking and the different therapies cannot be placed in a specific sequence, future clinical research will aim to clarify these issues in randomized trial.

RELEVENT Trial: Phase II Trial of Ramucirumab, Carboplatin, and Paclitaxel in Previously Untreated Thymic Carcinoma/B3 Thymoma With Area of Carcinoma

Abstract Thymic epithelial tumors are rare malignancies. Thymic carcinoma represents about 20% of all thymic epithelial tumors and has aggressive behavior, with a greater tendency to metastatic spread. Thymic carcinoma is often diagnosed in advanced stages for which systemic treatment is the main therapeutic option. The association of chemotherapy and antiangiogenic agents in the first‐line setting has never been investigated in this very rare cancer. However, preclinical and clinical evidence has suggested that inhibition of angiogenesis could be beneficial. The RELEVENT trial is a multicenter, open‐label, single‐arm, phase II study aimed at investigating the activity and safety of ramucirumab combined with paclitaxel and carboplatin in chemotherapy‐naive patients affected by thymic carcinoma or B3 thymoma with area of carcinoma. The primary endpoint of the trial is the overall response rate. Progression‐free survival, overall survival, and safety are secondary endpoints. Patient‐reported outcomes will be collected at each visit. The mutational status of a subset of genes, polymorphisms, and selected micro‐RNA expression will be evaluated.

Best practices for the management of thymic epithelial tumors: A position paper by the Italian collaborative group for ThYmic MalignanciEs (TYME)

Thymic epithelial tumors (TETs) are a heterogenous group of rare tumors, with a complex histopatological classification. Furthermore, the recent introduction of the first TNM staging system, that is scheduled to replace the Masaoka-Koga system, may create further difficulties in TET management, that remains challenging. Several guidelines for treatment of TETs are available and provide recommendations based mainly on non randomized trials and retrospective or limited series. Often the lack of evidence leads to formulation of indications based on expert opinions. As for other rare cancers it is crucial to create networks to coordinate the work among centres involved in treatment of these diseases in order to offer the best diagnostic and therapeutic tools. For this purpose, in 2014 a network named TYME (ThYmic MalignanciEs), was founded in Italy with the aim of improving care and research in TETs. In September 2017 a panel of multidisciplinary experts from TYME network and from other Italian centres strongly involved in TET diagnosis and treatment convened a first Italian Expert meeting together with representatives of association for patients affected by rare thoracic cancers Tu.To.R, to explore how these tumors are managed in the different centres of Italy compared to ESMO guidelines. In this paper we summarize the issues discussed during that meeting and we propose recommandations based on Masaoka Koga and the new TNM staging system.

AB005. OS01.05. Early prediction of response to target therapy by FDG-PET in thymic epithelial tumors: a monocentric experience

Background: Recently several data regarding the role of F-Fluorodeoxyglucose positron emission tomography (F-FDG PET) imaging in management of patients with thymic epithelial tumors (TET) have been published. The primary objective of this study was to demonstrate the role of early F-FDG-PET in patients with TETs treated with target therapy as surrogate of 12-month progression free survival (PFS) according to Response Evaluation Criteria in Solid Tumors (RECIST). Methods: Data from 50 patients with TETs treated with target therapy at the Rare Tumours Reference Center of Campania Region, were retrospectively analysed and those that underwent FDG-PET before and after the first 4-8 weeks of treatment were included in the study. Treatment response was expressed as the percent change in maximal standardized uptake values (SUV) of the most F-FDG avid lesion in each patient. Based on previous literature data, the patients were stratified as metabolic highly responders, metabolically partial responders and metabolically low/no responders using 25% and 25% thresholds for SUV variations from baseline. Tumor response was assessed by contrast-enhanced computed tomography (CE-CT) using RECIST criteria. Overall PFS and correlation between 12-month PFS and early metabolic response were assessed. Results: Thirty-two patients (10 with thymic carcinoma and 22 with thymoma) with unresectable Masaoka stage III or IV TETs were included. Median PFS rates were 28, 14, and 4 weeks, respectively for metabolic highly, partial, low/ no responders. Metabolic highly responders had significantly longer progression-free survival (P=0.0008). Twelve-month PFS was significantly correlated with early FDG-PET metabolic response (P=0.0349). No correlation has been found with overall survival (P=0.3008), stage disease (P=0.7658) and histotype (P=0.8088). Conclusions: Early metabolic response assessed by FDG-PET can be used as surrogate of 12-month PFS in patients with TETs treated with target therapy. In the real life clinical practice, metabolic response is useful for the prediction of clinical outcome and therefore for the optimization of treatment.

P07. Effectiveness of cytotoxic agent etoposide after target therapy in advanced thymic tumors

Background We describe three cases of thymic epithelial tumors (TET) heavily pretreated, which responded to oral etoposide, after progression to everolimus.

P09: Diagnosis of advanced thymic epithelial tumors in patients previously affected by thymic hyperplasia.

Background Thymic hyperplasia is a rare differential diagnosis of anterior mediastinal lesions. Histological and radiological criteria are used to distinguish this benign condition from other malignant diseases; it is often associated with Myasthenia gravis. Here we report our monocentric experience of five patients, affected by advanced thymic epithelial tumors (TETs), with a previous diagnosis of thymic hyperplasia.