Summary
Background Dose intensication with a combination of cyclophosphamide, doxorubicin, vincristine, and prednisolone Lancet 2013; 381: 181726
(CHOP) every 2 weeks improves outcomes in patients older than 60 years with diuse large B-cell lymphoma Published Online
compared with CHOP every 3 weeks. We investigated whether this survival benet from dose intensication persists April 22, 2013
http://dx.doi.org/10.1016/
in the presence of rituximab (R-CHOP) in all age groups.
S0140-6736(13)60313-X
See Comment page 1793
Methods Patients (aged 18 years) with previously untreated bulky stage IA to stage IV diuse large B-cell lymphoma in
*Joint rst authors
119 centres in the UK were randomly assigned centrally in a one-to-one ratio, using minimisation, to receive six cycles of
Royal Marsden NHS Foundation
R-CHOP every 14 days plus two cycles of rituximab (R-CHOP-14) or eight cycles of R-CHOP every 21 days (R-CHOP-21). Trust, London and Surrey, UK
R-CHOP-21 was intravenous cyclophosphamide 750 mg/m, doxorubicin 50 mg/m, vincristine 14 mg/m (maximum (Prof D Cunningham FMedSci,
dose 2 mg), and rituximab 375 mg/m on day 1, and oral prednisolone 40 mg/m on days 15, administered every 21 days E A Hawkes FRACP); St James
for a total of eight cycles. R-CHOP-14 was intravenous cyclophosphamide 750 mg/m, doxorubicin 50 mg/m, vincristine Institute of Oncology, Leeds, UK
(A Jack PhD); Cambridge Cancer
2 mg, rituximab 375 mg/m on day 1, and oral prednisolone 100 mg on days 15, administered every 14 days for six Trials Centre, Cambridge Clinical
cycles, followed by two further infusions of rituximab 375 mg/m on day 1 every 14 days. The trial was not masked. The Trials UnitCancer Theme and
primary outcome was overall survival (OS). This study is registered, number ISCRTN 16017947. Medical Research Council
Biostatistics Unit Hub for Trials
Methodology, Cambridge, UK
Findings 1080 patients were assigned to R-CHOP-21 (n=540) and R-CHOP-14 (n=540). With a median follow-up of (W Qian PhD); Cancer Research
46 months (IQR 3557), 2-year OS was 827% (795859) in the R-CHOP-14 group and 808% (775842) in the UK and UCL Cancer Trials Centre,
R-CHOP-21 (standard) group (hazard ratio 090, 95% CI 070115; p=03763). No signicant improvement was noted UCL Cancer Institute, London
in 2-year progression-free survival (R-CHOP-14 754%, 718791, and R-CHOP-21 748%, 710784; 094, 076117; UK (P Smith MSc,
P Mouncey MSc, J Gambell BSc);
p=05907). High international prognostic index, poor-prognosis molecular characteristics, and cell of origin were not East Kent Hospitals, Canterbury,
predictive for benet from either schedule. Grade 3 or 4 neutropenia was higher in the R-CHOP-21 group (318 [60%] of UK (C Pocock PhD); Mount
534 vs 167 [31%] of 534), with no prophylactic use of recombinant human granulocyte-colony stimulating factor Vernon Cancer Centre,
mandated in this group, whereas grade 3 or 4 thrombocytopenia was higher with R-CHOP-14 (50 [9%] vs 28 [5%]); other Northwood, UK
(K M Ardeshna FRCPath);
frequent grade 3 or 4 adverse events were febrile neutropenia (58 [11%] vs 28 [5%]) and infection (125 [23%] vs 96 [18%]). University of Manchester and
Frequencies of non-haematological adverse events were similar in the R-CHOP-21 and R-CHOP-14 groups. the Christie NHS Foundation
Trust, Manchester, UK
(Prof J A Radford MD);
Interpretation R-CHOP-14 is not superior to R-CHOP-21 chemotherapy for previously untreated diuse large B-cell
Nottingham City Hospital,
lymphoma; therefore, R-CHOP-21 remains the standard rst-line treatment in patients with this haematological Nottingham, UK
malignancy. No molecular or clinical subgroup beneted from dose intensication in this study. (A McMillan FRCPath); Western
General Hospital, Edinburgh,
UK (J Davies FRCPE); Torbay
Funding Chugai Pharmaceutical, Cancer Research UK, National Institute for Health Research Biomedical Research
Hospital, Torquay, UK
Centres scheme at both University College London and the Royal Marsden NHS Foundation Trust, and Institute of (D Turner FRCPath); Royal
Cancer Research. Cornwall Hospital, Truro, UK
(A Kruger FRCPath); Cancer
Research UK Centre,
Introduction Study Group phase 3 study showed superior overall
Southampton, UK
Diuse large B-cell lymphoma represents more than survival (OS) with six cycles of CHOP every 14 days (Prof P Johnson FRCP); and
30% of all diagnoses of non-Hodgkin lymphoma.1 (CHOP-14) compared with six cycles of CHOP-21 in University College London, UK
Combination chemotherapy with cyclophosphamide, patients aged 60 years and older,4 although these results (K M Ardeshna,
Prof D Linch FMedSci)
doxorubicin, vincristine, and prednisolone (CHOP) was were not replicated in a smaller Japanese study of eight
Correspondence to:
established as a standard treatment almost 40 years ago. cycles of CHOP-14 versus CHOP-21 in patients with
Prof David Cunningham,
Intensive regimens have not consistently improved aggressive non-Hodgkin lymphoma, only 58% of whom Department of Medicine, Royal
outcomes compared with CHOP every 3 weeks had diuse large B-cell lymphoma.5 Incorporation of Marsden Hospital, Downs Road,
(CHOP-21), including the use of high-dose treatment etoposide into CHOP improved response rates and Sutton, Surrey, SM2 5PT, UK
david.cunningham@rmh.
plus autologous stem-cell transplant.2,3 However, in event-free survival in young patients, but did not aect
nhs.uk
2004, the results of the German High-Grade Lymphoma overall survival in any age group.4,6 An alternative
dose-intense regimen of cyclophosphamide, vindesine, patients receiving rituximab remained uncertain. There-
bleomycin, and prednisolone followed by high-dose fore, in 2005, the UK National Cancer Research Institute
methotrexate, ifosfamide, and cytarabine (ACVBP) also Lymphoma Clinical Study Group commenced a large,
improved survival compared with standard CHOP-21 in randomised study of all patients older than 18 years with
both localised disease and poor-prognosis aggressive previously untreated diuse large B-cell lymphoma to
non-Hodgkin lymphoma but the results did not compare CHOP-14 with CHOP-21 in patients receiving
change clinical practice, probably due to toxicity of the rituximab. This phase 3, open-label randomised study
polydrug combination.7,8 was designed to detect superior OS of the dose-intense
Concurrent with these results, rituximab, an anti- regimen R-CHOP-14 versus standard R-CHOP-21 in
CD20 monoclonal antibody, combined with CHOP-21 patients of all age groups and all risk strata.
improved cure rates by 1015% compared with
CHOP-21 alone without serious additional toxicity in Methods
the pivotal phase 3 Groupe dEtude des Lymphomes de Patients
lAdulte (GELA) trial;9,10 the results were conrmed in a In this phase 3 study, patients with diuse large B-cell
subsequent US intergroup study.11 Rituximab also lymphoma were enrolled in 119 centres in the UK.
added benet to CHOP-14 (R-CHOP-14) in patients Eligible patients were aged 18 years and older with
older than 60 years in the RICOVER-60 trial,12 and in previously untreated, histologically conrmed, diuse
young patients (aged 1860 years) with a good prognosis large B-cell lymphoma according to the WHO classi-
in the MiNT study.13 cation.14 Patients were required to have Ann Arbor bulky
However, whether the improved survival reported with stage IA (tumour mass diameter >10 cm) or stage IBIV
CHOP-14 by the German group4 was still evident in disease, a good performance status (WHO grade 02),
adequate cardiac, renal, hepatic, and haematological
function (initial neutrophil count >15 10 per L, initial
1080 patients randomly assigned platelet count >100 10 per L unless the abnormality was
caused by lymphoma rather than another disease in
which case the patient was eligible). Patients with T-cell
lymphomas, transformed follicular lymphoma, or a
540 assigned to R-CHOP-21 540 assigned to R-CHOP-14
history of indolent lymphoma were excluded. However,
patients with previously undiagnosed concurrent small-
5 excluded 4 excluded
1 LVEF 4050% 1 incorrect diagnosis (chronic cell inltration in bone marrow or lymph node were
2 died before treatment lymphocytic leukaemia) eligible. Patients with CNS involvement, positive serology
1 incorrect diagnosis (Burkitts 1 coexisting illnesses
lymphoma) 2 died before treatment for HIV, hepatitis B or hepatitis C virus, a history of heart
1 withdrew consent failure or uncontrolled angina pectoris, active malignancy
in the preceding 10 years, or other illnesses precluding
535 commenced 536 commenced administration of study treatment were ineligible.
R-CHOP-21* R-CHOP-14
The trial was overseen by a trial steering committee
and an independent data monitoring committee. The
500 assessed for end-of- 502 assessed for end-of- protocol was approved by the UK Medicines and
treatment response treatment response Healthcare products Regulatory Agency and Hull and
East Riding Research Ethics Committee, and done in
113 did not complete treatment* 60 did not complete treatment
17 progressive disease 5 progressive disease
accordance with the Declaration of Helsinki and the
38 had toxicity 22 toxicity European Union Clinical Trials Directive 2001/20/EC.
11 deaths 12 deaths Patients provided written informed consent.
5 incorrect diagnosis 4 incorrect diagnosis
8 other disorders 8 other disorders
17 patients or clinicians decision 5 patients or clinicians decision Randomisation and masking
8 achieved maximum response 2 achieved maximum response
9 other 2 other
Randomisation was done centrally by the Cancer
Research UK and University College London Cancer
Trials Centre, London, UK, using a minimisation pro-
422 completed R-CHOP-21* 476 completed R-CHOP-14
cedure, stratied for international prognostic index
(IPI) and centre. Patients were allocated in a one-to-one
540 analysed 540 analysed ratio to R-CHOP-21 or R-CHOP-14 regimens. The trial
was not masked.
Figure 1: Trial prole
R-CHOP-21=cycles of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone every 21 days. Procedures
R-CHOP-14=cycles of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone every 14 days.
LVEF=left ventricular ejection fraction. *Includes 35 people who did not have an end-of-treatment scan and
The R-CHOP-21 regimen was based on the original doses
therefore were not assessable for end-of-treatment response. Includes 34 people who did not have an used by the GELA group9 and consisted of intravenous
end-of-treatment scan and therefore were not assessable for end-of-treatment response. cyclophosphamide 750 mg/m, doxorubicin 50 mg/m,
cycles. R-CHOP-14, designed by the German High Grade Median (years) 61 (1988) 61 (1985)
Lymphoma Study Group,4 consisted of intravenous 60 239 (44%) 237 (44%)
cyclophosphamide 750 mg/m, doxorubicin 50 mg/m, >60 301 (56%) 303 (56%)
vincristine 2 mg, rituximab 375 mg/m on day 1, and oral Sex
prednisolone 100 mg on days 15, administered every Male 293 (54%) 289 (54%)
14 days for six cycles followed by two further infusions Female 247 (46%) 251 (46%)
of rituximab 375 mg/m on day 1 every 14 days. WHO performance status
The recombinant human granulocyte-colony stimu- 0 258 (48%) 286 (53%)
lating factor (G-CSF) lenograstim was administered on 1 210 (39%) 182 (34%)
days 412 of each cycle to patients randomly assigned to 2 72 (13%) 72 (13%)
R-CHOP-14 whereas use of G-CSF for patients receiving Stage
R-CHOP-21 was at the discretion of the investigators. All Bulky IA 20 (4%) 26 (5%)
patients received allopurinol 300 mg/day for the rst cycle IB 16 (3%) 17 (3%)
and co-trimoxazole 480 mg twice daily for 3 days per week II 166 (31%) 157 (29%)
until 2 weeks after the end of treatment. Other supportive III 142 (26%) 175 (32%)
medications were given according to local protocols. IV 193 (36%) 162 (30%)
Prophylaxis for CNS relapse was at the discretion of the Bulky disease 272 (50%) 261 (48%)
investigators; however, the recommendation was that B symptoms 238 (44%) 251 (46%)
patients with large-cell lymphoma involvement of the bone Elevated lactate dehydrogenase 350 (65%) 351 (65%)
marrow, peripheral blood, nasal or paranasal sinuses, International prognostic index score
orbit, and testis receive 125 mg intrathecal methotrexate 0 43 (8%) 40 (7%)
for the rst three cycles of treatment, administered as per 1 117 (22%) 116 (21%)
local guidelines. Consolidation radiotherapy was also 2 143 (26%) 163 (30%)
permitted at the discretion of the investigators. 3 143 (26%) 136 (25%)
Patients were assessed before treatment; at each atten- 4 79 (15%) 75 (14%)
dance for treatment; and then after treatment every 5 15 (3%) 10 (2%)
3 months until 1 year, then every 6 months until 2 years, Phenotype 275 285
and thereafter every year. Reports by clinicians included
Germinal centre 145 (53%) 144 (51%)
details of treatment and adverse eects, performance
Non-germinal centre 130 (47%) 141 (49%)
status, and results of blood counts and other relevant
Proliferation rate 262 265
tests. CT scans of the chest, abdomen, pelvis, with or
MIB1 80% 127 (48%) 106 (40%)
without neck were done at baseline, after four cycles of
MIB1 90% 71 (27%) 49 (18%)
chemotherapy, at the end of treatment, and at 3 months
P53 overexpression 136/299 (45%) 171/309 (55%)
and 12 months after completion of treatment. In the
MYC rearrangement 16/175 (9%) 20/184 (11%)
event of clinical suspicion of relapse, additional imaging
BCL2 translocation 41/178 (23%) 49/190 (26%)
was done. F-uorodeoxyglucose (F-FDG) PET scans
BCL6 rearrangement 32/176 (18%) 44/185 (24%)
were not mandated and therefore no PET data were
gathered as part of the main study. MYC plus BCL2 (double-hit abnormality) 5/172 (3%) 11/182 (6%)
Central pathology review was done by an expert Other disease types diagnosed at central review 12 12
417 (77%), 439 (81%), 371 (69%), and 432 (80%) patients A
received at least 80% of the planned total dose of 100 R-CHOP-14
cyclosphosphamide, doxorubicin, prednisolone, vincris- R-CHOP-21
tine, and rituximab, respectively. In the R-CHOP-14 group, 75
497 (92%), 494 (91%), 500 (93%), 444 (82%), and 469 (87%)
Survival (%)
patients received at least 80% of the planned total dose of
50
cyclosphosphamide, doxorubicin, prednisolone, vincris-
tine, and rituximab, respectively. The median dose inten-
25
sity for individual drugs in the R-CHOP-14 group relative
to the R-CHOP-21 group was 152% for cyclophosphamide, Hazard ratio=094, 95% CI=076117, p=05907
0
152% for doxorubicin, 148% for vincristine, 191% for
prednisolone, and 151% for rituximab. Number at risk
R-CHOP-14 540 439 377 291 175 71 11 0
All 540 patients in the R-CHOP-14 group received G-CSF R-CHOP-21 540 431 375 276 177 75 7 0
as per-protocol treatment; 293 (54%) of 540 patients in
the R-CHOP-21 group were given G-CSF as secondary B
100
prophylaxis. 54 (10%) patients in the R-CHOP-21 group
and 51 (9%) in the R-CHOP-14 group underwent radio-
therapy after chemotherapy. 75
Survival (%)
R-CHOP-14 R-CHOP-21 Hazard ratio (95% CI) phenotype (germinal centre or non-germinal centre)
Events Total Events Total were predictive for benet in R-CHOP-14 or R-CHOP-21.
Subgroup 255 people died, 134 in the R-CHOP-21 group
Age (years)
<60 41 237 49 239 085 (056129)
(85 lymphoma-related, three treatment-related, nine
6065 25 102 17 101 151 (082277) secondary malignancies, eight cardiac causes, 25 other
>65 55 201 68 200 077 (054109) illnesses, and four unknown causes) and 121 in the
Subtotal (95% CI) 540 540 089 (070114)
Total events 121 134 R-CHOP-14 group (79 lymphoma-related, nine treat-
Heterogeneity: 2=366, df=2 (p=016); I2=45% ment-related, six secondary malignancies, six cardiac
Sex
Female 58 251 54 247 104 (072151) causes, 17 other illnesses, and four unknown causes;
Male 63 289 80 293 080 (057111) appendix p 5). All cardiac deaths occurred at least
Subtotal (95% CI) 540 540 090 (070114)
Total events 121 134 3 months after completion of treatment.
Heterogeneity: 2=112, df=1 (p=029); I2=11% Frequencies of grade 3 or 4 neutropenia and febrile
Stage
IA/IB 8 43 8 36 082 (031220) neutropenia were signicantly higher with R-CHOP-21,
II 25 157 31 166 084 (049141) probably due to the reduced use of G-CSF, whereas
III 35 175 36 142 117 (081171)
IV 53 162 58 193 093 (073119)
grade 3 or 4 thrombocytopenia was signicantly higher in
Subtotal (95% CI) 537 537 the R-CHOP-14 group (table 4). Of 422 patients in the
Total events 121 133
Heterogeneity: 2=276, df=3 (p=043); I2=0%
R-CHOP-21 group who received eight cycles of treatment,
B symptom 303 (72%) had a toxicity of grade 3 or greater from cycles
Absent 46 289 69 302 067 (046096) one to eight, and 282 (67%) from cycles one to six, and
Present 75 251 65 238 113 (081158)
Subtotal (95% CI) 540 540 089 (070114) 21 (5%) from cycles seven to eight. 13 grade 5 toxicities
Total events 121 134 were reportedneutropenic sepsis (one in R-CHOP-21
Heterogeneity: 2=440, df=1 (p=004); I2=77%
WHO performance status
group and one in R-CHOP-14 group), non-neutropenic
0 45 286 50 258 079 (053119) sepsis (one and two, respectively), suicide (two in
1 46 182 59 210 087 (060128) R-CHOP-21 group), renal failure (one in R-CHOP-14
2 30 72 25 72 138 (081235)
Subtotal (95% CI) 540 540 093 (073119) group), multiorgan failure (one in R-CHOP-14 group),
Total events 121 134 and not specied (four in R-CHOP-14 group).
Heterogeneity: 2=279, df=2 (p=025); I2=28%
Bulky disease
Absent 55 279 62 265 082 (057119) Discussion
Present 66 261 71 272 097 (069135)
Subtotal (95% CI) 540 537 090 (070115) The primary endpoint of superior overall survival with
Total events 121 133 R-CHOP-14 compared with R-CHOP-21 was not met,
Heterogeneity: 2=039, df=1 (p=053); I2=0%
Lactate dehydrogenase raised
and R-CHOP-14 did not improve response rates, PFS, or
No 28 189 29 190 095 (057160) safety despite preservation of dose intensity. The two
Yes 93 351 105 350 087 (066115) regimens were similar in all ecacy endpoints; however,
Subtotal (95% CI) 540 540 089 (070114)
Total events 121 134 the study was not powered to detect non-inferiority.
Heterogeneity: 2=009, df=1 (p=076); I2=0% Similar results were presented at the 2012 American
International prognostic index score
0 4 40 5 43 079 (021291) Society of Clinical Oncology conference by the GELA
1 14 116 17 117 080 (039162) group from their study of 602 patients aged 6080 years.18
2 26 163 34 143 066 (040110)
3 44 136 41 143 119 (078182) Patients were randomly assigned to eight cycles of
4 27 75 31 79 090 (054152) either R-CHOP-14 or R-CHOP-21; however, G-CSF was
5 6 10 6 15 138 (044436)
Subtotal (95% CI) 540 540 092 (072118)
administered at the investigators discretion in both
Total events 121 134 groups, resulting in a reduced dose intensity of doxo-
Heterogeneity: 2=368, df=5 (p=060); I2=0%
rubicin and cyclophosphamide in the R-CHOP-14 group
MIB1 90
<90% 49 216 52 191 082 (056122) compared with the dose intensity in our study, and that
90% 12 49 9 71 209 (087500) of the original German reports.4,6 The smaller GELA
Subtotal (95% CI) 265 262 096 (067137)
Total events 61 61 study was powered for superiority and the results showed
Heterogeneity: 2=363, df=1 (p=006); I2=72% no dierence in event-free survival, PFS, OS, response
MIB1 80
<80% 36 159 36 135 084 (053133) rate, or safety, supporting our ndings.18 Of note, in
80% 25 106 25 127 124 (071217) routine clinical practice many patients now receive only
Subtotal (95% CI) 265 262 098 (069141)
Total events 61 61
six cycles of R-CHOP.
Heterogeneity: 2=113, df=1 (p=029); I2=11% In our study, toxicities in the two groups were similar;
Phenotype R-CHOP-14 was associated with signicantly more
Germinal centre 27 144 29 145 095 (056160)
Non-germinal centre 37 141 31 130 113 (070283)
Subtotal (95% CI) 285 275 104 (073149)
Total events 64 60
Figure 3: Analysis of prognostic factors for overall survival
Heterogeneity: 2=025, df=1 (p=061); I2=0%
Data are number, unless otherwise indicated. R-CHOP-14=cycles of rituximab
02 05 1 2 5 plus cyclophosphamide, doxorubicin, vincristine, and prednisolone every
R-CHOP-14 better R-CHOP-21 better 14 days. R-CHOP-21=cycles of rituximab plus cyclophosphamide, doxorubicin,
vincristine, and prednisolone every 21 days. df=degrees of freedom.
thrombocytopenia than was R-CHOP-21, but less neutro- R-CHOP-14 R-CHOP-21 Hazard ratio (95% CI)
penia because of G-CSF primary prophylaxis. Treatment- Events Total Events Total
related deaths were numerically higher in the R-CHOP-14 Subgroup
Age (years)
group (nine vs three); however, the dierence was not <60 59 237 67 239 089 (063126)
signicant (p=0082). 6065 30 102 22 101 144 (084249)
Few studies have shown a benet of dose intensi- >65 67 201 77 200 083 (060116)
Subtotal (95% CI) 540 540 093 (075116)
cation with incorporation of rituximab versus standard Total events 156 166
rituximabchemotherapy combinations, despite the Heterogeneity: 2=299, df=2 (p=022); I2=33%
Sex
targeting of high-risk populations.1922 In a younger popu- Female 76 251 69 247 107 (077148)
lation, improved ecacy with the addition of etoposide to Male 80 289 97 293 085 (063114)
Subtotal (95% CI) 540 540 094 (076117)
CHOP-14 was lost when combined with rituximab.13 Total events 156 166
First-line high-dose chemotherapy plus rituximab Heterogeneity: 2=109, df=1 (p=030); I2=8%
Stage
followed by autologous stem-cell transplant has also not IA/IB 8 43 9 36 077 (029199)
improved outcomes compared with rituximabchemo- II 33 157 37 166 093 (058149)
III 51 175 45 142 088 (059131)
therapy alone.23,24 By contrast, in a study by the GELA IV 64 162 74 193 109 (078153)
group,25 a signicant survival advantage was reported Subtotal (95% CI) 537 537 097 (078121)
Total events 156 165
with R-ACVBP compared with R-CHOP-21 in 380 young Heterogeneity: 2=097, df=3 (p=081); I2=0%
patients with low-risk or low-intermediate-risk disease. B symptom
After a median follow-up of 44 months, the 3-year event- Absent 62 289 87 302 072 (052100)
Present 94 251 79 238 118 (088159)
free survival was 81% in the R-ACVBP group compared Subtotal (95% CI) 540 540 094 (076117)
with 67% with R-CHOP-21, and 3-year PFS was 87% and Total events 156 166
Heterogeneity: 2=483, df=1 (p=003); I2=79%
73%, respectively. However, this improvement was asso- WHO performance status
ciated with a three times increase in serious adverse 0 66 286 70 258 084 (060118)
events in the experimental group and febrile neutropenia 1 57 182 68 210 095 (067135)
2 33 72 28 72 136 (082226)
in 38% of patients, despite G-CSF prophylaxis, versus 7% Subtotal (95% CI) 540 540 097 (078120)
with R-CHOP-21. In the Comment accompanying this Total events 156 166
Heterogeneity: 2=243, df=2 (p=030); I2=18%
GELA trial, the recommendation was that R-ACVBP Bulky disease
should not be oered routinely until high-risk groups Absent 71 279 82 265 081 (059111)
Present 85 261 83 272 109 (080147)
can be accurately identied to justify the additional Subtotal (95% CI) 540 537 094 (076118)
toxicity.26 Of note, the 2-year PFS was 80% in patients in Total events 156 165
Heterogeneity: 2=178, df=1 (p=018); I2=44%
our study who were younger than 60 years with IPI 02 Lactate dehydrogenase raised
receiving R-CHOP-21. No 43 189 38 190 117 (076181)
Yes 113 351 128 350 087 (067112)
Molecular features such as high proliferation index, P53 Subtotal (95% CI) 540 540 093 (075116)
deletion, and BCL2, MYC, and BCL6 rearrangements Total events 156 166
have previously been identied as poor prognostic mar- Heterogeneity: 2=136, df=1 (p=024); I2=26%
International prognostic index score
kers in retrospective or small series.16,2729 In this study, 0 4 40 6 43 071 (021245)
only MYC rearrangement (10% of patients) was a poor 1 23 116 22 117 104 (058186)
2 37 163 48 143 067 (043102)
prognostic marker in the univariate analysis but was not 3 55 136 49 143 121 (083178)
predictive for benet of R-CHOP-14. Double-hit diuse 4 31 75 34 79 101 (062165)
5 6 10 7 15 114 (038343)
large B-cell lymphomas are known to have a worse Subtotal (95% CI) 540 540 096 (077119)
prognosis,16,3032 and although, in our study, this group of Total events 156 166
Heterogeneity: 2=469, df=5 (p=046); I2=0%
patients had poorer survival, in the multivariate analysis
MIB1 90
the dierence was not signicant and the eect of double- <90% 68 216 61 191 101 (071142)
hit rearrangements might have been overestimated in 90% 15 49 12 71 199 (092431)
Subtotal (95% CI) 265 262 113 (082155)
previous retrospective studies. Molecular analysis showed Total events 83 73
no other poor prognostic subgroup or a cohort that Heterogeneity: 2=249, df=1 (p=011); I2=60%
MIB1 80
beneted from R-CHOP-14. This nding was also <80% 50 159 44 135 097 (065146)
reected in the absence of signicantly improved out- 80% 33 106 29 127 146 (089242)
Subtotal (95% CI) 265 262 114 (083157)
comes from R-CHOP-14 in patients with high IPI. With Total events 83 73
respect to the cell of origin, germinal centre diuse large Heterogeneity: 2=152, df=1 (p=022); I2=34%
B-cell lymphoma has also been reported to have a better Phenotype
Germinal centre 35 144 34 145 106 (066169)
Non-germinal centre 51 141 40 130 124 (082287)
Subtotal (95% CI) 285 275 116 (085158)
Total events 86 74
Figure 4: Analysis of prognostic factors for progression-free survival
Heterogeneity: =026, df=1 (p=061); I2=0%
2
Data are number, unless otherwise indicated. R-CHOP-14=cycles of rituximab
02 05 1 2 5
plus cyclophosphamide, doxorubicin, vincristine, and prednisolone every
14 days. R-CHOP-21=cycles of rituximab plus cyclophosphamide, doxorubicin, R-CHOP-14 better R-CHOP-21 better
vincristine, and prednisolone every 21 days. df=degrees of freedom.
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S Stern (East Surrey Hospital); R Stockley (Worcester Royal Hospital);
9 Coier B, Lepage E, Briere J, et al. CHOP chemotherapy plus
G Summereld (Queen Elizabeth Hospital, Gateshead); D Turner rituximab compared with CHOP alone in elderly patients with
(Torbay Hospital); A Virchis (Barnet and Chase Farm Hospitals); A Webb diuse large-B-cell lymphoma. N Engl J Med 2002; 346: 23542.
(Royal Sussex County Hospital); P Williamson (Darlington Memorial 10 Coier B, Thieblemont C, Van Den Neste E, et al. Long-term
Hospital); S Willoughby (Hereford County Hospital); J Wimperis outcome of patients in the LNH-98.5 trial, the rst randomized
(Norfolk and Norwich University Hospital); B Woodcock (University study comparing rituximab-CHOP to standard CHOP
Hospital Aintree); D Wright (Dewsbury District, Pinderelds General chemotherapy in DLBCL patients: a study by the Groupe dEtudes
and Pontefract General Hospitals). des Lymphomes de lAdulte. Blood 2010; 116: 204045.
Conicts of interest 11 Habermann TM, Weller EA, Morrison VA, et al. Rituximab-CHOP
versus CHOP alone or with maintenance rituximab in older patients
DC received research grants from Roche, Amgen, Sano-Aventis,
with diuse large B-cell lymphoma. J Clin Oncol 2006; 24: 312127.
Novartis, Astra-Zeneca, Merck KGA, and Celgene; participated on
12 Pfreundschuh M, Schubert J, Ziepert M, et al, for the German
compensated advisory boards for Amgen, Roche, Merck, and
High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL).
Sano-Aventis, and uncompensated advisory boards for Roche Six versus eight cycles of bi-weekly CHOP-14 with or without
(honoraria), Merck, and Sano-Aventis; and provided uncompensated rituximab in elderly patients with aggressive CD20+ B-cell
expert testimony for Amgen. EAH has received travel expenses from lymphomas: a randomised controlled trial (RICOVER-60).
Roche. AJ has received research grants from Roche and Genentech. Lancet Oncol 2008; 9: 10516.
CP has participated on compensated advisory boards for Roche and 13 Pfreundschuh M, Trumper L, Osterborg A, et al, for the MabThera
Pzer, and received travel expenses from Roche. KMA has received International Trial (MInT) Group. CHOP-like chemotherapy plus
research funding and honoraria from Roche. JAR has received research rituximab versus CHOP-like chemotherapy alone in young patients
grants from Millennium, and provided expert testimony for with good-prognosis diuse large-B-cell lymphoma: a randomised
Millennium Pharmaceuticals, Bayer-Schering, Roche, Napp controlled trial by the MabThera International Trial (MInT) Group.
Pharmaceuticals, Novartis, and GlaxoSmithKline. AM has received a Lancet Oncol 2006; 7: 37991.
research grant from Roche, and consultancy fees, honoraria, and travel 14 Jae ES, Harris NL, Stein H, Vardiman JW. World Health
expenses from Roche. JD has received consultancy fees and travel Organisation Classication of Tumours. Pathology and genetics of
expenses from Roche. DT has received travel expenses from Roche. tumours of haematopoietic and lymphoid tissues. Lyon: IARC
Press, 2001.
PJ has participated on a compensated advisory board for and received
travel expenses from Roche. DL has received research grants from 15 Hans CP, Weisenburger DD, Greiner TC, et al. Conrmation of
the molecular classication of diuse large B-cell lymphoma by
Roche and Chugai Pharma; participated on compensated advisory
immunohistochemistry using a tissue microarray. Blood 2004;
boards for Roche, Chugai, Amgen, and Hospira; and received 103: 27582.
honoraria from Roche, Chugai, and Celgene. The other authors declare
16 Barrans S, Crouch S, Smith A, et al. Rearrangement of MYC is
that they have no conicts of interest. associated with poor prognosis in patients with diuse large B-cell
Acknowledgments lymphoma treated in the era of rituximab. J Clin Oncol 2010;
Cancer Research UK provided endorsement and funding, and National 28: 336065.
Health Service provided funding to the National Institute for Health 17 Cheson BD, Horning SJ, Coier B, et al. Report of an international
Research Biomedical Research Centres at both University College workshop to standardize response criteria for non-Hodgkins
London and the Royal Marsden NHS Foundation Trust and Institute of lymphomas. NCI Sponsored International Working Group.
J Clin Oncol 1999; 17: 1244.
Cancer Research (all London, UK). Chugai Pharmaceuticals provided an
educational grant and lenograstim. 18 Delarue R, Tilly H, Salles GA, et al. R-CHOP14 compared to
R-CHOP21 in elderly patients with diuse large B-cell lymphoma
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