PurposeThe aim of this study was to investigate the biodistribution of (super-)selective trans-arterial radioembolization (TARE) with holmium-166 microspheres (166Ho-MS), when administered as... Show morePurposeThe aim of this study was to investigate the biodistribution of (super-)selective trans-arterial radioembolization (TARE) with holmium-166 microspheres (166Ho-MS), when administered as adjuvant therapy after RFA of HCC 2-5 cm. The objective was to establish a treatment volume absorbed dose that results in an absorbed dose of >= 120 Gy on the hyperemic zone around the ablation necrosis (i.e., target volume).MethodsIn this multicenter, prospective dose-escalation study in BCLC early stage HCC patients with lesions 2-5 cm, RFA was followed by (super-)selective infusion of 166Ho-MS on day 5-10 after RFA. Dose distribution within the treatment volume was based on SPECT-CT. Cohorts of up to 10 patients were treated with an incremental dose (60 Gy, 90 Gy, 120 Gy) of 166Ho-MS to the treatment volume. The primary endpoint was to obtain a target volume dose of >= 120 Gy in 9/10 patients within a cohort.ResultsTwelve patients were treated (male 10; median age, 66.5 years (IQR, [64.3-71.7])) with a median tumor diameter of 2.7 cm (IQR, [2.1-4.0]). At a treatment volume absorbed dose of 90 Gy, the primary endpoint was met with a median absorbed target volume dose of 138 Gy (IQR, [127-145]). No local recurrences were found within 1-year follow-up.ConclusionAdjuvant (super-)selective infusion of 166Ho-MS after RFA for the treatment of HCC can be administered safely at a dose of 90 Gy to the treatment volume while reaching a dose of >= 120 Gy to the target volume and may be a favorable adjuvant therapy for HCC lesions 2-5 cm.Trial registrationClinicaltrials.gov NCT03437382. (registered: 19-02-2018) Show less
BackgroundSurgical resection followed by adjuvant mFOLFIRINOX (5-fluorouracil with leucovorin, irinotecan, and oxaliplatin) is currently the standard of care for patients with resectable pancreatic... Show moreBackgroundSurgical resection followed by adjuvant mFOLFIRINOX (5-fluorouracil with leucovorin, irinotecan, and oxaliplatin) is currently the standard of care for patients with resectable pancreatic cancer. The main concern regarding adjuvant chemotherapy is that only half of patients actually receive adjuvant treatment. Neoadjuvant chemotherapy, on the other hand, guarantees early systemic treatment and may increase chemotherapy use and thereby improve overall survival. Furthermore, it may prevent futile surgery in patients with rapidly progressive disease. However, some argue that neoadjuvant therapy delays surgery, which could lead to progression towards unresectable disease and thus offset the potential benefits. Comparison of perioperative (i.e., neoadjuvant and adjuvant) with (only) adjuvant administration of mFOLFIRINOX in a randomized controlled trial (RCT) is needed to determine the optimal approach.MethodsThis multicenter, phase 3, RCT will include 378 patients with resectable pancreatic ductal adenocarcinoma with a WHO performance status of 0 or 1. Patients are recruited from 20 Dutch centers and three centers in Norway and Sweden. Resectable pancreatic cancer is defined as no arterial contact and & LE; 90 degrees venous contact. Patients in the intervention arm are scheduled for 8 cycles of neoadjuvant mFOLFIRINOX followed by surgery and 4 cycles of adjuvant mFOLFIRINOX (2-week cycle of oxaliplatin 85 mg/m(2), leucovorin 400 mg/m(2), irinotecan 150 mg/m(2) at day 1, followed by 46 h continuous infusion of 5-fluorouracil 2400 g/m(2)). Patients in the comparator arm start with surgery followed by 12 cycles of adjuvant mFOLFIRINOX. The primary outcome is overall survival by intention-to-treat. Secondary outcomes include progression-free survival, resection rate, quality of life, adverse events, and surgical complications. To detect a hazard ratio of 0.70 with 80% power, 252 events are needed. The number of events is expected to be reached after the inclusion of 378 patients in 36 months, with analysis planned 18 months after the last patient has been randomized.DiscussionThe multicenter PREOPANC-3 trial compares perioperative mFOLFIRINOX with adjuvant mFOLFIRINOX in patients with resectable pancreatic cancer. Show less
Hondelink, L.M.; Ernst, S.M.; Atmodimedjo, P.; Cohen, D.; Wolf, J.L.; Dingemans, A.M.C.; ... ; Thüsen, J.H. von der 2023
ObjectivesThe landmark ADAURA study recently demonstrated a significant disease-free survival benefit of adjuvant osimertinibin patients with resected EGFR-mutated lung adenocarcinoma. However,... Show moreObjectivesThe landmark ADAURA study recently demonstrated a significant disease-free survival benefit of adjuvant osimertinibin patients with resected EGFR-mutated lung adenocarcinoma. However, data on prevalence rates and stage distribution of EGFR mutations in non-small cell lung cancer in Western populations are limited since upfront EGFR testing in early stage lung adenocarcinoma is not common practice. Here, we present a unique, real-world, unselected cohort of lung adenocarcinoma to aid in providing a rationale for routine testing of early stage lung cancers for EGFR mutations in the West-European population.Material and methodsWe performed routine unbiased testing of all cases, regardless of TNM stage, with targeted next-generation sequencing on 486 lung adenocarcinoma cases between 01- January 2014 and 01 February 2020. Clinical and pathological data, including co-mutations and morphology, were collected. EGFR-mutated cases were compared to KRAS-mutated cases to investigate EGFR-specific characteristics.ResultsIn total, 53 of 486 lung adenocarcinomas (11%) harboured an EGFR mutation. In early stages (stage 0-IIIA), the prevalence was 13%, versus 9% in stage IIIB-IV. Nine out of 130 (7%) stage IB-IIIA patients fit the ADAURA criteria. Early stage cases harboured more L858R mutations (p = 0.02), fewer exon 20 insertions (p = 0.048), fewer TP53 co-mutations (p = 0.007), and were more frequently never smokers (p = 0.04) compared to late stage cases with EGFR mutations. The KRAS-mutated cases were distributed more evenly across TNM stages compared to the EGFR-mutated cases.ConclusionAs (neo-)adjuvant targeted therapy regimes enter the field of lung cancer treatment, molecular analysis of early stage non-small cell lung cancer becomes relevant. Testing for EGFR mutations in early stage lung adenocarcinoma holds a substantial yield in our population, as our number needed to test ratio for adjuvant osimertinib was 14.4. The observed differences between early and late stage disease warrant further analysis to work towards better prognostic stratification and more personalised treatment. Show less
Background: Gene expression signatures have emerged to predict prognosis and guide the use of adjuvant therapy in patients with hormone receptor-positive breast cancer. The objective of this... Show moreBackground: Gene expression signatures have emerged to predict prognosis and guide the use of adjuvant therapy in patients with hormone receptor-positive breast cancer. The objective of this systematic review was to evaluate the prognostic and predictive value of commercially available gene expression signatures as a tool in adjuvant treatment decision-making in older patients with breast cancer.Methods: PubMed, MEDLINE, Embase, Web of Science, Cochrane Library, and Emcare were reviewed for relevant articles published before December 2021. Eligible studies were randomised trials and cohort studies that externally validated commercially available gene expression signatures in patients aged 65 years and older, including studies that presented subanalyses of this age group. Data extraction and risk of bias assessment was performed independently by two investigators.Results: Fifteen studies were included. Most studies investigated Oncotype DX, while results from other gene expression signatures were limited. Several studies underlined the prognostic performance of Oncotype DX and Prosigna Risk of Recurrence in older patients. Moreover, Oncotype DX was predictive for older patients with an intermediate-risk recurrence score; chemotherapy could be spared in both lymph node-positive and lymph node -negative disease.Conclusions: Prognostic performance has been demonstrated in older patients for several gene expression sig-natures. However, additional validation in patients with high-risk tumours is needed before gene expression signatures can be implemented in clinical practice as a prediction tool for adjuvant chemotherapy decision -making in the older age group. Show less
A proportion of patients with endometrial carcinoma are currently over- or undertreated due to the lack of reproducibility of some of the traditional factors used to assess risk of recurrence and... Show moreA proportion of patients with endometrial carcinoma are currently over- or undertreated due to the lack of reproducibility of some of the traditional factors used to assess risk of recurrence and death due to the cancer, aswell as intrinsic differences in the biological background of tumours within the same risk category. This underlinesthe need for additional biomarkers for the improvement of current risk classification systems and adjuvant treatment selection. In this context, the molecular endometrial carcinoma classification offers an opportunity to categorize tumours according to their molecular background, resulting in more biologically homogeneous groups of patients, with a more precise prognostic and, possibly, predictive value. However, before clinical implementation is possible, information regarding the interpretation of non-hotspot POLE exonuclease domain mutations, aswell as the molecular background and clinical outcome of EC with more than one molecular classifying feature (multiple classifier EC) is needed in order to obtain a reproducible and accurate classification system. Additionally, the integration of the molecular subgroups with clinicopathological features has proven to have a strong prognostic value in intermediate tohigh-risk and unselected cohorts, highlighting its potential to refine prognosis in high-risk patients and perhaps its predictive value. Finally, not all women in the molecularlyprofiled EC cohorts published were staged by lymphadenectomy and most patients had received adjuvant treatment. These features could have influenced the prognostic value of the molecular subgroups. The aims of this thesis were:1) To refine the molecular profiling of endometrial carcinoma by addressing essential remaining questionson the interpretation of POLE variants and characterization of multiple classifier ECs.2) To elucidate the prognostic role of the molecular subgroups in high-risk patients.3) To evaluate the value of the molecular classification to guide adjuvant treatment decisions.4) To investigate the natural behaviour of the molecular EC subgroups among patients staged with lymphadenectomy or not receiving adjuvant treatment. Show less
Objective The subset distribution and immunophenotype of circulating immune cells ("peripheral blood immune cell profile") may reflect tumor development and response to cancer treatment. In order... Show moreObjective The subset distribution and immunophenotype of circulating immune cells ("peripheral blood immune cell profile") may reflect tumor development and response to cancer treatment. In order to use the peripheral blood immune cell profile as biomarker to monitor patients over time, it is crucial to know how immune cell subsets respond to therapeutic interventions. In this study, we investigated the effects of tumor resection and adjuvant therapy on the peripheral blood immune cell profile in patients with colon carcinoma (CC). Methods The subset distribution and immunophenotype of T cells (CD3(+)CD56(-)), CD56(dim) NK cells (CD3(-)CD56(dim)), CD56(bright) NK cells (CD3(-)CD56(bright)) and NKT-like cells (CD3(+)CD56(+)) were studied in preoperative and postoperative peripheral blood mononuclear cell (PBMC) samples of 24 patients with CC by multiparameter flow cytometry. Changes in immunophenotype of circulating immune cells after tumor resection were studied in patients treated with and without (capecitabine-based) adjuvant therapy. Results The NKT-like cell (% of total PBMCs) and CD8(+) T cell (% of total T cells) populations expanded in the peripheral blood of non-adjuvant-treated CC patients after surgery. NK- and NKT-like cells showed upregulation of activating receptors and downregulation of inhibitory receptors in non-adjuvant-treated CC patients after surgery. These changes were not observed in the peripheral blood of adjuvant-treated CC patients. Conclusions Our results suggest tumor-induced suppression of NK- and NKT-like cells in CC patients, an effect that could not be detected after tumor resection. In contrast, adjuvant therapy maintained tumor-induced immunosuppression of NK- and NKT-like cells in CC patients. Show less
This thesis describes the preferences of both older patients with breast cancer and clinicians to optimize the current care of this patient group. The significant increase in the number of breast... Show moreThis thesis describes the preferences of both older patients with breast cancer and clinicians to optimize the current care of this patient group. The significant increase in the number of breast cancer patients above the age of 65 years necessitates insight into their preferences. Decision-making regarding treatment of early breast cancer is often difficult as decisions need to be made between two surgical options and about the addition of systemic therapy. Like younger patients, older patients are faced with these difficult decisions (together with their clinician). However, treatments for early breast cancer differ substantially between younger and older patients, which possibly can be explained by the preferences of older patients or their clinicians. Currently, little is known about the preferences of older patients, while this knowledge is particularly of great value. To assess how the current care of older patients and the treatment-decision-making process with this patient group can be optimised, we explore the preferences and motivations of older patients with early breast cancer; if and how their preferences for treatment and participation in decision-making differ from those of younger patients; and the treatment preferences of breast cancer specialists with regard to treatment of older patients. Show less
As a result of our ageing population, breast cancer is becoming a disease of the elderly. Unfortunately, most studies investigating the efficacy of treatment do not include older patients and are... Show moreAs a result of our ageing population, breast cancer is becoming a disease of the elderly. Unfortunately, most studies investigating the efficacy of treatment do not include older patients and are not representative for the older population. In this thesis, we investigated whether there is variation in treatment and survival among older women with breast cancer in five European countries. Moreover, we study the long term efficacy of two types of adjuvant endocrine therapy in postmenopausal women. In addition, the effect of age and comorbidities on breast cancer death in the presence of competing mortality is studied. Finally, we investigate whether other endpoints in clinical studies might be more relevant for the older population and we introduce a new endpoint for clinical research in the older population with cancer. Show less
Over the last decades, advances have been made in the treatment of endometrial cancer. The clinicopathological risk stratification for postoperative therapy has considerably reduced overtreatment... Show moreOver the last decades, advances have been made in the treatment of endometrial cancer. The clinicopathological risk stratification for postoperative therapy has considerably reduced overtreatment by refining indications and introducing treatment with fewer side effects. Despite refinement in the use of postoperative radiation therapy in EC, over- and under- treatment remain a clinical problem. This may be caused by the limited accuracy of the clinicopathological risk stratification to select patients of higher risk of recurrence. The lack of reproducibility of pathologists to diagnose tumor type and grade may also limit the accuracy of the clinicopathological risk stratification. Expert gyneco-pathology review and a two-tiered grading system will lead to more accurate and reproducible diagnoses. Nonetheless, there is pressing need to understand tumor behavior and design tailored treatments to further improve risk stratification. The identification of molecular markers predictive of recurrence risk or treatment benefit beyond current clinicopathological factors would represent a major advance. The aims of this thesis were to gain insight in the molecular alterations of endometrial cancer and to identify prognostic markers in endometrial cancer to refine clinicopathological risk assessment and direct adjuvant therapy. Show less
This thesis describes the results of the first en second Post Operative Radiation Therapy in Endometrial Cancer (PORTEC) trials. The 15-year results of PORTEC-1 confirm the importance of the... Show moreThis thesis describes the results of the first en second Post Operative Radiation Therapy in Endometrial Cancer (PORTEC) trials. The 15-year results of PORTEC-1 confirm the importance of the prognostic factors age, grade and depth of myometrial invasion for selection of patients with high-intermediate risk (HIR) features. Postoperative pelvic external beam radiotherapy (EBRT) reduces the risk of locoregional recurrence (mainly due to a decrease in vaginal recurrences), without a survival benefit compared to no additional therapy. The PORTEC-2 trial has shown that EBRT and vaginal brachytherapy (VBT) offer excellent rates of vaginal control and similar overall survival for HIR patients, while VBT has a clearly more favourable health related quality of life profile, with results similar to an age-matched norm population. EBRT is associated with a higher risk of long-lasting bowel symptoms that impact on patients__ daily lives and physical functioning. Therefore, VBT is the treatment of choice for HIR patients. Finally, a pilot study in PORTEC-2 patients showed that the presence of multiple activated oncogenic pathways was the most powerful independent prognostic factor for decreased disease free survival, indicating that molecular prognostic factors refine the currently used system for risk classification. Show less
