A Prospective randomized open label study to evaluate the response rate and toxicity of Gefitinib in the treatment of carcinoma cervix patients on chemoradiotherapy

Carcinoma cervix is the second most common malignancy among women and is a major cause of morbidity and mortality worldwide, where it accounts for 15% of all new female cancers with an estimated 2.75 lakhs deaths. 80% of incidental cervical cancer cases and deaths occur in developing countries because of socioeconomic  causes  pattern of health care delivery and other social factors. It is usually diagnosed at advanced stages in >80% of women in developing countries.In the last few years many advancement is seen in medical management of locally advanced cervical cancer, which includes preventive vaccination, chemoradiation and  neoadjuvant chemotherapy.

Active reasearches are taking place in molecular characterisation of cervical cancer, by which we may get better  outcomes with novel therapeutic targets. Many biological factors like EGFR, VEGF, Microvessel density, hypoxic mechanism and expression of cox 2 have been proposed as prognostic determinants of carcinoma cervix. Cervical cancer is staged according to International Federation Of Gynaecology And obstetrics (FIGO) guidelines, where early stage patients do not  require adjuvant systemic treatment unless there are high risk factors for recurrence in surgical specimen. These cases are usually prescribed with adjuvant chemoradiation. Systemic  chemotherapy is the treatment of choice for most advanced cases that comprise stage IVB as well as patient with recurrent or persistent disease amenable to curative treatment.

EGFR is present in many normal tissues and expressed in variety of solid tumours including cervical cancer.3EGFR activates tyrosine kinase domain to regulate multiple function such as cell growth, differentiation, gene expression and development. High expression of EGFR is thought to be the main mechanism by which EGFR signalling is increased in cancer cells , activating EGFR mutations, increased coexpression of receptor ligands ( EGFR, TGF alpha, amphiregulin), gene amplification, decreased levels of phosphatase , heterodimerisation etc. In particular HPV protein has an important role in EGFR expression. The HPV E5 oncoprotein inhibits degradation of internalised EGFR, resulting in an increase in EGFR recycling and overexpression of EGFR. Expression of HPV E6 has been linked to increase in EGFR levels and changes in functional levels of HPV E6/E7 protein may alter the growth rate of cervical cancer cell lines by decreasing the stability of EGFR at post transcriptional level.

Patients will be randomised intotwo arms. Control arm will receive concurrent chemoradiation. The dose ofradiation is 50Gy/25 fraction, along with cisplatin of 40mg/m2 weekly for 6 cycles.This is followed byHDR Brachytherapy 3 fractions. The experiment arm will receive same treatmentas above plus tab gefitinib 250mg starting one week prior to chemoradiation andcontinued throughout external radiation. Patients will be assessed for toxicityand graded .