© 2000 by Oxford University Press
Journal of the National Cancer Institute, Vol. 92, No. 9, 755,
May 3, 2000
© 2000 Oxford University Press
CORRESPONDENCE |
Unexpected Right Phrenic Nerve Injury During 5-Fluorouracil Continuous Infusion Plus Cisplatin and Vinorelbine in Breast Cancer Patients
Affiliations of authors: E. Munzone, F. Nolé, L. Orlando, M. Mandalà, A. Goldhirsch (Division of Medical Oncology), R. Biffi (Division of General Surgery), G. Villa (Division of Radiology), M. Civelli (Cardiology Unit), European Institute of Oncology, Milan, Italy; C. Ciano, National Neurologic Institute—C. Besta, Milan.
Correspondence to: Elisabetta Munzone, M.D., Division of Medical Oncology, Via Ripamonti, 435, 20144 Milan, Italy (e-mail: elisabetta. munzone{at}ieo.it).
Regimens containing 5-fluorouracil as continuous infusion are an effective treatment for breast cancer, with an impressive low incidence of overall toxicity when compared with bolus regimens (1,2).
From March 1998 up to March 1999, a novel regimen that combined 5-fluorouracil in continuous infusion at a dose of 200 mg/m2 per day, cisplatin at a dose of 60 mg/m2 given intravenously on day 1, and vinorelbine at 20 mg/dose given intravenously on days 1 and 3 (ViFUP regimen) was administered every 3 weeks to 186 patients with metastatic (n = 100) or locally advanced (n = 86) breast cancer, as a palliative or neoadjuvant treatment.
Continuous monitoring of toxic effects led to the observation of an unexpected side effect. A right diaphragmatic supraelevation was diagnosed by means of chest films in 15 patients (8%).
All patients had an implanted venous port (DomePortTM; Bard Access Systems, Salt Lake City, UT), which was on the left-sided subclavia in 14 patients and on the right side in only one patient. Eleven patients were treated for metastases, and four patients were treated for locally advanced disease. After a median time from the start of treatment of 1.8 months (range, 0.5–4 months), 14 patients developed pain in their right shoulder, followed, after a median time of 0.7 months (range, 0–2.5 months) in 10 patients (67%), by a mild to moderate dyspnea. The right diaphragmatic supraelevation was diagnosed after a median of 3.6 months (range, 2.2–8.1 months) from the start of the ViFUP treatment. Symptoms stopped in all of the patients when ViFUP treatment was interrupted.
The following additional examinations were performed: electromyography of the bilateral phrenic nerves plus peripheral nerves (seven patients), magnetic resonance imaging of the mediastinum (eight patients), and echocardiogram (10 patients). The electromyography showed clear right phrenic nerve injury concordant with axonal damage in all of the seven patients. In five patients, a mild pericardial effusion was reported, and magnetic resonance imaging was negative for mediastinal involvement in all of the patients. Electromyography of the peripheral nerve showed a normal sensory-motor conduction in all of the patients, a finding that does not support the hypothesis of a peripheral neurotoxicity of the regimen. After a median follow-up of 6.7 months (range, 0.4–12.8 months), none of the patients recovered from this toxicity, and 11 (73%) are alive with a clinically asymptomatic right diaphragmatic supraelevation.
To our knowledge, this is the first report of such a phenomenon in patients with breast cancer during infusional chemotherapy.
The only evidence in the literature of a similar clinical condition was reported in five patients with metastatic colon cancer treated with infusional 5-fluorouracil through a Hickman line, and it was hypothesized that right diaphragmatic supraelevation could be a late complication of an in-dwelling central venous catheter (3). However, previous trials (2,4) with other infusional regimens containing 5-fluorouracil and cisplatin, but not vinorelbine, do not report such a phenomenon.
Although the pathogenesis of this event is still unknown, we might hypothesize that vinorelbine, as previously reported in vitro (5), could have damaged the endothelial barrier permeability near the catheter tip, favoring the occurrence of the right phrenic nerve injury due to a chemical vasa nervorum vasculitis. Nevertheless, a critical role of 5-fluorouracil cannot be ruled out.
As a consequence, we strongly recommend careful monitoring of any shoulder pain occurring in the patient during continuous infusion of 5-fluorouracil, platinum, or vinca alkaloids.
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