Phase I/II study of daily carboplatin, 5-fluorouracil and concurrent radiation therapy for locally advanced non-small-cell lung cancer

Abstract

A study was undertaken to determine the maximum tolerated dose, the dose-limiting toxicities and the response rate of carboplatin and 5-fluorouracil administered daily with concurrent thoracic radiation therapy in patients with locally advanced non-small-cell lung cancer. In a phase I/II clinical trial, patients with histologically documented, unresectable stage IIIA or IIIB non-small-cell lung cancer (NSCLC) were enrolled. Carboplatin (20 -40 mg m À2 2-h infusion, daily) and 5-fluorouracil (200 mg m À2 24-h continuous infusion, daily) were administered concurrently with radiotherapy on days 1 -33. Radiotherapy, with a total dose of 60 Gy, was delivered in 30 fractions on days 1 -40. In the phase I portion, the daily dose of carboplatin was escalated from 20 to 40 mg m À2 . Once the maximum tolerated dose (MTD) and recommended dose (RD) of carboplatin was determined, the study entered the phase II portion. In the phase I portion, the daily MTD and RD of carboplatin were 40 and 35 mg m À2 , respectively. The dose-limiting toxicity was neutropenia. In the following phase II study, 30 patients were entered and the objective response rate was 76.7% (95% CI, 62 -92%) and the local control rate was 85.7%. The median survival time was 19.8 months, with a survival rate of 70% at 1 year, 36.7% at 2 years. The major toxicities of treatment were neutropenia (Xgrade 3, 87.9%) and thrombocytopenia (Xgrade 3, 23.3%). This combined therapy for locally advanced non-small-cell lung cancer is promising and shows acceptable toxicity.

Systemic 5-fluorouracil treatment causes a syndrome of delayed myelin destruction in the central nervous system

“…Although most reports of 5-FU-associated neurotoxicity indicate a relatively acute onset, a delayed demyelinating cerebral complication reminiscent of multifocal leukoencephalopathy has also been increasingly reported in patients treated with chemotherapy regimens that include 5-FU [ 24 , 53 - 78 ]. Although 5-FU is used most extensively in the treatment of colorectal cancers, it is also an important component of adjuvant therapies for the treatment of a variety of other cancers, including breast [ 121 - 128 ], gastric [ 129 - 136 ], pancreatic [ 137 - 142 ] and lung [ 129 , 143 , 144 ], and is thus given to large numbers of patients. Neurological symptoms may occur in some patients several months after adjuvant therapy with 5-FU and include declines in mental status, ataxia and the appearance of prominent multifocal enhancing white matter lesions detectable by MRI.…”

Clinical and dosimetric factors of radiation-induced esophageal injury: Radiation-induced esophageal toxicity

“…The relationship between the lumenal organ and the clinical/dosimetric factors is very difficult to investigate, thus both DVH and DSH are not ideal predictors of biologic outcome [8] . Yoshizawa et al [15] , reported that carboplatin and 5-fluorouracil administered daily with concurrent thoracic radiation therapy in patients with NSCLC induce acceptable injury. Antonadou et al [16] , found that amifostine, a radioprotector, reduces the incidence of pneumonitis and esophagitis without compromising the antitumor efficacy of radiation treatment in patients with lung cancer.…”

Deletion of proapoptotic Puma selectively protects hematopoietic stem and progenitor cells against high-dose radiation

“…Radiation and anticancer drugs cause apoptosis in both hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs), leading to severe anemia, bleeding, and infections. 1,2 Bone marrow (BM) injury and gastrointestinal toxicity are the 2 most common limiting factors for cancer therapies of anticancer DNA-damaging agents, such as ionizing radiation and chemotherapeutical drugs. It was established that ␥-irradiation (7-14 Gy) primarily causes damage to HSCs and HPCs in the BM.…”