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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 95 No. 12 (June 15), 2000:
pp. 3687-3692
CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
Quality of life-adjusted survival analysis of high-dose therapy
with autologous bone marrow transplantation versus sequential
chemotherapy for patients with aggressive lymphoma in first
complete remission
Nicolas Mounier,
Corinne Haioun,
Bernard F. Cole,
Christian Gisselbrecht,
Catherine Sebban,
Pierre Morel,
Gerald Marit,
Reda Bouabdallah,
Christophe Ravoet,
Gilles Salles,
Felix Reyes, and
Eric Lepage for the
Groupe d'Etude des Lymphomes de l'Adulte (GELA)
From the Département d'information hospitalier and Service
d'hématologie clinique Hôpital Henri Mondor, AP-HP,
Créteil, France; Dartmouth-Hitchcock Medical Center, Lebanon, NH;
Institut d'hématologie, Hôpital Saint Louis, AP-HP, Paris,
France; Service d'hématologie, Centre Léon Bérard,
Lyon, France; Service d'hématologie, Centre Hospitalier du Dr
Schaffner, Lens, France; Service d'hématologie, CHU de Bordeaux,
Pessac, France; Service d'hématologie, Institut Paoli Calmette,
Marseille, France; Service d'hématologie, Centre Jolimont, La
Louvière, Belgium; and Service d'hématologie, Centre
Hospitalier Lyon Sud, Pierre Bénite, France.
 |
Abstract |
Evaluating high-dose therapy (HDT) with autologous stem cell
transplantation (ASCT) in term of both duration and quality of life
(QOL) presents major interests for patients with non-Hodgkin lymphoma.
The quality-adjusted time without symptom and toxicity (Q-TWiST)
methodology was applied to the LNH87-2 trial comparing HDT with ASCT
versus sequential chemotherapy in 541 patients in first complete
remission (CR). Overall survival (OS) and disease-free survival (DFS)
curves were used to estimate duration of 4 health states: acute
short-term toxicity (Tox1), secondary toxicity (Tox2), time without
symptom and toxicity (TWiST), and relapse (Rel). Areas under survival
curves (AUC) were retrospectively weighted according to QOL
coefficients. HDT increased, but not significantly, TWiST (+2.4
months in AUC, P = .17) and decreased Rel ( 3 months, P < .01). Survival estimates did not differ between the 2 treatments (AUC 47.7 months for OS, 39.7 months for DFS). High-risk
patients treated by HDT versus chemotherapy had a significant benefit
in DFS (AUC 28.8 versus 24.9 months, P < .01) but not in OS
(AUC 37.3 versus 36 months, P = .27). Sensitivity analysis,
performed by varying QOL coefficients, demonstrated significant
quality-adjusted survival gain in high-risk patients treated by HDT. In
low-risk patients, a diagram provided an aid to clinical
decision-making. This analysis supports the use of HDT in these
patients with adverse prognostic factors in the first CR, even after
adjusting for QOL using the Q-TWiST method.
(Blood. 2000;95:3687-3692)
© 2000 by The American Society of Hematology.
| |
Introduction |
Aggressive non-Hodgkin lymphoma (NHL) is a
chemosensitive malignancy that displays a steep dose-response curve.
The disease is curable by first-line conventional chemotherapy in 50%
to 60% of patients. The use of high-dose chemotherapy (HDT) and
autologous stem cell transplantation (ASCT) for chemotherapy-sensitive
relapsed aggressive NHL is now the gold standard.1,2 What
is not clear is whether HDT should be withheld until the patient
relapses or used up-front as part of first-line therapy, particularly
for patients who have achieved remission. Three randomized studies have
shown some benefit of HDT over sequential chemotherapy in patients in
complete remission (CR).3-6
The importance of secondary end points, such as the impact of treatment
on functional status and quality of life (QOL), has been recently
recognized, particularly when alternative treatment options with
similar potential for long-term survival become available. Autotransplantation treatment has an intense toxicity period but a
short duration. On the other hand, chemotherapy is usually moderate, but the entire consolidative procedure generally takes longer. Therefore, QOL factors may contribute to the therapeutic decision between HDT or conventional chemotherapy. The methodologic challenges posed by the assessment of QOL are substantial. Although QOL research is progressing, most published studies of patients with ASCT are small,
nonrandomized, or retrospective.7 In addition, comparisons among studies are complicated by differences in definitions and methods
of QOL assessment. Ideally, detailed QOL assessment is made
prospectively using standardized questionnaires, validated for
transplantation trials. Given the relatively recent recognition of QOL
as an important study end point, many mature clinical trials lack
prospective information on QOL. Fortunately, techniques have been
developed for retrospective analysis of the tradeoffs between quantity
and quality of life in clinical trials. In particular, the
Quality-adjusted Time Without Symptoms and Toxicity (Q-TWiST) method
evaluates the risks and benefits of treatments by estimating the
duration of health states that may affect QOL (eg, toxicity, disease
relapse) and weighting these health state durations to arrive at a
QOL-adjusted end point.
The Q-TWiST method was developed initially for comparing adjuvant
chemotherapy regimens in solid tumors.8-11 It has also been useful in hematologic malignancies such as myeloma and
NHL12,13 and was recently used in a transplantation trial
in pediatric patients.14 To explore, in a large homogenous
study population, the benefit of ASCT in high- and low- risk NHL
patients, weighting the impact of treatment-related toxicity versus
potentially improved survival, we performed a Q-TWiST analysis on the
results of the Groupe d'Etude des Lymphomes de l'Adulte (GELA)
LNH87-2 trial that compared ASCT with sequential chemotherapy for
intermediate-grade and high-grade NHL in first CR.3,4
| |
Patients and methods |
Patients
LNH87-2 is a randomized, multicenter trial conducted in 35 European
centers to compare ASCT versus chemotherapy for the treatment of
aggressive NHL in adults. Details regarding study design and data
management have been previously published.3 Brief
descriptions of the patient population and treatment regimens are
provided below.
Newly diagnosed patients, aged 16 to 55 years, with intermediate- or
high-grade lymphoma, defined as group D to J in the Working Formulation, were eligible if they presented at least 1 of the following adverse factors: 2 or more extranodal sites, performance status of 2 to 4, maximal tumor burden of 10 cm or more, and bone marrow or central nervous system involvement. Patients with histologic progression of a previous low-grade lymphoma, those having positive serology for human immunodeficiency virus (HIV), or any
contraindication for high-dose doxorubicin or cyclophosphamide were
excluded. Initial staging procedures included bone marrow biopsy,
cerebrospinal fluid examination, and computed tomography (CT) of the
thorax and abdomen. Patients were staged according to the Ann Arbor
classification. Performance status was assessed according to the
Eastern Cooperative Oncology Group scale (ECOG). Serum lactate
dehydrogenase (LDH) was expressed as a percentage of the maximal normal
value. Patients were admitted to the trial between October 1, 1987, and
February 28, 1993. Written informed consent was obtained from each
patient before enrollment. A total of 916 patients were eligible, but the study population for this analysis consists of the 541 patients who
achieved CR.
Treatment
The induction treatment consisted of 4 courses of chemotherapy with
open randomization for the anthracycline: doxorubicin 75 mg/m2 (ACVBP arm) or mitoxantrone 12 mg/m2
(NCVBP arm) day 1, cyclophosphamide 1200 mg/m2 day 1, vindesine 2 mg/m2 days 1 and 5, bleomycin 10 mg days 1 and
5, methylprednisolone 60 mg/m2 days 1 to 5, and
IT methotrexate 15 mg. Courses were delivered every 2 weeks. Patients who achieved CR were subsequently randomized between
HDT with CBV (cyclophosphamide 1500 mg/m2 day 7 to day 4, carmustine 300 mg/m2 day 4, and etoposide 250 mg/m2 day 7 to day 4) followed by ASCT
(marrow infusion day 0) versus sequential consolidation regimen with 2 courses of high-dose methotrexate (3 g/m2) with leucovorin
rescue, 2 courses of ifosfamide (1.5 g/m2 days 1 and 2)
plus etoposide (300 mg/m2 days 1 and 2), and then
asparaginase and cytarabine every 2 weeks for a total of 8 courses.
After completion of therapy, patients had clinical examination and
routine blood count every 3 months during the first 2 years, every 6 months during another 2 years, and annually thereafter. Thoracic and
abdominal CT scans were performed at least annually during the first 4 years.
Q-TWiST method
The QOL-adjusted treatment comparison was performed using the
Q-TWiST method, which compares treatments by defining relevant clinical
health states and estimating their respective
durations.15-18 The health state durations are then
weighted according to patient utility, and the Q-TWiST end point is
determined by the sum of the weighted health state durations. Four
clinical health states were defined for this analysis:
-
 Tox1 the time period with acute,
treatment-related symptomatic toxicities requiring
hospitalization Tox2the time period with secondary
toxicity requiring out patient treatment
TWiSTthe time following toxicity but before relapse; and
period representing the best possible QOL after the treatment of NHL, during which patients experience no toxicities of treatment or symptoms of disease Relall time following
disease relapse until death (regardless of whether the patient recovers
from the relapse)
- The TWiST health state is assumed to represent the best
possible QOL for a patient with NHL because it is not associated with either treatment toxicity or disease relapse.
- Detailed data regarding the duration of toxicity after transplantation
was not available for individual patients. Therefore, following a
methodology similar to that used by Parsons et al,14 we
constructed a surrogate for the toxicity period as follows: the total
duration of toxicity (Tox = Tox1 + Tox2) was assumed to be 100 days
to reflect the usual period of peritransplant complications. The
durations of Tox1 and Tox2 were assumed to be 30 days and 70 days,
respectively. The 100-day period was also selected to incorporate the
total consolidation chemotherapy duration (14 weeks).
- The mean health state durations were obtained by first plotting
survival curves, up to the median follow-up duration, for disease-free
survival (DFS) and overall survival (OS) on the same graph according to
treatment group. The mean duration of TWiST for each treatment group
was computed as the area under the DFS curve, less the assumed duration
of toxicity of 100 days. The mean duration of Rel for each treatment
group was computed as the area between the survival curves for DFS and
OS (Figure 2).
- The mean durations of the clinical health states were weighted using
utility coefficients denoted by uTox1,
uTox2 and uRel, to reflect the average value (relative to TWiST) of time in the health
states Tox1, Tox2 and Rel, respectively. Each utility coefficient is a
scale from 0 to 1, where 0 represents QOL as bad as death, 1 represents
QOL as good as TWiST, and values between 0 and 1 represent degrees
between these extremes.
- The Q-TWiST end point was calculated as
Q-TWiST = uTox1 × Tox1 + uTox2 × Tox2 + TWiST + uRel × Rel where Tox1, Tox2, TWiST, and Rel
represent the respective mean clinical health state durations in
months. Treatment comparisons were made by subtracting the mean Q-TWiST
for the chemotherapy group from the mean Q-TWiST for the
transplantation group, and these differences were compared using a Z test.
- To investigate how prognostic factors, based on the International
Prognostic Index (IPI),19 affect the treatment comparison, we used a parametric regression model for Q-TWiST.20 A
brief technical description is given in the Appendix. Risk groups were defined according to the number of significant adverse factors. Using
this model, we obtained predictions of the Q-TWiST treatment effect for
various risk factor profiles.
Sensitivity analysis of utility
Because the LNH87-2 study did not collect QOL objective data,
patient assessments of the utility coefficients are not available. In
their absence, we performed a sensitivity analysis in which the Q-TWiST
treatment effect was evaluated for all possible combinations of utility
weight values. The results are presented graphically in a 2-dimensional
plot that shows, as the utility coefficient values vary, the magnitude
of the Q-TWiST treatment effect as well as whether the effect is
statistically significant. This graph provides an aid to clinical
decision-making by illustrating the QOL-adjusted treatment effect
according to varying values of the utility coefficients. We also
performed sensitivity analysis to assess the stability of the results
when different Tox1 and Tox2 durations (ranging from 2-6 weeks and 2-4 months, respectively) were used for HDT.
All statistical analyses were computed with SAS 6.12 for PC (SAS
Institute, Cary, NC).
| |
Results |
Univariate analysis
The study included 312 men and 229 women, with a median age of 40. Clinical characteristics are presented in Table
1. Figure 1
illustrates the possible health state transitions as well as the number
of patients in each treatment group making each transition. Three toxic
deaths were reported; 2 patients died of transplant-related complications and 1 of thromboembolic disease following asparaginase treatment. Among the 13 patients who died without relapsing, the cause
of death was known in 9; 2 second cancers, 3 cardiac events, 2 infections, and 2 accidents. Figure 2 shows
survival curves drawn out to the median follow-up of 5 years for the
entire patient sample. The mean durations of Tox, TWiST and Rel were
computed as areas under the curves (AUC). They were, respectively, 3.3 months, 36.6 months, and 7.8 months. ASCT increased, but not
significantly, the mean time in TWiST (AUC 39.7 versus 37.3 months,
P = .17) but decreased the time in Rel (6.4 versus 9.4 months, P < .01). The survival estimates did not differ
significantly between the 2 consolidation treatments either in OS (47.7 versus 47.8 months, P = .8) or in DFS (41 versus 38.4 months,
P = .17).
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| Fig 1.
Transitions between health states.
The number of patients making each transition is given in parentheses,
first for chemotherapy, second for ASCT.
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| Fig 2.
Survival curves for the study population.
Areas under the curves correspond to the mean duration of Tox (darkly
shaded area), TWiST (white area), and Rel (lightly shaded area).
Vertical line indicates the median follow-up.
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|
Multivariate analysis
To investigate how prognostic factors affect the treatment
comparison, we performed a multivariate regression analysis for Q-TWiST. Its other interest was to examine separately prognostic factors for competing events such as relapse or death. The predictive value of clinical characteristics used by the age-adjusted IPI was
investigated for each transition between health states. Table 2 shows relative risk estimates. After the
treatment period, performance status evaluated at diagnosis had no
independent predictive value. By contrast, factors reflecting tumor
invasive potential at diagnosis, such as disseminated stage or elevated
LDH, remained predictive for relapse (relative risk respectively 2.44, IC 95% [1.25; 4.74] and 1.77, IC 95% [1.15; 2.72]). After
relapse, first-line consolidative high-dose therapy was isolated as
independent adverse prognostic factor (relative risk 1.40 IC 95%
[1.08; 1.81]). This was partially due to an inability to tolerate
intensive salvage regimens for patients receiving HDT as first-line
treatment. Among the 112 patients who relapsed after consolidation
chemotherapy, 48 (42%) were treated by HDT in second-line therapy,
whereas only 24 (23%) of 104 who relapsed in the high-dose group could
benefit from a second HDT. No statistically significant interaction was found between treatment effects and IPI factors.
Because ECOG had no independent prognostic value in the study
population, the low-risk group was defined by the conjunction of LDH
less than N and localized stage. On the other hand, the high-risk group
was defined by LDH more than N and disseminated stage.
Intermediate-risk patients had only 1 adverse factor. Table 3 shows the health state durations, within
the median follow-up time, according to prognostic profile and
treatment group. HDT systematically increased the time in TWiST but
decreased the time in Rel. The OS did not differ significantly between
the 2 consolidation treatments. However, in high-risk patients, HDT had
a significant DFS gain (28.8 versus 24.9 months, P < .01).
Sensitivity analysis
To focus on tradeoff between quantity and quality of life, each
health state duration was weighted by a coefficient measuring QOL
and utility analysis was performed by varying QOL coefficient values.
The utility analysis applied to high-risk patients revealed that ASCT
was preferred over chemotherapy for all possible utility values,
although this difference was not statistically significant for any of
the utility value combinations. In contrast, treatment comparison among
low-risk patients revealed that chemotherapy was preferred over ASCT.
To illustrate the impact of QOL on treatment choice, Figures
3 and 4 show
Q-TWiST estimates according to various coefficients sets. In set A,
ASCT QOL during Tox1 was assumed 2 times worse than chemotherapy. In
set B, ASCT QOL during Tox1 was assumed 4 times worse than
chemotherapy. In set C, lifetime after relapse was not taken into
account (uRel = 0, eg DFS). For high- and
low-risk patients (Figure 3A and 3B, respectively), the preferred
therapy did not vary (ASCT and chemotherapy, respectively). But, in
case of intermediate-risk patients, Figure 4 provides an aid to
clinical decision-making. The physician may graphically evaluate
tradeoff between QOL and survival. Then, optimal treatment may be
proposed with respect to individual preferences regarding toxicity and
disease relapse. When considering the coefficients sets A or B,
ASCT showed no significant benefit. Conversely, if QOL during Rel
was not taken into account (set C), then ASCT presented significant
benefit.
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| Fig 3.
Utility analysis.
Utility analysis is shown for high-risk (A) and low-risk (B) patients,
assuming that QOL during Tox1 was better for chemotherapy than for ASCT
(uTox1 for ASCT ranging from 0 to 0.5) and that QOL during Tox2
was better for ASCT than for chemotherapy (uTox2 respectively
set to 0.75 and 0.5). Dashed lines indicate same amount
of Q-TWiST (eg, line 2 indicates ASCT provides 2 more months than
chemotherapy). Letters refer to examples given in text.
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| Fig 4.
Utility analysis.
Utility analysis is shown for intermediate-risk patients, assuming that
QOL during Tox1 was better for chemotherapy than for ASCT
(uTox1 for ASCT ranging from 0 to 0.5) and that QOL during Tox2
was better for ASCT than for chemotherapy (uTox2 respectively
set to 0.75 and 0.5). Dashed lines indicate same amount
of Q-TWiST (eg, line 3 indicates ASCT provides 3 fewer months
than chemotherapy). Letters refer to examples given in text.
|
|
Lastly, because our surrogate for the toxicity period was set at 100 days, we had to assess the stability of our results when different Tox1
and Tox2 durations were used. We reiterated the analysis with Tox1 and
Tox2 ranging, respectively, from 2 to 6 weeks and from 2 to 4 months
for ASCT. Conclusions were insensitive to changes in toxicity duration.
Figure 5 shows the effect of Tox1 and Tox2
variations in the case of intermediate-risk patients for coefficient
sets B and C. The amount of variation of Q-TWiST ranged between
0.45 and +0.25 months but did not reach significance.
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| Fig 5.
Effect of variation in toxicity duration for ASCT in
intermediate-risk patients.
The vertical lines figure the initial Tox1 = 30 days and Tox2 = 70
days. The gray bars figure effects of Tox1 and Tox2 variation on amount
of Q-TWiST (in months).
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| |
Discussion |
In the absence of a large international randomized trial with
uniform inclusion criteria, the benefit of ASCT in aggressive NHL has
to be assessed on the basis of a few trials. It seems unlikely, at
present, that ASCT will be appropriate for indiscriminate application
to all patients in first CR. However, QOL studies might offer
additional information. The difficulty is then to identify a group of
patients with a poor prognosis who could benefit from high-dose
consolidation regimens. Although it lacks biologic markers, the IPI
permits a standardized approach. Previous univariate subset analyses of
the LNH87-2 trial have demonstrated the benefit of ASCT over sequential
chemotherapy in high and high-intermediate (IPI score 2-3)
patients.4 The present multivariate analysis clarified
these results investigating separately prognostic factors for
competing events during the disease course. Among the IPI factors, only stage III to IV and elevated LDH were retained
as independent prognostic factors for relapse. This agrees with the point that performance status at diagnosis is a marker of a patient's response to the tumor but not of the invasive potential of the tumor,
and so, has no longer predictive value after the treatment period.3,21 More interesting was the negative impact of
first-line ASCT treatment on survival after relapse. Compared with
consolidation chemotherapy, ASCT diminished the mean time spent in
relapse. It might be explained by the difficulties to tolerate
intensive salvage therapy. Haioun et al4 have previously
found a marginally significant quantitative interaction between
treatment effect on OS and IPI score, suggesting that, for low-risk
patients, the benefit of ASCT was smaller than for high-risk patients.
In fact, autografting in first CR jeopardized their outcome after the
relapse, if even it occurred.
The QOL-adjusted treatment comparison was based on generalization of
the Q-TWiST method originally developed to evaluate adjuvant therapies
for breast cancer and later extended to therapies for HIV and various
solid tumors.8-11 The method is appropriate when the
disease course has well-defined health states, indicative of QOL
valuation. It provides logistical interests because computations are
based on standard survival curves and do not require QOL
questionnaires. However, it should be noted that Q-TWiST estimates
are expressed on a QOL weighted time scale, with weighting coefficients
less than 1, and so appear lower than on a real-time scale. There was only 1 previous Q-TWiST application to ASCT clinical issues in pediatric hematology by Parsons et al.14 But this study did not consider prognostic factors. Our fully parametric Q-TWiST approach
overcame this limitation providing predictions of the Q-TWiST
treatment effect for various risk factor profiles.
The more complex problem was to determine an appropriate quality
function for transplantation issues. Following a methodology similar to
that used by Parsons et al,14 we have to use a surrogate for individual Tox duration after completion of therapy. With the usual
100-day cutoff point, we focused on short-term toxicities because of
their likely negative impact on QOL. But, in ASCT trials, the impact of
long-term toxicity has to be discussed. Infertility, endocrinologic
disturbances, cataracts, and second cancers are commonly associated
with bone marrow transplantation.22-24 Psychosocial factors
have also to be considered with special attention for those heavily
treated patients.25,26 However, Chao et al27 have shown that, globally, during the first year after
autotransplantation, 90% of surviving patients reported an above
average to excellent QOL. Moreover, in a recent study, Duell et
al22 have reported that more than 90% of long-term
survivors of allogeneic transplantation are in good health and had
returned to full-time work. On the other hand, standard-dose
chemotherapy has also shown late sequelae.28 In the work by
Hjermstad et al,29 only cognitive function at 1 year was
different between patients receiving ASCT and chemotherapy. We share
the point that it may diminish QOL and that our approach was not
sensitive enough to discriminate. But the aim of our study was to
evaluate the tradeoff between quantity and quality of life in the
LNH87-2 trial. For such analysis, the impact of long-term fatigue seems
negligible when compared with relapse of the underlying malignancy or
second tumor. In our study population, we only found 1 secondary
leukemia but, among the other 12 deaths in patients in CR, cardiac
events and infection cannot be definitively ruled out. So, in absence
of prospective comparative data with long-term follow-up, our
restriction of the toxicity period to 100 days seems to be a good
clinical cutoff point. In addition, sensitivity analyses showed
no change in conclusion when Tox1 and Tox2 duration for
HDT varied.
In future studies, our approach will be easy to adapt. Tox1 should
estimate acute grade III to IV toxicities, and Tox2 chronic low-grade toxicities. In addition, because most of the QOL
questionnaire may be reduced to a single score, mean QOL
patterns may further be combined with survival curves to
improve Q-TWiST sensitivity.18
This study demonstrated that aggressive NHL patients in first remission
might benefit from HDT with ASCT, even after adjusting for QOL. As in
other Q-TWiST analyses, the gain seems small but mean Q-TWiST
difference of 2 or 3 months on a QOL-weighted time scale, aimed at a
large population, shows an important intervention. Between sequential
chemotherapy and high-dose regimen, the best consolidation treatment
was influenced by stage and LDH level as well as the relative valuation
placed on treatment toxicity and relapse times. In the LNH87-2, our
Q-TWiST analysis supports the use of ASCT for higher risk patients over
a wide range of QOL coefficient values. Although we did not observe
significant long-term toxicity of treatment in both arms, a longer
follow-up of the study is necessary to rule out imbalances in late
events. Future research may permit quality-adjusted survival
comparisons in transplantation fields, especially by integrating direct
assessment of long-term toxicity into traditional efficacy trials.
| |
Appendix |
Parametric Q-TWiST method20
The first step was to fit a model of the transitions between health
states, with each transition governed by competing risk and survival
given by the sum of the time spent in each health state. The events
studied were end of treatment toxicity, disease recurrence, and overall
survival. All the patients were assumed to initially present toxic
effects of treatment. As in other Q-TWiST analyses, the patients were
assumed to progress forward through the health states but not backward.
If a state was skipped, its duration was set at zero. If a transition
time was censored, all the subsequent transition times were similarly
censored. So, from each of the 541 patients, the amount of time spent
in Tox, TWiST, and Rel was computed.
Then, the health state durations were analyzed using separate
accelerated failure time models. Transition from TWiST to Rel had a
hazard function that corresponded to a Weibull distribution. Transition
from Tox to Rel and from Rel to death had an exponential distribution.
To have a sufficient sample size, we assumed that the hazard for moving
from Rel to death was the same for both the second and the third
transition. For each state, the duration was modeled parametrically and
the covariates were included in the model to adjust for the next state
entry time. The transition from TWiST to Rel was modeled with a Weibull
hazard function to account for the particular pattern of aggressive NHL
where relapses happen early on and then level off, late death being
attributed to a return to the underlying force of mortality of the
population at large. Other transitions were modeled with an exponential
hazard function. In addition to the factors used by the
IPI,19 the treatment group was also included as covariable.
The model parameters were estimated by maximum likelihood.
Lastly, model parameters were used in a simulation program to estimate
the amount of time spent in each state for various covariate
profiles. Independent random deviates were generated for each
competing risk and gave the latent transition time for each
possible health state. Minimum was taken and the process iterated until
death was selected at one of the transitions. Mean times were
computed on the simulated data (n = 500). Standard errors were obtained using 1000 bootstrap samples.30
| |
Footnotes |
Submitted April 26, 1999; accepted February 10, 2000.
Supported by grants from the Ligue Nationale contre le Cancer, the Fond
d'Etudes et de Recherche du Corps Médical des Hôpitaux de
Paris and the Direction de la Recherche Clinique de l'Assistance Publique, Hôpitaux de Paris (AP-HP), France.
Reprints: Eric Lepage, Département d'information
hospitalier, CHU Henri Mondor 51, avenue du Maréchal De Lattre de Tassigny, 94010 Créteil, France; e-mail:
eric.lepage{at}hmn.ap-hop-paris.fr.
The publication costs of this
article were defrayed in part by
page charge payment. Therefore,
and solely to indicate this fact,
this article is hereby marked
"advertisement"
in accordance with 18 U.S.C.
section 1734.
| |
References |
1.
Philip T, Guglielmi C, Hagenbeek A, et al.
Autologous bone-marrow transplantation as compared with salvage chemotherapy in relapses of chemotherapy-sensitive non-Hodgkin's lymphoma.
N Engl J Med.
1995;333:1540[Abstract/Free Full Text].
2.
Vose JM.
High-dose chemotherapy and hematopoietic stem-cells transplantation for relapsed or refractory diffuse large cell non Hodgkin's lymphoma.
Ann Oncol.
1998;9(suppl 1):1[Free Full Text].
3.
Haioun C, Lepage E, Gisselbrecht C, et al.
Comparison of autologous bone-marrow transplantation with sequential chemotherapy for intermediate-grade and high-grade non-Hodgkin's lymphoma in first complete remission.
J Clin Oncol.
1994;12:2543[Abstract/Free Full Text].
4.
Haioun C, Lepage E, Gisselbrecht C, et al.
Benefit of autologous bone-marrow transplantation over sequential chemotherapy in poor-risk aggressive non-Hodgkin's lymphoma: updated results of the prospective study LNH87-2.
J Clin Oncol.
1997;15:1131[Abstract/Free Full Text].
5.
Gianni AM, Bregni M, Siena S, et al.
High-dose chemotherapy and autologous bone-marrow transplantation compared with MACOP-B in aggressive non-Hodgkin's lymphoma.
N Engl J Med.
1997;336:1290[Abstract/Free Full Text].
6.
Santini G, Salvagno L, Leoni P, et al.
VACOP-B versus VACOP-B plus autologous bone-marrow transplantation for advanced diffuse non-Hodgkin's lymphoma: results of a prospective randomized trial by the Non-Hodgkin's lymphoma Cooperative Study Group.
J Clin Oncol.
1998;16:2796[Abstract].
7.
Hjermstad MJ, Kaasa S.
Quality of life in adult cancer patients treated with bone-marrow transplantation: a review of the literature.
Eur J Cancer.
1995;31A:163.
8.
Gelber RD, Goldhirsch A, Cavalli F.
Quality of life adjusted evaluation of a randomized trial comparing adjuvant therapy for operable breast cancer.
Ann Intern Med.
1991;114:621.
9.
Gelber RD, Cole BF, Goldhirsch A.
Adjuvant chemotherapy plus tamoxifen compared with tamoxifen alone for postmenopausal breast cancer: meta-analysis of quality adjusted survival.
Lancet.
1996;20:1066.
10.
Gelber RD, Goldhirsch A, Cole BF, Wieand HS, Schroeder G, Krook JE.
A quality adjusted time without symptoms or toxicity (Q-TWiST) analysis of adjuvant radiation therapy and chemotherapy for resectable rectal cancer.
J Natl Cancer Inst.
1996;88:1039[Abstract/Free Full Text].
11.
Cole BF, Gelber RD, Kirkwood JM, Goldhirsch A, Barylak E, Borden E.
Quality of life adjusted survival analysis of interferon alfa 2b adjuvant treatment of high-risk resected cutaneous melanoma: an Eastern Cooperative Oncology Group study.
J Clin Oncol.
1996;14:2666[Abstract/Free Full Text].
12.
Cole BF, Solal-Celigny P, Gelber RD, et al.
Quality of life adjusted survival analysis of interferon alfa2b treatment for follicular lymphoma: an aid to clinical decision making.
J Clin Oncol.
1998;16:2339[Abstract].
13.
Zee B, Cole B, Li T, et al.
Quality adjusted time without symptoms or toxicity analysis of interferon maintenance in multiple myeloma.
J Clin Oncol.
1998;16:2834[Abstract].
14.
Parsons SK, Gelber S, Cole BF, et al.
Quality-adjusted survival after treatment for acute myeloid leukemia in chilhood: a Q-TWiST analysis of the pediatric oncology group study 882.
J Clin Oncol.
1999;17:2144[Abstract/Free Full Text].
15.
Gelber RD, Gelman RS, Goldhirsch A.
Quality of life oriented endpoint for comparing therapies.
Biometrics.
1989;45:781[Medline]
[Order article via Infotrieve].
16.
Glasziou PP, Simes RJ, Gelber RD.
Quality adjusted survival analysis.
Stat Med.
1990;9:1259[Medline]
[Order article via Infotrieve].
17.
Cole BF, Gelber RD, Goldhirsch A.
Cox regression models for quality of life adjusted survival analysis.
Stat Med.
1993;12:975[Medline]
[Order article via Infotrieve].
18.
Glasziou PP, Cole BF, Gelber RD, Hilden J, Simes RJ.
Quality adjusted survival analysis, with repeated quality of life measures.
Stat Med.
1998;17:1215[Medline]
[Order article via Infotrieve].
19.
The International Non-Hodgkin's Lymphoma Prognostic Factors Project.
A predictive model for aggressive lymphoma.
N Engl J Med.
1993;329:987[Abstract/Free Full Text].
20.
Cole BF, Gelber RD, Anderson KM.
Parametricapproaches to quality adjusted survival analysis.
Biometrics.
1994;50:621[Medline]
[Order article via Infotrieve].
21.
Mounier N, Morel P, Haioun C, et al.
A multivariate analysis of the survival of patients with aggressive lymphoma: variations in the predictive value of prognostic factors during the course of the disease.
Cancer.
1998;82:1952[Medline]
[Order article via Infotrieve].
22.
Duel T, Van Lint MT, Ljungman P, et al.
Health and functional status of long term survivors of bone-marrow transplantation.
Ann Intern Med.
1997;126:184[Abstract/Free Full Text].
23.
Bhatia S, Ramsay NK, Steinbuch M, et al.
Malignant neoplasm following bone-marrow transplantation.
Blood.
1996;87:3633[Abstract/Free Full Text].
24.
Andre M, Henry-Amar M, Blaise D, et al.
Treatment-related deaths and second cancer risk after autologous stem-cells transplantation for Hodgkin's disease.
Blood.
1998;92:1933[Abstract/Free Full Text].
25.
Ahles TA, Tope DM, Furstenberg C, Hann D, Mills L.
Psychologic and neuropsychologic impact of autologous bone-marrow transplantation.
J Clin Oncol.
1996;14:1457[Abstract/Free Full Text].
26.
Van Dam FS, Schagen SB, Muller MJ, et al.
Impairment of cognitive function in women receiving adjuvant treatment for high-risk breast cancer: high-dose versus standard-dose chemotherapy.
J Natl Cancer Inst.
1998;90:210[Abstract/Free Full Text].
27.
Chao NJ, Tierney K, Bloom JR, et al.
Dynamic assessment of quality of life after autologous bone-marrow transplantation.
Blood.
1992;80:825[Abstract/Free Full Text].
28.
Liesner RJ, Leiper AD, Hann IM, Chessells JM.
Late effects of intensive treatment for acute myeloid leukemia and myelodysplasia in childhood.
J Clin Oncol.
1994;12:916[Abstract/Free Full Text].
29.
Hjermstad MJ, Evensen SA, Kvaloy SO, Fayers PM, Kaasa S.
Health-related quality of life 1 year after allogeneic or autologous stem-cells transplantation: a prospective study.
J Clin Oncol.
1999;17:706[Abstract/Free Full Text].
30.
DiCiccio TJ, Romano JP.
A review of bootstrap confidence intervals.
J R Stat Soc B.
1988;50:338.
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Abstract
Introduction