Purpose
The aim of this study was to assess the accuracy of
18
F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT to visualize lymph node metastases before the start of neoadjuvant ...chemotherapy and to determine how often the visualization is sufficiently prominent to allow monitoring of the axillary response.
Methods
Thirty-eight patients with invasive breast cancer of >3 cm and/or lymph node metastasis underwent FDG PET/CT before neoadjuvant chemotherapy. The results of the FDG PET/CT were compared with those from ultrasonography with fine-needle aspiration (FNA) cytology or sentinel node biopsy. Patients suitable for response monitoring of the axilla were defined as having either a maximum standardized uptake value (SUV
max
) ≥ 2.5 or a tumour to background ratio ≥5 in the most intense lymph node.
Results
The sensitivity and specificity of FDG PET/CT in detecting axillary involvement were 97 and 100%, respectively. No difference existed between the SUV
max
of the primary tumour and that from the related most intense lymph node metastasis. Moreover, the mean tumour to background ratio was 90% higher in the lymph nodes compared to the primary tumour (
p
= 0.006). Ninety-three per cent of the patients had sufficient uptake in the lymph nodes to qualify for subsequent response monitoring of the axilla. A considerable distinction in metabolic activity was observed between the different subtypes of breast cancer. The mean SUV
max
in lymph node metastases of oestrogen receptor (ER)-positive, triple-negative and human epidermal growth factor receptor 2 (HER2)-positive tumours was 6.6, 11.6 and 6.6, respectively.
Conclusion
The high accuracy in visualizing lymph node metastases and the sufficiently high SUV
max
and tumour to background ratio at baseline suggest that it is feasible to monitor the axillary response with FDG PET/CT, especially in triple-negative tumours.
Oral bioavailability of docetaxel is very low, which is, at least in part, due to its affinity for the intestinal drug efflux pump P-glycoprotein (P-gp). In addition, metabolism of docetaxel by ...cytochrome P450 (CYP) 3A4 in gut and liver may also contribute. The purpose of this study was to enhance the systemic exposure to oral docetaxel on coadministration of cyclosporine (CsA), an efficacious inhibitor of P-gp and substrate for CYP 3A4.
A proof-of-concept study was carried out in 14 patients with solid tumors. Patients received one course of oral docetaxel 75 mg/m(2) with or without a single oral dose of CsA 15 mg/kg. CsA preceded oral docetaxel by 30 minutes. During subsequent courses, patients received intravenous (IV) docetaxel 100 mg/m(2).
The mean (+/- SD) area under the concentration-time curve (AUC) in patients who received oral docetaxel 75 mg/m(2) without CsA was 0.37 +/- 0.33 mg.h/L and 2.71 +/- 1.81 mg.h/L for the same oral docetaxel dose with CsA. The mean AUC of IV docetaxel 100 mg/m(2) was 4.41 +/- 2.10 mg.h/L. The absolute bioavailability of oral docetaxel was 8% +/- 6% without and 90% +/- 44% with CsA. The oral combination of docetaxel and CsA was well tolerated.
Coadministration of oral CsA strongly enhanced the oral bioavailability of docetaxel. Interpatient variability in the systemic exposure after oral drug administration was of the same order as after IV administration. These data are promising and form the basis for the further development of a clinically useful oral formulation of docetaxel.
Previously, we demonstrated that oral docetaxel plus the P-glycoprotein (Pgp; ABCB1) inhibitor cyclosporin A (CsA) is safe and results in adequate exposure to docetaxel. This phase II study evaluates ...the anti-tumor activity, safety and pharmacokinetics of oral docetaxel in combination with CsA in women with advanced breast cancer.
Patients with measurable advanced breast cancer were given one flat dose of 100 mg oral docetaxel, preceded by one single dose of 15 mg/kg CsA, weekly for 6 weeks in a cycle of 8 weeks. Pharmacokinetic monitoring of docetaxel and CsA was performed in week 1 and 9.
Thirty-three patients with a median age of 50 years were recruited. Thirty patients were evaluable for toxicity and twenty-six for response. All had received prior anthracycline treatment. The treatment was generally well tolerated with manageable toxicity although many patients needed a dose reduction, most commonly because of fatigue and uncomplicated neutropenia. The median treatment duration was 16 weeks (range 6 - 32). The overall response rate in evaluable patients was 42% (95% CI: 23 - 63) and the median overall survival was 12.2 months (8.4 - 23.1). The interpatient variability in the area under the curve of 100 mg orally administered docetaxel was moderate, respectively 49 and 30% in week 1 and 9.
Weekly oral docetaxel, combined with the booster drug CsA, is an active and safe treatment in anthracycline pre-treated patients with advanced breast cancer.
Intravenous administration of paclitaxel is hindered by poor water solubility of the drug. Currently, paclitaxel is dissolved in a mixture of ethanol and Cremophor EL; however, this formulation ...(Taxol) is associated with significant side effects, which are considered to be related to the pharmaceutical vehicle. A new polymer-conjugated derivative of paclitaxel, PNU166945, was investigated in a dose-finding phase I study to document toxicity and pharmacokinetics. A clinical phase I study was initiated in patients with refractory solid tumors. PNU16645 was administered as a 1-h infusion every 3 weeks at a starting dose of 80 mg/m, as paclitaxel equivalents. Pharmacokinetics of polymer-bound and released paclitaxel were determined during the first course. Twelve patients in total were enrolled in the study. The highest dose level was 196 mg/m, at which we did not observe any dose-limiting toxicities. Hematologic toxicity of PNU166945 was mild and dose independent. One patient developed a grade 3 neurotoxicity. A partial response was observed in one patient with advanced breast cancer. PNU166945 displayed a linear pharmacokinetic behavior for the bound fraction as well as for released paclitaxel. The study was discontinued prematurely due to severe neurotoxicity observed in additional rat studies. The presented phase I study with PNU166945, a water-soluble polymeric drug conjugate of paclitaxel, shows an alteration in pharmacokinetic behavior when paclitaxel is administered as a polymer-bound drug. Consequently, the safety profile may differ significantly from standard paclitaxel.
OBJECTIVE:The MARI procedure marking the axillary lymph node with radioactive iodine (I) seeds is a new minimal invasive method to assess the pathological response of nodal metastases after ...neoadjuvant systemic treatment (NST) in patients with breast cancer. This method allows axilla-conserving surgery in patients responding well to NST.
METHODS:Prior to NST, proven tumor-positive axillary lymph nodes were marked with a I seed. This marked lymph node is the so-called MARI-node. After NST, the MARI node was selectively removed using a γ-detection probe. A complementary axillary lymph node dissection was performed in all patients to assess whether pathological response in the MARI node was indicative for the pathological response in the additional lymph nodes.
RESULTS:A tumor-positive axillary lymph node was marked with a I seed in 100 patients. The MARI node was successfully identified in 97 of these 100 patients (identification rate 97%). Two patients did not undergo subsequent axillary lymph node dissection, leaving 95 patients for further analysis. The MARI node contained residual tumor cells in 65 of these 95 patients. In the other 30 patients, the MARI node was free of tumor, but additional positive lymph nodes were found in 5 patients. Thus, the MARI procedure correctly identified 65 of 70 patients with residual axillary tumor activity (false negative rate 5/70 = 7%).
CONCLUSIONS:This study shows that marking and selectively removing metastatic lymph nodes after neoadjuvant systemic treatment has a high identification rate and a low false negative rate. The tumor response in the marked lymph node may be used to tailor further axillary treatment after NST.
To investigate the safety and pharmacokinetics of a new liposomal formulation of cisplatin, SPI-77, in patients with advanced malignancies.
Patients with histologically proven malignancies not ...amenable to other treatment were eligible for this study. The starting dose of SPI-77 (cisplatin in Stealth liposomes) was 40 mg/m(2) administered every 4 weeks in a 2-h infusion, and doses were escalated up to 420 mg/m(2). Pharmacokinetic monitoring was performed in all patients and samples were analysed for platinum content by atomic absorption spectroscopy. Platinum-DNA (Pt-DNA) adduct levels in leucocytes (white blood cells, WBC) and tumour tissue were quantified using a sensitive (32)P-postlabelling assay.
A total of 27 patients were accrued. The main toxicities observed were infusion-related reactions, which could be prevented by lowering the initial infusion rate, and anaemia. The pharmacokinetics of SPI-77-derived platinum were strikingly different from standard cisplatin. Free platinum levels in plasma ultrafiltrate samples were undetectable at the lowest dose levels (40 and 80 mg/m(2)), and low but highly variable at higher doses of SPI-77. Plasma pharmacokinetics of total platinum were linear with small interpatient variability. The total body clearance of SPI-77 varied from 14 to 30 ml/h and was significantly lower than reported clearance values for cisplatin of 20 l/m(2) per h, due to the slow release of cisplatin from the liposomes. Pt-DNA adduct levels in WBC ranged from 0.02 to 4.13 fmol/microg DNA for intrastrand Pt-GG (guanine-guanine) adducts and from 0.02 to 1.27 fmol/microg DNA for intrastrand Pt-AG (adenosine-guanine) adducts, which is more than tenfold lower than after administration of a comparable dose of non-liposomal cisplatin. In tumour samples obtained from two patients treated at the highest dose-levels, relatively low levels of Pt-DNA adducts were observed.
The results of this phase I trial show that the pharmacokinetic behaviour of cisplatin is significantly altered by its encapsulation in Stealth liposomes. The pharmacokinetics of SPI-77 are mainly dominated by the liposomal properties, resulting in high cholesterol concentrations and relatively low concentrations of (free) platinum in plasma, WBC and tumour tissue, which may explain the observed differences between the toxicity profiles of SPI-77 and cisplatin.
The strategy of combining endocrine therapy with PI3K-mTOR inhibition has shown promise in estrogen receptor (ER)-positive breast cancer, but new agents and combinations with a better therapeutic ...index are urgently needed. Taselisib is a potent, selective, beta-isoform-sparing PI3 kinase inhibitor.
30 patients with ER-positive, metastatic breast cancer who had failed prior endocrine therapy were treated with escalating doses of taselisib (2 or 4 mg in an intermittent or continuous schedule) combined with tamoxifen 20 mg once daily in this phase 1b study using a "rolling six" design.
Taselisib combined with tamoxifen was generally well tolerated, with treatment-emergent adverse events as expected for this class of drugs, including diarrhea (13 patients, 43%), mucositis (10 patients, 33%), and hyperglycemia (8 patients, 27%). No dose-limiting toxicities were observed. Objective responses were seen in 6 of 25 patients with RECIST-measurable disease (ORR 24%). Median time to disease progression was 3.7 months. Twelve of 30 patients (40%) had disease control for 6 months or more. Circulating tumor (ct)DNA studies using next-generation tagged amplicon sequencing identified early indications of treatment response and mechanistically relevant correlates of clinical drug resistance (e.g., mutations in
) in some patients.
Taselisib can be safely combined with tamoxifen at the recommended phase 2 dose of 4 mg given once daily on a continuous schedule. Preliminary evidence of antitumor activity was seen in both
mutant and wild-type cancers. The randomized phase 2 part of POSEIDON (testing tamoxifen plus taselisib or placebo) is currently recruiting.
Abstract Aim To determine the efficacy and safety of an anthracycline-free neo-adjuvant regimen consisting of weekly paclitaxel, carboplatin and trastuzumab in HER2-positive breast cancer. Patients ...and methods Patients with stage II or III HER2-positive breast cancer received weekly paclitaxel (P, 70 mg/m2 ), trastuzumab (T, 2 mg/kg, loading dose 4 mg/kg) and carboplatin (C, AUC = 3 mg ml−1 min) for 24 weeks. In weeks 7, 8, 15, 16, 23 and 24, trastuzumab was administered without chemotherapy. The primary end-point was pathologic complete response in the surgical resection specimen, defined as the absence of invasive tumour cells in breast and axilla. Results One hundred and eleven patients were included in the study, and 108 were evaluable for the primary end-point. The pathologic complete response rate was 43% (95% confidence interval CI: 33–52). Median follow-up was 52 months, and the 3-year event-free survival was 88% (95% CI: 82–94), and the 3-year overall survival was 92% (95% CI: 88–98). The most common grade 3–4 adverse events were neutropenia (67%) and thrombocytopenia (43%). Less than five percent of patients experienced febrile neutropenia. No symptomatic left ventricular systolic dysfunction was observed during neo-adjuvant treatment. Conclusion An anthracycline-free neo-adjuvant regimen of weekly paclitaxel, trastuzumab and carboplatin is highly effective in HER2-positive breast cancer with manageable toxicity.
Purpose: To establish the maximum dose intensity of cisplatin plus gemcitabine on a weekly or two-weekly schedule in patients with
advanced non-small cell lung cancer (NSCLC).
Methods: Patients with ...NSCLC stage IIIB or IV were randomized to receive weekly or two-weekly courses of gemcitabine on day 1 and
cisplatin on day 2. An interpatient dose escalation scheme was used, and pharmacokinetics were determined for both agents
in plasma and WBCs.
Results: Seventy-three patients were included, 32 on the weekly schedule and 41 on the two-weekly schedule. Fifty patients received
all planned courses. Dose-limiting toxicities were leukocytopenia, neutropenia, and trombocytopenia on the weekly schedule
and ototoxicity on the two-weekly schedule. Most common nonhematological toxicities consisted of nausea, vomiting, and fatigue.
The highest dose intensity of cisplatin could be achieved on the two-weekly schedule, and therefore, further development of
the weekly schedule was abandoned. The maximum tolerated dose was established at 1500 mg/m 2 gemcitabine in combination with cisplatin 90 mg/m 2 . More than half (53%) of patients achieved an objective response on the two-weekly schedule, versus 23% in the weekly treatment arm. The pharmacokinetic studies revealed a significant interaction: gemcitabine reduced both
GG and AG platinum-DNA intrastrand adducts in WBCs.
Conclusion: The combination of gemcitabine (1500 mg/m 2 ) with cisplatin at a dose intensity of 50 mg/m 2 /week is feasible on a two-weekly administration scheme in NSCLC patients.
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