Phase I Trial of Concurrent Hyperfractionated Split Course Radiotherapy (HFx RT), Cisplatin (cDDP), and Paclitaxel in Patients with Recurrent, Previously Irradiated, or Treatment-Naïve Locally Advanced Upper Aerodigestive Malignancy

Abstract

Purpose: Phase I study to determine the maximally tolerated dose (MTD) of cisplatin (cDDP), paclitaxel (P), and concurrent split course hyperfractionated (BID) RT in advanced squamous cell carcinoma of the head and neck (SCCHN) and other upper aerodigestive tumors. Materials and Methods: Eligibility stipulated ECOG performance status 0-2 and either Tx-naïve, locally advanced, or locally recurrent, previously radiated, surgically unresectable upper aerodigestive cancer. Metastases were permitted if disease was predominantly locoregional. RT-naïve patients received 150 cGy bid × 5 d Q 2 wks × 4. Previously radiated patients received 150 cGy bid × 5, wk 1; then 120 cGy bid × 5 Q 2 wk × 3 (later increased to 150 cGy BID for the entire treatment). Treatment fields included recurrent tumor only with 2 cm margins. Whenever possible, conventional and 3-D conformal techniques were used. Elective nodal radiation was not administered. Starting doses of cDDP and P were 12 mg/m²/d × 5 and 15 mg/m²/d × 5, respectively, Q 2 wk × 4, each given on RT days only. At dose level 2, cDDP was increased to 15 mg/m²/d × 5. At dose level 3, P was increased to 20 mg/m²/d × 5. Granulocyte colony stimulating factor (G-CSF) days 6-12 (off treatment week) was added if cumulative neutropenia precipitated treatment delays. Results: Thirty-one patients (21 men, 10 women) were treated. Eight had received prior chemotherapy, 27 prior RT. At dose level three, regular treatment delays of ≥1 week due to slow neutrophil recovery occurred. Addition of G-CSF (dose level 3b) reduced treatment delays from 100 percent to 28 percent and decreased the incidence of Grade ≥2 neutropenia and mucositis. Six of 7 patients at this dose level completed all 4 cycles of treatment and all received full dose RT (60 Gy). No other dose-limiting toxicities occurred. Of 22 assessable patients with locally recurrent SCCHN, 12 (55 percent) responded. Median time to progression in this group was 6 months, with median and one-year survival of 9.5 mos and 41 percent, respectively. Conclusion: Concurrent daily cisplatin/paclitaxel and split course hyperfractionated RT (60 Gy) is feasible in previously radiated patients. G-CSF, administered between each cycle, reduces the incidence of treatment delays. Activity is promising and toxicity acceptable.