Rituximab-dose-dense chemotherapy with or without high-dose chemotherapy plus autologous stem-cell transplantation in high-risk diffuse large B-cell lymphoma (DLCL04)

Annalisa Chiappella, Maurizio Martelli, Emanuele Angelucci, Ercole Brusamolino, Andrea Evangelista, Angelo Michele Carella, Caterina Stelitano, Giuseppe Rossi, Monica Balzarotti, Francesco Merli, Gianluca Gaidano, Vincenzo Pavone, Luigi Rigacci, Francesco Zaja, Alfonso D'Arco, Nicola Cascavilla, Eleonora Russo, Alessia Castellino, Manuel Gotti, Angela Giovanna CongiuMaria Giuseppina Cabras, Alessandra Tucci, Claudio Agostinelli, Giovannino Ciccone, Stefano A Pileri, Umberto Vitolo

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Abstract

BACKGROUND: The prognosis of young patients with diffuse large B-cell lymphoma at high risk (age-adjusted International Prognostic Index [aa-IPI] score 2 or 3) treated with R-CHOP (rituximab, cyclophosphamide, vincristine, doxorubicin, and prednisone) is poor. The aim of this study was to investigate the possible benefit of intensification with high-dose chemotherapy and autologous stem-cell transplantation as part of first-line treatment in these patients.METHODS: We did a multicentre, open-label, randomised, controlled, phase 3 trial with a 2 × 2 factorial design to compare, at two different R-CHOP dose levels, a full course of rituximab-dose-dense chemotherapy (no transplantation group) versus an abbreviated course of rituximab-dose-dense chemotherapy followed by consolidation with R-MAD (rituximab plus high-dose cytarabine plus mitoxantrone plus dexamethasone) and high-dose BEAM chemotherapy (carmustine, etoposide, cytarabine, and melphalan) plus autologous stem-cell transplantation (transplantation group) in young patients (18-65 years) with untreated high-risk diffuse large B-cell lymphoma (aa-IPI score 2-3). At enrolment, patients were stratified according to aa-IPI score and randomly assigned (1:1:1:1) to receive R-CHOP (intravenous rituximab 375 mg/m(2), cyclophosphamide 750 mg/m(2), doxorubicin 50 mg/m(2), and vincristine 1·4 mg/m(2) on day 1, plus oral prednisone 100 mg on days 1-5) delivered in a 14-day cycle (R-CHOP-14) for eight cycles; high-dose R-CHOP-14 (R-MegaCHOP-14; R-CHOP-14 except for cyclophosphamide 1200 mg/m(2) and doxorubicin 70 mg/m(2)) for six cycles; R-CHOP-14 for four cycles followed by R-MAD (intravenous rituximab 375 mg/m(2) on day 1 or 4 plus intravenous cytarabine 2000 mg/m(2) and dexamethasone 4 mg/m(2) every 12 h on days 1-3 plus intravenous mitoxantrone 8 mg/m(2) on days 1-3) plus BEAM (intravenous carmustine 300 mg/m(2) on day -7, intravenous cytarabine 200 mg/m(2) twice a day on days -6 to -3, intravenous etoposide 100 mg/m(2) twice a day on days -6 to -3, plus intravenous melphalan 140 mg/m(2) on day -2) and autologous stem-cell transplantation (day 0); or R-MegaCHOP-14 for four cycles followed by R-MAD plus BEAM and autologous stem-cell transplantation. The primary endpoint was failure-free survival at 2 years in the intention-to-treat population. This study is registered with EudraCT (2005-002181-14; 2007-000275-42) and with ClinicalTrials.gov, number NCT00499018.FINDINGS: Between Jan 10, 2006, and Sept 8, 2010, 399 patients were randomly assigned to receive transplantation (n=199) or no transplantation (n=200); 203 patients were assigned to receive R-CHOP-14 and 196 were assigned to receive R-MegaCHOP-14. With a median follow-up of 72 months (IQR 57-88), 2-year failure-free survival was 71% (95% CI 64-77) in the transplantation group versus 62% (95% CI 55-68) in the no transplantation group (hazard ratio [HR] 0·65 [95% CI 0·47-0·91]; stratified log-rank test p=0·012). No difference in 5-year overall survival was observed between these groups (78% [95% CI 71-83] versus 77% [71-83]; HR 0·98 [0·65-1·48]; stratified log-rank test p=0·91). Grade 3 or worse haematological adverse events were reported in 183 (92%) of 199 patients in the transplantation group versus 135 (68%) of 200 patients in the no transplantation group. Grade 3 or worse non-haematological adverse events were reported in 90 (45%) versus 31 (16%); the most common grade 3 or worse non-haematological adverse event was gastrointestinal (49 [25%] vs 19 [10%]). Treatment-related deaths occurred in 13 (3%) patients; eight in the transplantation group and five in the no transplantation group.INTERPRETATION: Abbreviated rituximab-dose-dense chemotherapy plus R-MAD plus BEAM and autologous stem-cell transplantation reduced the risk of treatment failure compared with full course rituximab-dose-dense chemotherapy in young patients with diffuse large B-cell lymphoma at high risk. However, these results might not be clinically meaningful, since this improvement did not reflect an improvement in overall survival. These results do not support further consideration of the use of intensification of R-CHOP as an upfront strategy in patients with diffuse large B-cell lymphoma with poor prognosis.FUNDING: Fondazione Italiana Linfomi.
Original languageEnglish
Pages (from-to)1076-1088
Number of pages13
JournalThe Lancet Oncology
Volume18
Issue number8
DOIs
Publication statusPublished - Aug 2017

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Lymphoma, Large B-Cell, Diffuse
Stem Cell Transplantation
Transplantation
Drug Therapy
Cytarabine
Doxorubicin
Cyclophosphamide
Carmustine
Mitoxantrone
Melphalan
Survival
Vincristine
Etoposide
Prednisone
Dexamethasone
Rituximab
Consolidation Chemotherapy
Treatment Failure

Keywords

  • Journal Article

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Rituximab-dose-dense chemotherapy with or without high-dose chemotherapy plus autologous stem-cell transplantation in high-risk diffuse large B-cell lymphoma (DLCL04). / Chiappella, Annalisa; Martelli, Maurizio; Angelucci, Emanuele; Brusamolino, Ercole; Evangelista, Andrea; Carella, Angelo Michele; Stelitano, Caterina; Rossi, Giuseppe; Balzarotti, Monica; Merli, Francesco; Gaidano, Gianluca; Pavone, Vincenzo; Rigacci, Luigi; Zaja, Francesco; D'Arco, Alfonso; Cascavilla, Nicola; Russo, Eleonora; Castellino, Alessia; Gotti, Manuel; Congiu, Angela Giovanna; Cabras, Maria Giuseppina; Tucci, Alessandra; Agostinelli, Claudio; Ciccone, Giovannino; Pileri, Stefano A; Vitolo, Umberto.

In: The Lancet Oncology, Vol. 18, No. 8, 08.2017, p. 1076-1088.

Research output: Contribution to journalArticle

Chiappella, A, Martelli, M, Angelucci, E, Brusamolino, E, Evangelista, A, Carella, AM, Stelitano, C, Rossi, G, Balzarotti, M, Merli, F, Gaidano, G, Pavone, V, Rigacci, L, Zaja, F, D'Arco, A, Cascavilla, N, Russo, E, Castellino, A, Gotti, M, Congiu, AG, Cabras, MG, Tucci, A, Agostinelli, C, Ciccone, G, Pileri, SA & Vitolo, U 2017, 'Rituximab-dose-dense chemotherapy with or without high-dose chemotherapy plus autologous stem-cell transplantation in high-risk diffuse large B-cell lymphoma (DLCL04)', The Lancet Oncology, vol. 18, no. 8, pp. 1076-1088. https://doi.org/10.1016/S1470-2045(17)30444-8
Chiappella, Annalisa ; Martelli, Maurizio ; Angelucci, Emanuele ; Brusamolino, Ercole ; Evangelista, Andrea ; Carella, Angelo Michele ; Stelitano, Caterina ; Rossi, Giuseppe ; Balzarotti, Monica ; Merli, Francesco ; Gaidano, Gianluca ; Pavone, Vincenzo ; Rigacci, Luigi ; Zaja, Francesco ; D'Arco, Alfonso ; Cascavilla, Nicola ; Russo, Eleonora ; Castellino, Alessia ; Gotti, Manuel ; Congiu, Angela Giovanna ; Cabras, Maria Giuseppina ; Tucci, Alessandra ; Agostinelli, Claudio ; Ciccone, Giovannino ; Pileri, Stefano A ; Vitolo, Umberto. / Rituximab-dose-dense chemotherapy with or without high-dose chemotherapy plus autologous stem-cell transplantation in high-risk diffuse large B-cell lymphoma (DLCL04). In: The Lancet Oncology. 2017 ; Vol. 18, No. 8. pp. 1076-1088.
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title = "Rituximab-dose-dense chemotherapy with or without high-dose chemotherapy plus autologous stem-cell transplantation in high-risk diffuse large B-cell lymphoma (DLCL04)",
abstract = "BACKGROUND: The prognosis of young patients with diffuse large B-cell lymphoma at high risk (age-adjusted International Prognostic Index [aa-IPI] score 2 or 3) treated with R-CHOP (rituximab, cyclophosphamide, vincristine, doxorubicin, and prednisone) is poor. The aim of this study was to investigate the possible benefit of intensification with high-dose chemotherapy and autologous stem-cell transplantation as part of first-line treatment in these patients.METHODS: We did a multicentre, open-label, randomised, controlled, phase 3 trial with a 2 × 2 factorial design to compare, at two different R-CHOP dose levels, a full course of rituximab-dose-dense chemotherapy (no transplantation group) versus an abbreviated course of rituximab-dose-dense chemotherapy followed by consolidation with R-MAD (rituximab plus high-dose cytarabine plus mitoxantrone plus dexamethasone) and high-dose BEAM chemotherapy (carmustine, etoposide, cytarabine, and melphalan) plus autologous stem-cell transplantation (transplantation group) in young patients (18-65 years) with untreated high-risk diffuse large B-cell lymphoma (aa-IPI score 2-3). At enrolment, patients were stratified according to aa-IPI score and randomly assigned (1:1:1:1) to receive R-CHOP (intravenous rituximab 375 mg/m(2), cyclophosphamide 750 mg/m(2), doxorubicin 50 mg/m(2), and vincristine 1·4 mg/m(2) on day 1, plus oral prednisone 100 mg on days 1-5) delivered in a 14-day cycle (R-CHOP-14) for eight cycles; high-dose R-CHOP-14 (R-MegaCHOP-14; R-CHOP-14 except for cyclophosphamide 1200 mg/m(2) and doxorubicin 70 mg/m(2)) for six cycles; R-CHOP-14 for four cycles followed by R-MAD (intravenous rituximab 375 mg/m(2) on day 1 or 4 plus intravenous cytarabine 2000 mg/m(2) and dexamethasone 4 mg/m(2) every 12 h on days 1-3 plus intravenous mitoxantrone 8 mg/m(2) on days 1-3) plus BEAM (intravenous carmustine 300 mg/m(2) on day -7, intravenous cytarabine 200 mg/m(2) twice a day on days -6 to -3, intravenous etoposide 100 mg/m(2) twice a day on days -6 to -3, plus intravenous melphalan 140 mg/m(2) on day -2) and autologous stem-cell transplantation (day 0); or R-MegaCHOP-14 for four cycles followed by R-MAD plus BEAM and autologous stem-cell transplantation. The primary endpoint was failure-free survival at 2 years in the intention-to-treat population. This study is registered with EudraCT (2005-002181-14; 2007-000275-42) and with ClinicalTrials.gov, number NCT00499018.FINDINGS: Between Jan 10, 2006, and Sept 8, 2010, 399 patients were randomly assigned to receive transplantation (n=199) or no transplantation (n=200); 203 patients were assigned to receive R-CHOP-14 and 196 were assigned to receive R-MegaCHOP-14. With a median follow-up of 72 months (IQR 57-88), 2-year failure-free survival was 71{\%} (95{\%} CI 64-77) in the transplantation group versus 62{\%} (95{\%} CI 55-68) in the no transplantation group (hazard ratio [HR] 0·65 [95{\%} CI 0·47-0·91]; stratified log-rank test p=0·012). No difference in 5-year overall survival was observed between these groups (78{\%} [95{\%} CI 71-83] versus 77{\%} [71-83]; HR 0·98 [0·65-1·48]; stratified log-rank test p=0·91). Grade 3 or worse haematological adverse events were reported in 183 (92{\%}) of 199 patients in the transplantation group versus 135 (68{\%}) of 200 patients in the no transplantation group. Grade 3 or worse non-haematological adverse events were reported in 90 (45{\%}) versus 31 (16{\%}); the most common grade 3 or worse non-haematological adverse event was gastrointestinal (49 [25{\%}] vs 19 [10{\%}]). Treatment-related deaths occurred in 13 (3{\%}) patients; eight in the transplantation group and five in the no transplantation group.INTERPRETATION: Abbreviated rituximab-dose-dense chemotherapy plus R-MAD plus BEAM and autologous stem-cell transplantation reduced the risk of treatment failure compared with full course rituximab-dose-dense chemotherapy in young patients with diffuse large B-cell lymphoma at high risk. However, these results might not be clinically meaningful, since this improvement did not reflect an improvement in overall survival. These results do not support further consideration of the use of intensification of R-CHOP as an upfront strategy in patients with diffuse large B-cell lymphoma with poor prognosis.FUNDING: Fondazione Italiana Linfomi.",
keywords = "Journal Article",
author = "Annalisa Chiappella and Maurizio Martelli and Emanuele Angelucci and Ercole Brusamolino and Andrea Evangelista and Carella, {Angelo Michele} and Caterina Stelitano and Giuseppe Rossi and Monica Balzarotti and Francesco Merli and Gianluca Gaidano and Vincenzo Pavone and Luigi Rigacci and Francesco Zaja and Alfonso D'Arco and Nicola Cascavilla and Eleonora Russo and Alessia Castellino and Manuel Gotti and Congiu, {Angela Giovanna} and Cabras, {Maria Giuseppina} and Alessandra Tucci and Claudio Agostinelli and Giovannino Ciccone and Pileri, {Stefano A} and Umberto Vitolo",
note = "Copyright {\circledC} 2017 Elsevier Ltd. All rights reserved.",
year = "2017",
month = "8",
doi = "10.1016/S1470-2045(17)30444-8",
language = "English",
volume = "18",
pages = "1076--1088",
journal = "The Lancet Oncology",
issn = "1470-2045",
publisher = "Lancet Publishing Group",
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TY - JOUR

T1 - Rituximab-dose-dense chemotherapy with or without high-dose chemotherapy plus autologous stem-cell transplantation in high-risk diffuse large B-cell lymphoma (DLCL04)

AU - Chiappella, Annalisa

AU - Martelli, Maurizio

AU - Angelucci, Emanuele

AU - Brusamolino, Ercole

AU - Evangelista, Andrea

AU - Carella, Angelo Michele

AU - Stelitano, Caterina

AU - Rossi, Giuseppe

AU - Balzarotti, Monica

AU - Merli, Francesco

AU - Gaidano, Gianluca

AU - Pavone, Vincenzo

AU - Rigacci, Luigi

AU - Zaja, Francesco

AU - D'Arco, Alfonso

AU - Cascavilla, Nicola

AU - Russo, Eleonora

AU - Castellino, Alessia

AU - Gotti, Manuel

AU - Congiu, Angela Giovanna

AU - Cabras, Maria Giuseppina

AU - Tucci, Alessandra

AU - Agostinelli, Claudio

AU - Ciccone, Giovannino

AU - Pileri, Stefano A

AU - Vitolo, Umberto

N1 - Copyright © 2017 Elsevier Ltd. All rights reserved.

PY - 2017/8

Y1 - 2017/8

N2 - BACKGROUND: The prognosis of young patients with diffuse large B-cell lymphoma at high risk (age-adjusted International Prognostic Index [aa-IPI] score 2 or 3) treated with R-CHOP (rituximab, cyclophosphamide, vincristine, doxorubicin, and prednisone) is poor. The aim of this study was to investigate the possible benefit of intensification with high-dose chemotherapy and autologous stem-cell transplantation as part of first-line treatment in these patients.METHODS: We did a multicentre, open-label, randomised, controlled, phase 3 trial with a 2 × 2 factorial design to compare, at two different R-CHOP dose levels, a full course of rituximab-dose-dense chemotherapy (no transplantation group) versus an abbreviated course of rituximab-dose-dense chemotherapy followed by consolidation with R-MAD (rituximab plus high-dose cytarabine plus mitoxantrone plus dexamethasone) and high-dose BEAM chemotherapy (carmustine, etoposide, cytarabine, and melphalan) plus autologous stem-cell transplantation (transplantation group) in young patients (18-65 years) with untreated high-risk diffuse large B-cell lymphoma (aa-IPI score 2-3). At enrolment, patients were stratified according to aa-IPI score and randomly assigned (1:1:1:1) to receive R-CHOP (intravenous rituximab 375 mg/m(2), cyclophosphamide 750 mg/m(2), doxorubicin 50 mg/m(2), and vincristine 1·4 mg/m(2) on day 1, plus oral prednisone 100 mg on days 1-5) delivered in a 14-day cycle (R-CHOP-14) for eight cycles; high-dose R-CHOP-14 (R-MegaCHOP-14; R-CHOP-14 except for cyclophosphamide 1200 mg/m(2) and doxorubicin 70 mg/m(2)) for six cycles; R-CHOP-14 for four cycles followed by R-MAD (intravenous rituximab 375 mg/m(2) on day 1 or 4 plus intravenous cytarabine 2000 mg/m(2) and dexamethasone 4 mg/m(2) every 12 h on days 1-3 plus intravenous mitoxantrone 8 mg/m(2) on days 1-3) plus BEAM (intravenous carmustine 300 mg/m(2) on day -7, intravenous cytarabine 200 mg/m(2) twice a day on days -6 to -3, intravenous etoposide 100 mg/m(2) twice a day on days -6 to -3, plus intravenous melphalan 140 mg/m(2) on day -2) and autologous stem-cell transplantation (day 0); or R-MegaCHOP-14 for four cycles followed by R-MAD plus BEAM and autologous stem-cell transplantation. The primary endpoint was failure-free survival at 2 years in the intention-to-treat population. This study is registered with EudraCT (2005-002181-14; 2007-000275-42) and with ClinicalTrials.gov, number NCT00499018.FINDINGS: Between Jan 10, 2006, and Sept 8, 2010, 399 patients were randomly assigned to receive transplantation (n=199) or no transplantation (n=200); 203 patients were assigned to receive R-CHOP-14 and 196 were assigned to receive R-MegaCHOP-14. With a median follow-up of 72 months (IQR 57-88), 2-year failure-free survival was 71% (95% CI 64-77) in the transplantation group versus 62% (95% CI 55-68) in the no transplantation group (hazard ratio [HR] 0·65 [95% CI 0·47-0·91]; stratified log-rank test p=0·012). No difference in 5-year overall survival was observed between these groups (78% [95% CI 71-83] versus 77% [71-83]; HR 0·98 [0·65-1·48]; stratified log-rank test p=0·91). Grade 3 or worse haematological adverse events were reported in 183 (92%) of 199 patients in the transplantation group versus 135 (68%) of 200 patients in the no transplantation group. Grade 3 or worse non-haematological adverse events were reported in 90 (45%) versus 31 (16%); the most common grade 3 or worse non-haematological adverse event was gastrointestinal (49 [25%] vs 19 [10%]). Treatment-related deaths occurred in 13 (3%) patients; eight in the transplantation group and five in the no transplantation group.INTERPRETATION: Abbreviated rituximab-dose-dense chemotherapy plus R-MAD plus BEAM and autologous stem-cell transplantation reduced the risk of treatment failure compared with full course rituximab-dose-dense chemotherapy in young patients with diffuse large B-cell lymphoma at high risk. However, these results might not be clinically meaningful, since this improvement did not reflect an improvement in overall survival. These results do not support further consideration of the use of intensification of R-CHOP as an upfront strategy in patients with diffuse large B-cell lymphoma with poor prognosis.FUNDING: Fondazione Italiana Linfomi.

AB - BACKGROUND: The prognosis of young patients with diffuse large B-cell lymphoma at high risk (age-adjusted International Prognostic Index [aa-IPI] score 2 or 3) treated with R-CHOP (rituximab, cyclophosphamide, vincristine, doxorubicin, and prednisone) is poor. The aim of this study was to investigate the possible benefit of intensification with high-dose chemotherapy and autologous stem-cell transplantation as part of first-line treatment in these patients.METHODS: We did a multicentre, open-label, randomised, controlled, phase 3 trial with a 2 × 2 factorial design to compare, at two different R-CHOP dose levels, a full course of rituximab-dose-dense chemotherapy (no transplantation group) versus an abbreviated course of rituximab-dose-dense chemotherapy followed by consolidation with R-MAD (rituximab plus high-dose cytarabine plus mitoxantrone plus dexamethasone) and high-dose BEAM chemotherapy (carmustine, etoposide, cytarabine, and melphalan) plus autologous stem-cell transplantation (transplantation group) in young patients (18-65 years) with untreated high-risk diffuse large B-cell lymphoma (aa-IPI score 2-3). At enrolment, patients were stratified according to aa-IPI score and randomly assigned (1:1:1:1) to receive R-CHOP (intravenous rituximab 375 mg/m(2), cyclophosphamide 750 mg/m(2), doxorubicin 50 mg/m(2), and vincristine 1·4 mg/m(2) on day 1, plus oral prednisone 100 mg on days 1-5) delivered in a 14-day cycle (R-CHOP-14) for eight cycles; high-dose R-CHOP-14 (R-MegaCHOP-14; R-CHOP-14 except for cyclophosphamide 1200 mg/m(2) and doxorubicin 70 mg/m(2)) for six cycles; R-CHOP-14 for four cycles followed by R-MAD (intravenous rituximab 375 mg/m(2) on day 1 or 4 plus intravenous cytarabine 2000 mg/m(2) and dexamethasone 4 mg/m(2) every 12 h on days 1-3 plus intravenous mitoxantrone 8 mg/m(2) on days 1-3) plus BEAM (intravenous carmustine 300 mg/m(2) on day -7, intravenous cytarabine 200 mg/m(2) twice a day on days -6 to -3, intravenous etoposide 100 mg/m(2) twice a day on days -6 to -3, plus intravenous melphalan 140 mg/m(2) on day -2) and autologous stem-cell transplantation (day 0); or R-MegaCHOP-14 for four cycles followed by R-MAD plus BEAM and autologous stem-cell transplantation. The primary endpoint was failure-free survival at 2 years in the intention-to-treat population. This study is registered with EudraCT (2005-002181-14; 2007-000275-42) and with ClinicalTrials.gov, number NCT00499018.FINDINGS: Between Jan 10, 2006, and Sept 8, 2010, 399 patients were randomly assigned to receive transplantation (n=199) or no transplantation (n=200); 203 patients were assigned to receive R-CHOP-14 and 196 were assigned to receive R-MegaCHOP-14. With a median follow-up of 72 months (IQR 57-88), 2-year failure-free survival was 71% (95% CI 64-77) in the transplantation group versus 62% (95% CI 55-68) in the no transplantation group (hazard ratio [HR] 0·65 [95% CI 0·47-0·91]; stratified log-rank test p=0·012). No difference in 5-year overall survival was observed between these groups (78% [95% CI 71-83] versus 77% [71-83]; HR 0·98 [0·65-1·48]; stratified log-rank test p=0·91). Grade 3 or worse haematological adverse events were reported in 183 (92%) of 199 patients in the transplantation group versus 135 (68%) of 200 patients in the no transplantation group. Grade 3 or worse non-haematological adverse events were reported in 90 (45%) versus 31 (16%); the most common grade 3 or worse non-haematological adverse event was gastrointestinal (49 [25%] vs 19 [10%]). Treatment-related deaths occurred in 13 (3%) patients; eight in the transplantation group and five in the no transplantation group.INTERPRETATION: Abbreviated rituximab-dose-dense chemotherapy plus R-MAD plus BEAM and autologous stem-cell transplantation reduced the risk of treatment failure compared with full course rituximab-dose-dense chemotherapy in young patients with diffuse large B-cell lymphoma at high risk. However, these results might not be clinically meaningful, since this improvement did not reflect an improvement in overall survival. These results do not support further consideration of the use of intensification of R-CHOP as an upfront strategy in patients with diffuse large B-cell lymphoma with poor prognosis.FUNDING: Fondazione Italiana Linfomi.

KW - Journal Article

U2 - 10.1016/S1470-2045(17)30444-8

DO - 10.1016/S1470-2045(17)30444-8

M3 - Article

VL - 18

SP - 1076

EP - 1088

JO - The Lancet Oncology

JF - The Lancet Oncology

SN - 1470-2045

IS - 8

ER -