Accelerated, normofractionated radiotherapy is the treatment of choice in stage II-III
laryngeal and oropharyngeal squamous cell carcinoma (SCC). However, twenty to thirty percent
of patients with stage II-III laryngeal and HPV negative oropharyngeal SCC develop disease
progression, mainly due to lack of locoregional control. Radiosensitizers such as cisplatin
and cetuximab are added to radiotherapy in more advanced stage of head and neck (H&N) cancer.
These radiosensitizers improve loco-regional control and overall survival. Unfortunately, as
these radiosensitizers, notably cisplatin, also dose intensify the radiation dose in normal
tissues, they also significantly increase toxicity. Adding a more tumor-specific
radiosensitizing agent could improve loco-regional control and overall survival without
significantly increasing toxicity.
Radiotherapy kills tumor cells by inducing DNA damage. The efficacy of radiotherapy is
limited by the ability of tumor cells to repair this DNA damage. Poly(ADP-ribose)polymerase
(PARP) is an essential enzyme in base excision repair and single strand break DNA repair, DNA
lesions arising from radiation treatment. PARP inhibition and consequently the inhibition of
PARP-facilitated DNA repair enhances the anti-tumor activity of radiotherapy, as shown in
preclinical studies including head and neck xenograft studies. This radiosensitization is
thought to be proliferation dependent and is more pronounced in homologous recombination (HR)
deficient cells, providing an opportunity for tumor specific targeting. Genetic analyses
suggest that HR deficiency is commonly found in H&N SCC: ATM loss has been reported in 60% of
human H&N SCC biopsies and FANC-F defects were reported in 15-21% of human H&N SCC biopsies
and cell lines.
The efficacy of radiotherapy is also limited by tumor hypoxia, as tumor hypoxia results in
radioresistance. Some PARP inhibiting compounds increase tumor perfusion in xenograft models,
thereby reducing hypoxia and specifically sensitizing tumor cells to radiotherapy. Hypoxia is
commonly found in H&N SCC and a high pre-treatment hypoxic fraction in H&N SCC tumors is
associated with worse outcome. The high prevalence of both hypoxia and HR deficiencies in H&N
SCC support the concept of tumor-specific radiosensitization by PARP inhibition in head and
neck cancer patients.
Olaparib is a potent PARP inhibitor developed as an anti-cancer drug for HR defected tumors
and as a dose intensifier for chemo- and radiotherapy. In humans, olaparib has a low toxicity
profile as a single agent, with increasing bone marrow toxicity when combined with
chemotherapy. The combination of olaparib and radiotherapy for H&N SCC is expected to improve
locoregional control and thereby overall survival. However, this combination treatment has
never been tested in humans before. The purpose of this study is to determine the safety and
tolerability of radiotherapy for stage II-III laryngeal and stage II-III HPV-negative
oropharyngeal SCC with concurrent olaparib.