Chemotherapy for Lung Cancer in HIV-positive Patients
Condition: Non-small Cell Lung Cancer; Hiv-positive
MeSH terms: HIV Seropositivity; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung
Study type: Interventional
Phase: Phase 2

Summary: 
      This is a phase II, multicenter, non-randomized, open-label study evaluating the combination
      of pemetrexed plus carboplatin in HIV-positive patients with lung cancer.
    

Detailed description: 
      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.
    

Intervention name(s): Chemotherapy
Intervention type(s): Drug
Intervention description(s): Pemetrexed + Carboplatin
On D1 of a 21-day cycle:
Pemetrexed 500 mg/m² IV in 10 minutes followed 30 minutes later by:
Carboplatin AUC 5 in 30 minutes in 100 ml sterile water or 5% glucose or physiological serum. The carboplatin dose will be calculated by the Calvert formula with a target AUC of 5 mg/mL.min as follows:
Carboplatin dose in mg = 5 x (GFR + 25) GFR is estimated according to the MDRD equation for creatinine clearance
• 4 cycles total
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: IFCT