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Ghadjar P.,University of Bern | Simcock M.,Swiss Group for Clinical Cancer Research Coordinating Center | Studer G.,University of Zürich | Allal A.S.,Kantonsspital Fribourg | And 7 more authors.
International Journal of Radiation Oncology Biology Physics | Year: 2012

Purpose: To compare the long-term outcome of treatment with concomitant cisplatin and hyperfractionated radiotherapy versus treatment with hyperfractionated radiotherapy alone in patients with locally advanced head and neck cancer. Methods and Materials: From July 1994 to July 2000, a total of 224 patients with squamous cell carcinoma of the head and neck were randomized to receive either hyperfractionated radiotherapy alone (median total dose, 74.4 Gy; 1.2 Gy twice daily; 5 days per week) or the same radiotherapy combined with two cycles of cisplatin (20 mg/m 2 for 5 consecutive days during weeks 1 and 5). The primary endpoint was the time to any treatment failure; secondary endpoints were locoregional failure, metastatic failure, overall survival, and late toxicity assessed according to Radiation Therapy Oncology Group criteria. Results: Median follow-up was 9.5 years (range, 0.1-15.4 years). Median time to any treatment failure was not significantly different between treatment arms (hazard ratio [HR], 1.2 [95% confidence interval {CI}, 0.9-1.7; p = 0.17]). Rates of locoregional failure-free survival (HR, 1.5 [95% CI, 1.1-2.1; p = 0.02]), distant metastasis-free survival (HR, 1.6 [95% CI, 1.1-2.5; p = 0.02]), and cancer-specific survival (HR, 1.6 [95% CI, 1.0-2.5; p = 0.03]) were significantly improved in the combined-treatment arm, with no difference in major late toxicity between treatment arms. However, overall survival was not significantly different (HR, 1.3 [95% CI, 0.9-1.8; p = 0.11]). Conclusions: After long-term follow-up, combined-treatment with cisplatin and hyperfractionated radiotherapy maintained improved rates of locoregional control, distant metastasis-free survival, and cancer-specific survival compared to that of hyperfractionated radiotherapy alone, with no difference in major late toxicity. © 2012 Elsevier Inc.


PubMed | Swiss Group for Clinical Cancer Research Coordinating Center, Hospital Simmental Thun Saanenland AG, University of Lausanne, University of Zürich and 9 more.
Type: | Journal: Clinical lung cancer | Year: 2016

Pemetrexed and bevacizumab as single agents have been approved for maintenance therapy after platinum-based induction in patients with advanced nonsquamous non-small-cell lung cancer. It is currently unknown whether bevacizumab plus pemetrexed is superior to pemetrexed alone.We conducted a nonrandomized phase II trial with 2 sequential cohorts. In the first cohort, 77 patients were treated with 4 cycles of cisplatin, bevacizumab, and pemetrexed every 3 weeks, followed by bevacizumab plus pemetrexed maintenance until progression. In the second cohort, we treated 52 patients without bevacizumab, using maintenance with pemetrexed alone. Progression-free survival (PFS), overall survival (OS), overall response rate (ORR), adverse events, and the treatment costs of the 2 cohorts were compared.The median PFS from the time of registration was 6.9 months in cohort 1 and 5.6 months in cohort 2. The ORR was 62.3% in cohort 1% and 44.2% in cohort 2. The PFS (hazard ratio, 0.7; 95% confidence interval [CI], 0.5-1.0; P= .041) and ORR (odds ratio, 2.1; 95% CI, 1.0-4.3; P=.049) were better in cohort 1 than in cohort 2. No OS difference was found (hazard ratio, 1.0; 95% CI, 0.7-1.6; P=.890) after a median follow-up period of 47 months for cohort 1 and 27 months for cohort 2. The rate of grade 3 adverse events was greater in cohort 1. The treatment costs per patient were on average 1.4 times greater for cohort1.The addition of bevacizumab increased the ORR and PFS, but not OS, in our nonrandomized trial. Furthermore, the addition of bevacizumab was associated with greater toxicity and higher costs.


PubMed | Cantonal Hospital, Lady Davis Institute for Medical Research, Erasmus University Rotterdam, Swiss Group for Clinical Cancer Research Coordinating Center and The Netherlands 2 Pharmacy Foundation of Haarlem Hospitals
Type: Journal Article | Journal: Prostate cancer and prostatic diseases | Year: 2015

This study was initiated to explore the impact of organic cation transporter 1 (OCT1) and multidrug and toxin extrusion transporter 1 (MATE1) genetic polymorphisms on toxicity, and clinical activity of metformin in patients with castration-resistant prostate cancer (CRPC).The SAKK 08/09 trial included 44 patients with CRPC to receive single-agent metformin 1000mg two times a day until disease progression or unwanted toxicity. Drug pathway-associated gene polymorphisms of OCT1 (rs622342) and MATE1 (rs2289669) were assessed. The primary objective of this study was to define the relationship between mutations in OCT1, MATE1 and progression-free survival (PFS) at 12 weeks absolute PFS and PSA response in consenting patients of SAKK 08/09. The secondary objective of this study was to analyze the association between mutations in OCT1, MATE1, metformin-related toxicity, PSA response at 12 weeks and overall survival.Thirty-six patients were evaluable for pharmacogenetic analysis. Homozygous carriers of the polymorphic OCT1 C-allele had no metformin-related toxicity as compared with 41.9% for any metformin-related toxicity in carriers of at least one wild-type A-allele (P=0.07). Disease progression according to RECIST (Response Evaluation Criteria In Solid Tumors) was significantly more frequent in homozygous carriers of the polymorphic OCT1 C-allele (80%) as compared with carriers of at least one wild-type A-allele (28.6%) (P=0.002). Disease progression according to RECIST was also more frequent in carriers of at least one polymorphic MATE1 A-allele (44%) as compared with homozygous carriers of the wild-type G-allele (12.5%) (P=0.07). OCT1 and MATE1 were not associated with PFS.The polymorphic OCT1 C-allele has been shown to be associated with less metformin-related toxicity and a higher risk of tumor progression in patients with CRPC receiving metformin as an anticancer treatment. Polymorphisms in metformin drug transporters are attractive molecular markers to serve as potential predictors of efficacy in future clinical studies.


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 | Year: 2015

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.


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 | Year: 2010

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.


Cathomas R.,Oncology Haematology | Klingbiel D.,Swiss Group for Clinical Cancer Research Coordinating Center | Geldart T.R.,Poole and Royal Bournemouth Hospitals | Mead G.M.,University of Southampton | And 6 more authors.
Annals of Oncology | Year: 2014

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.


Ghadjar P.,University of Bern | Bojaxhiu B.,University of Bern | Simcock M.,Swiss Group for Clinical Cancer Research Coordinating Center | Terribilini D.,University of Bern | And 8 more authors.
International Journal of Radiation Oncology Biology Physics | Year: 2012

Purpose: To analyze the outcome after low-dose-rate (LDR) or high-dose-rate (HDR) brachytherapy for lip cancer. Methods and Materials: One hundred and three patients with newly diagnosed squamous cell carcinoma of the lip were treated between March 1985 and June 2009 either by HDR (n = 33) or LDR brachytherapy (n = 70). Sixty-eight patients received brachytherapy alone, and 35 received tumor excision followed by brachytherapy because of positive resection margins. Acute and late toxicity was assessed according to the Common Terminology Criteria for Adverse Events 3.0. Results: Median follow-up was 3.1 years (range, 0.3-23 years). Clinical and pathological variables did not differ significantly between groups. At 5 years, local recurrence-free survival, regional recurrence-free survival, and overall survival rates were 93%, 90%, and 77%. There was no significant difference for these endpoints when HDR was compared with LDR brachytherapy. Forty-two of 103 patients (41%) experienced acute Grade 2 and 57 of 103 patients (55%) experienced acute Grade 3 toxicity. Late Grade 1 toxicity was experienced by 34 of 103 patients (33%), and 5 of 103 patients (5%) experienced late Grade 2 toxicity; no Grade 3 late toxicity was observed. Acute and late toxicity rates were not significantly different between HDR and LDR brachytherapy. Conclusions: As treatment for lip cancer, HDR and LDR brachytherapy have comparable locoregional control and acute and late toxicity rates. HDR brachytherapy for lip cancer seems to be an effective treatment with acceptable toxicity. © 2012 Elsevier Inc.


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.
PharmacoEconomics | Year: 2014

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.


PubMed | University of Basel, Cantonal Hospital Lucerne, Swiss Group for Clinical Cancer Research Coordinating Center, Swiss Medical Group and University of Zürich
Type: Journal Article | Journal: Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer | Year: 2016

Nivolumab (NIV) was recently approved in several countries for patients with pretreated advanced NSCLC. NIV is not cost-effective compared with docetaxel (DOC) for the treatment of squamous NSCLC. However, its cost-effectiveness for nonsquamous NSCLC and the consequences of programmed death ligand 1 (PD-L1) testing are unknown.This literature-based health economic study used CheckMate-057 trial data to model the incremental cost-effectiveness ratio (ICER) of NIV versus DOC in the Swiss health care setting. The effect of PD-L1 positivity for patient selection was assessed.In the base case model, NIV (mean cost CHF66,208; mean effect 0.69 quality-adjusted life-years [QALYs]) compared with DOC (mean cost CHF37,618; mean effect 0.53 QALYs) resulted in an ICER of CHF177,478/QALY gained. Treating only patients with PD-L1-positive tumors (threshold 10%) with NIV compared with treating all patients with DOC produced a base case ICER of CHF124,891/QALY gained. Reduced drug price, dose, or treatment duration decreased the ICER partly below a willingness-to-pay threshold of CHF100,000/QALY. Health state utilities strongly influenced cost-effectiveness.Compared with DOC, NIV is not cost-effective for the treatment of nonsquamous NSCLC at current prices in the Swiss health care setting. Price reduction or PD-L1 testing and selection of patients for NIV on the basis oftest positivity improves cost-effectiveness compared withDOC.


PubMed | Instituto Nazionale Tumori Fondazione G Pascale and Swiss Group for Clinical Cancer Research Coordinating Center
Type: | Journal: Cancer treatment reviews | Year: 2016

Endometrial Cancer (EC) is still a challenge for gynecological oncologists because the treatment of the advanced disease remains an unmet need for patients. The Cancer Genome Atlas Research Network (TCGA) recently provided a comprehensive genomic and transcriptomic analysis of EC, offering a new classification of the disease, based on genetic features, which defines four subgroups of cancer rather than the two traditionally recognized. In the molecular classification two types of EC, the polymerase epsilon (POLE)-ultramutated and the microsatellite instability (MSI)-hypermutated, seem to present an enhanced immune microenvironment and a high mutation burden. The blockade of the immune checkpoints is an innovative approach that has largely demonstrated to be effective in solid malignancies, such as lung, renal and melanoma; it acts by reducing the cancer-induced immune-suppression through inhibition of the PD-1/PD-L1 (Programmed Death and PD-Ligand) axis. All available evidence supporting an over-expression of the PD-1/PD-L1 pathway in EC has been reviewed. In particular in the POLE and MSI ECs an up-regulation of this pathway was found, aiming to suggest a rationale for testing the PD-1/PD-L1 immunotherapy in these cancer subgroups.

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