Efficacy of Temozolomide Therapy in Patients With Aggressive Pituitary Adenomas and Carcinomas-A German Survey.

CONTEXT: Despite growing evidence that temozolomide (TMZ) therapy is effective for the treatment of aggressive pituitary tumors (APTs) or carcinomas (PCs), individual therapy decisions remain challenging. OBJECTIVE: We therefore aimed to report on clinical characteristics leading to initiation of TMZ therapy and to add evidence on TMZ long-term effectiveness. DESIGN AND SUBJECTS: Retrospective survey on TMZ treatment in patients with APTs or PCs. TMZ therapy was initiated in 47 patients (22 females) with APTs (n = 34) or PCs (n = 13). Mean age at diagnosis was 45 ± 15 years. The immunohistochemical subtypes were corticotroph (n = 20), lactotroph (n = 18), and nonfunctioning (n = 9) tumors. TMZ therapy started 8 years after initial diagnosis using a standard regimen (median 6 cycles) for the majority of patients. RESULTS: Long-term radiological response to TMZ after a median follow-up of 32 months with 4 patients still on TMZ therapy was tumor regression for 9 (20%), stable disease for 8 (17%), and tumor progression for 29 patients (63%) (outcome data available for 46 patients). Progression occurred 16 months after initiation of TMZ. Median estimated progression-free survival was 23 months. Disease stabilization and median progression-free survival did not differ between patients with APTs or PCs. Predictors of tumor response were not identified. Overall, TMZ was well tolerated. CONCLUSION: We performed a nationwide survey on TMZ therapy in patients with APTs and PCs. While early response rates to TMZ are promising, long-term outcome is less favorable. Prolonged TMZ administration should be considered. We were not able to confirm previously reported predictors of tumor response to TMZ.

Sunitinib in refractory adrenocortical carcinoma: a phase II, single-arm, open-label trial.

CONTEXT: Treatment of refractory adrenocortical carcinoma (ACC) is not established. Animal experiments pointed toward adrenal toxicity of sunitinib. OBJECTIVE: The objective of the study was to determine the antitumor effects of sunitinib in refractory ACC. DESIGN: This was a phase II, open-label trial using a two-stage accrual design. SETTING: The study was conducted at two tertiary referral centers. PATIENTS: Thirty-eight patients with refractory ACC progressing after mitotane and one to three cytotoxic chemotherapies participated in the study. INTERVENTION: The intervention included sunitinib at a standard dose (50 mg/d, 4 wk on, 2 wk off). MAIN OUTCOME MEASURE: Response was defined as progression-free survival (PFS) of 12 wk or longer (first tumor evaluation). RESULTS: Thirty-five patients could be evaluated for response. Five patients experienced stable disease, 24 had progressive disease, and six patients died from ACC before the first evaluation (naïve estimate five of 35=14.3%, median unbiased response rate 15.4%, 95% confidence interval 5.0-33.4%). The median PFS was 2.8 months. In responders, PFS ranged between 5.6 and 11.2 months and overall survival between 14.0 and 35.5 months. Of 36 serious adverse events, only nine were possibly related to sunitinib. Concomitant mitotane appeared to negatively impact on outcome. Furthermore, a negative correlation between the serum concentrations of sunitinib plus its active metabolite N-desethylsunitinib (SU12662) and mitotane (r=-0.650; P=0.114) was observed in seven evaluable patients suggestive of a relevant drug interaction. CONCLUSION: Sunitinib has modest activity in advanced refractory ACC, which compares favorably with other targeted treatments in these patients. Sunitinib serum levels might have been profoundly reduced by mitotane induced cytochrome P450-3A4 activity attenuating its antitumor activity and adverse effects. Together these findings suggest that sunitinib deserves further investigation in mitotane-naïve ACC patients.

Sunitinib Inhibits Cell Proliferation and Alters Steroidogenesis by Down-Regulation of HSD3B2 in Adrenocortical Carcinoma Cells.

The multi-tyrosine kinase inhibitor sunitinib is used in the treatment of several solid tumors. Animal experiments pointed to an adrenotoxic effect of sunitinib. Therefore, we evaluated the expression of key targets of sunitinib in human adrenocortical carcinoma (ACC) tumor samples and investigated its in vitro effects in ACC cell lines. We carried out immunohistochemistry for vascular endothelial growth factor (VEGF) and its receptor (VEGF-R2) in 157 ACC samples and nine normal adrenal glands. VEGF and VEGF-R2 protein were expressed in 72 and 99% of ACC samples, respectively. Using NCI-H295 and SW13 ACC cell lines, we investigated the effects of sunitinib on cell proliferation. Sunitinib reduced dose-dependently cell viability of both NCI-H295 and SW13 cells (SW13: 0.1 µM 96 ± 7%, 1 µM 90 ± 9%*, 5 µM 62 ± 6%*, controls 100 ± 9%; *p < 0.05). To determine sunitinib effects on steroidogenesis, we measured steroid hormones in cell culture supernatant by gas chromatography-mass spectrometry. We observed a pronounced decrease of cortisol secretion (1 µM 90.1 ± 1.5%*, 5 µM 57.2 ± 0.3%*, controls 100 ± 2.4%) and a concomitant increase in the DHEA/4-androstenedione and 17-hydroxypregnenolone/17-hydroxyprogesterone ratios, indicating specific inhibition of 3ß-hydroxysteroid dehydrogenase (HSD3B2). In yeast microsomes transformed with HSD3B2, no direct inhibition of HSD3B2 by sunitinib was detected. Sunitinib induced down-regulation of HSD3B2 mRNA and protein in ACC cell lines (mRNA: 1 µM 44 ± 16%*; 5 µM 22 ± 2%*; 10 µM 19 ± 4%*; protein: 1 µM 82 ± 8%; 5 µM 63 ± 8%*; 10 µM 55 ± 9%*). CYP11B1 was down-regulated at mRNA but not at protein level and CYP11A1 remained unchanged. In conclusion, target molecules of sunitinib are expressed in the vast majority of ACC samples. Sunitinib exhibits anti-proliferative effects in vitro, and appears to specifically block adrenal steroidogenesis by down-regulation of HSD3B2, rendering it a promising option for treatment of ACC.

Improved survival in patients with stage II adrenocortical carcinoma followed up prospectively by specialized centers.

CONTEXT: Median survival in stage II adrenocortical carcinoma (ACC) differs widely in published series ranging between 23 and more than 60 months. We hypothesized that these results may have been affected by a referral bias because many patients may contact specialized centers only after recurrence. OBJECTIVE: The objective of the study was a comparison of outcome in patients with stage II ACC who were followed up prospectively early after surgery and were counseled by a specialized center (prospective group) with patients who registered with the German ACC registry later than 4 months after diagnosis (retrospective group). PATIENTS/METHODS: The study was a cohort analysis in 149 adult patients with stage II ACC. RESULTS: Patients who were followed up prospectively (n = 30) had a lower recurrence rate and a superior 5-yr survival compared with the 119 patients in the retrospective group (30 vs. 74%, P < 0.01 and 96 vs. 55%, P < 0.05, respectively). In the retrospective group, 67% of the patients had registered only after disease recurrence. In the remaining patients, the recurrence rate was low (21%), and the 5-yr survival was greater than 95%. More patients in the prospective group received adjuvant mitotane (53 vs. 16%, P < 0.001), and adjuvant mitotane was associated with improved survival [hazard risk 0.35 (95% confidence interval 0.13-0.97); P = 0.04]. However, the survival advantage was maintained when only patients without mitotane therapy were analyzed. CONCLUSIONS: Patients who are followed up prospectively after surgery for stage II ACC and receive early specialized care have a much better prognosis than previously reported due to a major referral bias in previous series and use of adjuvant mitotane. These findings will impact on the perception of prognosis in newly diagnosed stage II ACC.

Deficits in the management of patients with adrenocortical carcinoma in Germany.

BACKGROUND: Adrenocortical carcinoma (ACC) is a rare tumor with a poor prognosis. Often, the physicians who first treat patients with ACC have no prior experience with the disease. The aim of our study was to evaluate the quality of medical care for patients with ACC in Germany. METHODS: Data from the German ACC registry were analyzed with regard to the patients' preoperative diagnostic evaluation, histopathological reporting, and clinical follow-up. The findings were compared with the recommendations of the European Network for the Study of Adrenal Tumors (ENSAT). RESULTS: Data were analyzed from 387 patients who had been given an initial diagnosis of ACC in the years 1998 to 2009. 21% of them underwent no hormonal evaluation before surgery, and 59% underwent an inadequate hormonal evaluation. This exposed the patients to unnecessary perioperative risks and impaired their follow-up. 48% did not undergo CT scanning of the chest, even though the lungs are the most frequent site of metastases of ACC. For 13% of the patients, the diagnosis of ACC was later revised by a reference pathologist. For 11% of the patients, the histopathology report contained no information about resection status, even though this is an important determinant of further treatment and prognosis. Optimal management requires re-staging at three-month intervals, yet some patients underwent re-staging only after a longer delay, or not at all. CONCLUSION: We have identified significant deficits in the care of patients with ACC in Germany. We suspect that the situation is similar for other rare diseases. The prerequisite to better care is close and early cooperation of the treating physicians with specialized centers.

Bevacizumab plus capecitabine as a salvage therapy in advanced adrenocortical carcinoma.

OBJECTIVE: No standard therapy for advanced adrenocortical carcinoma (ACC) is established by any randomized trial but a consensus conference 2003 recommended mitotane as monotherapy or combined with etoposide, doxorubicin and cisplatin or with streptozotocin as first-line systemic therapy. However, there is no evidence for any therapy beneficial in patients failing these therapies. Therefore, we evaluated the effects of the anti-VEGF antibody bevacizumab plus capecitabine as salvage therapy in ACC. METHODS: Patients registered with the German ACC Registry with refractory ACC progressing after cytotoxic therapies were offered treatment with bevacizumab (5 mg/kg body weight i.v. every 21 days) and oral capecitabine (950 mg/m(2) twice daily for 14 days followed by 7 days of rest) in 2006-2008. Evaluation of tumour response was performed by imaging according to response evaluation criteria in solid tumours every 12 weeks. RESULTS: Ten patients were treated with bevacizumab plus capecitabine. None of them experienced any objective response or stable disease. Two patients had to stop therapy after few weeks due to hand-foot syndrome, and three patients died on progressive disease within 12 weeks. Other adverse events were mild (grade I-II). Median survival after treatment initiation was 124 days. CONCLUSIONS: Bevacizumab plus capecitabine has no activity in patients with very advanced ACC. Hence, this regimen cannot be recommended as a salvage therapy.

Glucose transporter GLUT1 expression is an stage-independent predictor of clinical outcome in adrenocortical carcinoma.

Owing to the rarity of adrenocortical carcinoma (ACC) no prognostic markers have been established beyond stage and resection status. Accelerated glycolysis is a characteristic feature of cancer cells and in a variety of tumour entities key factors in glucose metabolism like glucose transporter 1 and 3 (GLUT1 and -3), transketolase like-1 enzyme (TKTL1) and pyruvate kinase type M2 (M2-PK) are overexpressed and of prognostic value. Therefore, we investigated the role of these factors in ACC. Immunohistochemical analysis was performed on tissue microarrays of paraffin-embedded tissue samples from 167 ACCs, 15 adrenal adenomas and 4 normal adrenal glands. Expression was correlated with baseline parameters and clinical outcome. GLUT1 and -3 were expressed in 33 and 17% of ACC samples respectively, but in none of the benign tumours or normal adrenals glands. By contrast, TKTL1 and M2-PK were detectable in all benign tissues and the vast majority of ACCs. GLUT1 expression was strongly associated with prognosis in univariate and multivariate analysis (P<0.01), whereas GLUT3, TKTL1 and M2-PK did not correlate with clinical outcome. Patients with strong GLUT1 staining showed a considerably higher overall mortality (hazard ratio (HR) 6.34 (95% confidence interval 3.10-12.90) compared with patients with no GLUT1 staining. When analysing patients in their early stages and advanced disease separately, similar results were obtained. HR for survival was 5.31 (1.80-15.62) in patients with metastatic ACC and in patients after radical resection the HR for disease-free survival was 6.10 (2.16-16.94). In conclusion, GLUT1 is a highly promising stage-independent, prognostic marker in ACC.

Radiotherapy in adrenocortical carcinoma.

Adrenocortical carcinoma (ACC) is a rare malignancy, and patients with ACC have a poor prognosis. Even after radical surgery, up to 85% of patients develop recurrent disease. Systemic treatment options still have limited efficacy. Because the role of radiotherapy is not defined well and because ACC often is considered radioresistant, the authors reviewed the available data on radiotherapy for ACC. Original articles and reviews were identified using a PubMed search strategy that included the period up to July 2008. Ten articles were identified that covered radiotherapy in a total of 129 patients with ACC (64 patients received postoperative irradiation, and 65 patients received palliative therapy for advanced disease). In addition, 26 patients were identified in the German ACC Registry who received palliative radiotherapy. Furthermore, patterns of failure after adjuvant radiotherapy were investigated, and the authors provided recommendations for patient selection, treatment planning, and treatment protocols. In an adjuvant setting, postoperative radiotherapy was able to prevent local recurrence in the majority of patients. In those with advanced disease, a response to radiotherapy was observed in 57% of patients who received palliative radiotherapy. Therefore, the authors concluded that radiotherapy may play an important role in the care of patients with ACC. Until better evidence is available, the authors recommended the following approach: Adjuvant radiotherapy to the tumor bed should be considered in patients at high risk for local recurrence (eg, incomplete/R1 resection); a total dose of >40 grays (Gy) with single fractions of 1.8 Gy to 2 Gy should be administered (including a boost volume to reach from 50 Gy to 60 Gy in individual patients); and radiotherapy in a palliative setting may be used for symptomatic metastases to bone, brain, or vena cava obstruction. With state-of-the-art technology, acute and long-term toxicities mostly were mild to moderate. However, the authors concluded that prospective investigations would be required to fully define the therapeutic potential of this important treatment option.

Osteopontin stimulates invasion of NCI-h295 cells but is not associated with survival in adrenocortical carcinoma.

Gene array studies indicated that osteopontin (OPN) mRNA is highly expressed in adrenocortical carcinomas (ACCs). OPN enhances invasiveness, proliferation, and metastasis formation, and is associated with poor survival in some malignant diseases. Integrin alphavbeta3 has been shown to mediate OPN effects on invasion. In this study, we demonstrated OPN and integrin alphavbeta3 expression in normal adrenal glands and benign adenomas, with staining seen exclusively in adrenocortical cells as well as even stronger staining in ACC. Western blot analysis confirmed overexpression of OPN in ACC (p < 0.01). With Matrigel invasion assays, we have shown that OPN greatly stimulates the invasiveness of NCI-h295 cells (>six-fold increase, p < 0.001). Transfection with integrin alphavbeta3 further increased invasiveness after OPN stimulation (p < 0.001). This increase was reversed by the addition of an anti-integrin beta3 antibody, indicating a functional relationship of OPN and integrin alphavbeta3 in ACC. With tissue arrays, we confirmed high OPN expression in 147 ACC samples. However, no association with survival was seen in Kaplan-Meier analysis including 111 patients with primary tumours graded for OPN staining and follow-up data available. In conclusion, our in vitro data indicate that OPN and integrin alphavbeta3 may act as a functional complex facilitating the invasiveness of adrenocortical tumours. This relationship remains of relevance to our understanding of carcinogenesis, but further studies are needed to address the physiological and pathological function of OPN in adrenal tissue.

Expression of excision repair cross complementing group 1 and prognosis in adrenocortical carcinoma patients treated with platinum-based chemotherapy.

Therapeutic progress in adrenocortical carcinoma (ACC) is severely hampered by its low incidence. Platinum-based chemotherapies are the most effective cytotoxic treatment regimens in ACC but response rates remain <50%. In other tumor entities, expression of excision repair cross complementing group 1 (ERCC1) predicts resistance to platinum compounds. Therefore, we correlated ERCC1 protein expression and clinical outcome. We have retrolectively established adrenal tissue microarrays and analyzed prospectively samples from 163 ACCs, 15 benign adrenal adenomas, and 8 normal adrenal glands by immunohistochemistry for ERCC1 protein expression. Detailed clinical data were available by the German ACC Registry. ERCC1 protein was highly expressed in all normal adrenal glands, 14 benign tumors (93%) and in 75 ACCs (47%). In ACC, no differences in baseline parameters were found between patients with and without ERCC1 expression. Detection of ERCC1 was not correlated with survival in patients who never received platinum-based chemotherapy. In platinum-treated patients (n=45), objective response to platinum compounds was observed in 3/21 patients (14.3%) with high ERCC1 expression and in 7/24 patients (29.2%) with low ERCC1 expression (P=0.23). ERCC1 expression was strongly correlated with overall survival after platinum treatment (median: eight months in patients with high ERCC1 versus 24 months in low ERCC1 expression, hazard ratio (HR) 2.95 (95% confidence interval (CI) 1.4-6.2), P=0.004). Multivariate analysis confirmed that high ERCC1 expression was a predictive factor for poor prognosis in platinum treated patients (HR 2.2, 95% CI 1.0-4.5, P=0.038). Our findings suggest that ERCC1 expression is the first factor for predicting survival in ACC patients treated with platinum-based chemotherapy.

Limited prognostic value of the 2004 International Union Against Cancer staging classification for adrenocortical carcinoma: proposal for a Revised TNM Classification.

BACKGROUND: Adrenocortical carcinoma (ACC) is a rare malignancy, and it was only in 2004 that the International Union Against Cancer (UICC) defined TNM criteria and published the first staging classification. However, to date, the prognostic value of the proposed classification has not been evaluated. METHODS: The German ACC Registry comprising 492 patients was searched for patients who were diagnosed between 1986 and 2007 with detailed information on primary diagnosis and a minimum follow-up of 6 months. Patients were assigned to UICC tumor stage, and disease-specific survival (DSS) was assessed. In addition, the contribution of potential risk factors for DSS was evaluated. RESULTS: In total, 416 patients with a mean follow-up of 36 months met the inclusion criteria (stage I, n=23 patients; stage II, n=176 patients; stage III, n=67 patients; stage IV, n=150 patients). Kaplan-Meier analysis revealed a stage-dependent DSS. However, DSS in patients with stage II ACC did not differ significantly from DSS in patients with stage III ACC (hazard ratio, 1.38; 95% confidence interval, 0.89-2.16). Furthermore, patients who had stage IV ACC without distant metastases had an improved DSS compared with patients who had metastatic disease (P=.004). An analysis of different potential risk factors for defining stage III ACC revealed important roles in DSS for tumor infiltration in surrounding tissue, venous tumor thrombus (VTT), and positive lymph nodes; whereas tumor invasion in adjacent organs carried a prognosis similar to that of infiltration in surrounding tissue only. CONCLUSIONS: The 2004 UICC staging classification for ACC has significant limitations. On the basis of the current analysis, a revised classification with superior prognostic accuracy is proposed (the European Network for the Study of Adrenal Tumors classification). In this system, stage III ACC is defined by the presence of positive lymph nodes, infiltration of surrounding tissue, or VTT; and stage IV ACC is restricted to patients with distant metastasis.

Treatment of advanced adrenocortical carcinoma with erlotinib plus gemcitabine.

CONTEXT: Adrenocortical carcinoma (ACC) is a rare malignancy with poor prognosis. In advanced disease, mitotane given as monotherapy or combined either with etoposide, doxorubicin, and cisplatin or with streptozotocin is the recommended first-line therapy. However, many patients have progressive disease despite treatment with these regimens. OBJECTIVE: Our objective was to evaluate the efficacy of the epidermal growth factor receptor inhibitor erlotinib plus gemcitabine as salvage therapy in ACC patients with very advanced ACC. DESIGN/SETTING: The study consisted of case series collected from different centers (primary care and referral centers) in Germany in 2006-2007. PATIENTS AND INTERVENTION: Patients registered with the German ACC Registry with progressive ACC after two to four previous systemic therapies were offered treatment with erlotinib and gemcitabine. Oral erlotinib (100 mg/d) was administered on a daily basis and gemcitabine (800 mg/m(2)) iv every 14 d. MAIN OUTCOME MEASURE: We evaluated tumor response according to response evaluation criteria in solid tumors (RECIST) criteria after 12 wk of treatment. RESULTS: Ten patients have been treated with erlotinib and gemcitabine. Only one in 10 patients experienced a minor response (progression-free survival 8 months), whereas eight patients had progressive disease at the first staging. One patient had to stop therapy after the first administration of gemcitabine due to cerebral seizure. Nine of 10 patients had died after a median of 5.5 months after treatment initiation. In addition to the seizure, one patient experienced severe pneumonia (grade III), and in one, gemcitabine administration had been delayed due to prolonged neutropenia. All other adverse events were mild (grade I-II). CONCLUSIONS: Salvage chemotherapy using erlotinib plus gemcitabine has very limited to no activity in patients with very advanced ACC.

Mifepristone (RU 486) in Cushing's syndrome.

CONTEXT: Mifepristone (RU 486) blocks the action of cortisol by binding to the glucocorticoid receptor and, therefore, is of potential therapeutic value in Cushing's syndrome. However, research in endogenous hypercortisolism has been hampered by the controversy related to the use of mifepristone for inducing abortion. Currently, new studies are planned to better define the role of RU 486 in Cushing's syndrome. This paper reviews the available evidence concerning the therapeutic effects and adverse events of RU 486 in Cushing's syndrome. EVIDENCE ACQUISITION: Original articles and reviews were identified using a PubMed search strategy covering the time period until February 2007. EVIDENCE SYNTHESIS: Treatment of Cushing's syndrome with mifepristone has been reported in a total of 18 patients, with daily doses ranging from 5 to 30 mg/kg. Case reports indicate that the mifepristone-induced receptor blockade may lead to significant clinical improvement in patients with Cushing's syndrome in whom surgery and inhibitors of adrenal steroidogenesis fail to control hypercortisolism. Due to its rapid onset of action, mifepristone may be particularly useful in acute crises, e.g. in cortisol-induced psychosis. Side effects include adrenal insufficiency and, as a result of its antiprogestin action, endometrial hyperplasia in long-term treatment. Adrenal insufficiency can be assessed only by careful clinical evaluation, as the hormonal parameters are not reliable during receptor blockade, and is rapidly reversed by exogenous dexamethasone. Well-designed larger clinical trials are needed to better assess the value of this interesting drug in the treatment of Cushing's syndrome.

The yield of wireless capsule endoscopy in the detection of neuroendocrine tumors in comparison with CT enteroclysis.

BACKGROUND: Patients with neuroendocrine tumors (NET) of the small bowel often present with metastatic disease, and localization of the primary tumor still is a diagnostic challenge. Wireless capsule endoscopy (WCE) is an established method that improves the diagnostic evaluation of diseases of the small intestine. OBJECTIVE: The aim of this study was to determine the diagnostic accuracy of WCE in imaging neuroendocrine tumors of the small bowel in these patients. DESIGN: We retrospectively compared the findings of capsule endoscopy to the findings of CT enteroclysis in patients with histopathological confirmation of NET. PATIENTS: Eight patients with newly established diagnosis of metastatic NET were included. INTERVENTIONS: All patients underwent CT enteroclysis and wireless capsule endoscopy within a maximum of 2 weeks. MAIN OUTCOME MEASUREMENTS: Number of primary tumors detected. The results of surgery were used as a gold standard for both methods. RESULTS: CT enteroclysis detected the primary tumor in 4 of 8 patients whereas WCE found the primary in 3 patients. On the contrary, CT enteroclysis provided more false-positive results. LIMITATIONS: Frequent extraluminal tumor growth. CONCLUSIONS: In patients with NET, wireless capsule endoscopy may be helpful in individual cases but the general diagnostic value of this method may be limited due to frequent extraluminal growth of these tumors.