Background & Rationale: Both metronomic chemotherapy (MCT) and maximum tolerable dose chemotherapy (MTD)  provide modest survival improvement in palliative setting in head and neck cancers.. The mechanism of action of MTD chemotherapy and metronomic chemotherapy differ. They inhibit different aspects of cancer environment. The resistance mechanism of MTD is overcome by metronomic chemotherapy. The toxicity of metronomic chemotherapy alone is minimal. Hence it can be assumed that the combination of MTD chemotherapy and metronomic might lead to an improvement in outcomes with minimal increase in toxicity. To test this rationale the study is planned.

Aim: To study whether administration of metronomic chemotherapy with MTD chemotherapy  would lead to an improvement  outcome in palliative setting in head and neck cancer.

Objective:

Phase  2 : To determine whether the combination of metronomic methotrexate (9 mg/m2) with fixed dose of celecoxib (200 mg PO BD), erlotinb (150 mg PO OD) with MTD  combination of Paclitaxel (175 mg/m2)  and Carboplatin ( AUC-5) leads to an improvement in 6 month progression free survival over the MTD combination of Paclitaxel (175 mg/m2)  and Carboplatin (AUC-5)

Phase 3 : To compare the OS between the  arms.

Trial design: Multi-stage, parallel design, open label, explanatory, superiority design,  randomized controlled study.

Study setting: The study would be conducted over the next 5 years in Head and Neck Medical oncology unit  in Tata Memorial Centre. Patients sent for the study would be consented and post consenting would be screened for this study.

Interventions: Arms of the study

Arm A – Paclitaxel plus Carboplatin

Arm B  - Paclitaxel plus Carboplatin with  Celecoxib 200 mg PO twice daily plus Tab Methotrexate 9 mg/m2  weekly ( D1,D8,D15) plus erlotinib ( 150 mg OD) { Concurrent administration}

Arm C-  Paclitaxel plus Carboplatin followed by  Celecoxib 200 mg PO twice daily plus Tab Methotrexate 9 mg/m2  weekly ( D1,D8,D15) plus erlotinib ( 150 mg OD) {Maintenance administration}

Allocation: The patients will be randomly allocated to each arm by minimization. The allocation would be stratified according to the site (oral versus non oral) and previous treatment (previous chemotherapy versus none) and presence or absence of metastatic disease.

Method : In stage  II & III : Patients would be administered the interventions and would be followed by till death. The adverse events (CTCAE version 5), response (RECIST criteria version 1.1), quality of life (FACIT) , date of progression and date of death would be noted .

Significance: Head and neck cancers are one of the commonest cancers in the country. Approximately 85% are seen in locally advanced stage and nearly 70-80% of these require palliative chemotherapy. The current survival with palliative chemotherapy is modest. The proposal  aims to improve this survival by adding a relatively non toxic and affordable therapy. This intervention has the potential to impact nearly 1,08,537 patients in India itself who succumb to this malignancy