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Switzerland

Cancer Statistics
Population in 2012: 7.7m
People newly diagnosed with cancer (excluding NMSC) / yr: 42,000
Age-standardised rate, incidence per 100,000 people/yr: 287.0
Risk of getting cancer before age 75:28.8%
People dying from cancer /yr: 16,400
Data from IARC GlobalCan (2012)
Swiss Cancer Organisations
Recent Research Publications from Switzerland

Swiss Cancer Organisations (14 links)


Recent Research Publications from Switzerland

Cheson BD, Trask PC, Gribben JG, et al.
Health-related quality of life and symptoms in patients with rituximab-refractory indolent non-Hodgkin lymphoma treated in the phase III GADOLIN study with obinutuzumab plus bendamustine versus bendamustine alone.
Ann Hematol. 2017; 96(2):253-259 [PubMed] Free Access to Full Article Related Publications
We present health-related quality of life (HRQoL) data from GADOLIN, comparing bendamustine (B) alone or combined with obinutuzumab (G-B) in rituximab-refractory indolent non-Hodgkin lymphoma patients. The Functional Assessment of Cancer Treatment-Lymphoma (FACT-Lym) questionnaire was administered on day 1 of cycles 1, 3, and 5 during treatment, at end of induction (EOI), bi-monthly for 2 years during maintenance/follow-up, and annually during extended follow-up until progression/death. Time to first ≥6-point worsening from baseline in the FACT-Lym trial outcome index (TOI) was estimated. Minimally important differences at individual subscale and total score level were used to define the proportion of patients reporting improvement on the FACT-Lym lymphoma-specific subscale (≥3 points), FACT-Lym TOI (≥6 points), and FACT-Lym total score (≥7 points). Overall, 396 patients were randomized. Analysis was conducted when 175 Independent Review Committee-assessed progression-free survival (PFS) events were observed. Questionnaire completion rates were generally balanced between arms at baseline, EOI, and final follow-up. Median time to ≥6-point worsening from baseline on the FACT-Lym TOI was 8.0 months in the G-B arm and 4.6 months in the B arm (HR 0.74; 95% CI 0.56-0.98). More G-B patients reported meaningful improvements on the FACT-Lym questionnaire subscales. Results were similar when follicular lymphoma patients were analyzed separately. The delayed time to worsening and greater proportion of patients reporting meaningful improvement in HRQoL in the G-B arm suggest that benefit in PFS is not at the expense of an increase in treatment-related toxicity that could lead to reduced HRQoL.

Kollár A, Jones RL, Stacchiotti S, et al.
Pazopanib in advanced vascular sarcomas: an EORTC Soft Tissue and Bone Sarcoma Group (STBSG) retrospective analysis.
Acta Oncol. 2017; 56(1):88-92 [PubMed] Related Publications
BACKGROUND: Pazopanib is a multitargeted tyrosine kinase inhibitor approved for the treatment of patients with selective subtypes of advanced soft tissue sarcoma (STS) who have previously received standard chemotherapy including anthracyclines. Data on the efficacy in vascular sarcomas are limited. The main objective of this study was to investigate the activity of pazopanib in vascular sarcomas.
PATIENTS AND METHODS: A retrospective study of patients with advanced vascular sarcomas, including angiosarcoma (AS), epithelioid hemangioendothelioma (HE) and intimal sarcoma (IS) treated with pazopanib in real life practice at EORTC centers as well as patients treated within the EORTC phase II and III clinical trials (62043/62072) was performed. Patient and tumor characteristics were collected. Response was assessed according to RECIST 1.1. and survival analysis was performed.
RESULTS: Fifty-two patients were identified, 40 (76.9%), 10 (19.2%) and two (3.8%) with AS, HE and IS, respectively. The response rate was eight (20%), two (20%) and two (100%) in the AS, HE and IS subtypes, respectively. There was no significant difference in response rate between cutaneous and non-cutaneous AS and similarly between radiation-associated and non-radiation-associated AS. Median progression-free survival (PFS) and median overall survival (OS; from commencing pazopanib) were three months (95% CI 2.1-4.4) and 9.9 months (95% CI 6.5-11.3) in AS, respectively.
CONCLUSION: The activity of pazopanib in AS is comparable to its reported activity in other STS subtypes. In this study, the activity of pazopanib was similar in cutaneous/non-cutaneous and in radiation/non-radiation-associated AS. In addition, pazopanib showed promising activity in HE and IS, worthy of further evaluation.

Hortobagyi GN, Stemmer SM, Burris HA, et al.
Ribociclib as First-Line Therapy for HR-Positive, Advanced Breast Cancer.
N Engl J Med. 2016; 375(18):1738-1748 [PubMed] Related Publications
Background The inhibition of cyclin-dependent kinases 4 and 6 (CDK4/6) could potentially overcome or delay resistance to endocrine therapy in advanced breast cancer that is positive for hormone receptor (HR) and negative for human epidermal growth factor receptor 2 (HER2). Methods In this randomized, placebo-controlled, phase 3 trial, we evaluated the efficacy and safety of the selective CDK4/6 inhibitor ribociclib combined with letrozole for first-line treatment in 668 postmenopausal women with HR-positive, HER2-negative recurrent or metastatic breast cancer who had not received previous systemic therapy for advanced disease. We randomly assigned the patients to receive either ribociclib (600 mg per day on a 3-weeks-on, 1-week-off schedule) plus letrozole (2.5 mg per day) or placebo plus letrozole. The primary end point was investigator-assessed progression-free survival. Secondary end points included overall survival, overall response rate, and safety. A preplanned interim analysis was performed on January 29, 2016, after 243 patients had disease progression or died. Prespecified criteria for superiority required a hazard ratio of 0.56 or less with P<1.29×10(-5). Results The duration of progression-free survival was significantly longer in the ribociclib group than in the placebo group (hazard ratio, 0.56; 95% CI, 0.43 to 0.72; P=3.29×10(-6) for superiority). The median duration of follow-up was 15.3 months. After 18 months, the progression-free survival rate was 63.0% (95% confidence interval [CI], 54.6 to 70.3) in the ribociclib group and 42.2% (95% CI, 34.8 to 49.5) in the placebo group. In patients with measurable disease at baseline, the overall response rate was 52.7% and 37.1%, respectively (P<0.001). Common grade 3 or 4 adverse events that were reported in more than 10% of the patients in either group were neutropenia (59.3% in the ribociclib group vs. 0.9% in the placebo group) and leukopenia (21.0% vs. 0.6%); the rates of discontinuation because of adverse events were 7.5% and 2.1%, respectively. Conclusions Among patients receiving initial systemic treatment for HR-positive, HER2-negative advanced breast cancer, the duration of progression-free survival was significantly longer among those receiving ribociclib plus letrozole than among those receiving placebo plus letrozole, with a higher rate of myelosuppression in the ribociclib group. (Funded by Novartis Pharmaceuticals; ClinicalTrials.gov number, NCT01958021 .).

Wu YL, Zhang LI, Trandafir L, et al.
Phase I Study of the Pan-PI3K Inhibitor Buparlisib in Adult Chinese Patients with Advanced Solid Tumors.
Anticancer Res. 2016; 36(11):6185-6194 [PubMed] Related Publications
BACKGROUND/AIM: The phosphatidylinositol-3-kinase (PI3K) signaling pathway is frequently activated in cancer. Buparlisib (BKM120), an oral pan-PI3K inhibitor, inhibits proliferation of human cancer in preclinical models. Studies of buparlisib in Western and Japanese adults with advanced solid tumors established a recommended dose of 100 mg/day and showed an acceptable safety profile and evidence of efficacy. This phase I dose-escalation/expansion study aimed to establish the maximum tolerated dose (MTD) of single-agent, once daily oral buparlisib in Chinese patients with advanced solid tumors.
MATERIALS AND METHODS: Patients (n=32; primary tumor site: lung (n=15), breast (n=10) or head and neck (n=7); ≥2 prior lines of antineoplastic therapy (n=26)) received 80 mg (n=15) or 100 mg (n=17) daily buparlisib.
RESULTS: Five patients experienced dose-limiting toxicities: grade (G)3 depression (n=1), G2 hyperglycemia (n=3) and G3 hyperglycemia (n=1). Most frequent buparlisib-related adverse events were hyperglycemia (n=18; 56%), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) increase (n=9; 28%), as well as anxiety (n=6; 19%); most common buparlisib-related G3/4 adverse events: hyperglycemia (n=3; 9%), ALT and AST increase (n=2; 6%), as well as gamma-glutamyltransferase increase (n=2; 6%). Best response was stable disease (SD) in 10 patients (31%).
CONCLUSION: The MTD of buparlisib was declared as 100 mg/day. Safety, efficacy and pharmacokinetic data from this study were similar to those previously reported in Western and Japanese populations.

Engstrand J, Toporek G, Harbut P, et al.
Stereotactic CT-Guided Percutaneous Microwave Ablation of Liver Tumors With the Use of High-Frequency Jet Ventilation: An Accuracy and Procedural Safety Study.
AJR Am J Roentgenol. 2017; 208(1):193-200 [PubMed] Related Publications
OBJECTIVE: The purpose of the present study is to evaluate the accuracy and safety of antenna placement performed with the use of a CT-guided stereotactic navigation system for percutaneous ablation of liver tumors and to assess the safety of high-frequency jet ventilation for target motion control.
MATERIALS AND METHODS: Twenty consecutive patients with malignant liver lesions for which surgical resection was contraindicated or that were not readily visible on ultrasound or not accessible by ultrasound guidance were included in the study. Patients were treated with percutaneous microwave ablation performed using a CT-guided stereotactic navigation system. High-frequency jet ventilation was used to reduce liver motion during all interventions. The accuracy of antenna placement, the number of needle readjustments required, overall safety, and the radiation doses were assessed.
RESULTS: Microwave ablation was completed for 20 patients (28 lesions). Performance data could be evaluated for 17 patients with 25 lesions (mean [± SD] lesion diameter, 14.9 ± 5.9 mm; mean lesion location depth, 87.5 ± 27.3 mm). The antennae were placed with a mean lateral error of 4.0 ± 2.5 mm, a depth error of 3.4 ± 3.2 mm, and a total error of 5.8 ± 3.2 mm in relation to the intended target. The median number of antenna readjustments required was zero (range, 0-1 adjustment). No major complications were related to either the procedure or the use of high-frequency jet ventilation. The mean total patient radiation dose was 957.5 ± 556.5 mGy × cm, but medical personnel were not exposed to irradiation.
CONCLUSION: Percutaneous microwave ablation performed with CT-guided stereotactic navigation provides sufficient accuracy and requires almost no repositioning of the needle. Therefore, it is technically feasible and applicable for safe treatments.

Ferris RL, Blumenschein G, Fayette J, et al.
Nivolumab for Recurrent Squamous-Cell Carcinoma of the Head and Neck.
N Engl J Med. 2016; 375(19):1856-1867 [PubMed] Related Publications
Background Patients with recurrent or metastatic squamous-cell carcinoma of the head and neck after platinum chemotherapy have a very poor prognosis and limited therapeutic options. Nivolumab, an anti-programmed death 1 (PD-1) monoclonal antibody, was assessed as treatment for this condition. Methods In this randomized, open-label, phase 3 trial, we assigned, in a 2:1 ratio, 361 patients with recurrent squamous-cell carcinoma of the head and neck whose disease had progressed within 6 months after platinum-based chemotherapy to receive nivolumab (at a dose of 3 mg per kilogram of body weight) every 2 weeks or standard, single-agent systemic therapy (methotrexate, docetaxel, or cetuximab). The primary end point was overall survival. Additional end points included progression-free survival, rate of objective response, safety, and patient-reported quality of life. Results The median overall survival was 7.5 months (95% confidence interval [CI], 5.5 to 9.1) in the nivolumab group versus 5.1 months (95% CI, 4.0 to 6.0) in the group that received standard therapy. Overall survival was significantly longer with nivolumab than with standard therapy (hazard ratio for death, 0.70; 97.73% CI, 0.51 to 0.96; P=0.01), and the estimates of the 1-year survival rate were approximately 19 percentage points higher with nivolumab than with standard therapy (36.0% vs. 16.6%). The median progression-free survival was 2.0 months (95% CI, 1.9 to 2.1) with nivolumab versus 2.3 months (95% CI, 1.9 to 3.1) with standard therapy (hazard ratio for disease progression or death, 0.89; 95% CI, 0.70 to 1.13; P=0.32). The rate of progression-free survival at 6 months was 19.7% with nivolumab versus 9.9% with standard therapy. The response rate was 13.3% in the nivolumab group versus 5.8% in the standard-therapy group. Treatment-related adverse events of grade 3 or 4 occurred in 13.1% of the patients in the nivolumab group versus 35.1% of those in the standard-therapy group. Physical, role, and social functioning was stable in the nivolumab group, whereas it was meaningfully worse in the standard-therapy group. Conclusions Among patients with platinum-refractory, recurrent squamous-cell carcinoma of the head and neck, treatment with nivolumab resulted in longer overall survival than treatment with standard, single-agent therapy. (Funded by Bristol-Myers Squibb; CheckMate 141 ClinicalTrials.gov number, NCT02105636 .).

Eggermont AM, Chiarion-Sileni V, Grob JJ, et al.
Prolonged Survival in Stage III Melanoma with Ipilimumab Adjuvant Therapy.
N Engl J Med. 2016; 375(19):1845-1855 [PubMed] Related Publications
Background On the basis of data from a phase 2 trial that compared the checkpoint inhibitor ipilimumab at doses of 0.3 mg, 3 mg, and 10 mg per kilogram of body weight in patients with advanced melanoma, this phase 3 trial evaluated ipilimumab at a dose of 10 mg per kilogram in patients who had undergone complete resection of stage III melanoma. Methods After patients had undergone complete resection of stage III cutaneous melanoma, we randomly assigned them to receive ipilimumab at a dose of 10 mg per kilogram (475 patients) or placebo (476) every 3 weeks for four doses, then every 3 months for up to 3 years or until disease recurrence or an unacceptable level of toxic effects occurred. Recurrence-free survival was the primary end point. Secondary end points included overall survival, distant metastasis-free survival, and safety. Results At a median follow-up of 5.3 years, the 5-year rate of recurrence-free survival was 40.8% in the ipilimumab group, as compared with 30.3% in the placebo group (hazard ratio for recurrence or death, 0.76; 95% confidence interval [CI], 0.64 to 0.89; P<0.001). The rate of overall survival at 5 years was 65.4% in the ipilimumab group, as compared with 54.4% in the placebo group (hazard ratio for death, 0.72; 95.1% CI, 0.58 to 0.88; P=0.001). The rate of distant metastasis-free survival at 5 years was 48.3% in the ipilimumab group, as compared with 38.9% in the placebo group (hazard ratio for death or distant metastasis, 0.76; 95.8% CI, 0.64 to 0.92; P=0.002). Adverse events of grade 3 or 4 occurred in 54.1% of the patients in the ipilimumab group and in 26.2% of those in the placebo group. Immune-related adverse events of grade 3 or 4 occurred in 41.6% of the patients in the ipilimumab group and in 2.7% of those in the placebo group. In the ipilimumab group, 5 patients (1.1%) died owing to immune-related adverse events. Conclusions As adjuvant therapy for high-risk stage III melanoma, ipilimumab at a dose of 10 mg per kilogram resulted in significantly higher rates of recurrence-free survival, overall survival, and distant metastasis-free survival than placebo. There were more immune-related adverse events with ipilimumab than with placebo. (Funded by Bristol-Myers Squibb; ClinicalTrials.gov number, NCT00636168 , and EudraCT number, 2007-001974-10 .).

Maury S, Chevret S, Thomas X, et al.
Rituximab in B-Lineage Adult Acute Lymphoblastic Leukemia.
N Engl J Med. 2016; 375(11):1044-53 [PubMed] Related Publications
BACKGROUND: Treatment with rituximab has improved the outcome for patients with non-Hodgkin's lymphoma. Patients with B-lineage acute lymphoblastic leukemia (ALL) may also have the CD20 antigen, which is targeted by rituximab. Although single-group studies suggest that adding rituximab to chemotherapy could improve the outcome in such patients, this hypothesis has not been tested in a randomized trial.
METHODS: We randomly assigned adults (18 to 59 years of age) with CD20-positive, Philadelphia chromosome (Ph)-negative ALL to receive chemotherapy with or without rituximab, with event-free survival as the primary end point. Rituximab was given during all treatment phases, for a total of 16 to 18 infusions.
RESULTS: From May 2006 through April 2014, a total of 209 patients were enrolled: 105 in the rituximab group and 104 in the control group. After a median follow-up of 30 months, event-free survival was longer in the rituximab group than in the control group (hazard ratio, 0.66; 95% confidence interval [CI], 0.45 to 0.98; P=0.04); the estimated 2-year event-free survival rates were 65% (95% CI, 56 to 75) and 52% (95% CI, 43 to 63), respectively. Treatment with rituximab remained associated with longer event-free survival in a multivariate analysis. The overall incidence rate of severe adverse events did not differ significantly between the two groups, but fewer allergic reactions to asparaginase were observed in the rituximab group.
CONCLUSIONS: Adding rituximab to the ALL chemotherapy protocol improved the outcome for younger adults with CD20-positive, Ph-negative ALL. (Funded by the Regional Clinical Research Office, Paris, and others; ClinicalTrials.gov number, NCT00327678 .).

Vrieling C, van Werkhoven E, Maingon P, et al.
Prognostic Factors for Local Control in Breast Cancer After Long-term Follow-up in the EORTC Boost vs No Boost Trial: A Randomized Clinical Trial.
JAMA Oncol. 2017; 3(1):42-48 [PubMed] Related Publications
Importance: Prognostic factors of ipsilateral breast tumor recurrence (IBTR) may change over time following breast-conserving therapy.
Objective: The EORTC "boost no boost" trial showed that young age and high-grade invasive carcinoma were the most important risk factors for IBTR. This study reanalyses pathological prognostic factors related to IBTR using long-term follow-up.
Design, Setting, and Participants: Participants included 5569 early-stage breast cancer patients, treated with breast-conserving surgery (BCS) and whole-breast irradiation (WBI), who were randomized between no boost and a 16-Gy boost in the EORTC phase III "boost no boost" trial (1989-1996). A total of 1616 patients with a microscopically complete resection (according to local pathologists), included in the central pathology review, have been analyzed in this study. Median follow-up was 18.2 years.
Interventions: No further treatment or 16-Gy boost, after BCS and 50-Gy WBI.
Main Outcomes and Measures: Time to ipsilateral breast tumor recurrence (IBTR) as first event.
Results: The 20-year cumulative incidence of IBTR in 1616 patients (160 events observed) was 15% (95% CI, 12%-17%). Young age (P < .001) and presence of ductal carcinoma in situ (DCIS) (HR, 2.15; 95% CI, 1.36-3.38; P = .001) were associated with an increased risk of IBTR in multivariable analysis. The cumulative incidence of IBTR at 20 years was 34% (95% CI, 25%-41%), 14% (95% CI, 10%-18%), and 11% (95% CI, 8%-15%), in patients 40 years or younger, 41 to 50 years and 50 years or older, respectively (P < .001). This incidence was 18% (95% CI, 14%-22%) and 9% (95% CI, 6%-12%) for tumors with and without DCIS (P < .001). High-grade tumors relapsed more frequently early during follow-up but the relative effect of age and presence of DCIS seemed stable over time. The boost reduced the 20-year IBTR incidence from 31% (95% CI, 22%-39%) to 15% (95% CI, 8%-21%) (HR, 0.37; 95% CI, 0.22-0.62; P < .001) in high-risk patients (≤50 years with DCIS present).
Conclusions and Relevance: The association of high-grade invasive tumor with IBTR diminished during follow-up, while the effect of DCIS adjacent to invasive tumor seemed to remain stable. Therefore, patients with high-grade invasive tumors should be monitored closely, especially in the first 5 years, while additional DCIS is an indication for longer follow-up, emphasizing the importance of long-term trial follow-up to estimate absolute effects accurately.
Trial Registration: clinicaltrials.gov Identifier: NCT02295033.

Sachpekidis C, Hillengass J, Goldschmidt H, et al.
Treatment response evaluation with (18)F-FDG PET/CT and (18)F-NaF PET/CT in multiple myeloma patients undergoing high-dose chemotherapy and autologous stem cell transplantation.
Eur J Nucl Med Mol Imaging. 2017; 44(1):50-62 [PubMed] Related Publications
AIM: The aim of this study was to assess the combined use of the radiotracers (18)F-FDG and (18)F-NaF in treatment response evaluation of a group of multiple myeloma (MM) patients undergoing high-dose chemotherapy (HDT) followed by autologous stem cell transplantation (ASCT) by means of static (whole-body) and dynamic PET/CT (dPET/CT).
PATIENTS AND METHODS: Thirty-four patients with primary, previously untreated MM scheduled for treatment with HDT followed by ASCT were enrolled in the study. All patients underwent PET/CT scanning with (18)F-FDG and (18)F-NaF before and after therapy. Treatment response by means of PET/CT was assessed according to the European Organization for Research and Treatment of Cancer (EORTC) 1999 criteria. The evaluation of dPET/CT studies was based on qualitative evaluation, semi-quantitative (SUV) calculation, and quantitative analysis based on two-tissue compartment modelling and a non-compartmental approach leading to the extraction of fractal dimension (FD).
RESULTS: An analysis was possible in 29 patients: three with clinical complete response (CR) and 26 with non-CR (13 patients near complete response-nCR, four patients very good partial response-VGPR, nine patients partial response-PR). After treatment, (18)F-FDG PET/CT was negative in 14/29 patients and positive in 15/29 patients, showing a sensitivity of 57.5 % and a specificity of 100 %. According to the EORTC 1999 criteria, (18)F-FDG PET/CT-based treatment response revealed CR in 14 patients ((18)F-FDG PET/CT CR), PR in 11 patients ((18)F-FDG PET/CT PR) and progressive disease in four patients ((18)F-FDG PET/CT PD). In terms of (18)F-NaF PET/CT, 4/29 patients (13.8 %) had a negative baseline scan, thus failed to depict MM. Regarding the patients for which a direct lesion-to-lesion comparison was feasible, (18)F-NaF PET/CT depicted 56 of the 129 (18)F-FDG positive lesions (43 %). Follow-up (18)F-NaF PET/CT showed persistence of 81.5 % of the baseline (18)F-NaF positive MM lesions after treatment, despite the fact that 64.7 % of them had turned to (18)F-FDG negative. Treatment response according to (18)F-NaF PET/CT revealed CR in one patient ((18)F-NaF PET/CT CR), PR in five patients ((18)F-NaF PET/CT PR), SD in 12 patients ((18)F-NaF PET/CT SD), and PD in seven patients ((18)F-NaF PET/CT PD). Dynamic (18)F-FDG and (18)F-NaF PET/CT studies showed that SUVaverage, SUVmax, as well as the kinetic parameters K1, influx and FD from reference bone marrow and skeleton responded to therapy with a significant decrease (p < 0.001).
CONCLUSION: F-FDG PET/CT demonstrated a sensitivity of 57.7 % and a specificity of 100 % in treatment response evaluation of MM. Despite its limited sensitivity, the performance of (18)F-FDG PET/CT was satisfactory, given that 6/9 false negative patients in follow-up scans (66.7 %) were clinically characterized as nCR, a disease stage with very low tumor mass. On the other hand, (18)F-NaF PET/CT does not seem to add significantly to (18)F-FDG PET/CT in treatment response evaluation of MM patients undergoing HDT and ASCT, at least shortly after therapy.

Cardoso F, van't Veer LJ, Bogaerts J, et al.
70-Gene Signature as an Aid to Treatment Decisions in Early-Stage Breast Cancer.
N Engl J Med. 2016; 375(8):717-29 [PubMed] Related Publications
BACKGROUND: The 70-gene signature test (MammaPrint) has been shown to improve prediction of clinical outcome in women with early-stage breast cancer. We sought to provide prospective evidence of the clinical utility of the addition of the 70-gene signature to standard clinical-pathological criteria in selecting patients for adjuvant chemotherapy.
METHODS: In this randomized, phase 3 study, we enrolled 6693 women with early-stage breast cancer and determined their genomic risk (using the 70-gene signature) and their clinical risk (using a modified version of Adjuvant! Online). Women at low clinical and genomic risk did not receive chemotherapy, whereas those at high clinical and genomic risk did receive such therapy. In patients with discordant risk results, either the genomic risk or the clinical risk was used to determine the use of chemotherapy. The primary goal was to assess whether, among patients with high-risk clinical features and a low-risk gene-expression profile who did not receive chemotherapy, the lower boundary of the 95% confidence interval for the rate of 5-year survival without distant metastasis would be 92% (i.e., the noninferiority boundary) or higher.
RESULTS: A total of 1550 patients (23.2%) were deemed to be at high clinical risk and low genomic risk. At 5 years, the rate of survival without distant metastasis in this group was 94.7% (95% confidence interval, 92.5 to 96.2) among those not receiving chemotherapy. The absolute difference in this survival rate between these patients and those who received chemotherapy was 1.5 percentage points, with the rate being lower without chemotherapy. Similar rates of survival without distant metastasis were reported in the subgroup of patients who had estrogen-receptor-positive, human epidermal growth factor receptor 2-negative, and either node-negative or node-positive disease.
CONCLUSIONS: Among women with early-stage breast cancer who were at high clinical risk and low genomic risk for recurrence, the receipt of no chemotherapy on the basis of the 70-gene signature led to a 5-year rate of survival without distant metastasis that was 1.5 percentage points lower than the rate with chemotherapy. Given these findings, approximately 46% of women with breast cancer who are at high clinical risk might not require chemotherapy. (Funded by the European Commission Sixth Framework Program and others; ClinicalTrials.gov number, NCT00433589; EudraCT number, 2005-002625-31.).

Stamenković M, Knežević A, Knežević I, et al.
High-risk human papilloma virus genotypes in cervical carcinoma of Serbian women: Distribution and association with pathohistological findings.
Biologicals. 2016; 44(5):412-6 [PubMed] Related Publications
A significant role of high-risk Human papilloma viruses (HR HPV) in the development of cervical carcinoma is well known. HR HPV 16 and 18 account for approximately 70% of all cases of cervical cancer worldwide. The incidence of cervical cancer in Serbia, is one of the highest in Europe. The aim of our study was to investigate the distribution of HR HPV types in cervical carcinoma of Serbian women, as well as association between the HPV types and pathohistological findings. The study included 80 archival cervical cancer tissues from the same number of patients. The presence of HPV DNA was determined using MY09/MY11 primers for L1 gene and GP1/GP2 primers for E1 gene. HPV was detected in 78.75% tissues. HR HPV genotypes found in the decreasing order of frequency were: HPV16 (80.39%), HPV33 (7.84%), HPV58 (5.88%), HPV18 (1.96%), HPV45 (1.96%) and HPV53 (1.96%). The examined tissues were 91.25% squamous cell carcinomas and 8.75% adenocarcinoma. The high frequency of HPV 16 was observed in both types of carcinoma (80.8% and 75%, respectively) while the prevalence of HPV18 was low. These results may contribute to the implementation of cervical carcinoma prevention program in Serbia, including the selection of the most appropriate vaccine and immunization program.

Gotlib J, Kluin-Nelemans HC, George TI, et al.
Efficacy and Safety of Midostaurin in Advanced Systemic Mastocytosis.
N Engl J Med. 2016; 374(26):2530-41 [PubMed] Related Publications
BACKGROUND: Advanced systemic mastocytosis comprises rare hematologic neoplasms that are associated with a poor prognosis and lack effective treatment options. The multikinase inhibitor midostaurin inhibits KIT D816V, a primary driver of disease pathogenesis.
METHODS: We conducted an open-label study of oral midostaurin at a dose of 100 mg twice daily in 116 patients, of whom 89 with mastocytosis-related organ damage were eligible for inclusion in the primary efficacy population; 16 had aggressive systemic mastocytosis, 57 had systemic mastocytosis with an associated hematologic neoplasm, and 16 had mast-cell leukemia. The primary outcome was the best overall response.
RESULTS: The overall response rate was 60% (95% confidence interval [CI], 49 to 70); 45% of the patients had a major response, which was defined as complete resolution of at least one type of mastocytosis-related organ damage. Response rates were similar regardless of the subtype of advanced systemic mastocytosis, KIT mutation status, or exposure to previous therapy. The median best percentage changes in bone marrow mast-cell burden and serum tryptase level were -59% and -58%, respectively. The median overall survival was 28.7 months, and the median progression-free survival was 14.1 months. Among the 16 patients with mast-cell leukemia, the median overall survival was 9.4 months (95% CI, 7.5 to not estimated). Dose reduction owing to toxic effects occurred in 56% of the patients; re-escalation to the starting dose was feasible in 32% of those patients. The most frequent adverse events were low-grade nausea, vomiting, and diarrhea. New or worsening grade 3 or 4 neutropenia, anemia, and thrombocytopenia occurred in 24%, 41%, and 29% of the patients, respectively, mostly in those with preexisting cytopenias.
CONCLUSIONS: In this open-label study, midostaurin showed efficacy in patients with advanced systemic mastocytosis, including the highly fatal variant mast-cell leukemia. (Funded by Novartis Pharmaceuticals and others; ClinicalTrials.gov number, NCT00782067.).

Hohloch K, Zeynalova S, Chapuy B, et al.
Modified BEAM with triple autologous stem cell transplantation for patients with relapsed aggressive non-Hodgkin lymphoma.
Ann Hematol. 2016; 95(7):1121-8 [PubMed] Related Publications
Treatment of relapse and primary progression in aggressive lymphoma remains unsatisfactory; outcome is still poor. Better treatment strategies are much needed for this patient population. The R1 study is a prospective multi-center phase I/II study evaluating a dose finding approach with a triple transplant regimen in four BEAM dose levels in patients with relapsed aggressive non-Hodgkin lymphoma. The aim of the study was to determine feasibility, toxicity, and remission rate. In a total of 39 patients (pts.) enrolled in the study, 24 pts. were evaluated in the following analysis. Twenty pts. had aggressive B cell lymphoma, and two pts. had T cell lymphoma. All evaluated patients responded to DexaBEAM with a sufficient stem cell harvest. The phase I/II study was started with BEAM dose level II. Four patients were treated at dose level II, and 20 pts. were treated at dose level III. Due to the early termination of the study, dose levels I and IV were never administered. Sixteen pts. completed therapy according to protocol, and eight pts. (33.3 %) stopped treatment early. Infections (27 %) and stomatitis (13 %) were the most frequent grade III/IV non-hematologic toxicities. Thirteen percent of patients presented with severe grade III/IV lung toxicity during modified BEAM (m-BEAM). Fourteen pts. achieved a complete response (CR), one pt. achieved no change (NC), six pts. had progressive disease (PD), and two pts. died; for one pt., outcome is not known. One-year and 3-year event-free survival (EFS) was 38 and 33 %, respectively. Overall survival (OS) after 1 and 3 years was 50 and 38 %. In conclusion, dose escalation of standard BEAM is not feasible due to toxicity.

Franzen D, Diacon AH, Freitag L, et al.
Ultrathin bronchoscopy for solitary pulmonary lesions in a region endemic for tuberculosis: a randomised pilot trial.
BMC Pulm Med. 2016; 16(1):62 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The evaluation of solitary pulmonary lesions (SPL) requires a balance between procedure-related morbidity and diagnostic yield, particularly in areas where tuberculosis (TB) is endemic. Data on ultrathin bronchoscopy (UB) for this purpose is limited. To evaluate feasibility and safety of UB compared to SB for diagnosis of SPL in a TB endemic region.
METHODS: In this prospective randomised trial we compared diagnostic yield and adverse events of UB with standard-size bronchoscopy (SB), both combined with fluoroscopy, in a cohort of patients with SPL located beyond the visible range of SB.
RESULTS: We included 40 patients (mean age 55.2 years, 45 % male) with malignant SPL (n = 16; 40 %), tuberculous SPL (n = 11; 27.5 %) and other benign SPL (n = 13; 32.5 %). Mean procedure time in UB and SB was 30.6 and 26.0 min, respectively (p = 0.15). By trend, adverse events were recorded more often with UB than with SB (30.0 vs. 5.0 %, p = 0.091), including extensive coughing (n = 2), blocked working channel (n = 2), and arterial hypertension requiring therapeutic intervention (n = 1), all with UB. The overall diagnostic yield of UB compared to SB was 55.0 % vs. 80.0 %, respectively (p = 0.18). Sensitivity for the diagnosis of malignancy of UB and SB was 50.0 % and 62.5 %, respectively (p = 0.95).
CONCLUSION: UB is not superior to SB for the evaluation of SPL in a region endemic with tuberculosis, when combined with fluoroscopic guidance only.
TRIAL REGISTRATION: ClinicalTrials.gov (Identifier: NCT02490059 ).

Schorb E, Finke J, Ferreri AJ, et al.
High-dose chemotherapy and autologous stem cell transplant compared with conventional chemotherapy for consolidation in newly diagnosed primary CNS lymphoma--a randomized phase III trial (MATRix).
BMC Cancer. 2016; 16:282 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Primary central nervous system lymphoma (PCNSL) is a highly aggressive Non-Hodgkin lymphoma (NHL) with rising incidence over the past 30 years in immunocompetent patients. Although outcomes have improved, PCNSL is still associated with inferior prognosis compared to systemic NHL. Many questions regarding the optimal therapeutic approach remain unanswered.
METHODS/DESIGN: This is a randomized, open-label, international phase III trial with two parallel arms. We will recruit 250 patients with newly diagnosed PCNSL from approximately 35 centers within the networks of the German Cooperative PCNSL study group and the International Extranodal Lymphoma Study Group. All enrolled patients will undergo induction chemotherapy consisting of 4 cycles of rituximab 375 mg/m(2)/d (days 0 & 5), methotrexate 3.5 g/m(2) (d1), cytarabine 2 × 2 g/m(2)/d (d2-3), and thiotepa 30 mg/m(2) (d4) every 21 days. All patients will undergo stem-cell harvest after the second cycle. After 4 cycles of induction chemotherapy, patients achieving partial or complete response will be centrally randomized to 2 different consolidation treatments: (A) conventional-dose immuno chemotherapy with rituximab 375 mg/m(2) (d0), dexamethasone 40 mg/d (d1-3), etoposide 100 mg/m(2)/d (d1-3), ifosfamide 1500 mg/m(2)/d (d1-3) and carboplatin 300 mg/m(2) (d1) (R-DeVIC) or (B) high-dose chemotherapy with BCNU (or busulfan) and thiotepa followed by autologous stem cell transplantation (HCT-ASCT). The objective is to demonstrate superiority of HCT-ASCT compared to R-DeVIC with respect to progression-free survival (PFS, primary endpoint). Secondary endpoints include overall survival (OS), treatment response and treatment-related morbidities. Minimal follow-up after treatment completion is 24 months.
DISCUSSION: The rationale for consolidation treatment in PCNSL is to eliminate residual lymphoma cells and to decrease the risk for relapse. This can be achieved by agents crossing the blood brain barrier either applied at conventional doses or at high doses requiring autologous stem cell support. HCT-ASCT has been shown to be feasible and highly effective in patients with newly-diagnosed PCNSL. However, it is unclear whether HCT-ASCT is really superior compared to conventional-dose chemotherapy after an intensified antimetabolites-based immunochemotherapy in patients with newly-diagnosed PCNSL. To answer this question, we designed this investigator initiated randomized phase III trial.
TRIAL REGISTRATION: German clinical trials registry DRKS00005503 registered 22 April 2014 and ClinicalTrials.gov NCT02531841 registered 24 August 2015.

Watanabe K, Otsu S, Hirashima Y, et al.
A phase I study of binimetinib (MEK162) in Japanese patients with advanced solid tumors.
Cancer Chemother Pharmacol. 2016; 77(6):1157-64 [PubMed] Related Publications
PURPOSE: Binimetinib is a potent, selective MEK1/2 inhibitor with demonstrated efficacy against BRAF- and RAS-mutant tumors. Retinal adverse events associated with MEK inhibitors have been reported in some cases. The aim of this study was to assess single-agent binimetinib, with detailed ophthalmologic monitoring, in Japanese patients with advanced solid tumors.
METHODS: This was an open-label phase I dose-escalation and dose-expansion study (NCT01469130). Adult patients with histologically confirmed, evaluable, advanced solid tumors were enrolled and treated with binimetinib 30 or 45 mg twice daily (BID). The primary objective was to determine the maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D) of single-agent binimetinib in Japanese patients.
RESULTS: Twenty-one patients were enrolled; 3 and 8 patients had documented BRAF and KRAS mutations, respectively. Two of 6 patients (33 %) receiving binimetinib 45 mg BID in dose-escalation experienced recurrent grade 2 retinal adverse events (AEs) which were reversible, and this dose was declared the MTD and RP2D. All patients experienced ≥1 AE suspected to be treatment related; the most common (>50 %) were blood creatine phosphokinase increase (76 %), retinal detachment and aspartate aminotransferase increase (62 % each), and diarrhea (52 %). There were no complete or partial responses; 14 patients (67 %) had stable disease, which lasted >180 days in 5 patients. Expression of phospho-ERK decreased in the skin following binimetinib treatment at both dose levels, indicating target inhibition.
CONCLUSIONS: Binimetinib demonstrated efficacy and acceptable safety in Japanese patients with solid tumors, supporting the 45 mg BID dose of binimetinib as the RP2D.

De Bari B, Jumeau R, Bouchaab H, et al.
Efficacy and safety of helical tomotherapy with daily image guidance in anal canal cancer patients.
Acta Oncol. 2016; 55(6):767-73 [PubMed] Related Publications
Background and purpose Intensity-modulated radiotherapy (IMRT), also using volumetric modulated arc therapy (VMAT) and helical tomotherapy (HT) techniques, has been only recently introduced for treating anal cancer patients. We report efficacy and safety HT, and daily image-guided RT (IGRT) for anal cancer. Materials and methods We retrospectively analyzed efficacy and toxicity of HT with or without chemotherapy for anal cancer patients. Local control (LC) and grade 3 or more toxicity rate (CTC-AE v.4.0) were the primary endpoints. Overall (OS), disease-free (DFS), and colostomy-free survival (CFS) are also reported. Results Between October 2007 and May 2014, 78 patients were treated. Fifty patients presented a stage II or stage IIIA (UICC 2002), and 33 presented a N1-3 disease. Radiotherapy consisted of 36 Gy (1.8 Gy/fraction) delivered on the pelvis and on the anal canal, with a sequential boost up to 59.4 Gy (1.8 Gy/fraction) delivered to the anal and to nodal gross tumor volumes. Concomitant chemotherapy was delivered in 73 patients, mainly using mitomycin C and 5-fluorouracil (n = 30) or mitomycin C and capecitabine combination (n = 37). After a median follow-up period of 47 months (range 3-75), the five-year LC rate was 83.8% (95% CI 76.2-91.4%). Seven patients underwent a colostomy because of local recurrence (n = 5) or pretreatment dysfunction (n = 2). Overall incidence of grade 3 acute toxicity was 24%, mainly as erythema (n = 15/19) or diarrhea (n = 7/19). Two patients presented a late grade 3 gastrointestinal toxicity (anal incontinence). No grade 4 acute or late toxicity was recorded. Conclusions HT with daily IGRT is efficacious and safe in the treatment of anal canal cancer patients, and is considered in our department standard of care in this clinical setting.

Hacker UT, Escalona-Espinosa L, Consalvo N, et al.
Evaluation of Angiopoietin-2 as a biomarker in gastric cancer: results from the randomised phase III AVAGAST trial.
Br J Cancer. 2016; 114(8):855-62 [PubMed] Article available free on PMC after 12/04/2017 Related Publications
BACKGROUND: In the phase III AVAGAST trial, the addition of bevacizumab to chemotherapy improved progression-free survival (PFS) but not overall survival (OS) in patients with advanced gastric cancer. We studied the role of Angiopoietin-2 (Ang-2), a key driver of tumour angiogenesis, metastasis and resistance to antiangiogenic treatment, as a biomarker.
METHODS: Previously untreated, advanced gastric cancer patients were randomly assigned to receive bevacizumab (n=387) or placebo (n=387) in combination with chemotherapy. Plasma collected at baseline and at progression was analysed by ELISA. The role of Ang-2 as a prognostic and a predictive biomarker of bevacizumab efficacy was studied using a Cox proportional hazards model. Logistic regression analysis was applied for correlations with metastasis.
RESULTS: Median baseline plasma Ang-2 levels were lower in Asian (2143 pg ml(-1)) vs non-Asian patients (3193 pg ml(-1)), P<0.0001. Baseline plasma Ang-2 was identified as an independent prognostic marker for OS but did not predict bevacizumab efficacy alone or in combination with baseline VEGF. Baseline plasma Ang-2 correlated with the frequency of liver metastasis (LM) at any time: Odds ratio per 1000 pg ml(-1) increase: 1.19; 95% CI 1.10-1.29; P<0.0001 (non-Asians) and 1.37; 95% CI 1.13-1.64; P=0.0010 (Asians).
CONCLUSIONS: Baseline plasma Ang-2 is a novel prognostic biomarker for OS in advanced gastric cancer strongly associated with LM. Differences in Ang-2 mediated vascular response may, in part, account for outcome differences between Asian and non-Asian patients; however, data have to be further validated. Ang-2 is a promising drug target in gastric cancer.

Endris V, Stenzinger A, Pfarr N, et al.
NGS-based BRCA1/2 mutation testing of high-grade serous ovarian cancer tissue: results and conclusions of the first international round robin trial.
Virchows Arch. 2016; 468(6):697-705 [PubMed] Related Publications
With the approval of olaparib as monotherapy treatment in platinum-sensitive, relapsed high-grade serous ovarian cancer by the European Medical Agency (EMA), comprehensive genotyping of BRCA1 and BRCA2 in tumor tissue has become a mandatory pre-therapeutic test. This requires significant advances in routine tumor test methodologies due to the large size of both genes and the lack of mutational hot spots. Classical focused screening approaches, like Sanger sequencing, do not allow for a sensitive, rapid, and economic analysis of tumor tissue. Next-generation sequencing (NGS) approaches employing targeted panels for BRCA1/2 to interrogate formalin-fixed and paraffin-embedded tumor samples from either surgical resection or biopsy specimens can overcome these limitations. Although focused NGS methods have been implemented by few centers in routine molecular diagnostics for the analysis of some druggable oncogenic mutations, the reliable diagnostic testing of the entire coding regions of BRCA1 and BRCA2 was a new challenge requiring extensive technological improvement and quality management. Here, we describe the implementation and results of the first round robin trial for BRCA1/2 mutation testing in tumor tissue that was conducted in central Europe on May 2015, shortly after the approval and prior to the official release of olaparib. The high success rate of 81 % (21/26 test centers) demonstrates that BRCA1/2 multicenter mutation testing is well feasible in FFPE tumor tissue, extending to other tumor entities beyond ovarian cancer. The high number of test centers passing the trial demonstrates the success of the concerted efforts by German, Swiss, and Austrian pathology centers to ensure quality-controlled NGS-based testing and proves the potential of this technology in routine molecular pathology. On the basis of our results, we provide recommendations for predictive testing of tumor tissue for BRCA1/2 to clinical decision making in ovarian cancer patients.

Hénin E, Meille C, Barbolosi D, et al.
Revisiting dosing regimen using PK/PD modeling: the MODEL1 phase I/II trial of docetaxel plus epirubicin in metastatic breast cancer patients.
Breast Cancer Res Treat. 2016; 156(2):331-41 [PubMed] Related Publications
The MODEL1 trial is the first model-driven phase I/II dose-escalation study of densified docetaxel plus epirubicin administration in metastatic breast cancer patients, a regimen previously known to induce unacceptable life-threatening toxicities. The primary objective was to determine the maximum tolerated dose of this densified regimen. Study of the efficacy was a secondary objective. Her2-negative, hormone-resistant metastatic breast cancer patients were treated with escalating doses of docetaxel plus epirubicin every 2 weeks for six cycles with granulocyte colony stimulating factor support. A total of 16 patients were treated with total doses ranging from 85 to 110 mg of docetaxel plus epirubicin per cycle. Dose escalation was controlled by a non-hematological toxicity model. Dose densification was guided by a model of neutrophil kinetics, able to optimize docetaxel plus epirubicin dosing with respect to pre-defined acceptable levels of hematological toxicity while ensuring maximal efficacy. The densified treatment was safe since hematological toxicity was much lower compared to previous findings, and other adverse events were consistent with those observed with this regimen. The maximal tolerated dose was 100 mg given every 2 weeks. The response rate was 45 %; median progression-free survival was 10.4 months, whereas 54.6 months of median overall survival was achieved. The optimized docetaxel plus epirubicin dosing regimen led to fewer toxicities associated with higher efficacy as compared with standard or empirical densified dosing. This study suggests that model-driven dosage adjustment can lead to improved efficacy-toxicity balance in patients with cancer when several anticancer drugs are combined.

Trimboli P, Centanni M, Virili C
Liquid liothyronine to obtain target TSH in differentiated thyroid cancer patients.
Endocr J. 2016; 63(6):563-7 [PubMed] Related Publications
In the last ten years a liquid formulation of liothyronine (L-T3) became available. To date, no studies on its systematic use have been reported. This study is aimed at assessing the reliability of liquid L-T3 in achieving target TSH in patients with differentiated thyroid cancers (DTC). Twenty-one high risk DTC patients in whom levothyroxine treatment up to 2.0 μg/kg/day did not suppress TSH levels (i.e. >0.1 mIU/L) were selected. Maintaining the same L-T4 dose, they started to assume liquid L-T3 at an initial fixed dose of 3.55 μg (5 drops). Further adjustments of L-T3 dose were tailored according to individual assessment. Initial serum TSH ranged from 0.8 to 12.0 mIU/L, when patients assumed high dose of L-T4 alone. Following the addition of a daily single dose of 3.55 μg L-T3, the target TSH was attained in five patients (23.8%). After increasing L-T3 dose up to a mean of 7.3±3.4 μg/day all patients reached target serum TSH (<0.1 mIU/L). The mean individual L-T3 dose was significantly correlated with the body weight and was 0.11±0.04 μg/kg/day (p=0.013). Mean L-T4:L-T3 ratio was 21:1. No patients showed skewed free-T3 or free-T4 values, neither experienced discomfort nor reported adverse events. Liquid L-T3 can be useful to achieve optimal TSH suppression in high risk DTC with not suppressed TSH on L-T4 alone. This formulation allows an individual tailoring of L-T3, minimizing risks of side effects as well as of overtreatment in these clinical conditions.

Beaumont JL, Salsman JM, Diaz J, et al.
Quality-adjusted time without symptoms or toxicity analysis of pazopanib versus sunitinib in patients with renal cell carcinoma.
Cancer. 2016; 122(7):1108-15 [PubMed] Article available free on PMC after 12/04/2017 Related Publications
BACKGROUND: In a phase 3, randomized, open-label trial (Pazopanib versus Sunitinib in the Treatment of Locally Advanced and/or Metastatic Renal Cell Carcinoma, COMPARZ; NCT00720941), pazopanib was found to be noninferior to sunitinib in terms of progression-free survival in patients with metastatic renal cell carcinoma with no prior therapy. Overall treatment differences were evaluated in a post hoc analysis with a quality-adjusted time without symptoms or toxicity (Q-TWiST) methodology.
METHODS: Each patient's overall survival was partitioned into 3 mutually exclusive health states: time with grade 3 or 4 toxicity (TOX), time without symptoms of disease or grade 3/4 toxicity of treatment, and time after tumor progression or relapse (REL). The time spent in each state was weighted by a health-state utility associated with that state and summed to calculate the Q-TWiST. A threshold utility analysis was used, and utilities were applied across the range of 0 (similar to death) to 1 (perfect health).
RESULTS: A total of 1110 patients were enrolled (557 on pazopanib and 553 on sunitinib). The mean TOX was 31 days (95% confidence interval, 13-48 days) longer for sunitinib versus pazopanib. In the threshold utility analysis, the difference in the Q-TWiST ranged from -11 days (utility for TOX, 1; utility for REL, 0) to 43 days (utility for TOX, 0; utility for REL, 1) in favor of pazopanib across most utility combinations. Differences were significant in less than half of the utility combinations examined, and this typically occurred when the utility for TOX was lower than the utility for REL.
CONCLUSIONS: Patients randomized to pazopanib had a slightly longer Q-TWiST in comparison with sunitinib patients, and this was primarily due to the reduced length of TOX.

Gratwohl A, Iacobelli S, Bootsman N, et al.
Splenic irradiation before hematopoietic stem cell transplantation for chronic myeloid leukemia: long-term follow-up of a prospective randomized study.
Ann Hematol. 2016; 95(6):967-72 [PubMed] Related Publications
In the context of discussions on the reproducibility of clinical studies, we reanalyzed a prospective randomized study on the role of splenic irradiation as adjunct to the conditioning for hematopoietic stem cell transplantation (HSCT) for chronic myeloid leukemia (CML). Between 1986 and 1989, a total of 229 patients with CML were randomized; of these, 225 (98 %; 112 with, 113 without splenic irradiation) could be identified in the database and their survival updated. Results confirmed the early findings with no significant differences in all measured endpoints (overall survival at 25 years: 42.7 %, 32.0-52.4 % vs 52.9 %, 43.2-62.6 %; p = 0.355, log rank test). Additional splenic irradiation failed to reduce relapse incidence. It did not increase non-relapse mortality nor the risk of late secondary malignancies. Comforting are the long-term results from this predefined consecutive cohort of patients: more than 60 % were alive at plus 25 years when they were transplanted with a low European Society for Blood and Marrow Transplantation (EBMT) risk sore. This needs to be considered today when treatment options are discussed for patients who failed initial tyrosine kinase inhibitor therapy and have an available low risk HLA-identical donor.

Krop IE, Modi S, LoRusso PM, et al.
Phase 1b/2a study of trastuzumab emtansine (T-DM1), paclitaxel, and pertuzumab in HER2-positive metastatic breast cancer.
Breast Cancer Res. 2016; 18(1):34 [PubMed] Article available free on PMC after 12/04/2017 Related Publications
BACKGROUND: In pre-clinical studies, the anti-tumor activity of T-DM1 was enhanced when combined with taxanes or pertuzumab. This phase 1b/2a study evaluated the safety/tolerability of T-DM1 + paclitaxel ± pertuzumab in HER2-positive advanced breast cancer.
METHODS: In phase 1b (n = 60), a 3 + 3 dose-escalation approach was used to determine the maximum tolerated dose (MTD) of T-DM1 + paclitaxel ± pertuzumab. The primary objective of phase 2a was feasibility, with 44 patients randomized to T-DM1 + paclitaxel ± pertuzumab at the MTD identified in phase 1b.
RESULTS: The MTD was T-DM1 3.6 mg/kg every three weeks (q3w) or 2.4 mg/kg weekly + paclitaxel 80 mg/m(2) weekly ± pertuzumab 840 mg loading dose followed by 420 mg q3w. Phase 2a patients had received a median of 5.0 (range: 0-10) prior therapies for advanced cancer. In phase 2a, 51.2 % received ≥12 paclitaxel doses within 15 weeks, and 14.0 % received 12 paclitaxel doses by week 12. Common all-grade adverse events (AEs) were peripheral neuropathy (90.9 %) and fatigue (79.5 %). A total of 77.3 % experienced grade ≥3 AEs, most commonly neutropenia (25.0 %) and peripheral neuropathy (18.2 %). Among the 42 phase 2a patients with measurable disease, the objective response rate (ORR) was 50.0 % (95 % confidence interval (CI) 34.6-65.4); the clinical benefit rate (CBR) was 56.8 % (95 % CI 41.6-71.0). No pharmacokinetic interactions were observed between T-DM1 and paclitaxel.
CONCLUSIONS: This regimen showed clinical activity. Although there is potential for paclitaxel to be added to T-DM1 ± pertuzumab, peripheral neuropathy was common in this heavily pretreated population.
TRIAL REGISTRATION: ClinicalTrials.gov NCT00951665 . Registered August 3, 2009.

Bühler A, Wendtner CM, Kipps TJ, et al.
Lenalidomide treatment and prognostic markers in relapsed or refractory chronic lymphocytic leukemia: data from the prospective, multicenter phase-II CLL-009 trial.
Blood Cancer J. 2016; 6:e404 [PubMed] Article available free on PMC after 12/04/2017 Related Publications
Efficacy of lenalidomide was investigated in 103 patients with relapsed/refractory chronic lymphocytic leukemia (CLL) treated on the prospective, multicenter randomized phase-II CLL-009 trial. Interphase cytogenetic and mutational analyses identified TP53 mutations, unmutated IGHV, or del(17p) in 36/96 (37.5%), 68/88 (77.3%) or 22/92 (23.9%) patients. The overall response rate (ORR) was 40.4% (42/104). ORRs were similar irrespective of TP53 mutation (36.1% (13/36) vs 43.3% (26/60) for patients with vs without mutation) or IGHV mutation status (45.0% (9/20) vs 39.1% (27/68)); however, patients with del(17p) had lower ORRs than those without del(17p) (21.7% (5/22) vs 47.1% (33/70); P=0.049). No significant differences in progression-free survival and overall survival (OS) were observed when comparing subgroups defined by the presence or absence of high-risk genetic characteristics. In multivariate analyses, only multiple prior therapies (⩾3 lines) significantly impacted outcomes (median OS: 21.2 months vs not reached; P=0.019). This analysis indicates that lenalidomide is active in patients with relapsed/refractory CLL with unfavorable genetic profiles, including TP53 inactivation or unmutated IGHV. (ClinicalTrials.gov identifier: NCT00963105).

Kluge R, Chavdarova L, Hoffmann M, et al.
Inter-Reader Reliability of Early FDG-PET/CT Response Assessment Using the Deauville Scale after 2 Cycles of Intensive Chemotherapy (OEPA) in Hodgkin's Lymphoma.
PLoS One. 2016; 11(3):e0149072 [PubMed] Article available free on PMC after 12/04/2017 Related Publications
PURPOSE: The five point Deauville (D) scale is widely used to assess interim PET metabolic response to chemotherapy in Hodgkin lymphoma (HL) patients. An International Validation Study reported good concordance among reviewers in ABVD treated advanced stage HL patients for the binary discrimination between score D1,2,3 and score D4,5. Inter-reader reliability of the whole scale is not well characterised.
METHODS: Five international expert readers scored 100 interim PET/CT scans from paediatric HL patients. Scans were acquired in 51 European hospitals after two courses of OEPA chemotherapy (according to the EuroNet-PHL-C1 study). Images were interpreted in direct comparison with staging PET/CTs.
RESULTS: The probability that two random readers concord on the five point D score of a random case is only 42% (global kappa = 0.24). Aggregating to a three point scale D1,2 vs. D3 vs. D4,5 improves concordance to 60% (kappa = 0.34). Concordance if one of two readers assigns a given score is 70% for score D1,2 only 36% for score D3 and 64% for D4,5. Concordance for the binary decisions D1,2 vs. D3,4,5 is 67% and 86% for D1,2,3 vs D4,5 (kappa = 0.36 resp. 0.56). If one reader assigns D1,2,3 concordance probability is 92%, but only 64% if D4,5 is called. Discrepancies occur mainly in mediastinum, neck and skeleton.
CONCLUSION: Inter-reader reliability of the five point D-scale is poor in this interobserver analysis of paediatric patients who underwent OEPA. Inter-reader variability is maximal in cases assigned to D2 or D3. The binary distinction D1,2,3 versus D4,5 is the most reliable criterion for clinical decision making.

Zech CJ, Justo N, Lang A, et al.
Cost evaluation of gadoxetic acid-enhanced magnetic resonance imaging in the diagnosis of colorectal-cancer metastasis in the liver: Results from the VALUE Trial.
Eur Radiol. 2016; 26(11):4121-4130 [PubMed] Article available free on PMC after 12/04/2017 Related Publications
OBJECTIVES: To assess the costs of diagnostic workup and surgery of three strategies for patients with colorectal cancer liver-metastases (CRCLM): gadoxetic-acid-enhanced MRI (Gd-EOB-DTPA-MRI), MRI with extracellular contrast-media (ECCM-MRI) or contrast-enhanced MDCT (CE-MDCT).
METHODS: The within-trial cost evaluation was modelled as a decision-tree to calculate the cost of diagnosis and surgery. The model used clinical outcomes and resource utilization data from a prospective randomized multicentre study. Analyses were performed for the 354-patient safety population from eight participating countries.
RESULTS: The diagnostic workup cost using Gd-EOB-DTPA-MRI upfront resulted in savings compared to ECCM-MRI in all countries except Thailand (difference <2 %). Compared to CE-MDCT, initial imaging with Gd-EOB-DTPA-MRI was less costly in all countries except Korea and Spain (differences 4 and 8 %, respectively). Significantly more patients in the Gd-EOB-DTPA-MRI group were eligible for surgery (39.3 % (48/122) vs. 31.0 % (36/116) and 26.7 % (31/116) for ECCM-MRI and CE-MDCT, respectively), allowing more patients to undergo potentially curative surgery, but resulting in higher treatment costs for the strategy starting with Gd-EOB-DTPA-MRI.
CONCLUSIONS: The benefits of Gd-EOB-DTPA-MRI due to less additional imaging and similar diagnostic workup costs in the three groups suggest that Gd-EOB-DTPA-MRI should be the preferred initial imaging procedure to evaluate hepatic resectability in patients with CRCLM.
KEY POINTS: • Diagnostic imaging cost to evaluate resectability was similar among the groups • Cost for imaging was rather small compared to the cost of surgery • Significantly more patients in the Gd-EOB-DTPA-MRI arm were eligible for surgery • Gd-EOB-DTPA-MRI is recommended for evaluating hepatic resectability in patients with CRCLM.

Trněný M, Lamy T, Walewski J, et al.
Lenalidomide versus investigator's choice in relapsed or refractory mantle cell lymphoma (MCL-002; SPRINT): a phase 2, randomised, multicentre trial.
Lancet Oncol. 2016; 17(3):319-31 [PubMed] Related Publications
BACKGROUND: Lenalidomide, an immunomodulatory drug with antineoplastic and antiproliferative effects, showed activity in many single-group studies in relapsed or refractory mantle cell lymphoma. The aim of this randomised study was to examine the efficacy and safety of lenalidomide versus best investigator's choice of single-agent therapy in relapsed or refractory mantle cell lymphoma.
METHODS: The MCL-002 (SPRINT) study was a randomised, phase 2 study of patients with mantle cell lymphoma aged 18 years or older at 67 clinics and academic centres in 12 countries who relapsed one to three times, had Eastern Cooperative Oncology Group performance status of 0-2, at least one measurable lesion to be eligible, and who were ineligible for intensive chemotherpy or stem-cell transplantation. Using a centralised interactive voice response system, we randomly assigned (2:1) patients in a permuted block size of six to receive lenalidomide (25 mg orally on days 1-21 every 28 days) until progressive disease or intolerability, or single-agent investigator's choice of either rituximab, gemcitabine, fludarabine, chlorambucil, or cytarabine. Randomisation was stratified by time from diagnosis, time from last anti-lymphoma therapy, and previous stem-cell transplantation. Individual treatment assignment between lenalidomide and investigator's choice was open label, but investigators had to register their choice of comparator drug before randomly assigning a patient. Patients who progressed on investigator's choice could cross over to lenalidomide treatment. We present the prespecified primary analysis results in the intention-to-treat population for the primary endpoint of progression-free survival, defined as the time from randomisation to progressive disease or death, whichever occurred first. Patient enrolment is complete, although treatment and collection of additional time-to-event data are ongoing. This study is registered with ClinicalTrials.gov, number NCT00875667.
FINDINGS: Between April 30, 2009, and March 7, 2013, we enrolled 254 patients in the intention-to-treat population (170 [67%] were randomly assigned to receive lenalidomide, 84 [33%] to receive investigator's choice monotherapy). Patients had a median age of 68·5 years and received a median of two previous regimens. With a median follow-up of 15·9 months (IQR 7·6-31·7), lenalidomide significantly improved progression-free survival compared with investigator's choice (median 8·7 months [95% CI 5·5-12·1] vs 5·2 months [95% CI 3·7-6·9]) with a hazard ratio of 0·61 (95% CI 0·44-0·84; p=0·004). In the 167 patients in the lenalidomide group and 83 patients in the investigator's choice group who received at least one dose of treatment the most common grade 3-4 adverse events included neutropenia (73 [44%] of 167 vs 28 [34%] of 83) without increased risk of infection, thrombocytopenia (30 [18%] vs 23 [28%]), leucopenia (13 [8%] vs nine [11%]), and anaemia (14 [8%] vs six [7%]).
INTERPRETATION: Patients with relapsed or refractory mantle cell lymphoma ineligible for intensive chemotherapy or stem-cell transplantation have longer progression-free survival, with a manageable safety profile when treated with lenalidomide compared with monotherapy investigator's choice options.
FUNDING: Celgene Corporation.

Fazio N, Buzzoni R, Baudin E, et al.
A Phase II Study of BEZ235 in Patients with Everolimus-resistant, Advanced Pancreatic Neuroendocrine Tumours.
Anticancer Res. 2016; 36(2):713-9 [PubMed] Article available free on PMC after 12/04/2017 Related Publications
BACKGROUND: This was a two-stage, phase II trial of the dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor BEZ235 in patients with everolimus-resistant pancreatic neuroendocrine tumours (pNETs) (NCT01658436).
PATIENTS AND METHODS: In stage 1, 11 patients received 400 mg BEZ235 orally twice daily (bid). Due to tolerability concerns, a further 20 patients received BEZ235 300 mg bid. Stage 2 would be triggered by a 16-week progression-free survival (PFS) rate of ≥60% in stage 1.
RESULTS: As of 30 June, 2014, 29/31 patients had discontinued treatment. Treatment-related grade 3/4 adverse events were reported in eight (72.7%) patients at 400 mg and eight (40.0%) patients at 300 mg, including hyperglycaemia, diarrhoea, nausea, and vomiting. The estimated 16-week PFS rate was 51.6% (90% confidence interval=35.7-67.3%).
CONCLUSION: BEZ235 was poorly tolerated by patients with everolimus-resistant pNETs at 400 and 300 mg bid doses. Although evidence of disease stability was observed, the study did not proceed to stage 2.

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