A PHASE-I TRIAL OF CONCOMITANT CHEMORADIOTHERAPY WITH CISPLATIN DOSE INTENSIFICATION AND GRANULOCYTE-COLONY-STIMULATING FACTOR SUPPORT FOR ADVANCED MALIGNANCIES OF THE CHEST

Concomitant chemoradiotherapy with cisplatin and combination chemother apy in the neoadjuvant setting have both shown promising results. Purp ose: To identify a locally and systemically active concomitant chemora diotherapy regimen incorporating high-dose cisplatin, interferon alfa- 2a (IFN), fluorouracil (5-FU), hydroxyurea (HU) and radiotherapy. Meth ods: Phase I cohort design establishing the maximal tolerated dose (MT D) of cisplatin with and without granulocyte colony stimulating factor (GCSF). For the first six dose levels, a 4-week cycle consisted of es calating doses of cisplatin during weeks 1 and 2, IFN (week 1), and 5- FU and HU (week 2) with single daily radiation fractions of 200 cGy du ring days 1-5 of weeks 1-3 and no treatment in week 4. When dose-limit ing neutropenia was encountered, GCSF was added during weeks 1, 3, and 4. Finally, to decrease esophagitis, the radiotherapy schedule was al tered to 150 cGy twice daily during weeks 1 and 2, followed by a 2-wee k break (level 7). Results: Forty-nine patients with refractory chest malignancies were treated. The MTD of this regimen without GCSF was ci splatin 50 mg/m(2) in weeks 1 and 2, IFN 5 million Units (MU)/m(2) per day on days 1-5 in week 1, 5-FU 800 mg/m(2) per day for 5 days by con tinuous infusion, and HU 500 mg every 12 h for 11 doses during week 2. The addition of GCSF during weeks 1, 3, and 4 allowed for escalation of cisplatin to 100 mg/m(2) during weeks 1 and 2, with a decreased dos e of IFN at 2.5 MU/m(2) per day to avoid renal toxicity. Dose-limiting toxicity (DLT) included severe neutropenia, thrombocytopenia, and eso phagitis in 5 of 13 patients. Increased thrombocytopenia in patients r eceiving GCSF was not observed. During hyperfractionated radiotherapy (level 7) chemotherapy doses were as above except for a reduction of 5 -FU to 600 mg/m(2) per day. While severe esophagitis was reduced, grad e 4 thrombocytopenia became more prevalent and was seen in 6 of 7 pati ents. In-field tumor responses were observed in 17 of 28 evaluated pat ients with non-small-cell lung cancer. The median times to progression and survival were 4 and 6 months, respectively. When only patients wi th all known disease confined to the radiotherapy field were considere d the corresponding times were 6 and 15 months, respectively. Most tre atment failures occurred outside of the irradiated field. Conclusions: (1) This intensive multimodality regimen can be given with aggressive supportive care incorporating GCSE The recommended phase II doses for a 4-week cycle are cisplatin 50 mg/m(2) week 1, and 100 mg/m(2) week 2, IFN 2.5 MU, HU 500 mg every 12 h x 11 and 5-FU 800 mg/m(2) per day with single fraction radiotherapy during weeks 1-3 and GCSF during wee ks 1, 3, and 4. (2) GCSF can be safely administered and provides effec tive support of neutrophils when administered simultaneously with IFN, cisplatin, and chest radiotherapy. (3) There is synergistic renal tox icity when high doses of IFN and cisplatin are given together. (4) Hyp erfractionated radiotherapy decreases the severity of esophagitis but increases thrombocytopenia. (5) Although highly toxic, response rates, time to progression and survival figures with this regimen are encour aging and support its investigation in the phase II setting.