The different impact of BRCA mutations on the survival of epithelial ovarian cancer patients: a retrospective single-center experience.

OBJECTIVES: The objective of this study was to examine whether the oncologic outcomes of BRCA1-associated and BRCA2-associated ovarian cancers correlate differently. METHODS: Genetic data and clinical characteristics were correlated with progression-free survival (PFS) and overall survival (OS). RESULTS: Data from 147 BRCA-mutated patients (119 BRCA1-positive and 28 BRCA2-positive) were analyzed. At a median follow-up of 69 months, the median PFS was 27.2 and 45.46 months for BRCA1 and BRCA2 patients, respectively (p = 0.03). Median OS was 77.23 and 111.47 months for BRCA1 and BRCA2 patients, respectively (p = 0.08). CONCLUSION: BRCA2 mutations confer PFS and a trend to OS advantage compared with the BRCA1 mutation in BRCA-mutated epithelial ovarian cancer patients.

A comparative study of p53 gene mutations, protein accumulation, and response to cisplatin-based chemotherapy in advanced ovarian carcinoma.

The p53 protein is a multifunctional transcriptional regulator involved in cellular response to DNA damage and has been implicated as a putative determinant of sensitivity of tumor cells to cytotoxic agents. Since the p53 gene becomes inactivated in over one-half of advanced ovarian carcinoma, in this study we have examined the relationships between p53 gene alterations, p53 immunoreactivity, and response to cisplatin-based chemotherapy in ovarian cancer patients. All patients had advanced (FIGO stage III or IV) ovarian carcinoma and, with one exception, were untreated at the time of collection of tumor specimens. After initial debulking surgery, patients received high-dose cisplatin therapy. Tumor samples were analyzed for p53 gene mutations and for p53 protein accumulation, and the findings were correlated with tumor responsiveness. Of the 33 tumors examined, p53 gene mutations were found in 20 cases, including 15 missense mutations, 2 deletions, 2 nonsense mutations, and a base substitution at splice site. Twenty tumors showed positive immunostaining for p53. Only missense mutations were associated with positive immunostaining. In addition, p53 overexpression was detected in five tumors in the absence of mutations. Most (12 of 14) of the missense mutations associated with p53 protein stabilization were found refractory to therapy, as well as tumors overexpressing wild-type p53 (4 of 5). A significant correlation has been found between p53 accumulation, type of mutation (i.e., missense mutations), and pathological response to cisplatin-based therapy. In conclusion, the present results are consistent with a role of p53 as a determinant of chemosensitivity of ovarian carcinoma.

Screening for mutations in exon 11 of the BRCA1 gene in 70 Italian breast and ovarian cancer patients by protein truncation test.

The most common mutations in the familial breast and ovarian cancer susceptibility gene BRCA1 are frameshift and nonsense mutations, which lead to the synthesis of truncated proteins. On this ground, we have analysed BRCA1 exon 11, which includes about 61% of coding region, in germline DNA from 70 Italian breast and/or ovarian cancer patients, using the protein truncation test (PTT). BRCA1 mutations were identified in nine of 29 (approximately 31%) patients with a family history of cancer and in three of 41 (approximately 7%) women with early-onset breast carcinomas, and were subsequently characterized by sequence analysis. In addition, BRCA1 mutations were also detected in six affected relatives of two positive index cases. The observed frequencies of mutations were not significantly different from those expected on the basis of the phenotypic characteristics of patients and their families, indicating that PTT is a rapid and sensitive method that can be used for a first BRCA1 mutational screening. The histological findings in BRCA1 mutated cases showed that eight of nine (approximately 89%) breast carcinomas were of grade III and nine of 9 (100%) ovarian carcinomas were of the endometrioid type (eight of grade III and one of grade II). This suggests that specific histological characteristics may represent additional criteria for selection of cases eligible to BRCA1 mutational analysis.

Efficacy and safety of high-dose cisplatin and cyclophosphamide with glutathione protection in the treatment of bulky advanced epithelial ovarian cancer.

Recent efforts to improve the response rates in advanced ovarian cancer with the use of high-dose cisplatin have been limited by unacceptable toxicity. Based on experimental and clinical studies indicating that reduced glutathione (GSH) is a protective agent against cisplatin-induced toxicity, a new high-dose regimen including GSH as a chemoprotector was designed in an attempt to improve the efficacy and therapeutic index of cisplatin. A total of 40 consecutive patients with stage III (bulky) and IV ovarian carcinoma were treated with cisplatin (40 mg/m2 daily for 4 consecutive days) and cyclophosphamide (600 mg/m2 i.v. on day 4). The treatment was repeated every 3-4 weeks for five courses unless progression or severe toxicity occurred. Before each cisplatin administration, patients received GSH (1,500 mg/m2) i.v. over 15 min, with a standard i.v. hydration (2,000 ml fluid) without diuretics. Debulking surgery was initially attempted in 18 patients and, after 2-3 courses, in 16 patients; it could not be carried out in 6 patients. Three patients were not evaluable for response because they prematurely discontinued their treatment. In all, 23 patients (62%) achieved complete clinical remission (negative second-look laparotomy in 16), with an overall (complete + partial) response rate of 86%; 2 patients achieved disease-free status following second surgery. Nausea/vomiting was the most severe acute toxic effect; myelosuppression was acceptable. Renal impairment was effectively prevented by GSH. Neurotoxicity that was not associated with motor dysfunction was the most significant cumulative toxicity in patients (24/32) receiving 4-5 courses. The results of this study indicate that the use of GSH is a safe new method for high-dose cisplatin administration. This regimen is well-tolerated and very effective in ovarian cancer patients with bulky disease and warrants further evaluation.

Intraperitoneal hyperthermic perfusion (IPHP).

Intraperitoneal hyperthermic perfusion (IPHP) with a solution that contains CDDP (25 mg/m(2)/l) and MMC (3.3 mg/m(2)/l) was clinically introduced in the treatment of peritoneal carcinomatosis. Twenty-six patients underwent surgical treatment and IPHP. Peritoneal carcinomatosis was classified at laparotomy using the Japanese classification: P1 (n=3), P2 (n=5), P3 (n=15), unclassifiable (n=3). In this series of patients only the creatinine and amylase values were significant in biological toxicity evaluation. The surgical complication rate (2 duodenal fistulas) does not differ from the general extensive abdominal surgery.

A feasibility study of cisplatin administration with low-volume hydration and glutathione protection in the treatment of ovarian carcinoma.

Glutathione (GSH) is a sulfur-containing nucleophile that protects against cisplatin-induced renal toxicity without reducing the antitumor activity of the cytotoxic agent. To document further the clinical role of GSH in improving the outcome of cisplatin-containing regimens, the feasibility of the GSH/cisplatin combination using a low-volume hydration protocol was evaluated in untreated ovarian cancer patients. Twelve patients at stage III (minimal residual disease) and 23 with localized disease at high risk for recurrence were treated with cisplatin (90 mg/m2, i.v. in 250 ml of normal saline over 30 min) and cyclophosphamide (600 mg/m2 i.v.) every 3 weeks. GSH (5 g in 200 ml of normal saline) was administered by a short-term infusion (15 min) prior to cisplatin. The hydration protocol consisted of 1 liter of fluids without diuretics. The treatment was well tolerated; no nephrotoxic or neurotoxic manifestations were observed. The renal excretion of cisplatin (23%) at 24 hours following infusion was lower than expected using a standard i.v. hydration protocol. No reduction of renal elimination of cisplatin could be detected in subsequent courses, thus suggesting a minimal degree of impairment in renal function. In the series of evaluable patients (11) with stage III disease, 9 had complete pathological response. In the series of patients with no clinically detectable disease initially, all were disease-free at treatment completion. Taken together with previous observations, these results support the view that the use of GSH is a successful approach in the attempt to optimize cisplatin treatment, providing a new modality of drug administration for out-patient treatment.

First-line chemotherapy with intraperitoneal cisplatin and intravenous cyclophosphamide in ovarian carcinoma. A preliminary report.

Between August 1982 and October 1986, the feasibility and activity of five cycles of intraperitoneal (i.p.) cisplatin (CDDP) (90 mg/m2 in 6 h dwelling) and i.v. cyclophosphamide (600 mg/m2) were studied in 24 previously untreated patients with ovarian carcinoma having small or no residual disease after cytoreductive surgery. Six patients (25%) had local complications requiring catheter removal before the end of therapy. Fifteen of the 21 patients (71%) evaluable for activity achieved or maintained a pathologic complete remission. The median disease-free survival was 29+ months (range 18-58+ months). Three patients with tumor progression (two patients previously without evidence of disease, and one patient with minimal residual disease), and three partial responders were documented by laparotomy at the end of therapy. Two patients who achieved pathologic complete response relapsed at 20 and 36 months. All treatment failures (eight cases, 38%) occurred in the peritoneal cavity. Since patients were selected for having the most favorable tumor characteristics to benefit from i.p. treatment, our findings may cast some doubt on the actual contribution of i.p. CDDP at a dose of 90 mg/m2 in the treatment of patients with ovarian carcinoma and small residual disease in the peritoneal cavity.

Cisplatin and cyclophosphamide in advanced ovarian carcinoma: activity and toxicity of an ambulatory regimen.

Chemotherapy with cisplatin (CDDP, 90 mg/m2) and cyclophosphamide (CTX, 600 mg/m2) was administered to 54 consecutive patients with advanced epithelial ovarian cancer (37 stage III and 17 stage IV). In 51 patients, surgery was performed prior to chemotherapy. Of the 37 stage III patients, 13 had only minimal residual disease after surgical debulking. The overall response rate was 69%, with 44% patients achieving clinical (cCR; n = 2) or pathological (pCR; n = 20) complete response. Median follow-up and overall survival time was 26 months, and median CR duration was 30 months. CR was achieved in 6 of 14 patients (43%) who were partial responders after five cycles of chemotherapy and had continued treatment for three to five more cycles. Severe bone marrow toxicity or renal function impairment was never observed, but eight patients presented peripheral signs of dose-related neurotoxicity. These findings indicate that CDDP and CTX in combination are an effective treatment for patients with advanced ovarian carcinoma, and can be administered with tolerable toxicity. In selected cases, prolonged chemotherapy administration can result in durable complete remissions.

BMRI in early detection of breast cancer in patients with increased genetic risk: our preliminary results.

Because of the higher risk of developing breast cancer and the early onset of the disease in women proved or suspected to be carriers of a breast cancer susceptibility gene, a dedicated screening should be offered as a less invasive approach with respect to the otherwise suggested prophylactic mastectomy. This should be optimized in order to overcome the limitations of conventional breast imaging with the application of new technologies such as Breast Magnetic Resonance Imaging (BMRI). A diagnostic protocol for routine control in patients with high risk for developing breast cancer has been prepared. Within a 7 months period, 23 patients suspected or proved to carry a breast cancer susceptibility gene underwent BMRI. Four breast cancers were identified with BMRI. In these cases mammography was negative because of the density of the parenchyma or for its fibroglandular pattern. US was negative in two cases, not specific for malignancy in one case and considered as only possibly malignant but with biopsy recommendation on the basis of MR findings in the last one. Clinic analysis was positive for mass in two cases. The accuracy of BMRI is known to be higher than that of conventional imaging in the study of breast parenchyma. High spatial resolution and no breast density influence can give more detailed information about smaller lesions and the right extent of the disease.

The Italian multi-centre project on evaluation of MRI and other imaging modalities in early detection of breast cancer in subjects at high genetic risk.

This report presents the preliminary results of the first phase (21 months) of a multi-centre, non-randomised, prospective study, aimed at evaluating the effectiveness of contrast-enhanced magnetic resonance imaging (MRI), X-ray mammography (XM) and ultrasound (US) in early diagnosis of breast cancer (BC) in subjects at high genetic risk. This Italian national trial (coordinated by the Istituto Superiore di Sanità, Rome) so far recruited 105 women (mean age 46.0 years; median age 51.0; age range 25-77 years), who were either proven BRCA1 or BRCA2 mutation carriers or had a 1 in 2 probability of being carriers (40/105 with a previous personal history of BC). Eight cases of breast carcinomas were detected in the trial (mean age 55.3 years, median age 52.5; age range 35-70 years; five with previous personal history of BC). All trial-detected BC cases (8/8) were identified by MRI, while XM and US correctly classified only one. MRI had one false positive case, XM and US none. Seven "MRI-only" detected cancers (4 invasive, 3 in situ) occurred in both pre- (n = 2) and post-menopausal (n = 5) women. With respect to the current XM screening programmes addressed to women in the age range 50-69 years, the global incidence of BC in the trial (7.6%) was over ten-fold higher. The cost per "MRI-only" detected cancer in this particular category of subjects at high genetic risk was substantially lower than that of an XM-detected cancer in the general women population. These preliminary results confirmed that MRI is a very useful tool to screen subjects at high genetic risk for breast carcinoma, not only in pre-, but also in post-menopausal age, with a low probability of false positive cases.

Pilot study with adjuvant hormone therapy in FIGO stage I endometrial carcinoma with myometrial invasion.

A pilot study with adjuvant hormone therapy in FIGO stage I endometrial carcinoma with myometrial invasion was carried out. All patients received total abdominal hysterectomy and bilateral salpingo-oophorectomy plus complementary radium therapy on the vaginal stump. After the conventional treatment, patients were randomly allocated to adjuvant hormone therapy or no further treatment. Hormone therapy consisted of gestonorone caproate (17 alpha-hydroxy-19-norpregn-4-en 3, 20 dione caproate) administered i.m. at the dose of 200 mg/week for 1 year. Of the 62 patients who entered the study, 51 were considered evaluable (24 with adjuvant hormone therapy and 27 with no further treatment). Five patients had a relapse: four of these were in the group with no further treatment. Actuarial relapse-free survival analysis at 5 years was 95.7% in the group of adjuvant-treated patients and 82.8% in the control group. Although there is no statistical significance, adjuvant therapy appears to result in an increase in relapse-free survival in the group of patients with deep myometrial invasion and undifferentiated carcinoma. Further studies are necessary to assess the effectiveness of hormone adjuvant treatment in FIGO stage I endometrial carcinoma with myometrial invasion.

A preliminary clinical experience with reduced glutathione as protector against cisplatin-toxicity.

A total of 16 consecutive patients (15 with ovarian cancer and 1 with unknown adenocarcinoma) were treated with a standard regimen including cisplatin and cyclophosphamide or with the same regimen in combination with reduced glutathione as potential protective agent against cisplatin nephrotoxicity, in a non-randomized study. Reduced glutathione (1500 mg/m2) was administered prior to each cisplatin administration (90 mg/m2) to seven patients for a maximum of five consecutive courses. A standard hydration protocol without diuretics was used. The patients received a total of 33 courses with glutathione. Glutathione was well tolerated, since it did not produce appreciable side effects. Cisplatin and glutathione combination did not produce unexpected toxicity. Two patients treated with standard regimen without glutathione developed a transient nephrotoxicity. The severity of myelosuppression was reduced following glutathione administration. Moreover, the therapeutic efficacy was not impaired by glutathione pretreatment.

Adjuvant treatment with melphalan in ovarian carcinoma with no residual disease following surgery.

Forty-nine patients classified after surgery and complete non-surgical restaging as "no residual disease" were treated with adjuvant chemotherapy. Thirty-nine patients had ovarian carcinoma and 10 borderline tumors. All patients had geographic inaccessibility. Domiciliary treatment with melphalan at the dose of 10 mg/day p.o. for 5 consecutive days every 4 weeks for 12 cycles was used. Within 6 months from the end of adjuvant treatment a second restaging with peritoneoscopy and peritoneal cytology was performed. The median administered dose of melphalan was 575 mg. No patient with a borderline tumor relapsed. Nine patients with ovarian carcinoma relapsed (23%): 4/10 at stage II-III and 5/29 (17%) at stage I. The relapse-free survival at 96 months was 77% for stage I patients and 73% for all patients. The overall survival was 87% for stage I patients and 81% for all patients. Mild myelo-depression was evident in 65% of patients. No case of acute nonlymphocytic leukemia was observed.

Peripheral neurotoxicity following high-dose cisplatin with glutathione: clinical and neurophysiological assessment.

The use of high-dose cisplatin is limited by development of severe peripheral neurotoxicity and gradual worsening of renal function. In an ongoing study of high-dose cisplatin glutathione has been employed with the aim of preventing major cisplatin-induced toxicities. Neurotoxicity was examined in detail in 32 patients with ovarian cancer treated with cisplatin (160 mg/m2) and cyclophosphamide (600 mg/m2) every 3-4 weeks for five courses. In addition to serial complete neurological examination, sensory action potentials (SAPs) and motor conduction velocities (MCVs) were also assessed. We confirmed the development of a predominant sensory involvement, characterized by mild distal paresthesias and decrease in vibratory sensibility and in deep tendon reflexes, with a slight reduction of SAPs, observed after three courses of treatment. After five courses, distal paresthesias and disesthesias, decreased proprioception and loss of vibratory sensibility with ataxic signs, absence of deep tendon reflexes, unobtainable SAPs and only moderately reduced MCVs were seen. We did not observe any case of disabling neuropathy. There was a tendency to a more severe involvement of peripheral nerves in patients aged more than fifty. The 3 patients presenting the most serious neuropathy were the oldest in the whole group. Low degree of neurotoxicity observed in this study supports a glutathione protection against cisplatin-induced neurotoxicity. As the urinary excretion of platinum indicated no changes in the renal clearance of cisplatin following repeated courses, the lack of drug accumulation and high plasma peak due to preserved renal function might explain the reduced neurotoxicity observed.

Laparoscopy combined with peritoneal cytology in staging and restaging ovarian carcinoma.

The merits of laparoscopy, with inspection of the diaphragmatic leaves, and of peritoneal cytology (free fluid or washing) in staging and restaging were studied in 153 patients with ovarian carcinoma. Of 153 patients examined, 83 were new cases, 34 were restaging in patients without clinical and/or radiological signs of disease, and 36 in patients with evident disease. The conversion rate for diaphragmatic metastases alone was 6%. Information about the spread of disease (diaphragmatic metastases) was obtained in 33 new cases (39.7%). In pretreated patients, laparoscopy was positive in 4 of 34 NED restaging and in 24 of 36 ED restaging. The conversion rate for peritoneal cytology was 6.6%, but information about the cellular intraperitoneal spread of the disease was obtained in 31 new cases (37.8%). In pretreated patients, peritoneal cytology was positive in 4 of 34 NED restaging and in 13 of 36 ED restaging.

Hormonal and receptor status in postmenopausal women with endometrial carcinoma before and after treatment with tamoxifen.

Twenty-four patients with endometrial carcinoma received tamoxifen (Nolvadex) for 7 days. Before and after administration, circulating hormones (estradiol, testosterone, progesterone, gonadotropins FSH and LH) were evaluated. Estrogen (ER) and progesterone receptors (PgR) in neoplastic tissue were also assayed. Our results show a net increase in PgR content and a significant decrease in gonadotropin levels after the treatment. The authors suggest that clinical trials be conducted using tamoxifen and progestins for adjuvant therapy after surgery of endometrial carcinoma and for the therapeutic approach of advanced carcinoma.

An intensive treatment with mitoxantrone and ifosfamide in second-line therapy of epithelial ovarian cancer.

AIMS AND BACKGROUND: Both mitoxantrone (DHAD) and ifosfamide (IFO) have given promising results when administered as single agents in advanced ovarian cancer pretreated with platinum compounds. The aim of this I.T.M.O. group pilot trial was to evaluate, in a selected population of ovarian cancer patients, the efficacy and tolerability of the following intensive second-line regimen: DHAD, 12 mg/m2 i.v., day 1; IFO, 4,000 mg/m2 i.v., days 1 and 2; Mesna, 800 mg/m2 i.v. t.i.d., days 1 and 2. Filgrastim (5 micrograms/kg/day i.m.) was given from day 6 to day 19 to reduce the expected neutropenia. Cycles were repeated every 21 days. METHODS: Nineteen platinum-pretreated patients were enrolled and 14 were evaluated for tumor response; the disease of 5 patients was not measurable clinically or radiologically. RESULTS: Seven responses were observed (3 CRs), with a median response duration of 5 months. The median time to treatment failure and overall survival for all 19 patients was respectively 8 and 13 months. Anemia was observed in all of the treated patients (grade 3-4 in 9 cases). Only 6 of the 19 patients ended the five planned cycles of chemotherapy without any delay. CONCLUSIONS: Although DHAD plus IFO induced a considerable number of objective responses, the limited response duration time to treatment failure, and overall survival as well as the reported side effects suggest that this is not a recommended regimen for the palliative treatment of ovarian cancer patients undergoing second-line chemotherapy.

Adult granulosa cell tumor of the ovary: a clinico pathologic study of 35 cases.

AIMS AND BACKGROUND: Adult granulosa cell tumor has a low malignant potential but requires an extensive follow-up of more than 5 years to accurately assess tumor activity. The aim of the present study was to evaluate the clinical characteristics, the treatment and the outcome of this rare ovarian tumor. STUDY DESIGN: A retrospective review of 35 cases treated at primary onset of disease during a 23-year period from 1971 to 1993. RESULTS: The disease-free survival rate for stages IA-B-C at 5 and 10 years was 90% and 84%, respectively; for stages III-IV the 5-year freedom from progression rate was 16%. CONCLUSIONS: The most important prognostic factor appears to be the extent of tumor involvement outside of the ovary.

Color-Doppler ultrasound in ovarian masses: anatomo-pathologic correlation.

BACKGROUND AND AIMS: In the radiologic assessment of ovarian masses, the major difficulty consists in the late recognition and lack of parameters for a differential diagnosis between benign and malignant lesions, especially in the post-menopause when the incidence of cancer is higher. The use of a transvaginal probe and the color-Doppler examination have recently improved the study of the female pelvis. This study is aimed to verify the possibility of the color-Doppler imaging to differentiate between malignant and benign ovarian lesions during transvaginal echographies, on the basis of the qualitative and quantitative characteristics of the vascular pattern of the ovarian lesions. RESULTS: Twenty-six expansive ovarian lesions were studied: 8/26 showed no vascular signals and were considered benign as confirmed at histology. In the remaining lesions with some vascularization, the resistance index (RI) was evaluated: those with RI > 0.40 were considered benign, those with RI < 0.40 malignant. In 8/9 benign lesions and 7/9 malignant neoplasms, the results of color-Doppler were coherent with histology. The results showed a sensibility of 87.5% and a specificity of 88.8% for the transvaginal examination. CONCLUSIONS: The main advantages of the color-Doppler transvaginal examination are: the high frequency of visualization of the ovaries, even in postmenopausal patients; the definition of small lesions; the visualization of small parenchymal vessels, both physiologic and pathologic, and their quantitative analysis. The importance of the RI cutoff was critical for the differential diagnosis between benign and malignant lesions; we think that a cutoff of 0.50, instead of 0.40 proposed by other authors, would be far more appropriate.