Fentanyl buccal tablet for breakthrough cancer pain in clinical practice: results of the non-interventional prospective study ErkentNIS.

PURPOSE: Several patients with advanced cancer suffer from breakthrough cancer pain (BTcP). BTcP is pain exacerbation despite opioid baseline therapy. Fentanyl buccal tablet (FBT) is a rapid-onset opioid for the treatment of BTcP. The aim of this study is to document the feasibility of FBT in patients with BTcP. METHODS: The study was performed in 64 centers. Basic pain score was rated on a numeric rating scale (NRS) before and after treatment. BTcP episodes, baseline opioid therapy, and FBT dose were rated as well as individual dose titration, findings on tolerability, patient satisfaction, and safety of the drug. RESULTS: Two hundred sixty-three patients were available for analysis. Patients rated a basic pain score of 6 (range 2-10) points on an NRS and described an average of 2 to 5 BTcP episodes per day. After titration of FBT, BTcP control was achieved within 5 min in 36%, within 10 min in 68%, and within 15 min in 95%. Basic pain score decreased to a mean NRS of 4 and BTcP episodes decreased to < 1 to 3 episodes per day. BTcP control, onset of action of FBT, potency of FBT, tolerability of FBT, and safety of FBT were rated as excellent or good by 89 to 99% of the patients. Adverse drug reactions were registered in 3%. CONCLUSIONS: Treatment with FBT led to rapid pain relief and reductions in the number of BTcP episodes and patient satisfaction was rated as excellent or good.

Detection of EpCAM positive and negative circulating tumor cells in metastatic breast cancer patients.

BACKGROUND: Immunomagnetic EpCAM based methods are used to enrich circulating tumor cells (CTCs) in metastatic breast cancer (mBC) patients. EpCAM negative CTCs may be missed. We addressed the question of the reliability of an EpCAM dependent assay to enrich CTCs. METHODS: To elucidate this issue, our study has been designed to assess two different CTC enrichment technologies (i) in EpCAM positive (+) and EpCAM negative cell lines and (ii) in mBC patients in dependency on their respective EpCAM expression. These two technologies encompass one anti-EpCAM immunomagnetic enrichment technology, MACS HEA MicroBeads(®) (MACS), and one EpCAM independent density centrifugation method, OncoQuick(®) plus (OQ+). Furthermore, the coherence between EpCAM expression in the primary tumor tissue of mBC patients and the CTC detection rates in the corresponding patients is analyzed. RESULTS: (i) MACS recovered significantly more EpCAM (+) than EpCAM (-) tumor cells (p < 0.001) in spiked blood samples. With OQ+ no significantly different recovery rates between EpCAM (+) and EpCAM (-) tumor cells (p = 0.796) were detected. (ii) In mBC patients MACS yielded a significantly higher (p = 0.024) detection rate of EpCAM (+) CTCs. No statistically significant difference (p = 0.070) was found concerning the EpCAM status-based detection rate of CTCs by OQ+. (iii) CTC detection rates are independent of the primary tumors' EpCAM expression. CONCLUSIONS: EpCAM (-) CTCs can not be detected by immunomagnetic EpCAM dependent enrichment methods. EpCAM independent enrichment technologies seem to be superior to detect the entire CTC population. Evaluation of CTCs as prognostic marker should compromise EpCAM (+) and (-) subpopulations.

Circulating tumor cells in metastatic colorectal cancer: efficacy and feasibility of different enrichment methods.

Comprehensive in vitro and in vivo studies comparing EpCAM-based methods with other cytometric CTC enrichment technologies in metastatic colorectal cancer (mCRC) patients are lacking. We compare four manual cytometric methods to detect CTCs in vitro and in mCRC patients. The EpCAM-based technology, MACS HEA MicroBeads((R)), showed a significant better tumor cell recovery rate compared to other cytometric methods (p-value<0.0001). CTCs of 38 mCRC patients were enriched with MACS HEA MicroBeads(R). Progression-free survival did significantly differ between mCRC patients without detectable and with >or= 1 CTCs (p=0.007). CTC enrichment with EpCAM coupled antibodies is superior to other cytometric methods and is a feasible method for CTC detection in mCRC patients.

[Organization, administration, and performance of clinical studies]. / Organisation, Administration und Durchfuhrung von klinischen Studien.

This contribution deals with all important organizational and administrative aspects of clinical studies in German speaking countries. All trials are to be executed in accordance with the Good Clinical Practice (GCP) Guidelines. GCP applies to the process of designing, conducting, recording, and reporting of clinical studies. Compliance with GCP facilitates the mutual acceptance of resulting clinical data by the respective regulatory authorities worldwide. Before initiating a clinical study the investigator has to obtain written and dated approval from the responsible ethics committee, the competent authorities, and the hospital administration. The investigator's study file contains all essential study documents. One of the most important tasks of an investigator is to properly inform the prospective subjects and to obtain their informed consent. All relevant treatment-related information has to be recorded in the patient files. These source data are transferred to case report forms. During monitoring visits, audits, and inspections, source data verification will be performed routinely. Any adverse events (AEs) must be documented according to the CTCAE, the Common Terminology Criteria for Adverse Events. All serious adverse events (SAEs) have to be reported to the sponsor immediately. At the end of the study a termination visit is performed, and all authorities are officially informed about the termination of the trial.

Pharmacokinetics of oxaliplatin in patients with severe hepatic dysfunction.

PURPOSE: Data are lacking on the pharmacokinetics of oxaliplatin in patients with severe hepatic dysfunction. The aim of this study was to determine the pharmacokinetic parameters of platinum after administration of oxaliplatin in cancer patients with severe hepatic impairment due to extended metastases into the liver. PATIENTS AND METHODS: Two female breast cancer patients and one male colon cancer patient were treated with oxaliplatin monotherapy at 130 mg/m(2) given as a 3-h intravenous infusion. The patients exhibited bilirubin concentrations of 9.6, 22.5 and 41.1 mg/dl indicating severe hepatic dysfunction. Serial blood samples were collected immediately before treatment, and at fixed intervals up to 27 h after start of therapy. Platinum concentrations in plasma, ultrafilterable plasma, and whole blood were determined using a validated flameless atomic absorption spectrometry (FAAS) method. Pharmacokinetic data analysis was performed assuming a two-compartment model. Individual pharmacokinetic parameters were compared with a reference population with normal hepatic function. RESULTS: The area under the curve (AUC from 0 to infinity) as well as the elimination half-life of platinum in ultrafilterable plasma were substantially increased and clearance accordingly decreased in the three patients with severe hepatic dysfunction. In plasma and whole blood, the deviations from the reference population were less pronounced. However, partial AUC from 0 up to 2 h after end of infusion reflecting better the exposure with cytotoxic platinum species was not different or only slightly altered. Moreover, no acute oxaliplatin-associated neurotoxicity was observed. CONCLUSIONS: The comparable platinum exposure early after administration in conjunction with the lack of acute toxicity do not support a dose reduction of oxaliplatin in patients with markedly elevated bilirubin concentrations. However, a larger number of patients must be examined before valid dose recommendations can be derived.

Clinical complete long-term remission of a patient with metastatic malignant melanoma under therapy with indisulam (E7070).

The objective of this study is to report on long-term survival of a patient with metastatic melanoma treated with indisulam showing a distinct genetic pattern of repression of subsets of genes involved in mitochondrial energy metabolism. Gene expression profiling was performed with oligonucleotide microarray analysis. A 45-year-old patient with metastatic malignant melanoma was treated in third-line with indisulam (goal, E7070), a new chloroindolyl-sulphonamide cell-cycle inhibitor. The patient was treated weekly with a dose of 40 mg/m within a phase I study. On the basis of an amendment, the dose was escalated to 320 mg/m at maximum and de-escalated to 160 mg/m for long-term application in this individual patient. At the start of treatment the tumour burden consisted of two-in-transit-metastases, two further skin lesions, two cervical lymph nodes and four pulmonary metastases. Under a 2.5-year treatment with indisulam the tumour shrunk markedly although the objective response only reached stable disease. Lymph node biopsy revealed absence of vital melanoma cells. Therapy was stopped upon request of the patient. The gene expression profile indicated a profound transcriptional repression of subsets of genes involved in mitochondrial energy metabolism; namely NDUFB8, NDUFS1, NDUFV1, ACADVL and Homo sapiens clone 24408. The survival of this patient with metastatic melanoma lasted now 9 years, the progression-free interval 105 months. It can be assumed that this treatment effect is attributed to the down-regulating effect of indisulam on metabolic genes involved in energy production. Thus, knowledge on individual's tumour gene regulation may predict sensitivity and resistance to antitumoural agents.

A phase I study of pemetrexed (ALIMTA) and cyclophosphamide in patients with locally advanced or metastatic breast cancer.

PURPOSE: Determine the maximum tolerated dose (MTD) of pemetrexed and cyclophosphamide combination therapy for patients with locally advanced or metastatic breast cancer. EXPERIMENTAL DESIGN: Patients with locally advanced or metastatic breast cancer and WHO performance status 0 to 2 were eligible. Pemetrexed (range, 400-2,400 mg/m(2)) was administered on day 1 of a 21-day schedule followed by cyclophosphamide (range, 400-800 mg/m(2)). Folic acid and vitamin B(12) supplementation began 1 to 2 weeks before the first pemetrexed dose. RESULTS: Fifty-seven pretreated patients were enrolled and received 342 cycles (median, 4 cycles; range, 1-26) through 14 dose levels. The MTD of pemetrexed was 2,400 mg/m(2) (combined with cyclophosphamide, 600 mg/m(2)) with dose-limiting toxicities of grade 4 neutropenia with grade 4 infection and grade 3 diarrhea. Other grade 3 or 4 toxicities included (febrile) neutropenia, thrombocytopenia, anemia, elevated alanine aminotransferase/aspartate aminotransferase, and diarrhea. Pharmacokinetic analysis indicated that pemetrexed clearance and central volume of distribution were 40% lower than single-agent reference data, yielding a 68% increase in total systemic exposure and a 56% increase in maximal plasma concentration. Among the 50 patients evaluable for efficacy, 13 (26%) patients had a partial response and 17 (34%) patients had stable disease. CONCLUSIONS: Pemetrexed was generally well tolerated. The observed toxicities were consistent with the known toxicity profiles of pemetrexed and cyclophosphamide. Considering the MTD and the toxicity and efficacy results in this and prior studies, a low (600 mg/m(2)) and a high (1,800 mg/m(2)) dose of pemetrexed with cyclophosphamide (600 mg/m(2)) will be evaluated in the consecutive prospective randomized phase II study.