HIV and Cancer Sarah Wilcox Jan 2006

Case Report 36 yr old lady 36 yr old lady HIV +ve for 3 years (husband diagnosed at the same time) HIV +ve for 3 years (husband diagnosed at the same time) Not on treatment as CD4 count in normal range and low viral load Not on treatment as CD4 count in normal range and low viral load 18 month history of metastatic adenocarcinoma ? Primary 18 month history of metastatic adenocarcinoma ? Primary Referred to palliative care clinic for symptom control Referred to palliative care clinic for symptom control

Complex cancer diagnostic path Presented with 9/12 of low back pain and suprapubic mass on USS Presented with 9/12 of low back pain and suprapubic mass on USS MRI: bilateral complex multilocular cysts in the pelvis (?ovarian origin and benign) and r hydronephrosis MRI: bilateral complex multilocular cysts in the pelvis (?ovarian origin and benign) and r hydronephrosis Raised CA 125 and CA 19.9 Raised CA 125 and CA 19.9 Upper GI investigations arranged Upper GI investigations arranged

Progress admitted acutely with perforated DU admitted acutely with perforated DU CT abdomen: soft tissue mass around the gastric pylorus, omental deposits, low volume ascites and hypodense region in neck of pancreas CT abdomen: soft tissue mass around the gastric pylorus, omental deposits, low volume ascites and hypodense region in neck of pancreas Bx of omental mass: metastatic adenocarcinoma strongly +ve for CA 125 Bx of omental mass: metastatic adenocarcinoma strongly +ve for CA 125

Oncology Input Differential diagnosis: Differential diagnosis: –Pancreatic carcinoma –Gastric carcinoma –Gynaecological carcinoma Had 6 cycles of ECCAP with PR (25% dose reduced).Had 6 cycles of ECCAP with PR (25% dose reduced). Further 2 cycles then DP in pancreasFurther 2 cycles then DP in pancreas 20 Gy in 5# to pancreas20 Gy in 5# to pancreas

Symptoms Back pain Back pain Low mood/anxiety Low mood/anxiety Questions around diagnosis and uncertainty of prognosis Questions around diagnosis and uncertainty of prognosis Issues around HIV: Issues around HIV: son not aware of diagnosis “have I got cancer because of my HIV?”

Unanswered Questions Does HIV +ve status increase risk of developing a solid tumour? Does HIV +ve status increase risk of developing a solid tumour? Does treatment for cancer need to be modified by co-existent HIV? Does treatment for cancer need to be modified by co-existent HIV? Any guidelines for modifying treatments in HIV +ve patients? Any guidelines for modifying treatments in HIV +ve patients?

Overview of HIV and Cancer risk Several studies have addressed the possible relationship between HIV infection, the resulting immune depression and incidence of non-AIDS defining tumours Several studies have addressed the possible relationship between HIV infection, the resulting immune depression and incidence of non-AIDS defining tumours Most are retrospective analyses which cross-link cancer registry databases with AIDS databases and look for patterns of cancer incidence in a period of time prior to AIDS diagnosis to a period of time afterwards Most are retrospective analyses which cross-link cancer registry databases with AIDS databases and look for patterns of cancer incidence in a period of time prior to AIDS diagnosis to a period of time afterwards Most common malignant disorders have not been shown to have increased incidence in patients with HIV Most common malignant disorders have not been shown to have increased incidence in patients with HIV Breast cancer is actually associated with a reduced incidence in HIV positive women Breast cancer is actually associated with a reduced incidence in HIV positive women

AIDS-defining malignancies caused by the severe immunodeficiency associated with advanced HIV infection (by definition) caused by the severe immunodeficiency associated with advanced HIV infection (by definition) 1.Kaposi’s sarcoma 2.Non Hodgkin’s lymphoma (NHL) 3.Cervical cancer Risk of NHL parallels degree of immunodeficiency and is associated with EBV infection Risk of NHL parallels degree of immunodeficiency and is associated with EBV infection

Other malignancies associated with HIV infection Hodgkin’s disease (HD) Hodgkin’s disease (HD) Anogenital cancers Anogenital cancers SCC of conjunctiva/skin SCC of conjunctiva/skin Increased rates of the above malignancies are also seen in transplant patients on immunosuppressants Increased rates of the above malignancies are also seen in transplant patients on immunosuppressants increased incidence of leukaemia in HIV patients could be explained by leukaemoid transformation of AIDS-related NHL increased incidence of leukaemia in HIV patients could be explained by leukaemoid transformation of AIDS-related NHL

Non-Aids Defining Cancers(NADC) in HIV RR of developing a non-AIDS defining cancer (NADC) in AIDS patients is quoted between 1.5 and 3.0 (cf 178 for KS and 73 for NHL in one study) RR of developing a non-AIDS defining cancer (NADC) in AIDS patients is quoted between 1.5 and 3.0 (cf 178 for KS and 73 for NHL in one study) Estimates of RR for individual cancer types in HIV +ve patients are generally small and vary between papers Estimates of RR for individual cancer types in HIV +ve patients are generally small and vary between papers Other cancers which may have increased RR include primary brain tumours and soft tissue sarcomas but these may represent misclassified AIDS-related cancers Other cancers which may have increased RR include primary brain tumours and soft tissue sarcomas but these may represent misclassified AIDS-related cancers [Relative risks (RR) is defined as the ratio of observed to expected cancers derived from population-based incidence]

Confounding factors Increased medical surveillance may be a bias in these estimates Increased medical surveillance may be a bias in these estimates sexual and other lifestyle variables e.g. smoking and lung cancer sexual and other lifestyle variables e.g. smoking and lung cancer ? Human herpes virus 8 infection linked to Kaposi’s and other cutaneous cancers including malignant melanoma ? Human herpes virus 8 infection linked to Kaposi’s and other cutaneous cancers including malignant melanoma Anal and cervical cancers linked to HPV 16 and 18 infection and cigarette smoking Anal and cervical cancers linked to HPV 16 and 18 infection and cigarette smoking

HAART Highly active anti-retroviral therapy (HAART) has dramatically decreased mortality rates for HIV- infected patients since 1996 Highly active anti-retroviral therapy (HAART) has dramatically decreased mortality rates for HIV- infected patients since 1996 Cohort studies have shown a concomitant shift in causes of death in this population with an increase in malignant disease due to modification of competitive risks Cohort studies have shown a concomitant shift in causes of death in this population with an increase in malignant disease due to modification of competitive risks NADCs accounted for 10% NADCs accounted for 10%

Consequences of HAART Improved survival of HIV infected patients Improved survival of HIV infected patients Reduced incidence of KS and NHL Reduced incidence of KS and NHL Reduced rates of opportunistic infection Reduced rates of opportunistic infection The fact that HAART has not reduced the overall incidence of NADCs suggests that they are not triggered by immune suppression alone The fact that HAART has not reduced the overall incidence of NADCs suggests that they are not triggered by immune suppression alone Difficult to study NADC due to small nos involved Difficult to study NADC due to small nos involved

Possible Mechanisms Chronicity of HIV infection / immunodeficiency Chronicity of HIV infection / immunodeficiency Ageing of the HIV-infected population Ageing of the HIV-infected population Higher level of exposure to risk factors eg tobacco use, alcohol use, viral co- infection, inadequate nutrition Higher level of exposure to risk factors eg tobacco use, alcohol use, viral co- infection, inadequate nutrition Possible oncogenic role of Hep B,C and HIV virus Possible oncogenic role of Hep B,C and HIV virus

Oncogenic Role of HIV? HIV infection results in chronic B cell stimulation due to HIV replication HIV infection results in chronic B cell stimulation due to HIV replication This effect is magnified by co-infection with oncogenic viruses e.g. EBV, HPV This effect is magnified by co-infection with oncogenic viruses e.g. EBV, HPV HIV interacts with cell cycling and growth mechanisms HIV interacts with cell cycling and growth mechanisms HIV tat gene may modify the expression of certain proto-oncogenes in malignant cells HIV tat gene may modify the expression of certain proto-oncogenes in malignant cells HIV may alter the expression of cytokines involved in promoting tumour growth HIV may alter the expression of cytokines involved in promoting tumour growth

Survey in CANCER Bonnet et al 2004 Investigated all causes of death among HIV- infected patients in France in 2000 Investigated all causes of death among HIV- infected patients in France in 2000 Used ICD-10 to classify cause of death Used ICD-10 to classify cause of death Patients who died of solid, non-AIDS defining tumours were compared with those who died of non-malignancy related causes to identify comorbidities associated with fatal malignancies Patients who died of solid, non-AIDS defining tumours were compared with those who died of non-malignancy related causes to identify comorbidities associated with fatal malignancies

Results 964 deaths were reported in 64,000 HIV- infected patients 964 deaths were reported in 64,000 HIV- infected patients Malignant disease accounted for 28% of deaths Malignant disease accounted for 28% of deaths 120 (12%) deaths were classified as NADC 120 (12%) deaths were classified as NADC Patients who died of solid tumours were more likely to be male, to smoke, to be older, to have longer duration of HIV infection and to have a higher CD4 count compared to patients dying of non-malignancy related causes Patients who died of solid tumours were more likely to be male, to smoke, to be older, to have longer duration of HIV infection and to have a higher CD4 count compared to patients dying of non-malignancy related causes

HIV and lung cancer (LC) An increased risk of LC in HIV patients cf general population was identified in the early 1990s An increased risk of LC in HIV patients cf general population was identified in the early 1990s Adenocarcinoma is the most frequent histological type Adenocarcinoma is the most frequent histological type Patients tend to be male, younger than the general population, have advanced stage at diagnosis (III or IV) and a poor prognosis (10% 1 yr survival cf 40%) Patients tend to be male, younger than the general population, have advanced stage at diagnosis (III or IV) and a poor prognosis (10% 1 yr survival cf 40%) CD4 count/viral load do not appear to affect prognosis CD4 count/viral load do not appear to affect prognosis LC is now the leading fatal NADC in the HIV-infected population LC is now the leading fatal NADC in the HIV-infected population

HAART era HAART has further increased the proportion of deaths due to LC in AIDS patients, although the degree of immunosuppression in these patients has actually decreased HAART has further increased the proportion of deaths due to LC in AIDS patients, although the degree of immunosuppression in these patients has actually decreased One study of 8640 HIV +ve patients reported an incidence of lung cancer of 0.8% per 10,000 patient years in the pre-HAART era, similar to that in the general population. In the post-HAART era this figure rose to 6.7%, significantly above that for the general population. This equates to a RR of 9. One study of 8640 HIV +ve patients reported an incidence of lung cancer of 0.8% per 10,000 patient years in the pre-HAART era, similar to that in the general population. In the post-HAART era this figure rose to 6.7%, significantly above that for the general population. This equates to a RR of 9.

Possible Explanations Increase in life-expectancy conferred by HAART Increase in life-expectancy conferred by HAART Decline in deaths from AIDS may permit the expression of competing risks e.g. smoking Decline in deaths from AIDS may permit the expression of competing risks e.g. smoking Smoking is a big confounding factor, but even when this is taken into account by assuming that all HIV patients smoke, the risk of LC compared to that in the general population was still 2.5 times higher Smoking is a big confounding factor, but even when this is taken into account by assuming that all HIV patients smoke, the risk of LC compared to that in the general population was still 2.5 times higher Increased susceptibility to carcinogens in cigarette smoke in the immunosuppressed has also been hypothesised but not proven Increased susceptibility to carcinogens in cigarette smoke in the immunosuppressed has also been hypothesised but not proven

Modification of treatment regimes in HIV patients There are no published trials assessing efficacy and toxicity of chemoradiotherapy regimes in cancer patients with HIV There are no published trials assessing efficacy and toxicity of chemoradiotherapy regimes in cancer patients with HIV In general, HIV patients should be assessed and treated in the same way as the general population In general, HIV patients should be assessed and treated in the same way as the general population Immunosuppression by HIV does not appear to influence surgical outcome or increase post-op complications Immunosuppression by HIV does not appear to influence surgical outcome or increase post-op complications Chemotherapy is used less frequently in HIV-infected patients but this probably reflects their poorer performance status at presentation Chemotherapy is used less frequently in HIV-infected patients but this probably reflects their poorer performance status at presentation CD4 count should be monitored monthly and 1 month after completion of chemo CD4 count should be monitored monthly and 1 month after completion of chemo

Chemotherapy in HIV +ve patients Drug interactions and additive toxicity of cytotoxic and anti-retroviral drugs may explain poorer results in HIV positive patients. Drug interactions and additive toxicity of cytotoxic and anti-retroviral drugs may explain poorer results in HIV positive patients. Nadir neutrophil counts are often significantly lower and hence neutropenic sepsis more common Nadir neutrophil counts are often significantly lower and hence neutropenic sepsis more common Therapeutic combinations carrying a high risk of toxicity and interactions should be avoided Therapeutic combinations carrying a high risk of toxicity and interactions should be avoided Bone marrow toxicity and peripheral neuropathy can also be additive Bone marrow toxicity and peripheral neuropathy can also be additive No specific recommendations have been made on primary prophylaxis for opportunistic infections in HIV- infected patients receiving chemo No specific recommendations have been made on primary prophylaxis for opportunistic infections in HIV- infected patients receiving chemo

Conclusions 1. Solid tumours are likely to become a major cause of morbidity and mortality among HIV- infected individuals in the coming years. 2. Progression of HIV infection may have a synergistic or additive effect with cancer in producing an increased mortality rate. 3. Solid tumours can affect patients with controlled HIV infection 4. Shorter survival in HIV-infected patients with cancer is influenced by the fact that such patients are often not clinically fit to undergo surgical resection, adjuvant chemo and/or DXT

Prevention is better than cure 1. Controlling exposure to risk factors, particularly tobacco and alcohol use is a key factor in preventing HIV-infected patients from developing solid malignancies 2. Annual X ray screening for lung cancer and cytological screening for cervical and rectal malignancies has been advocated

References Risk of cancer in people with AIDS. Grulich et al AIDS 13: Risk of cancer in people with AIDS. Grulich et al AIDS 13: Spectrum of AIDS-associated malignant disorders. Goedert et al Lancet 351: Spectrum of AIDS-associated malignant disorders. Goedert et al Lancet 351: Malignancy-related causes of death in HIV infected patients in the era of HAART. Bonnet et al, Cancer : Malignancy-related causes of death in HIV infected patients in the era of HAART. Bonnet et al, Cancer : Association of cancer with AIDS-related immunosuppression in adults. JAMA (13): Association of cancer with AIDS-related immunosuppression in adults. JAMA (13): Incidence of Non-AIDS defining cancers before and during the HAART era in a cohort of HIV-infected patients. Herida et al Journal of Clinical Oncology 21(18): Incidence of Non-AIDS defining cancers before and during the HAART era in a cohort of HIV-infected patients. Herida et al Journal of Clinical Oncology 21(18): Lung cancer, a new challenge in the HIV-infected population. Lavole et al 2006 Lung Cancer 51: Lung cancer, a new challenge in the HIV-infected population. Lavole et al 2006 Lung Cancer 51: HIV-related lung cancer in the era of highly active anti-retroviral therapy. Bower et al AIDS : HIV-related lung cancer in the era of highly active anti-retroviral therapy. Bower et al AIDS : 371-5