Vibeke Kruse

Predictive and prognostic value of metabolic tumour volume and total lesion glycolysis in solid tumours

Data available in patients suffering from squamous cell carcinoma of the head and neck, lung carcinoma, oesophageal carcinoma and gynaecological malignancies suggest that metabolic tumour volume and to a lesser extent total lesion glycolysis have the potential to become valuable in the imaging of human solid tumours as prognostic biomarkers for short- to intermediate-term survival outcomes, adding value to clinical staging, for assessment of response to treatment with neoadjuvant and concurrent chemotherapy, and for treatment optimization; for example, based on early treatment response assessment using changes in metabolic tumour volume over time, it might be possible to select patients who require a more aggressive treatment to improve their outcome. Prospective studies enrolling consecutive patients, adopting standardized protocols for FDG PET acquisition and processing, adjusting for potential confounders in the analysis (tumour size and origin) and determining the optimal methodology for determination of these novel markers are mandatory.

Nephrotoxicity of anticancer drugs--an underestimated problem?

Abstract Nephrotoxicity is an inherent adverse effect of certain anticancer drugs and may result in a variety of functional consequences that include any combination of glomerular or tubular dysfunction, hypertension and disturbance of the renal endocrine function. The nephrotoxic potential of most anticancer agents dramatically increases in the presence of borderline or overt pre-existing chronic kidney disease and measurement of renal function is therefore of utmost importance in the cancer patient before any treatment is initiated. This review summarizes some clinical nephrotoxic side effects of a selection of the most frequently used anticancer drugs. The drugs discussed are cisplatin, methotrexate, ifosfamide, citumixab and panitumumab, mitocin C and gemcitabine and antiangiogenesis drugs.

PARP INHIBITORS IN ONCOLOGY: A NEW SYNTHETIC LETHAL APPROACH TO CANCER THERAPY

Abstract Damage to DNA has emerged as a major culprit in cancer. Mammalian cells are continuously exposed to DNA damage, caused by exogenous toxins as well as endogenous activities such as DNA replication and cellular free radical generation. It is therefore essential that cells have DNA repair mechanisms in place to preserve its genomic integrity. Interestingly, cancer cells frequently harbour defects in DNA repair pathways, leading to genomic instability. This can foster tumorigenesis, but also provides a weakness in the tumour that can be exploited therapeutically. In this context, it has been shown that homologous recombination (HR)- deficient tumour cells – including those with defects in BRCA1/2 – are highly sensitive to blockade of the base excision repair (BER) pathway via inhibition of the poly (ADPribose) polymerase (PARP) enzyme. This provides the basis for a novel ‘synthetic lethal’ approach to cancer therapy. Recent clinical trials have shown an enhancement of the cytotoxic effect of chemotherapy by adding a PARP inhibitor to the standard treatment. Still, clinical outcome may be even further improved if these drugs would be used as firstline therapy. In conclusion, it can be stated that an exciting new class of drugs has entered the arena of cancer therapy. However, additional clinical studies are needed before PARP inhibitors can definitely enter daily clinical practice.

Peritumoral indoleamine 2,3‐dioxygenase expression in melanoma: an early marker of resistance to immune control?

Indoleamine 2,3‐dioxygenase (IDO) is an emerging immunomodulating factor in cancer. IDO expression in tumour‐negative sentinel lymph nodes (SLNs) of patients with melanoma has a negative prognostic value.

Combination of dabrafenib plus trametinib for BRAF and MEK inhibitor pretreated patients with advanced BRAFV600-mutant melanoma: an open-label, single arm, dual-centre, phase 2 clinical trial

BACKGROUND Patients with BRAFV600-mutant melanoma benefit from treatment with the combination of BRAF and MEK inhibitors, but resistance and disease progression develops in most patients. Preclinical studies and case studies have indicated that acquired resistance to BRAF inhibition can be reversible. We aimed to assess the anti-tumour activity of rechallenge with BRAF plus MEK inhibition in a prospective clinical trial. METHODS In this open-label, single arm, dual-centre, phase 2 academic study in Belgium, patients aged 18 years or older with BRAFV600-mutant melanoma who had previously progressed on BRAF inhibitors (with or without MEK inhibitors) and were off-treatment for at least 12 weeks, were treated with dabrafenib 150 mg orally twice per day plus trametinib 2 mg orally once per day. The primary endpoint was the proportion of patients with investigator-assessed overall response at any time (defined as complete response or partial response according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 confirmed on two occasions, at least 28 days after the first response was recorded). Analyses were done in the intention-to-treat population. The study is ongoing but no longer recruiting patients. This trial is registered with ClinicalTrials.gov, number NCT02296996. FINDINGS Between April 5, 2014, and Feb 2, 2016, 25 patients were enrolled and initiated treatment in our study. A partial response was documented in eight (32%) of 25 patients (95% CI 15-54; six patients had progressed on previous treatment with dabrafenib plus trametinib and two patients had progressed on previous BRAF inhibitor monotherapy). Stable disease was noted in ten patients (40%; 95% CI 21-61). Rechallenge with dabrafenib plus trametinib was well tolerated. There were no unexpected or grade 4 or 5 treatment-related adverse events. Grade 3 adverse events occurred in two patients (8%; panniculitis [n=1] and pyrexia [n=1]). Serious adverse events which occurred on study were one patient with an Addison crisis triggered by grade 2 pyrexia symptoms that resolved after discontinuation of dabrafenib and trametinib. No patients died as a result of study treatment. INTERPRETATION Rechallenge with dabrafenib plus trametinib showed anti-tumour activity in patients who had previously progressed on BRAF inhibitors and as such, rechallenge represents a potential new treatment option for these patients. FUNDING Vlaamse Liga Tegen Kanker, Novartis.

Sunitinib for metastatic renal cell cancer patients: observational study highlighting the risk of important drug–drug interactions

Sunitinib, a CYP3A4 substrate, is standard of care treatment in metastatic renal cell carcinoma (mRCC) and is administered orally as a single dose of 50 mg, in a 4 weeks on/2 weeks off regimen. Frequently, dose reduction is necessary because of toxicity, as is the association of comedication to treat side effects. In addition, existing comorbidities in these patients necessitate the intake of various classes of chronic medication. Only limited data are available on the risk of drug–drug interactions (DDI). The objective of our paper was to evaluate prescribed dose, comedication, risk of drug–drug interactions and outcome among patients with mRCC treated with sunitinib.

Burden of skin cancer in Belgium and cost-effectiveness of primary prevention by reducing ultraviolet exposure

Skin cancer (melanoma- and non-melanoma skin cancer) is one of the most rapidly increasing cancers worldwide. This study analysed the current and future economic burden of skin cancer in Belgium and the cost-effectiveness of primary prevention of skin cancer. A retrospective bottom-up cost-of-illness study was performed, together with a Markov model in order to analyse the cost-effectiveness and the budget impact analysis of primary prevention of skin cancer in Belgium. Total prevalence of skin cancer in Belgium was estimated to triple in the next 20years. The total economic burden of skin cancer in 2014 in Belgium was estimated at €106 million, with a cumulative cost of €3 billion in 2034. The majority of this total cost was due to melanoma (65%). Over a period of 50years, both a sensitisation campaign and a total ban on sunbed use would lead to a gain in quality-adjusted life-years and cost-savings. For every euro invested in the campaign, €3.6 would be saved on the long-term for the healthcare payer. Policy makers and clinicians should promote UV protection strategies, as they were estimated to be dominant strategies.

Cost-effectiveness and Budget Effect Analysis of a Population-Based Skin Cancer Screening

Importance Several epidemiological studies show an alarming global increase in incidence of melanoma and nonmelanoma skin cancer. Objectives To examine the cost-effectiveness of 2 population-based skin cancer screening methods and to assess their budget effect and the influence on skin cancer epidemiological findings. Design, Setting, and Participants A Markov model with a latent period of 20 years and a time horizon of 50 years was used to analyze the cost-effectiveness (societal perspective) and budget effect (public health care payer perspective) of 2 population-based skin cancer screening programs in Belgium compared with the absence of a screening program. A health economic analysis was based on a clinical trial performed in 2014 in Belgium. In the economic model, the total Belgian population 18 years or older was assumed to have been invited for the screening program. Main Outcomes and Measures The influence of the screening program on skin cancer epidemiological findings and the cost per quality-adjusted life-year (QALY) gained, as well as the budget effect, expressed as the net costs for the health care payer over 50 years. Results All participants (1668 total-body skin examination [TBSE] and 248 lesion-directed screening [LDS]) were screened by a team of 6 dermatologists from March 14 to 18, 2014, for TSBE and April 22 and 25 to 27, 2014, for LDS. Both screening strategies produced a gain in QALYs, resulting in incremental cost-effectiveness ratios of &OV0556;33 072 (US

CA 15.3 measurements for separating FDG PET/CT positive from negative findings in breast carcinoma recurrence. Factors influencing the area under the ROC curve.

35 475) per QALY in men and &OV0556;18 687 (US

CA15.3-Messungen zur Unterscheidung positiver und negativer FDG-PET/CT-Befunde bei Mammakarzinomrezidiven

20 044) per QALY in women for TBSE and &OV0556;34 836 (US