Annals of Oncology Advance Access originally published online on June 13, 2008
Annals of Oncology 2008 19(11):1915-1920; doi:10.1093/annonc/mdn391
hematologic malignancies |
Analysis of factors influencing inclusion of 102 patients with stage III/IV Hodgkin's lymphoma in a randomized trial for first-line chemotherapy
1 Hematology Service, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
2 Centre Hospitalier Universitaire Saint-Louis, Paris, France
* Correspondence to: Dr P. Brice, Hôpital Saint-Louis 1, Avenue Claude Vellefaux, 75475 Paris Cedex 10, France. Tel: +33 01 42 49 98 40; Fax: +33 01 42 49 99 72; E-mail: pauline.brice{at}sls.aphp.fr
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Abstract |
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Background: Data on factors influencing inclusion of Hodgkin's lymphoma (HL) patients in randomized clinical trials (RCT) are limited and, for the present study they were analyzed in a RCT for III/IV HL.
Patients and methods: All patients with stage III/IV HL referred to the Saint-Louis Hospital between January 2003 and May 2007 were studied. A Groupe d'Etudes des Lymphomes de l'Adulte/European Organisation for Research and Treatment of Cancer RCT, to compare ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) with increased-dose BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone), was open for recruitment. Noninclusion criteria and physician's reasons for non-recruitment were prospectively recorded. The reasons for patient's refusal were collected retrospectively. Logistic regression analyses were carried out in order to identify factors predicting inclusion.
Results: A total of 102 patients were diagnosed, among whom 51% were included. Seven patients were ineligible, 22 refused to participate, and 21 were not enrolled due to the physician's decision. Main reasons for patients’ refusal were standard treatment preference and concerns about experimental arm toxicity, mainly infertility risk. Conditions that could hamper accurate follow-up and toxicity concerns accounted for most of the physicians’ reasons. Adverse prognostic factors [B symptoms (odds ratio, OR = 5.35) and international prognostic score 
3 (OR = 2.69)] were independently associated with inclusion.
Conclusion: Despite an attractive protocol, only 51% of patients were included. It highlights concerns about selection of patients and the difficulty to obtain informed consent with better prognostic profile patients.
Key words: advanced stages, Hodgkin's lymphoma, patient refusal of treatment, randomized clinical trial, recruitment
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introduction |
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New strategies to improve Hodgkin's lymphoma (HL) treatment outcomes in randomized clinical trials (RCT) should take into account two major concerns: first, to limit long-term treatment-related complications and, second, to lower the failure rates for advanced stages [1]. Currently, chemotherapy alone with a doxorubicin-containing regimen is considered the treatment of choice for advanced-stage HL and the most widely accepted regimen is ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) [2, 3]. The results of a large trial run by the German Hodgkin Study Group showed better freedom from treatment failure and overall survival rates with the increased-dose BEACOPP regimen (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone) [4]. In 2002, the Groupe d'Etudes des Lymphomes de l'Adulte (GELA) and the (European Organisation for Research and Treatment of Cancer (EORTC) launched a prospective RCT for stage III/IV HL to compare the efficacies and toxic effects of eight cycles of the standard ABVD regimen with four cycles of the increased-dose BEACOPP plus four cycles of standard BEACOPP.
The good accrual of patients in randomized studies constitutes a critical step in their good functioning. Data on actual participation rates and factors influencing the recruitment of patients with hematological malignancies in RCT are limited [5, 6]. Many patients often refuse participation because of their own concerns about the proposed treatment or uncertainties of random assignment. Moreover, physicians might fail to offer patients a place in RCT because of time constraints, fear of loss of autonomy, or concerns about the toxicity of the experimental treatment arm [5, 7–9]. Therefore, we decided to examine why patients were not included in this prospective RCT for stage III/IV HL in a single center and determine the factors predicting inclusion or not.
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patients and methods |
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All patients with stage III/IV HL referred to the Saint-Louis Hospital between January 2003 and May 2007 were followed by two physicians (PF-R and PB). During that period, the EORTC-20012/GELA intergroup trial prospective randomized trial (H3/4) for stage III/IV HL was open for inclusions (http://clinicaltrials.gov NCT00049595 [ClinicalTrials.gov] ). That trial was designed to compare the efficacy and toxicity of the standard ABVD regimen with the increased-dose BEACOPP regimen. The primary objective was to detect a difference of 10% between the two arms on the basis of a 70% 3-year event-free survival (EFS) in the standard arm (
= 0.05 and β = 0.20). The study involves >50 institutions in Europe and should remain open until 2009. Patients eligible for the RCT were 16–60 years old with newly diagnosed HL, classified as Ann Arbor stage III/IV, that do not meet any of the following noninclusion criteria: diagnosis of the nodular lymphocyte-predominant HL subtype, prior renal disease, pulmonary fibrosis, cirrhosis or hepatic insufficiency, previous hepatitis B, contraindication for doxorubicin, positive human immunodeficiency virus or humanT-lymphotropic virus type 1 serology, cancer during the preceding 5 years (except in situ cervical carcinoma or skin epithelioma), or pregnancy. Randomization in the trial was stratified according to the international prognostic score (IPS) and participating center [10]. GELA investigators (but not EORTC investigators) opted to include all IPS categories in the trial, because the benefits of increased-dose BEACOPP have been observed in all IPS risk categories in the study of Diehl et al. [4]. The study protocol was approved by the Ethics Committee of Saint-Louis Hospital, Paris (CPPRB, Comite de Protection des Personnes pour la Recherche Biomédicale). All new patients with stage III/IV HL seen in our center were evaluated to participate in this RCT, and those who accepted gave their written informed consent. Baseline clinical and sociodemographic characteristics recorded in were sex, age at diagnosis, date of diagnosis, institution where HL was diagnosed (Saint-Louis Hospital or other), Ann Arbor stage, presence or absence of B symptoms, IPS [10] (0–2 factors versus >2 factors), region of residence (Paris region or elsewhere), professional category [11], marital status (single or not single), number of children, nationality and inclusion or noninclusion in the RCT and treatment.
The reasons for patient noninclusion were carefully scrutinized. Exclusion criteria rendering patients ineligible and physicians’ reasons for non-recruitment were recorded prospectively. The reasons for every patient's refusal were retrospectively collected from their medical records.
treatment and evaluation of response
All patients included in this RCT were randomly assigned to eight cycles of ABVD every 28 days or eight cycles of BEACOPP every 21 days (four cycles of increased-dose BEACOPP and after restaging, four cycles of standard BEACOPP) as first-line treatment. The patients not included in the RCT were treated according to the GELA recommendations [3, 12].
Response criteria were defined according to the International Working Group criteria published in 1999 [13] and were assessed 1 month after the end of chemotherapy. Complete remission (CR) was defined as the complete disappearance of clinical and radiological evidence of disease.
statistical analysis
Standard descriptive analyses were carried out. For a crude analysis association, categorical data were analyzed using the chi-square or Fisher's exact test (two-sided), whereas the Mann–Whitney test was used for ordinal data.
Univariate and multivariate logistic regression analyses were conducted to identify factors associated with inclusion of eligible patients in the RCT. Variables yielding P values <0.2 in the univariate analysis were included in a forward multivariate logistic regression analysis. The variables were entered in the model with a critical entry and removal P values of 0.05 and 0.1. Odds ratios (ORs) with their 95% confidence intervals (CIs) were computed. Colinearity and interactions were tested. Two-tailed P values <0.05 were considered statistically significant.
Failure was defined as disease progression, relapse, or death. EFS was measured from the date of diagnosis to the date of failure, the date of death for any cause or the date of last follow-up for the patients who remained in their first CR. Survival curves were established using the Kaplan–Meier method and compared using the log-rank test. Statistical analyses were carried out using SPSS software (Chicago, IL).
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results |
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patients characteristics
Advanced HL was diagnosed in 102 patients between January 2003 and May 2007. The median patient age was 26.5 (range 16–66) years. A flowchart illustrates patient status from the time of diagnosis to inclusion or not (Figure 1). Overall, 51% (52 of 102) of all patients were included in the RCT.
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reasons for noninclusion in the RCT
The detailed reasons for noninclusion in this RCT are shown in Table 1. Only seven patients were ineligible according to protocol criteria, 55% (52 of 95) of eligible patients participated. The 95 patients eligible for this trial, 43 of whom were not included, are the subject of this report.
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ineligibility.
The percentages of clinically ineligible patients as a function of patients not included in the RCT and all patients were 14% (7 of 50) and 7% (7 of 102), respectively. Notably, two patients were excluded after pathological review: one diagnosed with nodular lymphocyte-predominant HL and the other who had concomitant follicular lymphoma diagnosed in the bone-marrow biopsy. The remaining five patients were excluded because of their comorbid conditions and/or advanced age.
patient refusal.
Twenty-two patients refused to participate after having read the informed consent form. One of the main reasons for this refusal was the preference to receive standard treatment. The frequency of visits and potential hospitalization (with the experimental arm) that could interfere with professional activities were the underlying explanations. Regarding their baseline clinical characteristics, half of them were men, 57% (4 of 7) had B symptoms, 75% (6 of 8) were classified as stage IV and 75% (6 of 8) had IPS 0–2. Notably, after signing the informed consent and being assigned to the experimental arm, one patient refused to participate preferring to receive the ABVD regimen.
Another frequent reason for patient refusal was concern of the toxicity of the experimental arm and, among them the risk of infertility was the most important (86%, 6 of 7). These patients were predominantly female (6 of 7, 86%), single (5 of 7, 71%), and childless (6 of 7, 86%). Six patients (86%) were classified as stage IV and 57% (4 of 7) had IPS 0–2. B symptoms were present in two patients.
physician decision.
Twenty-one patients were not enrolled because of the physician's decision (PB). There were clear and objective reasons for this in most cases. Among them, seven presented with some conditions that could prevent accurate long-term follow-up. These conditions were clearly stated in the instructions of the RCT and allow the doctors to not include patients who specifically have characteristics that would interfere with the follow-up of patients (presence of mental disorders or social/geographic problems). The other reasons were detailed in Table 1.
In eight patients, there were concerns about toxicity of the experimental regimen. All of them were classified as IPS 0–2 and none had B symptoms. Also, 63% (5 of 8) of these patients were female and 75% (6 of 8) had stage III.
comparisons between included and not-included eligible patients in the RCT
The comparisons between baseline characteristics of the included and not-included 95 eligible patients are reported in Table 2. According to univariate analysis, male sex, B symptoms, and an IPS 3 were significantly associated with trial inclusion and a trend was observed for age 45 years. These parameters entered into the multivariate logistic regression analysis. The multivariate analysis retained the presence of B symptoms (OR = 5.35, 95% CI = 2.12–13.47) and IPS 3 (OR = 2.69, 95% CI = 1.8–6.72) as being independently associated with inclusion in the RCT. (Table 3)
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therapeutic modalities.
Fifty-two patients were enrolled in the RCT and received chemotherapy in accordance with randomization: 26 patients (50%) were allocated to ABVD and 26 patients (50%) were allocated to BEACOPP. Eligible patients not enrolled in the trial were given a protocol with curative intent: 35 (81%) were treated with ABVD and two of them had their treatment followed in another institution; four (9%) received four cycles of increased-dose BEACOPP and four cycles of standard BEACOPP and four (9%) received four cycles of increased-dose BEACOPP and three cycles of ABVD.
outcome.
Among the 95 eligible patients, two patients were treated in another institution, leaving 93 patients for the outcome analysis. Median follow-up was 2 (0.07–4.5) years. The CR rate at the end of treatment was at 98% (51 of 52) for patients treated in the RCT and 90% (37 of 41) for those not included (P = 0.16). EFS did not differ between included and not-included patients (Figure 2).
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discussion |
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The EORTC-20012/GELA intergroup trial was designed to evaluate whether it is possible to improve upon ABVD outcomes with increased-dose BEACOPP by having fewer patients with primary refractory disease and less relapses after CR. However, despite the attractiveness of the experimental arm as a therapeutic option, investigators were aware of its higher toxicity. In this study, we sought to investigate the reasons for noninclusion of patients with advanced HL in a prospective RCT conducted in a large center with extensive experience in treating hematological malignancies and to identify factors predicting RCT inclusion. Overall, 51% of patients from this center were enrolled and they represent 14% of all patients in the trial as of May 2007. Patient- and physician-related aversions accounted for the majority of non-enrollments in roughly equal proportions. Moreover, the presence of B symptoms and high IPS was independently associated with the inclusion of eligible patients in this RCT, even when controlled for other pertinent clinical covariables.
The authors of previous oncology studies have reported similar overall participation rates. Since HL predominantly affects young patients, the low frequencies of comorbid conditions and elderly patients was fully expected [14]. However, ineligibility because of comorbid conditions, advanced age, or poor performance status represented major barriers to enrollment in those studies, while in this article only 7% of our patients were deemed ineligible [6, 14–17].
The significantly higher enrollment of symptomatic patients and those with more unfavorable prognostic factors suggests that patient's perceptions of a major health problem, and patient and physician expectations regarding efficacy and toxicity of both treatment arms might have a role in their decision-making processes. Currently, HL is potentially curable, even for advanced-stage disease, and ABVD is widely considered the gold standard obtaining good outcomes in terms of overall survival and EFS with the advantage of less toxicity, especially related to infertility, and secondary acute leukemia. In a previous study, increased-dose BEACOPP yielded superior freedom from treatment failure and overall survival rates compared with COPP/ABVD for all IPS categories, but mainly for high-risk groups [4]. However, it was associated with increased grades 3 and 4 hematological toxicity. Also, fertility is impaired in men and women, and the incidence of secondary acute leukemia/myelodysplasia is a matter of concern [18, 19]. Our findings highlight the current challenge of treating HL, which is to counterbalance the good outcome obtained with intensified chemotherapy regimens with long-term complications.
The infertility risk attributed to the experimental arm was a major reason for refusal raised by a subgroup of patients comprised mainly of young women and was also an important reason for investigators. Some evidence suggests that patients may choose a less effective treatment to avoid long-term complications. In a Web-based survey of early-stage breast cancer young women, 39% of the patients reported that infertility concerns influenced their treatment decisions and, if given the choice, they might choose a less toxic regimen, even if it confers slightly less protection from recurrence [20]. That observation has important practical implications, given that most HL patients are diagnosed in the third decade of life and many young childless female patients are affected. Currently, for most of our male patients were offered the possibility of sperm cryopreservation before starting therapy and this strategy seems to be feasible to overcome this problem. Unfortunately, for female patients, no standard and rapid cryopreservation is available. Another reason for the patients was their preference for the standard treatment, mainly reflecting logistic differences between the two treatment arms that could interfere with professional activities (in the present study, 90% of the patients had a professional activity or were students). Specifically, ABVD is administered biweekly and completely intravenously, while BEACOPP is administered weekly for two consecutive weeks every 21 days with oral and intravenous drugs and subcutaneous growth factors. Likewise, it was observed that obtaining informed consent was more difficult when the treatment characteristics were divergent [21]. In a recently published meta-analysis, interruptions of the patients’ lifestyle was one of most important specific barriers identified to obtaining the patient's consent to participate [22]. The authors of an American study found that one-third of the patients were excluded from RCT participation by physicians, even before their eligibility criteria had been reviewed [23]. In our study, the main reason physicians decided against enrollment was concerns about toxicity, mostly for patients with good prognostic profiles and the second most important explanation was the presence of psychological, social/geographical conditions that would most likely interfere with accurate follow-up. It is noteworthy that this trial was conducted in a center whose dedicated research professionals have an extensive experience with RCT and some of them participated actively in the conceptual design of the protocols of the cooperative group. Furthermore, ongoing RCT are comprehensively discussed among physicians. Nevertheless, explanation of the randomization process, accepting uncertainty in medical decision making, and ethically disclosing potential long-term treatment complications appear to be issues particularly difficult to address [21].
Some investigators examined the impact of RCT participation on the outcome and some argued that better outcomes of trial participants could be attributed to a ‘trial effect’ [16]. In our study, outcomes of included and nonincluded patients did not differ, which can be taken as indication that no such trial effect occurred, since all patients non-enrolled in the trial were treated with curative intent and were cared by the same team of physicians. However, comparisons between enrolled and non-enrolled patients must be taken cautiously, due to imbalances in prognostic factors between these groups.
Currently, ongoing or recently published trials are evaluating other approaches to improve treatment-related toxicity, such as reduction of the cumulative dose of BEACOPP by risk adaptation using IPS, or modified BEACOPP schedules [1, 24, 25]. Another alternative is response adaptation using early positron emission tomography for tailoring therapy, given its predictive accuracy [26].
In summary, half of the advanced-stage HL patients were included in this RCT, and high IPS and presence of B symptoms were factors predicting inclusion. Infertility risk and preference for standard treatment on the basis of the scheduled interference of their professional activity emerged as a major concern for patients. Taken together, our data provide new insights into RCT recruitment for a disease that affects mostly young patients, and whose standard treatment yields good results. Also, it highlights concerns about selection of patients in randomized studies and the difficulty to obtain informed consent in patients with good conditions.
Recruitment in RCT should be encouraged since they are the best approach for evaluation of new therapeutic strategies.
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Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) to I.B.
Received for publication April 8, 2008. Revision received May 14, 2008. Accepted for publication May 15, 2008.
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