Biomarkers for improving the (cost-)effectiveness and safety of pemetrexed

In Holland over 10.000 patients are diagnosed with lungcancer anually. A major
part of these patients will be treated with chemotherapy during the course of
their disease. Malignant pleural mesothelioma is a rare thoracic malignancy,
which is diagnosed in approximately 500 patients in Holland annually. The
treatment of this disease also often consists of chemotherapy. One of the
newest most effective chemotherapeutic agents used for the treatment of these
malignancies is pemetrexed. It is a very expensive chemotherapeutic agent.
It is known that some patients do respond better then others. It is however
possible to identify patients who respond well. At present this can only be
established during treatment of patients, when responses are assessed. In case
of a non-reponsiveness of the tumor patients haven been treated unnecessarily
and other possible effective treatments are started later or not.

We have performed studies on the responsiveness of tumorcells to pemetrexed (
Hou et al, J Thor Oncol 2012). Also we already studied the possibility to
measure blood and intracellular levels of agents (Meesters et al 2011).

Een zeldzamere thoracale maligniteit is het pleurale maligne mesothelioom,
waarmee ongeveer 500 mensen per jaar gediagnosticeerd worden. Ook bij deze
maligniteit wordt een groot deel van de patiënten behandeld met chemotherapie.

The objective of this study proposal is to investigate whether use of
biomarkers (intracellular pemetrexed levels and/or genetic
loci) for response and toxicity to pemetrexed improves the effectiveness of
therapy and cost-effectiveness ratio. This objective
consists of the following research questions:
1. What is the association between predefined candidate pharmacogenetic
determinants and tumor response, time to
progression, toxicity, and survival in those on pemetrexed.
2. What is the association between cellular pharmacokinetics and tumor
response, time to progression, toxicity, and survival in
those on pemetrexed.
3. What is the improvement in overall effectiveness and cost-effectiveness if
non-responders and those vulnerable to toxicity
are not treated with pemetrexed.
4. What is the relation between predetermined immunohistochemic stainings on
available tumortissue and tumor response, time to
progression, toxicity, and survival in those on pemetrexed.

We will perform a prospective cohort study in the first 200 patients who
started treatment with pemetrexed, and gave written
informed consent to participate in the study. They will be followed from first
treatment with pemetrexed until the first occurrence
of one of the following events: death, discontinuation of pharmacotherapy with
pemetrexed, toxicity or the end of the study
period of two years of follow-up.

The decision to start a treatment with pemetrexed is taken by the treating
physician. If a patient is willing to participate in the trial they will be
asked to cede extra blood during a regular bloodsample. This gives no extra
risks. Also patients are asked to fill quality of life questionairs. This will
take time for a patient and can give extra discomfort as for patients with
cancer it can be extra burdensome to answer questions regarding quality of life