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Matter-Walstra K.,University of Basel | Matter-Walstra K.,Swiss Group for Clinical Cancer Research Coordinating Center | Klingbiel D.,Swiss Group for Clinical Cancer Research Coordinating Center | Szucs T.,University of Basel | And 2 more authors.

Background: The European Quality of Life-5 Dimensions (EQ-5D) instrument combines questionnaire responses into a single utility estimate using country-specific value sets. Countries without a national value set are advised to select one based on geographic proximity. In the absence of a Swiss value set, we used foreign value sets to gain insights into their appropriateness for use with Swiss cancer patients. Methods: EQ-5D health states and visual analogue scale (VAS) ratings were collected in one German and three Swiss oncology trials. Utilities were calculated based on the United Kingdom (UK), German (GE), French (FR) and European Union (EU) value sets. Resulting differences and Pearson partial correlation coefficients with corresponding VAS ratings were assessed. Results: In total, 202 Swiss and 154 German patients undergoing cancer treatment completed at least two EQ-5D forms. The mean difference between GE-based and FR-, UK- or EU-based utilities was significantly larger than the differences between the latter. The absolute mean difference between utilities and VAS ratings was highest for GE-based utilities, for Swiss (0.170, 95 % confidence interval [CI] 0.146-0.194) and German patients (0.174, 95 % CI 0.145-0.202). The correlation between GE-based utilities and VAS ratings was the lowest (r = 0.36, 95 % CI 0.33-0.40); the highest was between FR-based utilities and VAS ratings (r = 0.43, 95 % CI 0.39-0.46). Conclusion: For Switzerland, utility calculations based on the German or French value set would be an obvious choice. Our results suggest that the German value set may not be the most appropriate for use with Swiss cancer patients. The French and EU value sets may be relevant alternatives and improve international comparability. © 2014 Springer International Publishing. Source

Chau C.,University of Southampton | Cathomas R.,Kantonsspital Graubunden | Wheater M.,University of Southampton | Klingbiel D.,Swiss Group for Clinical Cancer Research Coordinating Center | And 6 more authors.
Annals of Oncology

Background: Following inguinal orchidectomy, management options for patients with stage I seminoma include initial surveillance or treatment with adjuvant radiotherapy or chemotherapy. The anticipated relapse rate for patients followed by surveillance alone is ~15%, with adjuvant treatment this risk is reduced to ~4%-5% at 5 years. After carboplatin treatment, follow-up strategies vary and there are no validated, predictive markers of relapse. Patients and methods: We conducted a retrospective analysis of all patients presenting with stage I seminoma who received a single cycle of adjuvant carboplatin in South Central England between 1996 and 2013. We report on outcome and the results of univariate and multivariate analysis evaluating possible risk factors for post carboplatin relapse. Results: A total of 517 eligible patients were identified. All underwent nuclear medicine estimation of glomerular filtration rate before treatment with carboplatin (dosed at area under the curve × 7). With a median follow-up of 47.2 months (range 0.4-214 months), 21/517 patients have relapsed resulting in a 5-year estimated relapse-free survival of 95.0% (95% confidence interval 92.8% to 97.3%). Median time to relapse was 22.7 months (range 12.5-109.5 months). Relapse beyond 3 years was rare (4/517; 0.8%). Twenty of 21 (95%) relapsed patients had retroperitoneal lymph node metastases. The majority (16/21; 76%) of patients had elevated tumour markers at relapse. Twenty of 517 (3.9%) patients developed a new contralateral testicular germ-cell cancer. There were no seminoma-related deaths. Tumour size was the only variable significantly associated with an increased risk of relapse. Conclusions: Overall results for this large cohort of patients confirm an excellent prognosis for these patients with outcomes equivalent to those seen in prospective clinical trials. Increasing tumour size alone appears to be associated with an increased risk of post chemotherapy relapse. © The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. Source

Cathomas R.,Oncology Haematology | Klingbiel D.,Swiss Group for Clinical Cancer Research Coordinating Center | Geldart T.R.,Medical Oncology | Mead G.M.,University of Southampton | And 6 more authors.
Annals of Oncology

Background: Seminoma stage I is the most frequent testis cancer and single-dose carboplatin (AUC7) is an effective and widely used adjuvant treatment. Underdosing of carboplatin by 10% has been shown to almost double the rate of relapse and hence correct dosing based on accurate GFR measurement is crucial. The gold standard of GFR measurement with a radiolabelled isotope is expensive and not readily available. In many institutions, it is replaced by GFR estimation with the Cockcroft-Gault formula, which might lead to significant carboplatin underdosing and potentially inferior clinical outcome. Methods: Retrospective analysis of all patients with stage I seminoma treated with adjuvant carboplatin between 1999 and 2012. All patients had serum creatinine measured and underwent GFR measurement with a radioisotope (51Cr EDTA or 99mTc DTPA), which was compared with seven standard GFR estimation formulae (Cockcroft-Gault, CKD-EPI, Jelliffe, Martin, Mayo, MDRD, Wright) and a flat dosing strategy. Bias, precision, rates of under- and overdosing of GFR estimates were compared with measured GFR. Bland-Altman plots were done. Results: A total of 426 consecutive Caucasian male patients were included: median age 39 years (range 19-60 years), median measured GFR 118ml/min (51-209), median administered carboplatin dose 1000mg (532-1638). In comparison to isotopic GFR measurement, a relevant proportion of patients would have received ≤90% of carboplatin dose through the use of GFR estimation formulae: 4% using Mayo, 9% Martin, 18% Cockcroft-Gault, 24% Wright, 63% Jelliffe, 49% MDRD and 41% using CKD-EPI. The flat dosing strategy, Wright and Cockcroft-Gault formulae, showed the smallest bias with mean percentage error of +1.9, +0.4 and +2.1, respectively. Conclusions: Using Cockcroft-Gault or any other formula for GFR estimation leads to underdosing of adjuvant carboplatin in a relevant number of patients with Seminoma stage I and should not be regarded as standard of care. © The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. Source

Ghadjar P.,University of Bern | Schreiber-Facklam H.,University of Bern | Grater R.,University of Bern | Evers C.,University of Bern | And 7 more authors.
International Journal of Radiation Oncology Biology Physics

Purpose: We performed a histopathologic analysis to assess the extent of the extracapsular extension (ECE) beyond the capsule of metastatic lymph nodes (LN) in head and neck cancer to determine appropriate clinical target volume (CTV) expansions. Methods and Materials: All tumor-positive LN of 98 patients who underwent a neck dissection with evidence of ECE in at least one LN were analyzed by a single pathologist. The largest diameters of all LN, and in the case of ECE, the maximal linear distance, from the capsule to the farthest extent of tumor or tumoral reaction were recorded. Results: A total of 231 LN with ECE and 200 tumor-positive LN without ECE were analyzed. The incidence of ECE was associated with larger LN size (p < 0.001). Of all tumor-positive LN with a diameter of < 10 mm or < 5 mm, 105/220 (48%) nodes or 17/59 (29%) nodes, respectively, showed evidence of ECE. The mean and median extent values of ECE were 2 and 1 mm (range, 1-10 mm) and the ECE was ≤ 5 mm in 97% and ≤ 3 mm in 91% of the LN, respectively. Overall, the extent of ECE was significantly correlated with larger LN size (Spearman's correlation coefficient = 0.21; p = 0.001). Conclusions: The incidence of ECE is associated with larger LN size. However, ECE is found in a substantial number of LN with a diameter of < 10 mm. The use of 10-mm CTV margins around the gross tumor volume seems appropriate to account for ECE in radiotherapy planning of head and neck cancer. © 2010 Elsevier Inc. All rights reserved. Source

Schraml P.,University of Zurich | Von Teichman A.,University of Zurich | Mihic-Probst D.,University of Zurich | Simcock M.,Swiss Group for Clinical Cancer Research Coordinating Center | And 7 more authors.
Oncology Reports

The O6-methylguanine-DNA-methyltransferase (MGMT) promoter methylation status is a predictive parameter for the response of malignant gliomas to alkylating agents such as temozolomide. First clinical trials with temozolomide plus bevacizumab therapy in metastatic melanoma patients are ongoing, although the predictive value of the MGMT promoter methylation status in this setting remains unclear. We assessed MGMT promoter methylation in formalin-fixed, primary tumor tissue of metastatic melanoma patients treated with first-line temozolomide and bevacizumab from the trial SAKK 50/07 by methylation-specific polymerase chain reaction. In addition, the MGMT expression levels were also analyzed by MGMT immunohistochemistry. Eleven of 42 primary melanomas (26%) revealed a methylated MGMT promoter. Promoter methylation was significantly associated with response rates CR + PR versus SD + PD according to RECIST (response evaluation criteria in solid tumors) (p<0.05) with a trend to prolonged median progression-free survival (8.1 versus 3.4 months, p>0.05). Immunohistochemically different protein expression patterns with heterogeneous and homogeneous nuclear MGMT expression were identified. Negative MGMT expression levels were associated with overall disease stabilization CR + PR + SD versus PD (p=0.05). There was only a poor correlation between MGMT methylation and lack of MGMT expression. A significant proportion of melanomas have a methylated MGMT promoter. The MGMT promoter methylation status may be a promising predictive marker for temozolomide therapy in metastatic melanoma patients. Larger sample sizes may help to validate significant differences in survival type endpoints. Source

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