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Netherlands

Cancer Statistics
Population in 2012: 16.7m
People newly diagnosed with cancer (excluding NMSC) / yr: 93,400
Age-standardised rate, incidence per 100,000 people/yr: 304.8
Risk of getting cancer before age 75:30.2%
People dying from cancer /yr: 42,500
Data from IARC GlobalCan (2012)
Dutch Cancer Organisations and Resources
Dutch Cancer Centres
Recent Research Publications from The Netherlands

Dutch Cancer Organisations and Resources (8 links)


Dutch Cancer Centres (5 links)


Recent Research Publications from The Netherlands

Strosberg J, El-Haddad G, Wolin E, et al.
Phase 3 Trial of (177)Lu-Dotatate for Midgut Neuroendocrine Tumors.
N Engl J Med. 2017; 376(2):125-135 [PubMed] Related Publications
Background Patients with advanced midgut neuroendocrine tumors who have had disease progression during first-line somatostatin analogue therapy have limited therapeutic options. This randomized, controlled trial evaluated the efficacy and safety of lutetium-177 ((177)Lu)-Dotatate in patients with advanced, progressive, somatostatin-receptor-positive midgut neuroendocrine tumors. Methods We randomly assigned 229 patients who had well-differentiated, metastatic midgut neuroendocrine tumors to receive either (177)Lu-Dotatate (116 patients) at a dose of 7.4 GBq every 8 weeks (four intravenous infusions, plus best supportive care including octreotide long-acting repeatable [LAR] administered intramuscularly at a dose of 30 mg) ((177)Lu-Dotatate group) or octreotide LAR alone (113 patients) administered intramuscularly at a dose of 60 mg every 4 weeks (control group). The primary end point was progression-free survival. Secondary end points included the objective response rate, overall survival, safety, and the side-effect profile. The final analysis of overall survival will be conducted in the future as specified in the protocol; a prespecified interim analysis of overall survival was conducted and is reported here. Results At the data-cutoff date for the primary analysis, the estimated rate of progression-free survival at month 20 was 65.2% (95% confidence interval [CI], 50.0 to 76.8) in the (177)Lu-Dotatate group and 10.8% (95% CI, 3.5 to 23.0) in the control group. The response rate was 18% in the (177)Lu-Dotatate group versus 3% in the control group (P<0.001). In the planned interim analysis of overall survival, 14 deaths occurred in the (177)Lu-Dotatate group and 26 in the control group (P=0.004). Grade 3 or 4 neutropenia, thrombocytopenia, and lymphopenia occurred in 1%, 2%, and 9%, respectively, of patients in the (177)Lu-Dotatate group as compared with no patients in the control group, with no evidence of renal toxic effects during the observed time frame. Conclusions Treatment with (177)Lu-Dotatate resulted in markedly longer progression-free survival and a significantly higher response rate than high-dose octreotide LAR among patients with advanced midgut neuroendocrine tumors. Preliminary evidence of an overall survival benefit was seen in an interim analysis; confirmation will be required in the planned final analysis. Clinically significant myelosuppression occurred in less than 10% of patients in the (177)Lu-Dotatate group. (Funded by Advanced Accelerator Applications; NETTER-1 ClinicalTrials.gov number, NCT01578239 ; EudraCT number 2011-005049-11 .).

Mok TS, Wu YL, Ahn MJ, et al.
Osimertinib or Platinum-Pemetrexed in EGFR T790M-Positive Lung Cancer.
N Engl J Med. 2017; 376(7):629-640 [PubMed] Related Publications
Background Osimertinib is an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that is selective for both EGFR-TKI sensitizing and T790M resistance mutations in patients with non-small-cell lung cancer. The efficacy of osimertinib as compared with platinum-based therapy plus pemetrexed in such patients is unknown. Methods In this randomized, international, open-label, phase 3 trial, we assigned 419 patients with T790M-positive advanced non-small-cell lung cancer, who had disease progression after first-line EGFR-TKI therapy, in a 2:1 ratio to receive either oral osimertinib (at a dose of 80 mg once daily) or intravenous pemetrexed (500 mg per square meter of body-surface area) plus either carboplatin (target area under the curve, 5 [AUC5]) or cisplatin (75 mg per square meter) every 3 weeks for up to six cycles; maintenance pemetrexed was allowed. In all the patients, disease had progressed during receipt of first-line EGFR-TKI therapy. The primary end point was investigator-assessed progression-free survival. Results The median duration of progression-free survival was significantly longer with osimertinib than with platinum therapy plus pemetrexed (10.1 months vs. 4.4 months; hazard ratio; 0.30; 95% confidence interval [CI], 0.23 to 0.41; P<0.001). The objective response rate was significantly better with osimertinib (71%; 95% CI, 65 to 76) than with platinum therapy plus pemetrexed (31%; 95% CI, 24 to 40) (odds ratio for objective response, 5.39; 95% CI, 3.47 to 8.48; P<0.001). Among 144 patients with metastases to the central nervous system (CNS), the median duration of progression-free survival was longer among patients receiving osimertinib than among those receiving platinum therapy plus pemetrexed (8.5 months vs. 4.2 months; hazard ratio, 0.32; 95% CI, 0.21 to 0.49). The proportion of patients with adverse events of grade 3 or higher was lower with osimertinib (23%) than with platinum therapy plus pemetrexed (47%). Conclusions Osimertinib had significantly greater efficacy than platinum therapy plus pemetrexed in patients with T790M-positive advanced non-small-cell lung cancer (including those with CNS metastases) in whom disease had progressed during first-line EGFR-TKI therapy. (Funded by AstraZeneca; AURA3 ClinicalTrials.gov number, NCT02151981 .).

Balar AV, Galsky MD, Rosenberg JE, et al.
Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial.
Lancet. 2017; 389(10064):67-76 [PubMed] Related Publications
BACKGROUND: First-line chemotherapy for patients with cisplatin-ineligible locally advanced or metastatic urothelial carcinoma is associated with short response duration, poor survival, and high toxicity. This study assessed atezolizumab (anti-programmed death-ligand 1 [PD-L1]) as treatment for metastatic urothelial cancer in cisplatin-ineligible patients.
METHODS: For this single-arm, multicentre, phase 2 study, in 47 academic medical centres and community oncology practices in seven countries in North America and Europe, we recruited previously untreated patients with locally advanced or metastatic urothelial cancer who were cisplatin ineligible. Patients were given 1200 mg intravenous atezolizumab every 21 days until progression. The primary endpoint was independently confirmed objective response rate per Response Evaluation Criteria in Solid Tumors version 1.1 (central review), assessed in prespecified subgroups based on PD-L1 expression and in all patients. All participants who received one or more doses of atezolizumab were included in the primary and safety analyses. This study was registered with ClinicalTrials.gov, number NCT02108652.
FINDINGS: Between June 9, 2014, and March 30, 2015, we enrolled 123 patients, of whom 119 received one or more doses of atezolizumab. At 17·2 months' median follow-up, the objective response rate was 23% (95% CI 16 to 31), the complete response rate was 9% (n=11), and 19 of 27 responses were ongoing. Median response duration was not reached. Responses occurred across all PD-L1 and poor prognostic factor subgroups. Median progression-free survival was 2·7 months (2·1 to 4·2). Median overall survival was 15·9 months (10·4 to not estimable). Tumour mutation load was associated with response. Treatment-related adverse events that occurred in 10% or more of patients were fatigue (36 [30%] patients), diarrhoea (14 [12%] patients), and pruritus (13 [11%] patients). One treatment-related death (sepsis) occurred. Nine (8%) patients had an adverse event leading to treatment discontinuation. Immune-mediated events occurred in 14 (12%) patients.
INTERPRETATION: Atezolizumab showed encouraging durable response rates, survival, and tolerability, supporting its therapeutic use in untreated metastatic urothelial cancer.
FUNDING: F Hoffmann-La Roche, Genentech.

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 .).

Haj Mohammad N, De Rooij S, Hulshof M, et al.
Activities of daily living and quality of life during treatment with neoadjuvant chemoradiotherapy and after surgery in patients with esophageal cancer.
J Surg Oncol. 2016; 114(6):684-690 [PubMed] Related Publications
BACKGROUND AND OBJECTIVES: Neoadjuvant chemoradiation (nCRT) followed by esophagectomy is a treatment with curative intent for resectable esophageal cancer. The aim of this study was to measure activities of daily living (ADL) and quality of life (QoL), and to examine correlates of changes in ADL and QoL.
METHODS: A prospective study was performed with three time points (baseline, 1 week after the end of nCRT, 3-months post-surgery) together with a cross-sectional post-treatment study. ADL was measured with the Amsterdam Linear Disability Score (ALDS), and QoL with the EORTC QLQ-C30 and the OES-18. Regression analysis was performed to identify factors associated with changes in ADL and QoL.
RESULTS: Seventy-six patients were included in the prospective study, 79 in the cross-sectional study. After nCRT, ALDS decreased from 90 to 88 (P < 0.01) and remained stable after surgery. Global QoL decreased from 75 to 61 (P < 0.01); no significant changes were observed after surgery. Only timing of the measurement of ALDS was negatively associated with non-maximum ALDS (n = 155, based on both studies) and QoL (n = 76) (P < 0.01).
CONCLUSIONS: Patients who undergo nCRT plus surgery should be prepared to experience a short-term decline in ADL and QoL. The findings of this study can support patients and healthcare workers to guide expectations. J. Surg. Oncol. 2016;114:684-690. © 2016 Wiley Periodicals, Inc.

Janssen SJ, Paulino Pereira NR, Raskin KA, et al.
A comparison of questionnaires for assessing physical function in patients with lower extremity bone metastases.
J Surg Oncol. 2016; 114(6):691-696 [PubMed] Related Publications
OBJECTIVES: To assess, (i) the degree to which the: PROMIS Physical Function Cancer, PROMIS Neuro-QoL Mobility, Toronto Extremity Salvage Score (TESS), Lower Extremity Function Score (LEFS), and Musculoskeletal Tumor Society score (MSTS), measure physical function; (ii) differences in coverage and reliability; and (iii) difference in completion time.
METHODS: One hundred of 115 (87%) patients with lower extremity metastases participated in this prospective study. We used exploratory factor analysis-correlating questionnaires with an underlying trait-to assess if questionnaires measure the same. Coverage was assessed by floor and ceiling effect and reliability by the standard error of measurement (SEM). Completion time was compared using the Friedman test.
RESULTS: All questionnaires measured the same concept; demonstrated by high correlations (>0.7). Floor effect was absent, while ceiling effect was present in all, but highest for the PROMIS Neuro-QoL Mobility (7%). The SEM was below the threshold-indicating reliability-over a wide range of ability levels for the PROMIS-Physical Function, TESS, and LEFS. Completion time differed between questionnaires (P < 0.001) and was shortest for the PROMIS questionnaires.
CONCLUSIONS: The PROMIS Physical Function is the most useful questionnaire. This is due to its reliability over a wide range of ability levels, validity, brevity, and good coverage. J. Surg. Oncol. 2016;114:691-696. © 2016 Wiley Periodicals, Inc.

Okusaka T, Otsuka T, Ueno H, et al.
Phase I study of nintedanib in Japanese patients with advanced hepatocellular carcinoma and liver impairment.
Cancer Sci. 2016; 107(12):1791-1799 [PubMed] Related Publications
This phase I, dose-escalation study evaluated the safety, preliminary efficacy and pharmacokinetics of nintedanib, a triple angiokinase inhibitor, in Japanese patients with advanced hepatocellular carcinoma and mild/moderate liver impairment. Thirty patients with unresectable hepatocellular carcinoma were enrolled to groups, depending on whether liver impairment was mild (group I, aspartate aminotransferase and alanine aminotransferase ≤2× upper limit of normal and Child-Pugh score 5 [n = 14] or 6 [n = 2]) or moderate (group II, Child-Pugh score 5-6 and aspartate aminotransferase or alanine aminotransferase >2× to ≤5× upper limit of normal [n = 7] or Child-Pugh score 7 [n = 7]); 22 patients had prior sorafenib treatment. Nintedanib was given twice daily in 28-day cycles until disease progression or unacceptable adverse events, starting at 150 mg (group I) or 100 mg (group II) and escalating to 200 mg. The primary objective was to define the maximum tolerated dose based on occurrence of dose-limiting toxicities during cycle 1 (grade ≥3 non-hematological and grade 4 hematological adverse events). No dose-limiting toxicities were reported during cycle 1 and the maximum tolerated dose for both groups was 200 mg twice daily. The most frequent adverse events were gastrointestinal (diarrhea, nausea, vomiting, and decreased appetite). No patients discontinued nintedanib due to adverse events; 31% of group I and 21% of group II had dose reductions. Median time to progression was 2.8 months (95% confidence interval, 1.05-5.52) for group I and 3.2 months (95% confidence interval, 0.95-6.70) for group II. Nintedanib showed a manageable safety profile and efficacy signals, including in patients previously treated with sorafenib. Clinical trial registration NCT01594125; 1199.120 (ClinicalTrials.gov).

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.

de Jong EE, van Elmpt W, Leijenaar RT, et al.
[18F]FDG PET/CT-based response assessment of stage IV non-small cell lung cancer treated with paclitaxel-carboplatin-bevacizumab with or without nitroglycerin patches.
Eur J Nucl Med Mol Imaging. 2017; 44(1):8-16 [PubMed] Free Access to Full Article Related Publications
PURPOSE: Nitroglycerin (NTG) is a vasodilating drug, which increases tumor blood flow and consequently decreases hypoxia. Therefore, changes in [18F] fluorodeoxyglucose positron emission tomography ([18F]FDG PET) uptake pattern may occur. In this analysis, we investigated the feasibility of [18F]FDG PET for response assessment to paclitaxel-carboplatin-bevacizumab (PCB) treatment with and without NTG patches. And we compared the [18F]FDG PET response assessment to RECIST response assessment and survival.
METHODS: A total of 223 stage IV non-small cell lung cancer (NSCLC) patients were included in a phase II study (NCT01171170) randomizing between PCB treatment with or without NTG patches. For 60 participating patients, a baseline and a second [18F]FDG PET/computed tomography (CT) scan, performed between day 22 and 24 after the start of treatment, were available. Tumor response was defined as a 30 % decrease in CT and PET parameters, and was compared to RECIST response at week 6. The predictive value of these assessments for progression free survival (PFS) and overall survival (OS) was assessed with and without NTG.
RESULTS: A 30 % decrease in SUVpeak assessment identified more patients as responders compared to a 30 % decrease in CT diameter assessment (73 % vs. 18 %), however, this was not correlated to OS (SUVpeak30 p = 0.833; CTdiameter30 p = 0.557). Changes in PET parameters between the baseline and the second scan were not significantly different for the NTG group compared to the control group (p value range 0.159-0.634). The CT-based (part of the [18F]FDG PET/CT) parameters showed a significant difference between the baseline and the second scan for the NTG group compared to the control group (CT diameter decrease of 7 ± 23 % vs. 19 ± 14 %, p = 0.016, respectively).
CONCLUSIONS: The decrease in tumoral FDG uptake in advanced NSCLC patients treated with chemotherapy with and without NTG did not differ between both treatment arms. Early PET-based response assessment showed more tumor responders than CT-based response assessment (part of the [18F]FDG PET/CT); this was not correlated to survival. This might be due to timing of the [18F]FDG PET shortly after the bevacizumab infusion.

Lens E, van der Horst A, Versteijne E, et al.
Considerable pancreatic tumor motion during breath-holding.
Acta Oncol. 2016; 55(11):1360-1368 [PubMed] Related Publications
BACKGROUND: Breath-holding (BH) is often used to reduce abdominal organ motion during radiotherapy. However, for inhale BH, abdominal tumor motion during BH has not yet been investigated. The aim of this study was to quantify tumor motion during inhale BH and tumor position variations between consecutive inhale BHs in pancreatic cancer patients.
MATERIAL AND METHODS: Twelve patients with intratumoral fiducials were included and asked to perform three consecutive 30-second inhale BHs on each of three measurement days. During BH, lateral fluoroscopic movies were obtained and a two-dimensional (2D) image correlation algorithm was used to track the fiducials and the diaphragm, yielding the tumor and diaphragm motion during each BH. The tumor position variation between consecutive BHs was obtained from the difference in initial tumor position between consecutive BHs on a single measurement day.
RESULTS: We observed tumor motion during BH with a mean absolute maximum displacement over all BHs of 4.2 mm (range 1.0-11.0 mm) in inferior-superior (IS) direction and 2.7 mm (range 0.5-8.0 mm) in anterior-posterior (AP) direction. We found only a moderate correlation between tumor and diaphragm motion in the IS direction (Pearson's correlation coefficient |r|>0.6 in 45 of 76 BHs). The mean tumor position variation between consecutive BHs was 0.2 [standard deviation (SD) 1.7] mm in the inferior direction and 0.5 (SD 0.8) mm in the anterior direction.
CONCLUSION: We observed substantial pancreatic tumor motion during BH as well as considerable position variation between consecutive BHs on a single day. We recommend further quantifying these uncertainties before introducing breath-hold during radiation treatment of pancreatic cancer patients. Also, the diaphragm cannot be used as a surrogate for pancreatic tumor motion.

de Morrée ES, Vogelzang NJ, Petrylak DP, et al.
Association of Survival Benefit With Docetaxel in Prostate Cancer and Total Number of Cycles Administered: A Post Hoc Analysis of the Mainsail Study.
JAMA Oncol. 2017; 3(1):68-75 [PubMed] Related Publications
Importance: The optimal total number of docetaxel cycles in patients with metastatic castration resistant prostate cancer (mCPRC) has not been investigated yet. It is unknown whether it is beneficial for patients to continue treatment upon 6 cycles.
Objective: To investigate whether the number of docetaxel cycles administered to patients deriving clinical benefit was an independent prognostic factor for overall survival (OS) in a post hoc analysis of the Mainsail trial.
Design, Setting, and Participants: The Mainsail trial was a multinational randomized phase 3 study of 1059 patients with mCRPC receiving docetaxel, prednisone, and lenalidomide (DPL) or docetaxel, prednisone, and a placebo (DP). Study patients were treated until progressive disease or unacceptable adverse effects occurred. Median OS was found to be inferior in the DPL arm compared with the DP arm. As a result of increased toxic effects with the DPL combination, patients on DPL received fewer docetaxel cycles (median, 6) vs 8 cycles in the control group. As the dose intensity was comparable in both treatment arms, we investigated whether the number of docetaxel cycles administered to patients deriving clinical benefit on Mainsail was an independent prognostic factor for OS. We conducted primary univariate and multivariate analyses for the intention-to-treat population. Additional sensitivity analyses were done, excluding patients who stopped treatment for reasons of disease progression and those who received 4 or fewer cycles of docetaxel for other reasons, minimizing the effect of confounding factors.
Main Outcomes and Measures: Total number of docetaxel cycles delivered as an independent factor for OS.
Results: Overall, all 1059 patients from the Mainsail trial were included (mean [SD] age, 68.7 [7.89] years). Treatment with 8 or more cycles of docetaxel was associated with superior OS (hazard ratio [HR], 1.909; 95% CI, 1.660-2.194; P < .001), irrespective of lenalidomide treatment (HR, 1.060; 95% CI, 0.924-1.215; P = .41). Likewise, in the sensitivity analysis, patients who received a greater number of docetaxel cycles had superior OS; patients who received more than 10 cycles had a median OS of 33.0 months compared with 26.9 months in patients treated with 8 to 10 cycles; and patients who received 5 to 7 cycles had a median OS of 22.8 months (P < .001).
Conclusions and Relevance: These findings suggest that continuation of docetaxel chemotherapy contributes to the survival benefit. Prospective validation is warranted.

Palumbo A, Chanan-Khan A, Weisel K, et al.
Daratumumab, Bortezomib, and Dexamethasone for Multiple Myeloma.
N Engl J Med. 2016; 375(8):754-66 [PubMed] Related Publications
BACKGROUND: Daratumumab, a human IgGκ monoclonal antibody that targets CD38, induces direct and indirect antimyeloma activity and has shown substantial efficacy as monotherapy in heavily pretreated patients with multiple myeloma, as well as in combination with bortezomib in patients with newly diagnosed multiple myeloma.
METHODS: In this phase 3 trial, we randomly assigned 498 patients with relapsed or relapsed and refractory multiple myeloma to receive bortezomib (1.3 mg per square meter of body-surface area) and dexamethasone (20 mg) alone (control group) or in combination with daratumumab (16 mg per kilogram of body weight) (daratumumab group). The primary end point was progression-free survival.
RESULTS: A prespecified interim analysis showed that the rate of progression-free survival was significantly higher in the daratumumab group than in the control group; the 12-month rate of progression-free survival was 60.7% in the daratumumab group versus 26.9% in the control group. After a median follow-up period of 7.4 months, the median progression-free survival was not reached in the daratumumab group and was 7.2 months in the control group (hazard ratio for progression or death with daratumumab vs. control, 0.39; 95% confidence interval, 0.28 to 0.53; P<0.001). The rate of overall response was higher in the daratumumab group than in the control group (82.9% vs. 63.2%, P<0.001), as were the rates of very good partial response or better (59.2% vs. 29.1%, P<0.001) and complete response or better (19.2% vs. 9.0%, P=0.001). Three of the most common grade 3 or 4 adverse events reported in the daratumumab group and the control group were thrombocytopenia (45.3% and 32.9%, respectively), anemia (14.4% and 16.0%, respectively), and neutropenia (12.8% and 4.2%, respectively). Infusion-related reactions that were associated with daratumumab treatment were reported in 45.3% of the patients in the daratumumab group; these reactions were mostly grade 1 or 2 (grade 3 in 8.6% of the patients), and in 98.2% of these patients, they occurred during the first infusion.
CONCLUSIONS: Among patients with relapsed or relapsed and refractory multiple myeloma, daratumumab in combination with bortezomib and dexamethasone resulted in significantly longer progression-free survival than bortezomib and dexamethasone alone and was associated with infusion-related reactions and higher rates of thrombocytopenia and neutropenia than bortezomib and dexamethasone alone. (Funded by Janssen Research and Development; ClinicalTrials.gov number, NCT02136134.).

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.).

Burke CA, Dekker E, Samadder NJ, et al.
Efficacy and safety of eflornithine (CPP-1X)/sulindac combination therapy versus each as monotherapy in patients with familial adenomatous polyposis (FAP): design and rationale of a randomized, double-blind, Phase III trial.
BMC Gastroenterol. 2016; 16(1):87 [PubMed] Related Publications
BACKGROUND: Molecular studies suggest inhibition of colorectal mucosal polyamines (PAs) may be a promising approach to prevent colorectal cancer (CRC). Inhibition of ornithine decarboxylase (ODC) using low-dose eflornithine (DFMO, CPP-1X), combined with maximal PA export using low-dose sulindac, results in greatly reduced levels of normal mucosal PAs. In a clinical trial, this combination (compared with placebo) reduced the 3-year incidence of subsequent high-risk adenomas by >90 %. Familial Adenomatous Polyposis (FAP) is characterized by marked up-regulation of ODC in normal intestinal epithelial and adenoma tissue, and therefore PA reduction might be a potential strategy to control progression of FAP-related intestinal polyposis. CPP FAP-310, a randomized, double-blind, Phase III trial was designed to examine the safety and efficacy of sulindac and DFMO (alone or in combination) for preventing a clinically relevant FAP-related progression event in individuals with FAP.
METHODS: Eligible adults with FAP will be randomized to: CPP-1X 750 mg and sulindac 150 mg, CPP-1X placebo and sulindac 150 mg, or CPP-1X 750 mg and sulindac placebo once daily for 24 months. Patients will be stratified based on time-to-event prognosis into one of the three treatment arms: best (ie, longest time to first FAP-related event [rectal/pouch polyposis]), intermediate (duodenal polyposis) and worst (pre-colectomy). Stage-specific, "delayed time to" FAP-related events are the primary endpoints. Change in polyp burden (upper and/or lower intestine) is a key secondary endpoint.
DISCUSSION: The trial is ongoing. As of February 1, 2016, 214 individuals have been screened; 138 eligible subjects have been randomized to three treatment groups at 15 North American sites and 6 European sites. By disease strata, 26, 80 and 32 patients are included for assessment of polyp burden in the rectum/pouch, duodenal polyposis and pre-colectomy groups, respectively. Median age is 40 years; 59 % are men. The most common reasons for screening failure include minimal polyp burden (n = 22), withdrawal of consent (n = 9) and extensive polyposis requiring immediate surgical intervention (n = 9). Enrollment is ongoing.
TRIAL REGISTRATION: This trial is registered at ClinicalTrials.gov ( NCT01483144 ; November 21, 2011) and the EU Clinical Trials Register( EudraCT 2012-000427-41 ; May 15, 2014).

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.).

Boekhout AH, Gietema JA, Milojkovic Kerklaan B, et al.
Angiotensin II-Receptor Inhibition With Candesartan to Prevent Trastuzumab-Related Cardiotoxic Effects in Patients With Early Breast Cancer: A Randomized Clinical Trial.
JAMA Oncol. 2016; 2(8):1030-7 [PubMed] Related Publications
IMPORTANCE: This is the first randomized placebo-controlled evaluation of a medical intervention for the prevention of trastuzumab-related cardiotoxic effects.
OBJECTIVE: To determine as the primary end point whether angiotensin II antagonist treatment with candesartan can prevent or ameliorate trastuzumab-related cardiotoxic effects, defined as a decline in left ventricular ejection fraction (LVEF) of more than 15% or a decrease below the absolute value 45%.
DESIGN: This randomized, placebo-controlled clinical study was conducted between October 2007 and October 2011 in 19 hospitals in the Netherlands, enrolling 210 women with early breast cancer testing positive for human epidermal growth factor receptor 2 (HER2) who were being considered for adjuvant systemic treatment with anthracycline-containing chemotherapy followed by trastuzumab.
INTERVENTIONS: A total of 78 weeks of candesartan (32 mg/d) or placebo treatment; study treatment started at the same day as the first trastuzumab administration and continued until 26 weeks after completion of trastuzumab treatment.
MAIN OUTCOMES AND MEASURES: The primary outcome was LVEF. Secondary end points included whether the N-terminal of the prohormone brain natriuretic peptide (NT-proBNP) and high-sensitivity troponin T (hs-TnT) can be used as surrogate markers and whether genetic variability in germline ERBB2 (formerly HER2 or HER2/neu) correlates with trastuzumab-related cardiotoxic effects.
RESULTS: A total of 206 participants were evaluable (mean age, 49 years; age range, 25-69 years) 103 in the candesartan group (mean age, 50 years; age range, 25-69 years) and 103 in the placebo group (mean age, 50 years; age range, 30-67 years). Of these, 36 manifested at least 1 of the 2 primary cardiac end points. There were 3.8% more cardiac events in the candesartan group than in the placebo group (95% CI, -7% to 15%; P = .58): 20 events (19%) and 16 events (16%), respectively. The 2-year cumulative incidence of cardiac events was 0.28 (95% CI, 0.13-0.40) in the candesartan group and 0.16 (95% CI, 0.08-0.22) in the placebo group (P = .56). Candesartan did not affect changes in NT-proBNP and hs-TnT values, and these biomarkers were not associated with significant changes in LVEF. The Ala1170Pro homozygous ERBB2 genotype was associated with a lower likelihood of the occurrence of a cardiac event compared with Pro/Pro + Ala/Pro genotypes in multivariate analysis (odds ratio, 0.09; 95% CI, 0.02-0.45; P = .003).
CONCLUSIONS AND RELEVANCE: The findings do not support the hypothesis that concomitant use of candesartan protects against a decrease in left ventricular ejection fraction during or shortly after trastuzumab treatment in early breast cancer. The ERBB2 germline Ala1170Pro single nucleotide polymorphism may be used to identify patients who are at increased risk of trastuzumab-related cardiotoxic effects.
TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00459771.

Zegers CM, Hoebers FJ, van Elmpt W, et al.
Evaluation of tumour hypoxia during radiotherapy using [(18)F]HX4 PET imaging and blood biomarkers in patients with head and neck cancer.
Eur J Nucl Med Mol Imaging. 2016; 43(12):2139-2146 [PubMed] Free Access to Full Article Related Publications
BACKGROUND AND PURPOSE: Increased tumour hypoxia is associated with a worse overall survival in patients with head and neck squamous cell carcinoma (HNSCC). The aims of this study were to evaluate treatment-associated changes in [(18)F]HX4-PET, hypoxia-related blood biomarkers, and their interdependence.
MATERIAL AND METHODS: [(18)F]HX4-PET/CT scans of 20 patients with HNSCC were acquired at baseline and after ±20Gy of radiotherapy. Within the gross-tumour-volumes (GTV; primary and lymph nodes), mean and maximum standardized uptake values, the hypoxic fraction (HF) and volume (HV) were calculated. Also, the changes in spatial uptake pattern were evaluated using [(18)F]HX4-PET/CT imaging. For all patients, the plasma concentration of CAIX, osteopontin and VEGF was assessed.
RESULTS: At baseline, tumour hypoxia was detected in 69 % (22/32) of the GTVs. During therapy, we observed a significant decrease in all image parameters. The HF decreased from 21.7 ± 19.8 % (baseline) to 3.6 ± 10.0 % (during treatment; P < 0.001). Only two patients had a HV > 1 cm(3) during treatment, which was located for >98 % within the baseline HV. During treatment, no significant changes in plasma CAIX or VEGF were observed, while osteopontin was increased.
CONCLUSIONS: [(18)F]HX4-PET/CT imaging allows monitoring changes in hypoxia during (chemo)radiotherapy whereas the blood biomarkers were not able to detect a treatment-associated decrease in hypoxia.

Backes Y, Moons LM, van Bergeijk JD, et al.
Endoscopic mucosal resection (EMR) versus endoscopic submucosal dissection (ESD) for resection of large distal non-pedunculated colorectal adenomas (MATILDA-trial): rationale and design of a multicenter randomized clinical trial.
BMC Gastroenterol. 2016; 16(1):56 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Endoscopic mucosal resection (EMR) is currently the most used technique for resection of large distal colorectal polyps. However, in large lesions EMR can often only be performed in a piecemeal fashion resulting in relatively low radical (R0)-resection rates and high recurrence rates. Endoscopic submucosal dissection (ESD) is a newer procedure that is more difficult resulting in a longer procedural time, but is promising due to the high en-bloc resection rates and the very low recurrence rates. We aim to evaluate the (cost-)effectiveness of ESD against EMR on both short (i.e. 6 months) and long-term (i.e. 36 months). We hypothesize that in the short-run ESD is more time consuming resulting in higher healthcare costs, but is (cost-) effective on the long-term due to lower patients burden, a higher number of R0-resections and lower recurrence rates with less need for repeated procedures.
METHODS: This is a multicenter randomized clinical trial in patients with a non-pedunculated polyp larger than 20 mm in the rectum, sigmoid, or descending colon suspected to be an adenoma by means of endoscopic assessment. Primary endpoint is recurrence rate at follow-up colonoscopy at 6 months. Secondary endpoints are R0-resection rate, perceived burden and quality of life, healthcare resources utilization and costs, surgical referral rate, complication rate and recurrence rate at 36 months. Quality-adjusted-life-year (QALY) will be estimated taking an area under the curve approach and using EQ-5D-indexes. Healthcare costs will be calculated by multiplying used healthcare services with unit prices. The cost-effectiveness of ESD against EMR will be expressed as incremental cost-effectiveness ratios (ICER) showing additional costs per recurrence free patient and as ICER showing additional costs per QALY.
DISCUSSION: If this trial confirms ESD to be favorable on the long-term, the burden of extra colonoscopies and repeated procedures can be prevented for future patients.
TRIAL REGISTRATION: NCT02657044 (Clinicaltrials.gov), registered January 8, 2016.

Janssens GO, Langendijk JA, Terhaard CH, et al.
Quality-of-life after radiotherapy for advanced laryngeal cancer: Results of a phase III trial of the Dutch Head and Neck Society.
Radiother Oncol. 2016; 119(2):213-20 [PubMed] Related Publications
BACKGROUND/PURPOSE: To report on health-related quality-of-life (HRQoL) of patients with laryngeal cancer, treated in a randomized trial comparing accelerated radiotherapy with carbogen and nicotinamide (ARCON) against accelerated radiotherapy alone (AR).
MATERIAL/METHODS: HRQoL was assessed using the HRQoL Questionnaire-C30 (QLQ-C30) and the Head & Neck cancer module (QLQ-H&N35) at baseline, at completion of radiotherapy and at 6, 12, and 24months post-baseline.
RESULTS: From 269/345 patients (AR: 136/174; ARCON: 133/171) data on HRQoL were available for analysis. Moderate to severe clinical impact of the treatment was observed for nearly all items of the QLQ-C30 and QLQ-H&N35 between baseline and end-of-treatment. At 6months, scores returned to baseline level with exception of dry mouth, sticky saliva, and taste/smell. No difference between AR and ARCON was observed. At 2years from baseline, the percentage of patients reporting moderate to severe complaints of dry mouth, sticky saliva, or changes in taste/smell was 30%, 22% and 18%, respectively, while the majority of patients had no or few complaints of swallowing (79%) or speech (64%).
CONCLUSIONS: With accelerated radiotherapy, high local tumor control was obtained while maintaining good speech and swallowing function. Long-term dry mouth, sticky saliva and changes in taste/smell are limited to one quarter of patients. (ClinicalTrials.gov number, NCT00147732).

Scheltema MJ, van den Bos W, de Bruin DM, et al.
Focal vs extended ablation in localized prostate cancer with irreversible electroporation; a multi-center randomized controlled trial.
BMC Cancer. 2016; 16:299 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Current surgical and ablative treatment options for prostate cancer (PCa) may result in a high incidence of (temporary) incontinence, erectile dysfunction and/or bowel damage. These side effects are due to procedure related effects on adjacent structures including blood vessels, bowel, urethra and/or neurovascular bundle. Ablation with irreversible electroporation (IRE) has shown to be effective and safe in destroying PCa cells and also has the potential advantage of sparing surrounding tissue and vital structures, resulting in less impaired functional outcomes and maintaining men's quality of life.
METHODS/DESIGN: In this randomized controlled trial (RCT) on IRE in localized PCa, 200 patients with organ-confined, unilateral (T1c-T2b) low- to intermediate-risk PCa (Gleason sum score 6 and 7) on transperineal template-mapping biopsies (TTMB) will be included. Patients will be randomized into focal or extended ablation of cancer foci with IRE. Oncological efficacy will be determined by multiparametric Magnetic Resonance Imaging, Contrast-Enhanced Ultrasound imaging if available, TTMP and Prostate Specific Antigen (PSA) follow-up. Patients will be evaluated up to 5 years on functional outcomes and quality of life with the use of standardized questionnaires.
DISCUSSION: There is critical need of larger, standardized RCTs evaluating long-term oncological and functional outcomes before introducing IRE and other focal therapy modalities as an accepted and safe therapeutic option for PCa. This RCT will provide important short- and long-term data and elucidates the differences between focal or extended ablation of localized, unilateral low- to intermediate-risk PCa with IRE.
TRIAL REGISTRATION: Clinicaltrials.gov database registration number NCT01835977. The Dutch Central Committee on Research Involving Human Subjects registration number NL50791.018.14.

Jacobs BA, Meulenaar J, Rosing H, et al.
A phase 0 clinical trial of novel candidate extended-release formulations of capecitabine.
Cancer Chemother Pharmacol. 2016; 77(6):1201-7 [PubMed] Related Publications
PURPOSE: To examine the pharmacokinetic (PK) profile of several candidate extended-release (ER) formulations of capecitabine in patients.
METHODS: In a phase 0 clinical study, PK profiles of several oral candidate ER formulations of capecitabine were compared to the PK profile of capecitabine after administration of the commercially available immediate-release (IR) tablet. A single dose of 1000 mg IR formulation (two 500 mg tablets) was administered on day 1, and a single dose of a 1000 mg candidate ER formulation of capecitabine (two 500 mg tablets) was administered on day 2. Candidate ER formulations of capecitabine differed with regard to the amount of the ER excipient (Kollidon(®) SR) in tablet matrix (0-5 % w/w) and coating (0-12 mg/cm(2)).
RESULTS: PK profiles of nine different candidate ER formulations were examined. The tablet coating seemed the main determinant for ER of capecitabine and tablet integrity. Average (±standard deviation) AUC0-2h, relative to AUC0-2h after oral administration of the IR tablet, were 43.3 % (±34.9 %) and 1.2 % (±1.2 %) for candidate ER formulations coated with 3 and 6 mg/cm(2), respectively. Corresponding AUC0-last were 93.6 % (±40.2 %) and 44.0 % (±5.4 %).
CONCLUSION: Modulation of capecitabine release in patients can be accomplished by varying tablet coating content. Proof of principle was demonstrated for candidate ER formulations with coating content of 3 mg/cm(2).

Lutkenhaus LJ, Vestergaard A, Bel A, et al.
A biological modeling based comparison of two strategies for adaptive radiotherapy of urinary bladder cancer.
Acta Oncol. 2016; 55(8):1009-15 [PubMed] Related Publications
Background Adaptive radiotherapy is introduced in the management of urinary bladder cancer to account for day-to-day anatomical changes. The purpose of this study was to determine whether an adaptive plan selection strategy using either the first four cone beam computed tomography scans (CBCT-based strategy) for plan creation, or the interpolation of bladder volumes on pretreatment CT scans (CT-based strategy), is better in terms of tumor control probability (TCP) and normal tissue sparing while taking the clinically applied fractionation schedules also into account. Material and methods With the CT-based strategy, a library of five plans was created. Patients received 55 Gy to the bladder tumor and 40 Gy to the non-involved bladder and lymph nodes, in 20 fractions. With the CBCT-based strategy, a library of three plans was created, and patients received 70 Gy to the tumor, 60 Gy to the bladder and 48 Gy to the lymph nodes, in 30-35 fractions. Ten patients were analyzed for each adaptive plan selection strategy. TCP was calculated applying the clinically used fractionation schedules, as well as a rescaling of the dose from 55 to 70 Gy for the CT-based strategy. For rectum and bowel, equivalent doses in 2 Gy fractions (EQD2) were calculated. Results The CBCT-based strategy resulted in a median TCP of 75%, compared to 49% for the CT-based strategy, the latter improving to 72% upon rescaling the dose to 70 Gy. A median rectum V30Gy (EQD2) of 26% [interquartile range (IQR): 8-52%] was found for the CT-based strategy, compared to 58% (IQR: 55-73%) for the CBCT-based strategy. Also the bowel doses were lower with the CT-based strategy. Conclusions Whereas the higher total bladder TCP for the CBCT-based strategy is due to prescription differences, the adaptive strategy based on CT scans results in the lowest rectum and bowel cavity doses.

Welters MJ, van der Sluis TC, van Meir H, et al.
Vaccination during myeloid cell depletion by cancer chemotherapy fosters robust T cell responses.
Sci Transl Med. 2016; 8(334):334ra52 [PubMed] Related Publications
Therapeutic vaccination with human papillomavirus type 16 synthetic long peptides (HPV16-SLPs) results in T cell-mediated regression of HPV16-induced premalignant lesions but fails to install clinically effective immunity in patients with HPV16-positive cervical cancer. We explored whether HPV16-SLP vaccination can be combined with standard carboplatin and paclitaxel chemotherapy to improve immunity and which time point would be optimal for vaccination. This was studied in the HPV16 E6/E7-positive TC-1 mouse tumor model and in patients with advanced cervical cancer. In mice and patients, the presence of a progressing tumor was associated with abnormal frequencies of circulating myeloid cells. Treatment of TC-1-bearing mice with chemotherapy and therapeutic vaccination resulted in superior survival and was directly related to a chemotherapy-mediated altered composition of the myeloid cell population in the blood and tumor. Chemotherapy had no effect on tumor-specific T cell responses. In advanced cervical cancer patients, carboplatin-paclitaxel also normalized the abnormal numbers of circulating myeloid cells, and this was associated with increased T cell reactivity to recall antigens. The effect was most pronounced starting 2 weeks after the second cycle of chemotherapy, providing an optimal immunological window for vaccination. This was validated with a single dose of HPV16-SLP vaccine given in this time window. The resulting proliferative HPV16-specific T cell responses were unusually strong and were retained after all cycles of chemotherapy. In conclusion, carboplatin-paclitaxel therapy fosters vigorous vaccine-induced T cell responses when vaccination is given after chemotherapy and has reset the tumor-induced abnormal myeloid cell composition to normal values.

Rietjens JA, Korfage IJ, Dunleavy L, et al.
Advance care planning--a multi-centre cluster randomised clinical trial: the research protocol of the ACTION study.
BMC Cancer. 2016; 16:264 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Awareness of preferences regarding medical care should be a central component of the care of patients with advanced cancer. Open communication can facilitate this but can occur in an ad hoc or variable manner. Advance care planning (ACP) is a formalized process of communication between patients, relatives and professional caregivers about patients' values and care preferences. It raises awareness of the need to anticipate possible future deterioration of health. ACP has the potential to improve current and future healthcare decision-making, provide patients with a sense of control, and improve their quality of life.
METHODS/DESIGN: We will study the effects of the ACP program Respecting Choices on the quality of life of patients with advanced lung or colorectal cancer. In a phase III multicenter cluster randomised controlled trial, 22 hospitals in 6 countries will be randomised. In the intervention sites, patients will be offered interviews with a trained facilitator. In the control sites, patients will receive care as usual. In total, 1360 patients will be included. All participating patients will be asked to complete questionnaires at inclusion, and again after 2.5 and 4.5 months. If a patient dies within a year after inclusion, a relative will be asked to complete a questionnaire on end-of-life care. Use of medical care will be assessed by checking medical files. The primary endpoint is patients' quality of life at 2.5 months post-inclusion. Secondary endpoints are the extent to which care as received is aligned with patients' preferences, patients' evaluation of decision-making processes, quality of end-of-life care and cost-effectiveness of the intervention. A complementary qualitative study will be carried out to explore the lived experience of engagement with the Respecting Choices program from the perspectives of patients, their Personal Representatives, healthcare providers and facilitators.
DISCUSSION: Transferring the concept of ACP from care of the elderly to patients with advanced cancer, who on average are younger and retain their mental capacity for a larger part of their disease trajectory, is an important next step in an era of increased focus on patient centered healthcare and shared decision-making.
TRIAL REGISTRATION: International Standard Randomised Controlled Trial Number: ISRCTN63110516. Date of registration: 10/3/2014.

Teixeira SC, Rebolleda JF, Koolen BB, et al.
Evaluation of a Hanging-Breast PET System for Primary Tumor Visualization in Patients With Stage I-III Breast Cancer: Comparison With Standard PET/CT.
AJR Am J Roentgenol. 2016; 206(6):1307-14 [PubMed] Related Publications
OBJECTIVE: The purposes of this study were to evaluate the performance of a mammography with molecular imaging PET (MAMMI-PET) system for breast imaging in the hanging-breast position for the visualization of primary breast cancer lesions and to compare this method with whole-body PET/CT.
SUBJECTS AND METHODS: Between March 2011 and March 2014, a prospective evaluation included women with one or more histologically confirmed primary breast cancer lesions (index lesions). After injection of 180-240 MBq of (18)F-FDG, whole-body PET/CT and MAMMI-PET acquisitions were performed, index lesions were scored 0, 1, or 2 for FDG uptake relative to background. Detection and FDG uptake were compared by breast length, maximal tumor diameter, affected breast quadrants, tumor grade, and histologic and immunologic sub-types. Finally, the two PET modalities were compared for detection of index lesions.
RESULTS: For 234 index lesions (diameter, 5-170 mm), the overall sensitivity was 88.9% for MAMMI-PET and 91% for PET/CT (p = 0.61). Twenty-three (9.8%) index lesions located too close to the pectoral muscle were missed with MAMMI-PET, and 20 index lesions were missed with PET/CT. Lesion visibility on MAMMI-PET images was influenced by tumor grade (p = 0.034) but not by cancer subtype (p = 0.65).
CONCLUSION: Although in an overall evaluation MAMMI-PET was not superior to PET/CT, MAMMI-PET does have higher sensitivity for primary breast cancer lesions within the scanning range of the device. Optimization of the positioning device may increase visualization of the most dorsal lesions.

Tummers QR, Boogerd LS, de Steur WO, et al.
Near-infrared fluorescence sentinel lymph node detection in gastric cancer: A pilot study.
World J Gastroenterol. 2016; 22(13):3644-51 [PubMed] Free Access to Full Article Related Publications
AIM: To investigate feasibility and accuracy of near-infrared fluorescence imaging using indocyanine green: nanocolloid for sentinel lymph node (SLN) detection in gastric cancer.
METHODS: A prospective, single-institution, phase I feasibility trial was conducted. Patients suffering from gastric cancer and planned for gastrectomy were included. During surgery, a subserosal injection of 1.6 mL ICG:Nanocoll was administered around the tumor. NIR fluorescence imaging of the abdominal cavity was performed using the Mini-FLARE™ NIR fluorescence imaging system. Lymphatic pathways and SLNs were visualized. Of every detected SLN, the corresponding lymph node station, signal-to-background ratio and histopathological diagnosis was determined. Patients underwent standard-of-care gastrectomy. Detected SLNs outside the standard dissection planes were also resected and evaluated.
RESULTS: Twenty-six patients were enrolled. Four patients were excluded because distant metastases were found during surgery or due to technical failure of the injection. In 21 of the remaining 22 patients, at least 1 SLN was detected by NIR Fluorescence imaging (mean 3.1 SLNs; range 1-6). In 8 of the 21 patients, tumor-positive LNs were found. Overall accuracy of the technique was 90% (70%-99%; 95%CI), which decreased by higher pT-stage (100%, 100%, 100%, 90%, 0% for respectively Tx, T1, T2, T3, T4 tumors). All NIR-negative SLNs were completely effaced by tumor. Mean fluorescence signal-to-background ratio of SLNs was 4.4 (range 1.4-19.8). In 8 of the 21 patients, SLNs outside the standard resection plane were identified, that contained malignant cells in 2 patients.
CONCLUSION: This study shows successful use of ICG:Nanocoll as lymphatic tracer for SLN detection in gastric cancer. Moreover, tumor-containing LNs outside the standard dissection planes were identified.

van Roozendaal LM, Smit LH, Duijsens GH, et al.
Risk of regional recurrence in triple-negative breast cancer patients: a Dutch cohort study.
Breast Cancer Res Treat. 2016; 156(3):465-72 [PubMed] Free Access to Full Article Related Publications
Triple-negative breast cancer is associated with early recurrence and low survival rates. Several trials investigate the safety of a more conservative approach of axillary treatment in clinically T1-2N0 breast cancer. Triple-negative breast cancer comprises only 15 % of newly diagnosed breast cancers, which might result in insufficient power for representative results for this subgroup. We aimed to provide a nationwide overview on the occurrence of (regional) recurrences in triple-negative breast cancer patients with a clinically T1-2N0 status. For this cohort study, 2548 women diagnosed between 2005 and 2008 with clinically T1-2N0 triple-negative breast cancer were selected from the Netherlands Cancer Registry. Follow-up data until 2014 were analyzed using Kaplan-Meier. Sentinel lymph node biopsy was performed in 2486 patients, and (completion) axillary lymph node dissection in 562 patients. Final pathologic nodal status was pN0 in 78.5 %, pN1mi in 4.5 %, pN1 in 12.3 %, pN2-3 in 3.6 %, and pNx in 1.1 %. During a follow-up of 5 years, regional recurrence occurred in 2.9 %, local recurrence in 4.2 % and distant recurrence in 12.2 %. Five-year disease-free survival was 78.7 %, distant disease-free survival 80.5 %, and 5-year overall survival 82.3 %. Triple-negative clinically T1-2N0 breast cancer patients rarely develop a regional recurrence. Their disease-free survival is more threatened by distant recurrence, affecting their overall survival. Consequently, it seems justified to include triple-negative breast cancer patients in randomized controlled trials investigating the safety of minimizing axillary staging and treatment.

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.

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