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Reality Check Needed: Comorbidities Loom in Practice, But Not in Clinical Trials

Maurie Markman, MD
Published Online: Thursday, January 2, 2014
Maurie Markman, MD

Maurie Markman, MD

Editor-in-Chief of OncologyLive

Senior vice president for Clinical Affairs and National Director for Medical Oncology

Cancer Treatment Centers of America, Eastern Regional Medical Center

How should the dose and schedule of antineoplastic therapies be modified in patients with known chronic liver, cardiac, or pulmonary disease when these conditions were excluded from the trials that permitted their routine clinical use? How should treatment be changed in the presence of significant obesity?

All oncologists know their management plans can be substantially influenced by the presence of clinically relevant comorbidities. Curative surgery may not be possible in a patient with clinical stage I lung cancer due to symptomatic heart or chronic obstructive pulmonary disease. Radiation may result in severe skin toxicity in a patient with known collagen vascular disease, and chemotherapy may be prohibited in an individual with severe liver dysfunction due to alcohol abuse or hepatitis C infection.

However, despite the general recognition of the impact of comorbidities on cancer management, the increasing frequency of such interactions between the presence of comorbidities and the provision of optimal cancer management has neither been sufficiently studied by cancer investigators nor adequately discussed in the oncology literature.1,2

For example, consider the following: It is routine in the conduct of clinical trials of new antineoplastic agents to specifically exclude from entry patients with common serious medical conditions, including active cardiac or vascular diseases such as recent myocardial infarction, inadequately managed high blood pressure, and anticoagulation for deep venous thrombosis, as well as poorly controlled diabetes and chronic renal or liver disease.

Yet, as the overall population ages, the prevalence of such comorbid medical conditions among the group of individuals most likely to develop cancer will sharply increase. And, while it is well recognized that the elderly themselves are woefully inadequately represented in registration trials designed to demonstrate the efficacy and safety of a new antineoplastic strategy,3 patients with common symptomatic comorbid medical conditions are essentially completely absent from trials—and that is even more problematic.

While one may reasonably argue that a 75-yearold woman with advanced ovarian cancer without any serious comorbid medical condition can likely be managed in a manner similar if not identical to a 60-year-old woman with the same clinical features of her cancer, such a statement could surely not be made about that same 75-year-old or even 65-yearold individual with known chronic liver, cardiac, or pulmonary disease.

How should the dose and schedule of antineoplastic therapies be modified in such individuals when patients with these conditions were excluded from the registration trials that permitted their routine clinical use? And how should treatment be changed in the presence of significant obesity, an increasingly common serious problem in our society?

As cancer becomes more of a chronic condition appropriately managed like other chronic medical illnesses, the chances that an oncologist caring for a given patient with cancer will be confronted with the problem of optimizing care in the face of a comorbid condition will certainly substantially increase.

Recent Studies Illustrate Gap

Just how far are our clinical trials from addressing the real issues within the general population of patients with malignant disease? Consider a provocative report examining the incidence of venous thromboembolism in patients receiving chemotherapy (Figure).4 Prior studies examining the risk of this serious event in the life of a patient with cancer receiving chemotherapy have reported an incidence (not impacted by any pharmacologic intervention) of somewhere between 3%-4%.5,6 In addition, the risk of bleeding complications associated with anticoagulation in these studies was reported to be relatively modest.

However, Lyman et al evaluated population-based health claims data and found a far higher incidence of both venous thromboembolism (13.5% at 12 months) and bleeding complications associated with anticoagulation,4 suggesting that the patients who participate in trials of these common complications of cancer and its management simply may not be terribly representative of the general population of individuals who develop and need to be treated for malignant disease.

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