78 results on '"Lopez‐Yurda, M."'
Search Results
2. Predictive Factors for Hypertrophy of the Future Liver Remnant After Portal Vein Embolization: A Systematic Review
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Soykan, E. A., Aarts, B. M., Lopez-Yurda, M., Kuhlmann, K. F. D., Erdmann, J. I., Kok, N., van Lienden, K. P., Wilthagen, E. A., Beets-Tan, R. G. H., van Delden, O. M., Gomez, F. M., and Klompenhouwer, E. G.
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- 2021
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3. Peroperative extent of peritoneal metastases affects the surgical outcome and survival in advanced ovarian cancer
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van Stein, R M, Engbersen, M P, Stolk, T, Lopez-Yurda, M, Lahaye, M J, Beets-Tan, R G H, Lok, C A R, Sonke, G S, Van Driel, W J, RS: GROW - R3 - Innovative Cancer Diagnostics & Therapy, and Faculteit FHML Centraal
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Oncology ,Obstetrics and Gynecology - Abstract
OBJECTIVE: Determining whether cytoreductive surgery (CRS) is feasible in patients with advanced ovarian cancer and whether extensive surgery is justified is challenging. Accurate patient selection for CRS based on pre- and peroperative parameters will be valuable. The aim of this study is to assess the association between the extent of peritoneal metastases as determined during surgery and completeness of interval CRS and survival.METHODS: This single-center observational cohort study included consecutive patients with newly diagnosed stage III-IV epithelial ovarian cancer who received neoadjuvant chemotherapy and underwent interval CRS. The 7 Region Count (7RC) was recorded during surgical exploration to systematically quantify the extent of peritoneal metastases. Logistic regression analysis was performed to predict surgical outcomes, and Cox regression analysis was done for survival outcomes.RESULTS: A total of 316 patients were included for analyses. The median 7RC was 4 (interquartile range: 2-6). Complete CRS was performed in 58%, optimal CRS in 30%, and incomplete CRS in 12% of patients. A higher 7RC was independently associated with lower odds of complete or optimal CRS in multivariable analysis (odds ratio [OR] = 0.45, 95% confidence interval [CI]: 0.33-0.63, p < 0.001). Similarly, a higher 7RC was independently associated with worse progression-free survival (hazard ratio [HR] = 1.17, 95% CI 1.08-1.26, p < 0.001) and overall survival (HR = 1.14, 95% CI 1.04-1.25, p = 0.007).CONCLUSION: The extent of peritoneal metastases, as expressed by the 7RC during surgery, is an independent predictor for completeness of CRS and has independent prognostic value for progression-free survival and overall survival in addition to completeness of CRS.
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- 2022
4. First-line Systemic Treatment Strategies in Patients with Initially Unresectable Colorectal Liver Metastases: Phase III CAIRO5 Study of the Dutch Colorectal Cancer Group
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Bond, M.J., primary, Bolhuis, K., additional, Kazemier, G., additional, Klaase, J.M., additional, Liem, M.S., additional, Rijken, A.M., additional, Verhoef, C., additional, de Wilt, J.H., additional, Lopez-Yurda, M., additional, Punt, C.J., additional, and Swijnenburg, R.-J., additional
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- 2023
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5. Hearing loss in survivors of childhood head and neck rhabdomyosarcoma: a long-term follow-up study
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Schoot, R. A., Theunissen, E. A.R., Slater, O., Lopez-Yurda, M., Zuur, C. L., Gaze, M. N., Chang, Y.-C., Mandeville, H. C., Gains, J. E., Rajput, K., Pieters, B. R., Fajardo, R. Davila, Talwar, R., Caron, H. N., Balm, A. J.M., Dreschler, W. A., and Merks, J. H.M.
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- 2016
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6. LBA39 Personalized combination of neoadjuvant domatinostat, nivolumab (NIVO) and ipilimumab (IPI) in stage IIIB-D melanoma patients (pts) stratified according to the interferon-gamma signature (IFN-γ sign): The DONIMI study
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Blank, C.U., primary, Reijers, I.L.M., additional, Versluis, J.M., additional, Menzies, A.M., additional, Dimitriadis, P., additional, Wouters, M.W., additional, Saw, R.P.M., additional, Klop, W.M.C., additional, Pennington, T.E., additional, Bosch, L.J.W., additional, Cornelissen, S., additional, Grijpink-Ongering, L.G., additional, Gregorio, M.J.C., additional, Lopez-Yurda, M., additional, Rawson, R.V., additional, Spillane, A.J., additional, van de Wiel, B.A., additional, Scolyer, R.A., additional, van Akkooi, A.C.J., additional, and Long, G.V., additional
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- 2021
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7. 1175P Return to work after neoadjuvant versus adjuvant immunotherapy in stage III melanoma patients
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Lijnsvelt, J., Lievense, Z., Albers, E., Lopez-Yurda, M., Van De Poll-franse, L.V., and Blank, C.U.
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- 2023
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8. 1112P Five-year survival after intermittent targeted therapy and anti-PD1 in stage IV melanoma: An update of the IMPemBra trial
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Hoeijmakers, L., Rozeman, E.A., Lopez-Yurda, M., Grijpink-Ongering, L., Heeres, B., van de Wiel, B., Flohil, C., Sari, A., Heijmink, S., Van Den Broek, D., Broeks, A., de Groot, J.W., Vollebergh, M., Wilgenhof, S., van Thienen, H.V., Haanen, J.B.A.G., and Blank, C.U.
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- 2023
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9. Adjuvant photodynamic therapy in head and neck cancer after tumor-positive resection margins
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van Doeveren, T.E.M., Karakullukçu, M.B., van Veen, R.L.P., Lopez-Yurda, M., Schreuder, W.H., Tan, I.B., MKA AMC (OII, ACTA), and Maxillofacial Surgery (AMC)
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SDG 3 - Good Health and Well-being - Abstract
Objective: In case of close or positive resection margins after oncological resection in head and neck surgery, additional treatment is necessary. When conventional options are exhausted, photodynamic therapy (PDT) can play a role in achieving clear margins. The purpose of the current study was to evaluate the clinical benefit of PDT as adjuvant therapy next to surgery with positive resection margins. The role of the time interval between surgery and PDT on survival outcomes also was investigated.STUDY DESIGN: Retrospective cohort analysis.Methods: Adjuvant PDT was performed in patients with a malignancy in the head and neck region with close or positive resection margins who were not eligible for conventional treatment options. The primary endpoint was progression-free survival. Secondary endpoints were disease-free survival, overall survival, and optimal time interval between surgery and PDT.Results: Fifty-four patients were treated with surgery followed by meta-tetrahydroxyphenylchlorin-mediated PDT. There was a large diversity in tumor location and histopathology, as well as in time interval between surgery and PDT. The 2-year progression-free survival rate was 30%; 2-year disease-free survival rate was 28%; and 2-year overall survival was 51%. Disease-free survival was significantly better when the time interval between surgery and PDT was ≥ 6 weeks (P = 0.02).Conclusion: PDT can be applied as adjuvant therapy after surgery in cases of a malignancy with close or positive tumor resection margins. However, the clinical benefits are yet to be determined. There is a significantly better disease-free survival with a time interval between surgery and PDT of minimal 6 weeks.LEVEL OF EVIDENCE: 4. Laryngoscope, 128:657-663, 2018.
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- 2018
10. Prognostic significance of age in 5631 patients with Wilms tumour prospectively registered in International Society of Paediatric Oncology (SIOP) 93-01 and 2001
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Hol, J. A., primary, Lopez-Yurda, M. I., additional, Van Tinteren, H., additional, Van Grotel, M., additional, Godzinski, J., additional, Vujanic, G., additional, Oldenburger, F., additional, De Camargo, B., additional, Ramírez-Villar, G. L., additional, Bergeron, C., additional, Pritchard-Jones, K., additional, Graf, N., additional, and Van den Heuvel-Eibrink, M. M., additional
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- 2019
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11. Intermittent versus continuous chemotherapy beyond first-line for patients with HER2-negative advanced breast cancer (BOOG 2010-02)
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Erdkamp, F.L.G., primary, Claessens, A.K.M., additional, Lopez-Yurda, M., additional, Bouma, J.M., additional, van Tinteren, H., additional, Rademaker-Lakhai, J.M., additional, Honkoop, A.H., additional, de Graaf, H., additional, Tjan-Heijnen, V.C.G., additional, and Bos, M.M.E.M., additional
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- 2019
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12. Neoadjuvant ipilimumab plus nivolumab in early stage colon cancer
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Chalabi, M., primary, Fanchi, L.F., additional, Van den Berg, J.G., additional, Beets, G.L., additional, Lopez-Yurda, M., additional, Aalbers, A.G., additional, Grootscholten, C., additional, Snaebjornsson, P., additional, Maas, M., additional, Mertz, M., additional, Nuijten, E., additional, Kuiper, M., additional, Kok, M., additional, Van Leerdam, M.E., additional, Schumacher, T.N., additional, Voest, E.E., additional, and Haanen, J.B., additional
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- 2018
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13. Late follow-up of the randomized radiation and concomitant high-dose intra-arterial or intravenous cisplatin (RADPLAT) trial for advanced head and neck cancer
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Heukelom, J., Lopez-Yurda, M., Balm, A.J.M., Wijers, O.B., Buter, J., Gregor, T., Wiggenraad, R., Boer, J.P. de, Tan, I.B., Verheij, M., Sonke, J.J., and Rasch, C.R.
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late results ,toxicity ,radiation oncology ,head and neck cancer ,intra-arterial cisplatin ,chemoradiotherapy - Abstract
Background. The radiation and concomitant high-dose intra-arterial or intravenous cisplatin (RADPLAT) phase III trial compared intra-arterial (IA) to intravenous (IV) cisplatin-based chemoradiation for head and neck cancer. Long-term efficacy and toxicity are reported after a median follow-up of 7.5 years.Methods. Patients with inoperable squamous cell carcinoma (SCC) of the oropharynx, oral cavity, or hypopharynx, were randomized between radiotherapy (RT) + IA cisplatin 150 mg/m(2), followed by systemic rescue or RT + I. V. cisplatin 100 mg/m(2). RT consisted of 46 Gy to the affected and elective areas, followed by a boost of 24 Gy.Results. Among 237 patients, 57 recurred locally, 35 regionally, and 80 locoregionally. There were 32 second primary tumors, 65 distant metastases, and 154 deaths. Locoregional control and overall survival were not different between the treatment arms. Late dysphagia was worse in the I.V. arm (log-rank p=.014).Conclusion. IA cisplatin did not improve tumor control compared to I.V. administered cisplatin, despite the higher dose in IA delivery of the drug. (C) 2015 Wiley Periodicals, Inc.
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- 2016
14. Irradiation of localized squamous cell carcinoma of the nasal vestibule
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Vanneste, B.G.L., Lopez-Yurda, M., Tan, I.B., Balm, A.J.M., Borst, G.R., Rasch, C.R., Maxillofacial Surgery (AMC), and MKA AMC (OII, ACTA)
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squamous cell carcinoma ,SDG 3 - Good Health and Well-being ,interstitial radiotherapy ,nasal vestibule ,external beam radiotherapy - Abstract
Background. The purpose of this study was to evaluate the long-term results of primary radiotherapy treatment for squamous cell carcinoma (SCC) of the nasal vestibule.Methods. Eighty-one patients were treated with external beam radiotherapy (EBRT) and/or interstitial radiotherapy (IRT) for a primary, localized, Wang classified SCC of the nasal vestibule.Results. Median follow-up was 38 months. T1 tumors were treated with IRT: we observed 1 local failure (at 13 months) among 48 patients (5-year local control rate of 97%). Most T2 tumors (20 of 26) were treated with EBRT. There were 8 local recurrences among 26 patients (5-year local control rate of 68%). For the T3 tumors (n = 7; all treated with EBRT), we observed local recurrence in 2 patients (5-year local control rate of 53%). The late-term side effects were relatively mild.Conclusion. Local primary radiotherapy (either IRT for T1 or EBRT for T2/3) is an adequate treatment for SCC of the nasal vestibule with little late sequelae. (C) 2015 Wiley Periodicals, Inc.
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- 2016
15. Efficacy of two times four versus continuous eight cycles of paclitaxel/bevacizumab as first-line chemotherapy in metastatic breast cancer: The Stop&Go study of the Dutch Breast Cancer Research Group (BOOG)
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Claessens, A., primary, Bos, M., additional, de Groot, S., additional, van Leeuwen-Stok, E., additional, Lopez-Yurda, M., additional, Honkoop, A., additional, de Graaf, H., additional, van Druten, E., additional, van Warmerdam, L., additional, van der Sangen, M., additional, Tjan-Heijnen, V., additional, and Erdkamp, F., additional
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- 2017
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16. Incidence Changes of Human Papillomavirus in Oropharyngeal Squamous Cell Carcinoma and Effects on Survival in the Netherlands Cancer Institute, 1980-2009
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Henneman, R., Monsjou, H. S., Verhagen, C. V. M., Marie-Louise van Velthuysen, Ter Haar, N. T., Osse, E. M., Lopez-Yurda, M. I., Balm, A. J. M., Den Brekel, M. W. M., and ACLC (FGw)
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Head and neck squamous cell carcinoma ,oropharynx ,human papillomavirus ,HNSCC ,survival ,HPV incidence ,Rare cancers Radboud Institute for Health Sciences [Radboudumc 9] - Abstract
Item does not contain fulltext AIM: Human papillomavirus (HPV) is a risk factor for oropharyngeal squamous cell carcinoma (OPSCC), with an increasing incidence. The present study aimed to determine the changing incidence of HPV in patients with OPSCC in the period 1980-2009 and its influence on survival. PATIENTS AND METHODS: We randomly sampled 158 patients from a cohort of 828 patients with OPSCC stratified by decade (1980-1989, 1990-1999, 2000-2009). Formalin-fixed paraffin-embedded material was tested for HPV DNA by SPF-10 polymerase chain reaction (PCR) and immunohistochemically stained for p16 and p53. RESULTS: DNA from 146 patients was suitable for HPV detection. HPV DNA was detected in 13/47 (28%), 18/47 (38%), and 20/52 (38%) patients in the cohorts of 1980-1989, 1990-1999, and 2000-2009, respectively (p-value for trend=0.269). Lack of further increase during the most recent decade is inconsistent with the rising incidence and higher prevalence reported in other Western countries. Patients with HPV-positive OPSCC had a better survival in spite of higher tumor stage.
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- 2015
17. Long-Term Hearing Loss After Chemoradiation in Patients With Head and Neck Cancer
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Theunissen, E.A.R., Zuur, C.L., Bosma, S.C.J., Lopez-Yurda, M., Hauptmann, M., Baan, S. van der, Boer, J.P. de, Molen, L. van der, Rasch, C.R.N., Dreschler, W.A., Balm, A.J.M., Maxillofacial Surgery (AMC), Faculteit der Geneeskunde, and MKA AMC (OII, ACTA)
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ototoxicity ,SDG 3 - Good Health and Well-being ,Chemoradiation ,otorhinolaryngologic diseases ,cisplatin ,head and neck cancer ,hearing loss - Abstract
Objectives/HypothesisThe purpose of this study was to determine whether concomitant chemoradiation (CCRT)-induced hearing loss is progressive over time or not.Study DesignLong-term (LT) follow-up study.MethodsBetween 1999 and 2004, 158 patients with head and neck cancer were treated with intravenous (IV) CCRT (n = 80) or intraarterial CCRT (n = 78). Audiometry was performed before, short-term (ST), and LT posttreatment. Differences in hearing were assessed with a multivariable linear regression analysis, incorporating the effect of aging.ResultsLong-term audiometry (median 4.5 years) was available in 67 patients (42%). At ST follow-up, a deterioration of 21.6 decibel was seen compared to baseline at pure-tone averages (PTA) 8-10-12.5 kHz. At LT follow-up, this deterioration further increased with 5 decibel (P = 0.005). Only in CCRT-IV patients was a significant progressive treatment-induced hearing loss seen, at PTA 8-10-12.5 kHz (P = 0.005), PTA 1-2-4 kHz air conduction (P = 0.014), and PTA 0.5-1-2 kHz bone conduction (P = 0.045).ConclusionCCRT-induced hearing impairment was progressive over time, especially in higher frequencies and only in CCRT-IV patients, with a modest deterioration of 5 decibel 4.5 years post-treatment.
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- 2014
18. LBA37_PR - Neoadjuvant ipilimumab plus nivolumab in early stage colon cancer
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Chalabi, M., Fanchi, L.F., Van den Berg, J.G., Beets, G.L., Lopez-Yurda, M., Aalbers, A.G., Grootscholten, C., Snaebjornsson, P., Maas, M., Mertz, M., Nuijten, E., Kuiper, M., Kok, M., Van Leerdam, M.E., Schumacher, T.N., Voest, E.E., and Haanen, J.B.
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- 2018
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19. 246PD - Efficacy of two times four versus continuous eight cycles of paclitaxel/bevacizumab as first-line chemotherapy in metastatic breast cancer: The Stop&Go study of the Dutch Breast Cancer Research Group (BOOG)
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Claessens, A., Bos, M., de Groot, S., van Leeuwen-Stok, E., Lopez-Yurda, M., Honkoop, A., de Graaf, H., van Druten, E., van Warmerdam, L., van der Sangen, M., Tjan-Heijnen, V., and Erdkamp, F.
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- 2017
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20. PD-125 IRRADIATION OF LOCALIZED SQUAMOUS CELL CARCINOMA OF THE NASAL VESTIBULE
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Vanneste, B.G.L., primary, Lopez-Yurda, M., additional, Tan, I.B., additional, Balm, A.J.M., additional, Borst, G.R., additional, and Rasch, C.R.N., additional
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- 2012
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21. Effect of preoperative radiotherapy on local recurrences in rectal cancer patients with PIK3CA mutation.
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He, Y., primary, van 'tVeer, L., additional, Lopez Yurda, M., additional, Mikolajewska-Hanclich, I., additional, Nagtegaal, I. D., additional, Van De Velde, C. J., additional, and Marijnen, C. A., additional
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- 2010
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22. The Addition of Gemcitabine to 131I-MIBG Therapy in Pediatric Patients with Relapsed or Progressive Neuroblastoma: An International Multi-Centre Phase II Trial (MIBG-GEM)
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Eijkelenburg, N., Tytgat, L., Noesel, M., Thorsten Simon, Hero, B., Li, C. K., Keizer, B., Ammerlaan, A. C. J., Lopez-Yurda, M., and Zwaan, C. M.
23. 158P_PR Intermittent versus continuous chemotherapy beyond first-line for patients with HER2-negative advanced breast cancer (BOOG 2010-02).
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Erdkamp, F L G, Claessens, A K M, Lopez-Yurda, M, Bouma, J M, Tinteren, H van, Rademaker-Lakhai, J M, Honkoop, A H, Graaf, H de, Tjan-Heijnen, V C G, and Bos, M M E M
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BREAST cancer , *CANCER chemotherapy , *ACADEMIC medical centers , *METASTATIC breast cancer - Published
- 2019
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24. Tumour microenvironment characterisation to stratify patients for hyperthermic intraperitoneal chemotherapy in high-grade serous ovarian cancer (OVHIPEC-1).
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Aronson SL, Walker C, Thijssen B, van de Vijver KK, Horlings HM, Sanders J, Alkemade M, Koole SN, Lopez-Yurda M, Lok CAR, Rottenberg S, van Rheenen J, Sonke GS, van Driel WJ, Kester LA, and Hahn K
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- Humans, Female, Middle Aged, Cystadenocarcinoma, Serous pathology, Cystadenocarcinoma, Serous therapy, Cystadenocarcinoma, Serous drug therapy, Aged, Biomarkers, Tumor genetics, Biomarkers, Tumor analysis, Macrophages pathology, Macrophages metabolism, Ovarian Neoplasms pathology, Ovarian Neoplasms therapy, Ovarian Neoplasms drug therapy, Ovarian Neoplasms genetics, Hyperthermic Intraperitoneal Chemotherapy methods, Tumor Microenvironment, Cytoreduction Surgical Procedures
- Abstract
Background: Hyperthermic intraperitoneal chemotherapy (HIPEC) improves survival in patients with Stage III ovarian cancer following interval cytoreductive surgery (CRS). Optimising patient selection is essential to maximise treatment efficacy and avoid overtreatment. This study aimed to identify biomarkers that predict HIPEC benefit by analysing gene signatures and cellular composition of tumours from participants in the OVHIPEC-1 trial., Methods: Whole-transcriptome RNA sequencing data were retrieved from high-grade serous ovarian cancer (HGSOC) samples from 147 patients obtained during interval CRS. We performed differential gene expression analysis and applied deconvolution methods to estimate cell-type proportions in bulk mRNA data, validated by histological assessment. We tested the interaction between treatment and potential predictors on progression-free survival using Cox proportional hazards models., Results: While differential gene expression analysis did not yield any predictive biomarkers, the cellular composition, as characterised by deconvolution, indicated that the absence of macrophages and the presence of B cells in the tumour microenvironment are potential predictors of HIPEC benefit. The histological assessment confirmed the predictive value of macrophage absence., Conclusion: Immune cell composition, in particular macrophages absence, may predict response to HIPEC in HGSOC and these hypothesis-generating findings warrant further investigation., Clinical Trial Registration: NCT00426257., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)
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- 2024
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25. Neoadjuvant Nivolumab and Ipilimumab in Resectable Stage III Melanoma.
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Blank CU, Lucas MW, Scolyer RA, van de Wiel BA, Menzies AM, Lopez-Yurda M, Hoeijmakers LL, Saw RPM, Lijnsvelt JM, Maher NG, Pulleman SM, Gonzalez M, Torres Acosta A, van Houdt WJ, Lo SN, Kuijpers AMJ, Spillane A, Klop WMC, Pennington TE, Zuur CL, Shannon KF, Seinstra BA, Rawson RV, Haanen JBAG, Ch'ng S, Naipal KAT, Stretch J, van Thienen JV, Rtshiladze MA, Wilgenhof S, Kapoor R, Meerveld-Eggink A, Grijpink-Ongering LG, van Akkooi ACJ, Reijers ILM, Gyorki DE, Grünhagen DJ, Speetjens FM, Vliek SB, Placzke J, Spain L, Stassen RC, Amini-Adle M, Lebbé C, Faries MB, Robert C, Ascierto PA, van Rijn R, van den Berkmortel FWPJ, Piersma D, van der Westhuizen A, Vreugdenhil G, Aarts MJB, Stevense-den Boer MAM, Atkinson V, Khattak M, Andrews MC, van den Eertwegh AJM, Boers-Sonderen MJ, Hospers GAP, Carlino MS, de Groot JB, Kapiteijn E, Suijkerbuijk KPM, Rutkowski P, Sandhu S, van der Veldt AAM, and Long GV
- Abstract
Background: Phase 1-2 trials involving patients with resectable, macroscopic stage III melanoma have shown that neoadjuvant immunotherapy is more efficacious than adjuvant immunotherapy., Methods: In this phase 3 trial, we randomly assigned patients with resectable, macroscopic stage III melanoma, in a 1:1 ratio, to receive two cycles of neoadjuvant ipilimumab plus nivolumab and then undergo surgery or to undergo surgery and then receive 12 cycles of adjuvant nivolumab. Only the patients in the neoadjuvant group who had a partial response or nonresponse received subsequent adjuvant treatment. The primary end point was event-free survival., Results: A total of 423 patients underwent randomization. At a median follow-up of 9.9 months, the estimated 12-month event-free survival was 83.7% (99.9% confidence interval [CI], 73.8 to 94.8) in the neoadjuvant group and 57.2% (99.9% CI, 45.1 to 72.7) in the adjuvant group. The difference in restricted mean survival time was 8.00 months (99.9% CI, 4.94 to 11.05; P<0.001; hazard ratio for progression, recurrence, or death, 0.32; 99.9% CI, 0.15 to 0.66). In the neoadjuvant group, 59.0% of the patients had a major pathological response, 8.0% had a partial response, 26.4% had a nonresponse (>50% residual viable tumor), and 2.4% had progression; in 4.2%, surgery had not yet been performed or was omitted. The estimated 12-month recurrence-free survival was 95.1% among patients in the neoadjuvant group who had a major pathological response, 76.1% among those who had a partial response, and 57.0% among those who had a nonresponse. Adverse events of grade 3 or higher that were related to systemic treatment occurred in 29.7% of the patients in the neoadjuvant group and in 14.7% in the adjuvant group., Conclusions: Among patients with resectable, macroscopic stage III melanoma, neoadjuvant ipilimumab plus nivolumab followed by surgery and response-driven adjuvant therapy resulted in longer event-free survival than surgery followed by adjuvant nivolumab. (Funded by Bristol Myers Squibb and others; NADINA ClinicalTrials.gov number, NCT04949113.)., (Copyright © 2024 Massachusetts Medical Society.)
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- 2024
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26. Gastric and duodenal cancer in individuals with Lynch syndrome: a nationwide cohort study.
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Caspers IA, Eikenboom EL, Lopez-Yurda M, van Grieken NCT, Bisseling TM, Dekker E, Bastiaansen BAJ, Cats A, and van Leerdam ME
- Abstract
Background: Lynch syndrome increases the risk of gastric cancer (GC) and duodenal cancer (DC), particularly in individuals with MLH1 and MSH2 pathogenic variants (PVs). To provide further insight into whether, and from what age, esophagogastroduodenoscopy (EGD) surveillance may be beneficial, we evaluated the cumulative incidence and tumour characteristics of GC and DC in a large nationwide cohort of Dutch individuals with LS., Methods: For this retrospective nationwide cohort study, clinical data of individuals with LS registered at the Dutch Hereditary Cancer Registry were matched with pathology reports filed by the Dutch Pathology registry. All individuals registered between Jan 1, 1989 and Dec 31, 2021 with proven or putative PVs in one of the mismatch repair genes were included. Cumulative incidences of GC and DC were estimated for high-risk ( MLH1, MSH2 and EpCAM ) and low-risk ( MSH6 and PMS2 ) PVs using competing risk methodology (Fine and Gray method) with death due to other causes as competing risk., Findings: Among 1002 individuals with high-risk and 765 individuals with low-risk PVs, 29 GCs (1.6%) and 39 DCs (2.2%) were diagnosed. Cumulative incidence of GC and DC under the age of 50 was very low (≤1%) for all individuals. At age 70 and 75, cumulative incidence of GC was 3% [95% CI 1%-5%] and 5% [3%-8%] for high-risk PVs and 1% [0%-2%] and 1% [0%-2%] for low-risk PVs (p = 0.006). For DC, cumulative incidence at age 70 and 75 was 5% [3%-7%] and 6% [3%-8%] in high-risk, 1% [0%-1%] and 2% [0%-4%] in low-risk PVs, respectively (p = 0.01). Primary tumour resection was performed in 62% (18/29) of GCs and 77% (30/39) of DC cases. Early-stage GC, defined as TNM stage I, was found in 32% (9/28) of GCs. Early-stage DC, defined as TNM stage I-IIa, was found in 39% (14/36) of DCs., Interpretation: Individuals with MLH1, MSH2, and EpCAM PVs have an increased risk of developing GC and DC at the age of 70 years, but this risk is very low before the age of 50 years. The age of onset of surveillance, the yield of GC and DC during EGD surveillance, and its cost-effectiveness should be subject of future studies., Funding: None., Competing Interests: IAC, ELE, MLY, NCTvG, TB, BJAB and AC declare no conflicts of interests. ED has received a research grant from FujiFilm; reports consulting fees from Olympus, Fujifilm, Ambu and InterVenn; has served as speaker for Olympus, GI Supply, Norgine, IPSEN, PAION, and Fujifilm; has received payments as a member of the supervisory board of the eNose company; and has endoscopic equipment on loan from Fujifilm. MEvL is medical director of the Netherlands Foundation for Detection of Hereditary Tumours (unpaid function)., (© 2024 The Author(s).)
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- 2024
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27. The Predictive Value of FDG PET/CT for Determining Progression-Free Survival in Advanced Stage III-IV BRAF -Mutated Melanoma Patients Treated With Targeted Therapy-What Can Be Learned From Progression?
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van der Hiel B, Aalbersberg EA, van den Eertwegh AJM, de Wit-van der Veen LJ, Stokkel MPM, Lopez-Yurda M, Boellaard R, Kapiteijn EW, Hospers GAP, Aarts MJB, de Vos FYFL, Boers-Sonderen MJ, van der Veldt AAM, de Groot JWB, and Haanen JBAG
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- Humans, Positron Emission Tomography Computed Tomography, Fluorodeoxyglucose F18, Proto-Oncogene Proteins B-raf genetics, Progression-Free Survival, Prospective Studies, Protein Kinase Inhibitors pharmacology, Protein Kinase Inhibitors therapeutic use, Melanoma diagnostic imaging, Melanoma drug therapy, Melanoma genetics, Skin Neoplasms pathology
- Abstract
Purpose: The aims of this study were to investigate whether (early) PERCIST response monitoring with 18 F-FDG PET/CT is predictive for progression-free survival (PFS) in unresectable stage III or IV melanoma patients treated with BRAF/MEK inhibitor (MEKi) and to define dissemination patterns at progression with a lesion-based evaluation in direct comparison to baseline to improve our understanding of 18 F-FDG PET/CT during BRAF/MEKi., Patients and Methods: This prospective multicenter single-arm study included 70 patients with unresectable stage III/IV BRAF -mutated melanoma who underwent contrast-enhanced CT and 18 F-FDG PET/CT at baseline and 2 and 7 weeks during treatment with vemurafenib plus cobimetinib and at progression if possible. Tumor response assessment was done with RECIST1.1 and PERCIST. Follow-up PET/CT scans were visually compared with baseline to assess dissemination patterns., Results: Using RECIST1.1, PFS was not significantly different between the response groups ( P = 0.26). At 2 weeks, PERCIST median PFS was 15.7 months for patients with complete metabolic response (CMR) versus 8.3 months for non-CMR ( P = 0.035). The hazards ratio (HR) for progression/death in non-CMR versus CMR was 1.99 (95% confidence interval [CI], 1.03-3.84; P = 0.040) and 1.77 (95% CI, 0.91-3.43; P = 0.0935) when adjusting for lactate dehydrogenase (LDH). At 7 weeks, median PFS for PERCIST CMR was 16.7 months versus 8.5 months for non-CMR ( P = 0.0003). The HR for progression/death in the non-CMR group was significantly increased (HR, 2.94; 95% CI, 1.60-5.40; P = 0.0005), even when adjusting for LDH (HR, 2.65; 95% CI, 1.43-4.91; P = 0.0020). At week 7, 18 F-FDG PET/CT was false-positive in all 4 (6%) patients with new FDG-avid lesions but CMR of known metastases. When 18 F-FDG PET/CT was performed at progressive disease, 18/22 (82%) patients had progression of known metastases with or without new 18 F-FDG-avid lesions., Conclusions: This study shows that PERCIST response assessment at week 7 is predictive for PFS, regardless of LDH. At 2 weeks, patients with CMR have longer PFS than patients with non-CMR, but different PET parameters should be investigated to further evaluate the added value of early 18 F-FDG PET/CT. Disease progression on PET/CT is predominated by progression of known metastases, and new 18 F-FDG-avid lesions during BRAF/MEKi are not automatically a sign of recurrent disease., Competing Interests: Conflicts of interest and sources of funding: The REPOSIT study is supported by an unrestricted grant by Roche Medical B.V. The company has approved the design of the study and provided cobimetinib free of charge. The company has no role in collection, analysis, and interpretation of data or in writing the article. A.J.M.v.d.E. received study grant from Sanofi, Roche, Bristol Myers Squibb, TEVA, and Idera; received travel expenses coverage from MSD Oncology, Roche, Pfizer, and Sanofi; received speaker honoraria from Bristol Myers Squibb and Novartis; and is part of the advisory board of Bristol Myers Squibb, MSD Oncology, Amgen, Roche, Novartis, Sanofi, Pfizer, Ipsen, Merck, and Pierre Fabre. E.W.K. has consultancy/advisory relationships with Bristol Myers Squibb, Novartis, Merck, Pierre Fabre, Lilly, and Bayer, all paid to the institute; and received research grants not related to this article from Bristol Myers Squibb, Delcath, Novartis, and Pierre Fabre. G.A.P.H. has consultancy/advisory relationships with Amgen, Bristol Myers Squibb, Roche, MSD, Pfizer, Novartis, Sanofi, and Pierre Fabre, all paid to the institute; and received research grants from Bristol Myers Squibb and Seerave, all paid to the institute. M.J.B.A. has advisory board/consultancy honoraria from Amgen, Bristol Myers Squibb, Novartis, MSD-Merck, Merck-Pfizer, Pierre Fabre, Sanofi, Astellas, and Bayer, and research grants from Merck-Pfizer, all paid to the institute and not related to current work. F.Y.F.L.d.V. received research grant from Foundation STOPBraintumors.org , Bristol Myers Squibb, Novartis, Servier, CureVac, and EORTC, all paid to the institute. A.A.M.v.d.V. has consultancy roles (all paid to the institute) for Bristol Myers Squibb, MSD, Roche, Sanofi, Novartis, Pierre Fabre, Merck, Ipsen, Eisai, and Pfizer, all paid to the institute. J.B.A.G.H. has advisory roles for Bristol Myers Squibb, CureVac, GSK, Ipsen, Iovance Biotherapeutics, Imcyse, Merck Serono, Molecular Partners, MSD, Novartis, Pfizer, Roche, Sanofi, and Third Rock Ventures; is a member of SAB of Achilles Tx, BioNTech, Gadeta, Immunocore, Instil Bio, PokeAcell, Scenic, T-Knife, and Neogene Tx, all paid to the institute except Neogene Tx and Scenic; and received grant support from Amgen, Asher Bio, BioNTech, Bristol Myers Squibb, MSD, Novartis, and Sastra Cell Therapy, all paid to the institute. The other authors declare no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)
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- 2024
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28. A Nomogram to Predict Severe Toxicity in DPYD Wild-Type Patients Treated With Capecitabine-Based Anticancer Regimens.
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Knikman JE, Lopez-Yurda M, Meulendijks D, Deenen MJ, Schellens JHM, Beijnen J, Cats A, and Guchelaar HJ
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- Humans, Capecitabine adverse effects, Antimetabolites, Antineoplastic adverse effects, Nomograms, Dihydrouracil Dehydrogenase (NADP) genetics, Genotype, Fluorouracil adverse effects, Neoplasms drug therapy, Neoplasms genetics, Neoplasms chemically induced
- Abstract
DPYD-guided dosing has improved the safety of fluoropyrimidine-based chemotherapy in recent years. However, severe toxicity remains in ~ 23% of patients not carrying DPYD variant alleles treated with capecitabine. Therefore, we developed a predictive model based on patient-related and treatment-related factors aimed at estimating the risk of developing severe capecitabine-related toxicity. The nomogram was developed using data from two large clinical trials (NCT00838370 and NCT02324452). Patients with cancer carrying a DPYD variant allele (DPYD*2A, c.1236G>A, c.2846A>T, and c.1679T>G) were excluded. Univariable and multivariable logistic regression using predetermined predictors based on previous findings, including age, sex, body surface area, type of treatment regimen, and creatinine levels were used to develop the nomogram. The developed model was internally validated using bootstrap resampling and cross-validation. This model was not externally or clinically validated. A total of 2,147 DPYD wild-type patients with cancer treated with capecitabine-based chemotherapy regimens were included of which complete data of 1,745 patients were available and used for the development of the nomogram. Univariable and multivariable logistic regression showed that age, sex, and type of treatment regimen were strong predictors of severe capecitabine-related toxicity in DPYD wild-type patients. Internal validation demonstrated a concordance index of 0.68 which indicates a good discriminative ability for prediction of severe capecitabine-related toxicity. The developed nomogram includes readily available parameters and may be a helpful tool for clinicians to assess the risk of developing severe capecitabine-related toxicity in patients without known risk DPYD variant alleles treated with capecitabine-based anticancer regimens., (© 2023 The Authors. Clinical Pharmacology & Therapeutics © 2023 American Society for Clinical Pharmacology and Therapeutics.)
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- 2024
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29. Squamous Cell Carcinoma Antigen in the Follow-up of Patients With Head and Neck Cancer.
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Schepens EJA, Al-Mamgani A, Karssemakers LHE, van den Broek D, van den Brekel MWM, and Lopez-Yurda M
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- Humans, Squamous Cell Carcinoma of Head and Neck, Prognosis, Follow-Up Studies, Retrospective Studies, Antigens, Neoplasm, Biomarkers, Tumor, Carcinoma, Squamous Cell pathology, Head and Neck Neoplasms, Serpins
- Abstract
Objective: to determine if the tumor marker squamous cell carcinoma antigen (SCC-Ag) observed over time may contribute to the early detection of recurrence, metastasis, and second primary tumors in the follow-up of patients with head and neck squamous cell carcinoma (HNSCC)., Study Design: A retrospective analysis of patients with HNSCC and at least one SCC-Ag measurement was conducted. Hazard ratios (HRs) were used to determine the correlation between SCC-Ag and an event., Setting: patients with HNSCC, treated in the Antoni van Leeuwenhoek Hospital in The Netherlands between 2010 and 2020 were used for the analysis., Methods: Data from 789 patients were used on event-free survival (EFS) with time-dependent Cox models. In addition to current (most recent) SCC-Ag (also dichotomized into high and low as done for clinical practice), average SCC-Ag and change between SCC-Ag measurements (delta SCC-Ag) were considered, using restricted cubic splines to explore nonlinear relationships., Results: Dichotomized SCC-Ag values (HR = 3.01, 95% confidence interval [CI]: 2.17-4.18) and the delta SCC-Ag (HR = 1.15, 95% CI: 1.07-1.22) predicted EFS better than models using the cumulative average or current value of SCC-Ag, also after adjusting for tumor site, stage, age, and gender. A strong association was observed when using delta SCC-Ag as a linear predictor in the subgroup of oropharynx patients (HR = 4.88, 95% CI: 2.71-8.79)., Conclusion: Dichotomized and delta SCC-Ag values can be important markers for EFS, during the follow-up of patients treated for HNSCC. These results were more evident in patients with oropharyngeal cancer., (© 2023 American Academy of Otolaryngology-Head and Neck Surgery Foundation.)
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- 2024
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30. Survival of Patients With Cancer With DPYD Variant Alleles and Dose-Individualized Fluoropyrimidine Therapy-A Matched-Pair Analysis.
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Knikman JE, Wilting TA, Lopez-Yurda M, Henricks LM, Lunenburg CATC, de Man FM, Meulendijks D, Nieboer P, Droogendijk HJ, Creemers GJ, Mandigers CMPW, Imholz ALT, Mathijssen RHJ, Portielje JEA, Valkenburg-van Iersel L, Vulink A, van der Poel MHW, Baars A, Swen JJ, Gelderblom H, Schellens JHM, Beijnen JH, Guchelaar HJ, and Cats A
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- Humans, Capecitabine, Alleles, Retrospective Studies, Prospective Studies, Matched-Pair Analysis, Dihydrouracil Dehydrogenase (NADP) genetics, Genotype, Fluorouracil, Neoplasms drug therapy, Neoplasms genetics
- Abstract
Purpose: DPYD -guided fluoropyrimidine dosing improves patient safety in carriers of DPYD variant alleles. However, the impact on treatment outcome in these patients is largely unknown. Therefore, progression-free survival (PFS) and overall survival (OS) were compared between DPYD variant carriers treated with a reduced dose and DPYD wild-type controls receiving a full fluoropyrimidine dose in a retrospective matched-pair survival analysis., Methods: Data from a prospective multicenter study (ClinicalTrials.gov identifier: NCT02324452) in which DPYD variant carriers received a 25% (c.1236G>A and c.2846A>T) or 50% ( DPYD *2A and c.1679T>G) reduced dose and data from DPYD variant carriers treated with a similarly reduced dose of fluoropyrimidines identified during routine clinical care were obtained. Each DPYD variant carrier was matched to three DPYD wild-type controls treated with a standard dose. Survival analyses were performed using Kaplan-Meier estimates and Cox regression., Results: In total, 156 DPYD variant carriers and 775 DPYD wild-type controls were available for analysis. Sixty-one c.1236G>A, 25 DPYD *2A, 13 c.2846A>T, and-when pooled-93 DPYD variant carriers could each be matched to three unique DPYD wild-type controls. For pooled DPYD variant carriers, PFS (hazard ratio [HR], 1.23; 95% CI, 1.00 to 1.51; P = .053) and OS (HR, 0.95; 95% CI, 0.75 to 1.51; P = .698) were not negatively affected by DPYD -guided dose individualization. In the subgroup analyses, a shorter PFS (HR, 1.43; 95% CI, 1.10 to 1.86; P = .007) was found in c.1236G>A variant carriers, whereas no differences were found for DPYD *2A and c.2846A>T carriers., Conclusion: In this exploratory analysis, DPYD -guided fluoropyrimidine dosing does not negatively affect PFS and OS in pooled DPYD variant carriers. Close monitoring with early dose modifications based on toxicity is recommended, especially for c.1236G>A carriers receiving a reduced starting dose.
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- 2023
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31. Association between pretreatment emotional distress and neoadjuvant immune checkpoint blockade response in melanoma.
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Fraterman I, Reijers ILM, Dimitriadis P, Broeks A, Gonzalez M, Menzies AMM, Lopez-Yurda M, Kapiteijn E, van der Veldt AAM, Suijkerbuijk KPM, Hospers GAP, Long GV, Blank CU, and van de Poll-Franse LV
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- Humans, Immune Checkpoint Inhibitors therapeutic use, Neoadjuvant Therapy, Glucocorticoids therapeutic use, Neoplasm Recurrence, Local pathology, Biomarkers, Tumor genetics, Interferon-gamma therapeutic use, Adrenergic Agents therapeutic use, Melanoma drug therapy, Melanoma genetics, Melanoma pathology, Psychological Distress
- Abstract
Neoadjuvant immune checkpoint blockade (ICB) outperforms adjuvant ICB for treatment of stage IIIB-D melanoma, but potential biomarkers of response, such as interferon-gamma (IFNγ) signature and tumor mutational burden (TMB), are insufficient. Preclinical studies suggest that emotional distress (ED) can negatively affect antitumor immune responses via β-adrenergic or glucocorticoid signaling. We performed a post hoc analysis evaluating the association between pretreatment ED and clinical responses after neoadjuvant ICB treatment in patients with stage IIIB-D melanoma in the phase 2 PRADO trial ( NCT02977052 ). The European Organisation for Research and Treatment of Cancer scale for emotional functioning was used to identify patients with ED (n = 28) versus those without (n = 60). Pretreatment ED was significantly associated with reduced major pathologic responses (46% versus 65%, adjusted odds ratio 0.20, P = 0.038) after adjusting for IFNγ signature and TMB, reduced 2-year relapse-free survival (74% versus 91%, adjusted hazard ratio 3.81, P = 0.034) and reduced 2-year distant metastasis-free survival (78% versus 95%, adjusted hazard ratio 4.33, P = 0.040) after adjusting for IFNγ signature. RNA sequencing analyses of baseline patient samples could not identify clear β-adrenergic- or glucocorticoid-driven mechanisms associated with these reduced outcomes. Pretreatment ED may be a marker associated with clinical responses after neoadjuvant ICB in melanoma and warrants further investigation. ClinicalTrials.gov registration: NCT02977052 ., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)
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- 2023
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32. Azacitidine (Vidaza ® ) in Pediatric Patients with Relapsed Advanced MDS and JMML: Results of a Phase I/II Study by the ITCC Consortium and the EWOG-MDS Group (Study ITCC-015).
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Rubio-San-Simón A, van Eijkelenburg NKA, Hoogendijk R, Hasle H, Niemeyer CM, Dworzak MN, Zecca M, Lopez-Yurda M, Janssen JM, Huitema ADR, van den Heuvel-Eibrink MM, Laille EJ, van Tinteren H, and Zwaan CM
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- Adult, Humans, Child, Azacitidine adverse effects, Remission Induction, Leukemia, Myelomonocytic, Juvenile drug therapy, Myelodysplastic Syndromes drug therapy, Myelodysplastic Syndromes chemically induced, Hematologic Neoplasms, Leukemia, Myeloid, Acute chemically induced, Leukemia, Myeloid, Acute drug therapy
- Abstract
Background: Advanced myelodysplastic syndrome (MDS) and juvenile myelomonocytic leukemia (JMML) are rare hematological malignancies in children. A second allograft is recommended if a relapse occurs after hematopoietic stem cell transplantation, but the outcome is poor., Objective: We conducted a phase I/II multicenter study to evaluate the safety, pharmacokinetics, and activity of azacitidine in children with relapsed MDS/JMML prior to the second hematopoietic stem cell transplantation., Methods: Patients enrolled from June 2013 to March 2019 received azacitidine intravenously/subcutaneously once daily on days 1-7 of a 28-day cycle. The MDS and JMML cohorts followed a two-stage design separately, with a safety run-in for JMML. Response and safety data were used to evaluate efficacy and establish the recommended dose. Pharmacokinetics was also analyzed. The study closed prematurely because of low recruitment., Results: Six patients with MDS and four patients with JMML received a median of three and five cycles, respectively. Azacitidine 75 mg/m
2 was well tolerated and plasma concentration-time profiles were similar to observed in adults. The most prevalent grade 3-4 adverse event was myelotoxicity. No responses were seen in patients with MDS, but 83% achieved stable disease; four patients underwent an allotransplant. Overall response rate in the JMML cohort was 75% (two complete responses; one partial response) and all responders underwent hematopoietic stem cell transplantation. One-year overall survival was 67% (95% confidence interval 38-100) in MDS and 50% (95% confidence interval 19-100) in JMML., Conclusions: Azacitidine 75 mg/m2 prior to a second hematopoietic stem cell transplantation is safe in children with relapsed MDS/JMML. Although the long-term advantage remains to be assessed, this study suggests that azacitidine is an efficacious option for relapsed JMML., Clinical Trial Registration: EudraCT 2010-022235-10., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)- Published
- 2023
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33. Atezolizumab With or Without Radiotherapy for Advanced Squamous Cell Carcinoma of the Penis (The PERICLES Study): A Phase II Trial.
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de Vries HM, Rafael TS, Gil-Jimenez A, de Feijter JM, Bekers E, van der Laan E, Lopez-Yurda M, Hooijberg E, Broeks A, Peters D, Seignette IM, Pos FJ, Horenblas S, van Rhijn BWG, Jordanova ES, Brouwer OR, Schaake E, and van der Heijden MS
- Subjects
- Male, Humans, CD8-Positive T-Lymphocytes, Penis, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Penile Neoplasms drug therapy, Penile Neoplasms radiotherapy, Penile Neoplasms etiology, Carcinoma, Squamous Cell drug therapy, Carcinoma, Squamous Cell radiotherapy
- Abstract
Purpose: Patients with advanced penile squamous cell carcinoma have a poor prognosis (21% 2-year overall survival [OS] from diagnosis). We assessed the activity of atezolizumab (anti-PD-L1) in patients with advanced penile cancer, with or without radiotherapy (RT)., Patients and Methods: A single-center, nonrandomized phase II study with two treatment arms was conducted in 32 patients with histologically confirmed advanced penile cancer. All patients received atezolizumab (1,200 mg) once every 3 weeks. Twenty patients, who were expected to benefit from RT for locoregional disease control, received additional irradiation. The primary end point was 1-year progression-free survival (PFS) for the complete cohort and was reached if the actual 1-year PFS was at least 35%. Secondary end points included OS, objective response rate (ORR), and tolerability. Exploratory biomarker analyses were conducted in pretreatment specimens., Results: Median follow-up was 29.1 months (IQR, 18.1-33.5). Grade 3-4 adverse events related to atezolizumab or RT were observed in 3/32 (9.4%) and 13/20 (65%) patients, respectively. One-year PFS was 12.5% (95% CI, 5.0 to 31.3), which did not meet the study's primary end point. Median OS was 11.3 months (95% CI, 5.5 to 18.7). In the objective response-evaluable population (n = 30; 93.8%), the ORR was 16.7% (95% CI, 6 to 35), including 2 (6.7%) complete responders and 3 (10%) partial responders. Improved PFS was observed in patients with high-risk human papillomavirus (hrHPV)-positive tumors ( P = .003) and those with high infiltration of intratumoral CD3
+ CD8+ T cells ( P = .037)., Conclusion: Although the primary end point of 1-year PFS was not met, durable antitumor activity to atezolizumab was observed in a subset of patients. Biomarkers, such as hrHPV and intratumoral CD3+ CD8+ T-cell infiltration, may help to better select responders.- Published
- 2023
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34. Cytoreductive surgery with or without hyperthermic intraperitoneal chemotherapy in patients with advanced ovarian cancer (OVHIPEC-1): final survival analysis of a randomised, controlled, phase 3 trial.
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Aronson SL, Lopez-Yurda M, Koole SN, Schagen van Leeuwen JH, Schreuder HWR, Hermans RHM, de Hingh IHJT, van Gent MDJM, Arts HJG, van Ham MAPC, van Dam PA, Vuylsteke P, Aalbers AGJ, Verwaal VJ, Van de Vijver KK, Aaronson NK, Sonke GS, and van Driel WJ
- Subjects
- Humans, Female, Carcinoma, Ovarian Epithelial surgery, Cytoreduction Surgical Procedures, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Carboplatin therapeutic use, Survival Analysis, Paclitaxel adverse effects, Hyperthermic Intraperitoneal Chemotherapy, Ovarian Neoplasms drug therapy, Ovarian Neoplasms surgery
- Abstract
Background: The OVHIPEC-1 trial previously showed that the addition of hyperthermic intraperitoneal chemotherapy (HIPEC) to interval cytoreductive surgery resulted in improved progression-free and overall survival compared with cytoreductive surgery alone at 4·7 years of follow-up in patients with stage III epithelial ovarian cancer who were ineligible for primary cytoreduction. We report the final survival outcomes after 10 years of follow-up., Methods: In this open-label, randomised, controlled, phase 3 trial, patients with primary epithelial stage III ovarian cancer were recruited at eight HIPEC centres in the Netherlands and Belgium. Patients were eligible if they were aged 18-76 years, had not progressed during at least three cycles of neoadjuvant carboplatin plus paclitaxel, had a WHO performance status score of 0-2, normal blood counts, and adequate renal function. Patients were randomly assigned (1:1) to undergo interval cytoreductive surgery without HIPEC (surgery group) or with HIPEC (100 mg/m
2 cisplatin; surgery-plus-HIPEC group). Randomisation was done centrally by minimisation with a masked web-based allocation procedure at the time of surgery when residual disease smaller than 10 mm diameter was anticipated, and was stratified by institution, previous suboptimal cytoreductive surgery, and number of abdominal regions involved. The primary endpoint was progression-free survival and a secondary endpoint was overall survival, analysed in the intention-to-treat population (ie, all randomly assigned patients). This study is registered with ClinicalTrials.gov, NCT00426257, and is closed., Findings: Between April 1, 2007, and April 30, 2016, 245 patients were enrolled and followed up for a median of 10·1 years (95% CI 8·4-12·9) in the surgery group (n=123) and 10·4 years (95% CI 9·5-13·3) in the surgery-plus-HIPEC group (n=122). Recurrence, progression, or death occurred in 114 (93%) patients in the surgery group (median progression-free survival 10·7 months [95% CI 9·6-12·0]) and 109 (89%) patients in the surgery-plus-HIPEC group (14·3 months [12·0-18·5]; hazard ratio [HR] 0·63 [95% CI 0·48-0·83], stratified log-rank p=0·0008). Death occurred in 108 (88%) patients in the surgery group (median overall survival 33·3 months [95% CI 29·0-39·1]) and 100 (82%) patients in the surgery-plus-HIPEC group (44·9 months [95% CI 38·6-55·1]; HR 0·70 [95% CI 0·53-0·92], stratified log-rank p=0·011)., Interpretation: These updated survival results confirm the long-term survival benefit of HIPEC in patients with primary stage III epithelial ovarian cancer undergoing interval cytoreductive surgery., Funding: Dutch Cancer Foundation (KWF Kankerbestrijding)., Competing Interests: Declaration of interests IHJTdH has received institutional research support from Roche and Quality in Products & Service/RanD. PV has received conference fees and travel expenses from Roche and honoraria from Roche (Genentech), Novartis, and MSD Oncology. KKVdV has served on advisory boards for Exact Sciences and AstraZeneca. GSS has received institutional research support from Merck Sharp & Dohme, Agendia, AstraZeneca, Roche, and Novartis, and consulting fees from Biovica and Seagen. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)- Published
- 2023
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35. First-line systemic treatment strategies in patients with initially unresectable colorectal cancer liver metastases (CAIRO5): an open-label, multicentre, randomised, controlled, phase 3 study from the Dutch Colorectal Cancer Group.
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Bond MJG, Bolhuis K, Loosveld OJL, de Groot JWB, Droogendijk H, Helgason HH, Hendriks MP, Klaase JM, Kazemier G, Liem MSL, Rijken AM, Verhoef C, de Wilt JHW, de Jong KP, Gerhards MF, van Amerongen MJ, Engelbrecht MRW, van Lienden KP, Molenaar IQ, de Valk B, Haberkorn BCM, Kerver ED, Erdkamp F, van Alphen RJ, Mathijssen-van Stein D, Komurcu A, Lopez-Yurda M, Swijnenburg RJ, and Punt CJA
- Subjects
- Humans, Male, Female, Middle Aged, Bevacizumab, Irinotecan therapeutic use, Oxaliplatin therapeutic use, Panitumumab therapeutic use, Leucovorin, Proto-Oncogene Proteins B-raf genetics, Camptothecin therapeutic use, Fluorouracil, Antineoplastic Combined Chemotherapy Protocols adverse effects, Colorectal Neoplasms drug therapy, Colorectal Neoplasms genetics, Colorectal Neoplasms pathology, Liver Neoplasms drug therapy, Liver Neoplasms genetics, Liver Neoplasms secondary, Hypertension chemically induced, Neutropenia chemically induced
- Abstract
Background: Patients with initially unresectable colorectal cancer liver metastases might qualify for local treatment with curative intent after reducing the tumour size by induction systemic treatment. We aimed to compare the currently most active induction regimens., Methods: In this open-label, multicentre, randomised, phase 3 study (CAIRO5), patients aged 18 years or older with histologically confirmed colorectal cancer, known RAS/BRAF
V600E mutation status, WHO performance status of 0-1, and initially unresectable colorectal cancer liver metastases were enrolled at 46 Dutch and one Belgian secondary and tertiary centres. Resectability or unresectability of colorectal cancer liver metastases was assessed centrally by an expert panel of liver surgeons and radiologists, at baseline and every 2 months thereafter by predefined criteria. Randomisation was done centrally with the minimisation technique via a masked web-based allocation procedure. Patients with right-sided primary tumour site or RAS or BRAFV600E mutated tumours were randomly assigned (1:1) to receive FOLFOX or FOLFIRI plus bevacizumab (group A) or FOLFOXIRI plus bevacizumab (group B). Patients with left-sided and RAS and BRAFV600E wild-type tumours were randomly assigned (1:1) to receive FOLFOX or FOLFIRI plus bevacizumab (group C) or FOLFOX or FOLFIRI plus panitumumab (group D), every 14 days for up to 12 cycles. Patients were stratified by resectability of colorectal cancer liver metastases, serum lactate dehydrogenase concentration, choice of irinotecan versus oxaliplatin, and BRAFV600E mutation status (for groups A and B). Bevacizumab was administered intravenously at 5 mg/kg. Panitumumab was administered intravenously at 6 mg/kg. FOLFIRI consisted of intravenous infusion of irinotecan at 180 mg/m2 with folinic acid at 400 mg/m2 , followed by bolus fluorouracil at 400 mg/m2 intravenously, followed by continuous infusion of fluorouracil at 2400 mg/m2 . FOLFOX consisted of oxaliplatin at 85 mg/m2 intravenously together with the same schedule of folinic acid and fluorouracil as in FOLFIRI. FOLFOXIRI consisted of irinotecan at 165 mg/m2 intravenously, followed by intravenous infusion of oxaliplatin at 85 mg/m2 with folinic acid at 400 mg/m2 , followed by continuous infusion of fluorouracil at 3200 mg/m2 . Patients and investigators were not masked to treatment allocation. The primary outcome was progression-free survival, analysed on a modified intention-to-treat basis, excluding patients who withdrew consent before starting study treatment or violated major entry criteria (no metastatic colorectal cancer, or previous liver surgery for colorectal cancer liver metastases). The study is registered with ClinicalTrials.gov, NCT02162563, and accrual is complete., Findings: Between Nov 13, 2014, and Jan 31, 2022, 530 patients (327 [62%] male and 203 [38%] female; median age 62 years [IQR 54-69]) were randomly assigned: 148 (28%) patients to group A, 146 (28%) patients to group B, 118 (22%) patients to group C, and 118 (22%) patients to group D. Groups C and D were prematurely closed for futility. 521 patients were included in the modified intention-to-treat population (147 in group A, 144 in group B, 114 in group C, and 116 in group D). The median follow-up at the time of this analysis was 51·1 months (95% CI 47·7-53·1) in groups A and B and 49·9 months (44·5-52·5) in in groups C and D. Median progression-free survival was 9·0 months (95% CI 7·7-10·5) in group A versus 10·6 months (9·9-12·1) in group B (stratified hazard ratio [HR] 0·76 [95% CI 0·60-0·98]; p=0·032), and 10·8 months (95% CI 9·9-12·6) in group C versus 10·4 months (9·8-13·0) in group D (stratified HR 1·11 [95% CI 0·84-1·48]; p=0·46). The most frequent grade 3-4 events in groups A and B were neutropenia (19 [13%] patients in group A vs 57 [40%] in group B; p<0·0001), hypertension (21 [14%] vs 20 [14%]; p=1·00), and diarrhoea (five [3%] vs 28 [19%]; p<0·0001), and in groups C and D were neutropenia (29 [25%] vs 24 [21%]; p=0·44), skin toxicity (one [1%] vs 29 [25%]; p<0·0001), hypertension (20 [18%] vs eight [7%]; p=0·016), and diarrhoea (five [4%] vs 18 [16%]; p=0·0072). Serious adverse events occurred in 46 (31%) patients in group A, 75 (52%) patients in group B, 41 (36%) patients in group C, and 49 (42%) patients in group D. Seven treatment-related deaths were reported in group B (two due to multiorgan failure, and one each due to sepsis, pneumonia, portal vein thrombosis, septic shock and liver failure, and sudden death), one in group C (multiorgan failure), and three in group D (cardiac arrest, pulmonary embolism, and abdominal sepsis)., Interpretation: In patients with initially unresectable colorectal cancer liver metastases, FOLFOXIRI-bevacizumab was the preferred treatment in patients with a right-sided or RAS or BRAFV600E mutated primary tumour. In patients with a left-sided and RAS and BRAFV600E wild-type tumour, the addition of panitumumab to FOLFOX or FOLFIRI showed no clinical benefit over bevacizumab, but was associated with more toxicity., Funding: Roche and Amgen., Competing Interests: Declaration of interests CJAP reports fees for an advisory role for Nordic Pharma, paid to their institution. KB reports fees for an advisory role for Amgen, paid to their institution. JWBdG reports personal fees from Bristol Myers Squibb. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)- Published
- 2023
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36. IMPemBra: a phase 2 study comparing pembrolizumab with intermittent/short-term dual MAPK pathway inhibition plus pembrolizumab in patients with melanoma harboring the BRAFV600 mutation.
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Rozeman EA, Versluis JM, Sikorska K, Hoefsmit EP, Dimitriadis P, Rao D, Lacroix R, Grijpink-Ongering LG, Lopez-Yurda M, Heeres BC, van de Wiel BA, Flohil C, Sari A, Heijmink SWTPJ, van den Broek D, Broeks A, de Groot JWB, Vollebergh MA, Wilgenhof S, van Thienen JV, Haanen JBAG, and Blank CU
- Subjects
- Mutation, Humans, Male, Female, Adult, Middle Aged, Aged, Melanoma drug therapy, Melanoma genetics, Proto-Oncogene Proteins B-raf genetics
- Abstract
Background: Continuous combination of MAPK pathway inhibition (MAPKi) and anti-programmed death-(ligand) 1 (PD-(L)1) showed high response rates, but only limited improvement in progression-free survival (PFS) at the cost of a high frequency of treatment-related adverse events (TRAE) in patients with BRAF
V600 -mutated melanoma. Short-term MAPKi induces T-cell infiltration in patients and is synergistic with anti-programmed death-1 (PD-1) in a preclinical melanoma mouse model. The aim of this phase 2b trial was to identify an optimal regimen of short-term MAPKi with dabrafenib plus trametinib in combination with pembrolizumab., Methods: Patients with treatment-naïve BRAFV600E/K -mutant advanced melanoma started pembrolizumab 200 mg every 3 weeks. In week 6, patients were randomized to continue pembrolizumab only (cohort 1), or to receive, in addition, intermittent dabrafenib 150 mg two times per day plus trametinib 2 mg one time per day for two cycles of 1 week (cohort 2), two cycles of 2 weeks (cohort 3), or continuously for 6 weeks (cohort 4). All cohorts continued pembrolizumab for up to 2 years. Primary endpoints were safety and treatment-adherence. Secondary endpoints were objective response rate (ORR) at week 6, 12, 18 and PFS., Results: Between June 2016 and August 2018, 33 patients with advanced melanoma have been included and 32 were randomized. Grade 3-4 TRAE were observed in 12%, 12%, 50%, and 63% of patients in cohort 1, 2, 3, and 4, respectively. All planned targeted therapy was given in 88%, 63%, and 38% of patients in cohort 2, 3, and 4. ORR at week 6, 12, and 18 were 38%, 63%, and 63% in cohort 1; 25%, 63%, and 75% in cohort 2; 25%, 50%, and 75% in cohort 3; and 0%, 63%, and 50% in cohort 4. After a median follow-up of 43.5 months, median PFS was 10.6 months for pembrolizumab monotherapy and not reached for patients treated with pembrolizumab and intermittent dabrafenib and trametinib (p=0.17). The 2-year and 3-year landmark PFS were both 25% for cohort 1, both 63% for cohort 2, 50% and 38% for cohort 3 and 75% and 60% for cohort 4., Conclusions: The combination of pembrolizumab plus intermittent dabrafenib and trametinib seems more feasible and tolerable than continuous triple therapy. The efficacy is promising and appears to be favorable over pembrolizumab monotherapy., Trial Registration Number: NCT02625337., Competing Interests: Competing interests: All authors declare no direct conflicts with this work. For unrelated conflicts, EAR, JMV, KS, EPH, PD, DR, RL, LGG-O, ML-Y, BCH, CF, AS, SWTPJH, AB, JWBdG, MAV and JVvT report no competing interests. BAvdW reports an advisory role for BMS. DvdB reports expert testimony and honoraria from Roche Diagnostics, both paid to the institution. JBAGH reports an advisory role for Achilles Therapeutics, BioNTech, Bristol-Myers Squibb, Immunocore, Instil Bio, Iovance Biotherapeutics, Ipsen, Molecular Partners, MSD Oncology, Neogene Therapeutics, Novartis, PokeAcel, Roche/Genentech, Sanofi, Third Rock Ventures and T-Knife; has received research funding, paid to the institute, from Amgen, Asher Biotherapeutics, BioNTech, Bristol-Myers Squibb, MSD, Neon Therapeutics, Novartis; and is stock owner of Neogene Therapeutics. SW reports serving on advisory boards for Eisai, Bristol-Myers Squibb, Pfizer, Novartis and Pierre Fabre all paid to the institution. CUB reports advisory roles for BMS, MSD, Roche, Novartis, GSK, AZ, Pfizer, Lilly, GenMab, Pierre Fabre, Third Rock Ventures, research funding from BMS, Novartis, Nanostring, and 4SC, co-founder, shareholder and advisor of Immagene B.V and co-founder of Signature Oncology., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)- Published
- 2023
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37. WEE1 inhibitor adavosertib in combination with carboplatin in advanced TP53 mutated ovarian cancer: A biomarker-enriched phase II study.
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Embaby A, Kutzera J, Geenen JJ, Pluim D, Hofland I, Sanders J, Lopez-Yurda M, Beijnen JH, Huitema ADR, Witteveen PO, Steeghs N, van Haaften G, van Vugt MATM, de Ridder J, and Opdam FL
- Subjects
- Female, Humans, Middle Aged, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Biomarkers, Carboplatin therapeutic use, Carcinoma, Ovarian Epithelial drug therapy, Cell Cycle Proteins genetics, Disease-Free Survival, Protein-Tyrosine Kinases antagonists & inhibitors, Tumor Suppressor Protein p53 genetics, Adult, Aged, Ovarian Neoplasms drug therapy, Ovarian Neoplasms genetics, Ovarian Neoplasms pathology
- Abstract
Objective: In the first part of this phase II study (NCT01164995), the combination of carboplatin and adavosertib (AZD1775) was shown to be safe and effective in patients with TP53 mutated platinum-resistant ovarian cancer (PROC). Here, we present the results of an additional safety and efficacy cohort and explore predictive biomarkers for resistance and response to this combination treatment., Methods: This is a phase II, open-label, non-randomized study. Patients with TP53 mutated PROC received carboplatin AUC 5 mg/ ml·min intravenously and adavosertib 225 mg BID orally for 2.5 days in a 21-day cycle. The primary objective is to determine the efficacy and safety of carboplatin and adavosertib. Secondary objectives include progression-free survival (PFS), changes in circulating tumor cells (CTC) and exploration of genomic alterations., Results: Thirty-two patients with a median age of 63 years (39-77 years) were enrolled and received treatment. Twenty-nine patients were evaluable for efficacy. Bone marrow toxicity, nausea and vomiting were the most common adverse events. Twelve patients showed partial response (PR) as best response, resulting in an objective ORR of 41% in the evaluable patients (95% CI: 23%-61%). The median PFS was 5.6 months (95% CI: 3.8-10.3). In patients with tumors harboring CCNE1 amplification, treatment efficacy was slightly but not significantly better., Conclusions: Adavosertib 225 mg BID for 2.5 days and carboplatin AUC 5 could be safely combined and showed anti-tumor efficacy in patients with PROC. However, bone marrow toxicity remains a point of concern, since this is the most common reason for dose reductions and dose delays., Competing Interests: Declaration of Competing Interest A list with conflicts of interest of all authors will be provided., (Copyright © 2023 Elsevier Inc. All rights reserved.)
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- 2023
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38. IFN-γ signature enables selection of neoadjuvant treatment in patients with stage III melanoma.
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Reijers ILM, Rao D, Versluis JM, Menzies AM, Dimitriadis P, Wouters MW, Spillane AJ, Klop WMC, Broeks A, Bosch LJW, Lopez-Yurda M, van Houdt WJ, Rawson RV, Grijpink-Ongering LG, Gonzalez M, Cornelissen S, Bouwman J, Sanders J, Plasmeijer E, Elshot YS, Scolyer RA, van de Wiel BA, Peeper DS, van Akkooi ACJ, Long GV, and Blank CU
- Subjects
- Humans, Animals, Mice, Nivolumab adverse effects, Ipilimumab therapeutic use, Ipilimumab adverse effects, Neoadjuvant Therapy, Interferon-gamma, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Melanoma, Cutaneous Malignant, Melanoma pathology, Skin Neoplasms drug therapy, Skin Neoplasms pathology
- Abstract
Neoadjuvant ipilimumab + nivolumab has demonstrated high pathologic response rates in stage III melanoma. Patients with low intra-tumoral interferon-γ (IFN-γ) signatures are less likely to benefit. We show that domatinostat (a class I histone deacetylase inhibitor) addition to anti-PD-1 + anti-CTLA-4 increased the IFN-γ response and reduced tumor growth in our murine melanoma model, rationalizing evaluation in patients. To stratify patients into IFN-γ high and low cohorts, we developed a baseline IFN-γ signature expression algorithm, which was prospectively tested in the DONIMI trial. Patients with stage III melanoma and high intra-tumoral IFN-γ scores were randomized to neoadjuvant nivolumab or nivolumab + domatinostat, while patients with low IFN-γ scores received nivolumab + domatinostat or ipilimumab + nivolumab + domatinostat. Domatinostat addition to neoadjuvant nivolumab ± ipilimumab did not delay surgery but induced unexpected severe skin toxicity, hampering domatinostat dose escalation. At studied dose levels, domatinostat addition did not increase treatment efficacy. The baseline IFN-γ score adequately differentiated patients who were likely to benefit from nivolumab alone versus patients who require other therapies., (© 2023 Reijers et al.)
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- 2023
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39. Therapeutic drug monitoring guided dosing versus standard dosing of alectinib in advanced ALK positive non-small cell lung cancer patients: Study protocol for an international, multicenter phase IV randomized controlled trial (ADAPT ALEC).
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Meertens M, Muntinghe-Wagenaar MB, Sikkema BJ, Lopez-Yurda M, Retèl VP, Paats MS, Ter Heine R, Schuuring E, Timens W, Touw DJ, van Boven JFM, de Langen AJ, Hashemi SMS, Hendriks LEL, Croes S, van den Heuvel MM, Dingemans AC, Mathijssen RHJ, Smit EF, Huitema ADR, Steeghs N, and van der Wekken AJ
- Abstract
Background: Alectinib is first-line therapy in patients with stage IV non-small cell lung carcinoma (NSCLC) and an anaplastic lymphoma kinase (ALK) fusion. A shorter median progression-free survival (mPFS) was observed when alectinib minimum plasma concentrations during steady state (C
min,SS ) were below 435 ng/mL. This may suggest that patients should have an alectinib Cmin,SS ≥ 435 ng/mL for a more favorable outcome. This potential target could be attained by using therapeutic drug monitoring (TDM), i.e. adjusting the dose based on measured plasma trough concentrations. Hypothetically, this will increase mPFS, but this has not yet been evaluated in a randomized controlled trial (RCT). Therefore, the ADAPT ALEC trial is designed, with the primary objective to prolong mPFS in NSCLC patients treated with alectinib by using TDM., Methods: ADAPT ALEC is a multicenter, phase IV RCT, in which patients aged ≥ 18 years with advanced ALK positive (+) NSCLC eligible for alectinib in daily care are enrolled. Participants will be randomized (1:1 ratio) into intervention arm A (TDM) or B (control), stratified by brain metastases and prior ALK treatments. Starting dose in both arms is the approved flat fixed dose of alectinib 600 mg taken twice daily with food. In case of alectinib Cmin,SS < 435 ng/mL, arm A will receive increased doses of alectinib till Cmin,SS ≥ 435 ng/mL when considered tolerable. The primary outcome is mPFS, where progressive disease is defined according to RECIST v1.1 or all-cause death and assessed by CT-scans and MRI brain. Secondary endpoints are feasibility and tolerability of TDM, patient and physician adherence, overall response rate, median overall survival, intracranial PFS, quality of life, toxicity, alectinib-M4 concentrations and cost-effectiveness of TDM. Exploratory endpoints are circulating tumor DNA and body composition., Discussion: The ADAPT ALEC will show whether treatment outcomes of patients with advanced ALK+ NSCLC improve when using TDM-guided dosing of alectinib instead of fixed dosing. The results will provide high quality evidence for deciding whether TDM should be implemented as standard of care and this will have important consequences for the prescribing of alectinib., Clinical Trial Registration: ClinicalTrials.gov, identifier NCT05525338., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. BM: nothing to disclose in relationship to this manuscript. Outside of current manuscript: BM received the AACR-Bristol Myers Squibb Scholar-in-Training award 2022 travel support to attend the AACR Annual Meeting 2022. MP has no relationship to disclose in relation to this manuscript. MP attended advisory boards and/or provided lectures for: Takeda, Eli Lilly, Bayer, Roche, AstraZeneca, Novartis, Janssen Pharmaceuticals and Pfizer; for which the institute received honoraria. ESc reports lectures for Bio-Rad, Seracare, Novartis, Roche, Biocartis, Illumina, Lilly, Janssen Cilag, Pfizer, AstraZeneca and Agena Bioscience; consultant in advisory boards for MSD/Merck, GSK, AstraZeneca, Astellas Pharma, Roche, Pfizer, Novartis, Bayer, BMS, Lilly, Amgen, Biocartis, Illumina, Agena Bioscience, Janssen Cilag Johnson&Johnson, Diaceutics, CC Diagnostics; and received research grants from Pfizer, Biocartis, Invitae-ArcherDX, AstraZeneca, Agena Bio-science, BMS, Bio-Rad, Roche, Boehringer Ingelheim honoria paid to UMCG account. WT: nothing to disclose in relationship to this manuscript. Outside of current manuscript: WT reports consultant in advisory boards for MSD/Merck, and BMS all payment to UMCG. DT reports grants from Chiesi and advisory boards from Sanquin and PureIMS, all outside the submitted work. Payments were made to the UMCG. JB reports consultancy fees, speaking fees and/or research grants from Aardex, AstraZeneca, Chiesi, European Commission COST Action 19132 “ENABLE”, GSK, Novartis, Teva, Trudell Medical and Vertex, all paid to his employer UMCG and unrelated to this study. AL reports grants from AstraZeneca, BMS, MSD, Boehringer Ingelheim, and non-financial support from Merck Serono and Roche, all outside the submitted work. SH: research grant and advisory board: AstraZeneca, Boehringer Ingelheim, BMS, Eli Lilly, Janssen, GSK, MSD, Novartis, Roche, Takeda, and Xcovery. LH: No relationship to disclose in relation to this manuscript. Outside of current manuscript: research funding Roche Genentech, AstraZeneca, Boehringer Ingelheim, Takeda all institution, Beigene under negotiation; advisory board: BMS, Eli Lilly, Roche Genentech, Pfizer, Takeda, MSD, Merck, Novartis, Boehringer Ingelheim, Amgen, Janssen all institution, Roche one time self; speaker: MSD, Lilly institution; travel/conference reimbursement: Roche Genentech self; mentorship program with key opinion leaders: funded by AstraZeneca; fees for educational webinars: Benecke, Medtalks, VJOncology self, high5oncology institution; interview sessions funded by Roche Genentech, Bayer, Lilly institution; local PI of clinical trials: AstraZeneca, Novartis, BMS, MSD, Merck, GSK, Takeda, Blueprint Medicines, Roche Genentech, Janssen Pharmaceuticals, Mirati, Abbvie, Gilead. MH has nothing to disclose in relationship to this manuscript. Outside of current manuscript: research grants by AZD, Bristol Myers Squibb, Merck, MSD, Novartis, Pfizer and Roche, all paid to the institute. AD: nothing to disclose in relationship to this manuscript. Outside of current manuscript: research funding from Amgen, Astra Zeneca, Chiesi, Eli Lilly, Janssen sponsored symposium, Pfizer, Takeda. AD attended advisory boards or Steering committee of Amgen, Astra Zeneca, Bayer, Boehringer Ingelheim, Pharmamar, Sanofi, Roche. All paid to the institute. RM: nothing to disclose in relationship to this manuscript. Research grants all paid to the institute during the last 2 years from Astellas, Bayer, Boehringer-Ingelheim, Cristal-Therapeutics, Novartis, Pamgene, Pfizer, Roche, Sanofi, Servier. ESm: nothing to disclose in relationship to this manuscript. Attended advisory boards for Astra Zeneca, BMS, Bayer, Boehringer Ingelheim, DSI, Eli Lilly, MSD, Merck, Novartis, Pfizer, Takeda, Roche Genentech. ESm received research funding from: Astra Zeneca, BMS, MSD, Merck, Roche Genentech. All of the above institutional, no personal financial interests. NS provided consultation or attended advisory boards for Boehringer Ingelheim, Ellipses Pharma, Luszana, Cogent Biosciences. NS received research grants from Abbvie, Actuate Therapeutics, Amgen, Array, Ascendis Pharma, Astex, AstraZeneca, Bayer, Blueprint Medicines, Boehringer Ingelheim, Bristol-Myers Squibb, Cantargia, CellCentric, Cogent Biosciences, Cresecendo Biologics, Cytovation, Deciphera, Eisai, Eli Lilly, Exelixis, Genentech, GlaxoSmithKline, Incyte, InteRNA, Janssen, Kinnate Biopharma, Luszana, Merck, Merck Sharp & Dohme, Merus, Molecular Partners, Navire Pharma, Novartis, Numab Therapeutics, Pfizer, Relay Pharmaceuticals, Revolution Medicin, Roche, Sanofi, Seattle Genetics, Taiho, Takeda. All outside the submitted work, all payment to the Netherlands Cancer Institute. AW reports grants and advisory board from AstraZeneca, grants and advisory board from Boehringer-Ingelheim, advisory board from Janssen, advisory board from Novartis, grants and advisory board from Pfizer, grants and advisory board from Roche, grants and advisory board from Takeda, all outside the submitted work. All payment to the UMCG., (Copyright © 2023 Meertens, Muntinghe-Wagenaar, Sikkema, Lopez-Yurda, Retèl, Paats, Ter Heine, Schuuring, Timens, Touw, van Boven, de Langen, Hashemi, Hendriks, Croes, van den Heuvel, Dingemans, Mathijssen, Smit, Huitema, Steeghs and van der Wekken.)- Published
- 2023
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40. Safety and efficacy of RFA versus MWA for T1a renal cell carcinoma: a propensity score analysis.
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Aarts BM, Gomez FM, Lopez-Yurda M, Bevers RFM, Herndriks J, Beets-Tan RGH, Bex A, Klompenhouwer EG, and van der Meer RW
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- Humans, Retrospective Studies, Propensity Score, Treatment Outcome, Microwaves, Carcinoma, Renal Cell diagnostic imaging, Carcinoma, Renal Cell surgery, Carcinoma, Renal Cell pathology, Radiofrequency Ablation methods, Kidney Neoplasms diagnostic imaging, Kidney Neoplasms surgery, Kidney Neoplasms pathology, Catheter Ablation methods, Liver Neoplasms pathology
- Abstract
Objectives: Percutaneous radiofrequency ablation (RFA) is stated as a treatment option for renal cell carcinoma (RCC) smaller than 4 cm (T1a). Microwave ablation (MWA) is a newer technique and is still considered experimental in some guidelines. The objective of this study was to compare the safety and efficacy of RFA and MWA for the treatment of RCC., Methods: Patients with T1a RCC treated by RFA or MWA in two referral centers were retrospectively analyzed. Patient records were evaluated to generate mRENAL nephrometry scores. Local tumor progression (LTP) was considered when new (recurrence) or residual tumor enhancement within/adjacent to the ablation zone was objectified. Differences in LTP-free interval (residual + recurrence) between ablation techniques were assessed with Cox proportional hazards models and propensity score (PS) methods., Results: In 164 patients, 87 RFAs and 101 MWAs were performed for 188 RCCs. The primary efficacy rate was 92% (80/87) for RFA and 91% (92/101) for MWA. Sixteen patients had residual disease (RFA (n = 7), MWA (n = 9)) and 9 patients developed recurrence (RFA (n = 7), MWA (n = 2)). LTP-free interval was significantly worse for higher mRENAL nephrometry scores. No difference in LTP-free interval was found between RFA and MWA in a model with inverse probability weighting using PS (HR = 0.99, 95% CI 0.35-2.81, p = 0.98) and in a PS-matched dataset with 110 observations (HR = 0.82, 95% CI 0.16-4.31, p = 0.82). Twenty-eight (14.9%) complications (Clavien-Dindo grade I-IVa) occurred (RFA n = 14, MWA n = 14)., Conclusion: Primary efficacy for ablation of RCC is high for both RFA and MWA. No differences in efficacy and safety were observed between RFA and MWA., Key Points: • Both RFA and MWA are safe and effective ablation techniques in the treatment of T1a renal cell carcinomas. • High modified RENAL nephrometry scores are associated with shorter local tumor progression-free interval. • MWA can be used as heat-based ablation technique comparable to RFA for the treatment of T1a renal cell carcinomas., (© 2022. The Author(s).)
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- 2023
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41. Individualised dosing of anti-thymocyte globulin in paediatric unrelated allogeneic haematopoietic stem-cell transplantation (PARACHUTE): a single-arm, phase 2 clinical trial.
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Admiraal R, Nierkens S, Bierings MB, Bredius RGM, van Vliet I, Jiang Y, Lopez-Yurda M, Versluijs AB, Zwaan CM, Lindemans CA, and Boelens JJ
- Subjects
- Antilymphocyte Serum therapeutic use, Child, Female, Humans, Neoplasm Recurrence, Local, Prospective Studies, Transplantation Conditioning, Graft vs Host Disease etiology, Graft vs Host Disease prevention & control, Hematopoietic Stem Cell Transplantation adverse effects
- Abstract
Background: Anti-thymocyte globulin, which is used in the conditioning of haematopoietic stem-cell transplantation (HSCT) to prevent graft-versus-host disease (GVHD) and graft failure, has highly variable pharmacokinetics. Overexposure to anti-thymocyte globulin leads to poor CD4
+ T-cell immune reconstitution, which is associated with inferior overall survival. We hypothesised that individualised anti-thymocyte globulin dosing would promote CD4+ immune reconstitution, while still preventing GVHD and graft failure., Methods: We report the results of a prospective, single-arm, phase 2 clinical trial done at the University Medical Center Utrecht and the Princess Máxima Center for Pediatric Oncology (Utrecht, Netherlands) to investigate individualised dosing of anti-thymocyte globulin for unrelated allogeneic HSCT in paediatric patients. Anti-thymocyte globulin dosing was based on bodyweight, absolute lymphocyte counts before the first dose, and the stem-cell source, with cumulative doses ranging from 2-10 mg/kg. Patients younger than 18 years receiving a first HSCT with a T-cell repleted graft for any indication and a Lansky/Karnofsky performance status of at least 70% were eligible for inclusion. The primary endpoint was CD4+ immune reconstitution (>0·05 × 109 CD4+ T-cells per L twice within 100 days [±3] after transplantation). The primary endpoint needed to be met in 38 of 53 evaluable patients (no death, relapse, or graft failure before day 100). Toxicity was registered according to Common Terminology Criteria for Adverse Events criteria version 4.0. The study is registered with the Dutch Trial Register, NL4836., Findings: Between July 1, 2015, and Aug 22, 2018, 58 patients were included in the study, of whom 51 were evaluable for the primary endpoint. Median follow-up was 25·6 months (IQR 15·0-37·0) and median age was 7·4 years (IQR 2·8-13·2). 29 (50%) of 58 patients were female. CD4+ immune reconstitution was reached in 41 (80%, 95% CI 67-90, in survival analysis) of 51 evaluable patients, hence the study met its primary endpoint. There was no difference in CD4+ immune reconstitution between patients who received different stem-cell sources (87% [95% CI 61-96] in cord blood, 77% [54-89] in bone marrow [p=0·62]). The most common grade 3-5 adverse events were infections (32 [50%] patients had grade 3, two [3%] patients had grade 4, and seven [11%] patients had fatal events) and immunological disorders (seven [11%] patients had grade 3, three [5%] patients had grade 4, and five [8%] patients had fatal events). Two (3%) of 64 patients died of GVHD, which might be indirectly related to the intervention., Interpretation: Individualised dosing of anti-thymocyte globulin led to a significant improvement in early CD4+ immune reconstitution without increasing GVHD and graft failure incidence. Promotion of early CD4+ immune reconstitution by individualising anti-thymocyte globulin dose might improve outcomes of allogeneic HSCT., Funding: Sanofi., Competing Interests: Declaration of interests CAL reports honoraria for a lecture from Genzyme (related to this topic). J-JB reports honoraria from BlueRock, Avrobio, Race Oncology, Medexus, and Omeros for consulting (not related to this topic) and from Sanofi (related to this topic), and participation on a data safety monitoring board for Advanced Clinical. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)- Published
- 2022
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42. Prophylactic fibrinogen concentrate administration in surgical correction of paediatric craniosynostosis: A double-blind placebo-controlled trial.
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Machotta A, Huisman EJ, Appel IM, Luijnenburg SE, Lopez-Yurda M, Cnossen MH, and van Ommen CH
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- Blood Loss, Surgical prevention & control, Child, Child, Preschool, Double-Blind Method, Fibrinogen, Humans, Infant, Craniosynostoses surgery, Hemostatics
- Abstract
Background: Surgical craniosynostosis repair in children is associated with massive blood loss and significant transfusion of blood products. Fibrinogen concentrate is claimed to be useful in reducing blood loss and transfusion requirements., Objective: We investigated whether prophylactic administration of fibrinogen concentrate will reduce blood loss and transfusion requirements during paediatric craniofacial surgery., Design: Randomised, placebo-controlled, double-blind clinical trial., Setting: University medical centre., Patients: A total of 114 infants and children up to 25 months of age (median age 10 months)., Intervention: Surgical craniosynostosis repair by calvarial remodelling was performed in each patient. Patients were randomised to receive prophylactic fibrinogen concentrate (Haemocomplettan P) at a mean dose of 79 mg kg-1 body weight or placebo., Main Outcome Measures: Primary outcome was the volume of transfused blood products. Secondary outcomes were peri-operative blood loss, duration of surgery, length of stay in the paediatric ICU, length of hospital stay, postoperative complications and adverse effects of fibrinogen concentrate infusion., Results: No significant differences (P < 0.05) were found in the volume of transfused blood products (median 29 ml kg-1 body weight vs. 29 ml kg-1 body weight), intra-operative estimated blood loss (45 vs. 46 ml kg-1), calculated blood loss (57 vs. 53 ml kg-1), or postoperative blood loss (24 vs. 24 ml kg-1) between the intervention and placebo groups. In addition, duration of surgery, length of stay in the paediatric ICU, hospital stay and complications were not significantly different between the two groups., Conclusion: During surgical craniosynostosis repair in young children, prophylactic administration of high-dose fibrinogen concentrate did not reduce the amount of transfused blood products or decrease peri-operative blood loss., Trial Registration: National Trial Register (NTR2975) and EudraCT (2011-002287-24)., (Copyright © 2020 European Society of Anaesthesiology and Intensive Care. Unauthorized reproduction of this article is prohibited.)
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- 2021
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43. Postoperative circulating tumour DNA is associated with pathologic response and recurrence-free survival after resection of colorectal cancer liver metastases.
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Bolhuis K, van 't Erve I, Mijnals C, Delis-Van Diemen PM, Huiskens J, Komurcu A, Lopez-Yurda M, van den Broek D, Swijnenburg RJ, Meijer GA, Punt CJA, and Fijneman RJA
- Subjects
- Aged, Female, Humans, Liver Neoplasms secondary, Male, Middle Aged, Neoplasm Recurrence, Local epidemiology, Postoperative Complications epidemiology, Postoperative Period, Survival Analysis, Biomarkers, Tumor blood, Cell-Free Nucleic Acids blood, Colorectal Neoplasms pathology, Liver Neoplasms surgery, Neoplasm Recurrence, Local blood, Postoperative Complications blood
- Abstract
Background: Recurrence rates after resection of colorectal cancer liver metastases (CRLM) are high and correlate with worse survival. Postoperative circulating tumour DNA (ctDNA) is a promising prognostic biomarker. Focusing on patients with resected CRLM, this study aimed to evaluate the association between the detection of postoperative ctDNA, pathologic response and recurrence-free survival (RFS)., Methods: Twenty-three patients were selected from an ongoing phase-3 trial who underwent resection of RAS-mutant CRLM after induction systemic treatment. CtDNA analysis was performed by droplet digital PCR using blood samples collected at baseline, before and after resection. Pathologic response of CRLM was determined via the Tumour Regression Grading system., Findings: With a median follow-up of 19.6 months, the median RFS for patients with detectable (N = 6, [26%]) and undetectable (N = 17, [74%]) postoperative ctDNA was 4.8 versus 12.1 months, respectively. Among 21 patients with available tumour tissue, pathologic response in patients with detectable compared to undetectable postoperative ctDNA was found in one of six (17%) and 15 of 15 (100%) patients, respectively (p < 0.001). In univariable Cox regression analyses both postoperative detectable ctDNA (HR = 3.3, 95%CI = 1.1-9.6, p = 0.03) and pathologic non-response (HR = 4.6, 95%CI = 1.4-15, p = 0.01) were associated with poorer RFS and were strongly correlated (r = 0.88, p < 0.001). After adjusting for clinical characteristics in pairwise multivariable analyses, postoperative ctDNA status remained associated with RFS., Interpretation: The detection of postoperative ctDNA after secondary resection of CRLM is a promising prognostic factor for RFS and appeared to be highly correlated with pathologic response., Funding: None., Competing Interests: Declaration of Competing Interest C.J.A.P. has an advisory role for Nordic Pharma. This funding is not related to the current research. G.A.M. reports non-financial support from Exact Sciences, non-financial support from Sysmex, non-financial support from Sentinel CH. SpA, non-financial support from Personal Genome Diagnostics (PGDX), other from Hartwig Medical Foundation, grants from CZ (OWM Centrale Zorgverzekeraars groep Zorgverzekeraar u.a), other from Royal Philips, other from GlaxoSmithKline, other from Keosys SARL, other from Open Clinica LLC, other from Roche Diagnostics Nederland BV, other from The Hyve BV, other from Open Text, other from SURFSara BV, other from Vancis BV, other from CSC Computer Sciences BV, outside the submitted work; In addition, G.A.M. has several patents pending. R.J.A.F. reports grants and non-financial support from Personal Genome Diagnostics, grants from MERCK BV, non-financial support from Pacific Biosciences, non-financial support from Cergentis BV, outside the submitted work; In addition, R.J.A.F. has several patents pending. The remaining authors declare no potential conflicts of interest., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)
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- 2021
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44. Combining brentuximab vedotin with dexamethasone, high-dose cytarabine and cisplatin as salvage treatment in relapsed or refractory Hodgkin lymphoma: the phase II HOVON/LLPC Transplant BRaVE study.
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Kersten MJ, Driessen J, Zijlstra JM, Plattel WJ, Morschhauser F, Lugtenburg PJ, Brice P, Hutchings M, Gastinne T, Liu R, Burggraaff CN, Nijland M, Tonino SH, Arens AIJ, Valkema R, van Tinteren H, Lopez-Yurda M, Diepstra A, De Jong D, and Hagenbeek A
- Subjects
- Antineoplastic Combined Chemotherapy Protocols adverse effects, Brentuximab Vedotin, Cisplatin, Cytarabine therapeutic use, Dexamethasone therapeutic use, Humans, Neoplasm Recurrence, Local, Positron Emission Tomography Computed Tomography, Recurrence, Salvage Therapy, Treatment Outcome, Hodgkin Disease drug therapy
- Abstract
Achieving a metabolic complete response (mCR) before high-dose chemotherapy (HDC) and autologous peripheral blood stem-cell transplant (auto-PBSCT) predicts progression free survival (PFS) in relapsed/refractory classical Hodgkin lymphoma (R/R cHL). We added brentuximab vedotin (BV) to DHAP to improve the mCR rate. In a Phase I dose-escalation part in 12 patients, we showed that BV-DHAP is feasible. This Phase II study included 55 R/R cHL patients (23 primary refractory). Treatment consisted of three 21-day cycles of BV 1.8 mg/kg on day 1, and DHAP (dexamethasone 40mg days 1-4, cisplatin 100mg/m2; day 1 and cytarabine 2x2g/m2; day 2). Patients with a metabolic partial response (mPR) or mCR proceeded to HDC/auto-PBSCT. Based on independent central FDG-PET-CT review, 42 of 52 evaluable patients (81% [95% CI: 67-90]) achieved an mCR before HDC/auto-PBSCT, five had an mPR and five had progressive disease (three were not evaluable). After HDC/auto-PBSCT, four patients with an mPR converted to an mCR. The 2-year PFS was 74% [95% CI: 63-86], and the overall survival 95% [95% CI: 90-100]. Toxicity was manageable and mainly consisted of grade 3/4 hematological toxicity, fever, nephrotoxicity, ototoxicity (grade 1/2) and transiently elevated liver enzymes during BV-DHAP. Eighteen patients developed new onset peripheral neuropathy (maximum grade 1/2) and all recovered. In conclusion, BV-DHAP is a very effective salvage regimen in R/R cHL patients, but patients should be monitored closely for toxicity. ClinicalTrials.gov identifier: NCT02280993.
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- 2021
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45. A phase 1 study of inotuzumab ozogamicin in pediatric relapsed/refractory acute lymphoblastic leukemia (ITCC-059 study).
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Brivio E, Locatelli F, Lopez-Yurda M, Malone A, Díaz-de-Heredia C, Bielorai B, Rossig C, van der Velden VHJ, Ammerlaan ACJ, Thano A, van der Sluis IM, den Boer ML, Chen Y, Sleight B, Brethon B, Nysom K, Sramkova L, Øra I, Vinti L, Chen-Santel C, and Zwaan CM
- Subjects
- Antineoplastic Agents, Immunological adverse effects, Child, Child, Preschool, Female, Humans, Infant, Inotuzumab Ozogamicin adverse effects, Male, Neoplasm Recurrence, Local drug therapy, Treatment Outcome, Antineoplastic Agents, Immunological therapeutic use, Inotuzumab Ozogamicin therapeutic use, Precursor Cell Lymphoblastic Leukemia-Lymphoma drug therapy
- Abstract
This phase 1 study investigated the recommended phase 2 dose (RP2D) of inotuzumab ozogamicin (InO), a CD22-directed antibody-drug conjugate, in pediatric patients with multiple relapsed/refractory (R/R) CD22+ acute lymphoblastic leukemia (ALL). Patients (age ≥1 year or <18 years) received 3 doses of InO (days 1, 8, and 15) per course. Dose escalation was based on dose-limiting toxicities (DLTs) during course 1. Dose level 1 (DL1) was 1.4 mg/m2 (0.6, 0.4, 0.4 mg/m2) and DL2 was 1.8 mg/m2 (0.8, 0.5, 0.5 mg/m2). Secondary end points included safety, antileukemic activity, and pharmacokinetics. Twenty-five patients (23 evaluable for DLTs) were enrolled. In course 1, the first cohort had 1 of 6 (DL1) and 2 of 5 (DL2) patients who experienced DLTs; subsequent review considered DL2 DLTs to be non-dose-limiting. Dose was de-escalated to DL1 while awaiting protocol amendment to re-evaluate DL2 in a second cohort, in which 0 of 6 (DL1) and 1 of 6 (DL2) patients had a DLT. Twenty-three patients experienced grade 3 to 4 adverse events; hepatic sinusoidal obstruction syndrome was reported in 2 patients after subsequent chemotherapy. Overall response rate after course 1 was 80% (95% confidence interval [CI], 59% to 93%) (20 of 25 patients; DL1: 75% [95% CI, 43% to 95%], DL2: 85% [95% CI, 55% to 98%]). Of the responders, 84% (95% CI, 60% to 97%) achieved minimal residual disease (MRD)-negative complete response, and 12-month overall survival was 40% (95% CI, 25% to 66%). Nine patients received hematopoietic stem cell transplantation or chimeric antigen receptor T cells after InO. InO median maximum concentrations were comparable to simulated adult concentrations. InO was well tolerated, demonstrating antileukemic activity in heavily pretreated children with CD22+ R/R ALL. RP2D was established as 1.8 mg/m2 per course, as in adults. This trial was registered at https://www.clinicaltrialsregister.eu as EUDRA-CT 2016-000227-71., (© 2021 by The American Society of Hematology.)
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- 2021
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46. Plasma thymus and activation-regulated chemokine (TARC) as diagnostic marker in pediatric Hodgkin lymphoma.
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Zijtregtop EAM, Meyer-Wentrup F, Wong WC, Hoogendijk R, Lopez-Yurda M, Zwaan CM, and Beishuizen A
- Abstract
Pediatric classical Hodgkin's lymphoma (cHL) is characterized by Hodgkin Reed-Sternberg cells located in an inflammatory microenvironment. Blood biomarkers result from active crosstalk between these cells. One promising biomarker in adult cHL patients is "thymus-and-activation-regulated chemokine" (TARC). The objectives of this study were to define normal TARC values in non-cHL children and to investigate and correlate pretherapy TARC as diagnostic marker in pediatric cHL. In this multicenter prospective study, plasma and serum samples were collected of newly diagnosed cHL patients before start of treatment (n = 49), and from randomly selected non-cHL patients (n = 81). TARC levels were measured by enzyme-linked immunosorbent assay. The non-cHL patients had a median plasma TARC value of 71 pg/mL (range: 18-762), compared to 14 619 pg/mL (range: 380-73 174) in cHL patients ( P < .001). TARC values had a high discriminatory power (AUC = .999; 95% confidence interval, .998-1). A TARC cutoff level of 942 pg/mL maximized the sum of sensitivity (97.9%) and specificity (100%). TARC plasma levels were associated with age, treatment level, bulky disease, B-symptoms, and erythrocyte sedimentation rate. TARC was found to be a highly specific and sensitive diagnostic marker for pediatric cHL. This noninvasive marker could be of great value as screening test in the work-up for pediatric patients with lymphadenopathy., Competing Interests: The authors declare no conflict of interest., (© 2020 The Authors. eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.)
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- 2020
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47. Secondary analyses of the randomized phase III Stop&Go study: efficacy of second-line intermittent versus continuous chemotherapy in HER2-negative advanced breast cancer.
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Claessens AKM, Erdkamp FLG, Lopez-Yurda M, Bouma JM, Rademaker-Lakhai JM, Honkoop AH, de Graaf H, Tjan-Heijnen VCG, and Bos MEMM
- Subjects
- Adult, Aged, Antineoplastic Combined Chemotherapy Protocols adverse effects, Bevacizumab administration & dosage, Bevacizumab adverse effects, Breast Neoplasms mortality, Capecitabine administration & dosage, Capecitabine adverse effects, Doxorubicin administration & dosage, Doxorubicin adverse effects, Doxorubicin analogs & derivatives, Drug Administration Schedule, Female, Humans, Kaplan-Meier Estimate, Middle Aged, Paclitaxel administration & dosage, Paclitaxel adverse effects, Polyethylene Glycols administration & dosage, Polyethylene Glycols adverse effects, Progression-Free Survival, Receptor, ErbB-2, Time Factors, Triple Negative Breast Neoplasms drug therapy, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Breast Neoplasms drug therapy
- Abstract
Background: Previously, we showed that reintroduction of the same (first-line) chemotherapy at progression could only partially make up for the loss in efficacy as compared to continuously delivered first-line chemotherapy. Here, we report the probability of starting second-line study chemotherapy in the Stop&Go trial, and the progression-free survival (PFS) and overall survival (OS) of patients who received both the first- and second-line treatment in an intermittent versus continuous schedule. Methods: First-line chemotherapy comprised paclitaxel plus bevacizumab, second-line capecitabine or non-pegylated liposomal doxorubicin, given per treatment line as two times four cycles (intermittent) or as eight consecutive cycles (continuous). Results: Of the 420 patients who started first-line treatment within the Stop&Go trial (210:210), a total of 270 patients continued on second-line study treatment (64% of all), which consisted of capecitabine in 201 patients and of non-pegylated liposomal doxorubicin in 69 patients, evenly distributed between the treatment arms. Median PFS was 3.7 versus 5.0 months (HR 1.07; 95% CI: 0.82-1.38) and median OS 10.9 versus 12.4 months (HR 1.27; 95% CI: 0.98-1.66) for intermittent versus continuous second-line chemotherapy. Second-line PFS was positively influenced by prior hormonal therapy for metastatic disease and longer first-line PFS duration, while triple-negative tumor status had a negative influence. Patients with a shorter time to progression (TTP) in first-line (≤10 months) had a higher probability of starting second-line treatment if they received intermittent compared to continuous chemotherapy (OR 1.97; 95% CI: 1.02-3.80). Conclusion: We recommend continuous scheduling of both the first- and second-line chemotherapy for advanced breast cancer.
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- 2020
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48. Neoadjuvant immunotherapy leads to pathological responses in MMR-proficient and MMR-deficient early-stage colon cancers.
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Chalabi M, Fanchi LF, Dijkstra KK, Van den Berg JG, Aalbers AG, Sikorska K, Lopez-Yurda M, Grootscholten C, Beets GL, Snaebjornsson P, Maas M, Mertz M, Veninga V, Bounova G, Broeks A, Beets-Tan RG, de Wijkerslooth TR, van Lent AU, Marsman HA, Nuijten E, Kok NF, Kuiper M, Verbeek WH, Kok M, Van Leerdam ME, Schumacher TN, Voest EE, and Haanen JB
- Subjects
- Adenocarcinoma genetics, Adenocarcinoma pathology, Adult, Aged, Aged, 80 and over, Antineoplastic Agents, Immunological administration & dosage, Cells, Cultured, Colonic Neoplasms genetics, Colonic Neoplasms pathology, Combined Modality Therapy, DNA Mismatch Repair drug effects, Digestive System Surgical Procedures, Drug Administration Schedule, Feasibility Studies, Female, Humans, Immunotherapy methods, Ipilimumab administration & dosage, Ipilimumab adverse effects, Male, Middle Aged, Neoadjuvant Therapy adverse effects, Neoadjuvant Therapy methods, Neoplasm Staging, Nivolumab administration & dosage, Nivolumab adverse effects, Treatment Failure, Adenocarcinoma therapy, Antineoplastic Agents, Immunological adverse effects, Colonic Neoplasms therapy, DNA Mismatch Repair genetics, Immunotherapy adverse effects
- Abstract
PD-1 plus CTLA-4 blockade is highly effective in advanced-stage, mismatch repair (MMR)-deficient (dMMR) colorectal cancers, yet not in MMR-proficient (pMMR) tumors. We postulated a higher efficacy of neoadjuvant immunotherapy in early-stage colon cancers. In the exploratory NICHE study (ClinicalTrials.gov: NCT03026140), patients with dMMR or pMMR tumors received a single dose of ipilimumab and two doses of nivolumab before surgery, the pMMR group with or without celecoxib. The primary objective was safety and feasibility; 40 patients with 21 dMMR and 20 pMMR tumors were treated, and 3 patients received nivolumab monotherapy in the safety run-in. Treatment was well tolerated and all patients underwent radical resections without delays, meeting the primary endpoint. Of the patients who received ipilimumab + nivolumab (20 dMMR and 15 pMMR tumors), 35 were evaluable for efficacy and translational endpoints. Pathological response was observed in 20/20 (100%; 95% exact confidence interval (CI): 86-100%) dMMR tumors, with 19 major pathological responses (MPRs, ≤10% residual viable tumor) and 12 pathological complete responses. In pMMR tumors, 4/15 (27%; 95% exact CI: 8-55%) showed pathological responses, with 3 MPRs and 1 partial response. CD8
+ PD-1+ T cell infiltration was predictive of response in pMMR tumors. These data indicate that neoadjuvant immunotherapy may have the potential to become the standard of care for a defined group of colon cancer patients when validated in larger studies with at least 3 years of disease-free survival data.- Published
- 2020
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49. Intermittent versus continuous first-line treatment for HER2-negative metastatic breast cancer: the Stop & Go study of the Dutch Breast Cancer Research Group (BOOG).
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Claessens AKM, Bos MEMM, Lopez-Yurda M, Bouma JM, Rademaker-Lakhai JM, Honkoop AH, de Graaf H, van Druten E, van Warmerdam LJC, van der Sangen MJC, Tjan-Heijnen VCG, and Erdkamp FLG
- Subjects
- Adult, Aged, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Breast Neoplasms genetics, Breast Neoplasms pathology, Capecitabine, Female, Humans, Longitudinal Studies, Middle Aged, Neoplasm Metastasis, Neoplasm Staging, Netherlands epidemiology, Progression-Free Survival, Bevacizumab administration & dosage, Breast Neoplasms drug therapy, Paclitaxel administration & dosage, Receptor, ErbB-2 genetics
- Abstract
Purpose: We determined if intermittent first-line treatment with paclitaxel plus bevacizumab was not inferior to continuous treatment in patients with HER2-negative, advanced breast cancer., Methods: Patients were randomized to 2 × 4 cycles or continuous 8 cycles of paclitaxel plus bevacizumab, followed by bevacizumab maintenance treatment until disease progression or unacceptable toxicity. The primary endpoint was overall progression-free survival (PFS). A proportional-hazards regression model was used to estimate the HR. The upper limit of the two-sided 95% CI for the HR was compared with the non-inferiority margin of 1.34., Results: A total of 420 patients were included with well-balanced characteristics. In the intention-to-treat analysis, median overall PFS was 7.4 months (95% CI 6.4-10.0) for intermittent and 9.7 months (95% CI 8.9-10.3) for continuous treatment, with a stratified HR of 1.17 (95% CI 0.88-1.57). Median OS was 17.5 months (95% CI 15.4-21.7) versus 20.9 months (95% CI 17.8-24.0) for intermittent versus continuous treatment, with a HR of 1.38 (95% CI 1.00-1.91). Safety results and actually delivered treatments revealed longer durations of treatment in the continuous arm, without significant unexpected findings., Conclusion: Intermittent first-line treatment cannot be recommended in patients with HER2-negative advanced breast cancer., Clinical Trial Registration: EudraCT 2010-021519-18; BOOG 2010-02.
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- 2018
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50. Relapse of Wilms' tumour and detection methods: a retrospective analysis of the 2001 Renal Tumour Study Group-International Society of Paediatric Oncology Wilms' tumour protocol database.
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Brok J, Lopez-Yurda M, Tinteren HV, Treger TD, Furtwängler R, Graf N, Bergeron C, van den Heuvel-Eibrink MM, Pritchard-Jones K, Olsen ØE, de Camargo B, Verschuur A, and Spreafico F
- Subjects
- Adolescent, Child, Child, Preschool, Databases, Factual, Female, Humans, Infant, Male, Retrospective Studies, Kidney Neoplasms diagnosis, Kidney Neoplasms pathology, Neoplasm Metastasis diagnosis, Wilms Tumor diagnosis, Wilms Tumor secondary
- Abstract
Background: Wilms' tumour is the most common renal cancer in childhood and about 15% of patients will relapse. There is scarce evidence about optimal surveillance schedules and methods for detection of tumour relapse after therapy., Methods: The Renal Tumour Study Group-International Society of Paediatric Oncology (RTSG-SIOP) Wilms' tumour 2001 trial and study is an international, multicentre, prospective registration, biological study with an embedded randomised clinical trial for children with renal tumours aged between 6 months and 18 years. The study covers 243 different centres in 27 countries grouped into five consortia. The current protocol of SIOP surveillance for Wilms' tumour recommends that abdominal ultrasound and chest x-ray should be done every 3 months for the first 2 years after treatment and be repeated every 4-6 months in the third and fourth year and annually in the fifth year. In this retrospective cohort study of the protocol database, we analysed data from participating institutions on timing, anatomical site, and mode of detection of all first relapses of Wilms' tumour. The primary outcomes were how relapse of Wilms' tumour was detected (ie, at or between scheduled surveillance and with or without clinical symptoms, scan modality, and physical examination) and to estimate the number of scans needed to capture one subclinical relapse. The RTSG-SIOP study is registered with Eudra-CT, number 2007-004591-39., Findings: Between June 26, 2001, and May 8, 2015, of 4271 eligible patients in the 2001 RTSG-SIOP Wilms' tumour database, 538 (13%) relapsed. Median follow-up from surgery was 62 months (IQR 32-93). The method used to detect relapse was registered for 410 (76%) of 538 relapses. Planned surveillance imaging captured 289 (70%) of these 410 relapses. The primary imaging modality used to detect relapse was reported for 251 patients, among which relapse was identified by abdominal ultrasound (80 [32%] patients), chest x-ray (78 [31%]), CT scan of the chest (64 [25%]) or abdomen (20 [8%]), and abdominal MRI (nine [4%]). 279 (68%) of 410 relapses were not detectable by physical examination and 261 (64%) patients did not have clinical symptoms at relapse. The estimated number of scans needed to detect one subclinical relapse during the first 2 years after nephrectomy was 112 (95% CI 106-119) and, for 2-5 years after nephrectomy, 500 (416-588)., Interpretation: Planned surveillance imaging captured more than two-thirds of predominantly asymptomatic relapses of Wilms' tumours, with most detected by abdominal ultrasound, chest x-ray, or chest CT scan. Beyond 2 years post-nephrectomy, a substantial number of surveillance scans are needed to capture one relapse, which places a burden on families and health-care systems., Funding: Great Ormond Street Hospital Children's Charity, the European Expert Paediatric Oncology Reference Network for Diagnostics and Treatment, The Danish Childhood Cancer Foundation, Cancer Research UK, the UK National Cancer Research Network and Children's Cancer and Leukaemia Group, Société Française des Cancers de l'Enfant and Association Leon Berard Enfant Cancéreux and Enfant et Santé, Gesellschaft für Pädiatrische Onkologie und Hämatologie and Deutsche Krebshilfe, Grupo Cooperativo Brasileiro para o Tratamento do Tumor de Wilms and Sociedade Brasileira de Oncologia Pediátrica, the Spanish Society of Pediatric Haematology and Oncology and the Spanish Association Against Cancer, and SIOP-Netherlands., (Copyright © 2018 Elsevier Ltd. All rights reserved.)
- Published
- 2018
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