Affiliations of authors: L. Collette, R. J. Sylvester, N. Neymark, European Organization for Research and Treatment of Cancer (EORTC) Data Center, Brussels, Belgium; S. P. Stenning, E. Lallemand, Medical Research Council (MRC) Cancer Trials Office, Cambridge, U.K.; S. D. Fossa, The Radium Hospital, Oslo, Norway; G. M. Mead, Royal South Hants Hospital, Southampton, U.K.; R. de Wit, Rotterdam Cancer Institute and University Hospital, The Netherlands; P. H. M. de Mulder, Sint Radboud University Hospital, Nijmegen, The Netherlands; S. B. Kaye, Western Infirmary, Glasgow, U.K.
Correspondence to: Laurence Collette, M.Sc., EORTC Data Center, Avenue Mounier 83/11, 1200 Brussels, Belgium (e-mail: lco{at}eortc.be).
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ABSTRACT |
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INTRODUCTION |
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SUBJECTS AND METHODS |
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Data on 380 patients treated in one of 49 institutions participating in the European Organization for Research and Treatment of Cancer (EORTC) and Medical Research Council (MRC) randomized trial 30895/TE13 were used in this analysis. From May 1990 through June 1994, patients were randomly assigned in a 2 x 2 factorial trial to receive one of four possible combinations of two treatments. For one treatment randomization, patients were randomly assigned to receive either four cycles of bleomycin-etoposide-cisplatin followed by two cycles of etoposide-cisplatin (BEP/EP) or three cycles of bleomycin-vincristine-cisplatin followed by three cycles of etoposide-ifosfamide-cisplatin-bleomycin (BOP/VIP-B). For the other treatment randomization, patients were randomly assigned to receive either granulocyte colony-stimulating factor (filgrastim) or nothing. This trial showed no statistically significant difference in efficacy between the two chemotherapy regimens (two-sided P = .190 for overall survival, two-sided P = .214 for time to disease progression, two-sided P = .101 for time to first treatment failure, and two-sided P = .687 for complete response rate) (8). The second comparison found no difference in efficacy between patients receiving filgrastim and those not receiving filgrastim, but this comparison found that arms with filgrastim had improved compliance with treatment (two-sided P = .031 for more patients receiving at least six cycles of chemotherapy, two-sided P = .001 for a substantially reduced number of treatment delays for hematologic reasons, and two-sided P = .001 for fewer patients who received a dose reduction because of myelosuppression). This comparison also showed an increased dose intensity associated with the use of filgrastim (9). In addition, there were fewer deaths related to toxicity in the filgrastim arm than in the no-filgrastim arms (9).
End Points
The main end point for analyzing the effect of the treating institution was overall survival. Secondary end points were time to progression, failure-free survival, and rate of complete response. Overall survival was defined as the time from randomization of treatment to the death of the patient, whether due to primary cancer or another cause, or the date of the most recent follow-up for those still alive. Time to progression was defined as the time from randomization of treatment to the first occurrence of disease progression or to the date of the most recent follow-up. Response to treatment was assessed at the end of the treatment period. A complete response was registered in patients whose tumor markers had reached normal levels at the end of the chemotherapy, if residual masses were absent or completely resected and were found to contain no viable cancer cells at histologic evaluation of resected specimens. Patients with normal tumor markers and residual radiologic abnormalities but without histologic evaluation were classified as nonassessable. A partial response was identified in patients whose tumor markers had reached a plateau above the upper limit of the normal range without further decrease or in whom viable cancer cells were detected at surgery. Treatment failure included rising levels of tumor markers over a 4-week period and/or the appearance of new lesions and/or regrowth of an existing lesion (excluding growing mature teratoma or expanding cystic lesion). Failure-free survival was defined as the time from randomization of treatment to a treatment failure, a partial response to the treatment, the first reported progression of the disease, or the death of the patient, whichever occurred first. All patients who were free of all these events at their last visit to the clinic were censored at the date of the most recent follow-up.
Classification of Institutions
The definition of the 49 institutions that participated in the trial (cancer institute, university hospital, or district general hospital) was available from the EORTC Data Center or from the MRC or was obtained by mail from the principal investigator at the institution. The institutions were also classified into one of four a priori-defined categories according to the total number of patients entered into the trial as follows: fewer than five patients, five to nine patients, 10 to 19 patients, or 20 patients or more. The first category corresponds to one patient entered every year during the accrual period of the trial (from May 1990 through June 1994). There were 26, seven, 12, and four institutions in each category, respectively. Institutions were also classified according to their annual rate of accrual in the trial (fewer than two patients per year versus two patients or more per year). Despite the fact that some institutions started their participation much later after the trial opened, this second classification gave results very similar to those using total numbers accrued; these data, therefore, are not included.
No analysis by country was planned or performed. Such an analysis would be against the collaborative agreement between the two cancer research organizations involved in the study.
Statistical Methods
The outcome of the patients treated in the various groups of institutions was estimated by the Kaplan-Meier technique (10). The Cox multivariate proportional hazards regression model (11) was used to compare the time to the event between the institutions. The comparisons with respect to the complete response rates were performed by use of logistic regression models (12). The landmark method (13) was used to study the effect of chemotherapy dose intensity and of surgery (landmark = 6 months).
To correct for known differences in prognosis among the patients, the analysis was stratified for the IGCCCG prognosis group of the patient (good/intermediate versus poor/unknown) and for treatment with filgrastim. The groups with a good and intermediate IGCCCG prognosis were combined because of the small number of patients included. The 28 patients with unknown IGCCCG classification were analyzed with the poor-prognosis group after we observed the similarity between the long-term outcome in these two groups, as assessed by the Kaplan-Meier analysis. No adjustment for the chemotherapy was made (BEP/EP versus BOP/VIP-B) because we wanted to avoid having strata of very small size and because the chemotherapy regimen showed no impact on the efficacy results.
All statistical tests were two-sided, and the type I error probability was set to .05. Hazard ratios with their 95% confidence intervals (CIs) were used to summarize the results on the time-to-event end points, and odds ratios were used for presenting the results concerning the response rates.
Institutions that participated in trial TE13/30895 cross-classified by the following two criteria
(see Table 2): the number of patients recruited in this particular
trial and the overall recruitment in earlier or concurrent EORTC and MRC trials (EORTC trials
30795, 30824, 30847, 30873, 30874, and 30896; MRC trials TE04, TE05, TE09, TE10, TE11,
and TE12). The cut points for this latter classification (30, 75, and 150 patients) were chosen to
obtain the same marginal distribution of the institutions for the rows and columns of Table 2
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RESULTS |
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The analyses by type of institution failed to detect any statistically significant influence of this factor on any of the end points. Because it was also thought that this classification was rather subjective, as a result of differences in definitions and health care policies between the European countries, this classification was dropped from further analyses.
The total recruitment by each institution in earlier or concurrent EORTC/MRC trials is
shown
in Table 2. A substantial amount of association between the total accrual
in this particular trial (30895/TE13) and the total accrual in EORTC/MRC germ cell tumor trials
from 1979 through 1995 is seen, particularly for the institutions that entered fewer than five
patients: Twenty of 26 such institutions recruited 30 patients or fewer in total in the other
EORTC/MRC trials, and two of them did not participate at all in these EORTC/MRC trials. This
observation shows that the recruitment of the institutions in trial 30895/TE13 is probably
indicative of the experience that institutions have with treating germ cell tumors, although this
statement is subject to the assumption that most of the patients with germ cell tumors in those
institutions were recruited into the EORTC/MRC clinical trials.
According to the current IGCCCG classification (3) (introduced after the study was completed), 65% of the patients meet the criteria of poor prognosis and 32% meet the criteria for the intermediate-risk category.
As far as the groups of patients being compared are concerned, no statistically significant
imbalances were found between the four groups of patients with respect to baseline
characteristics
or treatment allocation, except for country and IGCCCG classification (Table 3; P = .004 and P = .007, respectively;
2 test). With two groups of institutions (fewer than five patients versus five patients or
more), both imbalances lost statistical significance. However, a statistically significant trend was
found with respect to the year of entry into the trial; i.e., 51% of the patients recruited by
the institutions with a total accrual of one to four patients were recruited during the last 2 years of
recruitment, whereas the percentage was only 34% in the institutions that entered at least
five patients into this trial (P = .046). Nevertheless, there was no correlation
between the year of entry and the classification of the patients according to the IGCCCG
(35% good/intermediate risk from 1990 through 1991, 38% in 1992, and
35% from 1993 through 1994), which excludes a related difference in prognosis. At the
time of this analysis, the median follow-up duration was 3 years. There was no statistically
significant difference in the duration of follow-up when the institutions that entered five patients
or more were compared with the institutions that entered fewer than five patients (P
= .119; logrank test).
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The overall survival of the four groups was first compared by use of
the unstratified Cox proportional hazards regression model. This model
showed that the survival was similar in the three groups of
institutions that entered at least five patients in the trial and that
the survival in these three groups was statistically significantly
better than the survival in the institutions that entered fewer than
five patients (P = .006, when grouping all institutions with
five patients or more; Fig. 1). The risk of death in
the institutions entering fewer than five patients was estimated to be
about twice that observed in any of the three groups of institutions
with larger number of patients. The difference remained statistically
significant after stratification for the IGCCCG risk group and for
treatment with filgrastim (P = .010). By use of this
stratified model, the risk of death in the institutions that entered
fewer than five patients was estimated to be 1.85 times (95% CI =
1.16-3.03) that observed in the institutions that entered at least
five patients into the trial. The 1-year survival rate estimated from
the Kaplan-Meier curves was 70% (95% CI = 57%-82%) in
the institutions that entered fewer than five patients and 82%
(95% CI = 78%-87%) in the institutions that entered five
patients or more. At 2 years, the survival rates were 62% (95%
CI = 48%-75%) and 77% (95% CI =
72%-81%) in
the institutions that entered fewer than five patients and at least
five patients, respectively. The difference in survival rate was thus
12% after 1 year and 15% after 2 years. It is of note, however,
that the difference in survival may have been augmented by the fact
that, in five of the small institutions, recruitment was stopped after
entry of a patient who died within 3 months, despite the date of death
being more than a year before the closure of the trial.
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The comparisons in terms of failure-free survival (Fig.
2) showed statistically significant differences
between the institutions with fewer than or at least five patients in
the unstratified analyses (P = .014) and in the stratified
analyses (P = .018). The outcome in the three groups of
institutions with high total accrual in the trial was similarly better
than in the institutions that entered fewer than five patients. The
risk of failure in this latter group of patients was estimated to be
1.56 times higher (95% CI = 1.09-2.27) than in the institutions
that entered five or more patients. The 1-year and 2-year failure-free
survival rates for the patients treated in the institutions that
entered fewer than five patients were 43% (95% CI =
29%-56%) and 38% (95% CI = 25%-51%),
respectively. In the institutions that treated at least five patients
in this protocol, the 1-year and the 2-year survival rates were 59%
(95% CI = 54%-65%) and 55% (95% CI =
50%-61%), respectively. The difference in failure-free
survival rates was 16% at 1 year and does not appear to change thereafter.
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A comparison of the time to disease progression confirmed these
findings with statistically significantly lower progression-free rates
in the institutions that entered fewer than five patients (P =
.006 and P = .007 for the unstratified comparisons and
stratified comparisons, respectively) and a risk of progression that
was increased by a factor of 1.89 compared with the institutions that
entered five patients or more (95% CI = 1.19-4.35). The 1-year
progression-free rates in the two groups of institutions were 58%
(95% CI = 44%-71%) and 78% (95% CI =
74%-83%), respectively. In the institutions that entered fewer
than five patients, 55% (95% CI = 40%-69%) of the
patients were progression free at 2 years compared with 73%
(95% CI = 68%-78%) in the institutions that entered five
patients or more (Fig. 3).
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No statistically significant difference (P = .11) was observed in the rates of complete response achieved in the four groups of institutions, despite a slightly lower rate of complete response that was observed in the institutions that entered fewer than five patients (17 of 55 patients; 31%) compared with a 42% rate of complete response observed in the group of institutions that entered five patients or more (22 of 52, 73 of 174, and 43 of 99 patients in the groups of institutions that entered five to nine patients, 10 to 19 patients, and 20 patients or more, respectively). Adjustment of the model for IGCCCG classification and use of filgrastim did not change the results (P = .11).
To correct for any potential confounding effect of the country of residence in the analyses, all analyses were repeated with a stratification for the country (The Netherlands versus the U.K. versus other). The overall conclusions remained unchanged.
The above findings suggest that the patients treated in the institutions that entered fewer than five patients in this protocol have a poorer long-term outcome than those treated in the institutions that entered five patients or more. We explored potential explanations for the observed differences in prognosis by comparing the compliance with the protocol treatment and the extent of the surgery between the institutions that entered fewer than five patients and the institutions that treated at least five patients, as well as differences in treatment-induced toxicity. Other factors that might also differentiate the patient populations treated at the various hospitals, such as socio-educational factors or the performance status of the patients, could not be assessed because this information was not collected on the case report forms. (The performance status was collected only by the MRC and is not known to be a prognostic factor in this patient group.)
Compliance With the Chemotherapy Protocol
The distribution of the chemotherapy regimens BEP/EP or BOP/VIP-B
was similar in the two groups of patients (Table 4).
The relative dose intensity was computed as the percentage of the
planned dose that was received by the patient on the basis of the
number of cycles of treatment the patient actually started. Because
ifosfamide and vincristine were part of the BOP/VIP-B regimen only, the
comparison of the relative dose intensity of these two drugs between
the two groups of patients could not be performed because of the small
numbers of patients. The relative dose intensity of cisplatin and
etoposide was statistically significantly lower in the institutions
that treated fewer than five patients than in the institutions that
treated more patients (P = .007 for cisplatin and P =
.036 for etoposide; Wilcoxon rank sum test). This difference was larger
in the patients treated with the more dose-intensive BOP/VIP-B regimen
than in the patients treated with BEP/EP. Because no statistically
significant difference was found between the institutions with regard
to the percentage of patients who received the planned six cycles of
chemotherapy, the number of cycles with dose reduction, or the
frequency of dose delays, the decreased dose intensity observed in the
institutions that entered fewer than five patients must be related to
an increased duration in the delays and to larger dose reductions. The
rate of World Health Organization grade 3 or 4 hematologic toxicity was
similar in both groups of patients.
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Residual masses at the end of chemotherapy were present in 42 (76%) of 55 patients
treated in the institutions that entered fewer than five patients and in 266 (82%) of 325
patients treated in the institutions that entered five patients or more (P = .337;
Table 4). Surgery for residual disease was performed in 52% of the
patients treated in the
institutions that entered fewer than five patients in the trial compared with 65% in other
institutions (P = .093). The resection was macroscopically complete in
82% of the patients whose residual tumor masses were surgically removed, independent of
the number of patients treated in the institution. Viable cells were found during a histologic
examination of surgical specimens from five (23%) of the 22 patients whose residual
tumor masses were surgically removed in the institutions that entered fewer than five patients
and from 21 (12%) of the 173 patients in the institutions that entered five patients or more
(P = .183; Fisher's exact test).
Multivariate adjustment of the analyses for chemotherapy dose intensity and surgery that used a landmark of 6 months did not change the conclusions with regard to survival and time to progression. Because more than 65% of the events for failure-free survival occurred during the first 6 months, the landmark approach could not be applied to this end point.
Toxicity
Overall, 19 patients died of treatment-induced toxicity (i.e., neutropenic sepsis, bleeding, or pulmonary fibrosis). Of these 19 patients, five were treated in an institution that entered fewer than five patients (three patients with sepsis, one patient with bleeding, and one patient with pulmonary fibrosis) and 14 were treated in an institution that entered five patients or more (10 patients with sepsis, one patient with bleeding, and three patients with pulmonary fibrosis). Another six patients died of treatment-related toxicity in the institutions that entered five patients or more; four of these patients died of postoperative complications and two of secondary acute myeloid leukemia. Two deaths due to postoperative complications were reported in the institutions that entered fewer than five patients. Thus, in total, seven (13%) of 55 patients treated in the institutions that entered fewer than five patients died of causes induced by or related to the treatment compared with 20 (6%) of 325 patients in the institutions that entered five patients or more (P = .090; Fisher's exact test).
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DISCUSSION |
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This study involves the management of poor-prognosis testicular cancer, treatment for which
may be improved by more intensive chemotherapy, better protocol dose adherence, expert
surgery, and better management of treatment-induced toxicity. The management of patients with
poor-prognosis cancer of the testis clearly increases the need for an appropriate supporting
infrastructure of nursing and clinical care because of the increased attendant risks of treatment.
Our hypothesis is that the results of this form of treatment will vary depending on the experience
of the treating institution and that experience may simply be represented by the total numbers of
patients recruited into the trial. Although it is conceivable that the total number of treated patients
might misrepresent certain institutions (e.g., those that entered patients only in the last 1 or 2
years of the trial but had otherwise entered large numbers of patients into previous and
concurrent EORTC/MRC studies), our analysis (Table 2) indicates that
this is unlikely. Those centers with the worst outcome (institutions that entered fewer than five
patients) also had a low rate of accrual to other studies: Twenty of the 26 institutions that
recruited fewer than five patients in 30895/TE13 also recruited 30 patients or fewer for all
previous or concurrent EORTC/MRC
trials. Five of the institutions that entered fewer than five patients stopped recruitment when one
of their first patients died shortly after entry in the trial, but four of these five institutions had
recruited few or no patients in the earlier and concurrent EORTC/MRC trials. We may thus
assume that these centers would have been classified as institutions that entered fewer than five
patients anyway.
During recent years, MRC/EORTC trials have achieved high rates of recruitment throughout participating countries; therefore, most likely, these trends for trial recruitment accurately reflect institution experience. If recruitment is analyzed according to yearly accrual rather than according to total numbers, we conclude that those centers that entered two patients or fewer per year into this study had statistically significantly worse results than the rest of the centers. The extent of the differences is very similar to that shown for the differences according to total number recruited. Indeed, with few exceptions, the institutions that recruited two patients or fewer per year were also those that entered fewer than five patients in total.
What specific factors may underlie the observed differences? Our analysis indicates that a combination of factors may be involved in those centers that entered fewer than five patients. These factors include a greater tendency to reduce the dose of chemotherapy, to delay treatment cycles, and to have more frequent episodes of serious treatment toxicity (including deaths from toxicity). In addition, there is a greater possibility that surgery to remove residual lesions would not be performed in these institutions. Although none of these factors in itself reaches statistical significance, the combined impact is clinically important. Indeed, in this analysis, the treating institution appears to be a prognostic factor of the same magnitude as the established pretreatment characteristics, such as marker levels and visceral metastases.
Other potentially important factors, such as the performance status or the socio-educational level of the patients, could not be assessed because this information was not requested on the case report forms of the trial.
How can these results be improved? A prospective randomized trial addressing the issue of experienced/specialist versus nonspecialist treatment center is clearly not feasible. The alternative is a prospective audit in which all patients with testicular cancer referred to each center are registered and treatment results are monitored for each risk category. Such a prospective audit would also allow information to be collected on the infrastructures of care available in each hospital. This would be useful in explaining potential observed differences in performance of treatment between the institutions. Some countries (including the U.K.) are now in the process of organizing audit systems of this type. Meanwhile, it is conceivable that referral patterns for the treatment of germ cell tumors, particularly in patients with poor prognosis, will change as the results of the present study become available to a wide audience.
In conclusion, we have shown in this trial that patients treated for poor-prognosis germ cell cancer in institutions that entered fewer than five patients in the EORTC/MRC trial 30895/TE13 have a poorer outcome than those treated in larger institutions. In this analysis, the treating institution appears to be a prognostic factor of the same magnitude as the established pretreatment characteristics. Potential explanations are related to the protocol treatment compliance and management of treatment-related toxicity. A further effect of intrinsic differences between the patient populations not accounted for in the analysis cannot be completely excluded. The trends and effects revealed in this analysis should be interpreted with caution because the comparisons are data driven. A prospective study would be needed to confirm these findings.
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NOTES |
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Manuscript received September 14, 1999; revised March 15, 1999; accepted March 22, 1999.
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