Targeted therapy using EGFR inhibitors cetuximab and panitumumab has anti-tumor efficacy in colorectal cancer, though only in patients without a KRAS mutation in their tumor. This thesis aims to... Show moreTargeted therapy using EGFR inhibitors cetuximab and panitumumab has anti-tumor efficacy in colorectal cancer, though only in patients without a KRAS mutation in their tumor. This thesis aims to give insight on several aspects of EGFR inhibitors en RAS mutations in colorectal cancer. It reviews aspects of mutational analysis, aims to find ways to restore sensitivity to EGFR inhibitors in patients with KRAS mutated colorectal cancer and discusses the distinctive skin toxicity of cetuximab en pantiumumab. Show less
Although anti-cancer treatments have significantly advanced over the past decades, obstacles to accomplishing successful treatment still exist. The occurrence of treatment resistance is one of the... Show moreAlthough anti-cancer treatments have significantly advanced over the past decades, obstacles to accomplishing successful treatment still exist. The occurrence of treatment resistance is one of the major factors that limit the long-lasting efficacy of anti-cancer treatment. Additionally, substantial variability in pharmacokinetics (PK) / pharmacodynamics (PD) of anti-cancer drugs also challenges successful oncology treatment. Therefore, gaining knowledge of and ultimately better suppressing evolutionary resistance development during treatment, and applying personalized treatment are desired to improve anti-cancer treatment. In this thesis, we have applied quantitative modeling approaches to address these needs, aiming for improved treatment for oncology patients. Our work demonstrated that with the quantitative models, the evolutionary progression of tumors could be characterized and predicted, accounting for interactions among heterogeneous tumor cells and supported by mutant gene variants detected in circulating tumor DNA (ctDNA). In addition, we developed population PK /PD models which enabled quantitative description of the PK and PD of anti-cancer drugs and corresponding variabilities in real-world patients. The developed models have been further applied to support the identification of optimal treatment strategies and guide individualized treatment for oncology patients. Show less
Seghers, P.A.L.; Alibhai, S.M.H.; Battisti, N.M.L.; Kanesvaran, R.; Extermann, M.; O'Donovan, A.; ... ; O'Hanlon, S. 2023
Most cancers occur in older people and the burden in this age group is increasing. Over the past two decades the evidence on how best to treat this population has increased rapidly. However,... Show moreMost cancers occur in older people and the burden in this age group is increasing. Over the past two decades the evidence on how best to treat this population has increased rapidly. However, implementation of new best practices has been slow and needs involvement of policymakers. This perspective paper explains why older people with cancer have different needs than the wider population. An overview is given of the recommended approach for older people with cancer and its benefits on clinical outcomes and cost-effectiveness. In older patients, the geriatric assessment (GA) is the gold standard to measure level of fitness and to determine treatment tolerability. The GA, with multiple domains of physical health, functional status, psychological health and socio-environmental factors, prevents initiation of inappropriate oncologic treatment and recommends geriatric interventions to optimize the patient's general health and thus resilience for receiving treatments. Multiple studies have proven its benefits such as reduced toxicity, better quality of life, better patient-centred communication and lower healthcare use. Although GA might require investment of time and resources, this is relatively small compared to the improved outcomes, possible cost-savings and compared to the large cost of oncologic treatments as a whole. Show less
The findings in this thesis improve the understanding of 1) the relationship between exposure characteristics and toxicity of ENPs, 2) the joint toxic action of ENP mixtures and the comparison to... Show moreThe findings in this thesis improve the understanding of 1) the relationship between exposure characteristics and toxicity of ENPs, 2) the joint toxic action of ENP mixtures and the comparison to metal salt mixtures, 3) how NOM affects the individual and joint toxicity of ENPs, 4) the extent of trophic transfer of ENPs along aquatic food chains, 5) the influence factors on trophic transfer, and 6) bioaccumulation, distribution and toxic effect on predators. This knowledge would provide a basis for data on individual and joint toxicity, bioaccumulation, and trophic transfer of ENPs for more realistic environmental risk assessment. Show less
Rhun, E. le; Oppong, F.B.; Bent, M. van den; Wick, W.; Brandes, A.A.; Taphoorn, M.J.B.; ... ; Weller, M. 2022
BackgroundThrombocytopenia represents the main cause of stopping alkylating chemotherapy for toxicity. Here, we explored the incidence, and the consequences for treatment exposure and survival, of... Show moreBackgroundThrombocytopenia represents the main cause of stopping alkylating chemotherapy for toxicity. Here, we explored the incidence, and the consequences for treatment exposure and survival, of thrombocytopenia induced by lomustine in recurrent glioblastoma.MethodsWe performed a retrospective analysis of the associations of thrombocytopenia with treatment delivery and outcome in EORTC 26101, a randomised trial designed to define the role of lomustine versus bevacizumab versus their combination in recurrent glioblastoma.ResultsA total of 225 patients were treated with lomustine alone (median 1 cycle) (group 1) and 283 patients were treated with lomustine plus bevacizumab (median 3 lomustine cycles) (group 2). Among cycle delays and dose reductions of lomustine for toxicity, thrombocytopenia was the leading cause. Among 129 patients (57%) of group 1 and 187 patients (66%) of group 2 experiencing at least one episode of thrombocytopenia, 36 patients (16%) in group 1 and 93 (33%) in group 2 had their treatment modified because of thrombocytopenia. Lomustine was discontinued for thrombocytopenia in 16 patients (7.1%) in group 1 and in 38 patients (13.4%) in group 2. On adjusted analysis accounting for major prognostic factors, dose modification induced by thrombocytopenia was associated with inferior progression-free survival in patients with MGMT promoter-methylated tumours in groups 1 and 2. This effect was noted for overall survival, too, but only for group 2 patients. Conclusion: Drug-induced thrombocytopenia is a major limitation to adequate exposure to lomustine chemotherapy in recurrent glioblastoma. Mitigating thrombocytopenia to enhance lomustine exposure might improve outcome in patients with MGMT promoter-methylated tumours. Show less
Similarity assessment is one of the means of optimally using scarcely available experimental data on the fate and hazards of nanoforms (NFs) for regulatory purposes. For a set of NFs that are shown... Show moreSimilarity assessment is one of the means of optimally using scarcely available experimental data on the fate and hazards of nanoforms (NFs) for regulatory purposes. For a set of NFs that are shown to be similar it is allowed in a regulatory context to apply the information available on any of the NFs within the group to the whole set of NFs. Obviously, a proper justification for such a similarity assessment is to be provided. Within the context of exemplifying such a justification, a case study was performed aimed at assessing the similarity of a set of spherical metallic NFs that different with regard to chemical composition (three metals) and particle size (three different sizes). The endpoints of assessment were root elongation and biomass increase of lettuce (Lactuca sativa L.) seedlings and exposure assessment was performed in order to express the actual exposure concentration in terms of time-weighted average particle concentrations. The results of the study show that for the specific endpoints assessed, chemical composition is driving NF toxicity and this is mostly due to impacts on the fate of the NFs. On the other hand, particle size of Cu NFs had a negligible impact on the dose-response relationships for the specific endpoints assessed. It is thus concluded that hazard data available on spherical Cu NF tested in our case can be used to inform on the hazards of any spherical Cu NF within the size range of 25–100 nm, but only applies for the certain endpoints. Also, toxicity data for the Cu2+-ion are suited for such a similarity assessment. Show less
Aim: In the registration trial, cabozantinib exposure >= 750 ng/mL correlated to improved tumor size reduction, response rate and progression free survival (PFS) in patients with metastatic... Show moreAim: In the registration trial, cabozantinib exposure >= 750 ng/mL correlated to improved tumor size reduction, response rate and progression free survival (PFS) in patients with metastatic renal cell cancer (mRCC). Because patients in routine care often differ from patients in clinical trials, we explored the cabozantinib exposure-response relationship in patients with mRCC treated in routine care. Methods: Cabozantinib trough concentrations (C-min) were collected and average exposure was calculated per individual. Exposure-response analyses were performed using the earlier identified target of C-min > 750 ng/mL and median C-min. In addition, the effect of dose reductions on response was explored. PFS was used as measure of response. Results: In total, 59 patients were included:10% were classified as favourable, 61% as intermediate and 29% as poor IMDC risk group, respectively. Median number of prior treatment lines was 2 (0-5). Starting dose was 60 mg in 46%, 40 mg in 42% and 20 mg in 12% of patients. Dose reductions were needed in 58% of patients. Median C-min was 572 ng/mL (IQR: 496-701). Only 17% of patients had an average C-min >= 750 ng/mL. Median PFS was 52 weeks (95% CI: 40-64). No improved PFS was observed for patients with C-min >= 750 ng/mL or >= 572 ng/ml. A longer PFS was observed for patients with a dose reduction vs. those without (65 vs. 31 weeks, p = .001). After incorporating known covariates (IMDC risk group and prior treatment lines (< 2 vs. >= 2)) in the multivariable analysis, the need for dose reduction remained significantly associated with improved PFS (HR 0.32, 95% CI:0.14-0.70, p = .004). Conclusion: In these explorative analyses, no clear relationship between increased cabozantinib exposure and improved PFS was observed. Average cabozantinib exposure was below the previously proposed target in 83% of patients. Future studies should focus on validating the cabozantinib exposure required for long term efficacy. Show less
Introduction: With the introduction of tyrosine kinase inhibitors and systemic antibodies, including immune checkpoint inhibitors, the survival of advanced-stage cancer patients has improved for... Show moreIntroduction: With the introduction of tyrosine kinase inhibitors and systemic antibodies, including immune checkpoint inhibitors, the survival of advanced-stage cancer patients has improved for many tumor types. These patients are increasingly referred for radiotherapy, but it is unclear whether radiotherapy combined with these drugs is safe. No international guidelines exist on whether or how to combine these drugs with radiotherapy. Therefore, we investigated the current clinical practice in the Netherlands regarding hypofractionated radiotherapy in patients using targeted drugs and immunotherapy.Materials and methods: We sent a survey to all 21 Dutch radiotherapy institutes. Dedicated radiation oncologists, medical oncologists and pulmonologists were asked to fill out the survey. The questions explored their familiarity with the combination of targeted drugs and immunotherapy with radiotherapy, the encountered clinical difficulties and factors influencing treatment decisions.Results: The survey was filled out by 54 respondents from 19 different institutes. The median annual number of patients per radiation oncologist referred for radiotherapy when using targeted drugs or immunotherapy was 10 and 15, respectively. Despite this high number, only 11% of the radiation oncologists stated that they had sufficient information (resources) for adequate treatment decision making. Among all physicians, 44% stated that there was insufficient knowledge within their institute regarding this topic. Only 17% stated that there was a multidisciplinary protocol available. The application of radiotherapy treatment adaptations (technique, dose, fractionation, field size) varied widely. Generally, there seemed to be no consensus regarding the expected toxicity of combined drug-radiotherapy treatments and the expected risk of tumor flare upon temporary drug discontinuation.Conclusion: There is no consensus amongst involved medical specialties on expected toxicity. Consequently, it is necessary to perform clinical studies examining the safety of combined drug-radiotherapy treatments, to add radiotherapy to phase I-III clinical trials for new drugs and to incorporate outcomes into multidisciplinary, evidence-based guidelines. Show less
Aim: To determine the safety, feasibility, pharmacokinetics, and cost of UGT1A1 genotype-guided dosing of irinotecan.Patients and methods: In this prospective, multicentre, non-randomised study,... Show moreAim: To determine the safety, feasibility, pharmacokinetics, and cost of UGT1A1 genotype-guided dosing of irinotecan.Patients and methods: In this prospective, multicentre, non-randomised study, patients intended for treatment with irinotecan were pre-therapeutically genotyped for UGT1A1*28 and UGT1A1)93. Homozygous variant carriers (UGT1A1 poor metabolisers; PMs) received an initial 30% dose reduction. The primary endpoint was incidence of febrile neutropenia in the first two cycles of treatment. Toxicity in UGT1A1 PMs was compared to a historical cohort of UGT1A1 PMs treated with full dose therapy, and to UGT1A1 non-PMs treated with full dose therapy in the current study. Secondary endpoints were pharmacokinetics, feasi- bility, and costs.Results: Of the 350 evaluable patients, 31 (8.9%) patients were UGT1A1 PM and received a median 30% dose reduction. The incidence of febrile neutropenia in this group was 6.5% compared to 24% in historical UGT1A1 PMs (P = 0.04) and was comparable to the incidence in UGT1A1 non-PMs treated with full dose therapy. Systemic exposure of SN-38 of reduced dosing in UGT1A1 PMs was still slightly higher compared to a standard-dosed irinotecan patient cohort (difference: thorn 32%). Cost analysis showed that genotype-guided dosing was cost-saving with a cost reduction of V183 per patient.Conclusion: UGT1A1 genotype-guided dosing significantly reduces the incidence of febrile neutropenia in UGT1A1 PM patients treated with irinotecan, results in a therapeutically effec- tive systemic drug exposure, and is cost-saving. Therefore, UGT1A1 genotype-guided dosing of irinotecan should be considered standard of care in order to improve individual patient safety. (C) 2022 The Authors. Published by Elsevier Ltd. Show less
Bakker, A.; Valverde, C.P.T.; Tienhoven, G. van; Kolff, M.W.; Kok, H.P.; Slotman, B.J.; ... ; Crezee, H. 2022
Purpose: To investigate the impact of hyperthermia thermal dose (TD) on locoregional control (LRC), overall survival (OS) and toxicity in locoregional recurrent breast cancer patients treated with... Show morePurpose: To investigate the impact of hyperthermia thermal dose (TD) on locoregional control (LRC), overall survival (OS) and toxicity in locoregional recurrent breast cancer patients treated with postoperative re-irradiation and hyperthermia.Methods: In this retrospective study, 112 women with resected locoregional recurrent breast cancer treated in 2010-2017 with postoperative re-irradiation 8frx4Gy (n = 34) or 23frx2Gy (n = 78), combined with 4-5 weekly hyperthermia sessions guided by invasive thermometry, were subdivided into 'low' (n = 56) and 'high' TD (n = 56) groups by the best session with highest median cumulative equivalent minutes at 43 degrees C (Best CEM43T50) < 7.2 min and >7.2 min, respectively. Actuarial LRC, OS and late toxicity incidence were analyzed. Backward multivariable Cox regression and inverse probability weighting (IPW) analysis were performed.Results: TD subgroups showed no significant differences in patient/treatment characteristics. Median follow-up was 43 months (range 1-107 months). High vs. low TD was associated with LRC (p = 0.0013), but not with OS (p = 0.29) or late toxicity (p = 0.58). Three-year LRC was 74.0% vs. 92.3% in the low and high TD group, respectively (p = 0.008). After three years, 25.0% and 0.9% of the patients had late toxicity grade 3 and 4, respectively. Multivariable analysis showed that distant metastasis (HR 17.6; 95%CI 5.2-60.2), lymph node involvement (HR 2.9; 95%CI 1.2-7.2), recurrence site (chest wall vs. breast; HR 4.6; 95%CI 1.8-11.6) and TD (low vs. high; HR 4.1; 95%CI 1.4-11.5) were associated with LRC. TD was associated with LRC in IPW analysis (p = 0.0018).Conclusions: High thermal dose (best CEM43T50 >= 7.2 min) was associated with significantly higher LRC for patients with locoregional recurrent breast cancer treated with postoperative re-irradiation and hyperthermia, without augmenting toxicity. (C) 2021 The Authors. Published by Elsevier B.V. Show less
Spreafico, M.; Ieva, F.; Arlati, F.; Capello, F.; Fatone, F.; Fedeli, F.; ... ; Fiocco, M. 2021
Objectives This study aims at exploring and quantifying multiple types of adverse events (AEs) experienced by patients during cancer treatment. A novel longitudinal score to evaluate the Multiple... Show moreObjectives This study aims at exploring and quantifying multiple types of adverse events (AEs) experienced by patients during cancer treatment. A novel longitudinal score to evaluate the Multiple Overall Toxicity (MOTox) burden is proposed. The MOTox approach investigates the personalised evolution of high overall toxicity (high-MOTox) during the treatment.Design Retrospective analysis of the MRC-BO06/EORTC-80931 randomised controlled trial for osteosarcoma.Setting International multicentre population-based study.Participants A total of 377 patients with resectable high-grade osteosarcoma, who completed treatment within 180 days after randomisation without abnormal dosages (+25% higher than planned).Interventions Patients were randomised to six cycles of conventional versus dose-intense regimens of doxorubicin and cisplatin. Non-haematological toxicity data were collected prospectively and graded according to the Common Terminology Criteria for Adverse Events (CTCAE).Main outcome measures The MOTox score described the overall toxicity burden in terms of multiple toxic AEs, maximum-severity episode and cycle time-dimension. Evolution of high-MOTox was assessed through multivariable models, that investigated the impact of personalised characteristics (eg, achieved chemotherapy dose, previous AEs or biochemical factors) cycle-by-cycle.Results A cycle-by-cycle analysis identifies different evolutions of MOTox levels during treatment, detecting differences in patients' health. Mean MOTox values and percentages of patients with high-MOTox decreased cycle-by-cycle from 2.626 to 1.953 and from 57.8% to 36.6%, respectively. High-MOTox conditions during previous cycles were prognostic risk factors for a new occurrence (ORs range from 1.522 to 4.439), showing that patient's history of toxicities played an important role in the evolution of overall toxicity burden during therapy. Conventional regimen may be preferred to dose-intense in terms of AEs at cycles 2-3 (p<0.05).Conclusions The novel longitudinal method developed can be applied to any cancer studies with CTCAE-graded toxicity data. After validation in other studies, the MOTox approach may lead to improvements in healthcare assessment and treatment planning. Show less
Triest, B. van; Rasing, M.; Velden, J. van der; Hullu, J. de; Witteveen, P.O.; Beukema, J.C.; ... ; Jurgenliemk-Schulz, I. 2021
Objective. To evaluate feasibility of chemoradiation as alternative for extensive surgery in patients with locally advanced vulvar cancer and to report on locoregional control, toxicity and... Show moreObjective. To evaluate feasibility of chemoradiation as alternative for extensive surgery in patients with locally advanced vulvar cancer and to report on locoregional control, toxicity and survival. Methods. In a multicenter, prospective phase II trial patients with locally advanced vulvar cancer were treated with locoregional radiotherapy combined with sensitizing chemotherapy (capecitabine). Treatment feasibility, percentage locoregional control, survival and toxicity were evaluated. Results. 52 patients with mainly T2/T3 disease were treated according to the study protocol in 10 centers in the Netherlands from 2007 to 2019. Full dose radiotherapy (tumor dose of 64.8Gy) was delivered in 92% and full dose capecitabine in 69% of patients. Most prevalent acute >_ grade 3 toxicities were regarding skin/ mucosa and pain (54% and 37%). Late >_grade 3 toxicity was reported for skin/mucosa (10%), fibrosis (4%), GI incontinence (4%) and stress fracture or osteoradionecrosis (4%). Twelve weeks after treatment, local clinical complete response (cCR) and regional control (RC) rates were 62% and 75%, respectively. After 2 years, local cCR persisted in 22 patients (42%) and RC was 58%. Thirty patients (58%) had no evidence of disease at end of follow-up (median 35 months). In 9 patients (17%) extensive surgery with stoma formation was needed. Progression free survival was 58%, 51% and 45% and overall survival was 76%, 66%, 52% at 1,2, and 5 years. Conclusions. Definitive capecitabine-based chemoradiation as alternative for extensive surgery is feasible in locally advanced vulvar cancer and results in considerable locoregional control with acceptable survival rates with manageable acute and late toxicity. (c) 2021 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/). Show less
Bloom Syndrome (BS) is a genetic DNA repair disorder, caused by mutations in the BLM gene. The clinical phenotype includes growth retardation, immunodeficiency and a strong predisposition to... Show moreBloom Syndrome (BS) is a genetic DNA repair disorder, caused by mutations in the BLM gene. The clinical phenotype includes growth retardation, immunodeficiency and a strong predisposition to different types of malignancies. Treatment of malignancies in BS patients with radiotherapy or chemotherapy is believed to be associated with increased toxicity, but clinical and laboratory data are lacking. We collected clinical data of two Dutch BS patients with solid tumors. Both were treated with radiotherapy before the diagnosis BS was made and tolerated this treatment well. In addition, we collected fibroblasts from BS patients to perform in vitro clonogenic survival assays to determine radiosensitivity. BS fibroblasts showed less radiosensitivity than the severely radiosensitive Artemis fibroblasts. Moreover, studies of double strand break kinetics by counting 53BP1 foci after irradiation showed similar patterns compared to healthy controls. In combination, the clinical cases and laboratory experiments are valuable information in the discussion whether radiotherapy is absolutely contraindicated in BS, which is the Case in other DNA repair syndromes like Ataxia Telangiectasia and Artemis. Show less
Background and purpose: We aim to retrospectively investigate whether reducing GTV to high-risk CTV margin will significantly reduce acute and late toxicity without jeopardizing outcome in head-and... Show moreBackground and purpose: We aim to retrospectively investigate whether reducing GTV to high-risk CTV margin will significantly reduce acute and late toxicity without jeopardizing outcome in head-and neck squamous cell carcinoma (HNSCC) treated with definitive (chemo)radiation. Materials and methods: Between April 2015 and April 2019, 155 consecutive patients were treated with GTV to high-risk CTV margin of 10 mm and subsequently another 155 patients with 6 mm margin. The CTV-PTV margin was 3 mm for both groups. All patients were treated with volumetric-modulated arc therapy with daily image-guidance using cone-beam CT. End points of the study were acute and late toxicity and oncologic outcomes. Results: Overall acute grade 3 toxicity was significantly lower in 6 mm, compared to 10 mm group (48% vs. 67%, respectively, p < 0.01). The same was true for acute grade 3 mucositis (18% vs. 34%, p < 0.01) and grade > 2 dysphagia (67% vs. 85%, p < 0.01). Also feeding tube-dependency at the end of treatment (25% vs. 37%, p = 0.02), at 3 months (12% and 25%, p < 0.01), and at 6 months (6% and 15%, p = 0.01) was significantly less in 6 mm group. The incidence of late grade 2 xerostomia was also significantly lower in the 6 mm group (32% vs. 50%, p < 0.01). The 2-year rates of loco-regional control, disease-free and overall survival were 78.7% vs. 73.1%, 70.6% vs. 61.4%, and 83.2% vs. 74.4% (p > 0.05, all). Conclusion: The first study reporting on reduction of GTV to high-risk CTV margin from 10 to 6 mm showed significant reduction of the incidence and severity of radiation-related toxicity without reducing local-regional control and survival. (c) 2021 Elsevier B.V. All rights reserved. Radiotherapy and Oncology 162 (2021) 170-177 Show less
This thesis describes the effects of shortterm fasting on chemotherapy outcome in patients with breast cancer and the IGF-1 and insulin pathway as a target for cancer therapy and as a biomarker for... Show moreThis thesis describes the effects of shortterm fasting on chemotherapy outcome in patients with breast cancer and the IGF-1 and insulin pathway as a target for cancer therapy and as a biomarker for chemotherapy outcome.Preclinical research is evaluated, which shows that short-term fasting during chemotherapy is effective. The effects of short-term fasting in humans is not evident yet. Although the first small clinical studies of short-term fasting as adjunct to chemotherapy are promising in terms of decreased toxicity and enhanced efficacy, the exact mechanism and effects are not established yet. More studies and a longer follow-up are needed to prove this.Insulin-like growth factor 1 (IGF-1) and insulin are members of the IGF-1 pathway, which is involved in cell growth and proliferation. The effects of the IGF-1 pathway on chemotherapy outcome and the pathway itself as target for cancer therapy are described. The disappointing results of clinical studies of IGF-1R inhibitors may be caused by the complexity of the IGF-1R pathway. Lowering both insulin and IGF-1, perhaps with a short-term fasting intervention, serves as a possible target in cancer therapy. Show less
Dirven, L.; Luerding, R.; Beier, D.; Bumes, E.; Reinert, C.; Seidel, C.; ... ; Hau, P. 2020
Background Combined radiochemotherapy followed by maintenance chemotherapy with cisplatin, lomustine and vincristine within the NOA-07 study resulted in considerable short-term toxicity in adult... Show moreBackground Combined radiochemotherapy followed by maintenance chemotherapy with cisplatin, lomustine and vincristine within the NOA-07 study resulted in considerable short-term toxicity in adult medulloblastoma patients. Here we investigated the long-term impact of this treatment, focusing on neurocognitive functioning and health-related quality of life (HRQoL). Methods Neurocognitive functioning and HRQoL scores over time were determined, and differences between the post-treatment and follow-up assessments were calculated up to 18 months for neurocognition and 60 months for HRQoL. Results 28/30 patients were analyzed. The three preselected HRQoL scales (role, social and cognitive functioning) showed improved scores, to a clinically relevant extent (>= 10 points), compared to post-treatment levels up to 30 months, but decreased afterwards. Z-scores for verbal working memory were worse during follow-up compared to post-treatment scores and remained impaired during 18 months follow-up (i.e. z-score below - 1 standard deviation). Attention was impaired post-treatment, and remained impaired to a clinically relevant extent during follow-up. Coordination/processing speed and lexical verbal fluency improved compared to post-treatment scores, and remained within the normal range thereafter. Other tests of verbal fluency were stable over time, with z-scores within the normal range. Conclusions This long-term follow-up study showed that the NOA-07 treatment regimen was not associated with a deterioration in HRQoL in the post-treatment period. Verbal working memory deteriorated, while other neurocognitive domains did not seem to be impacted negatively by the treatment. Show less
Approximately 15–20% of women with endometrial cancer have high-risk disease features and are at increased risk of distant metastases. Standard treatment after surgery is pelvic radiotherapy to... Show moreApproximately 15–20% of women with endometrial cancer have high-risk disease features and are at increased risk of distant metastases. Standard treatment after surgery is pelvic radiotherapy to reduce the risk of recurrence. In the international PORTEC-3 trial we have investigated the added value of adjuvant chemotherapy during and after radiotherapy in terms of efficacy, toxicity and quality of life. It was found that both overall and recurrence-free survival were significantly improved with the addition of chemotherapy to radiotherapy, especially for women with more advanced disease (stage 3) or with serous histological type. This comes however at the expense of increased and more serious toxicity and an impaired quality of life during and in the first 6 months after treatment. About 25% of women treated with chemotherapy still reported tingling and numbness of hands and/or feet at 2 years after treatment. It is therefore important to discuss the benefits and costs of the addition of chemotherapy in shared decision making, for which the results discussed in this thesis provide valuable information. Currently molecular analysis of the PORTEC-3 tissue samples is done to evaluate which patients benefit most from added chemotherapy. Show less
Growing preclinical evidence shows that short-term fasting (STF) protects from toxicity while enhancing the efficacy of a variety of chemotherapeutic agents in the treatment of various tumour types... Show moreGrowing preclinical evidence shows that short-term fasting (STF) protects from toxicity while enhancing the efficacy of a variety of chemotherapeutic agents in the treatment of various tumour types. STF reinforces stress resistance of healthy cells, while tumor cells become even more sensitive to toxins, perhaps through shortage of nutrients to satisfy their needs in the context of high proliferation rates and/or loss of flexibility to respond to extreme circumstances. In humans, STF may be a feasible approach to enhance the efficacy and tolerability of chemotherapy. Clinical research evaluating the potential of STF is in its infancy. This review focuses on the molecular background, current knowledge and clinical trials evaluating the effects of STF in cancer treatment. Preliminary data show that STF is safe, but challenging in cancer patients receiving chemotherapy. Ongoing clinical trials need to unravel if STF can also diminish toxicity and increase efficacy of chemotherapeutic regimes in daily practice. Show less
Rijkmans, E.C.; Marijnen, C.A.M.; Triest, B. van; Ketelaars, M.; Cats, A.; Inderson, A.; ... ; Nout, R.A. 2019
