Neoplasms Associated with Acquired Immunodeficiency Syndrome - Perez & Brady's Principles and Practice of Radiation Oncology (Perez and Bradys Principles and Practice of Radiation Oncology), 6 Ed.

Perez & Brady's Principles and Practice of Radiation Oncology (Perez and Bradys Principles and Practice of Radiation Oncology), 6 Ed.

Chapter 34. Neoplasms Associated with Acquired Immunodeficiency Syndrome

Bernadine R. Donahue and Jay S. Cooper

We cannot deal with AIDS by making moral judgments or refusing to face unpleasant facts, and still less by stigmatizing those who are infected.

—Kofi Annan, former U.N. secretary general

HUMAN IMMUNODEFICIENCY VIRUS

One of the greatest public health challenges of the latter half of the 20th century has been emergence of human immunodeficiency virus (HIV). Although the biology of the virus has been elucidated, diagnostic tests have been created, and effective drugs and care systems have been established, HIV remains an epidemic in the 21st century, particularly in the developing world. HIV infection, immunosuppression, and enhanced tumor growth characterize the acquired immunodeficiency syndrome (AIDS).

Nearly 30 million people have died of AIDS in the past 30 years,¹ and despite gains that have been made, AIDS remains a health catastrophe in those parts of the world with little or no access to life-sustaining drugs. In 2009, the most recent year for which worldwide statistics are available, over 33 million people were living with AIDS (including 2.5 million children under the age of 15 years), 2.6 million people became infected, and 1.8 million people died of AIDS. Nearly 70% of these events occurred in Sub-Saharan Africa.¹ Although the toll of HIV infection in North America can be viewed as relatively small in comparison to other parts of the world, the statistics remain concerning. In 2009, 1.5 million persons in North America were living with HIV and there were 25,000 deaths attributable to AIDS.¹ Many HIV-infected persons in the United States do not receive optimal care: for some, the monetary cost of highly active antiretroviral therapy (HAART) is prohibitive, while for others, the toxicity associated with HAART is unbearable. Despite funded programs aimed at reducing the incidence of AIDS, 70,000 persons became infected with HIV in North America during 2009.¹ Thus, even in such resource-rich areas as North America, AIDS is likely to remain a serious problem in the foreseeable future.

Human Immunodeficiency Virus and Malignancy

AIDS-associated malignancies are a well-recognized, not-infrequent, and potentially lethal consequence of the disease. Early in the epidemic, three types of malignancies showed a sufficiently increased incidence that they qualified as AIDS-defining conditions when they occurred in conjunction with HIV infection: Kaposi’s sarcoma (KS), non-Hodgkin lymphoma (NHL), and carcinoma of the cervix. In 1981, the appearance of KS in young homosexual men heralded the association of tumors and HIV infection.² Intermediate- or high-grade B-cell lymphomas in HIV-infected individuals were classified as AIDS-defining events in 1985.³ Cervical carcinoma was recognized in 1993 as an AIDS-defining illness for HIV-infected women.⁴ Data reported from the AIDS Cancer Match Registry Study (including more than 300,000 adult persons with HIV/AIDS) demonstrated the expected increased relative risks of developing the three AIDS-defining tumors,⁵ however, in addition, this study as well as others suggested an increase in some other tumors, such as Hodgkin lymphoma, anal carcinomas, skin cancers, and prostate cancer, as well as unusual pediatric age malignancies in HIV-infected children.⁶^,⁷^,⁸^,⁹^–¹⁰

By 1993, the Centers for Disease Control (CDC) dropped the requirement of an AIDS-defining malignancy or other overt illnesses for a diagnosis of AIDS⁴; however, the burden of cancer in the HIV-infected population remains a substantial and potentially growing problem. The raw numbers from the HIV/AIDS Cancer Match Study and the CDC reflect the overall decrease in AIDS-defining neoplasms over the past decades: from 1991–1995 to 2001–2005, the estimated number of AIDS-defining cancers decreased from 34,587 to 10,325, whereas non-AIDS-defining cancers increased from 3,193 to 10,059,¹¹ and this finding is corroborated by multiple other datasets.⁸^,¹² It is likely that this trend will continue as the HIV-infected population ages,¹³^–¹⁴^,¹⁵^–¹⁷^,¹⁸^,¹⁹ and given that the AIDS population in the United States expanded fourfold from 1991 to 2005 primarily because of an increase in the number of people aged 40 years or older,¹¹ cancer in the setting of HIV infection will continue to require our attention.

This chapter subsequently is organized by histologic type of HIV-associated malignancy. Epidemiology, patterns of disease, pathology, diagnostic evaluation, treatment, and prognosis are included. The use of radiation as it relates specifically to each malignancy in the setting of HIV is discussed. For additional details regarding the delivery of radiation, the chapters in this text addressing each specific neoplasm should be consulted.

It is of historical interest to note that in June 2001, the International Atomic Energy Agency issued a monograph, “The Role of Radiotherapy in the Management of Cancer Patients Infected by Human Immunodeficiency Virus (HIV),” which, given the paucity of data and the immense scope of the problem, attempted to provide some guidance for the treatment of HIV-associated malignancies.²⁰ At the time, AIDS was an almost uniformly fatal disease, and it was against this background that the authors stated that for HIV-associated malignancies:

[T]he usual oncological rules of practice do not apply: cure at any cost is not a sensible option. Very often the best decision is simply to treat with the simplest, most effective, palliative regimen available. Any decision to treat radically has to be tempered by the realisation that the patient’s life span will be limited, regardless of the success or failure of the treatment for the malignant disease. Nowhere in oncology is an individualised approach to decision-making more important than in HIV oncology… for a patient with asymptomatic malignancy and HIV infection, active observation is a perfectly reasonable policy.²⁰

Fortunately, a decade later, the outlook for HIV-infected persons is much improved, and the era of therapeutic nihilism has past. There is now solid rationale for including patients with HIV and cancer in clinical trials. The Cancer Therapy Evaluation Program has advised researchers that individuals known to be HIV positive should not be arbitrarily excluded from participation in clinical cancer treatment trials, and the National Cancer Institute has advocated that persons with HIV and cancer should only be excluded from cancer trials if there is a scientific reason for doing so.²¹ In general, for persons with HIV, the procedure is to attempt to utilize “standard” stage-directed treatments for each malignancy discussed. However, the authors do so with the major caveat that the “standard” treatment may need to be modified based on the immunologic status, the viral load, coexisting opportunistic infections, and comorbidities in any given individual.

Treatment-related toxicity will continue to be a concern as HIV infection yields to better therapies and the incidence of unrelated tumors increases. Laboratory data suggest that certain protease inhibitors may increase radiosensitivity; however, this has not been borne out in the clinic. See et al.²² compared the toxicity rates of radiation therapy in patients who were taking or not taking a second-generation protease inhibitor and observed no difference. Baeyens et al.²³ demonstrated heightened sensitivity of HIV-infected T lymphocytes to damage from radiation, but the in vivo data are not uniformly supportive. Kaminuma et al.²⁴ concluded that radiotherapy is safe, but HIV infection was associated with earlier onset (i.e., with lower dose) and more severe acute skin and mucosal toxicity. Mallik et al.,²⁵ in a review of the literature, concluded that local control and disease-specific survival are not affected by HIV infection if the CD4 count exceeds 200 cells per cubic millimeter. This appears to be true even for tumors that are treated with relatively aggressive combinations of chemotherapy and radiation, such as carcinomas of the anal canal or of the head and neck region.²⁶^,²⁷ Thus, in general, it appears that curative radiation therapy (with or without chemotherapy as the extent of disease dictates) provides disease control without imparting a degree of toxicity substantially beyond that traditionally seen in HIV-uninfected individuals. Nevertheless, the myelosuppressive nature of some of the agents incorporated into HAART regimens and the neurotoxicity of others raise concern when radiation therapy is being delivered to large volumes of bone marrow or over the central nervous system (CNS).²⁸ If we are to continue to improve the outcome of HIV-infected persons with malignancies, close monitoring for toxicity, attention to immunologic parameters, and a strong emphasis on supportive care are essential when treating such patients with standard treatments.

FIGURE 34.1. Example of periventricular location of human immunodeficiency virus–associated primary central nervous system lymphoma.

LYMPHOMA

The incidence of lymphoma in association with HIV infection was reported as approximately 60 to 100 times greater than expected in the general population during the early years of the epidemic.²⁹^,³⁰ Although primary central nervous system lymphoma (PCNSL) was one of the initial CDC-approved criteria for a diagnosis of AIDS,³¹ the inclusion of systemic high-grade B-cell NHL did not occur until 1985.³ Its incidence was shown to correlate with the duration of immunosuppression, CD4 count 1 year prior to the diagnosis of NHL, and B-cell stimulation.³² Epstein-Barr virus (EBV) was implicated in its etiology by the finding of anti-EBV immunoglobulins and circulating EBV-infected B cells in the setting of HIV.³³ Where available, HAART appears to have decreased the incidence of both PCNSL and NHL, most likely secondary to an overall decrease in the proportion of patients with low CD4 counts.¹²

Primary Central Nervous System Lymphoma

Epidemiology and Risk Factors

At its height, the incidence of NHL originating in the brain without evidence of systemic involvement in persons with AIDS was 3,600-fold higher than in the general population.³⁴ HAART has decreased the high risk of developing this disorder in persons who are infected with HIV.³⁵

Patterns of Disease

In most patients who have HIV-associated PCNSL, the diagnosis is suggested by the onset of headaches or a change in mental status.³⁶^,³⁷ Unfortunately, PCNSL can be clinically and radiographically indistinguishable from other pathologic processes in HIV-infected patients. Neurocognitive dysfunction in HIV-infected patients is associated with a long differential diagnosis, including PCNSL, toxoplasmosis, herpetic infections, cryptococcus, progressive multifocal leukoencephalopathy, neuroimmune reconstitution inflammatory syndrome (IRIS), and HIV-associated dementia, leukoencephalopathy, and demyelination. In general, the typical radiographic findings of PCNSL are that of multiple contrast-enhancing lesions, often, but not exclusively, in a periventricular location (Fig. 34.1).

Diagnostic Workup

Prior to HAART, it was common for an HIV-infected patient to present with a clinical and radiographic picture that could be consistent with either toxoplasmosis or PCNSL (Fig. 34.2). A negative toxoplasmosis titer did not eliminate the diagnosis of toxoplasmosis, and similarly a positive toxoplasmosis titer did not preclude the presence of PCNSL.³⁸^,³⁹ Because there was a high incidence of toxoplasmosis in the HIV-infected population, the standard first-line treatment for an HIV-infected patient who developed a neurologic abnormality and had a radiographically visible brain lesion consistent with either toxoplasmosis or CNS lymphoma was the institution of antitoxoplasmosis antibiotics. During the first decade of the epidemic, it was common to administer empiric cranial radiation therapy in patients who did not manifest clinical or radiographic improvement by the second or third week of antitoxoplasmosis treatment. However, as our knowledge of the myriad HIV-related opportunistic infections expanded and the poor outcome with this empiric approach was recognized, the emphasis shifted to recommending biopsy for definitive diagnosis.⁴⁰

Pathology and Prognostic Factors

The majority of PCNSL are B-cell large immunoblastic types, and EBV DNA is identifiable in nearly all cases.⁴¹ Polymerase chain reaction amplification of EBV DNA in the cerebrospinal fluid is usually positive in these patients and may become negative following treatment.⁴² In general, PCNSL is seen later in the course of HIV infection than is systemic NHL. Patients usually have CD4 counts <50 cells per cubic millimeter before PCNSL becomes evident.⁴³ Although the overall median survival of these patients is poor, patients no older than 35 years who have Karnofsky performance scores of at least 80% tended to survive 5 to 6 months, rather than the 2 months typically observed in less favorable subgroups.⁴⁴

General Management

It has been suggested that the institution of HAART may result in regression of existing PCNSL, but to date scant evidence exists to support this claim.⁴⁵^–⁴⁷ Methotrexate-based chemotherapy with or without whole-brain radiation therapy (RT) has been shown to prolong the median survival in immunocompetent patients who have PCNSL,⁴⁸ and when possible, this approach should be considered for patients with HIV. However, many HIV-infected patients who are sufficiently immunosuppressed to develop PCNSL may be unable to tolerate methotrexate. In the pre-HAART era, chemotherapy was evaluated for HIV-associated PCNSL, with median survival on the order of 2 months.⁴⁹^,⁵⁰ More recently, in the HAART era, a subgroup of HIV-positive patients who can tolerate aggressive therapy consisting of either methotrexate with or without whole-brain radiotherapy, may achieve longer survivals, although their outcome remains worse than the median survival of 41 months reported in immunocompetent patients treated with methotrexate-based chemotherapy.⁴⁸^,⁵¹

Radiation

Cranial irradiation alone in the treatment of PCNSL was essentially palliative, produced short-lived clinical and radiographic evidence of tumor response, and resulted in mean overall survival of 2 months.³⁶^,⁴⁴^,⁴⁹^,⁵²^–⁵⁴^,⁵⁵^,⁵⁶^–⁵⁷^,⁵⁸Recent intriguing data from Japan showed a survival rate of 64% at 3 years in a cohort of irradiated patients who were receiving HAART.⁵⁹ Patients who received (or who were able to receive) doses 30 Gy or more fared better than those receiving lower doses. Unfortunately, one-third of persons who lived more than 12 months manifested leukoencephalopathy.

Although HAART appears to have decreased the incidence of HIV-associated PCNSL, it remains to be determined what the precise influence of aggressive antiretroviral treatment will be on the outcome of HIV-infected patients with PCNSL. However, it appears that survival is prolonged by HAART.⁶⁰^,⁶¹ There are anecdotal reports of regression of PCNSL with the institution of HAART and case reports of survival 2 years or more.⁴⁵^–⁴⁷^,⁶² Cohort data from Australia showed that in a subset analysis of 47 patients with biopsy-proven PCNSL, antiretroviral therapy with at least two agents along with RT was associated with better survival.⁶³ In addition to immunomodulation by targeting HIV, attempts have been made to target EBV, which is nearly uniformly found in HIV PCNSL. Combinations of zidovudine, ganciclovir, and interleukin-2 were piloted by the AIDS Malignancy Consortium.⁶⁴ The incidence of myelosuppression with this was high, and this remains an experimental approach.

FIGURE 34.2. Magnetic resonance image findings in a patient who presented with a change in mental status and was found to be human immunodeficiency virus positive. Differential diagnosis included primary central nervous system lymphoma; biopsy proved toxoplasmosis.

Systemic Non-Hodgkin Lymphoma

Epidemiology and Risk Factor

The incidence of NHL decreased with introduction of HAART, and this reflected the decreased number of HIV-infected persons with low CD4 counts.⁶⁵ Although it appears that nonnucleoside transcriptase inhibitor–based HAART is as protective as protease inhibitor–based HAART and more protective than nucleoside analogs alone,⁶⁶ cases of NHL among patients with multiclass antiretroviral resistance have been described as developing soon after newer-class antiretrovirals were initiated; this has raised the potential of IRIS-mediated NHL.⁶⁷^,⁶⁸

Diagnosis

Rapidly developing adenopathy or constitutional B symptoms (fevers, unexplained weight loss, night sweats) are the most common presentations of HIV-associated systemic NHL. Nearly 75% of all patients will present with advanced-stage disease (stage III or IV), will manifest B symptomatology, and frequently have extranodal involvement.⁶⁹ The most common histologic subtypes are high-grade B-cell lymphoma or Burkitt’s lymphoma; however, intermediate-grade (diffuse large cell type) lymphomas are not uncommon. As patients who have AIDS-NHL frequently have extranodal involvement, staging evaluation should include chest, abdomen, and pelvic computerized tomograms, bone marrow biopsy, and cerebrospinal fluid analysis.

Treatment

Treatment for AIDS-NHL lymphoma initially was based on high-dose chemotherapy regimens that proved to be toxic. Subsequently, therapy relied on attenuated doses of cytotoxic chemotherapy or standard-dose chemotherapy plus cytokine support; however, outcomes were still poor.⁷⁰^–⁷⁴ Further study helped to define a regimen with high efficacy with acceptable toxicity using infusional cyclophosphamide, doxorubicin, and etoposide (CDE), and a multicenter trial employing this regimen showed that the median 1-year survival of 48% achieved with CDE was approximately twice as high as was achievable with previously standard regimens such as methotrexate with leucovorin rescue, bleomycin, doxorubicin, cyclophosphamide, vincristine, and dexamethasone.⁷⁵ The advent of rituximab, an anti-CD20 antibody that has improved survival for patients with non-HIV-associated NHL, may improve the outcome in HIV-associated NHL. An AIDS Malignancies Consortium phase III trial that randomized patients to cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) versus CHOP plus rituximab (R-CHOP) showed a higher complete response rate (57%) in the R-CHOP arm as compared with CHOP alone (47%); this, however, was not statistically significant and there was an increased risk of death from infection in the R-CHOP arm.⁷⁶ A French trial also evaluated the safety and efficacy of R-CHOP for the treatment of AIDS-related NHL.⁷⁷ This trial included 61 patients, two-thirds of whom achieved a complete response. The overall survival at 2 years was 75%, and although infections were seen, only one patient died from infection. The AIDS Malignancies Consortium (AMC034) trial randomized patients to EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) with concurrent rituximab versus EPOCH followed sequentially by rituximab.⁷⁸^,⁷⁹ The patients who received concurrent rituximab achieved a complete response of 73%.

CNS prophylaxis with intrathecal chemotherapy has been controversial in the setting of high-grade NHL and HIV infection, but frequently was used, especially in patients with extranodal disease. However, it appears that patients who do not have EBV-infected tumors may not require such prophylaxis. The risk of CNS involvement was 10 times higher in patients who were EBV positive, as compared with those who were EBV negative.⁸⁰ It may be that prophylaxis can be reserved for a selected subset of patients. The sustained-release formulation of intrathecal cytarabine may have an important role to play in both the prophylaxis and treatment of CNS meningeal involvement.⁸¹

A previously unrecognized form of lymphoma, called primary effusion or body cavity lymphoma, was identified in HIV-infected patients during the second decade of the epidemic.⁸² It appeared to be associated with human herpesvirus-8,⁸³ and it accounted for approximately 4% of AIDS-related NHL.⁸⁴ Typically, such patients present with an effusion in a body cavity, in the absence of widespread lymphadenopathy. The effusion contains numerous atypical lymphoid cells with a plasmacytoid appearance and an indeterminate (non-B or T cell) immunophenotype and clonal immunoglobulin heavy- and light-chain gene rearrangements. Multiple myeloma-1/interferon regulatory factor-4 protein expression can be used to differentiate primary effusion lymphoma from other lymphomas.⁸⁵ Survival of patients who have primary effusion lymphoma remains very short, on the order of 2 to 5 months, even with aggressive therapy.

It is clear that with the availability of HAART, it became feasible to employ standard chemotherapy regimens, and a major question now is whether HAART should be administered in conjunction with, or after, chemotherapy. In general, it is recommended that zidovudine be avoided because of its myelosuppressive effects. The current thinking is that HIV-infected persons should be treated in the same aggressive fashion as noninfected persons, however, patients much be chosen carefully and monitored closely for toxicity.⁸⁶^,⁸⁷

Radiation Therapy

The role of consolidative radiation therapy following systemic treatment in AIDS patients who have NHL has not been evaluated methodically. It had been suggested that radiation should be used as a consolidative boost in patients with bulky disease who have demonstrated slow or partial response to chemotherapy.⁸⁸^,⁸⁹ More obviously, it also was indicated for palliation of bulky lesions and was used to provide palliative therapy for patients who develop lymphomatous meningitis. In lymphomatous meningitis, this approach was shown to result in a 60% to 70% clinical or cytological response, however, median time to progression was on the order of only 2 to 2.5 months.⁹⁰^,⁹¹

Results and Prognosis

Despite our best current therapies, patients who have AIDS-NHL generally have a poor overall survival. Early in the epidemic prognostic factors were identified that correlated with the length of survival.⁹²^–⁹⁴ Patients who had bone marrow involvement, low Karnofsky performance status at diagnosis (<70%), low CD4 counts, or a prior diagnosis of AIDS had a median survival on the order of 4 months; those without these adverse features had a median survival of 11 months. Rossi et al.⁹⁵ reported that the International Prognostic Index (IPI), a model designed to predict the outcome of NHL in general, is a reliable prognostic indicator of outcomes for patients who have AIDS-related NHL. Both the likelihood of complete response and median survival after treatment correlated appropriately with IPI score. Moreover, the IPI score correlated with the CD4 cell count, suggesting that the degree of immunodeficiency imparted by HIV infection influenced the aggressiveness of NHL. Ultimately, a prognostic model for systemic AIDS-related NHL treated in the era of highly active antiretroviral therapy was established based solely on the IPI and the CD4 count.⁹⁶

NHL remains an important cause of morbidity and mortality in AIDS patients. Registry data from San Diego suggest an improvement in median survival for these patients from approximately 4 months to 9 months after the introduction of HAART,³⁵ however, data from Kaiser Permanente in California demonstrate that HIV-infected patients with NHL in the HAART era continue to endure substantially higher mortality compared with HIV-uninfected patients with NHL, with 59% of HIV-infected patients dying within 2 years after NHL diagnosis as compared with 30% of HIV-uninfected patients.⁹⁷ There is hope that newer targeted agents, such as rituximab, which has shown an improvement in survival for patients with non-HIV-associated NHL, will improve the outcome in HIV-associated NHL. It is of interest that in developing countries challenged by the lack of HAART, efficacious regimens employing dose-modified oral chemotherapy have been developed, which result in outcomes comparable to the pre-HAART experience in the United States.⁹⁸

Hodgkin Lymphoma

The relative risk of developing Hodgkin lymphoma in the setting of HIV infection (HIV-HL) is increased as compared with the general population as demonstrated by a joint Danish and U.S study of 302,824 HIV-infected patients that showed a relative risk of 11.5.⁹⁹ Although data from the Multicenter AIDS Cohort Study showed a stable incidence of this disease before and after the introduction of HAART,¹² there is recent evidence that the incidence of this disease in the HIV-infected population increased after the introduction of HAART. Data from a large European cohort showed a rising standardized incidence ratio from 1983 through 2007, with multivariate analysis showing that HAART was associated with an increased risk of disease.¹⁸

The explanation for the rise in HIV-HL after combined antiretroviral therapy became widely available is unclear, however, one intriguing explanation involves the relationship between Reed-Sternberg cells and CD4 cells.¹⁰⁰ The risk of Hodgkin lymphoma appears to peak when HAART reconstitutes the immune system and CD4 cells reach levels of 150 to 190 cells per cubic millimeter. It is postulated that Reed-Sternberg cells produce growth factors that increase the influx of CD4 cells, which in turn provide signals that cause the proliferation of Reed-Sternberg cells. If CD4 cells stimulate the growth of Reed-Sternberg cells, it would stand to reason that as HAART improves the CD4 cell count, more of these cells are available to stimulate growth of the cell associated with Hodgkin lymphoma.

Hodgkin lymphoma in HIV-infected individuals tends to be advanced, associated with B symptoms, and can present with unusual manifestations, such as presentation with a gastric or intracranial mass.¹⁰¹^,¹⁰² In addition to the usual prognostic factors for Hodgkin lymphoma, low CD4 count and preexisting AIDS confer a worse prognosis.

In the past, only 50% of patients had a complete response following combination chemotherapy, and 2-year survival was on the order of 45%.¹⁰³^,¹⁰⁴ How to integrate RT into the management of HIV-HL was also problematic. A report from M.D. Anderson Cancer Center suggested that radiation therapy was “appropriate” for approximately 50% of patients who had HIV-HL, usually in combination with chemotherapy; nevertheless, even in that series (with a median follow-up of 64 months), 5-year overall survival was only 54%.¹⁰⁵

However, the outcome may be improving in the setting of HAART and combination chemotherapy.¹⁰⁶ A phase II study in 59 patients with HIV-HL (52 of whom also received concurrent HAART) resulted in a complete response rate of 81% with the Stanford V regimen, although 3-year overall survival was only 51%.¹⁰⁷ A more recent series from Germany reported a risk-adapted approach in 93 patients with HIV-HL.¹⁰⁸ Patients with early-stage favorable Hodgkin lymphoma were treated with 2 cycles of adriamycin, bleomycin, vinblastine, dacarbazine (ABVD) and 30 Gy involved field RT, those with unfavorable early-stage disease received 4 cycles of BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone) and 30 Gy involved field, and those with advanced stage disease were treated with 6 to 8 cycles of BEACOPP. Importantly, BEACOPP was replaced with ABVD for patients with “far-advanced” HIV infection, and HAART was given concomitantly with chemotherapy. Early results are encouraging with a 1-year overall survival of 88%, although the outcome was worse for those patients with advanced stage disease. Additionally, of concern, even with careful attention to the risks of toxicity, four patients died of neutropenic sepsis.

In general, radiation therapy should be considered for HIV-HL for the same indications it is considered in non-HIV-associated Hodgkin lymphoma; however, there continues to be a paucity of data on its use and tolerance in this setting.

FIGURE 34.3. Purple, 1.5-cm nodular classic Kaposi’s sarcoma on the ankle of an elderly man. (From Krigel RL, Friedman-Kien AE. Kaposi’s sarcoma of AIDS: diagnosis and treatment. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds. AIDS: etiology, diagnosis, treatment, and prevention, 2nd ed. Philadelphia: JB Lippincott, 1988, with permission.)

KAPOSI’S SARCOMA

Epidemiology and Risk Factors

At the start of the epidemic, AIDS often was identified by the diagnosis of KS, and KS in this setting became known as epidemic Kaposi’s sarcoma (EKS). People infected with HIV had at least a 20,000 times greater risk of developing KS than uninfected individuals.¹⁰⁹ The discovery that HIV-infected gay or bisexual men were more likely than HIV-infected heterosexual men to develop KS was one of the first clues that KS or its etiologic agent might somehow be sexually transmitted.

With the introduction of progressively more effective antiretroviral therapies, the incidence of KS in the United States, as a component of AIDS, has diminished over time. A report from the International Collaboration on HIV and Cancer evaluating the cancer incidence from 23 prospective studies that included 47,936 HIV-seropositive individuals from North America, Europe, and Australia showed that the adjusted incidence rate for KS declined from 15.2 in the period of time from 1992 through 1996 to 4.9 between 1997 and 1999.¹¹⁰ A report from the Swiss HIV Cohort Study showed that the risk of developing KS declined by 66% during the 15 months after HAART was initiated (p = .001), as compared to the pre-HAART era.¹¹¹

In December 1994, a herpes virus that appeared to be associated with the etiology of Kaposi’s sarcoma was identified.¹¹² This was called human herpesvirus-8 (HHV-8) as well as KS-associated herpesvirus (KSHV). The virus was detected in both the epidemic (AIDS-related) and endemic (previously typical African) forms of KS, as well as classic (elderly men of Eastern European or Mediterranean ancestry) KS. In a 1996 report from the Multicenter AIDS Cohort Study, antibodies to HHV-8 were detected in 80% of HIV-infected men who subsequently went on to develop KS.¹¹³ This suggested that KS resulted from infection with HHV-8, rather than being a direct result of HIV itself, or to cytokines induced by the HIV virus; HIV produced the immunosuppression that facilitated HHV-8 expression as KS. HHV-8 has a large number of genes that can encode homologues of host genes, many of which are involved in angiogenesis and the cell cycle. At present, six major subtypes (called A, B, C, D, E, and F) of HHV-8 are recognized based on the specific amino acid sequences of the gene K1 (ORF-K1) of the virus and further divided into subgroups known as clades (e.g., A1, A2, A3). Additionally, increased levels of interleukin-6, which is thought to be an important growth factor in HHV-8 associated neoplasms, have been found in tissues affected by HHV-8.¹¹⁴

Patterns of Disease

KS is characterized by purplish lesions on the skin or mucosal surfaces. The lesions can be macular, plaque-like, or nodular, with or without associated lymphadenopathy or lymphedema (Figs. 34.3–34.5). At presentation, skin lesions can be either single or multiple and may cause pain, bleeding, or disfigurement. As involvement of lymph nodes and lymphatic spaces occurs, progressive edema can result. This is seen most commonly in lesions involving the lower extremity, the inguinal regions, the genitalia, and the face. Visceral KS typically involves the aerodigestive tracts. Oropharyngeal lesions can result in life-threatening airway obstruction. Pulmonary involvement can result in life-threatening respiratory failure.

Diagnostic Workup

In addition to inspection of all visible skin and mucosal surfaces, the likelihood of visceral KS is sufficiently high that endoscopic evaluation of the gastrointestinal (GI) tract is appropriate for any patient with GI symptoms. In any patient who develops KS as the first sign of AIDS, a more comprehensive workup for HIV should be undertaken: complete physical examination, blood count and chemistries including CD4 lymphocyte count and viral load, chest x-ray, tuberculin test, anergy screen, and screen for sexually transmitted diseases.

Pathology

It is generally agreed that KS is a neoplasm of mesenchymal origin, and the histologic diagnosis of KS requires the identification of both spindle cell and vascular elements within the lesion. The spindle-shaped cells look much like fibroblasts and are generally considered the neoplastic element. Overall, the appearance often is suggestive of slitlike embryonic vascular channels filled with red blood cells; however, red cells characteristically are also found mixed within the spindle cell framework of the tumor.

FIGURE 34.4. A: Epidemic Kaposi’s sarcoma of the foot before treatment. B: Same patient approximately 1.5 years after 30 Gy was delivered in 10 fractions over 2 weeks by 6-MeV electron beam therapy (with bolus).

FIGURE 34.5. A: Epidemic Kaposi’s sarcoma of the upper and lower lateral eyelids before treatment. B: Same patient approximately 1 month after 30 Gy was delivered in 10 fractions over 2 weeks by kilovoltage x-rays. An eye shield was used to protect the lens of the eye. Residual pigmentation is visible.

Treatment

Alternatives to or in Association with Radiation Therapy

EKS typically exhibits multifocal distribution at the time of presentation, and radiation therapy has played a smaller and smaller role in its management over time as better alternatives have been discovered. The role of HAART is now well established and appears to result in durable clinical response rates of over 60% of patients.¹¹⁵ In one prospective cohort study of good risk (confined to skin or nodes or minimal oral disease) KS, treatment with HAART alone allowed 74% of patients to survive systemic-treatment free for 5 years.¹¹⁶ It is important to recognize, however, that a small subset of patients may experience a worsening of symptoms when HAART is instituted. Bower et al.¹¹⁷ have reported that after commencing HAART, 6.6% of patients with HIV-associated KS developed progressive immune reconstitution inflammatory syndrome KS (i.e., a worsening in their clinical status), despite control of virologic and immunologic parameters, felt to be secondary to an immune response against a preexisting pathogen.¹¹⁷

Systemic chemotherapy has been used for patients with advanced disease. A concern had been that cytotoxic chemotherapy potentially could further compromise the immune system and accelerate the effects of HIV infection. Also, the standard doses of chemotherapy used for solid tumors often resulted in unacceptable morbidity for these patients.¹¹⁸^,¹¹⁹ Consequently, treatment protocols were developed with low-dose chemotherapy to which epidemic KS was responsive.¹²⁰ The regimen of ABV became the gold standard in the 1990s.

Liposomal daunorubicin and doxorubicin were approved subsequently by the U.S. Food and Drug Administration (FDA) for the treatment of EKS. Randomized studies comparing these drugs with the standard ABV showed at least comparable activity with a more favorable toxicity profile,¹²¹^,¹²² and the liposomal drugs are generally now used as first-line therapy. Response rates of 25% with a median duration of 4 months can be expected.¹²¹^,¹²²

Paclitaxel is also approved for treatment. Toxicity is mild except for myelosuppression, which can be dealt with by growth factors when necessary.¹²³^,¹²⁴ Gill et al.¹²³ reported a 60% response rate (nearly all partial responses) with a 10-month median duration of response in one phase II trial. Although there are other active drugs available, such as VP-16, paclitaxel has become a common second- or third-line drug following the liposomal agents, due to its activity and acceptable toxicity.

Without HAART, patients often require ongoing therapy to control symptomatic KS. However, when HAART is available and decreases HIV RNA to undetectable levels, chronic chemotherapy frequently can be discontinued.¹²⁵

Radiation Therapy

Radiation therapy can also be useful for palliation of pain, bleeding, or edema. Typically, small fields that include only the distressing lesion and a small margin are treated, either with superficial quality x-rays or low-energy electrons (and bolus). One of the more commonly used dose-fractionation schemes is 30 Gy in 10 fractions delivered over 2 weeks, which has resulted in substantial benefit without substantial toxicity for the typical patient.¹²⁶ More than 90% of lesions respond to therapy and approximately 70% respond completely.¹²⁷ Stelzer and Griffin’s¹²⁸ prospective randomized trial demonstrated a correlation between dose and response within the tested range of 8 Gy in 1 fraction to 40 Gy in 20 fractions over 4 weeks. Greater dose was associated with a higher response rate, a lower incidence of residual pigmentation, and a longer duration of tumor control. However, these data should not be interpreted as a blanket recommendation for higher dose; rather, this suggests that doses should be tailored to individual patients’ needs. For patients who have far-advanced AIDS (where a briefer duration of palliation will suffice and the appearance of the lesion is not as important), a dose of 8 Gy in 1 fraction often is preferable.¹²⁹ In contrast, relatively healthy patients, who are treated to improve their cosmetic appearance, should receive relatively higher doses. Even then, it is prudent to remember that some residual purple pigmentation remains in approximately 55% of treated patients.¹²⁸

Gratifying short-term palliation of painful swollen extremities secondary to far advanced KS can be achieved by covering the limb in bolus (or placing it in a water bath) and delivering a single fraction of 8 Gy by parallel opposed photon portals.

Despite the relative sensitivity of KS to radiation, toxicity of treatment needs to be considered in every situation. Treatment of symptomatic oropharyngeal lesions with radiation has been problematic because of the high degree of radiation-induced mucositis that these patients develop even following low-dose radiation therapy.¹³⁰ Palliation of symptomatic visceral or mucosal disease should nearly always be attempted first with chemotherapy and HAART. However, there are rare instances in which patients’ lesions have failed to respond to systemic chemotherapy or in which patients are unable to tolerate systemic chemotherapy. These patients may benefit from attenuated doses of local radiation to palliate bleeding or obstructive lesions. Piedbois et al.¹³¹ have reported 88% objective response and “good palliation of symptoms” following 10 to 20 Gy (2.5 Gy per fraction, 4 fractions per week) for delicate anatomic sites, such as the penis, the palms, oral mucosa, or the conjunctivae. In one report of 25 patients who had pulmonary lesions treated with radiation therapy (10.5–15 Gy at 1.5 Gy per fraction), subjective improvement was observed in nearly 90% of patients, although only one-third of patients survived for 3 months.¹³²

CERVICAL CANCER

Epidemiology

Cervical carcinoma in the presence of HIV infection was accepted by the CDC as an AIDS-defining illness in 1993.⁴ The association between HIV and cervical cancer is complex and, although it has been clearly demonstrated that there is an increased incidence of preinvasive lesions in HIV-infected women, it is not clear that there is a substantially higher incidence of invasive disease.¹³³ Some authors argued that since the introduction of HAART, there was little evidence to support the continued status of cervical cancer as an AIDS-defining illness, because cervical cancer did not appear to have a strong relationship to immune function as determined by CD4 count or responsiveness to HAART.¹³⁴ However, recent reports from Africa, where the AIDS epidemic continues to rage, suggest a doubling of the risk of cervical cancer in women with AIDS as compared to African women without AIDS.¹³⁵

Not surprisingly, there appears to be an association between human papilloma virus (HPV) infection and risk for cervical epithelial abnormalities in HIV-infected women.¹³⁶^,¹³⁷^–¹³⁹ Data suggest that the introduction of HAART reduces the burden of HPV infection and intraepithelial neoplasia, which may in turn explain why rates of cervical cancer do not appear to have increased during the HAART era.¹⁴⁰^,¹⁴¹ A report on a prospective cohort of 286 HIV infected women who initiated HAART and were assessed semiannually for HPV infection and intraepithelial lesions showed that HAART initiation among adherent women was associated with a significant reduction in prevalence and incident detection of oncogenic HPV infection as well as a decreased prevalence and more rapid clearance of oncogenic HPV-positive intraepithelial lesions.¹⁴²

Diagnosis

Routine gynecologic evaluation, including Papanicolaou (PAP) smears (and colposcopy when warranted), is the most successful means of detecting the dysplastic and in situ lesions (cervical intraepithelial neoplasia [CIN]) that give rise to invasive lesions. Unfortunately, HIV-infected women often presented with advanced-stage disease, and, thus, in addition to vaginal bleeding and dyspareunia, the disease frequently manifested with abdominal or back pain, weight loss, or palpable cervical adenopathy. During the early years of the AIDS epidemic, up to 50% of HIV-infected women were diagnosed as having stage III or IV disease when they first sought care, as compared to approximately 20% of noninfected women.¹⁴³^,¹⁴⁴

Treatment

Treatment should be dictated by the extent of disease, taking into account the patient’s history of opportunistic infections and overall medical status. HIV-infected women treated with CIN should be approached in a fashion similar to non-HIV infected women, albeit with attention to the possible increased risk of complications.¹⁴⁵ Patients who have early-stage, nonbulky disease are usually treated with a radical hysterectomy and pelvic lymph node dissection. Patients who have more advanced local-regional disease should be treated in the same fashion as their non-HIV-infected counterparts. Although previously this would have been radiation therapy alone, in one series of patients treated by radiation alone for advanced disease, 50% had no or minimal response to treatment, and at a median follow-up of 3 months all had progression of disease.¹⁴⁶ In a series of 42 HIV-positive patients treated with definitive radiotherapy at Tata Memorial Hospital in India, only 22 patients completed the full course of RT; 50% achieved a complete response.¹⁴⁷ It should be noted that when RT alone was used to treat cervical cancer, the rates of acute toxicity in HIV-infected women, particularly genitourinary, GI, and cutaneous toxicity, were observed to be higher than expected.¹⁴⁸

The current standard of care for advanced cervical cancer is a combination of radiation therapy and cisplatin-based chemotherapy. At present there are insufficient data to demonstrate the routine feasibility or efficacy of this approach in the setting of AIDS; however, based on the tolerability of combined modality approaches in other AIDS-related malignancies and the evidence of improved outcome in advanced cervical cancer in the general population, it is believed that advanced cervical cancers in women who do not have a specific contraindication for chemotherapy should receive concurrent chemotherapy, external-beam radiotherapy, and an intracavitary boost. Patients who have hematogenously borne metastatic disease may benefit from palliative chemotherapy or radiation therapy in an effort to reduce symptoms such as pain and bleeding.

Results and Prognosis

Although there initially was concern over the ability to deliver standard treatment to HIV-infected patients with cervical carcinoma, available data suggest treatment can be delivered, albeit with a higher risk of complications and perhaps a worse outcome. In a study from the early years of the epidemic, 9 of 16 HIV-infected women who had cervical carcinoma died at a mean interval of only 9.2 months from diagnosis.¹⁴⁶ Data on the outcomes with chemoradiation in the HAART era are lacking.

Prevention and early diagnosis of cervical abnormalities prior to the development of invasive cancer appear to be critical if the outcomes for patients are to improve. Prospective data from the Women’s Interagency HIV Study have confirmed that with close monitoring (i.e., PAP smears every 6 months) and appropriate intervention, the incidence of invasive cervical cancer among women with HIV is not higher than in HIV-negative women.¹⁴⁹ The widespread use of the FDA-approved recombinant vaccine targeting HPV-16 and HPV-18 may further decrease the incidence of cervical cancer in the setting of HIV.

ANAL CANCER

Anal carcinomas, like cervical carcinomas, appear to be related to sexually transmitted HPV (primarily HPV-16), with anal intercourse being a risk factor.¹⁵⁰ HIV-infected homosexual men have increased serum HPV DNA as compared with HIV-seronegative homosexual men.¹⁵¹ In one study, more than 60% of HIV-infected men with abnormal anogenital examinations were found to have squamous intraepithelial lesions on biopsy.¹⁵² How HAART has impacted the development of anal intraepithelial neoplasia and the subsequent development of invasive anal cancer is still being defined. Some authors reported that antiretroviral treatment did not protect against the development of premalignant or malignant lesions,¹⁵³ while others reported that HAART decreased the prevalence of anal intraepithelial neoplasia in men with persistent HPV but did not affect the HPV.¹⁵⁴ However, recent data from a large European cohort of people with HIV evaluating the incidence of non-AIDS defining cancers showed an elevated incidence of anal cancer during the pre-HAART era (1983–1995), the early HAART era (1996–2001), and the established HAART era (2002–2007) with similar standardized incidence ratios in all three periods.¹⁸ Thus, at present, it appears that HAART does not diminish the excess risk of anal cancer in the HIV-positive population.

Early-stage lesions may present as an incidental finding during excision of condylomata or hemorrhoids or may be identified when patients present with anal fissures. However, many patients with HIV anal carcinoma present with more advanced disease, and signs and symptoms may include perianal or rectal pain, tenesmus, bleeding, mucous drainage, or palpable groin nodes. Evaluation and workup should include digital rectal examination, inguinal node evaluation with biopsy or fine-needle aspiration of suspicious nodes, anoscopy, gynecologic examination in women, body computed tomography, and consideration of positron emission tomography scan.

Carcinoma in situ frequently can be approached with measures employed for the treatment of genital warts (i.e., topical podophyllin, topical 5-fluorouacil [5-FU], and laser therapy). In patients with low-grade, early-stage lesions (T1) without any evidence of nodal involvement, local excision with wide margins may be acceptable if the sphincter function is preserved. However, for the patients with HIV anal carcinoma who present with more advanced T stages or nodal involvement, if treatment is to be definitive, chemoradiation (with 5-FU/mitomycin-C and radiation therapy as the standard of care in immunocompetent persons) is the treatment of choice when possible. Unfortunately, the administration of mitomycin-C to patients with advanced HIV may be associated with the potential for severe myelosuppression and hemolytic uremic syndrome, thus limiting its use in some patients. In early series, there was evidence that patients with HIV infection required longer breaks from chemoradiation because of severe skin reactions and almost uniformly required chemotherapy dose reductions because of neutropenia.^155,¹⁵⁶^–¹⁵⁷These toxicities led to various attempts to render treatment more tolerable in the setting of HIV.

In the early years of the AIDS epidemic, HIV-infected patients who had anal carcinoma appeared to have a shorter survival and a higher incidence of local failure as compared with non-HIV infected persons.¹⁵⁵^,¹⁵⁸ It appears that after the introduction of HAART, the outcome for persons with HIV-anal cancer improved.¹⁵⁹ Recent series have shown that with modern management, including intensity-modulated radiation therapy and growth factor support, hematologic toxicity in HIV patient was similar to immunocompetent patients.¹⁶⁰^,¹⁶¹ Additionally, in selected patients, local control and survival rates may now approach those of the non-HIV population when 5-FU/mitomycin–based chemotherapy and full-dose RT is delivered.

Seo et al.¹⁶² showed that at a median follow-up of 3 years, 14 HIV-infected patients had no differences in overall survival (91%) as compared with immunocompetent patients; disease-specific survival and colostomy-free survival were also similar. There were no differences in acute and late toxicity profiles between the two groups. In a multicentric cohort study comparing 40 HIV-positive patients with 81 HIV-negative patients treated for anal cancer, the 5-year overall survival was 61% and 65%, respectively; however, the local control was only 38% in the HIV-positive patients as compared with 87% in the HIV-negative patients.¹⁶³ In a series of 34 HIV-infected patients with anal carcinoma treated with various combinations of chemotherapy and irradiation, actuarial local control and overall survival at 3 years were 63% and 69%, respectively.²⁶ A series reported by Fraunholz et al.¹⁶⁰ from Germany described 21 HIV-positive patients who were receiving highly active antiretroviral therapy and who were treated with standard chemoradiation. Five patients required chemotherapy dose reduction and five patients required an interruption of RT. At a median follow-up of more than 4 years, the 5-year local control, cancer-specific, and overall survival rates were 59%, 75%, and 67%, respectively. There was one treatment-related death. The authors also noted that in the 3 to 7 weeks following completion of treatment, CD4 counts decreased, and one-third of patients experienced an increase in viral load. Thus, although standard chemoradiation should be considered in HIV-anal cancer, careful attention must be paid to immunologic parameters and risks of toxicity.

Newer strategies employing targeted agents, such as in an AIDS Malignancy Consortium phase II study employing cetuximab in addition to 5-FU, cisplatin, and radiation (1.8 Gy per fraction to a total of 45 Gy without a planned break), may improve the outcome of HIV-associated anal carcinoma.¹⁶⁴ This trial has accrued 45 patients and results are pending. However, it may be that, given an etiology similar to cervical carcinoma, a key to improving outcome in anal cancer would be to employ similar strategies as are used for cervical cancer with prevention and early diagnosis of mucosal abnormalities.¹⁶⁵ Rigorous surveillance for anal intraepithelial neoplasia with cytology and anoscopy in the population at risk should be considered,¹⁶⁶ and there is hope that widespread vaccination for HPV would be a major public health advance against anal cancer.

LUNG CANCER

The higher incidence of smoking in the HIV population has been a confounding variable in studies reporting an increased incidence of lung cancer in persons with HIV infection (HIV-LC),¹⁶⁷^,¹⁶⁸ however, after controlling for smoking, it appears that the rates of lung cancer are higher in HIV-infected than uninfected patients with large cohort studies and meta-analysis showing standardized incidence ratios of 2 to 4 for HIV-LC.¹⁵^,¹⁶⁹^,¹⁷⁰

The presentation of lung cancer in the HIV population is marked by young age at presentation (38–50 years) and advanced disease at diagnosis (75% of patients).¹⁷¹ The most common subtype of non–small cell lung cancer in this group has been reported to be adenocarcinoma.¹⁷²

In the pre-HAART the median survival of HIV-LC was only 4 to 5 months.¹⁷²^,¹⁷³^–¹⁷⁴ Case reports documented increased toxicity (particularly esophageal) in patients with HIV irradiated for lung cancer,¹⁷⁵ however, larger series do not necessarily report increased toxicity,¹⁷¹ although doses of >60 Gy usually were not employed.

It is unclear as to whether combined antiretroviral therapy improves the outcome in these patients.¹⁷⁶ The largest cohort study in the HAART era included 30 patients, 27 of whom presented with stage IIB to IV disease. Although patients diagnosed with very early-stage disease could undergo surgery, the median survival was only 5 months for those with advanced disease.¹⁷⁷ How to incorporate antiretroviral drug regimens into lung cancer treatment regimens remains undefined. In general, an attempt should be made to deliver standard treatment based on the stage of the disease with the caveat that the treatment approach may need to be modified based on the patient’s immunological status, viral load, and coexisting opportunistic infections.

HEAD AND NECK TUMORS

Given the increased smoking rate and HPV infection rate in persons with HIV, it would not be surprising to see an increased incidence of both squamous cell and HPV-related head and neck tumors in HIV-infected persons. Persons with HIV-AIDS have a threefold higher prevalence of oral HPV infection than the non-HIV population, and thus we may anticipate an increased incidence of HPV-associated oropharyngeal cancers in this population.¹⁷⁸ North American data provide some evidence that since the beginning of the HAART era, there has been an increased incidence of head and neck cancers in persons with HIV infection.¹⁶ A recent report of a large European cohort of HIV-infected persons documented a trend in increasing incidence from the pre-HAART era through the present, but this did not reach statistical incidence.¹⁸

A recent review of carcinomas arising in the head and neck region in HIV-positive patients indicates that patients with HIV-AIDS are at an increased risk of developing mucosal squamous cell carcinoma, nasopharyngeal carcinoma, lymphoepithelial carcinoma of the salivary gland, and Merkel cell carcinoma.¹⁷⁹ This review also suggested that HIV-positive patients with these cancers present at a younger age, with more aggressive disease and worse prognosis compared to HIV-negative patients.

Case reports describing the treatment of head and neck malignancies in patients with HIV do not suggest the same increased mucosal sensitivity as is seen in patients with HIV-KS.¹⁸⁰^,¹⁸¹ Larger series appear to corroborate this. Sanfilippo et al.¹⁸² reported a series of 12 HIV-positive patients with squamous cell carcinoma of the head and neck who underwent irradiation. Median radiation dose was 66.4 Gy and median duration of treatment was 51 days. Nearly two-thirds of patients developed grade 3 toxicity, but only one patient developed grade 4 confluent moist desquamation. Similar results were reported by Klein et al.²⁷ Twelve HIV-infected patients received a median dose of 68 Gy for squamous cell carcinomas of the head and neck; half also received chemotherapy. Local-regional control at 3 years was estimated to be 92% and survival was estimated at 78%. Nearly half the patients required treatment breaks of more than 10 days, however, no hospitalizations or treatment-related fatalities occurred. Toxicity appeared comparable to historical controls as did tumor control. However, it must be remembered that these patients were a relatively “healthy” group of HIV-infected persons, with all having Karnofsky performance status of 80 or higher and a median CD4 count of 460.

There is a paucity of data examining the tolerance and outcome in HIV-infected persons treated with combined chemoradiation; however, there is some hope that biologic agents such as cetuximab, a monoclonal antibody already approved for use in combination with radiation therapy for the treatment of locally or regionally advanced squamous cell carcinoma of the head and neck, may offer a viable option for HIV-infected patients with locally advanced disease.¹⁸³

LIVER CANCER

Increased levels of hepatitis B and C coinfections in the HIV population may explain the higher standardized incidence ratios of hepatocellular carcinoma reported in both North American and European datasets,¹³^,¹⁸ although the data are conflicting as to whether the incidence is higher for persons receiving combined antiretroviral therapy. The French have published on the feasibility of liver transplant for cirrhosis in persons with hepatitis and HIV,¹⁸⁴ but data on the treatment of hepatocellular carcinoma in the setting of HIV are lacking. A recent report detailing serious adverse effects in an HIV-positive patient who was also coinfected with HBV and treated with sorafenib reminds us that we have much to learn about potential interactions between the newer targeted agents for this disease and HAART.¹⁸⁵

PROSTATE CANCER

Recent data have shown an increase in the number of cases of prostate cancer in HIV-infected persons.¹¹ From 1991–1995 to 2001–2005, estimated counts increased from 87 to 759 cancers, seemingly driven by growth and aging of the AIDS population. There are no data to support approaching prostate cancer any differently in an otherwise healthy HIV-infected man than in a non-HIV infected one.¹⁸⁶^–¹⁸⁸ Pantanowitz et al.¹⁸⁹ reported on 17 HIV-positive patients from multiple institutions treated for prostate cancer with various standard treatments, including surgery, hormonal therapy, and radiotherapy. No serious treatment-related side effects were reported. Ng et al.¹⁹⁰ reported a series of 14 HIV-positive patients with prostate cancer treated with external beam radiation therapy with or without brachytherapy at St. Vincent’s Hospital in New York City. Following treatment, only one patient’s prostate-specific antigen (PSA) level remained above 1.1 ng/mL, the average CD4 count remained stable, and the viral load increased in only 2 of 14 patients. There were no unusual complications, and no infections related to treatment. Silberstein et al.¹⁹¹ reported on eight HIV-positive men who underwent robotic-assisted laparoscopic prostatectomy for treatment of prostate cancer. Preoperatively, all eight were on HAART and had undetectable viral loads. HIV-positive men required more perioperative transfusions and had a higher incidence of perioperative ileus as compared with HIV-negative men. The PSA level in all eight HIV-positive patients remained undetectable at the short median follow-up time of 2.6 months. Thus, although long-term treatment outcomes in HIV-positive patients remain uncertain, early results suggest acceptable response rates and toxicities in HIV-negative patients treated with standard treatments.

PEDIATRIC MALIGNANCIES

A major triumph in the war against AIDS has been the virtual elimination of the vertical transmission of HIV in the developed world. However, in Africa, 1,000 babies still acquire the virus every day,¹⁹² an appalling figure given that it has been more than 15 years since the first study that demonstrated the efficacy of zidovudine in reducing mother-to-child transmission of the virus.¹⁹³ Children who go on to develop AIDS appear to be at increased risk of developing tumors,⁶ particularly NHL (Burkitt’s lymphomas accounted for the most common histologic subtype), but also including leiomyosarcomas, primary CNS lymphomas, and KS.¹⁹⁴^–¹⁹⁵^,¹⁹⁶ The Pediatric Oncology Group reported 28 NHL, 4 B-cell acute lymphoblastic leukemias, 1 Hodgkin lymphoma, 8 leiomyosarcomas, 1 hepatoblastoma, and 1 schwannoma in a cohort of HIV-infected children.¹⁹⁷ Hopefully, the prevention of pediatric HIV ultimately will lead to a further decline in these cancers.

It appears that HAART has decreased the incidence of pediatric HIV malignancies.¹⁹⁸^,¹⁹⁹ In a study of more than 5,000 children who were under 15 years of at the time they were diagnosed as having AIDS, cancer was 40 times more frequent in children with HIV than in the general population in the pre-HAART era, as compared with 17 times more frequent in the HAART era.²⁰⁰

SUMMARY

HIV infection fosters immunosuppression, and immunosuppression fosters the appearance of malignancies. Progress requires therapies that counteract the immunosuppression associated with HIV infection. HAART appears to have decreased the incidence of KS and PCNSL; however, there appears to be an increase in many non-AIDS-defining malignancies in HIV-infected persons in the era of HAART. Data regarding the influence of HAART on prognosis of malignancies remain difficult to interpret, with some studies claiming improved survival and others claim no influence. Furthermore, even in areas where HAART is widely available, individual patients may not access or comply with treatment, and, if general adherence to or effectiveness of therapy is poor, the overall immune status of the population will remain low, and, consequently, there will be no decline in the incidence of HIV-associated malignancies. Although HAART has dramatically changed the face of AIDS, major challenges, not the least of which is the emergence of viral resistance, unfortunately ensure that improvements in the treatment of AIDS-associated malignancies will continue to be needed. Ultimately, the key to eradicating AIDS-associated malignancies will lie in the prevention of HIV transmission.

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