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

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

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.

The magnitude of this issue and the tremendous uncertainty associated with providing cancer care in this setting was further highlighted recently in a compelling article that examined the delivery of bevacizumab to patients with so-called “cardiac contraindications” to its use.⁷ In this analysis, the investigators employed data contained in the SEER-Medicare database (individuals ≥65 years) from 2004 to 2007, with follow-up to 2009. Of the population of approximately 16,000 patients with cancers of the colon, breast, or lung—conditions with formal FDA approval for use of the antiangiogenic agent—19% received bevacizumab during the course of their illness.

Rather remarkably, of the 3039 patients treated with this antiangiogenic drug for the indications noted above, 35.5% (n = 1082) were stated to have had a “contraindication” to its use, defined as “at least two billing claims before bevacizumab for thrombosis, cardiac disease, stroke, hemorrhage, hemoptysis, or GI perforation.”⁷

How can that be? Is it reasonable to believe that fully one-third of all patients older than 65 years of age (SEER-Medicare database) who received bevacizumab for a recognized clinical indication had a genuine “contraindication to the use of the agent”?

Or is it perhaps more likely that a substantial percentage of patients with these malignancies age 65 and older had these highly relevant comorbidities and the treating oncologists were attempting to do their best to help these individuals prolong survival by employing an antineoplastic strategy demonstrated to be of clinical value? The clinical trials that defined efficacy were so narrow in their eligibility criteria that it was simply not known how to utilize the agent in the very common situation of pre-existing cardiac abnormalities/dysfunction.

The point to be made here is that bevacizumab, like most antineoplastic drugs, is associated with significant potential risks.^7-9 However, use of this agent may also result in considerable clinical benefit.^10-12 And, it is reasonable to pointedly inquire how oncologists can optimally balance the risks versus the benefits of this drug in the absence of data to directly address this critically important question in patients with clinically relevant and common comorbidities. It would seem that simply stating or declaring that a drug is “contraindicated” based on preciously limited data is both objectively inappropriate and not helpful in informing optimal clinical practice.

Giving Patients a Voice

Finally, a discussion of this general topic should be expanded to include the broader issue of the definition of acceptable risk in the antineoplastic treatment arena, the individuals/groups that should be empowered to make this determination, and the required process to provide adequate informed consent regarding the nature of such risks.

Consider, for example, the recent reports of a rather substantial “risk” for the development of arterial thrombosis following the administration of ponatinib,¹³ an impressively active agent in the treatment of chronic myelogenous leukemia.^14,15

In October, the manufacturer halted distribution of ponatinib amid an FDA investigation into its safety that was prompted by a higher than expected incidence of severe arterial thrombosis and stenosis. The drug had received accelerated approval with a Boxed Warning about the potential for these adverse events. Now, its use is being severely restricted while labeling changes are under consideration—in turn upsetting those patients who were benefiting from the drug and some oncologists who believe in it.¹⁶

Considering the seriousness of the adverse events, the potential added risks for a patient with underlying cardiac dysfunction, and the prognosis of refractory cancer, is it perhaps reasonable to permit a patient to be given the opportunity to decide if the potential benefits justify the potential risks of treatment?¹⁶

Figure. VTE Incidence and Comorbidities Among Cancer Patients^a

^aPatients in study had cancers of lung, colon, ovary, bladder, stomach, or pancreas.

Lyman GH et al. Oncologist. Published online November 8, 2013.

References

1. Lee L, Cheung WY, Atkinson E, Krzyzanowska MK. Impact of comorbidity on chemotherapy use and outcomes in solid tumors: a systematic review [published online November 22, 2010]. J Clin Oncol. 2011;29(1):106-117.
2. Chia VM, O’Malley CD, Danese MD, et al. Prevalence and incidence of comorbidities in elderly women with ovarian cancer [published online February 17, 2013]. Gynecol Oncol. 2013;129(2):346-352.
3. Hutchins LF, Unger JM, Crowley JJ, et al. Underrepresentation of patients 65 years of age or older in cancer-treatment trials. N Engl J Med. 1999;341(27):2061-2067.
4. Lyman GH, Eckert L, Wang Y, et al. Venous thromboembolism risk in patients with cancer receiving chemotherapy: a real-world analysis [published online November 8, 2013]. Oncologist. doi: 10.1634/theoncologist.2013-0226.
5. Agnelli G, George DJ, Kakkar AK, et al. Semuloparin for thromboprophylaxis in patients receiving chemotherapy for cancer. N Engl J Med. 2012; 366(7):601-609.
6. Agnelli G, Gussoni G, Bianchini C, et al. Nadroparin for the prevention of thromboembolic events in ambulatory patients with metastatic or locally advanced solid cancer receiving chemotherapy: a randomized, placebo-controlled, double-blind study [published online September 1, 2009]. Lancet Oncol. 2009;10(10):943-949.
7. Hershman DL, Wright JD, Lim E, et al. Contraindicated use of bevacizumab and toxicity in elderly patients with cancer [published online September 3, 2013]. J Clin Oncol. 2013;31(28):3592-3599.
8. Choueiri TK, Mayer EL, Je Y, et al. Congestive heart failure risk in patients with breast cancer treated with bevacizumab [published online January 4, 2011]. J Clin Oncol. 2011; 29(6):632-638.
9. Ranpura V, Hapani S, Wu S. Treatment-related mortality with bevacizumab in cancer patients: a meta-analysis. JAMA. 2011; 305(5):487-494.
10. Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004;350(23):2335-2342.
11. Sandler A, Gray R, Perry MC, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med. 2006;355(24):2542-2550.
12. Miller K, Wang M, Gralow J, et al. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med. 2007; 357(26):2666-2676.
13. Groarke JD, Cheng S, Moslehi J. Cancer-drug discovery and cardiovascular surveillance [published online November 1, 2013]. N Engl J Med. 2013; 369(19):1779-1781.
14. Cortes JE, Kantarjian H, Shah NP, et al. Ponatinib in refractory Philadelphia chromosome-positive leukemias. N Engl J Med. 2012; 367(22):2075-2088.
15. Cortes JE, Kim D-W, Pinilla-Ibarz J, et al. A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias [published online November 1, 2013]. N Engl J Med. 2013; 369(19):1783-1796.
16. Grady D, Pollack A. Doctors fear losing leukemia drug deemed risky. New York Times. November 2, 2013:A3.

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 (