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Oncology Times:
doi: 10.1097/01.COT.0000441975.66025.ef
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New Focus on Comorbidity Could Improve Cancer Care on Many Levels

Lindsey, Heather

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A new review documents that cancer patients with comorbidities experience poorer survival than those without comorbidities, possibly due to compromised treatment, challenges with compliance, and several other factors.

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“Overall, the medical profession faces substantial challenges in providing proper care for patients with comorbidity,” said Mette Søgaard, PhD, the lead author of the study (Clin Epidemiol 2013;5[suppl 1]:3-29), a researcher in the Department of Clinical Epidemiology at the Institute of Clinical Medicine, Aarhus University Hospital in Denmark, writing in an email. “Increasing specialization may work well for patients with one disease, but may lead to suboptimal or fragmented care for patients with multiple diseases.”

Another of the coauthors, Henrik Toft Sørensen, MD, also a clinical epidemiologist at Aarhus, emphasized the importance of collaboration among a multidisciplinary team, needed to provide continuity of care and an individualized approach.

Also asked for his opinion for this article, Cary P. Gross MD, Professor of Medicine and of Epidemiology (Chronic Diseases) at Yale School of Medicine, said, “The take-home message here is that we need to recognize that, increasingly, the typical patient with cancer is going to have multiple chronic conditions, which may have a greater and longer-term impact on health than the cancer does.”

He said he is concerned that physicians may be overtreating some patients and undertreating others with aggressive cancer based on their comorbidities.

Similarly, Maurie Markman, MD, Senior Vice President of Oncology Services and National Director of Medical Oncology at Cancer Treatment Centers of America, said that unfortunately, clinical trials examining cancer treatment in patients with comorbidities are sorely lacking in the United States, leaving oncologists without evidence-based recommendations for the best approach.

HENRIK TOFT SRENSEN,...
HENRIK TOFT SRENSEN,...
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METTE SGAARD, PHD. M...
METTE SGAARD, PHD. M...
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CARY GROSS, MD. CARY...
CARY GROSS, MD. CARY...
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Study Details

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For the study, the researchers conducted a search of PubMed, MEDLINE, and Embase of English-language articles about the relationship between comorbidity and survival in patients with colon, breast, and lung cancers, published from 2002 to 2012. A total of 2,692 potentially eligible articles were identified, and after further narrowing down to focus on those most relevant, there were approximately 40 studies used as the focus of an assessment on comorbidity and treatment, cancer characteristics, and cancer stage at diagnosis.

“Our study selection was subjective, and we may have missed relevant papers,” Søgaard said. “On the other hand, if we had used explicit predefined criteria to select the articles as used in systematic reviews, we would probably have ended up with significantly fewer papers since only a few examined the impact of comorbidity as the primary aim.”

Overall, the literature review indicated that five-year mortality hazard ratios ranged from 1.1 to 5.8 in cancer patients with comorbidities versus those without. The researchers were uncertain, however, about whether a higher mortality was the result of the comorbidity or the cancer. The association between comorbidity and poorer cancer survival was present after adjusting for age, cancer stage, and treatment.

Generally, comorbidity was not associated with more aggressive cancer or differences in tumor biology. However, patients with diabetes had a higher cancer risk, as did those with inherited, acquired, or drug-induced immunosuppression. The researchers theorized that such risk factors may be associated with cancer growth, grade, differentiation, and prognosis.

Chronic diseases such as arthritis and stable coronary artery disease requiring regular check-ups were associated with earlier detection of malignancy, while severe comorbidities such as heart failure, end-stage pulmonary disease, and psychiatric illness potentially delayed diagnosis of cancer.

The researchers also found that patients with comorbidities do not receive standard cancer treatments such as surgery, chemotherapy, and radiation therapy as often as those without. The likelihood of these individuals completing their cancer treatment is also lower. To compound the problem, postoperative complications and mortality are higher in patients with comorbidity.

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Why Survival Has Not Increased

The reasons survival rates have not improved in cancer patients with comorbidities remain unclear, Søgaard said. However, in addition to patients not receiving or completing standard cancer treatment and having higher postoperative complications and mortality, poor survival might persist due to relatively inadequate handling of this population “caused by an increasing specialization of health facilities and physicians who work there.”

Moreover, Sørensen said, research and clinical guidelines seldom support patients with multiple chronic diseases.” Researchers need to determine whether comorbidity's prognostic impact is due to comorbidity-related deaths or a factor of how the specific comorbidity influences cancer-specific mortality, Søgaard continued.

In addition, Sørensen, said, “If cancer patients primarily die from their comorbidity, they will have relatively less benefit from improvements in cancer treatment than cancer patients without comorbidity.”

Several of the studies in the review demonstrated an association between increasing levels of comorbidity and higher cancer-specific mortality, but this finding was not universal, Søgaard noted. “The association between comorbidity and cancer-specific mortality seemed to vary according to cancer type and stage at diagnosis.”

Comorbidities may also increase cancer relapse, commented Martine Extermann, MD, PhD, senior member of the Moffitt Cancer Center. Diabetes is probably the most explored condition that has been found to increase risk of relapse from breast cancer, and cardiovascular disease may increase risk of lung cancer relapse postsurgery, she explained. “So not only do comorbidities increase mortality due to less treatment of the cancer, but they also influence the behavior of the cancer itself.”

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Why This Population Receives Different Treatment

EILEEN H. SHINN, PHD...
EILEEN H. SHINN, PHD...
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MARTINE EXTERMANN, M...
MARTINE EXTERMANN, M...
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Cancer patients with comorbidities may not receive the same treatment as those without comorbidities because they cannot tolerate therapies as well, Søgaard noted. It is unclear, though, whether such treatment changes are a reflection of care being taken because of the increased risk of toxicity due to comorbid illness or are a result of other factors such as patient preferences, lower quality of clinical care, or poor adherence.

Patients with comorbidities are also more likely to have poor functional status and to have multiple organs that aren't working well, said Cynthia Owusu, MD, Assistant Professor of Medicine specializing in hematology/oncology, at Case Western Reserve University School of Medicine. Because of the potential shortened life expectancy, treatment complications, and side effects, the risks of cancer therapy in these patients tend to far outweigh any benefits they might derive.

Factors such as nutrition, functional status, cognition, blood pressure, lactate dehydrogenase levels and renal function appear to have more impact on higher cancer treatment toxicity than the number of comorbidities a patient has, Extermann said. However, oncologists need to assess the individualized physiological effects of specific comorbidities on individuals, she added.

For example, said Eileen H. Shinn, PhD, Assistant Professor in the Department of Behavioral Science at the University of Texas MD Anderson Cancer Center, oncologists may consider using chemotherapy that is less toxic to the heart in ovarian cancer patients with severe hypertension or who have a previous history of heart attack.

Using optimal cancer therapy may be possible, though, while monitoring and treating these patients for tachycardia, venous thromboembolism, and pulmonary hypertension, she added, citing her research (Cancer Epidemiol Biomarkers Prev 2013;22:2102-2109).

Just because patients may have a high burden of comorbidity doesn't mean, though, that they won't benefit from cancer therapies, agreed Gross, noting a paper of his that was also referenced in the review (Cancer 2007;109:2410-2419). While some multiple conditions can decrease effectiveness of cancer therapy, “it's important not to avoid cancer treatment as a kneejerk reaction to multimorbidity,” he said.

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What Practitioners Can Do

To ensure comprehensive patient care, a multidisciplinary team comprised of oncologists, geriatricians, primary care physicians, social workers, dieticians, and physical therapists, for example, is essential, Owusu said.

Primary care physicians and oncologists also need to remain closely engaged when taking care of patients with multiple chronic illnesses to balance the burden of treatment and to guide treatment decisions, Gross said.

Shinn recommended that all cancer patients undergo a rigorous and comprehensive evaluation at diagnosis that includes assessment of comorbidity, especially because of the toxic effects of chemotherapy.

The risk of chemotherapy toxicity can be assessed in older patients, who often have several comorbidities, with available models such as the CRASH score, Extermann noted. Another general approach with older patients is to conduct an oncogeriatric workup in parallel with the standard oncology workup.

CYNTHIA OWUSU, MD. C...
CYNTHIA OWUSU, MD. C...
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Because patients with comorbidities do seem to be at increased risk of complications and adverse effects, treatment should be individualized, “weighing both patient and tumor characteristics,” Søgaard said. Overall, clinical decision-making is more difficult in this population because physicians and patients have to weigh the benefits and risks of multiple treatments, Sørensen added.

“Combining recommendations for patients with multimorbidity can result in harmful or overall burdensome treatment regimens, and polypharmacy can be an important consequence of following several guidelines.”

Surprisingly little is known about how the drugs patients are taking for their comorbidities may interact with chemotherapy, Gross noted. “Moreover, there's not a lot of data about what is safe as far as drug-drug interactions and how to best promote patient adherence to oral cancer therapies.”

And, said Extermann, very rarely do physicians work to trim down the list of drugs patients are taking—an action that could help to prevent drug interactions and reduce the risk of chemotherapy toxicity.

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Need for Clinical Trials

Clinical and epidemiological research on cancer prognosis has focused mainly on cancers “in isolation,” largely ignoring the impact of comorbidity and co-medication on the risk of complications and mortality, Søgaard noted.

Because trials in the U.S. are designed to maximize the opportunity of positive effects being observed, the protocols eliminate patients with comorbidities such as heart disease, diabetes, and severe obesity, Markman pointed out. “But once a new drug is approved, you don't have a clue as to how to treat these patients with it, period. This is the most critical deficiency in our clinical trial strategy and an incredibly important issue in an aging population. The typical patient in America isn't being included in clinical trials—an unbelievably bad situation.”

Research is also greatly needed to develop an instrument that can help predict the effect of comorbidities on treatment toxicity and cancer-specific and overall survival, Owusu said.

MAURIE MARKMAN, MD. ...
MAURIE MARKMAN, MD. ...
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Summing up, Extermann said that oncologists are on the verge of learning a lot about how comorbidities influence the behavior of cancer from the development of large data systems based on medical records—with the American Society of Clinical Oncology's CancerLinQ one such example. Analysis of tissue samples and gene-expression profiles can be correlated with comorbidity patterns to provide researchers with valuable information.

© 2014 by Lippincott Williams & Wilkins, Inc.

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