Careful phase I clinical trial design includes avoidance of unacceptable toxicity
to participating patients with cancer and minimisation of the number of patients treated
with ineffective drug doses. Despite the need for the development of new therapies,
and the importance attached to the findings of phase I trials in oncology, surprisingly
little information is published about patient selection and potential prognostic indices
that may aid the clinician in predicting, and discussing, the likely outcome for an
individual. Increasingly, with the development of biological therapies there is a
need to evaluate patient outcome in phase I studies with newer agents in comparison
to those treated with traditional cytotoxic drugs. This is important for determining
whether or not these trials can be considered as an ethical treatment option or whether
they compromise survival and quality of life.
Typically, in oncology, phase I trials have been offered to patients with cancer who
have a good performance status and have either failed standard treatment or for whom
no standard therapy exists. Despite the emphasis on evaluation of side effects, and
determination of a maximum tolerated dose (MTD), tumour responses remain an important
secondary end point. Reported response rates for phase I trials are generally between
1 and 10% (Estey et al, 1986; Decoster et al, 1990; Bachelot et al, 2000) with most
responses seen at 80–120% of the recommended phase II dose (Von Hoff and Turner, 1991).
Cytotoxic drugs that do not show antitumour activity in phase I trials rarely undergo
further evaluation (Von Hoff and Turner, 1991; American Society of Clinical Oncology,
1997; Sekine et al, 2002).
Previous reviews of phase 1 study data have used multivariable analyses to explore
factors associated with toxicity and prognosis. Dosage level and age over 65 years
are independently associated with grade 3 or 4 toxicity (Bachelot et al, 2000). Poor
performance status (WHO grade 2 or 3) (Janisch et al, 1994; Bachelot et al, 2000),
elevated lactate dehydrogenase (Bachelot et al, 2000), lower albumin, elevated platelet
counts and previous cisplatin therapy (Janisch et al, 1994) have all been identified
as independent adverse prognostic variables. Analyses have mostly been limited by
small sample sizes and have not compared cytotoxic (CT) with non-cytotoxic (non-CT)
drugs. For new non-CT agents such as antiangiogenic drugs or matrix metalloproteinase
inhibitors, tumour shrinkage may be less likely and chronic drug administration might
be required before side effects become apparent. Careful patient selection is therefore
important to maximise the information obtained from these clinical trials.
In this retrospective study, we compared patients from a single centre entered into
phase I studies with CT drugs or non-CT drugs. A range of clinical, biochemical and
haematological factors were assessed by both univariate and multivariate analysis
for toxicity and to provide prognostic indicators that could be used for development
of a predictive model for survival in patients entered into phase I studies.
METHODS
Patients
We identified 16 (CT drugs: five; non-CT drugs: 11) phase I clinical trials conducted
by the Cancer Research UK Medical Oncology Unit, Oxford, between 1991 and 2000 (Table
1
Table 1
Phase I trials included in analysis
Investigational agent/molecular target
Number of patients
Reference
Non-cytotoxic
Matrix metalloproteinase inhibitor
9
In preparation
Matrix metalloproteinase inhibitor
6
Macaulay et al (1999)
Mitochondrial inhibitor
11
Propper et al (1999)
Matrix metallo-proteinase inhibitor
92
Levitt et al (2001)
8-Chloro cyclic AMP
33
Propper et al (1999)
Antiangiogenesis
50
Jones et al (1999)
Dendritic cell therapy
5
Chao et al (2003)
Gene therapy
23
Unpublished
EGFR inhibitor
5
Twelves et al (2002)
Protein kinase C partial agonist
56
Philip et al (1993)
Retinoid
16
Jones et al (2003)
Cytotoxic
Topoisomerase I/II inhibitor
12
Propper et al (2003)
Topoisomerase I inhibitor
35
Braybrooke et al (2003)
Topoisomerase I inhibitor
21
Submitted for publication
Bio-modulation of 5-FU
21
Braybrooke et al (2000)
Cyclophosphamide, methotrexate and infusional 5-FU
25
O'Byrne et al (1998)
). A total of 420 individual patient records and case report forms were used as the
data source. Information collected included demography, performance status, diagnosis,
stage, number/sites of metastases, previous therapy, haematological and biochemical
indices, start/end date of study drug treatment, dose level, toxicity grades, date
last seen and date of death. Tumour response was assessed by WHO (Miller et al, 1981),
or South West Oncology Group (SWOG) criteria (Green and Weiss, 1992) according to
the phase I study protocol. Toxicity was assessed by the NCI-CTC criteria (National
Cancer Institute: Guidelines, 1988). When required by the individual trial protocol,
radiological review was performed by an independent review panel. In other cases,
tumour response was reported by an independent consultant radiologist blinded to the
treatment intervention. All studies were conducted in accordance with the Declaration
of Helsinki and were approved by Cancer Research UK and the local research ethics
committee.
Statistical methods
Contingency tables were analysed using the Pearson's χ
2 test. The survival was measured from the first day of treatment on the phase I trial
to the time of death or the time of last follow-up. The log-rank test was used to
perform univariate analysis for survival and the survival curves were estimated by
the Kaplan–Meier method. Prognostic factors for survival were evaluated in multivariate
analyses by Cox proportional hazards regression. Logistic regression was performed
for estimating the predictors of grade 3/4 toxicity in multifactorial analysis. All
statistics were performed using the Stata package release 7.0 (Stata Corporation,
TX, USA). Based on the five risk factors from the multivariate survival model, we
generated a prognostic index as a survival probability estimator (S(t)=exp[-H
0(t) × exp(PI)], where S(t)=survival time, H
0=a step function over time, t=time, and PI=prognostic index. The hazard and estimated
survival probability at any time depends only upon the PI.
RESULTS
Patients
A total of 420 patients (210 males, 210 females), median age 56 years (range 22–87
years) were included in the analysis. The cancer types reflect referral patterns to
the Oxford Medical Oncology Unit, with the majority of patients having colorectal
(78), melanoma (65), breast (45), renal (39), ovarian (38) and lung (37) cancers as
their primary tumour site. The overall response rate for all patients was 4.9% (0.3%
complete response, 4.6% partial response) with 19.2% patients obtaining disease stabilisation
for 3 months or longer.
Comparison of CT and non-CT groups
In all, 306 patients were treated with non-CT drugs and 114 with CT (Table 2
Table 2
Comparisons between CT and non-CT groups
Variable
Non-cytotoxic
Cytotoxic
P-value (test)
Number of patients
306
114
Female
Total 210
131 (42.8%)
79 (69.3%)
<0.001
Male
Total 210
175 (57.2%)
35 (30.7%)
(χ
2)
Median age (range)
58 (22–87)
55 (26–76)
0.04 (M–W)
WHO performance status
0
143 (48.2%)
35 (31.5%)
1
118 (39.7%)
61 (55.0%)
0.02
2
33 (11.1%)
14 (12.6%)
(Fisher's)
3
3 (1.0%)
1 (0.9%)
Number of metastatic sites
0–1
142 (48.6%)
47 (41.6%)
0.20
⩾2
150 (51.4%)
66 (58.4%)
(χ
2)
Lung involvement
No
221 (73.7%)
75 (65.8%)
0.11
Yes
79 (26.3%)
39 (34.2%)
(χ
2)
Liver involvement
No
228 (75.0%)
63 (55.3%)
<0.001
Yes
76 (25.0%)
51 (44.7%)
(χ
2)
Median overall survival, days (range)
192 (4–2405)
260 (10–1136)
0.47 (LR)
Number of deaths at 3 months (%)
63 (20.6%)
18 (16%)
Median overall survival (days)
Liver involvement
No
235
260
0.86 (LR)
Yes
137
228
0.02 (LR)
Lung involvement
No
202
271
0.40 (LR)
Yes
162
228
0.83 (LR)
Median duration of trial (days)
51
73
< 0.001 (M–W)
Response to treatment: (overall)
CR (0.3%)
0
1 (0.9%)
PR (4.6%)
3 (1.0%)
15 (13.2%)
< 0.001
SD (19.2%)
42 (13.7%)
36 (31.6%)
excluding NE
PD (64.8%)
221 (72.2%)
55 (48.2%)
(Fisher's)
NE (11.1%)
40 (13.1%)
7 (6.1%)
Lactate dehydrogenase
normal range
165 (56.1%)
67 (75.3%)
0.001
>normal range
129 (43.9%)
22 (24.7%)
(χ
2)
M–W=Mann–Whitney U-test; Fisher's=Fisher's exact t-test; LR=log-rank test; χ
2=chi-squared test; CR=complete response; PR=partial response; SD=stable disease;
PD=progressive disease; NE=not evaluable. All responses assessed using standard WHO
criteria.
). The median age was slightly lower for patients receiving CT drugs (55 vs 58 years;
P=0.04, Mann–Whitney U-test), although more patients had a performance status of zero
in the non-CT trials (P=0.02, Fisher's exact test). Significantly, more women were
treated with CT drugs (P<0.001, χ
2 test) reflecting inclusion of a study of a novel schedule of cyclophosphamide, methotrexate
and infusional 5-FU for women with breast cancer (O'Byrne et al, 1998). There was
no significant difference in the numbers of sites of metastases between groups (P=0.2,
χ
2 test) but significantly more patients in the CT studies had liver metastases (P<0.001,
χ
2 test). Objective tumour response rates were higher in patients receiving CT therapy
(P<0.001, χ
2 test). The median duration of time on trial was shorter for patients receiving non-CT
treatment (51 vs 73 days, P<0.001, Mann-Whitney U-test). There was no significant
difference in the median overall survival (192 days (range 4–2405), non-CT vs 260
days (range 10–1136), CT; P=0.47, Log-rank test) and no difference in the numbers
of patients who had died within 3 months of study start (20.6% non-CT vs 16% CT).
However, in patients with liver metastases (n=127), treatment with CT drugs resulted
in a significant survival advantage compared to non-CT drugs (median 228 vs 137 days,
P=0.02, log-rank test). There was no difference in survival between groups for patients
with lung metastases.
Survival analysis
When all patients were analysed together by univariate analyses, WHO performance status>1,
white blood count above the normal range, low haemoglobin (<12 g dl−1), raised platelets
(>450 × 109 l−1), lactate dehydrogenase above the normal range, low albumin, number
of metastatic sites>1, presence of liver and/or lung metastases and stage of disease
were all significant adverse factors for predicting reduced survival (Table 3
Table 3
Univariate survival analysis, all patients
Variable
Median OS (days)
No. of patients
Event (deaths)
Log-rank, P-value
Performance status: (WHO)
0
292
178
125
<0.001
⩾1
154
230
165
White blood count
Normal range
228
364
256
<0.001
>Normal range
120
51
37
Haemoglobin
⩽12 g dl−1
154
195
147
<0.001
>12 g dl−1
293
220
220
Lactate dehydrogenase
Normal range
281
232
169
<0.001
>Normal range
137
151
106
Platelets
⩽450 × 109 l−1
246
362
250
<0.001
>450 × 109 l−1
105
55
43
Stage
2 or 3
468
22
16
0.01
4
193
375
272
Lung/liver involved
No
249
207
125
0.03
Yes
189
207
165
Albumin
Low
162
173
120
<0.001
High
249
229
159
Drug
Non-cytotoxic
192
306
216
0.47
Cytotoxic
260
114
80
Number of sites of metastases
0–1
264
189
116
0.003
⩾2
186
216
167
). Tumour type and treatment with either CT or non-CT drugs were not significant predictors
of survival. Data on serial weight change were not available from the majority of
studies and could not be included in the analysis. In multivariate analysis, only
five factors remained as independent prognostic variables–performance status, white
blood count, haemoglobin, lactate dehydrogenase and the number of metastatic sites
(Table 4
Table 4
Multivariate survival analysis, all patients
Variable
Hazard ratio
95% CI
P-value
Performance Status (WHO)
0
Baseline
⩾1
1.48
1.15–1.92
0.003
White blood count
normal range
Baseline
above normal range
1.65
1.13–2.40
0.01
Haemoglobin
>12 g dl−1
Baseline
⩽12 g dl−1
1.60
1.23–2.08
<0.001
Lactate dehydrogenase
Normal range
Baseline
>Normal range
1.54
1.18–2.01
0.002
Number of sites of metastases
0–1
Baseline
⩾2
1.5
1.16–1.93
0.002
). These factors were used for development of a prognostic index as a predictive model
for survival (see Discussion).
Analysis of toxicity
In univariate analyses for grade 3 or 4 toxicity, treatment with CT or non-CT drugs,
gender, performance status and baseline creatinine, albumin and age were all significant
factors (Table 5
Table 5
Univariate analysis for WHO grade 3/4 toxicity, all patients
Variable
Odds ratio
Toxicity grade <3
Toxicity grade 3/4
P-value
Treatment
Non-cytotoxic drugs
Baseline
191
107
<0.001
Cytotoxic drugs
2.95
43
71
Sex
Female
Baseline
94
111
<0.001
Male
0.41
140
67
Performance status (WHO)
0
Baseline
114
64
0.01
⩾1
1.69
115
109
Creatinine (range)
Lower
Baseline
64
74
Middle
0.62
81
58
0.006
Upper
0.46
87
46
Age (Years)
<65
Baseline
163
141
0.03
⩾65
0.6
71
37
Albumin
Normal range
Baseline
87
83
0.03
>Normal range
0.63
141
85
). Haematological indices, lactate dehydrogenase, dose level and disease stage were
not significant. In multivariate analysis, the class of drug, elevated platelet count,
low white blood count and gender were the only significant independent variables for
toxicity (Table 6
Table 6
Multivariate analysis for WHO toxicity grade 3/4
Variable
Hazard ratio
95% CI
P-value
Drug
Non-cytotoxic
Baseline
Cytotoxic
2.65
1.66–4.24
<0.001
Platelet
⩽450 × 109 l−1
Baseline
>450 × 109 l−1
2.17
1.14–4.13
0.02
Sex
Female
Baseline
Male
0.48
0.31–0.73
<0.001
White blood count
Low
Baseline
Middle
0.66
0.40–1.10
0.11
High
0.52
0.31–0.89
0.02
).
DISCUSSION
The continued development of new anticancer drugs is dependent upon patient entry
into phase I clinical trials. Treating physicians have an ethical and moral responsibility
to be sure that they do not compromise patient survival or expose patients to unacceptable
toxicity. Equally, while not the primary end point of phase I studies, individual
trials have limited statistical powers and potentially beneficial therapies should
not be rejected without thorough assessment. This retrospective analysis of 420 patients,
treated in 16 phase I studies, is the first to address whether there are differences
in outcome for patients entered into CT and non-CT phase I trials. Conventional multivariate
analyses were used to elucidate which factors appear to be important for predicting
toxicity and survival. The extent to which physician bias may have influenced patient
entry into studies has not been determined in the analysis but must be considered.
All patients were treated at a single institution, by three physicians, using agreed
shared protocols to minimise bias.
Not surprisingly, treatment with a CT drug as opposed to a non-CT agent was an independent
variable for predicting grade 3 or 4 toxicity. Traditional phase I design includes
dose escalations, by cohort, until significant toxicities are observed. With studies
of non-CT agents, conventional criteria for achieving a maximum tolerated dose are
not always achieved. This may account for the lack of significance of dose level for
predicting grade 3/4 toxicity. Other factors that did predict toxicity included a
low white blood count, platelet count above the normal range and female sex. Haematological
indices provide nonspecific markers of inflammatory changes and thus may be expected
to predict for toxicity. A low white blood count may also reflect extensive prior
cytotoxic treatment or an immunocompromised patient. Gender was an unexpected predictor.
A report of patients with colorectal cancer found greater 5-fluorouracil (5-FU)-induced
toxicity in women (Sloan et al, 2002). In our analysis, data from a phase I study
of cyclophosphamide, methotrexate and infusional 5-FU in breast cancer patients was
included. However, if this study is excluded the toxicity results remain significant.
Female gender is also a significant factor for toxicity in non-CT trials. This may
be due to patients with breast or ovarian cancer entering phase I trials after extensive
previous cytotoxic chemotherapy and radiotherapy. The large number of trials of different
agents, with multiple mechanisms of action, suggest to us that physiological factors
are unlikely to account for the increased grade 3/4 toxicity in females although this
cannot be ruled out.
One of the aims of this analysis was to determine if there is a difference in outcome
between CT and non-CT phase I trials. Direct comparison from data in this analysis
has been restricted by the imbalance in number of patients receiving CT vs non-CT
trials (114 vs 306 patients respectively). Initial observations on patient demographics
found significantly more women and patients with liver metastases received CT drugs
while more patients with an initial performance status of zero were entered into studies
with non-CT drugs. These differences may indicate that oncologists are selective about
which trials are offered to patients. Alternatively, patients considering entry into
a phase I trial are selective about which drugs they prefer to receive, based on perceived
efficacy or toxicity. A previous study on perceptions of patients entering phase I
trials suggested that many were strongly motivated by the hope of therapeutic benefit
(Daugherty et al, 1995) and, if offered a choice of studies, may consider this carefully.
Tumour response and survival were secondary end points in every phase I trial conducted.
In this study, more patients obtained an objective tumour response and disease stabilisation
when treated with a CT drug compared to a non-CT drug (14.1% vs 1.0% and 31.6% vs
13.7%, respectively). The high response rates seen with CT drugs reflects the inclusion
of two phase I trials of novel schedules of drugs known to have significant antitumour
activity (i.e. cyclophosphamide, methotrexate and infusional 5-FU; 5-FU, folinic acid
and interferon). Subanalysis of response rates in the phase I studies of novel CT
drugs, excluding these two trials, still showed a partial response rate of 10.3%,
which is higher than many previous reports (Estey et al, 1986; Decoster et al, 1990;
Bachelot et al, 2000; Sekine et al, 2002). Several of these drugs were new selective
topoisomerase inhibitors and would be predicted to have antitumour activity. Tumour
type was not a significant predictor of outcome in this analysis, although numbers
of patients with each cancer site were small. It is not clear why patients in phase
I studies of CT drugs remained on trial medication for significantly longer (73 vs
51 days). Disease progression was the usual reason for discontinuing treatment. Disease
response and stabilisation favoured patients receiving CT rather than non-CT drugs.
It is possible that patients treated with cytotoxic agents stayed on study longer
because they responded or had stable disease. While higher response rates were seen
with CT drugs, there was no statistically significant difference in patient survival
between the classes of drugs (260 vs 192 days, P=0.47). This finding should be interpreted
with caution. More patients with a performance status of zero entered studies with
non-CT drugs (48.2% of patients vs 31.5% of patients in CT trials, P=0.02) and survival
may, therefore, reflect the natural history of the cancer rather than an effect of
treatment. However, when groups were matched for performance status there was still
no significant difference (P=0.45), although numbers of patients were small. Analysis
of patients with liver metastases found that those treated with a non-CT drug had
poorer survival compared to those treated with a CT drug (137 vs 228 days, P<0.02).
This may be of importance when considering the choice of phase I study although must
be considered with caution, as only 127 patients were included with liver metastases.
The extent of liver disease was not known.
No comparable data set exists for survival of patients who elected not to enter phase
I trials. Thus, assessment of how entry into phase I trials affects survival in this
patient population cannot be made. It would seem unlikely, based on the toxicity data,
that participation in a phase I clinical trial compromised survival. The impact on
quality of life is not known.
Establishing independent prognostic indices for survival of patients treated in phase
1 studies makes it possible to develop a predictive model for the likely survival
of individual patients. The five factors we identified in this analysis were: performance
status (zero vs one or greater), white blood count (normal range vs above normal range),
haemoglobin (less than or equal to 12 g dl−1 vs greater than 12 g dl−1), lactate dehydrogenase
(normal range vs above normal range) and number of sites of metastases (zero or one
vs two or more sites). These risk factors can be used to identify whether patients
have a good, intermediate or poor risk of survival (Table 7
Table 7
Prognostic model for prediction of survival
Formula
S(t)=exp[-H
0(t) × exp(PI)]
S(t)=suvival probability at time t
H
0
=a step function over time
PI=prognostic index
Group
Risk factors (n)
Patients (n)
Events (n)
Median survival (days)
Good risk
0–1
136
91
321
Intermediate risk
2
96
64
257
Poor risk
⩾3
127
105
117
Log-rank test:
Overall:
P< 0.001
Good vs Intermediate
P=0.004
Intermediate vs poor
P <0.001
Good vs poor
P<0.001
Patients were divided into three groups depending upon the number of adverse risk
factors (i.e performance status>1, white blood count>normal range, haemoglobin <12 g dl−1,
lactate dehydrogenase above normal range, number of sites of metastases>2). Each risk
factor counts as 1.
, Figure 1
Figure 1
Predicted survival for patients entered into phase I clinical trials using independent
prognostic indices identified from multivariate analysis (performance status, white
blood count, haemoglobin, lactate dehydrogenase and number metastastic sites). Patients
are categorised into good (0 or 1 risk factors), intermediate (2 risk factors) or
poor risk (⩾3 risk factors).
). Independent analysis shows a significant difference between each group for survival,
ranging from a median of 321 days for the good risk group to 117 days for the poor
risk group. Prognostic factors for individual patients can be entered into this model
and median survival estimated.
Of the 16 phase I studies included in uni- and multivariable analyses, two studies
employed ‘standard’ chemotherapy administered in a novel schedule or in combination
with biological modulators. These potentially more effective treatments might therefore
have biased the results of this study. Exclusion of these two studies, from the comparisons
of CT and non-CT phase I trials, univariables and multivariable analyses did not significantly
affect the statistical results.
The development of prognostic indices for toxicity and survival are important considerations
in the design of early phase clinical trials. This retrospective analysis is the first
to be reported, that directly considers phase I non-CT trials. Differences were identified
in baseline characteristics of patients entered into non-CT phase I studies compared
to CT trials. It is not clear whether this is due to physician bias or patient choice.
Most importantly, no significant difference in median overall survival was found between
the two treatment groups. The use of prognostic models, as proposed from this analysis,
may be important for discussing patient entry into trials and could, in future, be
helpful as part of the inclusion criteria. The model developed in this study uses
five independent factors and further work, with other large data sets from phase 1
trial centres, is required for validation and determination of its use prospectively.