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2. Continuation of fluoropyrimidine treatment with S-1 after cardiotoxicity on capecitabine- or 5-fluorouracil-based therapy in patients with solid tumours: a multicentre retrospective observational cohort study

Author

Osterlund, P., Kinos, S., Pfeiffer, P., Salminen, T., Kwakman, J.J.M., Frödin, J.-E., Shah, C.H., Sorbye, H., Ristamäki, R., Halonen, P., Soveri, L.M., Heervä, E., Ålgars, A., Bärlund, M., Hagman, H., McDermott, R., O’Reilly, M., Röckert, R., Liposits, G., Kallio, R., Flygare, P., Teske, A.J., van Werkhoven, E., Punt, C.J.A., and Glimelius, B.

Published
2022
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4. An Antiestrogenic Activity Score for tamoxifen and its metabolites is associated with breast cancer outcome

Author

de Vries Schultink, AHM, Alexi, X, van Werkhoven, E, Madlensky, L, Natarajan, L, Flatt, SW, Zwart, W, Linn, SC, Parker, BA, Wu, AHB, Pierce, JP, Huitema, ADR, and Beijnen, JH

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Cancer, Breast Cancer, Antineoplastic Agents, Hormonal, Breast Neoplasms, Dose-Response Relationship, Drug, Estrogen Antagonists, Female, Humans, Inhibitory Concentration 50, Kaplan-Meier Estimate, Prognosis, Proportional Hazards Models, Tamoxifen, Treatment Outcome, Metabolites, Algorithm, Recurrence-free survival, Clinical Sciences, Oncology & Carcinogenesis, Clinical sciences, Oncology and carcinogenesis
Abstract

PurposeEndoxifen concentrations have been associated with breast cancer recurrence in tamoxifen-treated patients. However, tamoxifen itself and other metabolites also show antiestrogenic anti-tumor activity. Therefore, the aim of this study was to develop a comprehensive Antiestrogenic Activity Score (AAS), which accounts for concentration and antiestrogenic activity of tamoxifen and three metabolites. An association between the AAS and recurrence-free survival was investigated and compared to a previously published threshold for endoxifen concentrations of 5.97 ng/mL.Patients and methodsThe antiestrogenic activities of tamoxifen, (Z)-endoxifen, (Z)-4-hydroxytamoxifen, and N-desmethyltamoxifen were determined in a cell proliferation assay. The AAS was determined by calculating the sum of each metabolite concentration multiplied by an IC50 ratio, relative to tamoxifen. The AAS was calculated for 1370 patients with estrogen receptor alpha (ERα)-positive breast cancer. An association between AAS and recurrence was investigated using Cox regression and compared with the 5.97 ng/mL endoxifen threshold using concordance indices.ResultsAn AAS threshold of 1798 was associated with recurrence-free survival, hazard ratio (HR) 0.67 (95% confidence interval (CI) 0.47-0.96), bias corrected after bootstrap HR 0.69 (95% CI 0.48-0.99). The concordance indices for AAS and endoxifen did not significantly differ; however, using the AAS threshold instead of endoxifen led to different dose recommendations for 5.2% of the patients.ConclusionsEndoxifen concentrations can serve as a proxy for the antiestrogenic effect of tamoxifen and metabolites. However, for the aggregate effect of tamoxifen and three metabolites, defined by an integrative algorithm, a trend towards improving treatment is seen and moreover, is significantly associated with breast cancer recurrence.

Published
2017

9. The Drug Rediscovery protocol facilitates the expanded use of existing anticancer drugs

Author

van der Velden, D.L., Hoes, L.R., van der Wijngaart, H., van Berge Henegouwen, J.M., van Werkhoven, E., Roepman, P., and Schilsky, R.L.

Subjects
Antineoplastic agents -- Usage, Medical protocols -- Evaluation, Antimitotic agents -- Usage, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

The large-scale genetic profiling of tumours can identify potentially actionable molecular variants for which approved anticancer drugs are available.sup.1-3. However, when patients with such variants are treated with drugs outside of their approved label, successes and failures of targeted therapy are not systematically collected or shared. We therefore initiated the Drug Rediscovery protocol, an adaptive, precision-oncology trial that aims to identify signals of activity in cohorts of patients, with defined tumour types and molecular variants, who are being treated with anticancer drugs outside of their approved label. To be eligible for the trial, patients have to have exhausted or declined standard therapies, and have malignancies with potentially actionable variants for which no approved anticancer drugs are available. Here we show an overall rate of clinical benefit--defined as complete or partial response, or as stable disease beyond 16 weeks--of 34% in 215 treated patients, comprising 136 patients who received targeted therapies and 79 patients who received immunotherapy. The overall median duration of clinical benefit was 9 months (95% confidence interval of 8-11 months), including 26 patients who were experiencing ongoing clinical benefit at data cut-off. The potential of the Drug Rediscovery protocol is illustrated by the identification of a successful cohort of patients with microsatellite instable tumours who received nivolumab (clinical benefit rate of 63%), and a cohort of patients with colorectal cancer with relatively low mutational load who experienced only limited clinical benefit from immunotherapy. The Drug Rediscovery protocol facilitates the defined use of approved drugs beyond their labels in rare subgroups of cancer, identifies early signals of activity in these subgroups, accelerates the clinical translation of new insights into the use of anticancer drugs outside of their approved label, and creates a publicly available repository of knowledge for future decision-making. Clinical benefit was observed in 34% of a cohort of 215 patients with cancer who received treatment with anticancer drugs outside of their approved label, in the Drug Rediscovery protocol trial., Author(s): D. L. van der Velden [sup.1] [sup.2] , L. R. Hoes [sup.1] [sup.2] [sup.3] , H. van der Wijngaart [sup.2] [sup.3] [sup.4] , J. M. van Berge Henegouwen [sup.2] [...]

Published
2019
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14. High-dose alkylating chemotherapy in BRCA-altered triple-negative breast cancer:the randomized phase III NeoTN trial

Author

Vliek, S, Hilbers, FS, van Werkhoven, E, Mandjes, I, Kessels, R, Kleiterp, S, Lips, EH, Mulder, L, Kayembe, MT, Loo, CE, Russell, NS, Peeters, MJTFDV, Holtkamp, MJ, Schot, M, Baars, JW, Honkoop, AH, Vulink, AJE, Imholz, ALT, Vrijaldenhoven, S, van den Berkmortel, FWPJ, Terwogt, JMM, Schrama, JG, Kuijer, P, Kroep, JR, van der Padt-pruijsten, A, Wesseling, J, Sonke, GS, Gilhuijs, KGA, Jager, A, Nederlof, P, Linn, SC, Vliek, S, Hilbers, FS, van Werkhoven, E, Mandjes, I, Kessels, R, Kleiterp, S, Lips, EH, Mulder, L, Kayembe, MT, Loo, CE, Russell, NS, Peeters, MJTFDV, Holtkamp, MJ, Schot, M, Baars, JW, Honkoop, AH, Vulink, AJE, Imholz, ALT, Vrijaldenhoven, S, van den Berkmortel, FWPJ, Terwogt, JMM, Schrama, JG, Kuijer, P, Kroep, JR, van der Padt-pruijsten, A, Wesseling, J, Sonke, GS, Gilhuijs, KGA, Jager, A, Nederlof, P, and Linn, SC

Abstract

Exploratory analyses of high-dose alkylating chemotherapy trials have suggested that BRCA1 or BRCA2-pathway altered (BRCA-altered) breast cancer might be particularly sensitive to this type of treatment. In this study, patients with BRCA-altered tumors who had received three initial courses of dose-dense doxorubicin and cyclophosphamide (ddAC), were randomized between a fourth ddAC course followed by high-dose carboplatin-thiotepa-cyclophosphamide or conventional chemotherapy (initially ddAC only or ddAC-capecitabine/decetaxel [CD] depending on MRI response, after amendment ddAC-carboplatin/paclitaxel [CP] for everyone). The primary endpoint was the neoadjuvant response index (NRI). Secondary endpoints included recurrence-free survival (RFS) and overall survival (OS). In total, 122 patients were randomized. No difference in NRI-score distribution (p = 0.41) was found. A statistically non-significant RFS difference was found (HR 0.54; 95% CI 0.23–1.25; p = 0.15). Exploratory RFS analyses showed benefit in stage III (n = 35; HR 0.16; 95% CI 0.03–0.75), but not stage II (n = 86; HR 1.00; 95% CI 0.30–3.30) patients. For stage III, 4-year RFS was 46% (95% CI 24–87%), 71% (95% CI 48–100%) and 88% (95% CI 74–100%), for ddAC/ddAC-CD, ddAC-CP and high-dose chemotherapy, respectively. No significant differences were found between high-dose and conventional chemotherapy in stage II-III, triple-negative, BRCA-altered breast cancer patients. Further research is needed to establish if there are patients with stage III, triple negative BRCA-altered breast cancer for whom outcomes can be improved with high-dose alkylating chemotherapy or whether the current standard neoadjuvant therapy including carboplatin and an immune checkpoint inhibitor is sufficient. Trial Registration: NCT01057069.

Published
2023

17. Trastuzumab and pertuzumab combination therapy for advanced pre-treated HER2 exon 20-mutated non-small cell lung cancer

Author

van Berge Henegouwen, J.M., primary, Jebbink, M., additional, Hoes, L.R., additional, van der Wijngaart, H., additional, Zeverijn, L.J., additional, van der Velden, D.L., additional, Roepman, P., additional, de Leng, W.W.J., additional, Jansen, A.M.L., additional, van Werkhoven, E., additional, van der Noort, V., additional, van der Wekken, A.J., additional, de Langen, A.J., additional, Voest, E.E., additional, Verheul, H.M.W., additional, Smit, E.F., additional, and Gelderblom, H., additional

Published
2022
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21. P1254: RESPONSE TO DA-EPOCH-R IN PATIENTS WITH HIGH GRADE B CELL LYMPHOMA IS ASSOCIATED WITH A REDUCTION OF PD1 POSITIVE EXHAUSTED CD8 T CELLS

Author

de Jonge, V., primary, Duetz, C., additional, Bruins, W., additional, van Werkhoven, E., additional, Nijland, M., additional, de Heer, K., additional, van der Poel, M., additional, Sandberg, Y., additional, Klerk, C., additional, de Jong, D., additional, Zijlstra, J., additional, Kersten, M. J., additional, Mutis, T., additional, and Chamuleau, M., additional

Published
2022
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24. Continuation of fluoropyrimidine treatment with S-1 after cardiotoxicity on capecitabine- or 5-fluorouracil-based therapy in patients with solid tumours:a multicentre retrospective observational cohort study

Author

Osterlund, P. (P.), Kinos, S. (S.), Pfeiffer, P. (P.), Salminen, T. (T.), Kwakman, J. J. (J. J. M.), Frödin, J.-E. (J.-E.), Shah, C. H. (C. H.), Sorbye, H. (H.), Ristamäki, R. (R.), Halonen, P. (P.), Soveri, L. .. (L .M.), Heervä, E. (E.), Ålgars, A. (A.), Bärlund, M. (M.), Hagman, H. (H.), McDermott, R. (R.), O’Reilly, M. (M.), Röckert, R. (R.), Liposits, G. (G.), Kallio, R. (R.), Flygare, P. (P.), Teske, A. J. (A. J.), van Werkhoven, E. (E.), Punt, C. J. (C. J A.), B. Glimelius, B. G. (B. Glimelius), Osterlund, P. (P.), Kinos, S. (S.), Pfeiffer, P. (P.), Salminen, T. (T.), Kwakman, J. J. (J. J. M.), Frödin, J.-E. (J.-E.), Shah, C. H. (C. H.), Sorbye, H. (H.), Ristamäki, R. (R.), Halonen, P. (P.), Soveri, L. .. (L .M.), Heervä, E. (E.), Ålgars, A. (A.), Bärlund, M. (M.), Hagman, H. (H.), McDermott, R. (R.), O’Reilly, M. (M.), Röckert, R. (R.), Liposits, G. (G.), Kallio, R. (R.), Flygare, P. (P.), Teske, A. J. (A. J.), van Werkhoven, E. (E.), Punt, C. J. (C. J A.), and B. Glimelius, B. G. (B. Glimelius)

Abstract

Background: Capecitabine- or 5-fluorouracil (5-FU)-based chemotherapy is widely used in many solid tumours, but is associated with cardiotoxicity. S-1 is a fluoropyrimidine with low rates of cardiotoxicity, but evidence regarding the safety of switching to S-1 after 5-FU- or capecitabine-associated cardiotoxicity is scarce. Patients and methods: This retrospective study (NCT04260269) was conducted at 13 centres in 6 countries. The primary endpoint was recurrence of cardiotoxicity after switch to S-1-based treatment due to 5-FU- or capecitabine-related cardiotoxicity: clinically meaningful if the upper boundary of the 95% confidence interval (CI; by competing risk) is not including 15%. Secondary endpoints included cardiac risk factors, diagnostic work-up, treatments, outcomes, and timelines of cardiotoxicity. Results: Per protocol, 200 patients, treated between 2011 and 2020 [median age 66 years (range 19-86); 118 (59%) males], were included. Treatment intent was curative in 145 (73%). Initial cardiotoxicity was due to capecitabine (n = 170), continuous infusion 5-FU (n = 22), or bolus 5-FU (n = 8), which was administered in combination with other chemotherapy, targeted agents, or radiotherapy in 133 patients. Previous cardiovascular comorbidities were present in 99 (50%) patients. Cardiotoxic events (n = 228/200) included chest pain (n = 125), coronary syndrome/infarction (n = 69), arrhythmia (n = 22), heart failure/cardiomyopathy (n = 7), cardiac arrest (n = 4), and malignant hypertension (n = 1). Cardiotoxicity was severe or life-threatening in 112 (56%) patients and led to permanent capecitabine/5-FU discontinuation in 192 (96%). After switch to S-1, recurrent cardiotoxicity was observed in eight (4%) patients (95% CI 2.02-7.89, primary endpoint met). Events were limited to grade 1-2 and occurred at a median of 16 days (interquartile range 7-67) from therapy switch. Baseline ischemic heart disease was a risk factor for recurrent cardiotoxicity (odds rat

Published
2022

25. Sex differences in patients with gastrointestinal stromal tumours:do they exist and does it affect survival?

Author

IJzerman, N S, van Werkhoven, E, Mohammadi, M, Hollander, D den, Bleckman, R F, Reyners, A K L, Desar, I M E, Gelderblom, H, Grünhagen, D J, Mathijssen, R H J, Steeghs, N, van der Graaf, W T A, IJzerman, N S, van Werkhoven, E, Mohammadi, M, Hollander, D den, Bleckman, R F, Reyners, A K L, Desar, I M E, Gelderblom, H, Grünhagen, D J, Mathijssen, R H J, Steeghs, N, and van der Graaf, W T A

Abstract

BACKGROUND: Sex differences in cancer have gained attention in recent years. The role of sex as a prognostic factor in gastrointestinal stromal tumours (GIST) has not been well established. The aim of this research was to elucidate potential sex differences in GIST patients and the influence of sex on disease-specific survival (DSS).METHODS: A review of the literature was carried out to obtain an overview of all literature with sex as a covariate on GIST survival analyses. Furthermore, in the Dutch GIST Registry, GIST characteristics between males and females were compared and the influence of sex on DSS was analysed.RESULTS: A total of 118 articles from the review of the literature met our selection criteria; 58% of the articles found no sex difference in survival and 42% did find a sex difference. All differences favoured female patients, although there was substantial overlap of individual patients in the various reported groups. The Dutch GIST Registry cohort consisted of 1425 patients (46% female). Compared with female patients, male patients had larger tumours (mean 9.0 cm versus 7.9 cm) and higher mitotic rates (34.4% versus 28.0% >5 mitoses/5 mm2). GIST in males was more often metastasized at diagnosis (21.3% versus 13.7%) and incurable (38.5% versus 31.0%). Male patients less often received surgery of the primary tumour (71.7% versus 78.9%), but did experience more tumour ruptures (18.2% versus 13.3%). Male patients had a worse DSS than females. This was not statistically significant when corrected for differences in GIST characteristics.CONCLUSIONS: In case of sex differences in GIST in the literature, male patients have a worse outcome. In our Dutch GIST cohort a similar finding was made, but sex was shown not to be an independent factor. Male patients more often had aggressive GISTs, with larger tumours, higher mitotic rates, more tumour ruptures, and metastases, which could explain the sex differences in DSS.

Published
2022

26. Continuation of fluoropyrimidine treatment with S-1 after cardiotoxicity on capecitabine- or 5-fluorouracil-based therapy in patients with solid tumours: a multicentre retrospective observational cohort study

Author

MS Medische Oncologie, Team Medisch, Circulatory Health, Epi Kanker Team B, Researchgr. Nucleaire Geneeskunde, Cancer, Osterlund, P, Kinos, S, Pfeiffer, P, Salminen, T, Kwakman, J J M, Frödin, J-E, Shah, C H, Sorbye, H, Ristamäki, R, Halonen, P, Soveri, L M, Heervä, E, Ålgars, A, Bärlund, M, Hagman, H, McDermott, R, O'Reilly, M, Röckert, R, Liposits, G, Kallio, R, Flygare, P, Teske, A J, van Werkhoven, E, Punt, C J A, Glimelius, B, MS Medische Oncologie, Team Medisch, Circulatory Health, Epi Kanker Team B, Researchgr. Nucleaire Geneeskunde, Cancer, Osterlund, P, Kinos, S, Pfeiffer, P, Salminen, T, Kwakman, J J M, Frödin, J-E, Shah, C H, Sorbye, H, Ristamäki, R, Halonen, P, Soveri, L M, Heervä, E, Ålgars, A, Bärlund, M, Hagman, H, McDermott, R, O'Reilly, M, Röckert, R, Liposits, G, Kallio, R, Flygare, P, Teske, A J, van Werkhoven, E, Punt, C J A, and Glimelius, B

Published
2022

27. Trastuzumab and pertuzumab combination therapy for advanced pre-treated HER2 exon 20-mutated non-small cell lung cancer

Author

Divisie Beeld & Oncologie, Pathologie Pathologen staf, Cancer, Pathologie Moleculair, Externen Med. Onco, van Berge Henegouwen, J M, Jebbink, M, Hoes, L R, van der Wijngaart, H, Zeverijn, L J, van der Velden, D L, Roepman, P, de Leng, W W J, Jansen, A M L, van Werkhoven, E, van der Noort, V, van der Wekken, A J, de Langen, A J, Voest, E E, Verheul, H M W, Smit, E F, Gelderblom, H, Divisie Beeld & Oncologie, Pathologie Pathologen staf, Cancer, Pathologie Moleculair, Externen Med. Onco, van Berge Henegouwen, J M, Jebbink, M, Hoes, L R, van der Wijngaart, H, Zeverijn, L J, van der Velden, D L, Roepman, P, de Leng, W W J, Jansen, A M L, van Werkhoven, E, van der Noort, V, van der Wekken, A J, de Langen, A J, Voest, E E, Verheul, H M W, Smit, E F, and Gelderblom, H

Published
2022

30. 1261P Trastuzumab/pertuzumab combination therapy in advanced pre-treated HER2-mutated non-small cell lung cancer: Results of a DRUP trial cohort

Author

van Berge Henegouwen, J., primary, Jebbink, M., additional, Hoes, L., additional, van der Wijngaart, H., additional, Zeverijn, L., additional, van der Velden, D., additional, Roepman, P., additional, de Leng, W., additional, Jansen, A., additional, van Werkhoven, E., additional, van der Noort, V., additional, van der Wekken, A.J., additional, Burgers, S., additional, Smit, E.F., additional, Verheul, H., additional, Voest, E., additional, and Gelderblom, H., additional

Published
2021
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33. OC-0103 Comparative study of brachytherapy vs. radical cystectomy for cT1-2 muscle-invasive bladder cancer

Author

Pieters, B., primary, Voskuilen, C., additional, Bosschieter, J., additional, van Werkhoven, E., additional, Hendricksen, K., additional, Vis, A., additional, Pos, F., additional, Burger, M., additional, van der Poel, H., additional, Moonen, L., additional, Horenblas, S., additional, Bex, A., additional, Nieuwenhuijzen, J., additional, and van Rhijn, B., additional

Published
2021
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34. Prospective experimental treatment of colorectal cancer patients based on organoid drug responses

Author

MS Medische Oncologie, CMM, CMM Groep Cuppen, Cancer, Ooft, S. N., Weeber, F., Schipper, L., Dijkstra, K. K., McLean, C. M., Kaing, S., van de Haar, J., Prevoo, W., van Werkhoven, E., Snaebjornsson, P., Hoes, L. R., Chalabi, M., van der Velden, D., van Leerdam, M., Boot, H., Grootscholten, C., Huitema, A. D.R., Bloemendal, H. J., Cuppen, E., Voest, E. E., MS Medische Oncologie, CMM, CMM Groep Cuppen, Cancer, Ooft, S. N., Weeber, F., Schipper, L., Dijkstra, K. K., McLean, C. M., Kaing, S., van de Haar, J., Prevoo, W., van Werkhoven, E., Snaebjornsson, P., Hoes, L. R., Chalabi, M., van der Velden, D., van Leerdam, M., Boot, H., Grootscholten, C., Huitema, A. D.R., Bloemendal, H. J., Cuppen, E., and Voest, E. E.

Published
2021

37. High versus low dose Stereotactic Body Radiation Therapy for hepatic metastases

Author

Kok, E.N.D, Jansen, EPM, Heeres, BC, Kok, NFM, Janssen, T, van Werkhoven, E, Sanders, FRK, Ruers, TJM, Nowee, ME, Kuhlmann, KFD, Kok, E.N.D, Jansen, EPM, Heeres, BC, Kok, NFM, Janssen, T, van Werkhoven, E, Sanders, FRK, Ruers, TJM, Nowee, ME, and Kuhlmann, KFD

Abstract

Introduction: Stereotactic Body Radiation Therapy (SBRT) is a treatment option for patients with liver metastases. This study evaluated the impact of high versus low dose image-guided SBRT of hepatic metastases. Methods and materials: This is a single-center retrospective study of patients with liver metastases treated with SBRT. For analyses, patients were divided into two groups: 100 Gy and >100 Gy near-minimum Biological Effective Doses (BED98%). The main outcomes were local control (LC), toxicity and overall survival (OS). Cox regression analyses were performed to determine prognostic variables on LC and OS Results: Ninety patients with 97 liver metastases (77% colorectal) were included. Median follow-up was 28.6 months. The two-year LC rates in the 100 Gy and >100 Gy BED98% group were 60% (CI: 41–80%) and 90% (CI: 80–100%), respectively (p = 0.004). Grade 3 toxicity occurred in 7% vs 2% in the 100 Gy and >100 Gy group (p = 0.23). Two-year OS rates in the 100 Gy and >100 Gy group were 48% (CI: 32–65%) and 85% (CI: 73–97%), respectively (p = 0.007). In multivariable Cox regression analyses, group dose and tumor volume were significantly correlated with LC (HR: 3.61; p = 0.017 and HR: 1.01; p = 0.005) and OS (HR: 2.38; p = 0.005 and HR: 1.01; p = <0.0001). Conclusion: High dose SBRT provides significantly better local control and overall survival than low dose SBRT without increasing toxicity. When surgical resection is not feasible, high dose SBRT provides an effective and safe treatment for liver metastases.

Published
2020

39. Implementing a patient decision aid, a process evaluation of a large-scale pre- and post-implementation trial

Author

Raphael Daniela, D. B., primary, Russell, N. S., additional, van Werkhoven, E., additional, Immink, J. M., additional, Westhoff, D. P. G., additional, Stenfert Kroese, M. C., additional, Stam, M. R., additional, van Maurik, L. M., additional, van Gestel, C. M. J., additional, van der Weijden, T., additional, and Boersma, L. J., additional

Published
2020
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40. Toward omitting sentinel lymph node biopsy after neoadjuvant chemotherapy in patients with clinically node-negative breast cancer

Author

van der Noordaa, M E M, primary, van Duijnhoven, F H, additional, Cuijpers, F N E, additional, van Werkhoven, E, additional, Wiersma, T G, additional, Elkhuizen, P H M, additional, Winter-Warnars, G, additional, Dezentje, V, additional, Sonke, G S, additional, Groen, E J, additional, Stokkel, M, additional, and Vrancken Peeters, M T F D, additional

Published
2020
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41. Minimally Invasive Complete Response Assessment of the breast after neoadjuvant systemic therapy (MICRA trial): Interim analysis of a multicenter observational cohort study

Author

Van Loevezijn, A., primary, van der Noordaa, M.E.M., additional, van Werkhoven, E., additional, Loo, C.E., additional, Winter-Warnars, G.H.A.O., additional, Wiersma, T., additional, van de Vijver, K.K., additional, Groen, E.J., additional, Sonke, G.S., additional, Blanken, C.F.J.M., additional, Zonneveld, B., additional, Duijnhoven, F.H., additional, and Vrancken-Peeters, M.J., additional

Published
2020
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42. 594P The Drug Rediscovery Protocol (DRUP): Results of the first 500 treated patients

Author

Hoes, L.R., primary, van der Wijngaart, H., additional, van Berge Henegouwen, J.M., additional, Zeverijn, L.J., additional, van der Velden, D.L., additional, Roepman, P., additional, de Leng, W., additional, Jansen, A.M.L., additional, van Werkhoven, E., additional, Huitema, A., additional, Smit, E.F., additional, Van Herpen, C., additional, Labots, M., additional, Hoeben, A., additional, Morreau, H., additional, Lolkema, M.P., additional, Cuppen, E., additional, Gelderblom, H., additional, Verheul, H.M.W., additional, and Voest, E.E., additional

Published
2020
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44. Abstract GS5-06: Towards omitting breast surgery in patients with a pathologic complete response after neoadjuvant systemic treatment: interim analysis of the MICRA trial (Minimally Invasive Complete Response Assessment)

Author

Peeters, Marie-Jeanne T.F.D. Vrancken, primary, van Loevezijn, A, additional, van der Noordaa, M EM, additional, van Duijnhoven, F H, additional, Loo, C E, additional, van Werkhoven, E, additional, van de Vijver, K K, additional, Wiersma, T, additional, Winter-Warnars, H AO, additional, Sonke, G S, additional, Blanken, C., additional, and Zonnevels, B., additional

Published
2020
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45. Study protocols of three parallel phase 1 trials combining radical radiotherapy with the PARP inhibitor olaparib

Author

de Haan, R, van Werkhoven, E, van den Heuvel, M M, Peulen, H M U, Sonke, G S, Elkhuizen, P, van den Brekel, M W M, Tesselaar, M E T, Vens, C, Schellens, J H M, van Triest, B, Verheij, M, Afd Pharmacoepi & Clinical Pharmacology, Pharmacoepidemiology and Clinical Pharmacology, Arbeids- en Organisatie Psychologie (Psychologie, FMG), FMG, MKA AMC (OII, ACTA), Afd Pharmacoepi & Clinical Pharmacology, Pharmacoepidemiology and Clinical Pharmacology, CCA - Cancer Treatment and quality of life, Academic Medical Center, and Maxillofacial Surgery (AMC)

Subjects
0301 basic medicine, Oncology, Cancer Research, Lung Neoplasms, medicine.medical_treatment, Piperazines, Study Protocol, chemistry.chemical_compound, Olaparib, 0302 clinical medicine, TITE-CRM, Surgical oncology, Carcinoma, Non-Small-Cell Lung, Neoplasms, Doselimiting toxicity, Dose limiting toxicity, Common Terminology Criteria for Adverse Events, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Tolerability, Head and Neck Neoplasms, 030220 oncology & carcinogenesis, PARP inhibitor, Carcinoma, Squamous Cell, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9], medicine.medical_specialty, Maximum Tolerated Dose, Antineoplastic Agents, Breast Neoplasms, Phase 1, Poly(ADP-ribose) Polymerase Inhibitors, Rare cancers Radboud Institute for Molecular Life Sciences [Radboudumc 9], lcsh:RC254-282, 03 medical and health sciences, Breast cancer, SDG 3 - Good Health and Well-being, Internal medicine, Genetics, medicine, Humans, Radiotherapy, Dose escalation, business.industry, Radiosensitisation, medicine.disease, Head and neck squamous-cell carcinoma, Radiation therapy, 030104 developmental biology, chemistry, Phthalazines, Radiotherapy, Adjuvant, business
Abstract

BackgroundPoly (ADP-ribose) Polymerase (PARP) inhibitors are promising novel radiosensitisers. Pre-clinical models have demonstrated potent and tumour-specific radiosensitisation by PARP inhibitors. Olaparib is a PARP inhibitor with a favourable safety profile in comparison to clinically used radiosensitisers including cisplatin when used as single agent. However, data on safety, tolerability and efficacy of olaparib in combination with radiotherapy are limited.MethodsOlaparib is dose escalated in combination with radical (chemo-)radiotherapy regimens for non-small cell lung cancer (NSCLC), breast cancer and head and neck squamous cell carcinoma (HNSCC) in three parallel single institution phase 1 trials. All trials investigate a combination treatment of olaparib and radiotherapy, the NSCLC trial also investigates a triple combination of olaparib, radiotherapy and concurrent low dose cisplatin. The primary objective is to identify the maximum tolerated dose of olaparib in these combination treatments, defined as the dose closest to but not exceeding a 15% probability of dose limiting toxicity. Each trial has a separate dose limiting toxicity definition, taking into account incidence, duration and severity of expected toxicities without olaparib. Dose escalation is performed using a time-to-event continual reassessment method (TITE-CRM). TITE-CRM enables the incorporation of late onset toxicity until one year after treatment in the dose limiting toxicity definition while maintaining an acceptable trial duration. Olaparib treatment starts two days before radiotherapy and continues during weekends until two days after radiotherapy. Olaparib will also be given two weeks and one week before radiotherapy in the breast cancer trial and HNSCC trial respectively to allow for translational research. Toxicity is scored using common terminology criteria for adverse events (CTCAE) version 4.03. Blood samples, and tumour biopsies in the breast cancer trial, are collected for pharmacokinetic and pharmacodynamic analyses.DiscussionWe designed three parallel phase 1 trials to assess the safety and tolerability of the PARP inhibitor olaparib in combination with radical (chemo-)radiotherapy treatment regimens. PARP inhibitors have the potential to improve outcomes in patients treated with radical (chemo-)radiotherapy, by achieving higher locoregional control rates and/or less treatment associated toxicity.Trial registrationClinicalTrials.govIdentifiers: NCT01562210 (registered March 23, 2012), NCT02227082 (retrospectively registered August 27, 2014), NCT02229656 (registered September 1, 2014).

Published
2019

46. The Drug Rediscovery protocol facilitates the expanded use of existing anticancer drugs

Author

van der Velden, D L, Hoes, L R, van der Wijngaart, H, van Berge Henegouwen, J M, van Werkhoven, E, Roepman, P, Schilsky, R L, de Leng, W W J, Huitema, A D R, Nuijen, B, Nederlof, P M, van Herpen, C M L, de Groot, D J A, Devriese, L A, Hoeben, A, de Jonge, M J A, Chalabi, M, Smit, E F, de Langen, A J, Mehra, N, Labots, M, Kapiteijn, E, Sleijfer, S, Cuppen, E, Verheul, H M W, Gelderblom, H, Voest, E E, van der Velden, D L, Hoes, L R, van der Wijngaart, H, van Berge Henegouwen, J M, van Werkhoven, E, Roepman, P, Schilsky, R L, de Leng, W W J, Huitema, A D R, Nuijen, B, Nederlof, P M, van Herpen, C M L, de Groot, D J A, Devriese, L A, Hoeben, A, de Jonge, M J A, Chalabi, M, Smit, E F, de Langen, A J, Mehra, N, Labots, M, Kapiteijn, E, Sleijfer, S, Cuppen, E, Verheul, H M W, Gelderblom, H, and Voest, E E

Published
2019

47. Personalised reimbursement : a risk-sharing model for biomarker-driven treatment of rare subgroups of cancer patients

Author

van Waalwijk van Doorn-Khosrovani, S B, Pisters-van Roy, A, van Saase, L, van der Graaff, M, Gijzen, J, Sleijfer, S, Hoes, L R, van Berge Henegouwen, J M, van der Wijngaart, H, van der Velden, D L, van Werkhoven, E, Retel, V P, van Harten, W H, Huitema, A D R, Timmers, L, Gelderblom, H, Verheul, H M W, Voest, E E, van Waalwijk van Doorn-Khosrovani, S B, Pisters-van Roy, A, van Saase, L, van der Graaff, M, Gijzen, J, Sleijfer, S, Hoes, L R, van Berge Henegouwen, J M, van der Wijngaart, H, van der Velden, D L, van Werkhoven, E, Retel, V P, van Harten, W H, Huitema, A D R, Timmers, L, Gelderblom, H, Verheul, H M W, and Voest, E E

Published
2019

48. Study protocols of three parallel phase 1 trials combining radical radiotherapy with the PARP inhibitor olaparib

Author

Afd Pharmacoepi & Clinical Pharmacology, Pharmacoepidemiology and Clinical Pharmacology, de Haan, R, van Werkhoven, E, van den Heuvel, M M, Peulen, H M U, Sonke, G S, Elkhuizen, P, van den Brekel, M W M, Tesselaar, M E T, Vens, C, Schellens, J H M, van Triest, B, Verheij, M, Afd Pharmacoepi & Clinical Pharmacology, Pharmacoepidemiology and Clinical Pharmacology, de Haan, R, van Werkhoven, E, van den Heuvel, M M, Peulen, H M U, Sonke, G S, Elkhuizen, P, van den Brekel, M W M, Tesselaar, M E T, Vens, C, Schellens, J H M, van Triest, B, and Verheij, M

Published
2019

49. Personalised reimbursement: a risk-sharing model for biomarker-driven treatment of rare subgroups of cancer patients

Author

Cancer, Apotheek Onderzoek, van Waalwijk van Doorn-Khosrovani, S B, Pisters-van Roy, A, van Saase, L, van der Graaff, M, Gijzen, J, Sleijfer, S, Hoes, L R, van Berge Henegouwen, J M, van der Wijngaart, H, van der Velden, D L, van Werkhoven, E, Retel, V P, van Harten, W H, Huitema, A D R, Timmers, L, Gelderblom, H, Verheul, H M W, Voest, E E, Cancer, Apotheek Onderzoek, van Waalwijk van Doorn-Khosrovani, S B, Pisters-van Roy, A, van Saase, L, van der Graaff, M, Gijzen, J, Sleijfer, S, Hoes, L R, van Berge Henegouwen, J M, van der Wijngaart, H, van der Velden, D L, van Werkhoven, E, Retel, V P, van Harten, W H, Huitema, A D R, Timmers, L, Gelderblom, H, Verheul, H M W, and Voest, E E

Published
2019

50. The Drug Rediscovery protocol facilitates the expanded use of existing anticancer drugs

Author

Pathologie Pathologen staf, Cancer, Apotheek Onderzoek, MS Medische Oncologie, CMM Groep Cuppen, CMM, Externen Med. Onco, van der Velden, D L, Hoes, L R, van der Wijngaart, H, van Berge Henegouwen, J M, van Werkhoven, E, Roepman, P, Schilsky, R L, de Leng, W W J, Huitema, A D R, Nuijen, B, Nederlof, P M, van Herpen, C M L, de Groot, D J A, Devriese, L A, Hoeben, A, de Jonge, M J A, Chalabi, M, Smit, E F, de Langen, A J, Mehra, N, Labots, M, Kapiteijn, E, Sleijfer, S, Cuppen, E, Verheul, H M W, Gelderblom, H, Voest, E E, Pathologie Pathologen staf, Cancer, Apotheek Onderzoek, MS Medische Oncologie, CMM Groep Cuppen, CMM, Externen Med. Onco, van der Velden, D L, Hoes, L R, van der Wijngaart, H, van Berge Henegouwen, J M, van Werkhoven, E, Roepman, P, Schilsky, R L, de Leng, W W J, Huitema, A D R, Nuijen, B, Nederlof, P M, van Herpen, C M L, de Groot, D J A, Devriese, L A, Hoeben, A, de Jonge, M J A, Chalabi, M, Smit, E F, de Langen, A J, Mehra, N, Labots, M, Kapiteijn, E, Sleijfer, S, Cuppen, E, Verheul, H M W, Gelderblom, H, and Voest, E E

Published
2019

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