Outcome of ATP-based tumor chemosensitivity assay directed chemotherapy in heavily pre-treated recurrent ovarian carcinoma

BACKGROUND: We wished to evaluate the clinical response following ATP-Tumor Chemosensitivity Assay (ATP-TCA) directed salvage chemotherapy in a series of UK patients with advanced ovarian cancer. The results are compared with that of a similar assay used in a different country in terms of evaluability and clinical endpoints. METHODS: From November 1998 to November 2001, 46 patients with pre-treated, advanced ovarian cancer were given a total of 56 courses of chemotherapy based on in-vitro ATP-TCA responses obtained from fresh tumor samples or ascites. Forty-four patients were evaluable for results. Of these, 18 patients had clinically platinum resistant disease (relapse < 6 months after first course of chemotherapy). There was evidence of cisplatin resistance in 31 patients from their first ATP-TCA. Response to treatment was assessed by radiology, clinical assessment and tumor marker level (CA 125). RESULTS: The overall response rate was 59% (33/56) per course of chemotherapy, including 12 complete responses, 21 partial responses, 6 with stable disease, and 15 with progressive disease. Two patients were not evaluable for response having received just one cycle of chemotherapy: if these were excluded the response rate is 61%. Fifteen patients are still alive. Median progression free survival (PFS) was 6.6 months per course of chemotherapy; median overall survival (OAS) for each patient following the start of TCA-directed therapy was 10.4 months (95% confidence interval 7.9-12.8 months). CONCLUSION: The results show similar response rates to previous studies using ATP-TCA directed therapy in recurrent ovarian cancer. The assay shows high evaluability and this study adds weight to the reproducibility of results from different centre

Lactate dehydrogenase is not a useful marker for relapse in patients on surveillance for stage I germ cell tumours

As part of surveillance protocols for stage I germ cell tumours, many centres routinely measure human chorionic gonadotrophin (HCG), alpha feto-protein (AFP) as well as lactate dehydrogenase (LDH). In conjunction with regular imaging and clinical examination, does routine measurement of LDH add anything to our relapse/pick up rate? Records of 494 patients at Mount Vernon Hospital who relapsed on surveillance between 1985 and 2005 were examined. Of the 494 patients who relapsed, 125 had raised LDH at the time of relapse. 112 of these had a concurrent rise in either AFP, HCG or both, 11 had their disease detected on CT before the rise in LDH, one had a clinically palpable para-aortic mass and the final patient complained of back pain and his retroperitoneal disease was thus discovered on imaging. Routine measurement of LDH in patients on surveillance for stage I germ cell tumours does not add to the early detection of relapse

Targeted anti-vascular therapies for ovarian cancer: current evidence

Ovarian cancer presents at advanced stage in around 75% of women, and despite improvements in treatments such as chemotherapy, the 5-year survival from the disease in women diagnosed between 1996 and 1999 in England and Wales was only 36%. Over 80% of patients with advanced ovarian cancer will relapse and despite a good chance of remission from further chemotherapy, they will usually die from their disease. Sequential treatment strategies are employed to maximise quality and length of life but patients eventually become resistant to cytotoxic agents. The expansion in understanding of the molecular biology that characterises cancer cells has led to the rapid development of new agents to target important pathways but the heterogeneity of ovarian cancer biology means that there is no predominant defect. This review attempts to discuss progress to date in tackling a more general target applicable to ovary cancer-angiogenesis

GEICO (Spanish Group for Investigation on Ovarian Cancer) treatment guidelines in ovarian cancer 2012

In 2006, under the auspices of The Spanish Research Group for Ovarian Cancer (Spanish initials GEICO), the first “Treatment Guidelines in Ovarian Cancer” were developed and then published in Clinical and Translational Oncology by Poveda Velasco et al. (Clin Transl Oncol 9(5):308–316, 2007). Almost 6 years have elapsed and over this time, we have seen some important developments in the treatment of ovarian cancer. Significant changes were also introduced after the GCIG-sponsored 4th Consensus Conference on Ovarian Cancer by Stuart et al. (Int J Gynecol Cancer 21:750–755, 2011). So we decided to update the treatment guidelines in ovarian cancer and, with this objective, a group of investigators of the GEICO group met in February 2012. This study summarizes the presentations, discussions and evidence that were reviewed during the meeting and during further discussions of the manuscript

High-throughput genomic technology in research and clinical management of breast cancer. Plasma-based proteomics in early detection and therapy

Protein-based breast cancer biomarkers are a promising resource for breast cancer detection at the earliest and most treatable stages of the disease. Plasma is well suited to proteomic-based methods of biomarker discovery because it is easily obtained, is routinely used in the diagnosis of many diseases, and has a rich proteome. However, due to the vast dynamic range in protein concentration and the often uncertain tissue and cellular origin of plasma proteins, proteomic analysis of plasma requires special consideration compared with tissue and cultured cells. This review briefly touches on the search for plasma-based protein biomarkers for the early detection and treatment of breast cancer

Randomised phase II study of ASA404 combined with carboplatin and paclitaxel in previously untreated advanced non-small cell lung cancer

ASA404 (5,6-dimethylxanthenone-4-acetic acid or DMXAA) is a small-molecule tumour-vascular disrupting agent (Tumour-VDA). This randomised phase II study evaluated ASA404 plus standard therapy of carboplatin and paclitaxel in patients with histologically confirmed stage IIIb or IV non-small cell lung cancer (NSCLC) not previously treated with chemotherapy. Patients were randomised to receive ⩽6 cycles of carboplatin area under the plasma concentration–time curve 6 mg ml−1 min and paclitaxel 175 mg m−2 (CP, n=36) or standard therapy plus ASA404 1200 mg m−2 (ASA404-CP, n=37). There was little change in the systemic exposure of either total or free carboplatin or paclitaxel on addition of ASA404. Safety profiles were similar and manageable in both groups, with most adverse effects attributed to standard therapy. Tumour response rate (31 vs 22%), median time to tumour progression (5.4 vs 4.4 months) and median survival (14.0 vs 8.8 months, hazard ratio 0.73, 95% CI 0.39, 1.38) were improved in the ASA404 combination group compared with the standard therapy group. In conclusion, this study establishes the feasibility of combining ASA404 with carboplatin and paclitaxel in patients with previously untreated, advanced NSCLC, demonstrating a manageable safety profile and lack of adverse pharmacokinetic interactions. The results indicate that there may be a benefit associated with ASA404, but this needs to be evaluated in a larger trial

External validation of serum hCG cutoff levels for prediction of resistance to single-agent chemotherapy in patients with persistent trophoblastic disease

Van Trommel et al have previously shown that serum human chorionic gonadotropin (hCG) cutoff levels can provide early prediction of resistance to first-line methotrexate (MTX) in patients with persistent trophoblastic disease (PTD). In this study, we validate this approach of prediction of resistance to single-agent chemotherapy in an independent and larger cohort of PTD patients using a different hCG assay. Receiver operating characteristics (ROC) curves were constructed to determine hCG cutoff levels and sensitivity between patients cured on single-agent chemotherapy (control group) and patients requiring change to combination chemotherapy (study group). Receiver operating characteristics analysis identified an hCG cutoff value of 737 IU l−1 that enabled us to predict the subsequent development of single-agent chemotherapy resistance in 52% of patients before their fourth MTX course at 97.5% specificity. This would have enabled an earlier switch to combination chemotherapy reducing the MTX exposure by an average of 2.5 courses. The present findings confirm that serum hCG cutoff levels predict resistance to single-agent therapy earlier than traditional methods. Change to combination chemotherapy should be considered for patients whose serum hCG levels exceed these hCG cutoff values. For patients not exceeding the hCG cutoff levels, static or rising hCG levels should still be included in the criteria for change of chemotherapy

Mouse Studies to Shape Clinical Trials for Mitochondrial Diseases: High Fat Diet in Harlequin Mice

BACKGROUND: Therapeutic options in human mitochondrial oxidative phosphorylation (OXPHOS) diseases have been poorly evaluated mostly because of the scarcity of cohorts and the inter-individual variability of disease progression. Thus, while a high fat diet (HFD) is often recommended, data regarding efficacy are limited. Our objectives were 1) to determine our ability to evaluate therapeutic options in the Harlequin OXPHOS complex I (CI)-deficient mice, in the context of a mitochondrial disease with human hallmarks and 2) to assess the effects of a HFD. METHODS AND FINDINGS: Before launching long and expensive animal studies, we showed that palmitate afforded long-term death-protection in 3 CI-mutant human fibroblasts cell lines. We next demonstrated that using the Harlequin mouse, it was possible to draw solid conclusions on the efficacy of a 5-month-HFD on neurodegenerative symptoms. Moreover, we could identify a group of highly responsive animals, echoing the high variability of the disease progression in Harlequin mice. CONCLUSIONS: These results suggest that a reduced number of patients with identical genetic disease should be sufficient to reach firm conclusions as far as the potential existence of responders and non responders is recognized. They also positively prefigure HFD-trials in OXPHOS-deficient patients

The effect of early pregnancy following chemotherapy on disease relapse and foetal outcome in women treated for gestational trophoblastic tumours

Little literature exists on the safety of early pregnancy following chemotherapy. Here we assess the rate of relapse and foetal outcome in women who have completed single and multi-agent chemotherapy for gestational trophoblastic tumours. The records of 1532 patients treated for persistent gestational trophoblastic tumours at Charing Cross Hospital between 1969 and 1998 were reviewed. Patients were defined as receiving single agent or multi-agent treatment. Relapse rates and foetal outcome were reviewed in the 230 patients who became pregnant within 12 months of completing chemotherapy. In the single agent group 153 (22%) of 691 patients conceived early. Three subsequently relapsed. In the multi-agent group, 77 (10%) of 779 patients conceived early, two then relapsed. Relapse rates were 2% (3 out of 153) and 2.5% (2 out of 77) for each group compared to 5% and 5.6% in the comparative non-pregnant groups. Outcomes of 230 early pregnancies: 164 (71%) delivered at full term, 35 (15%) terminations, 26 (11%) spontaneous abortions, three (1.3%) new hydatidiform moles and two (1%) stillbirths. Early pregnancies were more common in the single agent group (P<0.001), but spontaneous miscarriages and terminations were more likely to occur in the multi-agent group (P=0.04 and 0.03, respectively). Of the full-term pregnancies, three (1.8%) babies were born with congenital abnormalities. Patients in either group who conceive within 12 months of completing chemotherapy are not at increased risk of relapse. Though, we still advise avoiding pregnancy within 12 months of completing chemotherapy, those that do conceive can be reassured of a likely favourable outcome

Phase I trial of CYT997, a novel cytotoxic and vascular-disrupting agent

BACKGROUND: CYT997 is a novel microtubule inhibitor and vascular-disrupting agent with marked preclinical anti-tumour activity. METHODS: This phase I dose-escalation study assessed the safety, tolerability, pharmacokinetics and pharmacodynamics of CYT997 administered by continuous intravenous infusion over 24 h every 3 weeks to patients with advanced solid tumours