Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Cancer Chemotherapy and Pharmacology
Published in: Cancer Chemotherapy and Pharmacology 5/2019

Open Access 01-05-2019 | osteosarcoma | Original Article

A novel method to address the association between received dose intensity and survival outcome: benefits of approaching treatment intensification at a more individualised level in a trial of the European Osteosarcoma Intergroup

Authors: Carlo Lancia, Jakob K. Anninga, Matthew R. Sydes, Cristian Spitoni, Jeremy Whelan, Pancras C. W. Hogendoorn, Hans Gelderblom, Marta Fiocco

Published in: Cancer Chemotherapy and Pharmacology | Issue 5/2019

Login to get access

Abstract

Purpose

There is lack of consensus on the prognostic value of received high dose intensity in osteosarcoma survivorship. Many studies have not shown a clear survival benefit when dose intensity is increased. The aim of this study is to go beyond chemotherapy intensification by arm-wide escalation of intended dose and/or compression of treatment schedule, while conversely addressing the relationship between treatment intensity and survival at the patient level. The study focusses on the difference in outcome results, based on a novel, progressively more individualised approach to dose intensity.

Methods

A retrospective analysis of data from MRC BO06/EORTC 80931 randomised controlled trial for treatment of osteosarcoma was conducted. Three types of post hoc patient groups are formed using the intended regimen: the individually achieved cumulative dose and time on treatment, and the increase of individual cumulative dose over time. Event-free survival is investigated and compared in these three stratifications.

Results

The strata of intended regimen and achieved treatment yields equivalent results. Received cumulative dose over time produces groups with evident different survivorship characteristics. In particular, it highlights a group of patients with an estimated 3-year event-free survival much larger (more than 10%) than other patient groups. This group mostly contains patients randomised to an intensified regimen. In addition, adverse events reported by that group show the presence of increased preoperative myelotoxicity.

Conclusions

The manuscript shows the benefits of analyzing studies by using longitudinal data, e.g. recorded per cycle. This has impact on the drafting of future trials by showing why such a level of detail is needed for both treatment and adverse event data. The novel method proposed, based on cumulative dose received over time, shows that longitudinal treatment data might be used to link survival outcome with drug metabolism. This is particularly valuable when pharmacogenetics data for metabolism of cytotoxic agents are not collected.

Trial registration

ISRCTN86294690.
Appendix
Available only for authorised users
Literature
1.
Hryniuk WM, Goodyear M (1990) The calculation of received dose intensity. J Clin Oncol 8(12):1935–1937CrossRefPubMed
2.
Hryniuk WM, Frei E 3rd, Wright FA (1998) A single scale for comparing dose-intensity of all chemotherapy regimens in breast cancer: summation dose-intensity. J Clin Oncol 16(9):3137–3147CrossRefPubMed
3.
Citron ML (2004) Dose density in adjuvant chemotherapy for breast cancer. Cancer Investig 22(4):555–568CrossRef
4.
Wildiers H, Reiser M (2001) Relative dose intensity of chemotherapy and its impact on outcomes in patients with early breast cancer or aggressive lymphoma. Crit Rev Oncol Hematol 77(3):221–240CrossRef
5.
Yuan JQ, Wang SM, Tang LL, Mao J, Wu YH, Hai J et al (2015) Relative dose intensity and therapy efficacy in different breast cancer molecular subtypes: a retrospective study of early stage breast cancer patients treated with neoadjuvant chemotherapy. Breast Cancer Res Treat 151(2):405–413CrossRefPubMed
6.
Shirotake S, Yasumizu Y, Ito K, Masunaga A, Ito Y, Miyazaki Y et al (2016) Impact of second-line targeted therapy dose intensity on patients with metastatic renal cell carcinoma. Clin Genitourin Cancer 14(6):e575–e583CrossRefPubMed
7.
Yabusaki N, Fujii T, Yamada S, Murotani K, Sugimoto H, Kanda M et al. The significance of relative dose intensity in adjuvant chemotherapy of pancreatic ductal adenocarcinoma—including the analysis of clinicopathological factors influencing relative dose intensity. Medicine 2016;95(29):e4282CrossRefPubMedPubMedCentral
8.
Loschi S, Dufour C, Oberlin O, Goma G, Valteau-Couanet D, Gaspar N (2015) Tandem high-dose chemotherapy strategy as first-line treatment of primary disseminated multifocal Ewing sarcomas in children, adolescents and young adults. Bone Marrow Transplant 50(8):1083–1088CrossRefPubMed
9.
10.
Livingston RB (1994) Dose intensity and high dose therapy: two different concepts. Cancer 74(S3):1177–1183CrossRefPubMed
11.
Lewis IJ, Nooij MA, Whelan J, Sydes MR, Grimer R, Hogendoorn PC et al (2007) Improvement in histologic response but not survival in osteosarcoma patients treated with intensified chemotherapy: a randomized phase III trial of the European Osteosarcoma Intergroup. J Natl Cancer Inst 99(2):112–128CrossRefPubMed
12.
Marina N, Bielack S, Whelan J, Smeland S, Krailo M, Sydes MR et al (2009) International collaboration is feasible in trials for rare conditions: the EURAMOS experience. In: Jaffe N, Bruland OS, Bielack S (eds) Pediatric and adolescent osteosarcoma. Springer, Boston, pp 339–353CrossRef
13.
Marina NM, Smeland S, Bielack SS, Bernstein M, Jovic G, Krailo MD et al (2016) Comparison of MAPIE versus MAP in patients with a poor response to preoperative chemotherapy for newly diagnosed high-grade osteosarcoma (EURAMOS-1): an open-label, international, randomised controlled trial. Lancet Oncol 17(10):1396–1408CrossRefPubMedPubMedCentral
14.
Lewis IJ, Weeden S, Machin D, Stark D, Craft AW, European Osteosarcoma Intergroup (2000) Received dose and dose-intensity of chemotherapy and outcome in nonmetastatic extremity osteosarcoma. J Clin Oncol 18(24):4028–4037CrossRefPubMed
15.
Collins M, Wilhelm M, Conyers R, Herschtal A, Whelan J, Bielack S et al (2013) Benefits and adverse events in younger versus older patients receiving neoadjuvant chemotherapy for osteosarcoma: findings from a meta-analysis. J Clin Oncol 31(18):2303–2312CrossRefPubMed
16.
Windsor RE, Strauss SJ, Kallis C, Wood NE, Whelan JS (2012) Germline genetic polymorphisms may influence chemotherapy response and disease outcome in osteosarcoma. Cancer 118(7):1856–1867CrossRefPubMed
17.
Hagleitner MM, Coenen MJ, Gelderblom H, Makkinje RR, Vos HI, de Bont ES et al (2015) A first step toward personalized medicine in osteosarcoma: pharmacogenetics as predictive marker of outcome after chemotherapy-based treatment. Clin Cancer Res 21(15):3436–3441CrossRefPubMed
18.
Ray-Coquard I, Cropet C, Van Glabbeke M, Sebban C, Le Cesne A, Judson I et al (2009) Lymphopenia as a prognostic factor for overall survival in advanced carcinomas, sarcomas, and lymphomas. Cancer Res 69(13):5383–5391CrossRefPubMedPubMedCentral
19.
Lancia C, Anninga J, Spitoni C, Sydes MR, Whelan J, Hogendoorn PCW, Gelderblom AJ, Fiocco M (2018) A method to measure the mismatch between target and achieved received dose intensity of chemotherapy in cancer studies: the application to osteosarcoma randomised trial MRC-BO06. BMJ Open (Accepted)
20.
McKinney W. Data structures for statistical computing in Python. In: Proceedings of the 9th Python in science conference; 2010 Jun 28, Austin, TX, pp 51–56
21.
Pedregosa F, Varoquaux G, Gramfort A, Michel V, Thirion B, Grisel O et al (2011) Scikit-learn: machine learning in Python. J Mach Learn Res 12(Oct):2825–2830
22.
23.
Luetke A, Meyers PA, Lewis I, Juergens H (2014) Osteosarcoma treatment—where do we stand? A state of the art review. Cancer Treat Rev 40(4):523–532CrossRefPubMed
24.
Ta HT, Dass CR, Choong PF, Dunstan DE (2009) Osteosarcoma treatment: state of the art. Cancer Metastasis Rev 28:247–263CrossRefPubMed
25.
Kimura K, Takayanagi R, Fukushima T, Yamada Y (2017) Theoretical method for evaluation of therapeutic effects and adverse effects of epidermal growth factor receptor tyrosine kinase inhibitors in clinical treatment. Med Oncol 34(10):178CrossRefPubMed
26.
Van Cutsem E, Tejpar S, Vanbeckevoort D, Peeters M, Humblet Y, Gelderblom H et al (2012) Intrapatient cetuximab dose escalation in metastatic colorectal cancer according to the grade of early skin reactions: the randomized EVEREST study. J Clin Oncol 30(23):2861–2868CrossRefPubMed
27.
Kanekiyo S, Hazama S, Kondo H, Nagashima A, Eto R, Yoshida S et al (2013) UDP-glucuronosyltransferase (UGT) 1A1* 28 polymorphism-directed phase II study of irinotecan with 5′-deoxy-5-fluorouridine (5′-DFUR) for metastatic colorectal cancer. Anticancer Res 33(8):3423–3430PubMed
28.
McTiernan A, Jinks RC, Sydes MR, Uscinska B, Hook JM, van Glabbeke M et al (2012) Presence of chemotherapy-induced toxicity predicts improved survival in patients with localised extremity osteosarcoma treated with doxorubicin and cisplatin: a report from the European Osteosarcoma Intergroup. Eur J Cancer 48(5):703–712CrossRefPubMedPubMedCentral
Metadata
Title
A novel method to address the association between received dose intensity and survival outcome: benefits of approaching treatment intensification at a more individualised level in a trial of the European Osteosarcoma Intergroup
Authors
Carlo Lancia
Jakob K. Anninga
Matthew R. Sydes
Cristian Spitoni
Jeremy Whelan
Pancras C. W. Hogendoorn
Hans Gelderblom
Marta Fiocco
Publication date
01-05-2019
Publisher
Springer Berlin Heidelberg
Published in
Cancer Chemotherapy and Pharmacology / Issue 5/2019
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI
https://doi.org/10.1007/s00280-019-03797-3

Other articles of this Issue 5/2019

Cancer Chemotherapy and Pharmacology 5/2019 Go to the issue

Original Article

SCMCIE94: an intensified pilot treatment protocol known to be associated with cure in CD 56-negative non-pelvic isolated Ewing sarcoma (EWS) is also associated with no early relapses in non-metastatic extremity EWS

Original Article

Disruption of CTLA-4 expression on peripheral blood CD8 + T cell enhances anti-tumor efficacy in bladder cancer

Short Communication

Eligibility criteria for phase I clinical trials: tight vs loose?

Original Article

Potential drug–drug interactions and nephrotoxicity in hematopoietic stem cell transplant adult recipients during bone marrow transplantation unit stay

Original Article

Re-challenge of afatinib after 1st generation EGFR-TKI failure in patients with previously treated non-small cell lung cancer harboring EGFR mutation

Original Article

CDA and MTHFR polymorphisms are associated with clinical outcomes in gastroenteric cancer patients treated with capecitabine-based chemotherapy
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits