HIV and CancerHIV and Cancer

Sarah WilcoxSarah Wilcox

Jan 2006Jan 2006

Case ReportCase Report

• 36 yr old lady36 yr old lady• HIV +ve for 3 years (husband HIV +ve for 3 years (husband

diagnosed at the same time)diagnosed at the same time)• Not on treatment as CD4 count in Not on treatment as CD4 count in

normal range and low viral loadnormal range and low viral load• 18 month history of metastatic 18 month history of metastatic

adenocarcinoma ? Primaryadenocarcinoma ? Primary• Referred to palliative care clinic for Referred to palliative care clinic for

symptom controlsymptom control

Complex cancer diagnostic Complex cancer diagnostic pathpath

• Presented with 9/12 of low back pain Presented with 9/12 of low back pain and suprapubic mass on USSand suprapubic mass on USS

• MRI: bilateral complex multilocular MRI: bilateral complex multilocular cysts in the pelvis (?ovarian origin cysts in the pelvis (?ovarian origin and benign) and r hydronephrosis and benign) and r hydronephrosis

• Raised CA 125 and CA 19.9Raised CA 125 and CA 19.9

• Upper GI investigations arrangedUpper GI investigations arranged

ProgressProgress

• admitted acutely with perforated DUadmitted acutely with perforated DU

• CT abdomen: soft tissue mass around CT abdomen: soft tissue mass around the gastric pylorus, omental deposits, the gastric pylorus, omental deposits, low volume ascites and hypodense low volume ascites and hypodense region in neck of pancreasregion in neck of pancreas

• Bx of omental mass: metastatic Bx of omental mass: metastatic adenocarcinoma strongly +ve for CA adenocarcinoma strongly +ve for CA 125125

Oncology InputOncology Input

• Differential diagnosis:Differential diagnosis:– Pancreatic carcinomaPancreatic carcinoma– Gastric carcinomaGastric carcinoma– Gynaecological carcinomaGynaecological carcinoma

• Had 6 cycles of ECCAP with PR (25% dose Had 6 cycles of ECCAP with PR (25% dose reduced). 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

SymptomsSymptoms

• Back painBack pain

• Low mood/anxietyLow mood/anxiety

• Questions around diagnosis and Questions around diagnosis and uncertainty of prognosisuncertainty of prognosis

• Issues around HIV: Issues around HIV:

son not aware of diagnosisson not aware of diagnosis

““have I got cancer because of my HIV?”have I got cancer because of my HIV?”

Unanswered QuestionsUnanswered Questions

• Does HIV +ve status increase risk of Does HIV +ve status increase risk of developing a solid tumour?developing a solid tumour?

• Does treatment for cancer need to Does treatment for cancer need to be modified by co-existent HIV?be modified by co-existent HIV?

• Any guidelines for modifying Any guidelines for modifying treatments in HIV +ve patients?treatments in HIV +ve patients?

Overview of HIV and Cancer Overview of HIV and Cancer riskrisk• Several studies have addressed the possible Several studies have addressed the possible

relationship between HIV infection, the resulting relationship between HIV infection, the resulting immune depression and incidence of non-AIDS immune depression and incidence of non-AIDS defining tumoursdefining tumours

• Most are retrospective analyses which cross-link Most are retrospective analyses which cross-link cancer registry databases with AIDS databases cancer registry databases with AIDS databases and look for patterns of cancer incidence in a and look for patterns of cancer incidence in a period of time prior to AIDS diagnosis to a period period of time prior to AIDS diagnosis to a period of time afterwardsof time afterwards

• Most common malignant disorders have Most common malignant disorders have not not been been shown to have increased incidence in patients shown to have increased incidence in patients with HIV with HIV

• Breast cancer is actually associated with a Breast cancer is actually associated with a reduced incidence in HIV positive womenreduced incidence in HIV positive women

AIDS-defining malignanciesAIDS-defining malignancies

• caused by the severe immunodeficiency caused by the severe immunodeficiency associated with advanced HIV infection associated with advanced HIV infection (by definition) (by definition)

1.1. Kaposi’s sarcomaKaposi’s sarcoma2.2. Non Hodgkin’s lymphoma (NHL)Non Hodgkin’s lymphoma (NHL)3.3. Cervical cancerCervical cancer• Risk of NHL parallels degree of Risk of NHL parallels degree of

immunodeficiency and is associated with immunodeficiency and is associated with EBV infectionEBV infection

Other malignancies associated Other malignancies associated with HIV infectionwith HIV infection

• Hodgkin’s disease (HD)Hodgkin’s disease (HD)• Anogenital cancersAnogenital cancers• SCC of conjunctiva/skinSCC of conjunctiva/skin• Increased rates of the above malignancies Increased rates of the above malignancies

are also seen in transplant patients on are also seen in transplant patients on immunosuppressantsimmunosuppressants

• increased incidence of leukaemia in HIV increased incidence of leukaemia in HIV patients could be explained by leukaemoid patients could be explained by leukaemoid transformation of AIDS-related NHL transformation of AIDS-related NHL

Non-Aids Defining Cancers(NADC) in Non-Aids Defining Cancers(NADC) in HIVHIV

• RR of developing a non-AIDS defining cancer (NADC) in RR of developing a non-AIDS defining cancer (NADC) in AIDS patients is quoted between 1.5 and 3.0 (cf 178 AIDS patients is quoted between 1.5 and 3.0 (cf 178 for KS and 73 for NHL in one study)for KS and 73 for NHL in one study)

• Estimates of RR for individual cancer types in HIV +ve Estimates of RR for individual cancer types in HIV +ve patients are generally small and vary between paperspatients are generally small and vary between papers

• Other cancers which may have increased RR include Other cancers which may have increased RR include primary brain tumours and soft tissue sarcomas but primary brain tumours and soft tissue sarcomas but these may represent misclassified AIDS-related these may represent misclassified AIDS-related cancerscancers[Relative risks (RR) is defined as the ratio of observed [Relative risks (RR) is defined as the ratio of observed to expected cancers derived from population-based to expected cancers derived from population-based incidence]incidence]

Confounding factorsConfounding factors

• Increased medical surveillance may be a Increased medical surveillance may be a bias in these estimatesbias in these estimates

• sexual and other lifestyle variables e.g. sexual and other lifestyle variables e.g. smoking and lung cancer smoking and lung cancer

• ? Human herpes virus 8 infection linked to ? Human herpes virus 8 infection linked to Kaposi’s and other cutaneous cancers Kaposi’s and other cutaneous cancers including malignant melanomaincluding malignant melanoma

• Anal and cervical cancers linked to HPV 16 Anal and cervical cancers linked to HPV 16 and 18 infection and cigarette smokingand 18 infection and cigarette smoking

HAARTHAART

• Highly active anti-retroviral therapy (HAART) Highly active anti-retroviral therapy (HAART) has dramatically decreased mortality rates for has dramatically decreased mortality rates for HIV-infected patients since 1996HIV-infected patients since 1996

• Cohort studies have shown a concomitant shift Cohort studies have shown a concomitant shift in causes of death in this population with an in causes of death in this population with an increase in malignant disease due to increase in malignant disease due to modification of competitive risksmodification of competitive risks

• NADCs accounted for <1% of all causes of NADCs accounted for <1% of all causes of death prior to HAART. The current figure is death prior to HAART. The current figure is >10% >10%

Consequences of HAARTConsequences of HAART

• Improved survival of HIV infected patientsImproved survival of HIV infected patients

• Reduced incidence of KS and NHLReduced incidence of KS and NHL

• Reduced rates of opportunistic infectionReduced rates of opportunistic infection

• The fact that HAART has not reduced the The fact that HAART has not reduced the overall incidence of NADCs suggests that overall incidence of NADCs suggests that they are not triggered by immune they are not triggered by immune suppression alonesuppression alone

• Difficult to study NADC due to small nos Difficult to study NADC due to small nos involvedinvolved

Possible MechanismsPossible Mechanisms

• Chronicity of HIV infection / Chronicity of HIV infection / immunodeficiencyimmunodeficiency

• Ageing of the HIV-infected populationAgeing of the HIV-infected population• Higher level of exposure to risk factors Higher level of exposure to risk factors

eg tobacco use, alcohol use, viral co-eg tobacco use, alcohol use, viral co-infection, inadequate nutritioninfection, inadequate nutrition

• Possible oncogenic role of Hep B,C Possible oncogenic role of Hep B,C and HIV virusand HIV virus

Oncogenic Role of HIV?Oncogenic Role of HIV?

• HIV infection results in chronic B cell HIV infection results in chronic B cell stimulation due to HIV replicationstimulation due to HIV replication

• This effect is magnified by co-infection This effect is magnified by co-infection with oncogenic viruses e.g. EBV, HPVwith oncogenic viruses e.g. EBV, HPV

• HIV interacts with cell cycling and growth HIV interacts with cell cycling and growth mechanismsmechanisms

• HIV tat gene may modify the expression of HIV tat gene may modify the expression of certain proto-oncogenes in malignant cellscertain proto-oncogenes in malignant cells

• HIV may alter the expression of cytokines HIV may alter the expression of cytokines involved in promoting tumour growthinvolved in promoting tumour growth

Survey in CANCER Survey in CANCER Bonnet et al 2004Bonnet et al 2004

• Investigated all causes of death among Investigated all causes of death among HIV-infected patients in France in 2000HIV-infected patients in France in 2000

• Used ICD-10 to classify cause of deathUsed ICD-10 to classify cause of death

• Patients who died of solid, non-AIDS Patients who died of solid, non-AIDS defining tumours were compared with defining tumours were compared with those who died of non-malignancy related those who died of non-malignancy related causes to identify comorbidities associated causes to identify comorbidities associated with fatal malignancieswith fatal malignancies

ResultsResults

• 964 deaths were reported in 64,000 HIV-964 deaths were reported in 64,000 HIV-infected patientsinfected patients

• Malignant disease accounted for 28% of Malignant disease accounted for 28% of deathsdeaths

• 120 (12%) deaths were classified as NADC120 (12%) deaths were classified as NADC• Patients who died of solid tumours were more Patients who died of solid tumours were more

likely to be male, to smoke, to be older, to likely to be male, to smoke, to be older, to have longer duration of HIV infection and to have longer duration of HIV infection and to have a higher CD4 count compared to patients have a higher CD4 count compared to patients dying of non-malignancy related causesdying of non-malignancy related causes

HIV and lung cancer (LC)HIV and lung cancer (LC)

• An increased risk of LC in HIV patients cf general An increased risk of LC in HIV patients cf general population was identified in the early 1990spopulation was identified in the early 1990s

• Adenocarcinoma is the most frequent histological Adenocarcinoma is the most frequent histological typetype

• Patients tend to be male, younger than the general Patients tend to be male, younger than the general population, have advanced stage at diagnosis (III population, have advanced stage at diagnosis (III or IV) and a poor prognosis (10% 1 yr survival cf or IV) and a poor prognosis (10% 1 yr survival cf 40%)40%)

• CD4 count/viral load do not appear to affect CD4 count/viral load do not appear to affect prognosisprognosis

• LC is now the leading fatal NADC in the HIV-LC is now the leading fatal NADC in the HIV-infected populationinfected population

HAART eraHAART era

• HAART has further increased the proportion of HAART has further increased the proportion of deaths due to LC in AIDS patients, although the deaths due to LC in AIDS patients, although the degree of immunosuppression in these patients degree of immunosuppression in these patients has actually decreasedhas actually decreased

• One study of 8640 HIV +ve patients reported an One study of 8640 HIV +ve patients reported an incidence of lung cancer of 0.8% per 10,000 incidence of lung cancer of 0.8% per 10,000 patient years in the pre-HAART era, similar to that patient years in the pre-HAART era, similar to that in the general population. In the post-HAART era in the general population. In the post-HAART era this figure rose to 6.7%, significantly above that this figure rose to 6.7%, significantly above that for the general population. This equates to a RR for the general population. This equates to a RR of 9.of 9.

Possible ExplanationsPossible Explanations

• Increase in life-expectancy conferred by Increase in life-expectancy conferred by HAARTHAART

• Decline in deaths from AIDS may permit the Decline in deaths from AIDS may permit the expression of competing risks e.g. smokingexpression of competing risks e.g. smoking

• Smoking is a big confounding factor, but even Smoking is a big confounding factor, but even when this is taken into account by assuming when this is taken into account by assuming that all HIV patients smoke, the risk of LC that all HIV patients smoke, the risk of LC compared to that in the general population compared to that in the general population was still 2.5 times higherwas still 2.5 times higher

• Increased susceptibility to carcinogens in Increased susceptibility to carcinogens in cigarette smoke in the immunosuppressed cigarette smoke in the immunosuppressed has also been hypothesised but not provenhas also been hypothesised but not proven

Modification of treatment Modification of treatment regimes in HIV patientsregimes in HIV patients• There are no published trials assessing efficacy and There are no published trials assessing efficacy and

toxicity of chemoradiotherapy regimes in cancer toxicity of chemoradiotherapy regimes in cancer patients with HIVpatients with HIV

• In general, HIV patients should be assessed and In general, HIV patients should be assessed and treated in the same way as the general populationtreated in the same way as the general population

• Immunosuppression by HIV does not appear to Immunosuppression by HIV does not appear to influence surgical outcome or increase post-op influence surgical outcome or increase post-op complicationscomplications

• Chemotherapy is used less frequently in HIV-infected Chemotherapy is used less frequently in HIV-infected patients but this probably reflects their poorer patients but this probably reflects their poorer performance status at presentationperformance status at presentation

• CD4 count should be monitored monthly and 1 month CD4 count should be monitored monthly and 1 month after completion of chemoafter completion of chemo

Chemotherapy in HIV +ve Chemotherapy in HIV +ve patientspatients• Drug interactions and additive toxicity of cytotoxic and Drug interactions and additive toxicity of cytotoxic and

anti-retroviral drugs may explain poorer results in HIV anti-retroviral drugs may explain poorer results in HIV positive patients.positive patients.

• Nadir neutrophil counts are often significantly lower and Nadir neutrophil counts are often significantly lower and hence neutropenic sepsis more commonhence neutropenic sepsis more common

• Therapeutic combinations carrying a high risk of toxicity Therapeutic combinations carrying a high risk of toxicity and interactions should be avoidedand interactions should be avoided

• Bone marrow toxicity and peripheral neuropathy can Bone marrow toxicity and peripheral neuropathy can also be additivealso be additive

• No specific recommendations have been made on No specific recommendations have been made on primary prophylaxis for opportunistic infections in HIV-primary prophylaxis for opportunistic infections in HIV-infected patients receiving chemoinfected patients receiving chemo

ConclusionsConclusions

1.1. Solid tumours are likely to become a major Solid tumours are likely to become a major cause of morbidity and mortality among HIV-cause of morbidity and mortality among HIV-infected individuals in the coming years. infected individuals in the coming years.

2.2. Progression of HIV infection may have a Progression of HIV infection may have a synergistic or additive effect with cancer in synergistic or additive effect with cancer in producing an increased mortality rate.producing an increased mortality rate.

3.3. Solid tumours can affect patients with Solid tumours can affect patients with controlled HIV infectioncontrolled HIV infection

4.4. Shorter survival in HIV-infected patients with Shorter survival in HIV-infected patients with cancer is influenced by the fact that such cancer is influenced by the fact that such patients are often not clinically fit to undergo patients are often not clinically fit to undergo surgical resection, adjuvant chemo and/or DXTsurgical resection, adjuvant chemo and/or DXT

Prevention is better than Prevention is better than curecure1.1. Controlling exposure to risk factors, Controlling exposure to risk factors,

particularly tobacco and alcohol use is particularly tobacco and alcohol use is a key factor in preventing HIV-infected a key factor in preventing HIV-infected patients from developing solid patients from developing solid malignanciesmalignancies

2.2. Annual X ray screening for lung cancer Annual X ray screening for lung cancer and cytological screening for cervical and cytological screening for cervical and rectal malignancies has been and rectal malignancies has been advocatedadvocated

ReferencesReferences

• Risk of cancer in people with AIDS. Grulich et al 1999. AIDS Risk of cancer in people with AIDS. Grulich et al 1999. AIDS 1313: 839-43.: 839-43.

• Spectrum of AIDS-associated malignant disorders. Goedert Spectrum of AIDS-associated malignant disorders. Goedert et al 1998. Lancetet al 1998. Lancet 351 351: 1833-9.: 1833-9.

• Malignancy-related causes of death in HIV infected patients Malignancy-related causes of death in HIV infected patients in the era of HAART. Bonnet et al, Cancer 2004in the era of HAART. Bonnet et al, Cancer 2004 101 101: 317-24.: 317-24.

• Association of cancer with AIDS-related immunosuppression Association of cancer with AIDS-related immunosuppression in adults. JAMA 2001in adults. JAMA 2001 285 285 (13): 1737-45. (13): 1737-45.

• Incidence of Non-AIDS defining cancers before and during Incidence of Non-AIDS defining cancers before and during the HAART era in a cohort of HIV-infected patients. Herida et the HAART era in a cohort of HIV-infected patients. Herida et al 2003. Journal of Clinical Oncology al 2003. Journal of Clinical Oncology 2121(18): 3447-53.(18): 3447-53.

• Lung cancer, a new challenge in the HIV-infected population. Lung cancer, a new challenge in the HIV-infected population. Lavole et al 2006 Lung Cancer Lavole et al 2006 Lung Cancer 5151: 1-11.: 1-11.

• HIV-related lung cancer in the era of highly active anti-HIV-related lung cancer in the era of highly active anti-retroviral therapy. Bower et al AIDS 2003 retroviral therapy. Bower et al AIDS 2003 1717: 371-5: 371-5