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1. Tumor-infiltrating lymphocytes and immune-related adverse events in advanced melanoma

Author

Medisch Oncologische Disciplines, Unit Opleiding Aios, Cancer, MS Medische Oncologie, Beeldverwerking ISI, Medische Beeldanalyse, Pathologie Groep Van Diest, CTI, Pathologie, Pathologie patiënten zorg, Pathologie Pathologen staf, Infection & Immunity, van Duin, I. A.J., Schuiveling, M., ter Maat, L. S., Veta, M., van Eijs, M. J.M., Verheijden, R. J., van den Berkmortel, F. W.P.J., Boers-Sonderen, M. J., Hospers, G. A.P., Labots, M., de Groot, J. W.B., Kapiteijn, E., Piersma, D., Vreugdenhil, G., Westgeest, H., Schrader, A. M.R., van Diest, P. J., Blokx, W. A.M., Suijkerbuijk, K. P.M., Medisch Oncologische Disciplines, Unit Opleiding Aios, Cancer, MS Medische Oncologie, Beeldverwerking ISI, Medische Beeldanalyse, Pathologie Groep Van Diest, CTI, Pathologie, Pathologie patiënten zorg, Pathologie Pathologen staf, Infection & Immunity, van Duin, I. A.J., Schuiveling, M., ter Maat, L. S., Veta, M., van Eijs, M. J.M., Verheijden, R. J., van den Berkmortel, F. W.P.J., Boers-Sonderen, M. J., Hospers, G. A.P., Labots, M., de Groot, J. W.B., Kapiteijn, E., Piersma, D., Vreugdenhil, G., Westgeest, H., Schrader, A. M.R., van Diest, P. J., Blokx, W. A.M., and Suijkerbuijk, K. P.M.

Published
2024

2. Safe Stop IPI-NIVO trial: early discontinuation of nivolumab upon achieving a complete or partial response in patients with irresectable stage III or metastatic melanoma treated with first-line ipilimumab-nivolumab – study protocol

Author

Cancer, MS Medische Oncologie, Janssen, J. C., van Dijk, B., de Joode, K., Aarts, M. J.B., van den Berkmortel, F. W.P.J., Blank, C. U., Boers-Sonderen, M. J., van den Eertwegh, A. J.M., de Groot, J. W.B., Jalving, M., de Jonge, M. J.A., Joosse, A., Kapiteijn, E., Kamphuis-Huismans, A. M., Naipal, K. A.T., Piersma, D., Rikhof, B., Westgeest, H. M., Vreugdenhil, G., Oomen-de Hoop, E., Mulder, E. E.A.P., van der Veldt, Astrid A.M., Cancer, MS Medische Oncologie, Janssen, J. C., van Dijk, B., de Joode, K., Aarts, M. J.B., van den Berkmortel, F. W.P.J., Blank, C. U., Boers-Sonderen, M. J., van den Eertwegh, A. J.M., de Groot, J. W.B., Jalving, M., de Jonge, M. J.A., Joosse, A., Kapiteijn, E., Kamphuis-Huismans, A. M., Naipal, K. A.T., Piersma, D., Rikhof, B., Westgeest, H. M., Vreugdenhil, G., Oomen-de Hoop, E., Mulder, E. E.A.P., and van der Veldt, Astrid A.M.

Published
2024

3. Safe Stop IPI-NIVO trial:early discontinuation of nivolumab upon achieving a complete or partial response in patients with irresectable stage III or metastatic melanoma treated with first-line ipilimumab-nivolumab – study protocol

Author

Janssen, J. C., van Dijk, B., de Joode, K., Aarts, M. J.B., van den Berkmortel, F. W.P.J., Blank, C. U., Boers-Sonderen, M. J., van den Eertwegh, A. J.M., de Groot, J. W.B., Jalving, M., de Jonge, M. J.A., Joosse, A., Kapiteijn, E., Kamphuis-Huismans, A. M., Naipal, K. A.T., Piersma, D., Rikhof, B., Westgeest, H. M., Vreugdenhil, G., Oomen-de Hoop, E., Mulder, E. E.A.P., van der Veldt, Astrid A.M., Janssen, J. C., van Dijk, B., de Joode, K., Aarts, M. J.B., van den Berkmortel, F. W.P.J., Blank, C. U., Boers-Sonderen, M. J., van den Eertwegh, A. J.M., de Groot, J. W.B., Jalving, M., de Jonge, M. J.A., Joosse, A., Kapiteijn, E., Kamphuis-Huismans, A. M., Naipal, K. A.T., Piersma, D., Rikhof, B., Westgeest, H. M., Vreugdenhil, G., Oomen-de Hoop, E., Mulder, E. E.A.P., and van der Veldt, Astrid A.M.

Abstract

Background: Patients with irresectable stage III or metastatic melanoma presenting with poor prognostic factors are usually treated with a combination of immune checkpoint inhibitors (ICIs), consisting of ipilimumab and nivolumab. This combination therapy is associated with severe immune related adverse events (irAEs) in about 60% of patients. In current clinical practice, patients are usually treated with ICIs for up to two years or until disease progression or the occurrence of unacceptable AEs. The incidence of irAEs gradually increases with duration of treatment. While durable tumour responses have been observed after early discontinuation of treatment, no consensus has been reached on optimal treatment duration. The objective of the Safe Stop IPI-NIVO trial is to evaluate whether early discontinuation of ICIs is safe in patients with irresectable stage III or metastatic melanoma who are treated with combination therapy. Methods: The Safe Stop IPI-NIVO trial is a nationwide, multicentre, prospective, single-arm, interventional study in the Netherlands. A total of 80 patients with irresectable stage III or metastatic melanoma who are treated with combination therapy of ipilimumab-nivolumab and have a complete or partial response (CR/PR) according to RECIST v1.1 will be included to early discontinue maintenance therapy with anti-PD-1. The primary endpoint is the rate of ongoing response at 12 months after start of ICI. Secondary endpoints include ongoing response at 24 months, disease control at different time points, melanoma specific and overall survival, the incidence of irAEs and health-related quality of life. Discussion: From a medical, healthcare and economic perspective, overtreatment should be prevented and shorter treatment duration of ICIs is preferred. If early discontinuation of ICIs is safe for patients who are treated with the combination of ipilimumab-nivolumab, the treatment duration of nivolumab could be shortened in patients with a favourable

Published
2024

4. Upfront resection versus no resection of the primary tumor in patients with synchronous metastatic colorectal cancer: the randomized phase III CAIRO4 study conducted by the Dutch Colorectal Cancer Group and the Danish Colorectal Cancer Group

Author

Medisch Oncologische Disciplines, MS Medische Oncologie, Hart- en Vaatziekten Team A, Epi Kanker Team C, Cancer, JC onderzoeksprogramma Kanker, CTM & Statistical consultation, Epi Kanker Team B, Researchgr. Nucleaire Geneeskunde, Zorgeenheid Kinderchirurgie Medisch, MS CGO, van der Kruijssen, D. E.W., Elias, S. G., van de Ven, P. M., van Rooijen, K. L., Lam-Boer, J. ’t, Mol, L., Punt, C. J.A., Sommeijer, D. W., Tanis, P. J., Nielsen, J. D., Yilmaz, M. K., van Riel, J. M.G.H., Wasowiz-Kemps, D. K., Loosveld, O. J.L., van der Schelling, G. P., de Groot, J. W.B., van Westreenen, H. L., Jakobsen, H. L., Fromm, A. L., Hamberg, P., Verseveld, M., Jaensch, C., Liposits, G. I., van Duijvendijk, P., Oulad Hadj, J., van der Hoeven, J. A.B., Trajkovic, M., de Wilt, J. H.W., Koopman, M., van Grevenstein, W. M.U.Helma, CAIRO4 Working Group, Medisch Oncologische Disciplines, MS Medische Oncologie, Hart- en Vaatziekten Team A, Epi Kanker Team C, Cancer, JC onderzoeksprogramma Kanker, CTM & Statistical consultation, Epi Kanker Team B, Researchgr. Nucleaire Geneeskunde, Zorgeenheid Kinderchirurgie Medisch, MS CGO, van der Kruijssen, D. E.W., Elias, S. G., van de Ven, P. M., van Rooijen, K. L., Lam-Boer, J. ’t, Mol, L., Punt, C. J.A., Sommeijer, D. W., Tanis, P. J., Nielsen, J. D., Yilmaz, M. K., van Riel, J. M.G.H., Wasowiz-Kemps, D. K., Loosveld, O. J.L., van der Schelling, G. P., de Groot, J. W.B., van Westreenen, H. L., Jakobsen, H. L., Fromm, A. L., Hamberg, P., Verseveld, M., Jaensch, C., Liposits, G. I., van Duijvendijk, P., Oulad Hadj, J., van der Hoeven, J. A.B., Trajkovic, M., de Wilt, J. H.W., Koopman, M., van Grevenstein, W. M.U.Helma, and CAIRO4 Working Group

Published
2024

5. Upfront resection versus no resection of the primary tumor in patients with synchronous metastatic colorectal cancer:the randomized phase III CAIRO4 study conducted by the Dutch Colorectal Cancer Group and the Danish Colorectal Cancer Group

Author

van der Kruijssen, D. E.W., Elias, S. G., van de Ven, P. M., van Rooijen, K. L., Lam-Boer, J. ’t, Mol, L., Punt, C. J.A., Sommeijer, D. W., Tanis, P. J., Nielsen, J. D., Yilmaz, M. K., van Riel, J. M.G.H., Wasowiz-Kemps, D. K., Loosveld, O. J.L., van der Schelling, G. P., de Groot, J. W.B., van Westreenen, H. L., Jakobsen, H. L., Fromm, A. L., Hamberg, P., Verseveld, M., Jaensch, C., Liposits, G. I., van Duijvendijk, P., Oulad Hadj, J., van der Hoeven, J. A.B., Trajkovic, M., de Wilt, J. H.W., Koopman, M., van der Kruijssen, D. E.W., Elias, S. G., van de Ven, P. M., van Rooijen, K. L., Lam-Boer, J. ’t, Mol, L., Punt, C. J.A., Sommeijer, D. W., Tanis, P. J., Nielsen, J. D., Yilmaz, M. K., van Riel, J. M.G.H., Wasowiz-Kemps, D. K., Loosveld, O. J.L., van der Schelling, G. P., de Groot, J. W.B., van Westreenen, H. L., Jakobsen, H. L., Fromm, A. L., Hamberg, P., Verseveld, M., Jaensch, C., Liposits, G. I., van Duijvendijk, P., Oulad Hadj, J., van der Hoeven, J. A.B., Trajkovic, M., de Wilt, J. H.W., and Koopman, M.

Abstract

Background: Upfront primary tumor resection (PTR) has been associated with longer overall survival (OS) in patients with synchronous unresectable metastatic colorectal cancer (mCRC) in retrospective analyses. The aim of the CAIRO4 study was to investigate whether the addition of upfront PTR to systemic therapy resulted in a survival benefit in patients with synchronous mCRC without severe symptoms of their primary tumor. Patients and methods: This randomized phase III trial was conducted in 45 hospitals in The Netherlands and Denmark. Eligibility criteria included previously untreated mCRC, unresectable metastases, and no severe symptoms of the primary tumor. Patients were randomized (1 : 1) to upfront PTR followed by systemic therapy or systemic therapy without upfront PTR. Systemic therapy consisted of first-line fluoropyrimidine-based chemotherapy with bevacizumab in both arms. Primary endpoint was OS in the intention-to-treat population. The study was registered at ClinicalTrials.gov, NCT01606098. Results: Between August 2012 and February 2021, 206 patients were randomized. In the intention-to-treat analysis, 204 patients were included (n = 103 without upfront PTR, n = 101 with upfront PTR) of whom 116 were men (57%) with median age of 65 years (interquartile range 59-71 years). Median follow-up was 69.4 months. Median OS in the arm without upfront PTR was 18.3 months (95% confidence interval 16.0-22.2 months) compared with 20.1 months (95% confidence interval 17.0-25.1 months) in the upfront PTR arm (P = 0.32). The number of grade 3-4 events was 71 (72%) in the arm without upfront PTR and 61 (65%) in the upfront PTR arm (P = 0.33). Three deaths (3%) possibly related to treatment were reported in the arm without upfront PTR and four (4%) in the upfront PTR arm. Conclusions: Addition of upfront PTR to palliative systemic therapy in patients with synchronous mCRC without severe symptom

Published
2024

6. Seasonal variation of anti-PD-1 outcome in melanoma—Results from a Dutch patient cohort

Author

Borgers, J. S.W., Burgers, F. H., Schina, A., Van Not, O. J., van den Eertwegh, A. J.M., Blank, C. U., Aarts, M. J.B., van den Berkmortel, F. W.P.J., de Groot, J. W.B., Hospers, G. A.P., Kapiteijn, E., Piersma, D., van Rijn, R. S., Boer, A. M.Stevense den, van der Veldt, A. A.M., Vreugdenhil, G., Boers-Sonderen, M. J., Wouters, M. W.J.M., Suijkerbuijk, K. P.M., van Thienen, J. V., Haanen, J. B.A.G., Borgers, J. S.W., Burgers, F. H., Schina, A., Van Not, O. J., van den Eertwegh, A. J.M., Blank, C. U., Aarts, M. J.B., van den Berkmortel, F. W.P.J., de Groot, J. W.B., Hospers, G. A.P., Kapiteijn, E., Piersma, D., van Rijn, R. S., Boer, A. M.Stevense den, van der Veldt, A. A.M., Vreugdenhil, G., Boers-Sonderen, M. J., Wouters, M. W.J.M., Suijkerbuijk, K. P.M., van Thienen, J. V., and Haanen, J. B.A.G.

Abstract

Despite the improved survival rates of patients with advanced stage melanoma since the introduction of ICIs, many patients do not have (long-term) benefit from these treatments. There is evidence that the exposome, an accumulation of host-extrinsic factors including environmental influences, could impact ICI response. Recently, a survival benefit was observed in patients with BRAF wild-type melanoma living in Denmark who initiated immunotherapy in summer as compared to winter. As the Netherlands lies in close geographical proximity to Denmark and has comparable seasonal differences, a Dutch validation cohort was established using data from our nationwide melanoma registry. In this study, we did not observe a similar seasonal difference in overall survival and are therefore unable to confirm the Danish findings. Validation of either the Dutch or Danish findings in (combined) patient cohorts from other countries would be necessary to determine whether this host-extrinsic factor influences the response to ICI-treatment.

Published
2024

7. Perioperative or adjuvant mFOLFIRINOX for resectable pancreatic cancer (PREOPANC-3):study protocol for a multicenter randomized controlled trial

Author

van Dam, J. L., Verkolf, E. M.M., Dekker, E. N., Bonsing, B. A., Bratlie, S. O., Brosens, L. A.A., Busch, O. R., van Driel, L. M.J.W., van Eijck, C. H.J., Feshtali, S., Ghorbani, P., de Groot, D. J.A., de Groot, J. W.B., Haberkorn, B. C.M., de Hingh, I. H., van der Holt, B., Karsten, T. M., van der Kolk, M. B., Labori, K. J., Liem, M. S.L., Loosveld, O. J.L., Molenaar, I. Q., Polée, M. B., van Santvoort, H. C., de Vos-Geelen, J., Wumkes, M. L., van Tienhoven, G., Homs, M. Y.V., Besselink, M. G., Wilmink, J. W., Groot Koerkamp, B., van Dam, J. L., Verkolf, E. M.M., Dekker, E. N., Bonsing, B. A., Bratlie, S. O., Brosens, L. A.A., Busch, O. R., van Driel, L. M.J.W., van Eijck, C. H.J., Feshtali, S., Ghorbani, P., de Groot, D. J.A., de Groot, J. W.B., Haberkorn, B. C.M., de Hingh, I. H., van der Holt, B., Karsten, T. M., van der Kolk, M. B., Labori, K. J., Liem, M. S.L., Loosveld, O. J.L., Molenaar, I. Q., Polée, M. B., van Santvoort, H. C., de Vos-Geelen, J., Wumkes, M. L., van Tienhoven, G., Homs, M. Y.V., Besselink, M. G., Wilmink, J. W., and Groot Koerkamp, B.

Abstract

BACKGROUND: Surgical resection followed by adjuvant mFOLFIRINOX (5-fluorouracil with leucovorin, irinotecan, and oxaliplatin) is currently the standard of care for patients with resectable pancreatic cancer. The main concern regarding adjuvant chemotherapy is that only half of patients actually receive adjuvant treatment. Neoadjuvant chemotherapy, on the other hand, guarantees early systemic treatment and may increase chemotherapy use and thereby improve overall survival. Furthermore, it may prevent futile surgery in patients with rapidly progressive disease. However, some argue that neoadjuvant therapy delays surgery, which could lead to progression towards unresectable disease and thus offset the potential benefits. Comparison of perioperative (i.e., neoadjuvant and adjuvant) with (only) adjuvant administration of mFOLFIRINOX in a randomized controlled trial (RCT) is needed to determine the optimal approach. METHODS: This multicenter, phase 3, RCT will include 378 patients with resectable pancreatic ductal adenocarcinoma with a WHO performance status of 0 or 1. Patients are recruited from 20 Dutch centers and three centers in Norway and Sweden. Resectable pancreatic cancer is defined as no arterial contact and ≤ 90 degrees venous contact. Patients in the intervention arm are scheduled for 8 cycles of neoadjuvant mFOLFIRINOX followed by surgery and 4 cycles of adjuvant mFOLFIRINOX (2-week cycle of oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, irinotecan 150 mg/m2 at day 1, followed by 46 h continuous infusion of 5-fluorouracil 2400 g/m2). Patients in the comparator arm start with surgery followed by 12 cycles of adjuvant mFOLFIRINOX. The primary outcome is overall survival by intention-to-treat. Secondary outcomes include progression-free survival, resection rate, quality of life, adverse events, and surgical complications. To detect a hazard ratio of 0.70 with 80% power, 252 events are needed. The number of events is expected to be reached after the inclusion of

Published
2023

8. Neoadjuvant FOLFOXIRI prior to chemoradiotherapy for high-risk ('ugly') locally advanced rectal cancer:study protocol of a single-arm, multicentre, open-label, phase II trial (MEND-IT)

Author

van den Berg, K., Schaap, D. P., Voogt, E. L.K., Buffart, T. E., Verheul, H. M.W., de Groot, J. W.B., Verhoef, C., Melenhorst, J., Roodhart, J. M.L., de Wilt, J. H.W., van Westreenen, H. L., Aalbers, A. G.J., van 't Veer, M., Marijnen, C. A.M., Vincent, J., Simkens, L. H.J., Peters, N. A.J.B., Berbée, M., Werter, I. M., Snaebjornsson, P., Peulen, H. M.U., van Lijnschoten, I. G., Roef, M. J., Nieuwenhuijzen, G. A.P., Bloemen, J. G., Willems, J. M.W.E., Creemers, G. J.M., Nederend, J., Rutten, H. J.T., Burger, J. W.A., van den Berg, K., Schaap, D. P., Voogt, E. L.K., Buffart, T. E., Verheul, H. M.W., de Groot, J. W.B., Verhoef, C., Melenhorst, J., Roodhart, J. M.L., de Wilt, J. H.W., van Westreenen, H. L., Aalbers, A. G.J., van 't Veer, M., Marijnen, C. A.M., Vincent, J., Simkens, L. H.J., Peters, N. A.J.B., Berbée, M., Werter, I. M., Snaebjornsson, P., Peulen, H. M.U., van Lijnschoten, I. G., Roef, M. J., Nieuwenhuijzen, G. A.P., Bloemen, J. G., Willems, J. M.W.E., Creemers, G. J.M., Nederend, J., Rutten, H. J.T., and Burger, J. W.A.

Abstract

BACKGROUND: The presence of mesorectal fascia (MRF) invasion, grade 4 extramural venous invasion (EMVI), tumour deposits (TD) or extensive or bilateral extramesorectal (lateral) lymph nodes (LLN) on MRI has been suggested to identify patients with indisputable, extensive locally advanced rectal cancer (LARC), at high risk of treatment failure. The aim of this study is to evaluate whether or not intensified chemotherapy prior to neoadjuvant chemoradiotherapy improves the complete response (CR) rate in these patients. METHODS: This multicentre, single-arm, open-label, phase II trial will include 128 patients with non-metastatic high-risk LARC (hr-LARC), fit for triplet chemotherapy. To ensure a study population with indisputable, unfavourable prognostic characteristics, hr-LARC is defined as LARC with on baseline MRI at least one of the following characteristics; MRF invasion, EMVI grade 4, enlarged bilateral or extensive LLN at high risk of an incomplete resection, or TD. Exclusion criteria are the presence of a homozygous DPD deficiency, distant metastases, any chemotherapy within the past 6 months, previous radiotherapy within the pelvic area precluding standard chemoradiotherapy, and any contraindication for the planned treatment. All patients will be planned for six two-weekly cycles of FOLFOXIRI (5-fluorouracil, leucovorin, oxaliplatin and irinotecan) prior to chemoradiotherapy (25 × 2 Gy or 28 × 1.8 Gy with concomitant capecitabine). A resection will be performed following radiological confirmation of resectable disease after the completion of chemoradiotherapy. A watch and wait strategy is allowed in case of a clinical complete response. The primary endpoint is the CR rate, described as a pathological CR or a sustained clinical CR one year after chemoradiotherapy. The main secondary objectives are long-term oncological outcomes, radiological and pathological response, the number of resections with clear margins, treatment-related toxicity, perioperative com

Published
2022

9. Life-prolonging treatment restrictions and outcomes in patients with cancer and COVID-19:an update from the Dutch Oncology COVID-19 Consortium

Author

de Joode, Karlijn, Tol, Jolien, Hamberg, Paul, Cloos, Marissa, Kastelijn, Elisabeth A., Borgers, Jessica S.W., Nuij, Veerle J.A.A., Klaver, Yarne, Herder, Gerarda J.M., Mutsaers, Pim G.N.J., Dumoulin, Daphne W., Oomen-de Hoop, Esther, van Diemen, Nico G.J., Libourel, Eduard J., Geraedts, Erica J., Bootsma, Gerben P., van der Leest, Cor H., Peerdeman, Anne L., Herbschleb, Karin H., Visser, Otto J., Bloemendal, Haiko J., van Laarhoven, Hanneke W.M., de Vries, Elisabeth G.E., Hendriks, Lizza E.L., Beerepoot, Laurens V., Westgeest, Hans M., van den Berkmortel, Franchette W.P.J., Dingemans, Anne Marie C., van der Veldt, Astrid A.M., van Leeuwen, L., van der Meer, F. S., Tiemessen, M. A., van Diepen, D. M., Brocken, P., Drooger, J. C., de Groot, J. W.B., Stigt, J. A., Slingerland, M., Haberkorn, B. C.M., Aarts, M. J.B., Youssef, M., Faber, L. M., van de Wetering, R. A.W., Bard, M. P.L., Douma, G., Suijkerbuijk, K. P.M., Bakker, S. D., de Jong, W. K., Staal, A. J., Franken, B., de Joode, Karlijn, Tol, Jolien, Hamberg, Paul, Cloos, Marissa, Kastelijn, Elisabeth A., Borgers, Jessica S.W., Nuij, Veerle J.A.A., Klaver, Yarne, Herder, Gerarda J.M., Mutsaers, Pim G.N.J., Dumoulin, Daphne W., Oomen-de Hoop, Esther, van Diemen, Nico G.J., Libourel, Eduard J., Geraedts, Erica J., Bootsma, Gerben P., van der Leest, Cor H., Peerdeman, Anne L., Herbschleb, Karin H., Visser, Otto J., Bloemendal, Haiko J., van Laarhoven, Hanneke W.M., de Vries, Elisabeth G.E., Hendriks, Lizza E.L., Beerepoot, Laurens V., Westgeest, Hans M., van den Berkmortel, Franchette W.P.J., Dingemans, Anne Marie C., van der Veldt, Astrid A.M., van Leeuwen, L., van der Meer, F. S., Tiemessen, M. A., van Diepen, D. M., Brocken, P., Drooger, J. C., de Groot, J. W.B., Stigt, J. A., Slingerland, M., Haberkorn, B. C.M., Aarts, M. J.B., Youssef, M., Faber, L. M., van de Wetering, R. A.W., Bard, M. P.L., Douma, G., Suijkerbuijk, K. P.M., Bakker, S. D., de Jong, W. K., Staal, A. J., and Franken, B.

Abstract

Aim of the study: The coronavirus disease 2019 (COVID-19) pandemic significantly impacted cancer care. In this study, clinical patient characteristics related to COVID-19 outcomes and advanced care planning, in terms of non-oncological treatment restrictions (e.g. do-not-resuscitate codes), were studied in patients with cancer and COVID-19. Methods: The Dutch Oncology COVID-19 Consortium registry was launched in March 2020 in 45 hospitals in the Netherlands, primarily to identify risk factors of a severe COVID-19 outcome in patients with cancer. Here, an updated analysis of the registry was performed, and treatment restrictions (e.g. do-not-intubate codes) were studied in relation to COVID-19 outcomes in patients with cancer. Oncological treatment restrictions were not taken into account. Results: Between 27th March 2020 and 4th February 2021, 1360 patients with cancer and COVID-19 were registered. Follow-up data of 830 patients could be validated for this analysis. Overall, 230 of 830 (27.7%) patients died of COVID-19, and 60% of the remaining 600 patients with resolved COVID-19 were admitted to the hospital. Patients with haematological malignancies or lung cancer had a higher risk of a fatal outcome than other solid tumours. No correlation between anticancer therapies and the risk of a fatal COVID-19 outcome was found. In terms of end-of-life communication, 50% of all patients had restrictions regarding life-prolonging treatment (e.g. do-not-intubate codes). Most identified patients with treatment restrictions had risk factors associated with fatal COVID-19 outcome. Conclusion: There was no evidence of a negative impact of anticancer therapies on COVID-19 outcomes. Timely end-of-life communication as part of advanced care planning could save patients from prolonged suffering and decrease burden in intensive care units. Early discussion of treatment restrictions should therefore be part of routine oncological care, especially during the COVID-19 pandemic.

Published
2022

10. Neoadjuvant FOLFOXIRI prior to chemoradiotherapy for high-risk (“ugly”) locally advanced rectal cancer: study protocol of a single-arm, multicentre, open-label, phase II trial (MEND-IT)

Author

MS Medische Oncologie, Cancer, van den Berg, K., Schaap, D. P., Voogt, E. L.K., Buffart, T. E., Verheul, H. M.W., de Groot, J. W.B., Verhoef, C., Melenhorst, J., Roodhart, J. M.L., de Wilt, J. H.W., van Westreenen, H. L., Aalbers, A. G.J., van ‘t Veer, M., Marijnen, C. A.M., Vincent, J., Simkens, L. H.J., Peters, N. A.J.B., Berbée, M., Werter, I. M., Snaebjornsson, P., Peulen, H. M.U., van Lijnschoten, I. G., Roef, M. J., Nieuwenhuijzen, G. A.P., Bloemen, J. G., Willems, J. M.W.E., Creemers, G. J.M., Nederend, J., Rutten, H. J.T., Burger, J. W.A., MS Medische Oncologie, Cancer, van den Berg, K., Schaap, D. P., Voogt, E. L.K., Buffart, T. E., Verheul, H. M.W., de Groot, J. W.B., Verhoef, C., Melenhorst, J., Roodhart, J. M.L., de Wilt, J. H.W., van Westreenen, H. L., Aalbers, A. G.J., van ‘t Veer, M., Marijnen, C. A.M., Vincent, J., Simkens, L. H.J., Peters, N. A.J.B., Berbée, M., Werter, I. M., Snaebjornsson, P., Peulen, H. M.U., van Lijnschoten, I. G., Roef, M. J., Nieuwenhuijzen, G. A.P., Bloemen, J. G., Willems, J. M.W.E., Creemers, G. J.M., Nederend, J., Rutten, H. J.T., and Burger, J. W.A.

Published
2022

11. Life-prolonging treatment restrictions and outcomes in patients with cancer and COVID-19: an update from the Dutch Oncology COVID-19 Consortium

Author

MS Medische Oncologie, Infection & Immunity, Cancer, Longziekten, de Joode, Karlijn, Tol, Jolien, Hamberg, Paul, Cloos, Marissa, Kastelijn, Elisabeth A., Borgers, Jessica S.W., Nuij, Veerle J.A.A., Klaver, Yarne, Herder, Gerarda J.M., Mutsaers, Pim G.N.J., Dumoulin, Daphne W., Oomen-de Hoop, Esther, van Diemen, Nico G.J., Libourel, Eduard J., Geraedts, Erica J., Bootsma, Gerben P., van der Leest, Cor H., Peerdeman, Anne L., Herbschleb, Karin H., Visser, Otto J., Bloemendal, Haiko J., van Laarhoven, Hanneke W.M., de Vries, Elisabeth G.E., Hendriks, Lizza E.L., Beerepoot, Laurens V., Westgeest, Hans M., van den Berkmortel, Franchette W.P.J., Haanen, John B.A.G., Dingemans, Anne Marie C., van der Veldt, Astrid A.M., Becker-Commissaris, A., Terheggen, F., van den Borne, B. E.E.M., van Warmerdam, L. J.C., van Leeuwen, L., van der Meer, F. S., Tiemessen, M. A., van Diepen, D. M., Strobbe, L., Koekkoek, J. A.F., Brocken, P., Drooger, J. C., de Groot, J. W.B., Aarts, M. J.B., Cirkel, G. A., Claessens, N. J.M., Jalving, M., Suijkerbuijk, K. P.M., van Lindert, A. S.R., Bakker, S. D., MS Medische Oncologie, Infection & Immunity, Cancer, Longziekten, de Joode, Karlijn, Tol, Jolien, Hamberg, Paul, Cloos, Marissa, Kastelijn, Elisabeth A., Borgers, Jessica S.W., Nuij, Veerle J.A.A., Klaver, Yarne, Herder, Gerarda J.M., Mutsaers, Pim G.N.J., Dumoulin, Daphne W., Oomen-de Hoop, Esther, van Diemen, Nico G.J., Libourel, Eduard J., Geraedts, Erica J., Bootsma, Gerben P., van der Leest, Cor H., Peerdeman, Anne L., Herbschleb, Karin H., Visser, Otto J., Bloemendal, Haiko J., van Laarhoven, Hanneke W.M., de Vries, Elisabeth G.E., Hendriks, Lizza E.L., Beerepoot, Laurens V., Westgeest, Hans M., van den Berkmortel, Franchette W.P.J., Haanen, John B.A.G., Dingemans, Anne Marie C., van der Veldt, Astrid A.M., Becker-Commissaris, A., Terheggen, F., van den Borne, B. E.E.M., van Warmerdam, L. J.C., van Leeuwen, L., van der Meer, F. S., Tiemessen, M. A., van Diepen, D. M., Strobbe, L., Koekkoek, J. A.F., Brocken, P., Drooger, J. C., de Groot, J. W.B., Aarts, M. J.B., Cirkel, G. A., Claessens, N. J.M., Jalving, M., Suijkerbuijk, K. P.M., van Lindert, A. S.R., and Bakker, S. D.

Published
2022

12. Survival of stage IV melanoma in Belgium and the Netherlands

Author

MS Medische Oncologie, Infection & Immunity, Cancer, Anatomie, MS MOD, MS KNO, Suijkerbuijk, K. P.M., Haanen, J. B.A.G., Boers-Sonderen, M. J., Hospers, G. A.P., Blank, C. U., van den Berkmortel, F. W.P.J., de Groot, J. W.B., Piersma, D., Aarts, M. J.B., van Rijn, R. S., Vreugdenhil, G., Westgeest, H. M., Kapiteijn, E., van der Veldt, A. A.M., van den Eertwegh, A. J.M., MS Medische Oncologie, Infection & Immunity, Cancer, Anatomie, MS MOD, MS KNO, Suijkerbuijk, K. P.M., Haanen, J. B.A.G., Boers-Sonderen, M. J., Hospers, G. A.P., Blank, C. U., van den Berkmortel, F. W.P.J., de Groot, J. W.B., Piersma, D., Aarts, M. J.B., van Rijn, R. S., Vreugdenhil, G., Westgeest, H. M., Kapiteijn, E., van der Veldt, A. A.M., and van den Eertwegh, A. J.M.

Published
2022

13. Trends in survival and costs in metastatic melanoma in the era of novel targeted and immunotherapeutic drugs

Author

Franken, M. G., Leeneman, B., Aarts, M. J.B., van Akkooi, A. C.J., van den Berkmortel, F. W.P.J., Boers-Sonderen, M. J., van den Eertwegh, A. J.M., de Groot, J. W.B., Hospers, G. A.P., Kapiteijn, E., Piersma, D., van Rijn, R. S., Suijkerbuijk, K. P.M., van der Veldt, A. A.M., Westgeest, H. M., Wouters, M. W.J.M., Haanen, J. B.A.G., Uyl-de Groot, C. A., Franken, M. G., Leeneman, B., Aarts, M. J.B., van Akkooi, A. C.J., van den Berkmortel, F. W.P.J., Boers-Sonderen, M. J., van den Eertwegh, A. J.M., de Groot, J. W.B., Hospers, G. A.P., Kapiteijn, E., Piersma, D., van Rijn, R. S., Suijkerbuijk, K. P.M., van der Veldt, A. A.M., Westgeest, H. M., Wouters, M. W.J.M., Haanen, J. B.A.G., and Uyl-de Groot, C. A.

Abstract

BACKGROUND: The objective of this study was to evaluate trends in survival and health care costs in metastatic melanoma in the era of targeted and immunotherapeutic drugs.MATERIALS AND METHODS: Data on survival and health care resource use were retrieved from the Dutch Melanoma Treatment Registry. The Kaplan-Meier method was used to estimate overall survival. Health care costs and budget impact were computed by applying unit costs to individual patient resource use. All outcomes were stratified by year of diagnosis.RESULTS: Baseline characteristics were balanced across cohort years. The percentage of patients receiving systemic treatment increased from 73% in 2013 to 90% in 2018. Patients received on average 1.85 [standard deviation (SD): 1.14] lines of treatment and 41% of patients received at least two lines of treatment. Median survival increased from 11.8 months in 2013 [95% confidence interval (CI): 10.7-13.7 months] to 21.1 months in 2018 (95% CI: 18.2 months-not reached). Total mean costs were €100 330 (SD: €103 699); systemic treatments accounted for 84% of the total costs. Costs for patients who received systemic treatment [€118 905 (SD: €104 166)] remained reasonably stable over the years even after the introduction of additional (combination of) novel drugs. From mid-2013 to 2018, the total budget impact for all patients was €452.79 million.CONCLUSION: Our study shows a gain in survival in the era of novel targeted and immunotherapeutic drugs. These novel drugs came, however, along with substantial health care costs. Further insights into the cost-effectiveness of the novel drugs are crucial for ensuring value for money in the treatment of patients with metastatic melanoma.

Published
2021

14. Trends in survival and costs in metastatic melanoma in the era of novel targeted and immunotherapeutic drugs

Author

MS Medische Oncologie, Divisie Beeld & Oncologie, Infection & Immunity, Cancer, Franken, M. G., Leeneman, B., Aarts, M. J.B., van Akkooi, A. C.J., van den Berkmortel, F. W.P.J., Boers-Sonderen, M. J., van den Eertwegh, A. J.M., de Groot, J. W.B., Hospers, G. A.P., Kapiteijn, E., Piersma, D., van Rijn, R. S., Suijkerbuijk, K. P.M., van der Veldt, A. A.M., Westgeest, H. M., Wouters, M. W.J.M., Haanen, J. B.A.G., Uyl-de Groot, C. A., MS Medische Oncologie, Divisie Beeld & Oncologie, Infection & Immunity, Cancer, Franken, M. G., Leeneman, B., Aarts, M. J.B., van Akkooi, A. C.J., van den Berkmortel, F. W.P.J., Boers-Sonderen, M. J., van den Eertwegh, A. J.M., de Groot, J. W.B., Hospers, G. A.P., Kapiteijn, E., Piersma, D., van Rijn, R. S., Suijkerbuijk, K. P.M., van der Veldt, A. A.M., Westgeest, H. M., Wouters, M. W.J.M., Haanen, J. B.A.G., and Uyl-de Groot, C. A.

Published
2021

15. Survival outcomes of patients with advanced melanoma from 2013 to 2017: Results of a nationwide population-based registry

Author

MS Medische Oncologie, Infection & Immunity, Cancer, van Zeijl, M. C.T., de Wreede, L. C., van den Eertwegh, A. J.M., Wouters, M. W.J.M., Jochems, A., Schouwenburg, M. G., Aarts, M. J.B., van Akkooi, A. C.J., van den Berkmortel, F. W.P.J., de Groot, J. W.B., Hospers, G. A.P., Kapiteijn, E., Piersma, D., van Rijn, R. S., Suijkerbuijk, K. P.M., ten Tije, A. J., van der Veldt, A. A.M., Vreugdenhil, G., van der Hoeven, J. J.M., Haanen, J. B.A.G., MS Medische Oncologie, Infection & Immunity, Cancer, van Zeijl, M. C.T., de Wreede, L. C., van den Eertwegh, A. J.M., Wouters, M. W.J.M., Jochems, A., Schouwenburg, M. G., Aarts, M. J.B., van Akkooi, A. C.J., van den Berkmortel, F. W.P.J., de Groot, J. W.B., Hospers, G. A.P., Kapiteijn, E., Piersma, D., van Rijn, R. S., Suijkerbuijk, K. P.M., ten Tije, A. J., van der Veldt, A. A.M., Vreugdenhil, G., van der Hoeven, J. J.M., and Haanen, J. B.A.G.

Published
2021

16. Dutch Oncology COVID-19 consortium: Outcome of COVID-19 in patients with cancer in a nationwide cohort study

Author

MS Medische Oncologie, Cancer, Infection & Immunity, Longziekten, de Joode, Karlijn, Dumoulin, Daphne W., Tol, Jolien, Westgeest, Hans M., Beerepoot, Laurens V., van den Berkmortel, Franchette W.P.J., Mutsaers, Pim G.N.J., van Diemen, Nico G.J., Visser, Otto J., Oomen-de Hoop, Esther, Bloemendal, Haiko J., van Laarhoven, Hanneke W.M., Hendriks, Lizza E.L., Haanen, John B.A.G., de Vries, Elisabeth G.E., Dingemans, Anne Marie C., van der Veldt, Astrid A.M., van Loenhout, C. J., van der Leest, C. H., Becker-Commissaris, A., Borgers, J. S.W., Terhegggen, F., van den Borne, B. E.E.M., van Warmerdam, L. J.C., van Leeuwen, L., van der Meer, F. S., Tiemessen, M. A., van Diepen, D. M., Klaver, Y., Hamberg, A. P., Libourel, E. J., Strobbe, L., Cloos, M., Geraedts, E. J., Drooger, J. C., Heller, R., de Groot, J. W.B., Stigt, J. A., Nuij, V. J.A.A., Pitz, C. C.M., Slingerland, M., Borm, F. J., Haberkorn, B. C.M., Westeinde, S. C.van t., Aarts, M. J.B., van Putten, J. W.G., Youssef, M., Cirkel, G. A., Herder, G. J.M., van Rooijen, C. R., Citgez, E., Barlo, N. P., Scholtes, B. M.J., Koornstra, R. H.T., Claessens, N. J.M., Faber, L. M., Rikers, C. H., van de Wetering, R. A.W., Veurink, G. L., Bouter, B. W., Houtenbos, I., Bard, M. P.L., Herbschleb, K. H., Kastelijn, E. A., Brocken, P., Douma, G., Jalving, M., Hiltermann, T. J.N., Schuurbiers-Siebers, O. C.J., Suijkerbuijk, K. P.M., van Lindert, A. S.R., van de Wouw, A. J., van den Boogaart, V. E.M., Bakker, S. D., Looysen, E., Peerdeman, A. L., de Jong, W. K., Siemerink, E. J.M., Staal, A. J., Franken, B., van Geffen, W. H., Bootsma, G. P., MS Medische Oncologie, Cancer, Infection & Immunity, Longziekten, de Joode, Karlijn, Dumoulin, Daphne W., Tol, Jolien, Westgeest, Hans M., Beerepoot, Laurens V., van den Berkmortel, Franchette W.P.J., Mutsaers, Pim G.N.J., van Diemen, Nico G.J., Visser, Otto J., Oomen-de Hoop, Esther, Bloemendal, Haiko J., van Laarhoven, Hanneke W.M., Hendriks, Lizza E.L., Haanen, John B.A.G., de Vries, Elisabeth G.E., Dingemans, Anne Marie C., van der Veldt, Astrid A.M., van Loenhout, C. J., van der Leest, C. H., Becker-Commissaris, A., Borgers, J. S.W., Terhegggen, F., van den Borne, B. E.E.M., van Warmerdam, L. J.C., van Leeuwen, L., van der Meer, F. S., Tiemessen, M. A., van Diepen, D. M., Klaver, Y., Hamberg, A. P., Libourel, E. J., Strobbe, L., Cloos, M., Geraedts, E. J., Drooger, J. C., Heller, R., de Groot, J. W.B., Stigt, J. A., Nuij, V. J.A.A., Pitz, C. C.M., Slingerland, M., Borm, F. J., Haberkorn, B. C.M., Westeinde, S. C.van t., Aarts, M. J.B., van Putten, J. W.G., Youssef, M., Cirkel, G. A., Herder, G. J.M., van Rooijen, C. R., Citgez, E., Barlo, N. P., Scholtes, B. M.J., Koornstra, R. H.T., Claessens, N. J.M., Faber, L. M., Rikers, C. H., van de Wetering, R. A.W., Veurink, G. L., Bouter, B. W., Houtenbos, I., Bard, M. P.L., Herbschleb, K. H., Kastelijn, E. A., Brocken, P., Douma, G., Jalving, M., Hiltermann, T. J.N., Schuurbiers-Siebers, O. C.J., Suijkerbuijk, K. P.M., van Lindert, A. S.R., van de Wouw, A. J., van den Boogaart, V. E.M., Bakker, S. D., Looysen, E., Peerdeman, A. L., de Jong, W. K., Siemerink, E. J.M., Staal, A. J., Franken, B., van Geffen, W. H., and Bootsma, G. P.

Published
2020

19. Vemurafenib plus cobimetinib in unresectable stage IIIc or stage IV melanoma

Author

van der Hiel, Bernies, Haanen, John B A G, Stokkel, Marcel P M, Peeper, Daniel S., Jimenez, Connie R., Beijnen, Jos H, van de Wiel, Bart A., Boellaard, Ronald, van den Eertwegh, Alfons J M, van Tinteren, H., Wessels, Lodewyk F A, Lolkema, Martijn P J K, Hoekstra, Otto S, Hospers, Geke A P, Brouwers, Adrienne H, Koornstra, R.H.T., Arens, A. I. J., de Vos, F. Y.F.L., Hobbelink, M. G.G., Kapiteijn, H. W., de Geus-Oei, L. F., Kruit, W. H.J., Verzijlbergen, F.J., Aarts, M. J.B., Mottaghy, F. M., de Groot, J. W.B., Knollema, S., Piersma, D., Agool, A., Vreugdenhil, Art, Liem, I H, van den Berkmortel, Franchette W P J, Schreurs, M.W., Guided Treatment in Optimal Selected Cancer Patients (GUTS), ​Basic and Translational Research and Imaging Methodology Development in Groningen (BRIDGE), AGEM - Re-generation and cancer of the digestive system, Medical oncology laboratory, CCA - Cancer Treatment and quality of life, and Medical oncology

Subjects
0301 basic medicine, Oncology, Pathology, Cancer Research, Indoles, Skin Neoplasms, medicine.medical_treatment, Resistance, Targeted therapy, BRAF-MUTATED MELANOMA, chemistry.chemical_compound, Study Protocol, 0302 clinical medicine, Piperidines, Antineoplastic Combined Chemotherapy Protocols, Medicine, METASTATIC MELANOMA, Multicenter Studies as Topic, Vemurafenib, Stage IIIc/IV melanoma, Melanoma, IN-VIVO, Sulfonamides, medicine.diagnostic_test, IMPROVED SURVIVAL, MEK inhibitor, RANDOMIZED CONTROLLED-TRIAL, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Treatment Outcome, Positron emission tomography, Research Design, 030220 oncology & carcinogenesis, medicine.drug, F-FLT, BRAF inhibitor, medicine.medical_specialty, PET/CT, CELL LUNG-CANCER, F-FDG, lcsh:RC254-282, Disease-Free Survival, F-18-FDG, 03 medical and health sciences, Clinical Trials, Phase II as Topic, Internal medicine, Genetics, Journal Article, Humans, Stage IIIC, F-18-FLT, MEK INHIBITION, LYMPH-NODE, Neoplasm Staging, Cobimetinib, PET-CT, business.industry, MUTATIONS, medicine.disease, MUTANT MELANOMA, 18F-FDG, 030104 developmental biology, chemistry, Drug Resistance, Neoplasm, Positron-Emission Tomography, 18F-FLT, Azetidines, business
Abstract

In patients with BRAFV600 mutated unresectable stage IIIc or metastatic melanoma, molecular targeted therapy with combined BRAF/MEK-inhibitor vemurafenib plus cobimetinib has shown a significantly improved progression-free survival and overall survival compared to treatment with vemurafenib alone. Nevertheless, the majority of BRAFV600 mutation-positive melanoma patients will eventually develop resistance to treatment. Molecular imaging with 18F-Fluorodeoxyglucose (18F-FDG) PET has been used to monitor response to vemurafenib in some BRAFV600 mutated metastatic melanoma patients, showing a rapid decline of 18F-FDG uptake within 2 weeks following treatment. Furthermore, preliminary results suggest that metabolic alterations might predict the development of resistance to treatment. 18F-Fluoro-3′-deoxy-3’L-fluorothymidine (18F-FLT), a PET-tracer visualizing proliferation, might be more suitable to predict response or resistance to therapy than 18F-FDG. This phase II, open-label, multicenter study evaluates whether metabolic response to treatment with vemurafenib plus cobimetinib in the first 7 weeks as assessed by 18F-FDG/18F-FLT PET can predict progression-free survival and whether early changes in 18F-FDG/18F-FLT can be used for early detection of treatment response compared to standard response assessment with RECISTv1.1 ceCT at 7 weeks. Ninety patients with BRAFV600E/K mutated unresectable stage IIIc/IV melanoma will be included. Prior to and during treatment all patients will undergo 18F-FDG PET/CT and in 25 patients additional 18F-FLT PET/CT is performed. Histopathological tumor characterization is assessed in a subset of 40 patients to unravel mechanisms of resistance. Furthermore, in all patients, blood samples are taken for pharmacokinetic analysis of vemurafenib/cobimetinib. Outcomes are correlated with PET/CT-imaging and therapy response. The results of this study will help in linking PET measured metabolic alterations induced by targeted therapy of BRAFV600 mutated melanoma to molecular changes within the tumor. We will be able to correlate both 18F-FDG and 18F-FLT PET to outcome and decide on the best modality to predict long-term remissions to combined BRAF/MEK-inhibitors. Results coming from this study may help in identifying responders from non-responders early after the initiation of therapy and reveal early development of resistance to vemurafenib/cobimetinib. Furthermore, we believe that the results can be fundamental for further optimizing individual patient treatment. Clinicaltrials.gov identifier: NCT02414750. Registered 10 April 2015, retrospectively registered.

Published
2017

20. Vemurafenib plus cobimetinib in unresectable stage IIIc or stage IV melanoma : Response monitoring and resistance prediction with positron emission tomography and tumor characteristics (REPOSIT): Study protocol of a phase II, open-label, multicenter study

Author

van der Hiel, Bernies, Haanen, John B A G, Stokkel, Marcel P M, Peeper, Daniel S., Jimenez, Connie R., Beijnen, Jos H, van de Wiel, Bart A., Boellaard, Ronald, van den Eertwegh, Alfons J M, van Tinteren, H., Wessels, Lodewyk F A, Lolkema, Martijn P J K, Hoekstra, Otto S, Hospers, Geke A P, Brouwers, Adrienne H, Koornstra, R.H.T., Arens, A. I. J., de Vos, F. Y.F.L., Hobbelink, M. G.G., Kapiteijn, H. W., de Geus-Oei, L. F., Kruit, W. H.J., Verzijlbergen, F.J., Aarts, M. J.B., Mottaghy, F. M., de Groot, J. W.B., Knollema, S., Piersma, D., Agool, A., Vreugdenhil, Art, Liem, I H, van den Berkmortel, Franchette W P J, Schreurs, M.W., and REPOSIT study group

Subjects
F-FLT, BRAF inhibitor, MEK inhibitor, Cancer Research, Oncology, PET/CT, Resistance, F-FDG, Genetics, Journal Article, Stage IIIc/IV melanoma
Abstract

Background: In patients with BRAFV600 mutated unresectable stage IIIc or metastatic melanoma, molecular targeted therapy with combined BRAF/MEK-inhibitor vemurafenib plus cobimetinib has shown a significantly improved progression-free survival and overall survival compared to treatment with vemurafenib alone. Nevertheless, the majority of BRAFV600 mutation-positive melanoma patients will eventually develop resistance to treatment. Molecular imaging with 18F-Fluorodeoxyglucose (18F-FDG) PET has been used to monitor response to vemurafenib in some BRAFV600 mutated metastatic melanoma patients, showing a rapid decline of 18F-FDG uptake within 2 weeks following treatment. Furthermore, preliminary results suggest that metabolic alterations might predict the development of resistance to treatment. 18F-Fluoro-3'-deoxy-3'L-fluorothymidine (18F-FLT), a PET-tracer visualizing proliferation, might be more suitable to predict response or resistance to therapy than 18F-FDG. Methods: This phase II, open-label, multicenter study evaluates whether metabolic response to treatment with vemurafenib plus cobimetinib in the first 7 weeks as assessed by 18F-FDG/18F-FLT PET can predict progression-free survival and whether early changes in 18F-FDG/18F-FLT can be used for early detection of treatment response compared to standard response assessment with RECISTv1.1 ceCT at 7 weeks. Ninety patients with BRAFV600E/K mutated unresectable stage IIIc/IV melanoma will be included. Prior to and during treatment all patients will undergo 18F-FDG PET/CT and in 25 patients additional 18F-FLT PET/CT is performed. Histopathological tumor characterization is assessed in a subset of 40 patients to unravel mechanisms of resistance. Furthermore, in all patients, blood samples are taken for pharmacokinetic analysis of vemurafenib/cobimetinib. Outcomes are correlated with PET/CT-imaging and therapy response. Discussion: The results of this study will help in linking PET measured metabolic alterations induced by targeted therapy of BRAFV600 mutated melanoma to molecular changes within the tumor. We will be able to correlate both 18F-FDG and 18F-FLT PET to outcome and decide on the best modality to predict long-term remissions to combined BRAF/MEK-inhibitors. Results coming from this study may help in identifying responders from non-responders early after the initiation of therapy and reveal early development of resistance to vemurafenib/cobimetinib. Furthermore, we believe that the results can be fundamental for further optimizing individual patient treatment. Trial registration:Clinicaltrials.govidentifier: NCT02414750. Registered 10 April 2015, retrospectively registered.

Published
2017

21. Vemurafenib plus cobimetinib in unresectable stage IIIc or stage IV melanoma: Response monitoring and resistance prediction with positron emission tomography and tumor characteristics (REPOSIT): Study protocol of a phase II, open-label, multicenter study

Author

MS Medische Oncologie, Cancer, UMC Utrecht, Arts-assistenten Nucleaire Geneesk., van der Hiel, Bernies, Haanen, John B A G, Stokkel, Marcel P M, Peeper, Daniel S., Jimenez, Connie R., Beijnen, Jos H, van de Wiel, Bart A., Boellaard, Ronald, van den Eertwegh, Alfons J M, van Tinteren, H., Wessels, Lodewyk F A, Lolkema, Martijn P J K, Hoekstra, Otto S, Hospers, Geke A P, Brouwers, Adrienne H, Koornstra, R.H.T., Arens, A. I. J., de Vos, F. Y.F.L., Hobbelink, M. G.G., Kapiteijn, H. W., de Geus-Oei, L. F., Kruit, W. H.J., Verzijlbergen, F.J., Aarts, M. J.B., Mottaghy, F. M., de Groot, J. W.B., Knollema, S., Piersma, D., Agool, A., Vreugdenhil, Art, Liem, I H, van den Berkmortel, Franchette W P J, Schreurs, M.W., REPOSIT study group, MS Medische Oncologie, Cancer, UMC Utrecht, Arts-assistenten Nucleaire Geneesk., van der Hiel, Bernies, Haanen, John B A G, Stokkel, Marcel P M, Peeper, Daniel S., Jimenez, Connie R., Beijnen, Jos H, van de Wiel, Bart A., Boellaard, Ronald, van den Eertwegh, Alfons J M, van Tinteren, H., Wessels, Lodewyk F A, Lolkema, Martijn P J K, Hoekstra, Otto S, Hospers, Geke A P, Brouwers, Adrienne H, Koornstra, R.H.T., Arens, A. I. J., de Vos, F. Y.F.L., Hobbelink, M. G.G., Kapiteijn, H. W., de Geus-Oei, L. F., Kruit, W. H.J., Verzijlbergen, F.J., Aarts, M. J.B., Mottaghy, F. M., de Groot, J. W.B., Knollema, S., Piersma, D., Agool, A., Vreugdenhil, Art, Liem, I H, van den Berkmortel, Franchette W P J, Schreurs, M.W., and REPOSIT study group

Published
2017

Catalog

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