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Issue: July 25, 2011
July 25, 2011
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AIDS no longer an obstacle to effective cancer treatment

In patients with HIV/AIDS and cancer, oncologists worry about drug interactions and the mistaken belief that these patients cannot be helped.

Issue: July 25, 2011
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Thirty years ago, in June 1981, AIDS first appeared in the United States as a recognized condition and for the next 15 years, a diagnosis of AIDS was basically a death sentence. Advances in treatment since then have made it a manageable, chronic disease.

The AIDS epidemic was accompanied by a spike in what would come to be called “AIDS-defining cancers:” cervical cancer, non-Hodgkin’s lymphoma and Kaposi’s sarcoma, sometimes known as “gay cancer.”

Evan Douple, PhD, associate chief of research for the Radiation
Elizabeth Connick, MD, from the University of Colorado School of Medicine, Denver, said HIV-infected women are often poor, uneducated and lack the resources for treatment.

Photo courtesy of Elizabeth Connick

Although antiretroviral drugs were available before 1996, the introduction of highly active antiretroviral therapy (HAART) transformed AIDS into what is now a chronic disease. At that point, infectious disease specialists’ focus shifted from crisis management to finding a cure, a vaccine or both.

About the same time, oncologists noticed that the incidence of AIDS-defining cancers was beginning what would turn out to be a long downward trend. In an analysis of data collected by the CDC and published in the Journal of the National Cancer Institute earlier this year, Shiels and colleagues showed that incidence of AIDS-defining cancers such as Kaposi’s sarcoma and NHL decreased from 7,284 diagnoses in 1993 to 1,736 in 2005. Incidence of non-AIDS-defining cancers increased from 416 to 2,437 during the same time period.

“The HIV-positive population has evolved over these 30 years. Very early on in this epidemic, when patients were presenting with lymphoma or Kaposi’s sarcoma, many had a strong history of opportunistic infections such as Pneumocystis pneumonia (PCP). As a consequence, those patients did very poorly on the early clinical trials looking at combination immunochemotherapy,” said Robert Baiocchi, MD, PhD, who leads the HIV/AIDS Cancer Clinic at The Ohio State University Comprehensive Cancer Center and serves as the institutional principal investigator for the National AIDS Malignancy Clinical Trials Consortium, an NCI-sponsored supported clinical trials group founded in 1995 to support innovative trials for AIDS-related cancer.

“As HAART therapy became more commonly used, patients’ viremia was better controlled and the frequency of opportunistic infections has declined rapidly over the years; the HIV-positive patient presenting with cancer has been able to tolerate chemotherapy much, much better,” Baiocchi told HemOnc Today. “As a consequence, you look at the studies done in the early ’80s compared to the ’90s compared to now; what we’re seeing is a new patient population evolving. This patient population is tolerating chemotherapy just like HIV-negative patients. There has been a nice trend in favor of patients doing better.”

“Therapeutic nihilism”

Researchers are clearly making strides against HIV/AIDS and there has been a similar increase in survival for patients with cancer and HIV/AIDS. According to results published in 2002 in Journal of Acquired Immune Deficiency Syndromes, 24% of patients diagnosed with AIDS from 1996 to 1998 died within 24 months of diagnosis compared with 57% of those diagnosed between 1990 and 1995.

Similarly, the 24-month survival rate for patients with AIDS diagnosed with Kaposi’s sarcoma improved from 30% before 1996 to 58% from 1996 to 2000, according to an analysis of the New York State Cancer Registry published in Journal of Acquired Immune Deficiency Syndromes in 2005. For patients with non-central nervous system NHL, 24-month OS improved from less than 20% to 43% over the same time period.

Even as survival improves, oncologists treating this population are fighting what Joseph A. Sparano, MD, called “therapeutic nihilism.” Sparano is associate chairman of the department of oncology at Montefiore Medical Center in Bronx, N.Y. Montefiore is an AIDS Malignancy Consortium core site. Some physicians, especially those who do not specialize in working with this population, still believe there is little or nothing to be done to help these patients, he said.

“Many of these patients have underlying cancers that are potentially curable,” he said. “We have to re-educate physicians so that they know these patients can be approached in the same way as patients with cancer who do not have HIV.”

Baiocchi has developed educational and marketing materials to educate patients and physicians, and to encourage physicians to refer patients to oncologists experienced in treating patients with both AIDS and cancer.

Robert Baiocchi, MD, PhD
Robert Baiocchi

“It’s a huge problem [because] people are not educated in this area,” he said. “That’s the benefit in sending patients with AIDS and cancer to a physician who specializes in treating that population.”

Physicians may be working with these patients more frequently in the near future. Shiels and colleagues found that patients aged younger than 30 years made up just 5.9% of person-years with AIDS from 2001 to 2005, down from 15.1% in 1991 to 1995. In contrast, the proportion of person-years contributed by those with AIDS aged at least 50 years increased from 9.8% to 24.8% during that time.

Cancer incidence increases with age, and the great strides made in treating AIDS means that this population is aging alongside the population in general. Baiocchi said medical science does not have a good understanding about the long-term consequences of having a virus such as HIV. Patients whose HIV is unknown or untreated tend to have poorer outcomes for their cancers, he said.

“This patient population is a moving target. We’re seeing a completely new population — patients over 50 who are presenting with anal cancers, head and neck cancers and lung cancers in nonsmokers,” he said. “The cancers have aggressive histologies, they’re presenting in an unusual fashion and the patients probably aren’t being checked for HIV. When they get treated with chemotherapy, they don’t do well.”

Learning more about the population

One of the stumbling blocks to finding new therapies for patients with cancer and HIV/AIDS has been that patients with HIV have often been excluded, even from trials testing new agents that could benefit this population. NCI officials in 2008 published an editorial in the Journal of Clinical Oncology arguing that patients with HIV should be excluded only if there is a scientific reason.

NCI has recommendations calling for patients with HIV to be included in clinical trials, but results of a study conducted by physicians at Montefiore and presented at this year’s ASCO Annual Meeting, showed that those recommendations have been largely ignored. Sparano said the fear is that patients with compromised immune systems might skew the results.

“Certainly NCI is adhering to the recommendations in terms of NCI-sponsored trials,” Sparano said. “Otherwise, those recommendations have not been widely adopted.”

The other problem in treating this population is the potential for dangerous interactions between antiretroviral drugs and chemotherapy drugs. Adverse events associated with chemotherapy may result in dose reductions, which could mean under-treating the cancer, whereas reductions in antiretroviral therapy could result in the return of HIV. Baiocchi said it is an issue that the AIDS Malignancy Consortium has only recently begun to address.

“HAART therapy has several classes of drugs used to suppress HIV infection, many of which are processed by the same liver enzymes that process chemotherapy,” he said. “As a consequence, we see some profound toxicity from a chemotherapy standpoint.”

It is less clear what the combination of HAART and radiation therapy has on patients, but it appears that patients whose HIV is controlled tolerate radiotherapy as well as other patients.

In an analysis of the SEER database published by online by the Journal of Clinical Oncology in May, researchers identified Medicare beneficiaries who underwent computed tomography-based simulation for thoracic radiation therapy. Patients had been diagnosed with stage III non–small-cell lung cancer between 2000 and 2005.

Use of CT-based thoracic radiation therapy increased from 2.4% in 1994 to 77.6% in 2005. Researchers concluded that CT simulation was associated with lower risk for death compared with conventional simulation (HR=0.77; 95% CI, 0.73-0.82) after controlling for demographic and clinical factors.

In a retrospective cohort study Houston published in Journal of Clinical Oncology in 2007, researchers evaluated the records of 1,184 patients treated for squamous cell anal cancer. In the 175 patients who were also HIV positive, researchers found that 2-year survival was 77% among HIV-positive patients and 75% for HIV-negative patients. Multivariate Cox analysis showed that significant predictors of survival were age, sex, metastasis at diagnosis, and comorbidity score, while HIV infection did not affect survival.

Joseph A. Sparano, MD
Joseph A. Sparano

“Radiation hasn’t been excessively toxic,” said David H. Henry, MD, director of the AIDS Malignancy Program at the University of Pennsylvania Cancer Center and vice chair of Penn’s department of medicine at Pennsylvania Hospital. “It’s a primary treatment modality combined with chemotherapy in anal cancer. And these patients tolerate it as well as patients without HIV in my experience.”

In the 80s, the oncologist’s armamentarium for treating this population was limited because of the serious adverse events associated with chemotherapy and radiation, he said. The advent of new therapies allows oncologists to be much more aggressive when treating cancer.

“Often, we either had to stop therapy or the patient died,” Henry said. “Thanks to these new HIV medications, most of our patients are treated like everyone else because the HIV is so well-controlled, it’s almost a non-issue.”

Echoing Baiocchi, Henry said physicians are primarily concerned with drug-drug interactions. He added that the long-term effect of HAART is still unclear, especially in aging patients with cancer.

“Who takes more medications than these patients?” he said. “If you have HIV-related cancer, you’re on several HIV medications. You might be on some regular “older life” medications like statins or hypertension medications. Then we give you chemotherapy and/or radiation. We’re very worried about these drug-drug interactions.”

A moving target

Statistics from the CDC released last October indicate that despite an increase in the total number of people living with HIV in the US, the number of new infections has remained static, with about 56,300 cases reported annually. White men who have sex with men account for 53% of new infections, and the CDC said men who have sex with men remain most at risk for HIV/AIDS.

However, new HIV infections in black women reported by the CDC in 2006 totaled 7,340, 15 times higher than the rate of infection in white women and four times that of Hispanic women. Black women accounted for 27% of new HIV infections in 2006.

“HIV-infected women are often poor, from minority groups and uneducated, and they have little political clout,” said Elizabeth Connick, MD, associate professor of infectious diseases at the University of Colorado School of Medicine in Denver. “Currently, there is enormous emphasis on global health initiatives, which are indisputably important. It’s an enormous irony that it’s in vogue for American researchers to fly off to Africa to help women there, but it is not glamorous to get in their cars and drive down the street to help American women with HIV. More resources need to be devoted to HIV prevention and treatment in American women, such as studies of [pre-exposure prophylaxis].”

Not surprisingly, disparities research show that black women tend to get certain cancers at a higher rate than Asian or non-Hispanic white women and tend to have poorer outcomes. The CDC says black women diagnosed with breast cancer are more likely to die from the disease than white women, more likely to be diagnosed at a later stage and less likely to survive for 5 years after diagnosis. For black women, the rate of cervical cancer, an AIDS-defining cancer, is 45% higher compared with white women and black women are twice as likely to die from the disease.

Additionally, patients with HIV are more likely to smoke and develop coinfections such as HPV and hepatitis B and C that increase their risk for diseases such as anal and oropharyngeal cancers, liver cancer and lung cancer. Results published by Public Health Nursing in June showed that while there was a high level of awareness about HPV and HPV vaccine across racial and ethnic groups, 23% of white women got the vaccine compared with just 8% for black women and 6% for Hispanics.

“The behaviors that lead to HIV infection in the first place are associated with other behaviors such as smoking,” Sparano said. “Trying to reduce smoking in HIV-infected patients may pay off dividends in terms of reducing the risk for lung and head and neck cancers, which are fairly common.”

It is always easier and cheaper to prevent disease than to treat it. Henry noted that anal and cervical cancers are HPV-related and it is relatively easy to prevent and treat HPV.

“Prevention. Smoking cessation. Safe sex,” he said. “Hepatitis infection more often leads to hepatoma in the HIV-positive population. We’re all about prevention.”– by Jason Harris

POINT/COUNTER

Should all patients with cancer undergo HIV screening?

POINT

Patients with cancer are at greater risk for having undiagnosed HIV, and the presence of the virus can have serious effects on disease treatment and outcomes.

Ronald Mitsuyasu, MD
Ronald Mitsuyasu

Yes, all patients should be screened for a number of reasons, not the least of which is that the CDC currently recommends that HIV testing be part of routine medical care, unless the patient opts out. That recommendation was issued in 2006, and up to this point, it hasn’t been adopted as well as many of us would like. Some physicians are obviously very uncomfortable asking patients about HIV testing. Secondly, there are some concerns about the cost of HIV testing.

The CMS allows reimbursement for routine HIV testing, and most states have changed their statutes so that separate informed consent for HIV testing is not required. Physicians can easily order HIV testing if they feel it’s important, and as a person who takes care of a lot of patients with HIV and cancer, I feel that it is important and should be done fairly routinely.

Until now, risk-based HIV testing hasn’t been as effective as many of us would like, and as a result, many people in the United States who are infected are unaware of their HIV status. That can have significant bearing in terms of their outcome from the HIV and also their outcomes from their cancer. Patients with immunosuppression generally do worse than non-HIV-infected patients, and there are a number of side effects and drug interactions that can occur between chemotherapy and cancer treatment in general and treatment for HIV.

For patient care and general public health reasons, it’s important to be able to diagnose patients as early as possible. Patients with cancer are generally at higher risk for having undiagnosed HIV because, as we now know, cancers occur more frequently in people who are immunosuppressed. The likelihood of a patient with newly diagnosed cancer also having HIV is higher than most realize.

Ronald Mitsuyasu, MD, is the director of the UCLA Center for Clinical AIDS Research, and education and group chairman of the AIDS Malignancy Consortium. He reports no relevant financial disclosures.

COUNTER

Patients should be screened on a case-by-case basis.

Adrienne Phillips, MD, MPH
Adrienne Phillips

At this point, it is premature to state that all patients with cancer should undergo HIV screening but there are definitely cancers that make me think a patient may be co-infected with HIV, or where knowing HIV status would influence therapeutic decisions, and I would definitely want to know that upfront.

My general practice is to screen patients diagnosed with AIDS-defining malignancies: Kaposi’s sarcoma, certain subtypes of lymphoma, and cervical cancer. Increasingly, patients with HIV are living longer and have risk factors that increase their susceptibility to a variety of other cancers. Non-AIDS-defining malignancies such as anal cancer, hepatocellular cancer, lung cancer, etc. are seen in high rates among HIV-infected individuals and knowing a patient’s HIV status becomes important because it may affect their cancer treatment and overall prognosis.

With chemotherapy, for example, patients are at greater risk for immunosuppression and the development of opportunistic infections. For patients eligible for stem cell or solid organ transplantation, uncontrolled HIV may be a contraindication. In these situations, knowing the patient’s HIV status would improve treatment of their cancer. HIV-infected individuals are not at increased risk for all cancers, however. A number of recent cohort studies and even meta-analyses confirm HIV-infected individuals are at greatest risk for cancers associated with infection and smoking but not others such as prostate or pancreas.

Screening in general is a complicated recommendation. You have to consider the patient’s life expectancy, the nature of the screening test, and the harms, benefits and alternatives of the screening test. Patients diagnosed with cancer may have a limited life expectancy and testing for HIV at this time may not change overall prognosis. In addition, testing for HIV is still stigmatized. Patients faced with a dual cancer and HIV diagnosis may experience increased anxiety and psychiatric illness. Lastly, a recent ASCO abstract confirms many cancer clinical trials exclude patients with HIV infection without valid scientific justification (Weiss S. #6092. ASCO, 2011).

HIV screening of cancer patients should be provided in an individual, patient-focused manner. In patients diagnosed with cancer, if knowing their HIV status will affect their treatment and prognosis, I may offer HIV screening but this is not a “one-size-fits-all” approach. A number of individual factors must be taken into consideration.

Adrienne Phillips, MD, MPH, is an assistant professor of Clinical Medicine at New York Presbyterian Hospital-Columbia University Medical Center. She reports no relevant financial disclosures.

Disclosures: Drs. Baiocchi, Connick, Henry and Sparano reported no relevant financial disclosures.

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