Clinical Trial

. 2022 Mar;33(3):288-298.

doi: 10.1016/j.annonc.2021.12.002. Epub 2021 Dec 16.

The ECHELON-2 Trial: 5-year results of a randomized, phase III study of brentuximab vedotin with chemotherapy for CD30-positive peripheral T-cell lymphoma

S Horwitz¹, O A O'Connor², B Pro³, L Trümper⁴, S Iyer⁵, R Advani⁶, N L Bartlett⁷, J H Christensen⁸, F Morschhauser⁹, E Domingo-Domenech¹⁰, G Rossi¹¹, W S Kim¹², T Feldman¹³, T Menne¹⁴, D Belada¹⁵, Á Illés¹⁶, K Tobinai¹⁷, K Tsukasaki¹⁸, S-P Yeh¹⁹, A Shustov²⁰, A Hüttmann²¹, K J Savage²², S Yuen²³, P L Zinzani²⁴, H Miao²⁵, V Bunn²⁵, K Fenton²⁶, M Fanale²⁶, M Puhlmann²⁶, T Illidge²⁷

Affiliations

¹ Memorial Sloan Kettering Cancer Center, New York, USA. Electronic address: horwitzs@mskcc.org.
² University of Virginia Cancer Center, University of Virginia, Charlottesville, USA.
³ Division of Hematology and Oncology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, USA.
⁴ Universitätsmedizin Göttingen, Göttingen, Germany.
⁵ MD Anderson Cancer Center/University of Texas, Houston, USA.
⁶ Stanford Cancer Center, Blood and Marrow Transplant Program, Stanford, USA.
⁷ Washington University School of Medicine, St. Louis, USA.
⁸ Odense University Hospital, Odense, Denmark.
⁹ CHRU de Lille, Lille cedex, Nord-Pas-de-Calais, France.
¹⁰ Institut Catala D'oncologia, L'Hospitalet de Llobregat, Barcelona, Spain.
¹¹ Azienda Ospedaliera Spedali Civili di Brescia, Brescia, Italy.
¹² Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, Republic of Korea.
¹³ John Theurer Cancer Center, Hackensack Meridian Health School of Medicine, Hackensack, USA.
¹⁴ Freeman Hospital, Newcastle upon Tyne, UK.
¹⁵ Fourth Department of Internal Medicine - Haematology, Charles University Hospital and Faculty of Medicine, Hradec Králové, Czech Republic.
¹⁶ Debreceni Egyetem, Debrecen, Hajdu-Bihar, Hungary.
¹⁷ National Cancer Center Hospital, Tokyo, Japan.
¹⁸ Saitama Medical University International Medical Center, Saitama, Japan.
¹⁹ China Medical University Hospital, Taichung, Taiwan.
²⁰ University of Washington Medical Center, Seattle, USA.
²¹ Universitatsklinikum Essen, Essen, Nordrhein-Westfalen, Germany.
²² Department of Medical Oncology and University of British Columbia, BC Cancer, Vancouver, Canada.
²³ Calvary Mater Newcastle Hospital, Waratah, Australia.
²⁴ IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia 'Seràgnoli', Bologna, Italy; Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale, Università di Bologna, Bologna, Italy.
²⁵ Millennium Pharmaceuticals, Inc, Cambridge, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited.
²⁶ Seagen Inc., Bothell, USA.
²⁷ Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, NIHR Biomedical Research Centre, Manchester Academic Health Sciences Centre, Christie Hospital NHS Foundation Trust, Manchester, UK.

PMID: 34921960
PMCID: PMC9447792
DOI: 10.1016/j.annonc.2021.12.002

Clinical Trial

The ECHELON-2 Trial: 5-year results of a randomized, phase III study of brentuximab vedotin with chemotherapy for CD30-positive peripheral T-cell lymphoma

S Horwitz et al. Ann Oncol. 2022 Mar.

. 2022 Mar;33(3):288-298.

doi: 10.1016/j.annonc.2021.12.002. Epub 2021 Dec 16.

Authors

Affiliations

¹ Memorial Sloan Kettering Cancer Center, New York, USA. Electronic address: horwitzs@mskcc.org.
² University of Virginia Cancer Center, University of Virginia, Charlottesville, USA.
³ Division of Hematology and Oncology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, USA.
⁴ Universitätsmedizin Göttingen, Göttingen, Germany.
⁵ MD Anderson Cancer Center/University of Texas, Houston, USA.
⁶ Stanford Cancer Center, Blood and Marrow Transplant Program, Stanford, USA.
⁷ Washington University School of Medicine, St. Louis, USA.
⁸ Odense University Hospital, Odense, Denmark.
⁹ CHRU de Lille, Lille cedex, Nord-Pas-de-Calais, France.
¹⁰ Institut Catala D'oncologia, L'Hospitalet de Llobregat, Barcelona, Spain.
¹¹ Azienda Ospedaliera Spedali Civili di Brescia, Brescia, Italy.
¹² Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, Republic of Korea.
¹³ John Theurer Cancer Center, Hackensack Meridian Health School of Medicine, Hackensack, USA.
¹⁴ Freeman Hospital, Newcastle upon Tyne, UK.
¹⁵ Fourth Department of Internal Medicine - Haematology, Charles University Hospital and Faculty of Medicine, Hradec Králové, Czech Republic.
¹⁶ Debreceni Egyetem, Debrecen, Hajdu-Bihar, Hungary.
¹⁷ National Cancer Center Hospital, Tokyo, Japan.
¹⁸ Saitama Medical University International Medical Center, Saitama, Japan.
¹⁹ China Medical University Hospital, Taichung, Taiwan.
²⁰ University of Washington Medical Center, Seattle, USA.
²¹ Universitatsklinikum Essen, Essen, Nordrhein-Westfalen, Germany.
²² Department of Medical Oncology and University of British Columbia, BC Cancer, Vancouver, Canada.
²³ Calvary Mater Newcastle Hospital, Waratah, Australia.
²⁴ IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia 'Seràgnoli', Bologna, Italy; Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale, Università di Bologna, Bologna, Italy.
²⁵ Millennium Pharmaceuticals, Inc, Cambridge, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited.
²⁶ Seagen Inc., Bothell, USA.
²⁷ Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, NIHR Biomedical Research Centre, Manchester Academic Health Sciences Centre, Christie Hospital NHS Foundation Trust, Manchester, UK.

PMID: 34921960
PMCID: PMC9447792
DOI: 10.1016/j.annonc.2021.12.002

Abstract

Background: For patients with peripheral T-cell lymphoma (PTCL), outcomes using frontline treatment with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or CHOP-like therapy are typically poor. The ECHELON-2 study demonstrated that brentuximab vedotin plus cyclophosphamide, doxorubicin, and prednisone (A+CHP) exhibited statistically superior progression-free survival (PFS) per independent central review and improvements in overall survival versus CHOP for the frontline treatment of patients with systemic anaplastic large cell lymphoma or other CD30-positive PTCL.

Patients and methods: ECHELON-2 is a double-blind, double-dummy, randomized, placebo-controlled, active-comparator phase III study. We present an exploratory update of the ECHELON-2 study, including an analysis of 5-year PFS per investigator in the intent-to-treat analysis group.

Results: A total of 452 patients were randomized (1 : 1) to six or eight cycles of A+CHP (N = 226) or CHOP (N = 226). At median follow-up of 47.6 months, 5-year PFS rates were 51.4% [95% confidence interval (CI): 42.8% to 59.4%] with A+CHP versus 43.0% (95% CI: 35.8% to 50.0%) with CHOP (hazard ratio = 0.70; 95% CI: 0.53-0.91), and 5-year overall survival (OS) rates were 70.1% (95% CI: 63.3% to 75.9%) with A+CHP versus 61.0% (95% CI: 54.0% to 67.3%) with CHOP (hazard ratio = 0.72; 95% CI: 0.53-0.99). Both PFS and OS were generally consistent across key subgroups. Peripheral neuropathy was resolved or improved in 72% (84/117) of patients in the A+CHP arm and 78% (97/124) in the CHOP arm. Among patients who relapsed and subsequently received brentuximab vedotin, the objective response rate was 59% with brentuximab vedotin retreatment after A+CHP and 50% with subsequent brentuximab vedotin after CHOP.

Conclusions: In this 5-year update of ECHELON-2, frontline treatment of patients with PTCL with A+CHP continues to provide clinically meaningful improvement in PFS and OS versus CHOP, with a manageable safety profile, including continued resolution or improvement of peripheral neuropathy.

Keywords: CHOP; brentuximab vedotin; frontline treatment; overall survival; peripheral T-cell lymphoma; randomized clinical trial.

PubMed Disclaimer

Conflict of interest statement

Disclosure SH reports receiving research support from ADC Therapeutics, Affimed, Aileron, Celgene, Daiichi Sankyo, Forty Seven, Kyowa Hakko Kirin, Millennium/Takeda, Seagen, Trillium Therapeutics, and Verastem/Secura Bio; and consulting for Acrotech Biopharma, ADC Therapeutics, Astex, C4 Therapeutics, Celgene, Janssen, Kura Oncology, Kyowa Hakko Kirin, Myeloid Therapeutics, ONO Pharmaceuticals, Seagen, Secura Bio, Shoreline Biosciences, Takeda, Trillium Therapeutics, Tubulis, Verastem, and Vividion Therapeutics. OAO reports advisory membership for Mundipharma, Kymera, Dren Bio, Myeloid Therapeutics, NomoCan; corporate board membership for NomoCan; consultancy for Mundipharma, Servier, Ping; employment with TG therapeutics; equity ownership of TG Therapeutics, Myeloid Therapeutics, Kymera, NomoCan, Dren Bio; honoraria from Mundipharma, Servier, and Pint; research funding from Merck, Bristol Myers Squibb (BMS)/Celgene, Astex, Kymera; and travel expenses from Mundipharma, Servier, and TG Therapeutics. BP reports consultancy, honoraria, research funding, and travel expenses for Seagen; and honoraria and travel expenses for Takeda. LT reports consultancy for Janssen, Nordic Nanovector, and Takeda Europe; and research funding from Mundipharma, Roche, Seagen, and Takeda Europe. SI reports receiving research funding from Seagen, Merck, CRISPRx, Innate, Affimed, Rhizen, Spectrum, Trillium, and Cellectis; and honoraria from Targeted Oncology and Curio Science. RA reports consultancy for AstraZeneca, Bayer Healthcare Pharmaceuticals, Celgene, Cell Medica, Genentech/Roche, Gilead, Kite Pharma, Kyowa, Portola Pharmaceuticals, Sanofi, Seagen, and Takeda; and research funding from Celgene, Forty Seven, Genentech/Roche, Janssen Pharma, Kura, Merck, Millenium, Pharmacyclics, Regeneron, and Seagen. NLB reports advisory boards for ADC Therapeutics, Roche/Genentech, and Seagen; and research funding from ADC Therapeutics, Affimed, Autolus, BMS, Celgene, Forty Seven, Janssen, Kite Pharma, Merck, Millennium, Pharmacyclics, Roche/Genentech, and Seagen. FM reports advisory board membership for AbbVie, Celgene/BMS, Epizyme, Gilead, Roche; consultancy for Gilead, Roche, Servier; and honoraria from Janssen and Roche. ED-D reports advisory board and corporate board membership for Takeda, and travel expenses for BMS, Roche, and Takeda. GR reports advisory board membership for AbbVie, Amgen, Celgene, Gilead, Janssen, Jazz, Pfizer, Roche, Sanofi, Teva; honoraria from BMS, Daiichi, Mundipharma, Novartis, Sandoz; research funding from Seagen; and travel expenses from Alexion, Celgene, and Gilead. WSK reports receiving research funding/grants from Celltrion, Donga, Johnson & Johnson, Kyowa Hakko Kirin, Mundipharma, Pfizer, Roche, Seagen, and Takeda. TF reports advisory board membership for Bayer, BMS, Seagen, consultancy for AstraZeneca, Bayer, BMS, Kyowa Kirin, MorphoSys, Seagen; honoraria for AbbVie, Bayer, BMS, Kite Pharma, Pharmacyclics, Seagen, Takeda; research funding for Amgen, BMS, Celgene, Cell Medica, Corvus, Eisai, Kyowa Hakko Kirin, Pfizer, Portola Pharma, Roche, Seagen, Trillium, Viracta; speaker's bureau for AbbVie, Celgene, Janssen, Kite Pharma, Pharmacyclics, Seagen; and travel expenses for AbbVie, Kite Pharma, Pharmacyclics, Seagen, Takeda. TM reports receiving honoraria from Amgen, Atara, Celgene, Daiichi Sankyo, Janssen, Kite/Gilead, Novartis, Pfizer, Roche, and Takeda; research funding from AstraZeneca, Janssen, and Novartis, and travel expenses from Amgen, Bayer, Celgene, Jazz, Kite/Gilead, Kyowa Kirin, and Pfizer. DB reports advisory board membership for Gilead and Roche; consultancy for Gilead, Janssen, and Roche; research funding from Celgene, Janssen, Roche, and Takeda; and travel expenses from Gilead and Roche. ÁI reports advisory board membership and corporate board membership for Celgene, Janssen, Novartis, Roche, and Takeda; research funding from Seagen and Takeda; and travel expenses from Roche and Takeda. KTo reports consultancy for Celgene, Chugai Pharma, Daiichi Sankyo, HUYA Bioscience International, Kyowa Kirin, Mundipharma, Ono Pharmaceutical, SymBio, Takeda, Yakult, and Zenyaku Kogyo; and honoraria from BMS-Celgene, Chugai Pharma, Daiichi Sankyo, Eisai, HUYA Bioscience International, Kyowa Kirin, Mundipharma, Ono Pharma, Solasia Pharma, Takeda, Yakult, and Zenyaku Kogyo. KTs reports consultancy for Daiichi Sankyo, HUYA, Ono Pharma, Meiji Seika Pharma, and Yakuruto; honoraria from Celgene, Chugai Pharma, Kyowa Hakko Kirin, and Mundy Pharma; research funding from Chugai Pharma, Eisai, HUYA, Seagen, Kyowa Hakko Kirin, Byer, Celgene, and Daiichi-Sankyo. S-PY reports an advisory role for AbbVie, Amgen, Janssen, Astellas, Astex, Novartis, Sanofi, and Takeda. AS reports consulting for Acrotech, BMS-Celgene, Kyowa Hakko Kirin, TG Therapeutics, and Verastem. AH reports receiving research funding from Seagen and travel expenses from Celgene and Roche. KS reports consultancy for AbbVie, AstraZeneca, BMS, Gilead, Merck, Seagen, Servier, Kyowa, Novartis Canada; honoraria from AbbVie, AstraZeneca, BMS, Gilead, Kyowa Kirin, Merck, Novartis, Novartis Canada Pharma, Seagen; research funding from BMS, Roche; and travel expenses from Seagen. SY reports receiving research funding and travel expenses from Seagen. PLZ reports advisory board membership with AbbVie, Gilead, Incyte, Merck, Portola, Roche, Sanofi, Servier, and Takeda; consultancy for BMS, Celgene, Celltron, Eusapharma, Gilead, Immune Design, Janssen-Cilag, Kyowa Kirin, Merck Sharp & Dohme (MSD), Roche, Sandoz, Verastem; honoraria from AbbVie, ADC Therapeutics, BMS, Debiopharm, EUSA Pharma, Gilead, Incyte, Janssen, Kyowa Kirin, Merck, Roche, Servier, Takeda, TG Therapeutics, Verastem; research funding from Portola; and speaker's bureau for AbbVie, ADC Therapeutics, BMS, Celgene, Celltron, EUSA Pharma, Gilead, Immune Design, Incyte, Janssen, Janssen-Cilag, Kyowa Kirin, Merck, MSD, Portola, Roche, Sandoz, Servier, Takeda, TG Therapeutics, and Verastem. HM and VB report employment for Takeda. KF, MF, and MP report being employed by and holding shares in Seagen. TI reports advisory board membership and speaker's bureau for Takeda. All other authors have declared no conflicts of interest.

Figures

**Figure 1.. Progression-free survival per investigator by treatment arm.**
Kaplan–Meier estimates of progression-free survival per investigator by treatment arm for the intent-to-treat population (A) and for patients with systemic anaplastic large cell lymphoma (sALCL) (B). Tick marks indicate censored data. Hazard ratios (A+CHP/CHOP) and 95% CIs were based on a stratified Cox’s proportional hazard regression model with treatment as the explanatory variable. Stratification factors included histologic subtype (ALK+ sALCL versus all other histologies) and baseline international prognostic index (IPI) score (0–1 versus 2–3 versus 4–5). P values were calculated using a stratified log-rank test. P values are nominal and not adjusted for multiplicity. A+CHP, brentuximab vedotin, cyclophosphamide, doxorubicin, and prednisone; CHOP, cyclophosphamide, doxorubicin, vincristine, and prednisone; CI, confidence interval; HR, hazard ratio.

**Figure 2.. Hazard ratios for progression-free survival per investigator in key prespecified subgroups.**
This forest plot shows hazard ratios for progression-free survival per investigator in key prespecified subgroups. Hazard ratios are calculated based on a stratified Cox’s proportional hazard regression model considering stratified factors from randomization. A+CHP, brentuximab vedotin, cyclophosphamide, doxorubicin, and prednisone; AITL, angioimmunoblastic T-cell lymphoma; ALK, anaplastic lymphoma kinase; ATLL, adult T-cell leukemia/lymphoma; CHOP, cyclophosphamide, doxorubicin, vincristine, and prednisone; CI, confidence interval; EATL, enteropathy-associated T-cell lymphoma; ECOG, Eastern Cooperative Oncology Group; IPI, international prognostic index; ITT, intent-to-treat; PFS, progression-free survival; PTCL-NOS, peripheral T-cell lymphoma-not otherwise specified; sALCL, systemic anaplastic large cell lymphoma.

**Figure 3.. Overall survival by treatment arm.**
Kaplan-Meier estimates of overall survival by treatment arm for the intent-to-treat population (A) and for patients with sALCL (B). Tick marks indicate censored data. Hazard ratios (A+CHP/CHOP) and 95% CIs were based on a stratified Cox’s proportional hazard regression model with treatment as the explanatory variable. Stratification factors included histologic subtype (ALK+ sALCL versus all other histologies) and baseline IPI score (0–1 versus 2–3 versus 4–5). P values were calculated using a stratified log-rank test. P values are nominal and not adjusted for multiplicity. A+CHP, brentuximab vedotin, cyclophosphamide, doxorubicin, and prednisone; CHOP, cyclophosphamide, doxorubicin, vincristine, and prednisone; CI, confidence interval; HR, hazard ratio.

**Figure 4.. Hazard ratios for overall survival per investigator in key prespecified subgroups.**
This forest plot shows overall survival in key prespecified subgroups. Hazard ratios are calculated based on a stratified Cox’s proportional hazard regression model considering stratified factors from randomization. A+CHP, brentuximab vedotin, cyclophosphamide, doxorubicin, and prednisone; AITL, angioimmunoblastic T-cell lymphoma; ALK, anaplastic lymphoma kinase; ATLL, adult T-cell leukemia/lymphoma; CHOP, cyclophosphamide, doxorubicin, vincristine, and prednisone; CI, confidence interval; EATL, enteropathy-associated T-cell lymphoma; ECOG, Eastern Cooperative Oncology Group; IPI, international prognostic index; ITT, intent-to-treat; PFS, progression-free survival; PTCL-NOS, peripheral T-cell lymphoma-not otherwise specified; sALCL, systemic anaplastic large cell lymphoma.

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The ECHELON-2 Trial: 5-year results of a randomized, phase III study of brentuximab vedotin with chemotherapy for CD30-positive peripheral T-cell lymphoma

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The ECHELON-2 Trial: 5-year results of a randomized, phase III study of brentuximab vedotin with chemotherapy for CD30-positive peripheral T-cell lymphoma

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