– Christian Hoffmann –
HIV-infected patients have an increased risk of cancer. This applies not only to the three AIDS-defining malignancies (ADMs), namely Kaposi’s sarcoma, non-Hodgkin lymphoma and cervix carcinoma, but also to different Non-AIDS-defining malignancies (non-ADMs). The risk for non-ADMs is approximately two to three times higher in HIV-infected patients than in the non-infected population (Frisch 2001, Franceschi 2010).
Incidences of some diseases such as Hodgkin’s Disease (see Malignant lymphomas) and anal carcinoma in HIV-infected patients are so high that there is, according to many experts, a demand to classify them as ADM. Relative risk for anal carcinoma is 30-40 percent higher compared with the normal population (Goedert 2000, Frisch 2001, Clifford 2005).
One-third of all malignancies in HIV-infected patients today are non-ADMs. They are, therefore, as frequent as malignant lymphomas and Kaposi’s sarcoma (Engels 2006). The tendency is slightly rising (Simard 2011). As a result, non-ADMs are a significant mortality factor within the HIV-infected population. In industrial countries, more deaths are attributed to non-ADMs than to ADMs, hepatitis C or cardiovascular diseases (Lewden 2007, DAD 2010). The following diagram shows the percentage of malignant diseases relative to total causes of death in HIV-infected patients in France in 2000 and 2005 (Bonnet 2009).
Figure 1: Proportion of malignancies among all causes of death in HIV-infected patients in France in 2000 (grey,n= 924) and in 2005 (black, n=1013). Numbers according to Bonnet 2009. *Hepatitis-associated tumours.
Figure 1 clearly shows that the percentage of the AIDS-defining tumors, NHL and KS, are slightly in the decline, whereas the proportion of non-ADM are slightly rising. Different reasons explain this increase. In the D:A:D study, the main risks of non-ADMs resulting in death were advanced age and acute smoking, and interestingly also CD4 T-cell counts. Risk of non-ADMs increased, the lower the CD4 T-cell counts were. Patients with CD4 T cells below < 50/µl had a 15-fold higher risk than patients with > 500 CD4 T cells/µl (Monforte 2008). This correlation between non-ADM and immune deficiency was confirmed in an analysis of the EuroSIDA (Reekie 2010) and a large French study (Guiget 2009). In a US databank analysis which included 300,000 AIDS patients (Frisch 2001), some malignomas cases were associated with immunodeficiency: Hodgkin’s lymphoma, lung cancer, penis carcinoma, soft tissue sarcomas, testical- and lip cancer.
Apart from immunodeficiency, other factors certainly play a role, such as life style (smoking, alcohol, UV exposure) or co-infections (HPV, HBV, HCV). Given the fact that HIV-infected patients are aging, an increase of incidences of malignancies is to be expected (Shiels 2011). ART seems to have little influence on the occurrence of non-ADMs since therapy interruption does not increase the risk for non-ADMs, in contrast to ADMs (Silverberg 2007).
Early diagnosis and prevention
It remains unclear whether HIV-infected patients require cancer screening and preventive medical checkups more frequently than HIV-negative patients. There are some indications for a benefit regarding anal carcinomas (see below). Regarding colon carcinoma the situation is not clear; however, there is evidence that neoplastic changes are found more frequently in colorectal cancer screening with HIV-infected patients (Bini 2009). This examination, however, is not so popular with HIV-infected patients or with the treating physicians. Compared with the normal population colorectal cancer screening is utilized to a lesser degree than with HIV-infected patients (Reinhold 2005). With respect to PSA screening, which is discussed controversially in general, there is no specific recommendation for HIV-infected patients. Gynaecological examinations are discussed in the chapter HIV and Gynaecology. In patients coinfected with HCV, half-yearly ultrasound sonographies can have a benefit, as a recent study with 70 patients showed: hepatocellular carcinomas were less progressed at diagnosis in regularly screened patients resulting in a slightly better survival (Nunez 2010).
Finally, physicians should inform patients about the advantages of not smoking and support smoking cessation. Smoking contributes to substantial morbidity and mortality in the HIV-infected population (Lifson 2010). Patients often request and even insist upon more medical checkups, but it is repeatedly forgotten that abstinence from smoking is still the most important preventive measure for malignant diseases. Avoidance of adipositas and a healthy lifestyle are more helpful than expensive medical examinations.
One problem in the therapy of non-ADMs is that too little is known about chemotherapeutic substances and their interactions with ART. Especially since the new targeted substances have mostly not been investigated in HIV-infected patients. There are no prospective studies and very little data on imatinib, erlotinib, sunitinib, bortezomib, sorafenib or temsirolimus (Review: Deeken 2009). Furthermore, only few case reports exist for many malignant diseases. In most cases patients are younger compared to normal population which may be due to better monitoring (Shiels 2010). Publications of the last years on different entities such as glioblastoma (Hall 2009) or colon carcinoma (Chapman 2009), bladder cancer (Gaughan 2009), prostate cancer (Pantanowitz 2008) or esophageal cancer (Stebbing 2010) show that HIV-infected patients prosper from the recent and amazing progress made in the oncological field. There should be no difference in treatment of HIV-infected and non-infected patients – however, oncologists often need to be properly informed in order to avoid adhering to an outdated and nihilistic conception of HIV treatment.
Infections with human papilloma virus (HPV) are among the most frequently sexually transmitted virus infections. HPV belongs to the family of papova viridae and infect the basal cells of epithelial of skin and mucous membranes. HIV patients have a 2-to 6-fold higher risk for anal HPV infection, independent of sex and sexual practices (Palefsky 1998, Piketty 2003). Risk of persistent HPV infection is 7-fold and inversely correlated with CD4 T cell counts (Piketty 2003). By now almost 100 different HPV types are known, among them 20 are associated with anal- or cervix carcinomas. HPV-16 and -18 have an especially high oncogenic potential and carry an increased risk for anal carcinoma.
HIV-infected patients commonly have co-infections with several HPV subtypes. In a German study (Kreuter 2005), anal HPV infection was found in 86% of 103 male patients, among them especially HPV-16 (53%) and HPV-18 (27%), but also HPV-58 (22%) and HPV-83 (22%).
Persistent HPV infection may lead to precancerous preliminary stages, the anal intraepithelial neoplasia (AIN). AIN is histologically graded depending on the degree of dysplasia in grade 1 (mild), grade 2 (moderate) or grade 3 (severe). In severe cases of AIN the whole epidermis is affected and the risk of anal carcinoma is high (Berry 2009). Although there is a connection to the degree of immune deficiency (Melbye 1995), the influence of ART is not clear. In some studies prevalence of AIN remained high, albeit ART (Fox 2003, Gonzalez-Ruiz 2994, Palefsky 2005), another study observed a protective effect (Wilkin 2004). In our own cohort of 121 patients with anal carcinoma, the vast majority of patients were on ART, with a well suppressed viremia and a median CD4 T-cell count of 400/μl (Hoffmann 2011).
Incidence of anal carcinoma seem to be on the rise: In a study from San Francisco (Diamond 2005), rates in 1996-2000 were three times higher than in 1991-1995. Compared to the general population, risk of invasive anal carcinoma in HIV-infected male patients were 300-fold after 1996. Similar data were provided from France (Piketty 2008). However, one should note that data from San Francisco or France does not necessarily apply to other regions. A British cohort found no significant increase of incidences, although relative risk for anal carcinoma was almost 200-fold compared to general population in the last few years (Bower 2005). Interestingly, a study from California did not show an increase of the overall 80-fold higher risk, but rather decreases in rates from 172 between 1996-1999 to 45 in 2004-2007 (Silverberg 2009). The routinely repeated thesis of a worldwide dramatic increase of incidences in the last years has not been clearly verified.
The most common symptom in cases of anal carcinoma is rectal bleeding. A patient reporting blood in stool absolutely must visit a proctologist! Patients usually attribute the bleeding to hemorrhoids; however, this self-made diagnosis should not be trusted. Other symptoms are burning and pain during stool or pruritus. If an anal carcinoma has already developed squamous cell carcinoma and more seldom transitory epithel carcinoma are histologically present. Anal canal and sphincter can already be infiltrated at an early stage. Regional lymph nodes are affected depending upon where the anal carcinoma is localized. Deep seated anal carcinomas infiltrate inguinal, central pelvic, high lying mesentery. Distant metastases are rare. In addition to proctoscopy, if possible, an endosonography, a CT of the abdomen and the pelvis should be done.
If an anal carcinoma manifests and the lesion is smaller than 2 cm, a continence preserving operation is preferable. In these cases, an adjuvant chemo- or radiotherapy is not necessary. Larger lesions are treated with combined radio-chemotherapy (mitomycin 10 mg/m2 on day 1 and 29 and 5-FU 1000 mg/m2 on days 1-5 and days 29-33, with subsequent radiation therapy of up to 50 Gray in fractions). Other more intensive therapies are possible (Blazy 2005). Complications can occur under such regimens. If something can go wrong, it will go wrong: We have experienced a patient who had first developed severe paravasation under mitomycin, followed by myocardial infarction under 5-FU and then a perforating, feculent radiation colitis.
Additionally patients should always be treated in oncological departments. Following radiotherapy, a proctoscopy should take place every six months. Although positive effects are not certain (Bowler 2005), HIV-infected patients with anal carcinoma should receive ART. Overall prognosis is not worse than with HIV negative patients (Chiao 2008).
Treatment of pre-stages, early diagnosis
Early treatment is important, since usually many years can pass between AIN and manifestation of the anal carcinoma. In case of AIN 1, a topic therapy with imiquimod (or podophylotoxine) is adequate, AIN 2+3 should be removed either surgically (electrocaustic therapy) or via laser ablation. Infrared coagulation is also possible (Stier 2008). Condyloma should also be dissected by a proctologist (electroagulation, cryotherapy). A topic therapy alone with the immune modulator imiquimod (Aldaraâ cream) is possible, however the effects are often less powerful than with non-infected patients. Still, imiquimod clearly reduces the risk of a relapse in follow-up treatment. The mechanism of imiquimod is not directly antiviral, instead it almost certainly destroys tumor cells via cytokine induction. The most significant side effect is a local erythema (this means effect!), more seldom are burning and pruritis. Severe skin irritations are rare. In Germany a prevention program for early diagnosis of the anal carcinoma is being prepared (Kreuter 2005). Some experts insist that perianal and intra-anal smears be taken yearly. However, it seems to be too early to recommend preventive medical checkup to all HIV-infected patients (Palefsky 2009). HPV vaccines have proven to be protective for intraepithelial neoplasia and persistent HPV infections in cases of cervix carcinoma (Harper 2006), however it is not clear whether this success is transferable to anal carcinomas. First reports are promising (Anderson 2009, Wilkin 2010).
Testicular tumors are the most frequently occurring cancer in men between 20 and 35. The relative risk factor for HIV-infected patients compared to normal population in the same age group is 2.5-fold (Frisch 2001, Powles 2003). This especially applies to seminoma, yet not so much to non-seminoma (Goedert 2007). So far, the largest analysis report of 34 and 35 patients respectively (Powles 2003, Fizazi 2001). The median CD4 T cell counts were between 300 and 350/µl at time of diagnosis, however with great variation. Overall prognosis was good and a matched-pair analysis did not prove worse with HIV-infected patients (Powles 2004). Other studies confirm the positive course (Fizazi 2001). HIV-infected patients should be treated with the standard regimens that are also recommended for negative patients. Depending on histology and stage of cancer, the regimen consists of orchiectomy, lymph node extirpation or radiation, and or a platinum-based chemotherapy. High dose therapies are also possible (Hentrich 2009). Treatment should be performed in cooperation with an urologist experienced in oncology and an HIV specialist.
In the general population, lung cancer is the most frequent cancer disease that leads to death in male patients. This tendency is increasing in women and already ranks third. The risk seems to be rising with HIV-infected patients. More recent studies from France show that lung carcinoma accounts for 5% of all causes of death and leads more frequently to death than Kaposi’s sarcoma (Bonnet 2009). In a British cohort, the relative risk in the early years of the HIV epidemic was similar to that of the normal population and has now risen by factor 8 over the last years (Bower 2003). In other cohorts, relative risk remained constant between 3-10 (Engels 2006, Cadranel 2006, Dal Maso 2009). Overall risk seems to rise as immunodeficiency increases (Guiguet 2009, Reekie 2011). In our own retrospective study of 72 patients developing lung cancer during the last decade, most cases occurred in the setting of limited immune deficiency and a long-lasting sufficient viral suppression (Hoffmann 2011).
This increase can partly be explained by simple reasons: First, HIV patients live longer and have more time to develop lung cancer and second, HIV-infected patients smoke more than non-infected patients. In some HIV outpatient clinics, up to 60-70% of the patients are smokers. Thus, one should discuss the issue of smoking: “It’s time to quit” – there are possibilities to cease smoking (Niaura 2000). Apart from age and nicotine abuse, other factors also seem determine an increased risk (Kirk 2007, Chaturvedi 2007). This is underlined by the fact that the most frequent subtype found in HIV patients, adenocarcinoma, is the subtype that is least associated with nicotine consumption (Tirelli 2000, Cadranel 2006). As often immune deficiency is not present, other factors, such as specific lung infections and a resulting scarring, are assumed, but also increased proinflammatory cytokines in the lungs or reduced glutathione levels are found frequently in HIV-infected individuals. These factors can worsen the damage caused by smoking. Generally, HIV-infected patients seem to be more sensitive towards carcinogenesis (Engels 2006, Kirk 2007, Chaturvedi 2007). In the US veteran cohort, an increased risk for HIV-infected patients remained significant, even after adjusting for smoking, age, ethnicity and COPD (Sigel 2010).
From a diagnostic-therapeutic view, patients always stand a better chance when the lung cancer has been diagnosed early. Symptoms are unspecific and when they present, it is often too late. In the case of HIV-infected patients, diagnosis is seldom early enough (Brock 2006). In our own cohort of 72 cases of lung cancer diagnosed 2000-2010, only 34 % of the patients were in stages I-IIIa which are considered to be curable (Hoffmann 2011). Patients in early tumor stages should undergo surgery with curative intention since chemotherapy only suspends further progression for a few months. In most cohorts, survival is 4-8 months in the median (Tirelli 2000, Spano 2004, Powles 2003, Cadranel 2006, Lavolé 2006+2009). In our own cohort, median estimated overall survival (OS) was 1.12 yrs with a total 2-Years-OS of 23.7 %. Clinical stage was highly predictive and long-term OS could only be achieved in very limited disease stages (Hoffmann 2011).
If a chemotherapy is indicated, HIV-infected patients with non-small cell lung carcinoma (NSCLC) in otherwise good condition should receive standard therapy beginning with cis- or carboplatin plus either taxane (paclitaxel), gemcitabine or navelbine. These combinations have similar response in HIV-infected patients. Therapy studies with HIV-infected patients, however, are almost non-existent. Carboplatin/gemcitabine seem to be tolerated well (Bridges 2008). A second choice is pemetrexed or erlotinib, an inhibitor of EGFR-tyrosine kinase. HIV doctors should talk with and convince the oncologist not to expect the worst just because HIV-infection is involved and that HIV is not a contraindication for any drug. At times when even stem cell transplantations (with AIDS-NHL) do not comprise a principle problem, treatment should be orientated to the recommendations for HIV negative patients. If general condition is poor, a well-tolerated combination of gemcitabine and navelbine can be given, which has been known to stop progression for a short time.
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