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Assessment of Differences in Patient Populations Selected for or Excluded From Participation in Clinical Phase III Acute Myelogenous Leukemia Trials

From the Institute of Medical Oncology, Central Hematology Laboratory, Inselspital and University of Bern; and Swiss Federal Office of Information Technology, Systems and Telecommunication, Bern, Switzerland.

Address reprint requests to Martin F. Fey, MD, Institute of Medical Oncology, Inselspital, CH-3010 Bern, Switzerland; e-mail: martin.fey{at}insel.ch.

	ABSTRACT

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Purpose: To compare patients treated in or outside clinical protocols, using de novo acute myeloid leukemia (AML) as a model disorder.

Patients and Methods: We retrospectively compared the characteristics of all patients with de novo AML diagnosed in the referral area of our university hospital between 1985 and 1994.

Results: Of a total of 170 AML patients, 45% were included in a phase III trial for the treatment of AML and 55% were treated outside a protocol. Another 45 patients were registered only at diagnosis but were treated elsewhere. Nonstudy patients differed significantly from patients included in clinical trials with respect to age and performance status at clinical presentation, comorbidity, and type of AML. The great majority of patients excluded from trial participation showed distinct exclusion criteria, such as advanced age and severe comorbidity. Study patients were treated significantly more often with curative intent and achieved better response and survival. Patients treated in an equivalent manner but outside a protocol showed no significant difference in survival compared with patients enrolled onto a trial.

Conclusion: Study patients were not representative for the entire population of patients with AML; many patients were excluded from phase III trial participation for failure to meet stringent entry criteria. Therefore, results of phase III studies may not be extrapolated to all AML patients but should only be applied to patients who do not differ in substantial characteristics from the study population.

	INTRODUCTION

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THE RESULTS of prospective randomized phase III trials are the basis for establishing new guidelines and standards for the diagnosis and treatment of particular cancers. If results of such trials are extrapolated to advise patients treated outside clinical protocols, the patients’ clinical and biologic characteristics must correspond to those of the study population. However, patients selected for randomized studies are not always representative of the entire patient population affected with a particular disease. Elderly patients and those with severe comorbidity often are not included in studies. Other reasons for excluding patients from clinical trial participation may be logistical aspects, patient refusal, or an arbitrary decision of the treating physician. The selection bias of patient populations accrued for trials may jeopardize the general applicability of study results. Cottin et al¹ compared patients with small-cell lung cancer treated in or outside clinical trials. The subgroup of their patients included in clinical trials was not representative of the entire patient population because of restrictive eligibility criteria. Mayers et al² showed that patients treated with adjuvant chemotherapy for breast cancer had better survival when treated in a clinical trial. For many other types of cancers, including hematologic neoplasms, such data are scarce.

To assess potential differences between patients with a particular cancer treated in or outside a clinical trial at a given center, information on the total patient population available is required. Patients with acute myeloid leukemia (AML) registered at our university center provide a possibility to perform such a study, because in our defined referral area, patients with AML, or at least their diagnostic material, are always referred to us. This allows for a direct comparison of characteristics of our AML patients treated in protocols with those treated outside a clinical trial during a specified period, and would minimize the risk of an a priori selection bias of particular patients in the database.

We therefore analyzed the characteristics and outcome of all adult AML patients diagnosed with and (in part) treated for AML at our hospital between 1985 and 1994. During the specified period, serial clinical phase III AML trials were open to patient accrual.

	PATIENTS AND METHODS

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AML Studies
From January 1985 until December 1994, five clinical AML trials (Swiss Group for Clinical Cancer Research 30/84, 30/85, 30/92, and APL 93; and GCS 019) were open for patient accrual either sequentially or concomitantly. The selection criteria of these studies are summarized in Table 1. They were customary with respect to age limits, excluding patients with prior antileukemic treatment, patients with secondary leukemia, and patients with severe organ dysfunction except if caused by AML. Detailed patient characteristics and trial results have been published elsewhere.^3–8 All trials had been approved by the local ethics committee.

Patient Characteristics and Study Exclusion Criteria
Data on patients were retrieved from their charts, including laboratory reports on morphology and cytogenetic findings, and from clinical study report forms. Patient characteristics are listed in Tables 2 and 3. Clinical data included each patient’s sex, age at time of diagnosis, performance status, WHO grade of infection and bleeding, presence of hepatosplenomegaly and lymphadenopathy, and gum or skin infiltration (diagnosed by clinical examination and/or ultrasound).^9–11 Baseline laboratory data included hemoglobin, WBC, neutrophil, blast cell and platelet count, as well as coagulation markers and parameters of kidney and liver function.

In all patients not included in a clinical trial, the reasons for failure of accrual into a suitable study were specified.

Therapy, Response, and Survival
We distinguished between cytotoxic treatment with curative intent, palliative chemotherapy, and symptomatic treatment only. We also analyzed how patients were treated outside clinical trials.

The remission criteria applied were the following: complete remission (CR) was defined as a normocellular bone marrow with blast cells 5%; peripheral-blood cell counts with neutrophils 1.5 g/L, platelets 100 g/L, and no blast cells; and no extramedullary involvement. A bone marrow with blast cells between 5.1 and 25% and/or the presence of extramedullary leukemia was assessed as partial remission. Progression in nonremitting patients was diagnosed if any of the following conditions were met: increase in bone marrow or organ infiltration by blast cells, increase in the peripheral blast cell count, or decrease of neutrophils or platelets in the peripheral blood as a result of leukemia. Relapse was diagnosed if blasts in the bone marrow exceeded 5% in patients having achieved CR and more than 25% in patients with prior partial remission, in the case of new or progressive extramedullary leukemia involvement, increasing blast cell count, or decrease of neutrophils or platelets in the peripheral blood as a result of leukemia.

We assessed overall survival (OS), progression-free survival (PFS), disease-free survival (DFS), and the cause of death in all patients treated at our institution. In addition, we compared the survival of patients treated with curative intent in or outside a clinical trial.

PFS was defined as the time from diagnosis to disease progression or death, OS as the time from diagnosis to death, and DFS as the time from remission to relapse.

Comparative Analyses
Patients were separated into the following groups and compared with respect to the characteristics specified previously: First, we compared patients referred to our center with those from whom we only received diagnostic material, but who were treated elsewhere in our referral area. Patients treated at our center were then grouped into those registered in one of the available AML trials and those treated off protocol.

Statistical Analysis
Comparisons of quantitative values were calculated using the Mann-Whitney U test; for comparisons of frequencies in categorical variables we applied the ² test. A P value of .05 was considered statistically significant. All tests were two-sided. Statistical analysis was performed using SPSS 8.0 for Windows software (SPSS Inc, Chicago, IL). Survival was estimated with the Kaplan-Meier method.²⁰ Prognostic factor analysis was performed using the log-rank test²¹ for univariate analysis and the Cox regression model²² for multivariate analysis. All criteria differing significantly between study patients and those not included in a clinical trial were taken as variables for univariate analysis. The criteria influencing survival in univariate analysis were taken as covariates into the multivariate analysis (age, body mass index, performance status, infection at time of diagnosis, initial hemoglobin level, WBC count and creatinine concentration, AML subtype, degree of dysplasia, study participation, and myelotoxic treatment). Because of their known major impact on survival in AML, we performed a separate multivariate survival analysis including cytogenetic risk groups as a covariate, despite the small number of patients with complete cytogenetic data.

	RESULTS

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Patient Population
From January 1985 to December 1994, 215 adult patients were diagnosed with de novo AML at our center. With an annual incidence of 2.5 per 100,000 cases of AML in Switzerland, approximately 28 new cases are expected per year in our referral area of approximately 1.15 million inhabitants. Thus, the average number of 22 patients per year seen at out center corresponds well to the expected 160 new AML cases in Switzerland per year predicted by epidemiologic data. (Switzerland’s population is approximately 6.5 million.)

One hundred seventy of 215 patients (79%) were referred to our hospital. In 45 of 215 patients (21%), we only examined the bone marrow or peripheral-blood films for diagnostic purposes, but the patients were treated elsewhere in our referral area. Of 170 patients referred to our institution, 76 (45%) were included in a clinical trial, and 94 (55%) were treated outside a protocol. None of the 45 patients treated at peripheral hospitals was included in a treatment protocol.

Comparison of Patient Characteristics
We found a significant difference in the age at time of diagnosis between patients referred to our hospital (Table 2) and those treated outside: the median age of the latter group was 78 years (range, 38 to 92 years) versus 55 years (range, 16 to 82 years) in our university hospital population (P < .0005). In patients treated outside our hospital, certain AML subtypes occurred with significantly more frequency, particularly AML-MDS.

Patients who participated in a clinical trial had a median age of 46 years (range, 16 to 73 years), whereas those not included were significantly older (median age, 64 years; range, 21 to 82 years; P < .0005; Table 3). Patients excluded from clinical protocols presented a worse performance status and had more infectious complications at presentation. The occurrence of AML-MDS was significantly more frequent in patients treated outside clinical protocols.

Cytogenetic analysis was done significantly more often in study patients (99% v 42%; P < .05). Among 88 patients in whom the karyotype was determined, nonstudy patients showed significantly more karyotype abnormalities (normal karyotype in 27 study patients [47%] v seven nonstudy patients [23%]; simple abnormality in 27 patients [47%] v 18 patients [58%]; and complex abnormality in three patients [5.3%] v six patients [19%]; P = .023). The distribution of cytogenetic risk categories was significantly different between patients included in clinical protocols and those treated outside of a trial, with more study patients presenting with intermediate risk aberrations (P = .048) and fewer with favorable and unfavorable karyotypes.

Reasons for Noninclusion of Patients Onto Trials
Ninety-four of 170 patients (55%) referred to our hospital were not included in a clinical trial. Their characteristics are summarized in Table 4. Eighty-two of these 94 patients (87%) were ineligible and three patients (3%) refused to enter onto a study. Nine patients (10%) were eligible but were not included in a trial because of a decision of the treating physician. Detailed analysis of the patient data revealed that in four of these nine patients, advanced age was the reason for noninclusion, although there would have been a suitable protocol available. One patient was not included because of a history of pulmonary tuberculosis. The remaining patients were not included in a protocol because of features of myelodysplasia, although this was not an explicit exclusion criterion for the respective studies. Forty-seven of 94 patients (50%) presented with a single reason for trial exclusion, and 38 of 94 patients (40%) had two or more exclusion criteria. The most frequent reason of exclusion from a protocol was old age (35 of 94 patients [37%]), followed by severe comorbidity in 16 of 94 patients (17%; most importantly, cardiovascular disease and severe infections). Nine of 94 nonstudy patients (10%) had previous cancer or cytotoxic treatment, and two patients had undergone chemotherapy for nonmalignant disease. Nine of 94 patients (10%) were excluded because of their AML subtype and seven of 94 patients (7%) were excluded because of severe myelodysplasia. Six of 94 patients (6%) were not enrolled onto a study because their follow-up was not guaranteed.

Therapeutic Modalities
Seventy-three of 76 study patients (96%) underwent myelotoxic chemotherapy according to protocol; three patients did not receive the treatment specified in the respective trial. Thirty-seven of 94 nonstudy patients (39%) were treated with curative intent with commonly used chemotherapeutic regimens. Thirty-two nontrial patients (34%) received palliative chemotherapy, and 25 of 94 nonstudy patients (27%) received supportive treatment only.

Treatment Results, Survival, and Prognostic Factor Analysis
Response to treatment was assessable in 163 of 170 patients (96%; 74 of 76 study patients [97%] and 89 of 94 nonstudy patients [95%]). Seventy-eight percent of patients (59 of 74 patients) treated in a protocol experienced a CR, whereas only 22% of the nonstudy patients (21 of 89 patients), who received cytotoxic treatment, reached CR. In patients treated with curative intent—that is, who received myelotoxic therapy—the rate of CR was 80% (59 of 74 patients) in study patients and 57% (21 of 37 patients) in nonstudy patients (P < .0005). Primary progressive disease developed in nine study patients (12%) and in 65 nonstudy patients (69%). Of the patients treated with myelotoxic therapy, 24% (nine of 37 patients) nonstudy versus 10% (seven of 74 patients) study patients had primary progressive disease (P = .8).

Survival data were available for 169 patients (76 of 76 study patients and 93 of 94 nonstudy patients). Survival was significantly better in patients treated in a clinical protocol (median OS, 15 v 3.4 months; median PFS, 9.8 v 1.6 months; P < .0005; Fig 1A). If only the patients who underwent therapy with curative intent were considered, there was a trend toward a better prognosis in trial patients than in nontrial patients with respect to OS and PFS (median OS, 15.6 v 12.9 months; P = .054; median PFS, 10 v 7.2 months; P = .14; median DFS, 14.4 v 9.5 months; P = .87; Fig 1B).

View larger version (16K): [in this window] [in a new window]   Fig. 1. Overall survival for all patients referred to our institution (A) and for the patients who received intensive treatment in or outside a treatment protocol (B).

At the time of data assessment, 29 of 170 patients (17%) treated were alive, and three patients were not assessable for survival. One hundred twenty-three of 179 patients (72%) had died as a result of disease progression, 10 of 170 patients (6%) had died as a result of complications of cytotoxic treatment, and in five of 170 patients (3%), death was not related to AML.

	DISCUSSION

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Cancer patients in clinical trials are often highly selected, and their features may therefore provide a distorted image of the characteristics of the entire patient population with a given type of cancer. The amount of this bias is difficult to appraise, unless in a defined patient population trial patients can be suitably compared with patients not included in a study. The population of adult AML patients registered at our university center provides the unique possibility to compare trial and nontrial patients. Within our referral region, only a small minority of AML patients would escape our notice, and we are therefore in a position to study a virtually complete population of AML patients from a defined geographic region.

In the specified time frame of 10 years, a total of 215 AML patients came to our attention, of which 80% were referred to us for treatment, whereas one fifth were treated in peripheral hospitals. Only approximately half of the patients referred to the center were accrued for a clinical trial, and thus our AML study population represents only one third of all AML patients registered at our institution. We assume this problem may be encountered in many centers treating leukemia patients in trials. In many instances, scientific evaluation of new AML treatments and the assessment of their merits and problems therefore are based on a minority population of patients with the disease of interest.

Ideally, clinical decisions in an individual patient are made on the basis of evidence derived from clinical trials. However, this approach is only valid if a given patient shows the features of typical trial patients on whom published results are based. Our data reflect considerable patient selection within our AML trial population. Study patients had more favorable clinical characteristics than nonstudy patients. For example, they exhibited fewer cases of MDS-associated AML, and most notably, trial patients were significantly younger. Our finding is in keeping with observations by Cottin et al¹ in small-cell lung cancer, in which a large portion of patients were not eligible for trials because of their advanced age. Similarly, the Southwest Oncology Group reported that in its cancer trials, elderly patients were significantly underrepresented.²³ A significant number of AML patients are elderly and will not benefit from treatments designed for and tested in younger age groups. Elderly patients and AML patients with a history of antecedent MDS were excluded from most of our phase III trials that were available throughout the assessment period of this report. Clearly, our trials deliberately targeted patients with a relatively favorable risk profile, and hence, their results may not be extrapolated to all patients with a diagnosis of de novo AML.

We were able to identify the characteristics of AML patients referred to us for treatment and of those cared for in peripheral hospitals from our referral area. Our colleagues in peripheral hospitals chose to send us patients whom they considered likely candidates for intensive treatment, whereas elderly patients and those with significant comorbidity were often offered supportive care only and were therefore not referred. This bias is important because academic centers activating trials for poor-risk AML patients need to convince their colleagues in peripheral hospitals that such patients may benefit from investigational approaches and should be referred.

More than two thirds of nonstudy patients were excluded because of advanced age, comorbidity, myelodysplasia, or previous history of cancer. Nevertheless, an appreciable number of such patients were offered intensive off-study therapy. Their DFS and OS rates were not significantly different from those of patients treated in a clinical protocol with similar myelotoxic regimes. In retrospect, nonstudy patients treated intensively could have received their myelotoxic treatment within a trial, and their exclusion was perhaps not warranted, although it was dictated by rigid criteria in the protocols. This observation stresses the concept that functional assessment of an AML patient to be offered induction therapy might be more important than specific and rigid eligibility cutoffs (ie, fixed age limits). Interestingly, participation in a trial may confer a survival benefit independent of conventional prognostic factors. Such effects have been observed in patients with breast cancer² and multiple myeloma,²⁴ in whom treatment in a clinical protocol was an independent prognostic factor for survival.

Trial patients were more likely than nonstudy patients to have been karyotyped. Clinicians caring for AML patients should be aware of this bias, given that AML karyotyping provides important prognostic information, and currently represents a diagnostic standard procedure that should be available in each AML patient. As expected, patients with favorable cytogenetics had a better outcome than those with unfavorable cytogenetics.

Our AML patients treated in protocols showed an OS rate of approximately 26% at 10 years, which corresponds to published data.^25–27 A survey such as ours, which includes all AML patients in a region, illustrates that long-term survival rates in the range of 20% to 30% can only be expected in patients who qualify for intensive chemotherapy, and such results cannot be extrapolated to the entire population. Much information is now available from the Internet and other sources accessible to patients. Patients with adverse prognostic factors—and their doctors—need to understand that treatment results from published trials must be interpreted with caution, and advice as well as plans for management must be tailored to the individual patient’s clinical situation.

In summary, patients with AML who are not included in a clinical trial showed unfavorable initial characteristics and worse outcome in comparison with study patients (except for those who received intensive nonprotocol chemotherapy). As a corollary, patients included in a protocol were not representative of the AML patient population as a whole. We support the demand of Cottin et al¹ to specify the rate and major characteristics of noneligible patients in any publication of clinical cancer studies. However, this can only be done with appropriate safeguards to maintain patient confidentiality. As many patients as possible should be enrolled onto ongoing clinical trials, not only at academic centers but also in peripheral hospitals. To avoid unnecessary exclusion of patients from protocols, we recommend that future trials should be designed to include a patient population with the highest incidence of the respective disease. In AML, this would require the design of protocols for elderly people and for patients with myelodysplasia. In addition, study exclusion criteria should be designed so that rigid inclusion and exclusion criteria, such as unnecessary age limits and overly stringent criteria for visceral organ function, are abandoned.

	AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Acted as a consultant within the last 2 years: Martin F. Fey, Novartis.

	ACKNOWLEDGMENTS

 
We thank the data management team at the Institute of Medical Oncology at the University Hospital of Bern, the Swiss Group for Clinical Cancer Research, and our colleagues from the Dutch-Belgian Hemato-Oncology Cooperative Group for their valuable collaboration in our joint leukemia trials, and all physicians who referred their patients to our institution.

	REFERENCES

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4. Fopp M, Fey MF, Bacchi M, et al: Post-remission therapy of adult acute myeloid leukemia: One cycle of high-dose versus standard-dose cytarabine—Leukaemia Project Group of the Swiss Group for Clinical Cancer Research (SAKK). Ann Oncol 8:251–257, 1997[Abstract/Free Full Text]

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9. Löwenberg B, Downing JR, Burnett A: Acute myeloid leukemia. N Engl J Med 341:1051–1062, 1999[Free Full Text]

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12. Bennett JM, Catovsky D, Daniel MT, et al: Proposals for the classification of the acute leukemias: The French-American-British (FAB) Cooperative Group. Br J Haematol 33:451–458, 1976[Medline]

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15. Bennett JM, Catovsky D, Daniel MT, et al: Proposals for the recognition of minimally differentiated acute myeloid leukaemia (AML-M0): The French-American-British (FAB) Cooperative Group. Br J Haematol 78:325–329, 1991[Medline]

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Submitted March 28, 2003; accepted April 4, 2003.

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