Chemotherapy for Lung Cancer in HIV-positive Patients

The use of tritherapy in developed countries starting in 1996 led to a considerable reduction in AIDS mortality due to opportunistic infections and AIDS-defining cancers. However, increased life expectancies were accompanied by a diversification of the causes of death in HIV-infected individuals. In France between 2000 and 2005, non-AIDS-defining mortality rose from 53% to 64%: non-AIDS-defining cancers (apart from hepatocellular carcinoma) had the highest mortality rates, increasing from 11% to 17% in 2005, followed by liver disease (15% in 2005), cardiovascular disease (8% in 2005) and suicide (5%). Among all cancer-related deaths (AIDS- and non-AIDS-defining), the proportion due to non-AIDS-defining cancers (apart from hepatocellular carcinoma) increased from 38% to 50% and lung cancer (LC) accounted for 65% of deaths. Many epidemiological studies have demonstrated an elevated risk of LC in HIV-infected individuals HIV-positive subjects are younger at diagnosis of LC than the general population (45 versus 62 years). In the most recent studies, adenocarcinoma comprised 70% of cases. The prognosis of LC is worse in HIV-positive individuals. Some authors suggest that these poor outcomes may be related to interactions and additive toxicities of the cytotoxic and antiretroviral drugs. It is also likely that the disease is particularly aggressive. In the general population with a PS of 0 or 1 and under 70 years of age, bitherapy improves survival as compared to monotherapy. Survival is higher when the doublet comprises a platin. Since HIV-positive subjects with LC tend to be young, it is logical to offer them the best treatment which has demonstrated efficacy in the general population. In comparison to cisplatin, carboplatin causes less vomiting, nephrotoxicity and neurotoxicity. Survival is very slightly higher with cisplatin, but this comes at the cost of greater toxicity. Carboplatin is better tolerated in subjects with PS=2 or who are over 70 years of age

The HIV-positive population is specific in that:

• PS is more often altered but the subjects are young, which calls for a platin-based doublet.
• HAART is essential and its absorption should not be compromised by repeated vomiting which is more severe with cisplatin.
• Nephropathy occurs in 15-38% of cases; the causes are multifactorial and include the HIV virus itself and the antiretroviral drugs (Tenofovir®).
• Peripheral neuropathy is frequently related to HIV or to the antiretroviral treatments (especially didanosine or stavudine (2010 YENI report)).
• Premature ageing is seen in HIV-positive subjects; this exposes them to increased cardiovascular risk and a higher frequency of heart disease which can restrict the hyper-hydration required when using cisplatin.
• In 2010, virtually all patients are treated on an ambulatory basis whereas in the past they would have been hospitalized. Carboplatin is administered in the day hospital of all the centers, but not cisplatin.
• It is important to preserve an optimal quality of life during the first line of therapy in these patients whose life expectancy is such that very few will be eligible for a second round of therapy.

Scagliotti published a phase III trial comparing cisplatin plus pemetrexed with cisplatin plus gemcitabine in subjects < 70 years old with advanced-stage NSCLC. Overall survival was identical in both arms but the toxicity profile was in favor of the pemetrexed arm. The combination of first-line carboplatin plus pemetrexed has been evaluated in several phase II trials, particularly in subjects with a poor PS. In contrast to the taxanes or vinorelbine, for example, pemetrexed is not metabolized by CYP450, which facilitates its use in combination with protease inhibitors and NNRTI, which respectively inhibit or induce the CYP450 system.

Ancillary study BIO-IFCT-1001 will be made. Since the samples will be small, focus will be on the biomarkers associated with multiple or specific resistance to platinum salts or to pemetrexed, particularly those more specifically found in NSCLC of nonsquamous histology. Similarly, biomarkers for which IFCT pathologists have acquired an expertise will also be favored. This expertise mainly involves, on the one hand, detecting K-Ras mutations (15-25% of ADC) and RasSF1 methylation as well as TubIII expression by immunohistochemistry (IHC) and testing for mucosecretion by PAS diastase-resistant staining, and on the other hand, evaluating ERCC1 and/or MSH2 expression and thymidylate synthase (TS) expression by IHC.