BRCA mutations and outcome in epithelial ovarian cancer (EOC): experience in ethnically diverse groups.

BACKGROUND: Epithelial ovarian cancer (EOC) patients with BRCA mutations have better prognosis than nonhereditary cases matched for histology and stage and age at diagnosis, especially Ashkenazi Jews (AJ). MATERIALS AND METHODS: We retrospectively reviewed data on 700 highly ethnically heterogeneous patients diagnosed with stage Ic-IV EOC and evaluated for BRCA status between 1995 and 2009 in American, Israeli, and Italian medical centers. RESULTS: The ethnicities of the 190 patients (median age 55.5 years, range 31-83 years) were AJ, Jewish non-Ashkenazi, Caucasian, African-American, Hispanic, or unknown. Ninety were BRCA1/2 carriers (71 BRCA1 and 19BRCA2). The most common mutations in AJ and non-AJ origins were 185delAG and 6174delT. Non-Jewish Caucasians exhibited the widest variation (>20 mutation subtypes). BRCA carriers had significantly prolonged median overall survival (93.6 months) compared with noncarriers (66.6 months; 95% confidence interval 44.5-91.7, P = 0.0081). There was no difference in progression-free survival. CONCLUSIONS: Our data demonstrate a wide variety of BRCA mutations in a highly ethnically diverse EOC population, and confirm that EOC BRCA mutation carriers have better prognosis with longer median survival than patients with nonhereditary disease. The contribution of unclassified BRCA variants to cancer etiology remains undetermined.

Rare presentation of endometrial carcinoma with singular bone metastasis.

The major symptom at diagnosis of endometrial cancer is post-menopausal bleeding; it is present in around 90% of cases. Singular bone metastasis is described as an uncommon site for endometrial cancer at diagnosis, showing in just 5-6% of cases. In this report we describe a rare presentation of a singular bone metastasis because of endometrial cancer of a woman with previous diagnosis of early breast cancer. A review of literature uncovered some cases of bone metastasis at presentation of endometrial cancer and that it can occur as first symptom of cancer before vaginal bleeding. This rare presentation of uterine cancer needs to be studied and described because it may be seen and needs a homogeneous treatment to improve survival.

Long-term survival in a randomized study of nonplatinum therapy versus platinum in advanced epithelial ovarian cancer.

The purpose of this study was to compare long-term survival in first-line chemotherapy with and without platinum in advanced-stage ovarian cancer. From July 1987 to November 1992, 161 untreated patients with FIGO stage III-IV epithelial ovarian cancer were randomized: 81 patients received no platinum and 80 received platinum combination. Residual disease after surgery was <2 cm in 61 patients without platinum, 59 with platinum. Median age was 58 years in nonplatinum arm and 55 years in platinum arm (range: 15-73). Complete and partial responses were 51% and 10% for nonplatinum arm and 51% and 8% for platinum arm, respectively (P= 0.7960). Stable disease was observed in 18% of patients in nonplatinum arm and 15% of patients in platinum arm and progression in 20% of nonplatinum- and 21% of platinum-treated cases. Ten-year disease-free survival was 37% for therapy without platinum and 31% for platinum combination (P= 0.5679); 10-year overall survival was 23% without platinum and 31% with platinum combination (P= 0.2545). Fifteen-year overall survival showed a trend of short duration in favor of platinum (P= 0.0678). Relapses occurred after 60 months in ten patients (seven with and three without platinum). The overall and disease-free survivals at 5, 10, and 15 years show no statistically significant long-term advantage from the addition of cisplatin; however, there is a slight trend in its favor.

Sertoli cell tumor: a rare case in an elderly patient.

Sertoli-Leydig cell tumors constitute < 1% of ovarian tumors, mostly in young women with virilization; however, not all present endocrine manifestations. A 72-year-old female presented with an abdominal mass and no signs of virilization. Total abdominal hysterectomy with bilateral salpingo-oophorectomy, omentectomy and selective pelvic lymphadenectomy was performed. The pathologic diagnosis was poorly-differentiated sex cord-stromal tumor with Sertoli cells. No adjuvant chemotherapy or radiation was administered. At 12-month follow-up the patient showed no evidence of disease.

Phase II study of pegylated liposomal doxorubicin and oxaliplatin in relapsed advanced ovarian cancer.

OBJECTIVE: This phase II study evaluated the efficacy and safety of pegylated liposomal doxorubicin (PLD) 30 to 35 mg/m(2) plus oxaliplatin 70 mg/m(2) every 28 days in women with advanced ovarian cancer that recurred or progressed after a platinum-based regimen. METHODS: 43 women received a median of 6 courses of treatment. RESULTS: Objective response was 54% in the evaluable population and was higher in women with platinum-sensitive (67%) compared with platinum-resistant disease (29%). At a median duration of follow-up of 15.5 months, median overall survival was 15.8 months and time to tumor progression 7.3 months. Most toxicity was no greater than grade 1 or 2. There was no grade 3 or 4 palmar-plantar erythrodysesthesia. After 264 cycles administered, neutropenia was the most common cause of severe toxicity and required one patient to withdraw from the study. No cardiotoxicity was reported. CONCLUSION: PLD plus oxaliplatin is active and well tolerated in women with relapsed advanced ovarian cancer, regardless of platinum sensitivity.

A Randomized Study of Epithelial Ovarian Cancer: Is Chemotherapy Useful after Complete Remission?

Objective. The aim of this study is to verify whether consolidation chemotherapy with Cisplatin improves disease-free survival and/or overall survival in patients affected by epithelial ovarian cancer.Methods. A multicenter study examined 122 randomized patients in complete remission as judged by laparoscopy or laparotomy following first-line chemotherapy consisting of ACy (Adriamycin + Cyclophosphamide), PCy (Cisplatin + Cyclophosphamide), or Mitoxantrone + Carboplatin. Sixty-one of these patients were treated with 3 cycles of 5-Fluorouracil (FU) 500 mg/m2 for 5 days followed by Cisplatin at 100 mg/m2 on the 6th or 7th day every 28 days; the other 61 received no further treatment (nihil group).Results. Sixty patients in the Cisplatin arm were evaluable. There were 36 relapses in the FU+Cisplatin arm and 30 in the nihil arm. Peritoneal relapses were 25% for Cisplatin treatment vs. 16.4 % for nihil. There were 29 deaths in the Cisplatin arm vs. 27 for nihil. Median overall survival time (95 months with Cisplatin vs. 96 months in the nihil group) and median disease-free survival (66 months with Cisplatin vs. 73 in the nihil group) were similar in both arms (p=0.66 and p=0.41, respectively). There were no significant differences in tumor stage and grade between the two arms. Seven patients presented a second neoplasm during follow-up: six in the nihil arm, but only one patient in the Cisplatin arm. Death in these patients was due to the second neoplasm and not to progression of ovarian cancer.Conclusion. Three courses of additional platinum+FU treatment after five cycles of first-line chemotherapy without FU produced no increase in overall survival or disease-free survival.

Elderly ovarian cancer: treatment with mitoxantrone-carboplatin.

OBJECTIVE: Data concerning optimal treatment of elderly patients with ovarian cancer are scanty. The management of ovarian cancer in the aged patient is many-sided: the diagnosis can be difficult and delayed, and aggressive surgery is often not attempted because of concomitant morbidity. We tested a combination of carboplatin and mitoxantrone potentially associated with low toxicity in elderly patients with ovarian cancer. METHODS: Eighty-two patients older than 70 years (median age, 75; range, 70-88) with epithelial ovarian cancer were referred to our multicenter group and enrolled into this pilot study. Carboplatin (JM8) was given at the dose of 230 mg/m2 and mitoxantrone at the dose of 9 mg/m2 every 28 days. RESULTS: Dose-limiting toxicity was represented by 4 cases of thrombocytopenia and 1 case of gastrointestinal toxicity. These 5 episodes occurred in 328 assessable cycles, representing a low toxicity profile (3%). Of the 68 assessable patients, 36 (53%) did not respond to chemotherapy (no change + progressive disease), complete response was observed in 15 (22%), and partial remission was observed in 16 (23.5%), accounting for an overall response rate of 45%. CONCLUSION: The carboplatin-mitoxantrone combination, at the dosage tested in this study, appears to be well tolerated by elderly patients with advanced ovarian cancer and is associated with an acceptable response rate. Optimally debulked patients also showed improved survival when compared with patients with more extensive tumor.

BRCA-1 and BRCA-2 mutations as prognostic factors in clinical practice and genetic counselling.

Women in general have a 10% risk of developing breast cancer and a 2-3% chance of ovarian cancer in their life-times. Mutations in BRCA-1 and BRCA-2 are present in only a small portion (5-10%) of all breast cancers. Carriers of mutations in these genes have a greater risk of cancer, especially before menopause in the case of BRCA-1 carriers. In addition, their risk of contralateral breast cancer is significantly higher than for the general population (4.2-53% vs. 2%). The grade of contralateral tumours in these patients is more aggressive. BRCA-2 hereditary breast cancer seems more heterogeneous than the BRCA-1 phenotype, and not clearly different from sporadic forms. However, since 20-30% of carriers of BRCA mutations never develop breast or ovarian cancer, there must be other 'risk modifiers'. Survival is better for carriers of hereditary ovarian cancer. Patients with these mutations are referred for genetic counselling, a complex process which includes: an informative dialogue between the proband and the geneticist, drawing up a family history, informed consent, evaluation of risk, genetic testing and possible involvement of healthy family members.

Pharmacokinetics of intraperitoneal hyperthermic perfusion with mitoxantrone in ovarian cancer.

PURPOSE: Theoretical data and experimental assumptions indicate that intraperitoneal hyperthermic chemotherapy may play a role in the treatment of peritoneal carcinomatosis. The feasibility, tolerability and pharmacokinetics of intraperitoneal hyperthermic perfusion with mitoxantrone were studied in patients with pretreated ovarian cancer. METHODS: After cytoreductive surgery, 11 patients underwent intraperitoneal hyperthermic perfusion with mitoxantrone. A heated (42-43 degrees C) solution of the drug (28 mg/m2) was recycled through a perfusion apparatus into the abdominal cavity for 90 min. Treatment was repeated every month for two to four cycles. In six patients blood and peritoneal perfusate samples were collected at 0.5, 1, 1.5, 2, 4, 8, 16 and 24 h after drug administration and mitoxantrone was assayed by an HPLC method. RESULTS: Although treatment was generally well tolerated, all patients developed transient intestinal subocclusion. Maximal mitoxantrone plasma concentrations (Cmax), times to Cmax (Tpeak) and area under the curves (AUC) were highly variable between subjects (Cmax 14-337 ng/ml; Tpeak 0.5-8 h; AUC 222-4130 ng x ml(-1) x h). The plasma to peritoneal fluid AUC ratio was significantly higher during the second (0.177) than during the first cycle (0.066), suggesting a cycle-dependent increase in systemic bioavailability. Furthermore, when comparing present data with those reported previously, hyperthermic perfusion may have lowered the mitoxantrone levels in the peritoneal fluid without greatly influencing plasma levels. CONCLUSIONS: Intraperitoneal mitoxantrone administered under hyperthermia to advanced ovarian cancer patients is feasible and well tolerated. Mitoxantrone pharmacokinetics may be altered by repeated intraperitoneal administration (increased bioavailability) and by hyperthermic perfusion (possibly, increased peritoneal tissue uptake).

Surgical second look in ovarian cancer: a randomized study in patients with laparoscopic complete remission--a Northeastern Oncology Cooperative Group-Ovarian Cancer Cooperative Group Study.

PURPOSE: The usefulness of extensive and repetitive surgery for patients with ovarian cancer still remains unproven (at least for some conditions). We planned an accurate prospective test of the hypothesis that patients with advanced-stage disease, after they had reached a clinical complete remission (CR), may benefit from surgical second look (SSL). PATIENTS AND METHODS: One hundred two patients in CR (as assessed by clinical findings, markers, and visualization by computed tomographic [CT] scan and laparoscopy), after initial debulking and first-line chemotherapy, were randomized to two arms, which were well balanced for predictive criteria such as age, stage at presentation, histology, grading, date of randomization, and residua after first surgery. Forty-eight patients were randomly assigned to receive follow-up evaluation only, while 54 were assigned to receive second surgery (eight of them refused). Of 46 surgical patients, 35 had negative and 11 positive surgical findings (24% clinically false-negative). RESULTS: Despite the microscopic residua found at open surgery, and the fact that the patients were then treated with second-line chemotherapy, SSL did not increase the probability of survival in this setting. In an analysis of the results according to the intention-to-treat criteria, after a 60-month follow-up period, the overall survival rates in the two groups of patients (SSL v no SSL) were 65% and 78%, respectively (P = .14). Multivariate analysis according to predictive criteria confirmed there was no significant difference between the two groups (P = .39). CONCLUSION: Our study shows the following: (1) our second-line treatment is scarcely effective; (2) SSL accurately defines complete responders to first-line chemotherapy; (3) SSL per se does not prolong survival; and (4) if confirmed, a less invasive procedure could replace SSL as a valuable method in new first-line regimens in ovarian cancer patients with clinical CR confirmed by laparoscopy.

Combined use of urinary UGP and serum CA 125 in the diagnosis of gynecological cancers.

UGP, the beta-core fragment of human chorionic gonadotropin has been proposed as a tumor marker for gynecological malignancies. This fragment may be detected in a single morning-specimen of urine using an enzyme immunoassay. In this study, the diagnostic usefulness of urine UGP and serum CA 125 measurement for gynecological neoplasias (149 cases) was evaluated using a control group of patients with benign gynecological diseases (69 cases) and healthy females (99 cases). Considering the neoplastic patients in comparison to patients with benign diseases, the best diagnostic efficiency (78%) was found to correspond to a cut-off level of 120 pmol/mol creatinine the sensitivity being 73% and the specificity 90%. With this cut-off, an efficiency of 82% for healthy controls was obtained. Since the menopausal condition increases UGP levels, and though no significant difference for UGP was found between healthy subjects and patients with benign diseases, we decided to consider the reference populations as a single group. Thus, we evaluated the UGP performance on the basis of menopausal status. When a specificity of 95% was fixed, the cut-off values were 120 and 180 pmol/mol creatinine for pre- and postmenopausal women respectively, the sensitivity being 73% and 64%. Finally the combined evaluation of UGP and CA 125 improved their individual clinical efficiency for the diagnosis of ovarian serous cystadenocarcinomas, assuring a sensitivity of 86% and a specificity of 89%.

Continuous mitoxantrone infusion in pretreated epithelial ovarian cancer.

Mitoxantrone has shown moderate activity in advanced epithelial ovarian cancer following intermittent i.v. administration. Experiments and clinical data suggest that long-term continuous drug infusion may achieve a better therapeutic result with less toxicity. This hypothesis was tested in patients with advanced ovarian cancer who had been pretreated with other agents. Mitoxantrone was infused continuously in 21-day courses beginning every 6 weeks. If severe toxicity did not occur, the infusion rate was increased by 0.1-0.2 mg/m2 per day. The mitoxantrone solution proved to be stable over the 21-day infusion period. For ethical reasons an optimal two-stage design was employed. The trial was interrupted at the end of the first recruitment stage because the target of 3 responses out of 13 patients had not been achieved (only 1 patient had a partial response). Hematologic toxicity was observed in 11 patients, and 2 of them had a catheter occlusion. In conclusion, we found that 21-day of infusion of mitoxantrone apparently has no clinical benefit as compared with bolus administration in patients with advanced ovarian cancer.

Phase I-II intraperitoneal mitoxantrone in advanced pretreated ovarian cancer.

36 previously treated patients (25 with anthracyclines) with advanced epithelial ovarian cancer have been treated with intraperitoneal (i.p.) mitoxantrone (M) at increasing doses. The response was evaluated through repeated laparoscopy with multiple biopsies and serial measurement of Ovarian Cancer Antigen 125 (CA 125); 11/36 patients had a complete (6 patients) or partial (5 patients) response. Toxicity (both local and general) was observed starting from 25 mg/m2 of M per cycle. The amount of drug reaching systemic circulation was monitored by measuring M plasma value after i.p. treatment. This study showed wide variations in serum levels obtained after i.p. doses ranging from 23 to 36 mg/m2. The area under the curve (AUC) of mitoxantrone plasma samples, did not correlate with the i.p. administered dose. Conversely, a correlation seems to exist between the plasma AUC and the responder status. Patients who showed clinical responses to i.p. treatment with mitoxantrone had AUCs and plasma peak levels of the drug that were significantly higher than those in non-responders (P = 0.03, Fisher's exact test).

Experience with intraperitoneal alpha-2a interferon.

Eighteen patients affected with epithelial ovarian cancer have been treated by intraperitoneal alpha 2a-Interferon. The usual single dosage was 54 x 10(6) U at weekly intervals for four times (eight times in responders): 10 histologically confirmed complete remissions and 3 partial remissions have been obtained; the toxicity was represented by fever in the majority of the cases, by abdominal discomfort in some cases, and by a mild transitory neurological complication in 1 case. Seventeen of 18 patients were pretreated, and 11 of 18 had only cytologic and/or microscopic disease. alpha 2a-Interferon has proven to be very effective and moderately toxic in microscopic peritoneal disease of ovarian epithelial cancer previously treated with extensive surgery and intravenous cytotoxic chemotherapy.