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Advanced stage at diagnosis and elevated mortality among US patients with cancer infected with HIV in the National Cancer Data Base
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Cancer - May 2019 - Anna E. Coghill, PhD, MPH 1,2; Xuesong Han, PhD3; Gita Suneja, MD, MS4; Chun Chieh Lin, PhD, MBA3,5;
Ahmedin Jemal, DVM, PhD 3; and Meredith S. Shiels, PhD 1
People living with HIV (PLWH) have an elevated risk of certain cancer types, particularly those caused by viral coinfections.
Presented as a poster at the 16th International Conference on Malignancies in HIV/AIDS; October 23‐24, 2017; Bethesda, MD.
The data used in the current study were derived from a limited data set of the National Cancer Data Base (NCDB). The authors acknowledge the efforts of the American College of Surgeons, the Commission on Cancer, and the American Cancer Society in the creation of the National Cancer Data Base. The American College of Surgeons and the Commission on Cancer have not verified and are not responsible for the analytic or statistical methodology used, or the conclusions drawn from these data by the authors.
Abstract
Background
People living with HIV (PLWH) are at an increased risk of developing several cancers, but to the authors’ knowledge less is known regarding how HIV impacts the rate of progression to advanced cancer or death.
Methods
The authors compared stage of disease at the time of presentation and mortality after diagnosis between 14,453 PLWH and 6,368,126 HIV‐uninfected patients diagnosed with cancers of the oral cavity, stomach, colorectum, anus, liver, pancreas, lung, female breast, cervix, prostate, bladder, kidney, and thyroid and melanoma using data from the National Cancer Data Base (2004‐2014). Polytomous logistic regression and Cox proportional hazards regression were used to evaluate the association between HIV, cancer stage, and stage‐adjusted mortality after diagnosis, respectively. Regression models accounted for the type of health facility at which cancer treatment was administered and the type of individual health insurance.
Results
HIV‐infected patients with cancer were found to be more likely to be uninsured (HIV‐infected: 5.0% vs HIV‐uninfected: 3.3%; P < .0001) and were less likely to have private health insurance (25.4% vs 44.7%; P < .0001).
Compared with those not infected with HIV, the odds of being diagnosed at an advanced stage of disease were significantly elevated in PLWH for melanoma and cancers of the oral cavity, liver, female breast, prostate, and thyroid (odds ratio for stage IV vs stage I range, 1.24‐2.06). PLWH who were diagnosed with stage I to stage III disease experienced elevated mortality after diagnosis across 13 of the 14 cancer sites evaluated, with hazard ratios ranging from 1.20 (95% CI, 1.14‐1.26) for lung cancer to 1.85 (95% CI, 1.68‐2.04), 1.85 (95% CI, 1.51‐2.27), and 2.93 (95% CI, 2.08‐4.13), respectively, for cancers of the female breast, cervix, and thyroid.
Conclusions
PLWH were more likely to be diagnosed with advanced‐stage cancers and to experience elevated mortality after a cancer diagnosis, even after accounting for health care–related factors.
These data are consistent with prior work demonstrating higher mortality rates among patients with cancer within the setting of HIV.18, 24-26 Ultimately, patients with cancer with the same stage of disease at the time of presentation, the same initial treatment modality, reporting similar health insurance, and receiving cancer care at the same type of health care facility still died more often if they were infected with HIV at the time of their cancer diagnosis.
The results of the current study of >6 million patients with cancer in the United States demonstrated that those infected with HIV were more likely to be diagnosed with advanced‐stage cancers of the oral cavity, liver, female breast, prostate, and thyroid and melanoma. PLWH who were diagnosed with stage I to stage III cancer also experienced elevated mortality after diagnosis across a range of tumor etiologies. These associations persisted even after accounting for HIV‐related differences with regard to the type of treating cancer facility and patient‐reported individual health insurance. Although the possibility remains that the current study findings could be explained partly by unmeasured differences in health care use, differences in applied cancer treatment, or mortality from noncancer comorbidities, the results support a possible biological association between HIV and tumor behavior.
The data from the current study regarding >6 million patients with cancer in the United States are consistent with PLWH experiencing a more aggressive disease course for cancer: herein, we reported significant associations between HIV and both advanced stage of disease at the time of presentation and elevated mortality after a cancer diagnosis. Specifically, PLWH were significantly more likely to be diagnosed with advanced‐stage cancers of the oral cavity, liver, female breast, prostate, and thyroid and melanoma. Furthermore, HIV was associated with elevated mortality after a cancer diagnosis for 13 of the 14 cancer sites evaluated, including an almost doubling and tripling of mortality for female breast and thyroid cancers, respectively. The persistence of these associations after adjustment for factors related to the receipt of health care provides support for a biological link between HIV‐related immunosuppression and cancer progression.
PLWH were more likely to be diagnosed with advanced‐stage cancers of the oral cavity, liver, female breast, prostate, and thyroid and melanoma (P for trend <.05) (Table 2). After adjustment for both the type of treating health care facility and individual health insurance, statistically significant trends toward later‐stage disease remained, with the association between HIV and stage IV disease (vs stage I) ranging from 1.24 (95% CI, 1.02‐1.52) for liver cancer to 2.06 (95% CI, 1.70‐2.50) for female breast cancer.
-----Among patients with stage I to stage III disease, HIV was found to be significantly associated with elevated mortality after a cancer diagnosis for 13 of the 14 sites evaluated, even after adjustment for stage at diagnosis, first‐course cancer treatment type of treating cancer facility, and type of individual health insurance (Table 3) (see Supporting Table 2). The strength of the association between HIV and overall mortality ranged from hazard ratios of 1.20 (95% CI, 1.14‐1.26) for lung cancer to 1.85 (95% CI, 1.68‐2.04), 1.85 (95% CI, 1.51‐2.27), and 2.93 (95% CI, 2.08‐4.13), respectively, for cancers of the female breast, cervix, and thyroid. The 5 cancers with the most pronounced HIV‐associated elevations in mortality after diagnosis are illustrated in Figure 1 and included both virus‐associated and non–virus‐associated tumors. We also confirmed that PLWH experienced significantly elevated mortality even after including patients with metastatic (stage IV) disease (see Supporting Table 3).
The results of the current study do highlight one notable exception: PLWH were substantially more likely to be diagnosed with less advanced anal cancers compared with their HIV‐uninfected counterparts. This potentially represents an example of increased health care being directed toward the HIV‐infected population, a distinct possibility given the ongoing targeting of anal cancer screening procedures to HIV‐infected men who have sex with men.22 It is important to note that although these immunosuppressed patients were more likely to be diagnosed with less advanced disease, their stage‐adjusted mortality was higher than that of HIV‐uninfected patients. Mortality after an anal cancer diagnosis was found to be approximately 34% higher in PLWH compared with HIV‐uninfected patients diagnosed with the same stage of disease in the current study.
Introduction
People living with HIV (PLWH) have an elevated risk of certain cancer types, particularly those caused by viral coinfections.1-9 Rates of many infection‐associated cancers among PLWH have declined after the widespread availability of highly active antiretroviral therapy (HAART) to restore patient immunity, although the risk remains elevated compared with HIV‐uninfected individuals.10-13 Unlike infection‐associated cancers, some non–infection‐related cancers such as those of the prostate, female breast, and colon do not occur at elevated rates in PLWH.14 Nevertheless, these cancers are becoming increasingly prevalent among PLWH because of the widespread dissemination of HAART, which permits patients with HIV to live to older ages when cancers are more common.15, 16 This raises the important question of whether HIV‐related immunosuppression is associated with tumors progressing to higher stages before being diagnosed or resulting in poorer outcomes after diagnosis.
Both advanced stage of disease at the time of presentation and elevated mortality after diagnosis can reflect tumor aggressiveness, and recent data have suggested that immunosuppressed patients fare worse on both metrics. A prior registry‐based study demonstrated that PLWH were more likely to be diagnosed with distant‐stage cancers of the lung, female breast, prostate, and bladder and melanoma.17 Stage‐adjusted mortality after a cancer diagnosis also was elevated in HIV‐infected patients across a range of sites, including cancers of the colorectum, pancreas, larynx, lung, female breast, and prostate, and melanoma.18 It is plausible that advanced‐stage disease and elevated mortality after a cancer diagnosis among PLWH are related to the biological effects of HIV‐associated immunosuppression.
However, the more advanced‐stage cancers and elevated mortality reported among PLWH also could be related to receipt of suboptimal health care, a possibility supported by mounting data that PLWH are less likely to receive cancer treatment.19, 20 Available data have not been able to disentangle these possibilities. To begin addressing this issue of suboptimal health care, we evaluated the association between HIV, cancer stage at presentation, and mortality after a cancer diagnosis after accounting for the type of treating health facility and reported individual health insurance using data from >6 million US patients with cancer from the National Cancer Data Base (NCDB).
Discussion
The data from the current study regarding >6 million patients with cancer in the United States are consistent with PLWH experiencing a more aggressive disease course for cancer: herein, we reported significant associations between HIV and both advanced stage of disease at the time of presentation and elevated mortality after a cancer diagnosis. Specifically, PLWH were significantly more likely to be diagnosed with advanced‐stage cancers of the oral cavity, liver, female breast, prostate, and thyroid and melanoma.
Furthermore, HIV was associated with elevated mortality after a cancer diagnosis for 13 of the 14 cancer sites evaluated, including an almost doubling and tripling of mortality for female breast and thyroid cancers, respectively. The persistence of these associations after adjustment for factors related to the receipt of health care provides support for a biological link between HIV‐related immunosuppression and cancer progression.
To the best of our knowledge, only 1 prior study to date broadly examined cancer stage in PLWH; in that study, HIV was found to be associated with a more advanced stage of disease in patients with cancers of the lung, breast, prostate, and bladder and melanoma.17 However, that study did not have information regarding the type of care received by HIV status.17 To mitigate this fact, the authors compared their results with those observed among recipients of solid organ transplants, an immunosuppressed patient group that, unlike PLWH, has increased use of health care. Consistent results for more advanced‐stage diagnoses of bladder cancer and melanoma suggested a possible biological role for immunosuppression in the progression of these cancers. We believe the current study was unique in that the availability of health insurance information in the NCDB enabled us to more directly address potential nonbiological explanations for later‐stage cancer diagnoses in PLWH. We confirmed prior associations between HIV and later‐stage breast cancer, prostate cancer, and melanoma.17 In addition, herein we reported associations between HIV and advanced‐stage cancers of the oral cavity, liver, and thyroid. Because these associations were independent of the type of health insurance a patient reported, it appears that access to health care is not the sole explanation for the stage shifts.
The results of the current study do highlight one notable exception: PLWH were substantially more likely to be diagnosed with less advanced anal cancers compared with their HIV‐uninfected counterparts. This potentially represents an example of increased health care being directed toward the HIV‐infected population, a distinct possibility given the ongoing targeting of anal cancer screening procedures to HIV‐infected men who have sex with men.22 It is important to note that although these immunosuppressed patients were more likely to be diagnosed with less advanced disease, their stage‐adjusted mortality was higher than that of HIV‐uninfected patients. Mortality after an anal cancer diagnosis was found to be approximately 34% higher in PLWH compared with HIV‐uninfected patients diagnosed with the same stage of disease in the current study.
The association between HIV and elevated mortality after a cancer diagnosis was observed for patients with stage I to stage III tumors regardless of their initiating etiology. Elevations in mortality among patients with cancer ranged from 20% (lung cancer) to approximately 3‐fold (thyroid cancer) in PLWH, with the largest HIV‐related differences observed for cancers with a generally good prognosis (eg, breast and thyroid cancers).23 These data are consistent with prior work demonstrating higher mortality rates among patients with cancer within the setting of HIV.18, 24-26 However, this study not only accounted for clinically important prognostic factors such as cancer stage and treatment, but also demonstrated higher mortality in HIV‐infected patients with cancer after accounting for the type of treating health facility (quality of cancer care) and individual health insurance (access to care). Furthermore, the NCDB includes only patients with cancer who at least initiated cancer care, as opposed to our prior study that included diagnoses of cancer among all PLWH, regardless of health care use.18
Ultimately, patients with cancer with the same stage of disease at the time of presentation, the same initial treatment modality, reporting similar health insurance, and receiving cancer care at the same type of health care facility still died more often if they were infected with HIV at the time of their cancer diagnosis. A biological explanation for this persistent effect of immunosuppression on outcomes in patients with cancer is plausible when considered alongside data suggesting that immunosuppressed solid organ transplant recipients also experience elevated mortality after a cancer diagnosis,27 recent advances in cancer survival associated with immune‐boosting therapies,28-30 and data suggesting that additional cancer‐specific outcomes (ie, disease recurrence after successful first‐course treatment) are poorer in the presence of HIV.31 However, it must be acknowledged that this evaluation focused on overall mortality as the clinically relevant outcome rather than death due specifically to cancer. It is possible that PLWH in the current study died more often due in part to a higher risk of additional causes of death, including AIDS and other HIV‐associated comorbidities.
The current study is notable not only for the size and national scope of the NCDB but also because to the best of our knowledge prior studies have not been able to broadly examine the possibility that variations in health care could offer a nonbiological explanation for the more advanced‐stage cancer and elevated mortality after a cancer diagnosis noted among PLWH. Instead of proving a nonbiological explanation for the link between HIV and tumor aggressiveness, our data suggest that biology could underlie this association.
Certain limitations of the current study should be noted. First, we were unable to rule out the possibility of HIV‐related differences in access to health care that we were not able to account for in our models. For example, our classification of insurance into large groupings (eg, private insurance) may have failed to adequately adjust for variations according to insurance provider or coverage levels. Simple adjustment for receipt of health insurance also likely did not capture variations in the use of health services (ie, having and using insurance are not equivalent). Additional misclassification also may have existed for our exposure; hospital discharge diagnoses likely underascertain HIV status. As noted above, our evaluation of overall mortality after a cancer diagnosis was not able to capture potentially important HIV‐related differences in cancer‐specific mortality. Finally, we were not able to address the association between clinical measures of immunosuppression (eg, CD4 count) or HIV treatment (eg, antiretroviral therapy) and outcomes because the NCDB does not collect this information. Future studies that include clinical HIV data should evaluate these more refined metrics of patient immune status.
The results of the current study of >6 million patients with cancer in the United States demonstrated that those infected with HIV were more likely to be diagnosed with advanced‐stage cancers of the oral cavity, liver, female breast, prostate, and thyroid and melanoma. PLWH who were diagnosed with stage I to stage III cancer also experienced elevated mortality after diagnosis across a range of tumor etiologies. These associations persisted even after accounting for HIV‐related differences with regard to the type of treating cancer facility and patient‐reported individual health insurance. Although the possibility remains that the current study findings could be explained partly by unmeasured differences in health care use, differences in applied cancer treatment, or mortality from noncancer comorbidities, the results support a possible biological association between HIV and tumor behavior.
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