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Cristina Gurizzan, Manuel Zamparini, Marco Volante, Valeria Tovazzi, Vito Amoroso, Francesca Consoli, Fausto Petrelli, Salvatore Grisanti, Paolo Bossi, and Alfredo Berruti

Intrathyroidal thymic carcinoma (ITC) is a rare thyroid tumor that resembles thymic carcinoma, for which there are no recommendations on diagnostic and therapeutic approaches. We performed a pooled analysis of published ITC cases to describe the natural history of this disease and identify prognostic factors. We performed a systematic review of histopathological-confirmed ITC cases published in the English literature. The following keywords were used: “intrathyroidal thymic carcinoma”, “carcinoma showing thymus-like differentiation”, “CASTLE tumor”, “thyroid carcinoma showing thymus like differentiation”. Fifty eligible publications were identified, providing data from 132 patients, plus a case diagnosed at our Institution. Median disease-free survival (DFS) of this patient series was 144 months (range 91-197), while median overall survival (OS) was not reached. Upfront surgery was performed in 97% of patients and 24% of them experienced disease recurrence after a median of 19 months (range 13-25). Complaining of major symptoms, as a sign of more advanced local stage, was the only prognostic factor significantly associated with higher risk of death at multivariate analysis (HR 4.903, 95% CI: 1.092-22.008, p= 0.038). Postoperative radiation therapy was not associated with prognosis, while not enough data were available to assess the efficacy of chemotherapy. ITC is a rather indolent disease and ITC patients have a relatively good prognosis. Surgery is the mainstay of therapy. Survival outcome of patients depends on tumor burden and complete surgical resection. Postoperative radiation effect seems to be negligible. Data on the efficacy of chemotherapy in advanced patients are lacking.

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Vito Amoroso, Giorgio Maria Agazzi, Elisa Roca, Nicola Fazio, Alessandra Mosca, Marco Ravanelli, Francesca Spada, Roberto Maroldi, and Alfredo Berruti

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Alfredo Berruti, Massimo Terzolo, Paola Sperone, Anna Pia, Silvia Della Casa, David J Gross, Carlo Carnaghi, Paolo Casali, Francesco Porpiglia, Franco Mantero, Giuseppe Reimondo, Alberto Angeli, and Luigi Dogliotti

To investigate the activity of etoposide, doxorubicin, and cisplatin plus mitotane in the management of advanced adrenocortical carcinoma (ACC) patients, 72 patients with measurable disease not amenable to radical surgery were enrolled in a prospective, multicenter phase II trial. EDP schedule (etoposide 100 mg/m2 on days 5–7, doxorubicin 20 mg/m2 on days 1 and 8, and cisplatin 40 mg/m2 on days 1 and 9) was administered intravenously every 4 weeks. Concomitantly, patients were given up to 4 g/day of oral mitotane. Five patients achieved a complete response and 30 a partial response, for an overall response rate of 48.6% (95% CI: 37.1–60.3). Median time to progression in responding patients was 18 months. The EDP regimen was well tolerated, leukopenia being the dose limiting toxicity. One toxic related death due to septic shock, however, was registered. Radical surgical resection of residual disease after chemotherapy was performed in 10 patients. The overall survival of patients attaining a disease free status (clinical complete responders+radically resected) was significantly higher than that of patients with partial response or no response (P<0.002). Androgen secretion was associated with long survival, while glucocorticoid secretion was associated with poor prognosis both in univariate and multivariate analysis. In conclusion, EDP plus mitotane is an active and manageable combination scheme for ACC patients. Surgical resection of residual disease subsequent to chemotherapy leads to a more favourable outcome. The natural history of the disease is significantly influenced by the secretory status of the tumor.

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Elisa Roca, Alfredo Berruti, Silviu Sbiera, Ida Rapa, Ester Oneda, Paola Sperone, Cristina L Ronchi, Laura Ferrari, Salvatore Grisanti, Antonina Germano, Barbara Zaggia, Giorgio Vittorio Scagliotti, Martin Fassnacht, Marco Volante, Massimo Terzolo, and Mauro Papotti

Topoisomerase II alpha (TOP2A) and thymidylate synthase (TS) are known prognostic parameters in several tumors and also predictors of efficacy of anthracyclines, topoisomerase inhibitors and fluoropirimidines, respectively. Expression of TOP2A and TS mRNA was assessed in 98 patients with adrenocortical carcinoma (ACC) and protein expression was assessed by immunohistochemistry in a subset of 39 tumors. Ninety-two patients were radically resected for stage II–III disease and 38 of them received adjuvant mitotane. Twenty-six patients with metastatic disease received the EDP-M (etoposide, doxorubicin, Adriamycin, cisplatin plus mitotane). TOP2A and TS expression in ACC tissue was directly correlated with the clinical data. Both markers were not associated with either disease free survival (DFS) or overall survival (OS) in multivariate analyses and failed to be associated to mitotane efficacy. Disease response or stabilization to EDP-M treatment was observed in 12/17 (71%) and 1/9 (11%) patients with high and low TOP2A expressing tumors (P = 0.0039) and 9/13 (69%) and 4/13 (31%) patients with high and low TS expressing ACC, respectively (P = 0.049). High TOP2A expression was significantly associated with longer time to progression (TTP) after EDP-M. TOP2A and TS proteins assessed by immunohistochemistry significantly correlated with mRNA expression. Immunohistochemical TOP2A expression was associated with a non-significant better response and longer TTP after EDP-M. TOP2A and TS were neither prognostic nor predictive of mitotane efficacy in ACC patients. The predictive role of TOP2A expression of EDP-M activity suggests a significant contribution of Adriamycin and etoposide for the efficacy of the EDP scheme.

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Daniele Generali, Stephen B Fox, Alfredo Berruti, Maria P Brizzi, Leticia Campo, Simone Bonardi, Simon M Wigfield, Paolo Bruzzi, Alessandra Bersiga, Giovanni Allevi, Manuela Milani, Sergio Aguggini, Luigi Dogliotti, Alberto Bottini, and Adrian L Harris

The purpose of this study is to investigate the role of carbonic anhydrase IX (CAIX) expression in predicting the response to epirubicin and disease-free survival (DFS) in breast cancer patients enrolled in a single institution trial of primary anthracycline and tamoxifen therapy. CAIX expression was assessed in 183 patients with T2–4 N0–1 breast cancer enrolled in a randomized trial comparing four cycles of single agent epirubicin versus epirubicin + tamoxifen as primary systemic treatment. All patients received postoperatively four cycles of the four weekly i.v. cyclophosphamide, methotrexate, 5-fluorouracil regimen. Patients with estrogen receptor (ER)-positive primary tumors received 5 years of adjuvant tamoxifen. Pretreatment, p53 (P = 0.007), c-erbB2 (P < 0.01), and Ki67 (P = 0.02) were directly associated with CAIX expression, while bcl2 (P < 0.000) and ER (P = 0.000) and progesterone receptor (PgR; P < 0.01) were inversely correlated. In multivariate analysis, only high p53 and low bcl2 were independently associated with CAIX positivity. CAIX immunostaining was significantly associated with poor outcome for DFS (P < 0.002) and overall survival (P = 0.001). In multivariate analysis, a significant interaction was found between CAIX and markers of hormone sensitivity, bcl2 (P = 0.01), ER (P = 0.02), PgR (P = 0.02), and lymph node involvement (P = 0.04), in predicting DFS. Presently, there are few clinical markers of resistance to tamoxifen treatment in ER-positive tumors. CAIX expression in breast cancer patients shows a negative predictive role of treatment efficacy in ER-positive patients on the adjuvant tamoxifen after primary chemo-endocrine therapy. Studies investigating the effects of pH on tamoxifen uptake and the effects of therapy with CA inhibitors are planned.

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Paola Sperone, Anna Ferrero, Fulvia Daffara, Adriano Priola, Barbara Zaggia, Marco Volante, Daniele Santini, Bruno Vincenzi, Giuseppe Badalamenti, Chiara Intrivici, Sabrina Del Buono, Silvia De Francia, Emmanouil Kalomirakis, Riccardo Ratti, Alberto Angeli, Luigi Dogliotti, Mauro Papotti, Massimo Terzolo, and Alfredo Berruti

Adrenocortical carcinoma (ACC) is a rare neoplasm characterized by poor prognosis. First-line systemic treatments in advanced disease include mitotane, either alone or in combination with chemotherapy. Studies evaluating second-line therapy options have obtained disappointing results. This trial assessed the activity and toxicity of gemcitabine plus metronomic fluoropyrimidines in heavily pretreated advanced ACC patients. From 1998 to 2008, 28 patients with advanced ACC progressing after mitotane plus one or two systemic chemotherapy lines were enrolled. They received a combination of i.v. gemcitabine (800 mg/m2, on days 1 and 8, every 21 days) and i.v. 5-fluorouracil protracted infusion (200 mg/m2/daily without interruption until progression) in the first six patients, or oral capecitabine (1500 mg/daily) in the subsequent patients. Mitotane administration was maintained in all cases. The rate of non-progressing patients after 4 months of treatment was 46.3%. A complete response was observed in 1 patient (3.5%); 1 patient (3.5%) obtained a partial regression, 11 patients (39.3%) obtained a disease stabilization and 15 patients (53.7%) progressed. Treatment was well tolerated, with grade III and IV toxicities consisting of leukopenia in six patients (21.4%), thrombocytopenia in one patient (3.5%), and mucositis in one patient (3.5%). Median time to progression and overall survival in the patient population were 5.3 (range: 1–43) and 9.8 months (range: 3–73) respectively. Gemcitabine plus metronomic fluoropyrimidines is a well-tolerated and moderately active regimen in heavily pretreated ACC patients.

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Fulvia Daffara, Silvia De Francia, Giuseppe Reimondo, Barbara Zaggia, Emiliano Aroasio, Francesco Porpiglia, Marco Volante, Angela Termine, Francesco Di Carlo, Luigi Dogliotti, Alberto Angeli, Alfredo Berruti, and Massimo Terzolo

Toxicity of adjuvant mitotane treatment is poorly known; thus, our aim was to assess prospectively the unwanted effects of adjuvant mitotane treatment and correlate the findings with mitotane concentrations. Seventeen consecutive patients who were treated with mitotane after radical resection of adrenocortical cancer (ACC) from 1999 to 2005 underwent physical examination, routine laboratory evaluation, monitoring of mitotane concentrations, and a hormonal work-up at baseline and every 3 months till ACC relapse or study end (December 2007). Mitotane toxicity was graded using NCI CTCAE criteria. All biochemical measurements were performed at our center and plasma mitotane was measured by an in-house HPLC assay. All the patients reached mitotane concentrations >14 mg/l and none of them discontinued definitively mitotane for toxicity; 14 patients maintained consistently elevated mitotane concentrations despite tapering of the drug. Side effects occurred in all patients but were manageable with palliative treatment and adjustment of hormone replacement therapy. Mitotane affected adrenal steroidogenesis with a more remarkable inhibition of cortisol and DHEAS than aldosterone. Mitotane induced either perturbation of thyroid function mimicking central hypothyroidism or, in male patients, inhibition of testosterone secretion. The discrepancy between salivary and serum cortisol, as well as between total and free testosterone, is due to the mitotane-induced increase in hormone-binding proteins which complicates interpretation of hormone measurements. A low-dose monitored regimen of mitotane is tolerable and able to maintain elevated drug concentrations in the long term. Mitotane exerts a complex effect on the endocrine system that may require multiple hormone replacement therapy.