Effect of topical basic fibroblast growth factor on the healing of chronic diabetic neuropathic ulcer of the foot. A pilot,
randomized, double-blind, placebo-controlled study.
J L Richard ,
C ...Parer-Richard ,
J P Daures ,
S Clouet ,
D Vannereau ,
J Bringer ,
M Rodier ,
C Jacob and
M Comte-Bardonnet
Department of Dietetics and Diabetology, Centre Medical, Le Grau du Roi, France.
Abstract
OBJECTIVE--To assess the efficacy and safety of topical human recombinant basic fibroblast growth factor (bFGF) on the healing
of diabetic neurotrophic foot ulcers. RESEARCH DESIGN AND METHODS--Seventeen diabetic patients suffering from chronic neuropathic
ulcer of the plantar surface of the foot entered a pilot, randomized, double-blind study comparing local application of bFGF
with placebo. Main inclusion criteria were a typical neuropathic ulcer of Wagner grade I-III, more than 0.5 cm in the largest
diameter, with an abnormally high vibration perception threshold in the absence of significant peripheral vascular disease
or wound infection. bFGF or placebo was applied daily during the 6 weeks as inpatients then twice a week for 12 weeks. Evolution
of ulcer size was assessed through weekly clinical examination and computerized photographs. RESULTS--In the bFGF group, three
of nine ulcers healed compared with five of eight in the placebo group (NS). The weekly reduction in ulcer perimeter and area
was identical in both groups, as was the rate of linear advance from entry to the 6th week of treatment (bFGF: 0.053 +/- 0.048
mm vs. placebo: 0.116 +/- 1.129 mm): the same result was obtained at the 11th week. Moreover, percent healed area at the end
of the study did not differ significantly. No side effects were observed during bFGF application. CONCLUSIONS--Topical application
of bFGF has no advantage over placebo for healing chronic neuropathic diabetic ulcer of the foot. Because diabetes causes
significant wound-healing defects, we hypothesized that using a single growth factor might be insufficient to accelerate wound
closure of diabetic ulcers.
We investigated whether a high-dose chemotherapy regimen of cyclophosphamide 1,800 mg/m2, 4'-epidoxorubicin 60 mg/m2, etoposide 330 mg/m2, and cisplatin 120 mg/m2 given monthly for four cycles with ...recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) support (5 micrograms/kg daily for 10 days) could improve the survival of patients with extensive-stage small-cell lung cancer (SCLC) compared with a standard-dose regimen (cyclophosphamide 1,200 mg/m2, 4'-epidoxorubicin 40 mg/m2, etoposide 225 mg/m2, and cisplatin 100 mg/m2) given monthly for six cycles. Planned cumulative doses of the drugs were the same in both treatment arms except for cisplatin (which was 80% in the higher-dose plus rhGM-CSF group).
At the time of the preplanned interim analysis, 125 patients, 60 in the standard-dose group and 65 in the higher-dose plus rhGM-CSF group, had entered the study; 116 were eligible, 55 in the standard-dose group and 61 in the higher-dose group. All patients were included in the analyses. The cumulative doses of each drug actually delivered were significantly higher in the standard-dose group. No difference in response rates was observed between the two groups. There were significantly greater hematologic toxicities, documented infections, and transfusions of RBCs and platelets in the higher-dose plus rhGM-CSF group. Patients in this group proved to have a shorter survival duration and a shorter time to relapse than patients in the standard-dose group (median overall survival: standard-dose, 10.8 months; higher-dose, 8.9 months; log-rank test with adjustment for prognostic variables, P = .0005; respective probabilities of relapse at 1 year, 77 +/- 0.6 and 96 +/- 2.2; log-rank test, P = .013).
A 50% increase in dose-intensity for this four-drug regimen could not be achieved with GM-CSF due to excessive toxicity in patients with extensive-stage SCLC.
The purpose of this study was to search for the maximal tolerated dose of cisplatin in the cisplatin plus high-dose epirubicin combination for patients with non-small-cell lung cancer. The following ...range of cisplatin dosages were tested in a phase I study: 75, 90, 105, and 120 mg/m2 in combination with epirubicin 120 mg/m2 every 3 weeks. Eligibility consisted of previously untreated stage IIIb or IV non-small-cell lung cancers, Eastern Cooperative Oncology Group Performance Status less than or equal to 2, age less than or equal to 70 years, measurable disease, adequate blood counts, chemistry, cardiac function, and no brain metastasis. The maximal tolerated dose was defined as the dose level of cisplatin for which two of three patients or three of six patients developed one or more limiting toxicities during the first course of therapy. Afterward, the maximal tolerated dose of cisplatin was adopted in a subsequent phase II study. Three centers enrolled 42 patients: 18 in phase I and 24 in phase II. The maximal tolerated dose was almost reached at the last dose level (i.e., 120 mg/m2). Taking into account the total duration of the treatment, the real dose intensity for patients treated at the fourth dose level (120 mg/m2) did not differ from that of the third dose level (105 mg/m2). The latter dosage was therefore considered as the maximal tolerated one. In the subsequent phase II study, the median number of cycles received per patient was three (range: one to eight). Fifty percent required a dose reduction of either epirubicin, cisplatin, or both. The main toxicity was neutropenia, resulting in 10 episodes of febrile grade IV neutropenia requiring readmission. Other toxicities were mild to moderate. There was no toxic-related death. On intent-to-treat analysis, 10 patients (33%) achieved an objective response. Among them were three complete responders. Median survival was 8 months. We observed neither detraction nor improvement of quality of life as assessed using the European Organization for Research and Treatment of Cancer QLQ-C30-LC13. Given every 3 weeks in combination with epirubicin 120 mg/m2, the maximal tolerated cisplatin dose is 105 mg/m2. This combination yields activity in non-small-cell lung cancer.
