Mutational analysis of selected high-grade malignancies in a premenopausal gynecologic cancer population: a potential for targeted therapies?

Background: In 2017, there will be 107,000 cases of gynecologic cancer diagnosed in the US with an overall survival of around 70%-most occurring in post-menopausal individuals. In this study, we have examined a younger (≤ 40 years of age) subpopulation of these women with high grade/ high stage gynecologic malignancies, attempting to identify unique genetic abnormalities or combinations thereof through tissue block specimens. This information was then analyzed in light of known target therapies to see if genetic analysis in this setting would yield significant therapeutic advantage. Methods: We retrospectively evaluated patients with high grade/high stage gynecologic cancers (≤ 40 years of age), examined the presence and status of 400 oncogenes and tumors suppressor genes from Formalin-fixed, Paraffin-embedded (FFPE) tissue and functionally classified mutations by SIFT and Polyphen. Results: Twenty women were identified and stratified into positive and negative outcomes. No demographic, clinicopathologic or treatment factors were significant between these groups. Of the 400 genes evaluated, twelve mutations were significant between the groups, six with targeted therapies. Mutations associated with negative outcomes within histologies/locations were evaluated: ERBB3 in epithelial (ovarian), ALK/GPR124/KMT2D in neuroendocrine (ovarian/endometrial), ROS1/EGFR, ROS1/ERBB3/KMT2D/NIRK1 and GPR124 in sarcoma. All negative outcomes were void of mutations in APC/ABL2. A predictive model for negative outcomes in our cohort was developed from these data: AKAP9-/MBD1-/APC-/ABL2- with a mutation load of > 20.5. Conclusions: Unique multi-gene and mutational outcome correlations were identified in our cohort. Resulting complex mutational profiles in distinctly aggressive gynecologic cancers suggested potential for novel therapeutic treatment. Future larger scale studies will be needed to correlate the genotypic and phenotypic features identified here (AU)

New-onset congestive heart failure with gemcitabine in ovarian and other solid cancers.

OBJECTIVE: To assess clinical features that may predispose individuals taking gemcitabine to new-onset congestive heart failure. METHODS: A retrospective chart review was conducted with 156 female patients, 51 with ovarian cancer and 105 with breast, lung, pancreas, and bladder cancer, all of whom had received gemcitabine. Patients with new-onset congestive heart failure were compared with patients without new-onset congestive heart failure with the use of Wilcoxon rank-sum test for continuously distributed data and the Fisher exact test for proportions. RESULTS: Seven patients developed new-onset congestive heart failure (4.5%) during their treatment, which was significantly greater than that reported previously (0.76%). Patients with new-onset congestive heart failure did not differ from other patients in the study for age, weight, gravidity, parity, body mass index, and type of cancer. They also did not differ in history of myocardial infarction, hypertension, prior episodes of congestive heart failure, prior treatment with adriamycin, or use of tobacco. However, diabetes mellitus and coronary artery disease were more common, and all patients who developed new-onset congestive heart failure received >17,000 mg/m of gemcitabine. The incidence of new-onset congestive heart failure in this study is significantly higher than previously reported with the use of gemcitabine. CONCLUSIONS: The single-most predictive risk factor for new-onset congestive heart failure in this cohort of patients is the receipt of a minimum dose of 17,000 mg/m. Therefore, additional follow-up may be necessary for all patients receiving >15,000 mg/m of gemcitabine to screen for potential new-onset congestive heart failure.

Simultaneous occurrence of well differentiated papillary mesothelioma and endometrioid ovarian cancer: A case report.

► We present a case of endometrioid ovarian cancer with concomitant well differentiated papillary mesothelioma of the peritoneum. ► Endometrioid ovarian cancer with concomitant well differentiated papillary mesothelioma is an extremely rare surgical finding of uncertain prognostic significance. ► Treatment with carboplatin and gemcitabine was given with no evidence of disease six months after diagnosis.

Continuing routine cardiac surveillance in long-term use of pegylated liposomal doxorubicin: is it necessary?

OBJECTIVE: The objective of this study was to determine the cardiac safety of high cumulative doses of pegylated liposomal doxorubicin (PLD) in patients with gynecologic malignancies and the need for routine evaluation of left ventricular ejection fraction (LVEF). METHODS: Data were collected for all patients treated with PLD with at least one evaluation of LVEF with either Multi-Gated Acquisition (MUGA) scan or echocardiogram from January 2006 to May 2012. Evaluation of LVEF was used to detect PLD-related cardiac toxicity (defined as a decline in LVEF of greater than 10% compared to baseline measurements). RESULTS: A total of 141 patients were included. Twenty-two patients were treated with a cumulative dose of 500 mg/m(2) or more, and five patients with 1000 mg/m(2) or more. Ten patients (7%) had a reduction in LVEF of greater than 10%, 38 had no significant change or increase in LVEF throughout the duration of treatment, and 93 did not require a follow-up evaluation of LVEF. The LVEFs of two patients dropped below 50% at cumulative doses of 1110 mg/m(2) and 1670 mg/m(2); one began with a baseline of 52%. CONCLUSIONS: Only one patient had a clinically significant decrease in LVEF at a cumulative dose of 1670 mg/m(2), suggesting that PLD does not carry a significant risk of cardiotoxicity, as evidenced by the stability of LVEF even after treatment with large cumulative doses. Routine surveillance of LVEF does not seem to be necessary or cost effective in the absence of other risk factors.

A phase II evaluation of docetaxel and carboplatin followed by tumor volume directed pelvic plus or minus paraaortic irradiation for stage III endometrial cancer.

OBJECTIVE: To determine the feasibility and efficacy of administering docetaxel and carboplatin chemotherapy followed by tumor directed radiation in patients with advance stage endometrial cancer. METHODS: Patients with surgical stage III or IV (confined to the pelvis) endometrial cancer were eligible. Treatment consisted of six cycles of docetaxel (75 mg/m(2)) and carboplatin (AUC 6) followed by irradiation to the involved field (50.4 Gy pelvis ± 43.5 Gy paraaortic)±brachytherapy. Kaplan-Meier (KM) methods estimated overall survival (OS) and progression free survival (PFS). RESULTS: Forty-five patients were enrolled, 34 (76.0%) completed the prescribed therapy. Median age 63.5 (35-85 years). Stage IIIA 8 (17.8%), IIIB 1 (2.2%) and IIIC 36 (80.0%). 39/45 (86.7%) had endometroid histology. Serious grade 4 toxicities included 14 non-hematologic and 2 hematologic. Sixteen patients died following treatment, 6 from recurrent progressive cancer, with a median follow-up of 35.6 months (0.4-74.8). KM estimates and standard error (SE) for OS at 1 year were 84.5%, (5.4%), at 3 years, 65.8%, (7.2%) and at 5 years, 56.7%, (7.9%). Median overall survival was 74.5 months. Fourteen patients recurred with KM estimates and standard error (SE) for PFS at 1 year 77.8%, (6.2%) and 3 year 54.4%, (6.7%). Median progression free survival was 36.9 months. CONCLUSIONS: Docetaxel and carboplatin followed by tumor directed irradiation for advanced stage endometrial cancer has acceptable toxicity and efficacy that allows for this regimen to be considered a viable treatment option for these patients.

A multicenter, randomized, phase 2 clinical trial to evaluate the efficacy and safety of combination docetaxel and carboplatin and sequential therapy with docetaxel then carboplatin in patients with recurrent platinum-sensitive ovarian cancer.

BACKGROUND: The aim of this randomized clinical trial was to evaluate the efficacy and safety of combination (cDC) and sequential (sDC) weekly docetaxel and carboplatin in women with recurrent platinum-sensitive epithelial ovarian cancer (EOC). METHODS: Participants were randomized to either weekly docetaxel 30 mg/m(2) on days 1 and 8 and carboplatin area under the curve (AUC) = 6 on day 1, every 3 weeks or docetaxel 30 mg/m(2) on days 1 and 8, every 3 weeks for 6 cycles followed by carboplatin AUC = 6 on day 1, every 3 weeks for 6 cycles or until disease progression. The primary endpoint was measurable progression-free survival (PFS). RESULTS: Between January 2004 and March 2007, 150 participants were enrolled. The response rate was 55.4% and 43.2% for those treated with cDC and sDC, respectively. The median PFS was 13.7 months (95% confidence interval [CI], 9.9-16.8) for cDC and 8.4 months (95% CI, 7.1-11.0) for sDC. On the basis of an exploratory analysis, patients treated with sDC were at a 62% increased risk of disease progression compared to those treated with cDC (hazard ratio = 1.62; 95% CI, 1.08-2.45; P = .02). The median overall survival time was similar in both groups (33.2 and 30.1 months, P = .2). The incidence of grade 2 or 3 neurotoxicity and grade 3 or 4 neutropenia was higher with cDC than with sDC (11.7% vs 8.5%; 36.8% vs 11.3%). The sDC group demonstrated significant improvements in the Functional Assessment for Cancer Therapy-Ovarian, Quality of Life Trial Outcome Index scores compared with the combination cohort (P = .013). CONCLUSIONS: Both cDC and sDC regimens have activity in recurrent platinum-sensitive EOC with acceptable toxicity profiles. The cDC regimen may provide a PFS advantage over sDC.

Health-related quality of life outcomes of docetaxel/carboplatin combination therapy vs. sequential therapy with docetaxel then carboplatin in patients with relapsed, platinum-sensitive ovarian cancer: results from a randomized clinical trial.

OBJECTIVES: A phase II clinical trial compared docetaxel in combination with carboplatin to sequential single agent docetaxel followed by carboplatin for treatment of recurrent platinum-sensitive ovarian, peritoneal, or tubal cancer. This manuscript reports prospectively collected health-related quality of life (HRQL). METHODS: Participants were randomized to either weekly docetaxel 30 mg/m(2)/days 1 and 8 and carboplatin AUC 6/day 1 every 3 weeks (cDC) or docetaxel 30 mg/m(2)/days 1 and 8, repeated every 3 weeks for 6 cycles followed by carboplatin AUC 6/day 1 every 3 weeks for 6 cycles or until disease progression (sDC). The primary HRQL endpoint was the trial outcome index (TOI) score of the Functional Assessment of Cancer Therapy-Ovarian (FACT-O) instrument, and was assessed as an intent-to-treat analysis. The secondary HRQL endpoints included the FACT-O total score, the FACT-General, and several domain scores of the FACT-O instrument (physical well-being (PWB), social/family well-being (SWB), emotional well-being (EWB), functional well-being (FWB), and the ovarian cancer specific (OCS) module). The FACT-O was administered at randomization, prior to each of 6 cycles of treatment, and at study endpoint. RESULTS: One hundred forty-eight participants were randomized to each group. Sequential docetaxel followed by carboplatin (sDC) was associated with significant improvements in the FACT-O TOI (p=0.013), FACT-O total score (p=0.033), and OCS (p=0.029) compared to the combination docetaxel and carboplatin group (cDC). CONCLUSIONS: Sequential single agent docetaxel followed by carboplatin is associated with improved HRQL when compared to cDC. The improved progression-free survival observed with cDC should be weighed against lower quality of life during treatment.

A phase I-II trial of weekly topotecan in the treatment of recurrent cervical carcinoma.

In recent phase III studies, intravenous topotecan (0.75 mg/m(2)) plus cisplatin demonstrated significant progression-free and overall-survival benefits in patients with advanced and recurrent cervical cancer. However, the regimen demonstrated clinically significant myelotoxicity. The current study was undertaken to examine the safety, tolerability, and efficacy of weekly bolus topotecan in patients with advanced or metastatic disease. All patients had biopsy-confirmed disease not amenable to radiation treatment or surgery. Lesions were measurable bidimensionally, and patients had adequate hematologic, hepatic, and renal function. Patients received 3.5 mg/m(2) topotecan intravenously on days 1, 8, and 15 of a 28-day cycle. If no grade 3 or 4 hematologic toxicities occurred, the dose was escalated to 4 mg/m(2) in the third cycle. Safety, tolerability, and response rates were the primary endpoints. In addition to weekly hematologic assessments, Eastern Cooperative Oncology Group status was evaluated monthly, and tumor response was evaluated every alternate cycle. Twenty patients were enrolled and evaluated for toxicity and tumor response. Grade 3 toxicity occurred in 8/48 (17%) treatment cycles. There was only one drug-related adverse toxicity that required a dose reduction. Grade 1/2 hematologic toxicities were rare and only accounted for 1 (2%) of the dose delays (1 week). Two (10%) patients achieved stable disease for a mean of 5.3 months. The weekly bolus topotecan regimen used in the current study was well tolerated. Future phase II studies of weekly bolus topotecan in combination with cisplatin in this patient population may be warranted.

Closure of long surgical incisions with a new formulation of 2-octylcyanoacrylate tissue adhesive versus commercially available methods.

BACKGROUND: Topical 2-octylcyanoacrylate tissue adhesive is an alternative to traditional devices for closing short surgical incisions. METHODS: An open-label, randomized study compared a new high-viscosity formulation of 2-octylcyanoacrylate with commercially available devices, including low-viscosity 2-octylcyanoacrylate, for epidermal closure of incisions > or = 4 cm requiring subcutaneous and/or deep-dermal suturing. RESULTS: Of patients with 1 to 3 wounds, 106 were treated with high-viscosity 2-octylcyanoacrylate and 103 with commercially available devices. The day-10 rates of healing by wound were 96% and 97% for study versus control treatment and 97% and 95% for new and old 2-octylcyanoacrylate formulations versus other controls, respectively. Day-10 infection rates by wound were 4 of 145 versus 7 of 131 for study versus control treatment and 6 of 207 and 5 of 69 for new and old 2-octylcyanoacrylate versus other controls, respectively. CONCLUSIONS: The new tissue adhesive formulation provides epidermal wound closure equivalent to commercially available devices with a trend to decreased incidence of wound infection.

Confirmatory chest radiographs after central line placement: are they warranted?

OBJECTIVES: This study was designed to determine the ability of physicians to predict complications associated with the placement of central venous access devices and to decide whether a confirmatory chest radiograph is warranted after placement. METHODS: Patients receiving central venous access on an inpatient and outpatient gynecologic oncology service were studied. Data were collected regarding patient demographics, patient history, procedural details of the placement, and the type of catheter used. The physician then predicted which patients had a reasonable potential for placement complications. All of the patients then underwent radiography, which was then compared with the original prediction. RESULTS: Ninety-eight patients who had central venous access devices placed were included in the study. Eighty of the 81 central lines thought by the practitioner to have been placed without incident caused no significant complications; one individual in this group had a minor pneumothorax. Two of 17 patients predicted to have complications were noted to have a pneumothorax that required hospitalization. No patients in the low-risk group were hospitalized for a placement complication, whereas two hospitalizations occurred in the high-risk group. CONCLUSION: Confirmatory chest radiographs may potentially be omitted in certain cases after line placement when experienced clinicians use good technique, good clinical judgment, and discrimination.

Effect of topotecan infusion duration on hematologic toxicity in recurrent ovarian carcinoma.

In an open-label, multicenter, nonrandomized, counterbalanced study, we investigated the tolerability and antitumor profile of a 10-min infusion duration of topotecan. A total of 12 patients with evaluable recurrent ovarian cancer were enrolled into the study and treated with 1.5 mg/m2/d topotecan for 5 d of a 21-d course by either a 10-, 30-, or 120-min intravenous infusion. Patients were evaluated for tolerability and tumor response. The primary toxicity associated with topotecan was noncumulative myelosuppression. All 12 patients experienced grade 3/4 neutropenia. Grade 3/4 thrombocytopenia, leukopenia, and anemia were reported in five (42%), two (17%), and two (17%) patients, respectively. Likewise, the majority of courses were associated with hematologic toxicity, with grade 3/4 neutropenia, thrombocytopenia, leukopenia, and anemia reported in 97%, 19%, 6%, and 6% of courses, respectively. The infusion duration had little impact on the myelotoxicity profile of topotecan. The mean nadir levels for all hematologic parameters were similar for all infusion durations, and myelosuppression was reversible and returned to near-preinfusion levels prior to administering the subsequent course, irrespective of infusion duration. A complete response was obtained by three (25%) patients, and five (42%) patients achieved stable disease; therefore, 67% of patients obtained clinical benefit. The results of this study demonstrate that topotecan administered over a 10-min interval has a comparable tolerability and safety profile compared with a 30-min infusion. A 10-min infusion may result in greater patient convenience and a reduction in the consumption of healthcare resources.