Background Full Response (CR) at the primary tumor site as assessed

Background Full Response (CR) at the primary tumor site as assessed by clinical examination following induction chemotherapy with cisPlatin and 5-Fluorouracil (5-FU)[PF] is a favorable predictive factor for overall survival and disease-control in patients with locally advanced squamous cell carcinoma of the head and neck. SCH 900776 small molecule kinase inhibitor cisplatin 75 mg/m2 Day 1; 5-fluorouracil 750 mg/m2/day Days 1C3) every 21 days for 3 cycles followed by CRT (cisplatin 100 mg/m2 on days 1,22 and 43 of RT). CR at the primary tumor site after 2 cycles of ACPF was the primary endpoint. Results Thirty patients were enrolled, of which 22 (73%) had large (T3/T4) primary tumors. The CR rate at the primary tumor site after 2 cycles of ACPF was 53% and the overall response rate was 100%. Twenty-nine (96%) patients completed 3 cycles of ACPF, 26 (90%) completed definitive radiation therapy (RT) per protocol and 22 of the 27 evaluable patients (81%) received 2 of the 3 planned doses of cisplatin with RT. The estimated 2-year overall and progression-free survivals were 84% and 65%, respectively. Conclusion Induction ACPF resulted in a high CR rate (53%) at the primary tumor site even in large tumors and did not adversely affect delivery of definitive CRT. Further investigation of ACPF is usually warranted. strong class=”kwd-title” Keywords: head and neck cancer, phase 2, nab-paclitaxel, cetuximab, cisplatin, 5-fluorouracil INTRODUCTION Squamous cell carcinoma of the head and neck (HNSCC) afflicts more than 500,000 patients annually worldwide.1 Most individuals present with locally advanced disease and so are often treated with definitive radiation therapy (RT). Chemotherapy provided concurrently with RT (CRT) improved local-regional disease control and general survival (Operating-system) weighed against RT by itself but got minimal effect on the speed of faraway metastases.2 Randomized studies of induction chemotherapy confirmed a decrease in faraway failure prices, but just two trials demonstrated a noticable difference in OS.3,4 Recently, better Operating-system was observed by adding either docetaxel or cremaphor-based paclitaxel to induction cisplatin and 5-fluorouracil (5-FU)[PF] in sufferers subsequently treated with definitive RT5 or CRT.6,7 However, recurrent disease continues to be the root cause for treatment failure following induction chemotherapy and definitive CRT. Full response (CR) at the principal site pursuing induction PF correlated with improved Operating-system and disease control after definitive RT.8,9 Generally in most series, the speed of CR at the primary site after induction PF was 20C30%.4,9 Two strategies to improve CR rates at the primary site following induction chemotherapy include the use of novel taxanes and the addition of epidermal growth factor receptor (EGFR) inhibitors. Increased intratumoral paclitaxel accumulation and anti-tumor activity occurred with nanoparticle albumin-bound paclitaxel ( em nab /em -paclitaxel)(Celgene Company, Summit, NJ) in comparison to cremaphor-based paclitaxel in nude mice bearing many individual tumor xenografts.10 In breasts cancer, em nab /em -paclitaxel led to higher tumor response prices compared to cremophorCbased paclitaxel,11 which might be because of the high tumor expression of em S /em ecreted em P /em rotein em A /em cidic and em R /em ich in em C /em ysteine (SPARC). SPARC is important in albumin receptor-mediated endothelial transportation.12 SPARC appearance is common in tumor and stromal cells of HNSCC however, not in adjacent normal mouth mucosa13 and correlated with tumor response to em nab /em -paclitaxel Rabbit Polyclonal to CCT7 in sufferers with HNSCC.14 More specifically, the idea is that high tumor expression of SPARC shows tumor cells which have high prices of albumin-receptor-mediated endocytosis and can respond easier to albumin-bound chemotherapeutic agents because they accumulate more albumin in the tumor cells. Inhibition of EGFR by cetuximab decreases proliferation and induces apoptosis of HNSCC cell lines, and enhances the experience of cisplatin in xenograft versions.15 The addition of cetuximab to PF increased tumor response OS and rates in patients with metastatic HNSCC, and had a satisfactory safety profile.16 We hypothesized a book induction regimen of weekly em nab /em -paclitaxel and cetuximab given with every three week PF (ACPF) would create a high favorable tumor response price in sufferers with locally advanced HNSCC SCH 900776 small molecule kinase inhibitor subsequently treated with definitive CRT. The principal efficiency endpoint was CR price at the principal tumor site after two cycles of induction chemotherapy as evaluated by scientific examinations as this endpoint symbolizes a surrogate marker of improved disease control after definitive RT.8,9 We also searched for to determine whether this novel regimen will be associated with a satisfactory toxicity profile and whether it could adversely influence delivery of definitive CRT. Components AND METHODS Individual Selection Eligible sufferers were 18 years or old with untreated HNSCC stages III and IVa/b (T1 excluded) originating in the oropharynx, larynx and oral cavity.17 Other criteria included adequate performance status (ECOG 0C2) and vital organ function. Exclusion criteria included Grade 2 peripheral sensory neuropathy (PSN). The Washington University or college Human Research Protection Office approved the protocol and all study participants signed informed consent. This clinical trial was registered at ClinicalTrials.gov #”type”:”clinical-trial”,”attrs”:”text”:”NCT00736944″,”term_id”:”NCT00736944″NCT00736944. Treatment Plan Induction therapy consisted of every three week SCH 900776 small molecule kinase inhibitor cycles of intravenous (IV) em nab /em -paclitaxel 100 mg/m2 weekly on days 1, 8, and 15, cetuximab 400 mg/m2 day 1 and 250 mg/m2 weekly subsequently, cisplatin 75 mg/m2 on day 1 and 5-FU 750 mg/m2 continuous.