S.E. Taylor

Radical hysterectomy for early stage cervical cancer: laparoscopy versus laparotomy.

Laparoscopic radical hysterectomy appears to be a feasible alternative to laparotomy for early stage cervical cancer with similar surgical outcomes and lessened morbidity.

Molecular testing in oncology: Problems, pitfalls and progress

Recent advances in the understanding of the molecular basis of cancer and the development of molecular diagnostics based on this knowledge have done much to progress the fields of oncology and pathology. Technological developments such as Next Generation Sequencing (NGS) and multiplex assays have made feasible the widespread adoption of molecular diagnostics for clinical use. While these developments and advances carry much promise, there are pitfalls to implementing this testing. Choosing appropriate biomarkers is a vital first step for clinical use and being able to understand the complex relationship between predictive and prognostic biomarkers is a crucial component of this. Testing for standard of care biomarkers is not straightforward, one must choose carefully between clinical trial assays, assays that analyse the same biological phenomenon or surrogate biomarkers. Sample heterogeneity and population specific difference is assays may skew results and must be controlled for at the assay design stage. At a technical level, NGS has the potential to revolutionise laboratory practice and approaches to cancer treatment. However, use of this technology requires careful planning and implementation if one is to avoid technical and ethical quagmires. Finally, with FDA regulation of companion diagnostics one may be limited to therapy specific assays.

Placental site trophoblastic tumor: Immunohistochemistry algorithm key to diagnosis and review of literature.

Highlights • Histologic morphology is frequently equivocal for PSTTs.• Histology combined with immunohistochemical staining was necessary to make the diagnosis.• PSTT confined to the uterus was successfully treated with surgery alone.

An Evidence-Based Systematic Review of Gymnema (Gymnema sylvestre R. Br.) by the Natural Standard Research Collaboration

ABSTRACT An evidence-based systematic review of gymnema (Gymnema sylvestre R. Br.), including written and statistical analysis of scientific literature, expert opinion, folkloric precedent, history, pharmacology, kinetics/dynamics, interactions, adverse effects, toxicology, and dosing.

An Evidence-Based Systematic Review of Amaranth (Amaranthus spp.) by the Natural Standard Research Collaboration

ABSTRACT. An evidence-based systematic review including written and statistical analysis of scientific literature, expert opinion, folkloric precedent, history, pharmacology, kinetics/dynamics, interactions, adverse effects, toxicology, and dosing.

LC–MS/MS assay for the quantitation of the ribonucleotide reductase inhibitor triapine in human plasma

HIGHLIGHTSTriapineis a ribonucleotide reductase inhibitor and radiosensitizer in oncology Phase I and Phase II trials.An LC–MS/MS assay from 3–3000 ng/mL triapinein 0.05 mL plasma was validated.Triapine is chelated by metal ions. MS responses were increased by EDTA and decreased by Fe3+, while stable isotope IS corrected this.This assay was utilized to quantitate triapine in preclinical samples and will be applied to clinical samples. ABSTRACT The ribonucleotide reductase inhibitor and radiosensitizer triapine (3‐aminopyridine‐2‐carboxaldehyde thiosemicarbazone (3‐AP), NSC 663249) is clinically being evaluated via the intravenous (IV) route for the treatment of cervical and vulvar cancer in combination with primary cisplatin chemoradiation. The need for a 2‐h infusion and frequent administration of triapine is logistically challenging, prompting us to pursue oral (PO) administration. In support of the clinical trial investigating oral triapine in combination with chemoradiation, we developed and validated a novel LC–MS/MS assay for the quantification of triapine in 50 &mgr;L human plasma. After protein precipitation, chromatographic separation of the supernatant was achieved with a Shodex ODP2 column and an isocratic acetonitrile‐water mobile phase with 10% ammonium acetate. Detection with an ABI 4000 mass spectrometer utilized electrospray positive mode ionization. The assay was linear from 3 to 3,000 ng/mL and proved to be accurate (97.1–103.1%) and precise (<7.4% CV), and met the U.S. FDA guidance for bioanalytical method validation. This LC–MS/MS assay will be an essential tool to further define the pharmacokinetics and oral bioavailability of triapine.

Phase I study of intravenous (IV) docetaxel and intraperitoneal (IP) oxaliplatin in recurrent ovarian and fallopian tube cancer

OBJECTIVE The primary objective was to define the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of IV docetaxel and IP oxaliplatin in women with recurrent ovarian (OV), fallopian tube (FT) or peritoneal (PP) cancer. Secondary objectives included response rate, time to progression, pharmacokinetics (PK) and quality of life (QoL). METHODS Patients received docetaxel 75mg/m(2) IV day (d) 1 and oxaliplatin escalating from 50mg/m(2) IP d2 every 3weeks using a 3+3 design. Treatment continued until disease progression, remission, or intolerable toxicity. Plasma and IP samples were taken to determine drug concentrations. MD Anderson Symptom Inventory and symptom interference scale were completed weekly. RESULTS Thirteen patients were included. Median number of cycles was 6 (range 1-10). Ten patients had measureable disease. Best response was partial response (PR-2), stable disease (SD-7), and progressive disease (PD-1). Twenty-one Grades 3-4 toxicities were noted, commonly hematologic. Two patients had DLTs: prolonged neutropenia (1) and abdominal pain (1). MTD was d1 docetaxel 75mg/m(2) IV and d2 oxaliplatin 50mg/m(2) IP. Symptom burden peaked week one and returned to baseline by week two of each cycle on dose level 1. Dose level 2 had persistently high symptom burden and interference. At IP oxaliplatin doses of 50mg/m(2), total unbound drug exposure (AUC) averaged 8 times larger and Cmax reached concentrations 50-fold greater in IP fluid compared to plasma. CONCLUSIONS Docetaxel 75mg/m(2) IV d1 and oxaliplatin 50mg/m(2) IP d2 is the MTD. Most patients had PR or SD. Patient-reported outcomes demonstrate temporary but tolerable decrements in QoL. IP oxaliplatin provides PK advantages over IV administration.

Abstract CT412: Phase I study of intraveneous docetaxel and intraperitoneal oxaliplatin in recurrent ovarian, fallopian tube and peritoneal cancer

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Objective IP chemotherapy improves survival in advanced ovarian cancer but its use has been limited by toxicity with cisplatin-based regimens. The primary objective was to define the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of IV docetaxel and IP oxaliplatin in women with recurrent ovarian, fallopian tube or peritoneal cancer. Secondary objectives included response rate, time to progression, quality of life (QoL) and pharmacokinetics (PK). Methods Patients received docetaxel 75 mg/m2 IV on day (d) 1 and oxaliplatin escalating from 50 mg/m2 IP on d2 every 3 weeks using a 3 + 3 design. Response was evaluated every 2 cycles. Treatment continued until disease progression, remission, or intolerable toxicity. Plasma and IP samples were taken up to 72 hours after dosing to determine drug concentrations via inductively coupled plasma mass spectrometry. PK parameters were estimated for each patient with means then calculated for each dose level. Patients completed the Functional Assessment of Cancer Therapy - Ovarian before each treatment and the MD Anderson Symptom Inventory weekly to assess multi-dimensional QoL. Results Thirteen patients were included. Mean age was 60.9 years (range 38-76). Ten had ovarian and 3 had fallopian tube cancer. Six had ≥3 prior regimens. Two had secondary debulking immediately prior to study therapy. Median number of cycles was 6 (range 1-10). Ten patients had measureable disease. Of these, best response was partial response (PR-2), stable disease (SD-7), and progressive disease (1). A total of 21 grade 3-4 toxicities were noted, most commonly hematologic. Two patients had DLTs: prolonged neutropenia (1) and abdominal pain (1). Four patients had treatment delay and 3 had dose reduction. Treatment ended due to disease progression (7), toxicity (4), and remission (2). MTD was d1 docetaxel 75 mg/m2 IV and d2 oxaliplatin 50 mg/m2 IP as the escalated IP dose was deemed intolerable. Symptoms peaked during the first week after treatment and generally returned to baseline by the second. Well-being decreased initially but improved by cycle 4 for those on dose level 1. Average unbound platinum AUC0-24 and Cmax in IP fluid for 50mg/m2 were 21.01 µg/mL•h and 6.70 µg/mL, respectively. Mean AUC0-24 and Cmax pharmacological advantage for unbound platinum were estimated at 8.58 and 49.98. At 75mg/m2 the mean unbound platinum AUC and Cmax were 55.92 µg/mL•h and 13.89 µg/mL, respectively. Mean AUC and Cmax pharmacologic advantage were estimated at 17.9 and 73.13. Mean plasma AUC0-last for docetaxel was 2290 ng/mL•h. Conclusions Docetaxel 75 mg/m2 IV on d1 and oxaliplatin 50 mg/m2 IP on d2 is the MTD. Most patients had PR or SD, even in a heavily pretreated population. At this dose level, patient-reported outcomes demonstrate temporary but tolerable decrements in QoL, IP oxaliplatin provides a significant peritoneal PK advantage. Citation Format: Sarah E. Taylor, Ruosha Li, Jennifer S. Petschauer, Heidi Donovan, William C. Zamboni, Robert P. Edwards, Kristen K. Zorn. Phase I study of intraveneous docetaxel and intraperitoneal oxaliplatin in recurrent ovarian, fallopian tube and peritoneal cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT412. doi:10.1158/1538-7445.AM2014-CT412