A. Bosly

M Marangolo

M Pfreundschuh

M. Schwenkglenks

MS Aapro

R Pettengell

R. Pettengell

English

PubMed

Springer - Publisher Connector

Association of reduced relative dose intensity and survival in lymphoma patients receiving CHOP-21 chemotherapy

Pettengell, R

Schwenkglenks, M

Bosly, André

DIAL UCLouvain

Association of reduced relative dose intensity and survival in lymphoma patients receiving CHOP-21 chemotherapy.

Bosly, A

St George's Online Research Archive

LETTER TO THE EDITORAssociation of reduced relative dose intensity and survivalin lymphoma patients receiving CHOP-21 chemotherapyR. Pettengell & M. Schwenkglenks & A. BoslyReceived: 7 November 2007 /Accepted: 17 January 2008 /Published online: 26 February 2008# The Author(s) 2008Dear Editor,Reductions in average relative chemotherapy dose intensity(ARDI; i.e. administered compared with planned) compro-mise patient outcomes [3], and a recent Belgian studyshowed that survival for non-Hodgkin lymphoma (NHL)patients receiving CHOP-21 was reduced when ARDI fellbelow 90% [2]. We support these findings with similar datafrom the UK Audit of Lymphoma Patients (n=78 patientswho received CHOP-21 chemotherapy in 1999–2000) andfrom the combined Belgian and UK data (n=289) [4].Patient, disease and treatment characteristics were similarbetween the two studies, except that the UK patients wereyounger (mean age ± SD was 55±15 years versus 63±14 years) and fewer UK patients received colony stimulatingfactor (CSF). First cycle CSF use was 4% in the UK studycompared to 25% in the Belgian study. During an averagetime to death or censoring of 72 months, 35% of patients inthe UK study died. In the Belgian study, the averageobservation time was 30 months, during which 31% ofpatients died. After adjusting for the higher mean age of theBelgian patients, Kaplan–Meier survival functions weresimilar between the two populations (log-rank test stratifiedby 10-year age groups, p=0.38).Kaplan–Meier plots for patients with >90% ARDI versus≤90% ARDI showed reduced survival for the patients with≤90% ARDI (Fig. 1). A trend towards reduced survival wasapparent in the UK dataset alone (Fig. 1a; log-rank test-based p=0.090). For the combined dataset, the effect wasstatistically significant (p<0.001; Fig. 1b), as for theBelgian data alone [2].Potential predictors of reduced survival were assessedusing an extended Cox proportional hazards regressionmodel with robust standard errors allowing for clusteringby centre. Using the UK dataset, reduced survival wassignificantly associated with a higher Ann Arbor diseasestage (hazard ratio (HR) at treatment initiation 2.59 perstage increase by 1, 95% CI 1.45–4.66, p=0.001) andshowed a trend towards association with age (HR 1.02 peryear of age, CI 1.00–1.04, p=0.058) and RDI≤90% (HR1.42, CI 0.88–2.28, p=0.146). Using the combined dataset,reduced survival was associated with more advanceddisease stage (HR 2.00, CI 1.44–2.77, p<0.001), age (HR1.03, 95% CI 1.01–1.05, p=0.002) and RDI≤90% (HR1.77, CI 1.12–2.79, p=0.014). In both models, the strengthof the association with disease stage decreased over time.Approximately 23% and 30% of UK and Belgianpatients, respectively, received ARDI≤90% and were,therefore, at risk of reduced survival. There are manyfactors that result in a decision to reduce or delay che-motherapy, including local institutional practice. Particular-ly relevant is the higher proportion of elderly patients in theBelgian dataset; elderly patients are at high FN risk [1] andoften receive lower doses of chemotherapy [3]. Despite thiscommon practice, dose-dense CHOP-14 chemotherapyAnn Hematol (2008) 87:429–430DOI 10.1007/s00277-008-0447-2R. Pettengell (*)Cellular and Molecular Medicine,St. George’s University of London,Cranmer Terrace,London SW17 0RE, UKe-mail: rpetteng@sgul.ac.ukM. SchwenkglenksEuropean Center of Pharmaceutical Medicine,Executive Office, University Hospital, University of Basel,Basel 4031, SwitzerlandA. BoslyDepartment of Haematology,University Hospital of Mont-Godinne,avenue Dr G. Therasse 1,Yvoir 5530, Belgiumsupported with G-CSF has been shown to be efficacious andwell tolerated in both young and elderly NHL patients [5, 6].This study highlights the potential impact of receivingARDI≤90% on survival. While further investigation isneeded, delivering full chemotherapy dose intensityremains an important goal in NHL patients who receiveCHOP-21 chemotherapy.Acknowledgements The authors wish to thank the following forcontributing data: D Bron (Bruxelles, Belgium), P Johnson (South-ampton, UK), A Van Hoof (Brugge, Belgium), B Hancock (Sheffield,UK), R De Bock (Antwerpen, Belgium), A Pagliuca (London, UK), ZBerneman (Edegem, Belgium), R Thomasi (Cambridge, UK), AFerrant (Bruxelles, Belgium), M Joyner (Exeter, UK), M Dauwe(Bruxelles, Belgium), G Verhoef (Leuven, Belgium) and P Hoskins(Northwood, UK). The authors also wish to thank Amgen (Europe)GmbH, Zug, Switzerland for supporting this work with an unrestricted,educational grant, and Dr L. Woodford who provided medical writingservices on behalf of medcept Ltd, Switzerland.Open Access This article is distributed under the terms of theCreative Commons Attribution Noncommercial License which per-mits any noncommercial use, distribution, and reproduction in anymedium, provided the original author(s) and source are credited.References1. Aapro MS, Cameron DA, Pettengell R, Bohlius J, Crawford J, EllisM, Kearney N, Lyman GH, Tjan-Heijnen VC, Walewski J, WeberDC, Zielinski C (2006) EORTC guidelines for the use ofgranulocyte-colony stimulating factor to reduce the incidence ofchemotherapy-induced febrile neutropenia in adult patients withlymphomas and solid tumours. Eur J Cancer 42:2433–24532. Bosly A, Bron D, Van Hoof A, De Bock R, Berneman Z, Ferrant A,Kaufman L, Dauwe M, Verhoef G; for the Lymphoma Dose Project:a National Study (2008) Achievement of optimal average relativedose intensity and correlation with survival in diffuse large B-celllymphoma patients treated with CHOP. Ann Hematol 87:277–2833. Marangolo M, Bengala C, Conte PF, Danova M, Pronzato P, RostiG, Sagrada P (2006) Dose and outcome: the hurdle of neutropenia.Oncol Rep 16:233–2484. Pettengell R, Bosly A, Bron D, Schwenkglenks M, Johnson P, VanHoof A, Hancock B, De Brock R, Pagliuca A, Berneman Z, Thomas R,Ferrant A, Joyner M, Dauwe M, Verhoef G, Hoskin P (2006)Association of reduced relative dose intensity and survival in lymphomapatients receiving CHOP-21 chemotherapy. Haematologica/HematolJ 91:69 (Abs 0185)5. Pfreundschuh M, Trumper L, Kloess M, Schmits R, Feller AC,Rube C, Rudolph C, Reiser M, Hossfeld DK, Eimermacher H,Hasenclever D, Schmitz N, Loeffler M, The German High-GradeNon-Hodgkin's Lymphoma Study G (2004) Two-weekly or 3-weekly CHOP chemotherapy with or without etoposide for thetreatment of elderly patients with aggressive lymphomas: results ofthe NHL-B2 trial of the DSHNHL. Blood 104:634–6416. Pfreundschuh M, Trumper L, Kloess M, Schmits R, Feller AC,Rudolph C, Reiser M, Hossfeld DK, Metzner B, Hasenclever D,Schmitz N, Glass B, Rube C, Loeffler M, The German High-GradeNon-Hodgkin's Lymphoma Study G (2004) Two-weekly or 3-weekly CHOP chemotherapy with or without etoposide for thetreatment of young patients with good-prognosis (normal LDH)aggressive lymphomas: results of the NHL-B1 trial of theDSHNHL. Blood 104:626–6330.000.250.500.751.00Proportion surviving150Months of observationRDI > 90%RDI ≤ ≤ 90%*p = 0.0900 50 100RDI > 90%RDI 90%0.000.250.500.751.00Proportion survivingMonths of observation0 50 100 150 200*p < 0.001ab200Fig. 1 Kaplan–Meier survivor estimates by RDI for UK dataset alone(a) and the combined UK and Belgian datasets (b). Asterisk Log-ranktest-based p values430 Ann Hematol (2008) 87:429–430

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Pettengell, R.

Schwenkglenks, M.

Bosly, A.

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LETTER TO THE EDITOR
Association of reduced relative dose intensity and survival
in lymphoma patients receiving CHOP-21 chemotherapy
R. Pettengell & M. Schwenkglenks & A. Bosly
Received: 7 November 2007 /Accepted: 17 January 2008 /Published online: 26 February 2008
# The Author(s) 2008
Dear Editor,
Reductions in average relative chemotherapy dose intensity
(ARDI; i.e. administered compared with planned) compro-
mise patient outcomes [3], and a recent Belgian study
showed that survival for non-Hodgkin lymphoma (NHL)
patients receiving CHOP-21 was reduced when ARDI fell
below 90% [2]. We support these findings with similar data
from the UK Audit of Lymphoma Patients (n=78 patients
who received CHOP-21 chemotherapy in 1999–2000) and
from the combined Belgian and UK data (n=289) [4].
Patient, disease and treatment characteristics were similar
between the two studies, except that the UK patients were
younger (mean age ± SD was 55±15 years versus 63±
14 years) and fewer UK patients received colony stimulating
factor (CSF). First cycle CSF use was 4% in the UK study
compared to 25% in the Belgian study. During an average
time to death or censoring of 72 months, 35% of patients in
the UK study died. In the Belgian study, the average
observation time was 30 months, during which 31% of
patients died. After adjusting for the higher mean age of the
Belgian patients, Kaplan–Meier survival functions were
similar between the two populations (log-rank test stratified
by 10-year age groups, p=0.38).
Kaplan–Meier plots for patients with >90% ARDI versus
≤90% ARDI showed reduced survival for the patients with
≤90% ARDI (Fig. 1). A trend towards reduced survival was
apparent in the UK dataset alone (Fig. 1a; log-rank test-
based p=0.090). For the combined dataset, the effect was
statistically significant (p<0.001; Fig. 1b), as for the
Belgian data alone [2].
Potential predictors of reduced survival were assessed
using an extended Cox proportional hazards regression
model with robust standard errors allowing for clustering
by centre. Using the UK dataset, reduced survival was
significantly associated with a higher Ann Arbor disease
stage (hazard ratio (HR) at treatment initiation 2.59 per
stage increase by 1, 95% CI 1.45–4.66, p=0.001) and
showed a trend towards association with age (HR 1.02 per
year of age, CI 1.00–1.04, p=0.058) and RDI≤90% (HR
1.42, CI 0.88–2.28, p=0.146). Using the combined dataset,
reduced survival was associated with more advanced
disease stage (HR 2.00, CI 1.44–2.77, p<0.001), age (HR
1.03, 95% CI 1.01–1.05, p=0.002) and RDI≤90% (HR
1.77, CI 1.12–2.79, p=0.014). In both models, the strength
of the association with disease stage decreased over time.
Approximately 23% and 30% of UK and Belgian
patients, respectively, received ARDI≤90% and were,
therefore, at risk of reduced survival. There are many
factors that result in a decision to reduce or delay che-
motherapy, including local institutional practice. Particular-
ly relevant is the higher proportion of elderly patients in the
Belgian dataset; elderly patients are at high FN risk [1] and
often receive lower doses of chemotherapy [3]. Despite this
common practice, dose-dense CHOP-14 chemotherapy
Ann Hematol (2008) 87:429–430
DOI 10.1007/s00277-008-0447-2
R. Pettengell (*)
Cellular and Molecular Medicine,
St. George’s University of London,
Cranmer Terrace,
London SW17 0RE, UK
e-mail: rpetteng@sgul.ac.uk
M. Schwenkglenks
European Center of Pharmaceutical Medicine,
Executive Office, University Hospital, University of Basel,
Basel 4031, Switzerland
A. Bosly
Department of Haematology,
University Hospital of Mont-Godinne,
avenue Dr G. Therasse 1,
Yvoir 5530, Belgium
supported with G-CSF has been shown to be efficacious and
well tolerated in both young and elderly NHL patients [5, 6].
This study highlights the potential impact of receiving
ARDI≤90% on survival. While further investigation is
needed, delivering full chemotherapy dose intensity
remains an important goal in NHL patients who receive
CHOP-21 chemotherapy.
Acknowledgements The authors wish to thank the following for
contributing data: D Bron (Bruxelles, Belgium), P Johnson (South-
ampton, UK), A Van Hoof (Brugge, Belgium), B Hancock (Sheffield,
UK), R De Bock (Antwerpen, Belgium), A Pagliuca (London, UK), Z
Berneman (Edegem, Belgium), R Thomasi (Cambridge, UK), A
Ferrant (Bruxelles, Belgium), M Joyner (Exeter, UK), M Dauwe
(Bruxelles, Belgium), G Verhoef (Leuven, Belgium) and P Hoskins
(Northwood, UK). The authors also wish to thank Amgen (Europe)
GmbH, Zug, Switzerland for supporting this work with an unrestricted,
educational grant, and Dr L. Woodford who provided medical writing
services on behalf of medcept Ltd, Switzerland.
Open Access This article is distributed under the terms of the
Creative Commons Attribution Noncommercial License which per-
mits any noncommercial use, distribution, and reproduction in any
medium, provided the original author(s) and source are credited.
References
1. Aapro MS, Cameron DA, Pettengell R, Bohlius J, Crawford J, Ellis
M, Kearney N, Lyman GH, Tjan-Heijnen VC, Walewski J, Weber
DC, Zielinski C (2006) EORTC guidelines for the use of
granulocyte-colony stimulating factor to reduce the incidence of
chemotherapy-induced febrile neutropenia in adult patients with
lymphomas and solid tumours. Eur J Cancer 42:2433–2453
2. Bosly A, Bron D, Van Hoof A, De Bock R, Berneman Z, Ferrant A,
Kaufman L, Dauwe M, Verhoef G; for the Lymphoma Dose Project:
a National Study (2008) Achievement of optimal average relative
dose intensity and correlation with survival in diffuse large B-cell
lymphoma patients treated with CHOP. Ann Hematol 87:277–283
3. Marangolo M, Bengala C, Conte PF, Danova M, Pronzato P, Rosti
G, Sagrada P (2006) Dose and outcome: the hurdle of neutropenia.
Oncol Rep 16:233–248
4. Pettengell R, Bosly A, Bron D, Schwenkglenks M, Johnson P, Van
Hoof A, Hancock B, De Brock R, Pagliuca A, Berneman Z, Thomas R,
Ferrant A, Joyner M, Dauwe M, Verhoef G, Hoskin P (2006)
Association of reduced relative dose intensity and survival in lymphoma
patients receiving CHOP-21 chemotherapy. Haematologica/Hematol
J 91:69 (Abs 0185)
5. Pfreundschuh M, Trumper L, Kloess M, Schmits R, Feller AC,
Rube C, Rudolph C, Reiser M, Hossfeld DK, Eimermacher H,
Hasenclever D, Schmitz N, Loeffler M, The German High-Grade
Non-Hodgkin's Lymphoma Study G (2004) Two-weekly or 3-
weekly CHOP chemotherapy with or without etoposide for the
treatment of elderly patients with aggressive lymphomas: results of
the NHL-B2 trial of the DSHNHL. Blood 104:634–641
6. Pfreundschuh M, Trumper L, Kloess M, Schmits R, Feller AC,
Rudolph C, Reiser M, Hossfeld DK, Metzner B, Hasenclever D,
Schmitz N, Glass B, Rube C, Loeffler M, The German High-Grade
Non-Hodgkin's Lymphoma Study G (2004) Two-weekly or 3-
weekly CHOP chemotherapy with or without etoposide for the
treatment of young patients with good-prognosis (normal LDH)
aggressive lymphomas: results of the NHL-B1 trial of the
DSHNHL. Blood 104:626–633
0.00
0.25
0.50
0.75
1.00
Pr
o
po
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o
n 
su
rv
iv
in
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150
Months of observation
RDI > 90%
RDI ≤ 
≤ 
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*p = 0.090
0 50 100
RDI > 90%
RDI 90%
0.00
0.25
0.50
0.75
1.00
Pr
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Months of observation
0 50 100 150 200
*p < 0.001
a
b
200
Fig. 1 Kaplan–Meier survivor estimates by RDI for UK dataset alone
(a) and the combined UK and Belgian datasets (b). Asterisk Log-rank
test-based p values
430 Ann Hematol (2008) 87:429–430


Associationofreducedrelativedoseintensityandsurvivalinlymphoma patients receiving CHOP-21 chemotherapy. Haematologica/Hematol J 91:69 (Abs 0185) 5. Pfreundschuh

EORTC guidelines for the use of granulocyte-colony stimulating factor to reduce the incidence of chemotherapy-induced febrile neutropenia in adult patients with lymphomas and solid tumours.

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Association of reduced relative dose intensity and survival in lymphoma patients receiving CHOP-21 chemotherapy

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