Central nervous system (CNS) metastases occur in 30% of patients with advanced non-small cell lung cancer (NSCLC). Localized treatments targeting CNS metastases result in delays in systemic therapy administration and are associated with neurocognitive impairment. Nivolumab is an immune check-point inhibitor that is approved as a second-line treatment of NSCLC. Data regarding the intracranial activity of nivolumab is lacking. We retrospectively reviewed the efficacy and safety of nivolumab in five patients with advanced NSCLC and new/progressing intracranial metastases. Intracranial response was assessed by magnetic resonance imaging (MRI) using mRECIST v. 1.1 criteria. All patients had parenchymal brain metastases; two patients had leptomeningeal carcinomatosis diagnosed according to radiological criteria. All patients were asymptomatic and did not require corticosteroids or immediate local therapy. We observed one complete and one partial response in the brain. Stabilization of leptomeningeal carcinomatosis for 10 weeks was achieved in one additional patient. Two patients progressed in the CNS. Time-to-response comprised 5 weeks and 9 weeks; both responses are still ongoing at the time of the report (24+ and 28+ weeks since start of treatment). Systemic responses and intracranial responses were largely concordant. No treatment-related or CNS metastases-related grade≥3 adverse events were observed. Nivolumab might have intracranial activity and favorable safety profile in patients with CNS metastases secondary to NSCLC. Nivolumab CNS activity warrants further evaluation.

We evaluated 18F-FDG PET/CT in small cell lung cancer (SCLC) staging and assessed metabolic (SUVmax, MTV and TLG) and morphologic (CTvol) variables as predictors for overall survival (OS) and progression-free survival (PFS).

Targeted therapy significantly prolongs survival in adenocarcinoma of the lung. The current diagnostic practice includes EGFR and ALK testing, while other driver mutations may exist and their blockade may be beneficial as well. Next-Generation Sequencing (NGS) can accurately reveal more actionable genomic alterations than standard diagnostic methods, when performed either upfront, in reflex to initial diagnostic negative results or at treatment failure. However, limited data exists regarding the true influence of these tests on clinical decisions in lung cancer. This retrospective study includes 101 sequential stage IV lung cancer patients (predominantly adenocarcinoma), that were electively profiled with tumor somatic capture-based NGS between November, 2011 and October, 2015 at the Davidoff Cancer Center, Rabin Medical Center, Israel. Demographic data, clinico-pathologic characteristics and treatment outcomes were collected. 101 sequential advanced lung cancer patients who performed capture-based NGS (median age – 63 years, 53% females, 45% never smokers, 85% adenocarcinoma) were included. NGS was performed upfront or following previous negative/non-conclusive EGFR/ALK testing in 15% and 85% of patients, respectively. 50% of patients performed NGS before 1st line therapy and 50% after treatment failure. One or more actionable genomic alterations were found by NGS in 83% of the patients, with most common genes affected being KRAS (15.1%), EGFR (13.7%), STK11 (6.2%), ALK (5.5%), RET (5.5%), ERBB2 (4.8%) and MET (4.8%). Seventeen patients were diagnosed with an EGFR/ALK aberration after previous negative/false approved standard molecular testing. NGS testing resulted in a change in treatment strategy in 42 patients (42%). With targeted treatment based on the NGS results, overall response rate was 64.3% (complete response rate – 23.8%, partial response rate – 40.5%, stable disease – 9.5%). Survival analysis is not matured yet. This study indicates that NGS is crucial in lung adenocarcinoma with a decision change in almost half of the patients in spite of previous molecular testing. It also reassures the >60% response rate for targeted therapies in lung cancer, which will probably translate into a survival benefit in the future.

The aim of this study was to compare reproductive factors, use of oral contraceptives (OC) and hormone replacement therapy (HRT) in consecutive Jewish Ashkenazi breast cancer patients, with and without BRCA1/BRCA2 mutations. Jewish Israeli women with breast cancer (n=385) were genotyped for the three predominant Jewish mutations in BRCA1 and BRCA2, and data on reproductive factors, OC and HRT use, were analyzed using logistic regression analyses. Overall, 28/385 (7.3%) of participants were mutation carriers, the majority of whom were Ashkenazi (n=22; 78.6%) and were diagnosed with breast cancer at or under age 49 years (n=18; 64.3%). Mutation carriers were more likely than non-carriers to ever use OC (39.3% vs. 20.2%; P=0.053), HRT (35.7% vs. 13.7%; P=0.007), and have first menarche at or below 12 years of age (71.4% vs. 40.6%; P=0.03). Multivariate analysis showed that Ashkenazi women diagnosed with breast cancer under 40 years of age, with a family history of breast/ovarian cancer, who ever used HRT were more likely to be mutation carriers. This study has shown that HRT use is more prevalent among Jewish Ashkenazi mutation carriers, but its role in modifying breast cancer risk in mutation carriers remains unknown.

BAT is an immune-activating monoclonal antibody produced against Daudi cell membranes and selected for stimulating lymphocyte proliferation. The anti-tumor activity of BAT is related to its immunostimulatory properties. Both T and NK cells mediate the anti-tumor activity of BAT. CD4-positive T cells respond to BAT activation by proliferation and INF-gamma production. The aim of the study was to assess the probability that the BAT monoclonal antibody binding capacity to T cells is a marker for different cancers. Human peripheral blood T cells from colon, breast and prostate cancer patients, as well as healthy volunteer donors, were tested for the percentage of binding to BAT mAb (BAT/CD3 cells) by FACS analysis. All patients were tested before undergoing surgery or treatment, and their diagnosis was confirmed by histology. The results showed that the percentage of BAT monoclonal antibody binding to CD3-positive T cells in the peripheral blood was different in cancer patients with diverse tumor types. We found that lymphocytes from the blood of healthy donors contained 25% BAT/CD3 cells. In colon and breast cancer patients, a significant decrease to 13 and 11% of BAT/CD3 cells was found. In contrast, these cells increased ><50% in patients with prostate cancer. These findings may have a potential diagnostic significance and also assist in the evaluation of strategies for the therapeutic use of BAT for different cancer patients.

OBJECTIVES: Two APC germline mutations, E1317Q and I1307K, have been linked to colorectal cancer (CRC) risk. Whereas the I1307K variant is almost exclusively encountered in (Ashkenazi) Jews, E1317Q is not restricted to certain ethnic populations. Data on its contribution to CRC risk in Jewish patients are sparse.AIMS: To assess the contribution of E1317Q to CRC development in the Jewish population.METHODS: A total of 538 consecutive Israeli Jewish CRC patients and 440 controls were genotyped for E1317Q. In addition, the rate of the I1307K APC missense mutation and the two predominant Jewish mutations in hMSH2, A636P, and 324delCA, associated with hereditary nonpolyposis colon cancer (HNPCC), were determined.RESULTS: The E13117Q missense mutation was detected in 6/538 (1%) of CRC patients and 5/440 (1%) of controls. The I1307K variant was found in 8% of all patients and in 11% (35/322) of patients of Ashkenazi Jewish descent. Carriers and noncarrier CRC patients did not differ in age of onset or associated colonic adenomatous polyps. The carrier rate among controls was 5% among Ashkenazim and 1.6% among non-Ashkenazi individuals. The 324delCA hMSH2 mutation was not observed in this cohort, and 4 of 322 Ashkenazi patients (1.2%) displayed the A636P mutation.CONCLUSION: In Jewish CRC patients the E1317Q variant plays little if any role in colorectal cancer susceptibility and genetic testing for this variant is not warranted. The I1307K mutation is associated with a moderate excess risk for CRC, but age of onset seems not to be earlier and this variant is not associated with a multiple colonic polyp phenotype. Founder mutations in hMSH2 are rare in consecutive CRC patients.

While genetic factors clearly play a key role in colorectal cancer (CRC) pathogenesis and in determining its phenotypic features, the precise genes that involved are largely unknown. To gain insight into these genes, consecutive Israeli CRC patients were genotyped using SNPs from within candidate genes: APC, beta-Catenin, K-RAS, DCC, P16, PTEN, RB1, P15, APOE, ERCC2, P53, MTHFR and hMSH2. Genotyping of consecutive, unselected colorectal cancer patients was done mostly by utilizing the MassARRAY technology (Sequenom) and to a lesser extent DGGE, ARMS and direct DNA sequencing. Correlation of genotypes with specific phenotypic features was carried out for all patients and separately for the Ashkenazim. Overall, 456 patients were analyzed, the majority (64.25%) being of Ashkenazi origin; mean age at diagnosis was 65.6 +/- 14 (range 25-90 years), and the mean follow-up was 4.7 +/- 0.28 (range 0-30 years). Statistically significant associations were noted between SNPs in beta-catenin and APOE and a positive family history of cancer (beta-catenin: p=0.034, APOE: p=0.033); tumor location and a DCC SNP (p=0.038) and the P53 R72P mutation and survival (p=0.0336). In Ashkenazi patients, ERCC2 and MTHFR genes' SNPs were associated with age at diagnosis (ERCC2: p=0.025, MTHFR: p=0.0005); a P53 polymorphism, APOE and Rb SNPs with a family history of cancer (P53 p=0.034;APOE p=0.04, Rb p= 0.022); DCC SNP with tumor location (p=0.014); and p15 SNP with tumor grade (p=0.032). This preliminary study shows that genetic factors play a role in determining CRC phenotypic features and that a larger cohort with longer follow-up is clearly needed.

BACKGROUND:The precise genes involved in conferring prostate cancer risk in sporadic and familial cases are not fully known. OBJECTIVES:To evaluate the genetic profile within several candidate genes of unselected prostate cancer cases and to correlate this profile with disease parameters. METHODS:Jewish Israeli prostate cancer patients (n = 224) were genotyped for polymorphisms within candidate genes: p53, ER, VDR, GSTT1, CYP1A1, GSTP1, GSTM1, EPHX and HPC2/ELAC2, followed by analysis of the genotype with relevant clinical and pathologic parameters. RESULTS:The EPHX gene His113 allele was detected in 21.4% (33/154) of patients in whom disease was diagnosed above 61 years, compared with 5.7% (4/70) in earlier onset disease (P < 0.001). Within the group of late-onset disease, the same allele was noted in 5.5% (2/36) with grade I tumors compared with 18% (34/188) with grade II and up (P = 0.004). All other tested polymorphisms were not associated with a distinct clinical or pathologic feature in a statistically significant manner. CONCLUSIONS:In Israeli prostate cancer patients, the EPHX His113 allele is seemingly associated with a more advanced, late-onset disease. These preliminary data need to be confirmed by a larger and more ethnically diverse study.

Familial colorectal cancer (CRC) is noted in about 15% of incident CRC cases, and at times is hallmarked by an age at diagnosis less than 50 years. Familial adenomatous polyposis (FAP) and hereditary non-polyposis colon cancer (HNPCC) account for about 40% of familial cases. Thus, the majority of familial and early-onset CRC remain genetically elusive. Similarly, the majority of familial and early onset endometrial cancer (EC), the most prevalent extracolonic tumor in HNPCC, are genetically undefined. An attractive candidate is the hMSH6 gene. Israeli patients with early onset (age under 50 years) (n = 44) and familial nonsyndromic (n = 23) CRC, and women with familial clustering of EC or CRC (n = 12), and those diagnosed with EC at, or under, the age of 50 years (n = 5) were genotyped for germ-line mutations within the hMSH6 gene. Exon-specific PCR was followed by denaturing gradient gel electrophoresis (DGGE) analysis, complemented by DNA sequencing of abnormally migrating fragments. No patients displayed a truncating mutation, and 1 CRC patient harbored a novel missense mutation (V878A). In addition, 6 previously described polymorphisms were detected. In conclusion, mutations in the hMSH6 gene occur uncommonly in Israeli patients with familial and early-onset CRC and EC.

The I1307K APC germline mutation is associated with an increased risk to colo-rectal cancer (CRC). Whether and to what extent the phenotype of CRC in mutation carriers differs from sporadic cases, remains unknown. To gain insight into this issue, we analysed 307 unselected Israeli patients with CRC, who were treated in a single medical centre, for harbouring the I1307K mutation. Twenty-eight mutation carriers (9.1%) were detected. Two of 28 mutation carriers (7.1%) and 93/277 (33.6%) of non-carriers, were of non-Ashkenazi origin (P< 0.01). In 74/278 (26.6%) of the sporadic cases, and only 1/28 (3.6%) of mutation carriers (3.6%) the tumour was located in the right colon (P< 0.01). Mutation carriers had a more advanced disease stage (14/28 – 50% Dukes C), as compared with 60 (19.5%) of non-carriers (P= 0.02). The mean age at diagnosis was similar: 65 (+/– 9.7) years and 66.3 (+/– 11.6) years, for mutation carriers and non-carriers, respectively. No statistical differences were noted between the two groups in sex distribution, tumour grade, and family history of cancer. We conclude that early age at diagnosis and family history of cancer cannot be used to predict who is likely to harbour the I1307K APC germline mutation carriers. However, the tumours in patients with this mutation appear different than those without, are less likely to be proximal and more likely to be advanced than tumours in non-carriers. © 2001 Cancer Research Campaign http://www.bjcancer.com

Inherited predisposition occurs in 5–10% of all gastrointestinal (GI) cancer patients, but with the exception of colorectal cancer (CRC), the genes involved in conferring genetic susceptibility remain largely unknown. Indirect evidence indicates that germline mutations in BRCA2 might be associated with an increased risk for various GI malignancies. A single mutation (6174delT) occurs in the BRCA2 gene in high-risk breast ovarian cancer families of Jewish Ashkenazi origin, in about 1% of the general Ashkenazi population, and rarely in non-Ashkenazi Jews. In order to assess the contribution of this germline mutation to non-CRC GI cancer in Jewish Israeli patients, we tested 70 unselected, consecutive Jewish Ashkenazi patients with gastrointestinal malignancies for this mutation by PCR amplification and modified restriction enzyme digests. Patients’ age range was 38–90 years (mean 65.8±11.8 years). The most common malignancies were gastric cancer (n = 35) and exocrine pancreatic cancer (n = 23). Overall, 6 mutation carriers were detected: 3/23 (13%) of the patients with pancreatic cancer, 2/35 (5.7%) of patients with gastric cancer and 1/4 (25%) of patients with bile duct cancer. The 8.6% mutation carrier rate among patients is a rate significantly higher than that of the general Ashkenazi population (1.16%P = 0.0002). We conclude that the rate of the predominant Jewish BRCA2 mutation in patients with gastric and pancreatic cancer significantly differ from that of the general population of the same ethnic origin. Thus, BRCA2 mutations probably contribute to gastrointestinal tumorigenesis other then colon cancer, and the surveillance scheme for mutation carriers should incorporate this information. © 2001 Cancer Research Campaign

The genetic basis for the majority of early onset or non-syndromic ‘familial’ colorectal cancer (CRC) is unknown. Attenuated APC phenotype is characterized by relatively few colonic polyps, early age at onset of colon cancer compared with the general population, and inactivating germline mutations within specific regions of the APC gene. We hypothesized that germline mutations within these APC gene regions, might contribute to early onset or familial CRC susceptibility. To test this notion, we analysed 85 Israeli patients with either early onset (< 50 years at diagnosis) or familial CRC for harbouring mutations within the relevant APC gene regions: exons 1–5, exon 9 and a region within exon 15 (spanning nucleotides c.3900 to c.4034; codons 1294 to 1338) using denaturing gradient gel electrophoresis (DGGE), and all of exon 15 employing protein truncation test (PTT). No inactivating, disease-associated mutations were detected in any patient. A novel polymorphism in intron 5 was detected in 16 individuals, 8 patients were carriers of the 11307K variant, a mutation prevalent among Jewish individuals with colorectal cancer, and 4 displayed the E1317Q variant. We conclude that in Israeli individuals with early onset or familial CRC, truncating mutations in the APC gene regions associated with attenuated APC phenotype probably contribute little to disease pathogenesis. © 2001 Cancer Research Campaign http://www.bjcancer.com

Objectives: To describe the clinical parameters of low PSA, progressive metastatic androgen-independent prostate cancer.Methods: From April 1995 to May 1999, we selected 18 patients with clinically progressive androgen-independent prostate cancer and low PSA (less than or equal to 10 ng/ml). Patients received cisplatin based therapy. Specimens from the primary tumor were reviewed and neuroendocrine differentiation was determined with chromogranin-A and neuron-specific enolase immunocytochemical staining.Results: The median initial PSA level was 1.6 ng/ml (0-9.5). Each patient demonstrated elevation of at least one of the following markers: carcinoembryonic antigen, CA 19-9, CA 15-3 a nd CA 125 CA. Metastases involved bone in 11 patients (61.1%) - 5 (27.7%) blastic, 2 (11.1%) lytic, and 4 (22.2%) combined - liver in 10 patients (55.5%), lymph nodes in 8 (44.4%), and lung in 6 (33.3%); solitary sites as orbit, skin and spleen were noted as well. A prostatic pelvic mass was detected in 13 patients (72.2%). Of the 12 patients who consented to chemotherapy, 8 (66.6%) achieved an objective response (95% Cl, 34.8-90%), including 1 patient with complete response. Hematoxylin and eosin evaluation revealed two major groups: neuroendocrine tumors, either pure small cell cancer in 6 patients (37.5%) or combined small cell cancer and adenocarcinoma in 8 (50%), and predominant poorly differentiated prostate cancer in 2 (12.5%). Neuroendocrine immunoreactivity was detected in all the specimens.Conclusions: Progressive androgen-independent prostate cancer with low serum PSA is characterized by visceral metastases, high proportion of lytic bone disease, sensitivity to cisplatin-based chemotherapy, and histological features of small cell or poorly differentiated prostate cancer. In this subgroup of patients, selection of the therapeutic approach can be based on clinical parameters. The rise of the serum markers may aid in the diagnosis and follow-up of these patients. Copyright (C) 2000 S. Karger AG. Basel.

Objective To assess whether there is a decrease in endometrial thickness following discontinuation of tamoxifen treatment as measured by ultrasound.Design Prospective study.Setting Department of Obstetrics and Gynaecology, Sapir Medical Centre, Kfar-Saba, Israel. Population Fifty-eight postmenopausal women with breast cancer who were treated with tamoxifen.Methods Transvaginal ultrasonographic measurements of endometrial thickness.Main outcome measures Evaluation of the changes of endometrial thickness and the frequency the endometrium reached a thickness of less than or equal to 5 mm at different time intervals after stopping tamoxifen treatment.Results There was a significant decrease in median thickness of the endometrium, within six months after stopping tamoxifen, from 7.75 mm measured at the last ultrasonographic study performed before tamoxifen discontinuation down to 5.2 mm (P = 0.002). There were no further reductions in endometrial thickness, and it remained constantly low in subsequent ultrasonographic studies which were performed at various times up to 30 months following the discontinuation of tamoxifen treatment. While taking tamoxifen, only 25.9% of the women had an endometrial thickness of less than or equal to 5 mm, This proportion doubled in their first six months after stopping.Conclusions Median thickness of endometrial thickness significantly reduced within six months following tamoxifen discontinuation, and remained constantly low thereafter. This finding may support use of ultrasonographic imaging for the measurement of tamoxifen's effect on the endometrium of postmenopausal breast cancer patients.

Objectives: Recent trials with modern chemotherapy have demonstrated activity in androgen–independent prostate cancer, but all focused on patients with progression following androgen suppression or antiandrogen withdrawal. Limited data are available on the activity of chemotherapy in androgen–independent, hormone–refractory (progressing following adrenal suppression) prostate cancer. We evaluated the activity of estramustine combined with vinblastine in this subset of androgen–independent prostate cancer.Methods: From January 1995 until April 1999, 19 patients with hormone–refractory prostate cancer received estramustine 140 mg p.o., three times daily along with weekly vinblastine 5 mg/m2.Results: A decrease in prostate–specific antigen of 50% or more was noted in 12 patients (63.1%, 95% CI 38.3–83.7%). The median decrease in prostate–specific antigen was 71.2% (range 50.5–85.2%). None of the 7 patients with measurable soft–tissue disease showed an objective response. The median survival from onset of chemotherapy was 6 (range 1.4–27.7) months and from initiation of adrenal suppression 16.9 (range 3.8–40.5) months.Conclusions: The combination of estramustine and vinblastine is capable of inducing activity in androgen–independent prostate cancer progressing after adrenal suppression. In our small sample, the survival rate was low, and we obtained no response in soft–tissue sites. Future prospective trials are needed to determine the benefit of sequential versus simultaneous incorporation of adrenal suppression with chemotherapy in the management of androgen–independent prostate cancer.

AIMS: To evaluate whether endometrial pathology is more likely to be diagnosed in gynaecologically symptomatic rather than in gynaecologically asymptomatic postmenopausal breast cancer patients with tamoxifen treatment; and to evaluate the possible influence of various clinical factors on the incidence of endometrial pathology. METHODS: Endometrial histological findings, transvaginal ultrasonographic endometrial thickness, demographic characteristics, health habits, and risk factors for endometrial cancer were compared between 14 gynaecologically symptomatic (group I) and 224 gynaecologically asymptomatic (group II) postmenopausal breast cancer patients with tamoxifen treatment. RESULTS: Overall, 28.6% of the study population had endometrial pathology. The incidence of overall positive endometrial histological findings was significantly higher in group I than in group II (92.9% v 24.6%, p < 0.0001). Atrophic endometrium was more common in group II than in group I (75.3% v 7.1%, p < 0.0001). Most other endometrial pathology was significantly more common in group I than in group II (endometrial hyperplasia, 35.7% v 5.6%, p < 0.0001; endometrial polyps, 35.7% v 13.4%, p < 0.0111; endometrial carcinoma, 21.5% v 0.9%, p < 0.0001). Endometrial pathology appeared considerably later in the gynaecologically asymptomatic patients than in gynaecologically symptomatic patients (p = 0.0002). Vaginal bleeding or spotting occurred exclusively in group I. The incidence of endometrial pathology in the entire study population was consistent with that reported elsewhere, and higher than that reported for healthy postmenopausal women. CONCLUSIONS: Endometrial pathology is more likely to be diagnosed in gynaecologically symptomatic postmenopausal breast cancer patients with tamoxifen treatment, and after a shorter duration of time, than in gynaecologically asymptomatic patients.

OBJECTIVE The aim of this study was to evaluate changes in transvaginal ultrasonographic endometrial thickness with increased duration of tamoxifen treatment in postmenopausal breast cancer patients. MATERIAL AND METHODS In this prospective study we evaluated the changes (mean +/- SD) of endometrial thickness measured by transvaginal ultrasonography in 181 postmenopausal breast cancer patients, according to the duration of tamoxifen treatment. According to our protocol, the ultrasonographic evaluations were performed every 6 months for the first 2 years of the follow-up and every 12 months thereafter. Two such subsequent ultrasonographic evaluations were performed in 181 patients following 35.1 +/- 41.7 months of tamoxifen treatment, three studies in 127 patients following 44.7 +/- 47.98 months of treatment, four studies in 75 following 54.2 +/- 61.7 months of treatment, five studies in 51 patients following 65.3 +/- 74.4 months of treatment, and six studies in 27 patients following 79.5 +/- 98.8 months of treatment. RESULTS The measured endometrial thickness detected varied from 8.84 +/- 4.66 to 10.61 +/- 12.35 mm. There were no significant changes in mean +/- SD of endometrial thickness following various durations of tamoxifen treatment. CONCLUSIONS Extension of duration of tamoxifen treatment in postmenopausal breast cancer patients up to 79.48 +/- 98.79 consecutive months does not cause a significant increase in transvaginal ultrasonographic endometrial thickness.

The treatment of metastatic urothelial cancer is based on the combination of cisplatin, methotrexate, vinblastine and adriamycin (M-VAC). From November 1994 to May 1997 we treated 25 patients (51 men, 3 women, aged 50-77) with M-VAC. The tumor originated from the urinary bladder in 14 (56%) and the upper urinary tract in 11 (44%). Disease sites included: primary--5 (25%), lymph nodes--17 (68%), lungs--10 (40%), bones--8 (32%), pelvic mass and liver each--4 (16%), with an overall median of 2 (1-5) sites per patient. 9 patients (38%) had complete responses and 8 (32%) had partial responses, for an overall response rate of 68% (95% CI 48.5%-85%). The median duration of response was 15.3 (1.6-29.6+) months. Median survival of responders was 19.1 (4.8-35.7+) months compared to 6.2 (0.7-11.2) for the non-responders (p < 0.05). 13 (52%) of patients are alive, of whom 8 (32%) are free of disease and 5 with a single metastatic site on presentation at follow-up. In the 118 treatment cycles we observed grade III-IV toxicity: myelosuppression 53 (45%), thrombocytopenia 4 (3%), stomatitis 8 (6.7%), diarrhea 3 (2.5%). There were 22 infectious episodes and 1 patient died of sepsis. We achieved a high response rate with the combination M-VAC. However, only a third had long-term disease-free states and treatment was associated with excessive toxicity. Therapeutic approaches with new agents are required to improve the response rate and toxicity.

OBJECTIVES:To determine whether the antiandrogen withdrawal syndrome occurs with the steroidal antiandrogen cyproterone acetate.METHODS:Cyproterone acetate was withheld in 12 patients with progressing androgen-independent metastatic prostate cancer. Eight patients had been receiving cyproterone acetate concomitant with androgen ablation, and in 4 patients it was prescribed after failure of androgen suppression. Time to response and to disease progression were defined by serum prostate-specific antigen (PSA) levels and imaging studies.RESULTS:PSA levels decreased in 5 of the 1 2 patients; in 4 of them (33%), the decrease exceeded 50%. The decline lasted a median of 24 weeks (range 9 to 37.8). All 5 patients had received initial concomitant exposure to androgen ablation and cyproterone acetate.CONCLUSIONS:We recommend that the steroidal antiandrogen cyproterone acetate be added to the list of agents capable of inducing antiandrogen withdrawal syndrome.