{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T03:27:00Z","timestamp":1793330820853,"version":"4.5.0"},"reference-count":47,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2020,8,17]],"date-time":"2020-08-17T00:00:00Z","timestamp":1597622400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Time to next treatment (TTNT) is an emerging endpoint in clinical studies of primary cutaneous T-cell lymphomas (CTCL), with utility as a surrogate marker for the \u201cduration of clinical benefit\u201d. TTNT provides a highly clinically meaningful endpoint that uniquely reflects not only the duration of treatment efficacy on disease and symptom control, but also incorporates the patient experience by accounting for patient compliance and tolerance to the studied therapy(s). Given the distinct challenges of pin-pointing the exact date of progression in patients with multi-compartmental CTCL, TTNT overcomes many of the shortcomings of conventional, disease-focused, clinical endpoints in primary CTCL research. Although widely accepted in clinical research for numerous other incurable malignancies, TTNT currently lacks a standardised definition. In this paper, we describe the value of TTNT as a clinical endpoint, review the applications of TTNT in primary CTCL research, and propose a standardised definition of TTNT to be applied in future clinical research of primary CTCL therapies.<\/jats:p>","DOI":"10.3390\/cancers12082311","type":"journal-article","created":{"date-parts":[[2020,8,17]],"date-time":"2020-08-17T06:33:20Z","timestamp":1597646000000},"page":"2311","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":90,"title":["Time to Next Treatment as a Meaningful Endpoint for Trials of Primary Cutaneous Lymphoma"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7316-8723","authenticated-orcid":false,"given":"Belinda A.","family":"Campbell","sequence":"first","affiliation":[{"name":"Department of Radiation Oncology, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia"},{"name":"Department of Clinical Pathology, The University of Melbourne, Parkville, VIC 3010, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8011-4408","authenticated-orcid":false,"given":"Julia J.","family":"Scarisbrick","sequence":"additional","affiliation":[{"name":"Department of Dermatology, University Hospital Birmingham, Birmingham B15 2TH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Youn H.","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Stanford Cancer Institute, Stanford, CA 94305, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan A.","family":"Wilcox","sequence":"additional","affiliation":[{"name":"Division of Hematology and Medical Oncology, Department of Internal Medicine, University of Michigan Rogel Cancer Center, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"McCormack","sequence":"additional","affiliation":[{"name":"Department of Surgical Oncology, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia"},{"name":"Department of Dermatology, St Vincent\u2019s Hospital Melbourne, Fitzroy, VIC 3065, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H. Miles","family":"Prince","sequence":"additional","affiliation":[{"name":"Department of Clinical Haematology, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, VIC 3000, Australia"},{"name":"Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,8,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2598","DOI":"10.1200\/JCO.2010.32.0630","article-title":"Clinical end points and response criteria in mycosis fungoides and S\u00e9zary syndrome: A consensus statement of the international society for cutaneous lymphomas, the United states cutaneous lymphoma consortium, and the cutaneous lymphoma task force of the european organisation for research and treatment of cancer","volume":"29","author":"Olsen","year":"2011","journal-title":"J. Am. Soc. Clin. Oncol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1182\/blood-2014-07-588236","article-title":"Lack of durable disease control with chemotherapy for mycosis fungoides and Sezary syndrome: A comparative study of systemic therapy","volume":"125","author":"Hughes","year":"2015","journal-title":"Blood"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"E491","DOI":"10.1002\/ajh.24564","article-title":"A retrospective comparative outcome analysis following systemic therapy in mycosis fungoides and sezary syndrome","volume":"91","author":"Hanel","year":"2016","journal-title":"Am. J. Hematol."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Papps, T., McCormack, C., Buelens, O., Van der Weyden, C., Twigger, R., Campbell, B.A., Dickinson, M., and Prince, H.M. (2019). A comparative analysis of histone deacetylase inhibitors for the treatment of mycosis fungoides and sezary syndrome. Br. J. Dermatol.","DOI":"10.1111\/bjd.18522"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Campbell, B.A., Ryan, G., McCormack, C., Tangas, E., Bressel, M., Twigger, R., Buelens, O., van der Weyden, C., and Prince, H.M. (2019). Lack of durable remission with conventional-dose total skin electron therapy for the management of sezary syndrome and multiply relapsed mycosis fungoides. Cancers, 11.","DOI":"10.3390\/cancers11111758"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Gao, C., McCormack, C., van der Weyden, C., Goh, M.S., Campbell, B., Twigger, R., Buelens, O., Harrison, S.J., Khoo, C., and Lade, S. (2019). Prolonged survival with the early use of a novel extracorporeal photopheresis regimen in patients with S\u00e9zary Syndrome. Blood, 29.","DOI":"10.1182\/blood.2019000765"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1002\/hon.95_2630","article-title":"Time to next treatment in patients with previously treated cutaneous t-cell lymphoma (CTCL) receiving mogamulizumab or vorinostat: A post-hoc analaysis of the mavoric study","volume":"37","author":"Kim","year":"2019","journal-title":"Hematol. Oncol."},{"key":"ref_8","first-page":"1509","article-title":"Updated analyses of the international, open-label, randomized, phase 3 alcanza study: Longer-term evidence for superiority of brentuximab vedotin versus methotrexate or bexarotene for CD30-positive cutaneous T-cell lymphoma (CTCL)","volume":"130","author":"Horwitz","year":"2017","journal-title":"Blood"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1016\/j.jaad.2014.10.014","article-title":"Low-dose total skin electron beam therapy as an effective modality to reduce disease burden in patients with mycosis fungoides: Results of a pooled analysis from 3 phase-II clinical trials","volume":"72","author":"Hoppe","year":"2015","journal-title":"J. Am. Acad. Dermatol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1016\/j.ijrobp.2017.05.052","article-title":"The Results of Low-Dose Total Skin Electron Beam Radiation Therapy (TSEB) in Patients With Mycosis Fungoides From the UK Cutaneous Lymphoma Group","volume":"99","author":"Morris","year":"2017","journal-title":"Int. J. Radiat. Oncol. Biol. Phys."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"284","DOI":"10.3109\/10428194.2012.711829","article-title":"Clinically meaningful reduction in pruritus in patients with cutaneous T-cell lymphoma treated with romidepsin","volume":"54","author":"Kim","year":"2013","journal-title":"Leuk. Lymphoma"},{"key":"ref_12","unstructured":"Australian Government Department of Health Therapeutic Goods Administration (2020, August 15). Public Summary: 308832 UVADEX Methoxsalen 200 Microgram\/10 mL Concentrated Injection for Extracorporeal Circulation Via Photopheresis Vial, Available online: https:\/\/www.ebs.tga.gov.au\/servlet\/xmlmillr6?dbid=ebs\/PublicHTML\/pdfStore.nsf&docid=D6E54165349437D8CA2585880030E1FB&agid=(PrintDetailsPublic)&actionid=1."},{"key":"ref_13","unstructured":"Australian Government Department of Health Therapeutic Goods Administration (2020, August 15). Australian Product Information\u2014Uvadex\u00ae (Methoxsalen) Concentrated Injection, Available online: https:\/\/www.ebs.tga.gov.au\/ebs\/picmi\/picmirepository.nsf\/pdf?OpenAgent&id=CP-2019-PI-01966-1&d=202008151016933&d=202008151016933."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1016\/S0140-6736(17)31266-7","article-title":"Brentuximab vedotin or physician\u2019s choice in CD30-positive cutaneous T-cell lymphoma (ALCANZA): An international, open-label, randomised, phase 3, multicentre trial","volume":"390","author":"Prince","year":"2017","journal-title":"Lancet Lond. Engl."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1002\/hon.96_2630","article-title":"Final data from the phase 3 alcanza study: Brentuximab vedotin (BV) VS physician\u2019s choice (PC) in patients (PTS) with CD30-positive (CD30+) cutaneous T-cell lymphoma (CTCL)","volume":"37","author":"Horwitz","year":"2019","journal-title":"Hematol. Oncol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1192","DOI":"10.1016\/S1470-2045(18)30379-6","article-title":"Mogamulizumab versus vorinostat in previously treated cutaneous T-cell lymphoma (MAVORIC): An international, open-label, randomised, controlled phase 3 trial","volume":"19","author":"Kim","year":"2018","journal-title":"Lancet Oncol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1002\/hon.34_2629","article-title":"Efficacy of mogamulizumab in previously treated patients with less advanced mycosis fungoides: Results from the mavoric study","volume":"37","author":"Scarisbrick","year":"2019","journal-title":"Hematol. Oncol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1016\/j.jgo.2017.09.007","article-title":"The impact of age and comorbidities on practice patterns and outcomes in patients with relapsed\/refractory multiple myeloma in the era of novel therapies","volume":"9","author":"Hari","year":"2018","journal-title":"J. Geriatr. Oncol."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Hari, P., Ung, B., Abouzaid, S., Agarwal, A., and Parikh, K. (2019). Lenalidomide maintenance post-transplantation in newly diagnosed multiple myeloma: Real-world outcomes and costs. Future Oncol. Lond. Engl.","DOI":"10.2217\/fon-2019-0422"},{"key":"ref_20","first-page":"236","article-title":"Real-World Treatment Patterns, Time to Next Treatment, and Economic Outcomes in Relapsed or Refractory Multiple Myeloma Patients Treated with Pomalidomide or Carfilzomib","volume":"23","author":"Chen","year":"2017","journal-title":"J. Manag. Car. Spec. Pharm."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1210","DOI":"10.1038\/bmt.2010.283","article-title":"The outcome of high-dose chemotherapy and auto-SCT in patients with multiple myeloma: A UK\/Ireland and European benchmarking comparative analysis","volume":"46","author":"Cook","year":"2011","journal-title":"Bone Marrow Transplant."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Rifkin, R.M., Medhekar, R., Amirian, E.S., Aguilar, K.M., Wilson, T., Boyd, M., Mezzi, K., and Panjabi, S. (2019). A real-world comparative analysis of carfilzomib and other systemic multiple myeloma chemotherapies in a US community oncology setting. Ther. Adv. Hematol., 10.","DOI":"10.1177\/2040620718816699"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1345","DOI":"10.1007\/s00259-019-04312-9","article-title":"Low hexokinase-2 expression-associated false-negative (18)F-FDG PET\/CT as a potential prognostic predictor in patients with multiple myeloma","volume":"46","author":"Abe","year":"2019","journal-title":"Eur. J. Med. Mol. Imag."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1105","DOI":"10.1185\/03007995.2015.1031732","article-title":"Patterns of total cost and economic consequences of progression for patients with newly diagnosed multiple myeloma","volume":"31","author":"Arikian","year":"2015","journal-title":"Curr. Med. Res. Opin."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"E507","DOI":"10.1002\/ajh.24807","article-title":"The prognostic significance of polyclonal bone marrow plasma cells in patients with relapsing multiple myeloma","volume":"92","author":"Ghosh","year":"2017","journal-title":"Am. J. Hematol."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Djebbari, F., Srinivasan, A., Vallance, G., Moore, S., Kothari, J., and Ramasamy, K. (2018). Clinical outcomes of bortezomib-based therapy in myeloma. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0208920"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"645","DOI":"10.1016\/j.clml.2019.06.007","article-title":"Treatment Patterns and Clinical and Economic Outcomes in Patients With Newly Diagnosed Multiple Myeloma Treated With Lenalidomide- and\/or Bortezomib-containing Regimens Without Stem Cell Transplant in a Real-world Setting","volume":"19","author":"Chari","year":"2019","journal-title":"Clin. Lymphoma Myeloma Leuk."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1002\/ajh.25481","article-title":"Prognostic value of minimal residual disease and polyclonal plasma cells in myeloma patients achieving a complete response to therapy","volume":"94","author":"Tschautscher","year":"2019","journal-title":"Am. J. Hematol."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Emond, B., Sundaram, M., Romdhani, H., Lefebvre, P., Wang, S., and Mato, A. (2019). Comparison of Time to Next Treatment, Health Care Resource Utilization, and Costs in Patients with Chronic Lymphocytic Leukemia Initiated on Front-line Ibrutinib or Chemoimmunotherapy. Clin. Lymphoma Myeloma Leuk.","DOI":"10.1016\/j.clml.2019.08.004"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1038\/s41416-019-0502-x","article-title":"The combination of complex karyotype subtypes and IGHV mutational status identifies new prognostic and predictive groups in chronic lymphocytic leukaemia","volume":"121","author":"Visentin","year":"2019","journal-title":"Br. J. Cancer"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/j.leukres.2017.01.023","article-title":"Characterization of treatment and outcomes in a population-based cohort of patients with chronic lymphocytic leukemia referred for cytogenetic testing in British Columbia, Canada","volume":"55","author":"Huang","year":"2017","journal-title":"Leuk. Res."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Al-Sawaf, O., Bazeos, A., Robrecht, S., Bahlo, J., Gower, C., Fink, A.M., Tresckow, J., Cramer, P., Langerbeins, P., and Kutsch, N. (2019). Mode of progression after first line treatment correlates with outcome of chronic lymphocytic leukemia (CLL). Am. J. Hematol.","DOI":"10.1002\/ajh.25561"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1016\/j.clml.2018.06.023","article-title":"Chronic Lymphocytic Leukemia: Clinical Stages Maintain Their Prognostic Significance Over the Course of the Disease and Are Surrogates for Response to Therapy","volume":"18","author":"Vicente","year":"2018","journal-title":"Clin. Lymphoma Myeloma Leuk."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1111\/ejh.13129","article-title":"Outcomes of second-line treatment after fludarabine cyclophosphamide and rituximab in patients with chronic lymphocytic leukemia outside clinical trials","volume":"101","author":"Joffe","year":"2018","journal-title":"Eur. J. Haematol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1830","DOI":"10.1002\/cncr.28659","article-title":"The use and effectiveness of rituximab maintenance in patients with follicular lymphoma diagnosed between 2004 and 2007 in the United States","volume":"120","author":"Nastoupil","year":"2014","journal-title":"Cancer"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1977","DOI":"10.1200\/JCO.2012.45.6400","article-title":"90Yttrium-ibritumomab tiuxetan consolidation of first remission in advanced-stage follicular non-Hodgkin lymphoma: Updated results after a median follow-up of 7.3 years from the International, Randomized, Phase III First-LineIndolent trial","volume":"31","author":"Morschhauser","year":"2013","journal-title":"J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1002\/hon.968","article-title":"Follicular lymphoma at relapse after rituximab containing regimens: Comparison of time to event intervals prior to and after 90 Y-ibritumomab-tiuxetan","volume":"29","author":"Cicone","year":"2011","journal-title":"Hematol. Oncol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1182\/blood-2018-10-879643","article-title":"Short regimen of rituximab plus lenalidomide in follicular lymphoma patients in need of first-line therapy","volume":"134","author":"Zucca","year":"2019","journal-title":"Blood"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Kesavan, M., Boucek, J., MacDonald, W., McQuillan, A., and Turner, J.H. (2017). Imaging of Early Response to Predict Prognosis in the First-Line Management of Follicular Non-Hodgkin Lymphoma with Iodine-131-Rituximab Radioimmunotherapy. Diagnostics, 7.","DOI":"10.3390\/diagnostics7020026"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"520","DOI":"10.1093\/annonc\/mdn656","article-title":"Bortezomib in patients with relapsed or refractory mantle cell lymphoma: Updated time-to-event analyses of the multicenter phase 2 PINNACLE study","volume":"20","author":"Goy","year":"2009","journal-title":"Ann. Oncol. Off. J. Eur. Soc. Med. Oncol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1002\/ajh.24723","article-title":"Treatment patterns and outcome following initial relapse or refractory disease in patients with systemic light chain amyloidosis","volume":"92","author":"Tandon","year":"2017","journal-title":"Am. J. Hematol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1111\/bjh.14826","article-title":"Dexamethasone, rituximab and cyclophosphamide for relapsed and\/or refractory and treatment-naive patients with Waldenstrom macroglobulinemia","volume":"179","author":"Paludo","year":"2017","journal-title":"Br. J. Haematol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1016\/j.clml.2012.08.006","article-title":"Familial disease predisposition impacts treatment outcome in patients with Waldenstrom macroglobulinemia","volume":"12","author":"Treon","year":"2012","journal-title":"Clin. Lymphoma Myeloma Leuk."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"88","DOI":"10.5045\/br.2016.51.2.88","article-title":"Clinical characteristics and treatment outcomes of primary autoimmune hemolytic anemia: A single center study from South India","volume":"51","author":"Prabhu","year":"2016","journal-title":"Blood Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1097\/CMR.0000000000000453","article-title":"Vemurafenib in BRAF-mutant metastatic melanoma patients in real-world clinical practice: Prognostic factors associated with clinical outcomes","volume":"28","author":"Schouwenburg","year":"2018","journal-title":"Melanoma Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"249","DOI":"10.2147\/CMAR.S150960","article-title":"Comparative effectiveness of early-line nab-paclitaxel vs. paclitaxel in patients with metastatic breast cancer: A US community-based real-world analysis","volume":"10","author":"Mahtani","year":"2018","journal-title":"Cancer Manag. Res."},{"key":"ref_47","unstructured":"National Cancer Institute (2020, January 18). NCI Dictionary of Cancer Terms: End-of-Life Care, Available online: https:\/\/www.cancer.gov\/publications\/dictionaries\/cancer-terms\/def\/end-of-life-care."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/12\/8\/2311\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:01:57Z","timestamp":1760176917000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/12\/8\/2311"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,8,17]]},"references-count":47,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2020,8]]}},"alternative-id":["cancers12082311"],"URL":"https:\/\/doi.org\/10.3390\/cancers12082311","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,8,17]]}}}