Ahmad Halwani, MD
Division of Hematology
and Hematologic Malignancies
Huntsman Cancer Institute
University of Utah Healthcare
Salt Lake City, UT
ï¿¼Case Study: Mrs Smith
You’re in clinic and your next patient is Mrs Smith. She is a 66-year-old woman who was diagnosed with chronic lymphocytic leukemia (CLL) four years ago. Lately she has developed gradually worsening anemia and enlarging lymph nodes. She does not have deletion 17p by conventional karyotype analysis or FISH. You need to recommend a treatment option for her now symptomatic CLL.Best Treatment Option Unclear
Although CLL is the most common chronic leukemia, there remains no single agreed-upon standard of care for first-line treatment. In Mrs Smith’s case, it would be quite reasonable to attempt to apply evidence from the recently reported German CLL Study Group randomized con- trolled trial (RCT) of fludarabine, cyclophosphamide, and rituximab (FCR) versus bendamustine rituximab (BR) for first-line treatment of CLL.1
At first glance, FCR seems like the better option, as it is associated with a longer progression-free survival (PFS).
However, FCR is more toxic with almost twice the rate of severe infections. In an unplanned subgroup analysis, there was no benefit in patients who were older than 65 years, or in those with multiple and/or moderate comorbidities. The trial excluded patients with impaired kidney function. Despite being quite active, Mrs Smith was diagnosed with diabetes more than 7 years ago, and has diabetic nephropathy. Her renal function is borderline normal. On account of her comorbidities and renal function, it’s quite likely that she would not have been eligible for this trial.
This case illustrates a common context in hematological malignancies. Despite having the results of a phase III RCT, the best treatment option for many patients who are older or who have comorbidities remains unclear.Efficacy Established in Carefully Selected Populations
Treatment options for lymphoid malignancies have greatly increased over the past decade thanks to advances in cancer biology and therapeutics. For example, a clinician treating lymphoma or CLL can draw upon more than a dozen agents from a handful of modalities: chemoimmunotherapy,2
and tyrosine kinase inhibitors.7–9
As a result, some patients with advanced-stage indolent lymphoma or CLL can live for decades, and a significant proportion of patients with aggressive lymphomas can be definitively cured of their disease.
Clinical research in oncology has typically relied on prospective, often randomized, clinical trials as the gold standard methodology to generate evidence of the benefits and risks of novel treatments. Prospective clinical trials rely on a number of elements to achieve a high level of internal validity: strict eligibility criteria, consistent treatment delivery, predefined endpoints, and a priori statistical power considerations to accept or reject the null hypothesis.10
Randomization ensures the exchangeability of patients in different treatment arms and allows causal inference.
The resulting high internal validity of prospective clinical trials is often achieved at the expense of external validity, or applicability of evidence to patients in real world settings. Stringent eligibility criteria often lead to exclusion of patients with comorbidities. As a result, trials often accrue patients who are younger and healthier than patients in actual clinical practice.11,12
Patients who belong to ethnic minorities are also underrepresented in clinical trials.13
The technical and regulatory challenges involved in the conduct of clinical trials often lead to a predominance of patients treated in academic settings as opposed to community settings.