Elihu H. Estey, MD
USING THE National Cancer Database, Bhatt et al1 recently reported that of the 61,775 adults with acute myeloid leukemia (AML), those who received chemotherapy from 2003 to 2011 lived longer than those who, in those same years, did not; the study is reviewed in this issue of The ASCO Post. Although this may merely reflect better inherent prognoses in treated patients, the complete Swedish Acute Leukemia Registry observed lower death rates, even in patients aged 70 to 79 (n = 864), if they resided in regions of the country where a higher proportion of patients received standard “7+3” chemotherapy rather than “best supportive care” alone.2 There were no regional differences in performance status, and the 7+3 regimen was superior regardless of performance status. Although other potentially confounding covariates can only be accounted for by randomization between “chemotherapy” and best supportive care, such a trial is almost certainly not feasible.
Certainly, improvements in survival associated with, and likely due to, chemotherapy in AML can be quantitatively modest, particularly in older patients, although statistically “significant.” Furthermore, considerations of “quality of life” and cost are important, although the administration of chemotherapy might improve a poor quality of life if due to AML. “Chemotherapy” itself can vary in intensity and composition, and the National Cancer Database lacked the data to allow Bhatt et al1 to make these distinctions. Nonetheless, assuming prolongation of survival is generally desirable implies the administration of chemotherapy is generally desirable.
Under these circumstances, it is important that Bhatt et al found that 25% of their 61,775 adults did not receive chemotherapy.1 Multivariate analyses indicated that being female, African American, or older (regardless of insurance status); having a lower family income, more comorbidities (regardless of age), or “nonfavorable” AML subtypes; and being seen in lower-volume, “nonacademic” facilities made a person less likely to receive chemotherapy. This is problematic because none of these factors is readily remediable, although as Bhatt et al suggested, better understanding of how they influence the use of chemotherapy might increase such use.1
Does It Matter Where Chemotherapy Is Given?
AN EARLIER article by Bhatt et al found lower 30-day and 1- and 5-year mortality rates in “academic” centers.3 Although accounting via multivariate analysis for possible confounders such as receipt of chemotherapy or not and similar clinical and socioeconomic factors as in their more recent article,1 it was not clear whether there was an interaction between treatment at an “academic” center and chemotherapy, such that the superior results reported in the academic centers were also seen focusing attention solely on people who received chemotherapy.
Ho et al have done this, using the California Cancer Registry to divide 7,007 adults with AML treated from 1999 through 2014 into the 25% who received chemotherapy at a National Cancer Institute (NCI)-designated cancer center and the 75% who received chemotherapy at other cancer centers.4 Not unexpectedly, the probability of treatment at an NCI-designated cancer center independently increased with age < 65 years, being white or Asian, having Medicare or other public insurance, and having fewer comorbidities. Although death within the first 60 days of receipt of chemotherapy decreased with the time at both types of centers, such death remained less common in an NCI-designated cancer center (average 12% vs average 24%), and this difference persisted after accounting for the aforementioned covariates. Perhaps experience and supportive care account for some of these findings. However, similar to the findings of Bhatt et al,1,3 Ho et al4 ask us to assume chemotherapy is homogeneous and to ignore factors other than those examined in the multivariate analyses. And again, randomization between treatment of AML at an NCI-designated cancer center and other cancer centers is unlikely.
“A fundamental problem with these trials is the difficulty in knowing whether the often ‘promising’ initially reported results are widely applicable.”— Elihu H. Estey, MD
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Are Study Findings Widely Applicable?
FEW DOUBT that treatment of AML is unsatisfactory, regardless of where it is given. It is also widely accepted that “clinical trials” as conducted at NCI-designated cancer centers will play an important role in future improvement. However, a fundamental problem with these trials is the difficulty in knowing whether the often “promising” initially reported results are widely applicable.
To date, attempts to quantify potential selection biases have largely involved solid tumors. An article in the November 2017 issue of the Journal of Clinical Oncology reported that 63% of the 284 oncology new drug applications submitted to the U.S. Food and Drug Administration were based on data from trials that limited eligibility to patients with an Eastern Cooperative Oncology Group performance status of 0 or 1; only 1% had a performance status of 4.5 Another article in this issue noted that 61% of more than 12,000 Kaiser Permanente patients with breast, lung, or colorectal cancer would be ineligible for trials based on typical eligibility criteria or age older than 75 years.6
Although there is a dearth of such information for AML trials, the similarity of eligibility criteria to those in solid tumor trials, the association between older age and an inability to meet these criteria, and the median age of 65 to 70 years in AML suggest that many patients with AML are ineligible for trials. A subtler form of bias occurs when patients, although nominally eligible for a trial, are not enrolled.7 Experience suggests this often reflects a feeling the patient would “not do well” on the trial, thus worsening results and perhaps decreasing the chances of regulatory body approval. Nonetheless, a patient might still prefer to enroll in the trial, reasoning that results with standard therapy are completely unsatisfactory. Aggregated over many patients, these instances necessarily cast doubt on whether results reported from AML trials conducted in an NCI-designated cancer center are broadly applicable to the sites where most patients with AML are treated.
Should Eligibility Criteria Be Broadened?
“It might be useful to require advanced-phase clinical trial reports to indicate the number of randomized or treated subjects as a proportion of those screened and/or potentially eligible for the trial.”— Elihu H. Estey, MD
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GIVEN THESE circumstances, it might be useful to require advanced-phase clinical trial reports to indicate the number of randomized or treated subjects as a proportion of those screened and/ or potentially eligible for the trial.7 The proportion of all the subjects in each category (for example, > 60 years) seen in the trial center but considered ineligible might also be noted and the reason(s) for exclusion specified.7 Once safety is established in a modest number of patients, eligibility criteria might be broadened, particularly if the results with conventional treatments are poor.7 Although the structural obstacles noted by Bhatt et al might prevent more patients with AML from being treated in an NCI-designated cancer center,1 the changes in policy suggested here might make the results reported from an NCI-designated cancer center more relevant to other practice sites. ■
Dr. Estey is Professor of Medicine, Division of Hematology, University of Washington School of Medicine, and Member, Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle.
DISCLOSURE: Dr. Estey reported no conflicts of interest.
1. Bhatt VR, Shostrom V, Gundabolu K, et al: Utilization of initial chemotherapy for newly diagnosed acute myeloid leukemia in the United States. Blood Adv 2:1277-1282, 2018.
2. Juliusson G, Lazarevic V, Hörstedt AS, et al: Acute myeloid leukemia in the real world: Why population-based registries are needed. Blood 119:3890-3899, 2012.
3. Bhatt VR, Shostrom V, Giri S, et al: Early mortality and overall survival in acute myeloid leukemia based on facility type. Am J Hematol 92:764-771, 2017.
4. Ho G, Wun T, Muffly L, et al: Decreased early mortality associated with the treatment of acute myeloid leukemia at National Cancer Institute-designated cancer centers in California. Cancer 124:1938-1945, 2018.
5. Jin S, Pazdur R, Sridhara R: Re-evaluating eligibility criteria for oncology clinical trials: Analysis of investigational new drug applications in 2015. J Clin Oncol 35:3745-3752, 2017.
6. Lichtman SM, Harvey RD, Damiette Smit MA, et al: Modernizing clinical trial eligibility criteria: Recommendations of the American Society of Clinical Oncology–Friends of Cancer Research Organ Dysfunction, Prior or Concurrent Malignancy, and Comorbidities Working Group. J Clin Oncol 35:3753-3759, 2017.
7. Estey EH, Gale RP, Sekeres MA: New drugs in AML: Uses and abuses. Leukemia. June 6, 2018 (early release online).