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.

Proteasome inhibition with bortezomib (PS-341): a phase I study with pharmacodynamic end points using a day 1 and day 4 schedule in a 14-day cycle.

PURPOSE: We performed a phase I study of a day (D) 1 and D4 bortezomib administration once every 2 weeks to determine the recommended phase II dose and toxicity profile, and the extent of 20S proteasome inhibition obtained. PATIENTS AND METHODS: Patients with solid tumors or lymphomas were treated with bortezomib at 0.25 to 1.9 mg/m2 on D1 and D4, every 2 weeks. 20S proteasome levels in blood were assayed at baseline and at 1, 4, and 24 hours postdose in cycle 1. RESULTS: On this D1 and D4 every 2 weeks' schedule, dose-limiting toxicity (DLT) was evident at the 1.75 and 1.9 mg/m2 dose levels, most commonly in patients receiving individual total doses > or = 3.0 mg. The main DLT was peripheral neuropathy evident at the higher doses and in patients previously exposed to neurotoxic agents. Other DLTs included diarrhea and fatigue; grade 3 thrombocytopenia was also noted. Reversible inhibition of 20S proteasome activity was dose dependent and best fit a total dose (mg) per fraction rather than mg/m2; 70% of baseline activity was inhibited by a dose of 3.0 to 3.5 mg given on D1 and on D4 every other week. Antitumor effects short of confirmed partial responses were observed in patients with melanoma, non-small-cell lung cancer, and renal cell carcinoma. CONCLUSION: Bortezomib (PS-341) is a novel antineoplastic agent that is well tolerated at doses not exceeding 3.0 mg (equivalent to 1.75 mg/m2), repeated on D1 and D4 every other week. This dose correlates with 70% inhibition of 20S proteasome activity. DLTs include neuropathy, fatigue, and diarrhea.

Platinums: extending their therapeutic spectrum.

Three decades since the introduction of cisplatin into clinical cancer treatment, this drug and its second generation analogues, carboplatin and oxaliplatin, form an integral part of recent evolving achievements in the treatment of solid tumors. For example, landmark studies have established a role for cisplatin after resection in lung cancer, and improved survival from platinum-based chemoradiation in cancer of the uterine cervix and combination chemotherapy in mesothelioma, small cell lung, ovarian, and endometrial cancers. Colon cancer survival has improved with the addition of oxaliplatin to its treatment. Here we summarize how insights into the mechanism of action of platinum compounds and studies of their structure-activity relationships may identify platinums with unusual selectivity towards tumors such as melanoma, renal cell, and breast cancer and other cancers not usually treated with existing platinums. Both new drug development and mechanistic studies with established drugs should lead to the next generation of clinical studies with platinum compounds, and their integration with emerging 'targeted therapies'.

Sequential single agents as first-line chemotherapy for ovarian cancer: a strategy derived from the results of GOG-132.

First-line chemotherapy for ovarian cancer during the past decade has evolved toward the use of carboplatin and paclitaxel combinations. This has been based on randomized trials showing that combinations of these two drugs lead to a outcome similar to that obtained using cisplatin and paclitaxel (that had, in turn, proven superior in progression-free survival and overall survival to cisplatin and cyclophosphamide) but with less toxicity. Surprisingly, taxane-platinum combinations were not superior to control arms in two studies (ICON3 and GOG-132) utilizing carboplatin or cisplatin as the comparators. This has renewed interest in the role of single agents in first-line chemotherapy - a concept also supported by a number of prior clinical trials with single-agent platinum compounds yielding results not inferior to combinations. Early 'pre-emptive' crossover (prior to the stipulated clinical progression) to paclitaxel or a paclitaxel-containing regimen, however, occurred in 24% of patients initially treated with cisplatin on GOG-132. This has led to the interpretation of this trial as a combination versus sequential design. Although not subscribing to this interpretation, the results of GOG-132 and ICON3 not only raise doubts over a clear superiority of combinations over single agents but also lead to a consideration of sequential treatment designs for first line. Advantages of such designs are: (a) ability to provide 'dose-dense' platinums followed by 'dose-dense' paclitaxel and, perhaps, other drugs; and (b) the potential of acquiring biological data linked to the antitumor effects of a specific drug. Mathematical modeling and recent positive results in breast cancer adjuvant therapy support the use of 'dose-dense' strategies, and these should be considered in the design of future trials in ovarian cancer.

Complement activation following first exposure to pegylated liposomal doxorubicin (Doxil): possible role in hypersensitivity reactions.

BACKGROUND: Pegylated liposomal doxorubicin (Doxil) has been reported to cause immediate hypersensitivity reactions (HSRs) that cannot be explained as IgE-mediated (type I) allergy. Previous in vitro and animal studies indicated that activation of the complement (C) system might play a causal role in the process, a proposal that has not been tested in humans to date. PATIENTS AND METHODS: Patients with solid tumors (n = 29) treated for the first time with Doxil were evaluated for HSRs and concurrent C activation. HSRs were classified from mild to severe, while C activation was estimated by serial measurement of plasma C terminal complex (SC5b-9) levels. Increases in SC5b-9 were compared in patients with or without reactions, and were correlated with Doxil dose rate. RESULTS: Moderate to severe HSRs occurred in 45% of patients. Plasma SC5b-9 at 10 min after infusion was significantly elevated in 92% of reactor patients versus 56% in the non-reactor group, and the rise was greater in reactors than in non-reactors. We found significant association between C activation and HSRs, both showing direct correlation with the initial Doxil dose rate. CONCLUSIONS: C activation may play a key role in HSRs to Doxil. However, low-level C activation does not necessarily entail clinical symptoms, highlighting the probable involvement of further, as yet unidentified, amplification factors.

Role of complement activation in hypersensitivity reactions to doxil and hynic PEG liposomes: experimental and clinical studies.

Pegylated liposomal doxorubicin (Doxil) and 99mTc-HYNIC PEG liposomes (HPL) were reported earlier to cause hypersensitivity reactions (HSRs) in a substantial percentage of patients treated i.v. with these formulations. Here we report that (1) Doxil, HPL, pegylated phosphatidylethanolamine (PEG-PE)-containing empty liposomes matched with Doxil and HPL in size and lipid composition, and phosphatidylglycerol (PG)-containing negatively charged vesicles were potent C activators in human serum in vitro, whereas small neutral liposomes caused no C activation. (2) Doxil and other size-matched PEG-PE and/or PG-containing liposomes also caused massive cardiopulmonary distress with anaphylactoid shock in pigs via C activation, whereas equivalent neutral liposomes caused no hemodynamic changes. (3) A clinical study showed more frequent and greater C activation in patients displaying HSR than in non-reactive patients. These data suggest that liposome-induced HSRs in susceptible individuals may be due to C activation, which, in turn, is due to the presence of negatively charged PEG-PE in these vesicles.

Phase I and pharmacologic study of i.v. hydroxyurea infusion given with i.p. 5-fluoro-2'-deoxyuridine and leucovorin.

Preclinical data suggests that the action of fluoropyrimidines may be enhanced by the addition of hydroxyurea. We developed a phase I trial to determine the maximum tolerated dose and pharmacokinetics of i.v. hydroxyurea (HU) in combination with i.p. 5-fluoro-2'-deoxyuridine (FUdR) and leucovorin (LV). Eligible patients had metastatic carcinoma confined mostly to the peritoneal cavity, and adequate hepatic, renal and bone marrow function. Patients were treated with a fixed dose of FUdR (3 g) and LV (640 mg) administered on days 1--3. HU was administered as a 72-h infusion starting simultaneously with i.p. therapy on day 1. The following dose levels were studied: 2.0, 2.5, 3.0 and 3.6 g/m(2)/day. Pharmacokinetics were studied in blood and peritoneal fluid. Twenty-eight patients were accrued. Steady-state plasma and peritoneal fluid HU levels increased with increasing dose, and steady state was achieved within 12 h of continuous dosing. The steady-state HU plasma:peritoneal fluid concentration ratio ranged from 1.06 x 10(3) to 1.25 x 10(3) and the plasma HU clearance ranged from 4.63 to 5.81 l/h/m(2). Peritoneal fluid AUC = 137,639 +/- 43,914 microg/ml x min, t(1/2) = 100.9 +/- 56.4 min and Cl = 25.29 +/- 10.88 ml/min. Neutropenia represented the dose-limiting toxicity. We conclude that i.p. FUdR and LV in combination with i.v. HU is well tolerated. The addition of systemic HU increased the incidence of myelosuppression.

Liposomal encapsulated anthracyclines: new therapeutic horizons.

After two decades of work in liposomal formulations for clinical use, two preparations containing doxorubicin (Doxil, ALZA, Pablo Alto, CA; and Evacet, The Liposome Company, Princeton, NJ), and one containing daunorubicin (DaunoXome; Gilead Sciences, Foster City, CA) have been undergoing widespread clinical study. Results have lived up to the promise that liposomal encapsulation may lead to toxicity attenuation, while retaining or even enhancing the efficacy of the parent anthracyclines. The eventual role of these agents in clinical practice is being defined in a number of studies that are reviewed herein. Already, approved indications have been achieved for doxorubicin against Kaposi's sarcoma and ovarian cancers, and for daunorubicin against Kaposi's sarcoma. The three compounds vary widely in their pharmacology, and these differences may contribute to their preferential localization into certain tumors. Additional indications for these liposomal encapsulated anthracyclines are likely to be established in the ensuing years.

Treatment of patients with ovarian carcinoma with pegylated liposomal doxorubicin: analysis of toxicities and predictors of outcome.

BACKGROUND: Pegylated liposomal doxorubicin is a new formulation with activity against epithelial ovarian carcinoma (EOC). The authors sought to determine patient characteristics that may predict for response to this treatment and favorable time to failure as well as survival. METHODS: Eight patients in a Phase I study and 44 patients in two consecutive Phase II studies who were treated with pegylated liposomal doxorubicin (40-60 mg/m2 every 3 weeks for the first two cycles and 40 mg/m2 every 4 weeks thereafter) after failing initial platinum-based chemotherapies for ovarian carcinoma were analyzed. Associations were sought for response, time to failure (TTF), and survival after the treatment and various pretreatment characteristics. RESULTS: Treatment with pegylated liposomal doxorubicin yielded 23% objective responses in measurable disease and 31% overall responses, including serum CA 125-defined responses. The median TTF was 5.2 months (95% confidence interval, 4.1-6.9 months) in all patients, and the median response duration in all responders was 13.2 months (95% confidence interval, 11.9-18.5 months). The overall median survival was 15 months (95% confidence interval, 11-40 months). The main predictive factors were tumor size and baseline hemoglobin level for TTF, and these plus Karnofsky performance status were the main predictive factors for survival. CONCLUSIONS: Pegylated liposomal doxorubicin is an effective drug when it is given as secondary therapy to patients with EOC. Lack of bulky disease is the major predictor for a favorable response, TTF, and survival. The role of this treatment in combination with other effective drugs should be explored in both previously treated and untreated patients with ovarian carcinoma.

Challenges posed by non-random missing quality of life data in an advanced-stage colorectal cancer clinical trial.

Effects of variations in agent, dose, and route of treatment administration on patient reported quality of life (QOL) were examined for 279 patients enrolled on a seven-arm randomized clinical trial (S8905) of 5-FU and its modulation for advanced colorectal cancer. Patients completed QOL questionnaires at randomization and weeks 6, 11, and 21 post-randomization with five QOL endpoints considered primary: three treatment-specific symptoms (stomatitis, diarrhea, and hand/foot sensitivity); physical functioning; and emotional functioning. Patient compliance with the QOL assessment schedule was good, supporting the feasibility of including QOL measures in cooperative group trials. However, death and deteriorating health produced substantial missing data. Cross-sectional analyses indicated that the seven therapeutic arms did not differ in their impact on QOL. Unfortunately, longitudinal analyses of the QOL data were inappropriate given non-random missing data. Graphical presentation of non-random missing data identified the seriousness of this problem and its effect on potential conclusions about QOL during treatment. This problem appears to be particularly challenging in the context of advanced-stage disease. Failure to recognize the presence of non-random missing data can lead to serious overestimates of patient QOL over time.

Phase II study of liposomal doxorubicin in advanced gynecologic cancers.

OBJECTIVE: Pegylated liposomal doxorubicin (Doxil) may have enhanced therapeutic efficacy and reduced toxicity compared with the parent compound. This phase II study further evaluates the activity of Doxil in patients with ovarian cancer and explores activity in other gynecologic cancers. METHODS: Sixty-three patients were treated with Doxil 50 mg/m(2) infused over 1 h; 44 were evaluable. Forty-eight had epithelial ovarian cancer and all received prior treatment with cisplatin and paclitaxel: 27 received two to six prior regimens, 44 were platinum resistant, 21 patients had measurable disease, and 27 had evaluable disease only. RESULTS: The overall survival of these patients was 10 months (range, 0.25-33); progression-free survival was 3 months (range, 0.25-18). The response rate among those with measurable disease was 19%, with a median duration of 4.5 months (range, 3-12). The response rate of 22 patients with elevated CA-125 was 59%; median duration was 3.5 months (range, 1-12). Also, 27% achieved prolonged stabilization of disease for a median of 7 months (range, 5-18). Overall, treatment was well tolerated in this heavily pretreated population. Grade 3 and 4 toxic effects were: 5 grade 3 stomatitis, 3 grade 3 skin, 1 each grade 4 neutropenia and thrombocytopenia, 5 admits for infection, and no neutropenic fever; nausea and vomiting were uncommon in 204 cycles to ovarian cancer patients. CONCLUSION: This study demonstrates the activity of Doxil in heavily pretreated patients with ovarian cancer and poor prognostic features and confirms the prolonged responses and favorable toxicity profile. Encouraging findings were also observed in the patients with nonovarian gynecologic cancers.

Phase II study of combination taxol and estramustine phosphate in the treatment of recurrent glioblastoma multiforme.

Taxol has activity in the treatment of high grade gliomas but estramustine phosphate (EMP) has not been used in this setting. In vitro data demonstrates that EMP is cytotoxic to glioma cell lines and estramustine binding proteins are expressed by glioma cells. The combination of Taxol and EMP is reported to be active in the treatment of hormone-refractory prostate cancer and in taxane-resistant breast and ovarian cancer. We therefore performed a phase II study to assess the activity and toxicity of this combination in high grade gliomas. Taxol was given at a dose of 225 mg/m2 intravenously over three hours on day 1 and EMP was given at a dose of 900 mg/m2 orally on days 1 through 3. Cycles were repeated every three weeks. Twenty patients with recurrent glioblastoma multiforme (GBM) were enrolled: 11 male, median age 45 years. All patients received anti-epileptic medications and 17 (80%) had received prior chemotherapy. Of 18 evaluable patients, two had partial responses (11) and six had stable disease (33%) for a minimum of eight weeks. Treatment was well tolerated with grade 3 neutropenia occurring in only three patients. There were no other grade 3 or 4 toxicities. The median time to progression for the cohort was only six weeks (range 3-60+ weeks). The median overall survival was 12 weeks (range 3-60+ weeks). In conclusion, the combination of Taxol and EMP is well tolerated and has modest activity in the treatment of recurrent GBM.

BRCA1 germline mutation presenting as an adenocarcinoma of unknown primary.

BACKGROUND: The work-up of adenocarcinoma of unknown primary usually includes history, physical examination, radiographic imaging, tumor markers, and more recently molecular and genetic information. We report here on how the suggestion by family history of a BRCA1 mutation guided the diagnostic and therapeutic approach in a patient with metastatic carcinoma of unknown primary. METHODS: BRCA1 mutation was screened for by polymerase chain reaction (PCR) and single-strand conformational polymorphism analysis. Primers for PCR amplification included selected BRCA1 exons 2, 110, 11L, 13, and 20. The PCR product was cloned into a PCRII vector and sequenced with a Sequenase Version 2.0 Sequencing Kit. RESULTS: Single-strand conformational polymorphism analysis suggested a mutation in the region of exon 20 and sequencing confirmed the presence of a germline mutation 5382insC. CONCLUSIONS: This case illustrates an unusual presentation of adenocarcinoma of unknown primary in a patient with a germline BRCA1 mutation, the use of a suspected germline mutation to guide the work-up and treatment, and finally the value of positron emission tomography scanning in the work-up of an unknown primary.

Phase III randomized study of cisplatin versus paclitaxel versus cisplatin and paclitaxel in patients with suboptimal stage III or IV ovarian cancer: a gynecologic oncology group study.

PURPOSE: To assess progression-free survival (PFS) and overall survival (OS) in patients with suboptimally debulked epithelial ovarian cancer receiving cisplatin (100 mg/m(2)) or 24-hour infusion paclitaxel (200 mg/m(2)) or the combination of paclitaxel (135 mg/m(2)) followed by cisplatin (75 mg/m(2)). PATIENTS AND METHODS: After stratification for disease measurability, patients were randomized to receive six cycles of one of the treatments every 3 weeks. If measurable, complete response (CR) or partial response (PR) was determined. RESULTS: Six hundred fourteen of 648 patients who entered onto the trial were eligible. Monotherapies were discontinued more frequently (cisplatin because of toxicity or patient refusal [17%], and paclitaxel because of progression [20%]) compared with the combination therapy (7% and 6%, respectively). Neutropenia, fever, and alopecia were more severe with paclitaxel-containing regimens; whereas anemia, thrombocytopenia, neurotoxicity, nephrotoxicity, and gastrointestinal toxicity were more severe with cisplatin-containing regimens. The CR/PR rates on paclitaxel monotherapy were significantly lower compared with the cisplatin regimens (42% v 67%, respectively; P <.001). The relative hazard (RH) of first progression or death was significantly greater among those randomized to paclitaxel (RH = 1.41; 95% confidence interval [CI], 1.15 to 1.73; P <.001) when compared with cisplatin; however, RH did not differ significantly between the two cisplatin regimens (RH = 1.06; 95% CI, 0.895 to 1.30). Relative to cisplatin, the death rate on paclitaxel was 15% greater (RH = 1.15; 95% CI, 0. 929 to 1.42), and the death rate on the combination treatment was 1% less (RH = 0.99; 95% CI, 0.795 to 1.23). These differences among treatment groups were not statistically significant (P =.31). CONCLUSION: Cisplatin alone or in combination yielded superior response rates and PFS relative to paclitaxel. However, OS was similar in all three arms, and the combination therapy had a better toxicity profile. Therefore, the combination of cisplatin and paclitaxel remains the preferred initial treatment option.

Phase I trial of paclitaxel and etoposide for recurrent ovarian carcinoma: a Gynecologic Oncology Group Study.

A phase I study was performed to determine the maximum tolerated doses of intravenous etoposide and paclitaxel for women with previously treated persistent or recurrent ovarian cancer. Starting doses were paclitaxel 135 mg/m2 during 24 hours and etoposide 50 mg/m2/day for 3 consecutive days. The study was designed to escalate first the dose of etoposide, and then the dose of paclitaxel, in successive cohorts of patients. In an attempt to determine whether toxicity was affected by sequence of the drugs, the order of administration of the two drugs was reversed on alternate cycles. The starting doses of paclitaxel (135 mg/m2/24 hours) and etoposide (50 mg/m2/day x 3) caused severe neutropenia even with the addition of granulocyte colony-stimulating factor, and the trial was amended to administer the paclitaxel during 3 hours. However, this also proved too myelosuppressive without growth factor support. Twenty-one women were treated. A complete response was observed in one of nine patients with measurable disease, and a major decrease in CA-125 was noted in two patients who did not have measurable disease. Because of the severe myelosuppression observed in most patients, dose reduction was often required after the first cycle. The power to detect sequence-dependent variation in toxicity was minimal; however, no large differences were observed. A combination of the usual doses of these drugs will be difficult to administer in patients who have received previous chemotherapy for ovarian cancer.

Phase I study of AG 331, a novel thymidylate synthase inhibitor, in patients with refractory solid tumors.

PURPOSE: This was a phase I study of AG 331 to determine systemic tolerance and pharmacokinetics following single and multiple escalating intravenous doses. METHODS: The study was an open-label phase I trial that was divided into two components. In phase IA (single dose), six dose levels from 12.5 to 225 mg/m2 were administered to 18 patients (3 at each dose level) and serial blood samples were collected for 72 h. Upon achieving satisfactory pharmacologic parameters, the multiple dosing component (phase IB) was initiated. Six dose levels from 50 to 800 mg/m2 per day were administered for 5 consecutive days to 18 patients. Pre- and postdose blood samples were obtained on days 1-4 and serial blood samples were collected over 24 h following dose 5. Nonhematologic and hepatic toxicities were assessed, serum AG 331 concentrations were measured and pharmacokinetic parameters determined. RESULTS: Other than fatigue, no severe toxicities were encountered in phase IA. Liver toxicity was manifested by elevations in transaminase first noted at multiple doses of 200 mg/m2 per day for 5 days. Fever and malaise but no myelosuppression were noted. The mean terminal t1/2 following single doses was significantly shorter than the t1/2 following multiple dosing (6.8 vs 9.9 h) and clearance was significantly faster following single doses than following multiple dosing (81.7 vs 30.4 l/h), but no significant difference in Vd was noted. CONCLUSIONS: The dose-related toxicity profile precludes further clinical development at this time. The pharmacokinetics of AG 331 following single and multiple doses showed significant differences.