Japanese Journal of Clinical Oncology 34:206-209 (2004)
© 2004 Foundation for Promotion of Cancer Research
High Body Mass Index Correlates with Increased Risk of Venous Irritation by Vinorelbine Infusion
Division of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa, Chiba, Japan
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Background: Vinorelbine is currently one of the most active chemotherapeutic agents. However, it is also a moderate vesicant that is well known to cause venous irritation and phlebitis. We conducted this study to identify clinical risk factors related to the incidence of venous irritation caused by peripheral vinorelbine infusion.
Methods: Medical records were used to investigate retrospectively a total of 201 cases of non-small cell lung cancer treated with a chemotherapeutic regimen containing vinorelbine. Venous irritation was evaluated in every course and graded according to the National Cancer Institute Common Toxicity Criteria version 2.0. Gender, age, body mass index (BMI), chemotherapeutic regimen, dose of vinorelbine and prior chemotherapy were used as clinical variables.
Results: A total of 928 vinorelbine infusions were administered to the 201 patients, among whom venous irritation occurred in 63 (31%). The incidence of venous irritation was 28% in the normal BMI (<25) group and 45% in the high BMI (25 or more) group and the difference between the two groups was statistically significant (P = 0.037). There were no significant correlations between the incidence of venous irritation and the clinical variables except BMI. In the multivariate analysis BMI was also a significant independent variable that correlated with increased risk of venous irritation (P = 0.017).
Conclusions: Care is required when using vinorelbine to treat patients with a high BMI, especially with regard to the development of venous irritation.
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INTRODUCTION |
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Vinorelbine is a semi-synthetic Vinca alkaloid that differs chemically from vinblastine in a modification in the catharantine moiety of the molecule (1). Vinorelbine has been shown to have low neurotoxicity and clearly higher activity than other Vinca alkaloids. Vinorelbine is currently one of the most active agents for the treatment of a variety of solid tumors and it is especially used for the treatment of metastatic non-small-cell lung cancer (NSCLC) (2), breast cancer (3) and Hodgkin’s disease (4). The highly selective affinity of vinorelbine for mitotic tubulin-associated protein may account for this pattern of toxicity. In clinical studies, toxic side-effects frequently reported for vinorelbine included myelosuppression, constipation and peripheral neuropathy, all at mild to moderate levels.
Vinorelbine is also a moderate vesicant that is known to cause venous irritation and the incidences of venous irritation of ~10–50% have been reported in patients who received vinorelbine as a 6–30 min peripheral infusion (3,5–10). Venous irritation is generally characterized by injection site reactions, local reactions or superficial phlebitis. Symptoms include erythema, pain at the injection site, vein discoloration and tenderness along the vein (7).
Several investigators have tried to reduce the incidence of venous irritation by various methods (11–13). However, the exact mechanism responsible for this phenomenon remains unknown and the risk factors related to incidence of venous irritation caused by peripheral infusion of vinorelbine have never been reported. Since cure of patients with metastatic solid tumors is rare, an important approach for them is to decrease toxicity and to increase the effectiveness of treatment. We conducted this study to identify clinical risk factors related to the incidence of venous irritation caused by peripheral infusion of vinorelbine.
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SUBJECTS AND METHODS |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Patients
We retrospectively reviewed the medical records of 201 NSCLC patients treated with a chemotherapeutic regimen containing vinorelbine between July 1999 and August 2002 at the National Cancer Center Hospital East. The chemotherapeutic regimens consisted of vinorelbine (VNR) 20–25 mg/m2 weekly, alone or in combination with cisplatin (CDDP), gemcitabine (GEM) or mitomycin-C (MMC). VNR was diluted in 50 ml of normal saline and all infusions were administered through a peripheral vein over a period between 6 and 10 min, followed by flushing the vein with 200 ml of fluid to minimize the risk of venous irritation. All patients who received at least one dose of VNR were considered assessable for this study. The characteristics of all patients are listed in Table 1. Body mass index (BMI) (body weight in kilograms divided by the square of body height in meters) was used as the criterion for obesity. In accordance with the standard of the Japan Society for the Study of Obesity, a BMI of below 25 was defined as normal and 25 or more as high (14).
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Evaluation of Venous Irritation
The medical records were used to evaluate venous irritation for every course and it was graded according to the National Cancer Institute Common Toxicity Criteria (NCI-CTC) version 2.0 for injection site reaction: grade 0, none; grade 1, pain, itching or erythema; grade 2, pain or swelling, with inflammation or phlebitis; and grade 3, ulceration or necrosis that is severe or prolonged or requires surgery. Venous irritation was categorized as positive or negative, with positive being defined as experience of grade 1 or more venous irritation at least once during treatment.
Statistical Analysis
The correlations between the incidence of venous irritation and the clinical variables were evaluated by the chi-squared test or Fisher’s exact test, as appropriate. We used gender (male, female), age (lower, <70 years; higher, 
70 years), BMI (normal, <25, high, 25), chemotherapeutic regimen (VNR alone, VNR in combination: VNR + CDDP, VNR + GEM, VNR + CDDP + MMC or VNR + CDDP + GEM), dose of VNR per body (<40, 40 mg/body) and prior chemotherapy (positive, negative) as clinical variables. Multivariate analysis was performed by the logistic regression procedure to determine the relationship between the incidence of venous irritation and the clinical variables. P values <0.05 were considered significant. A two-sided statistical test was used in all analyses. Statistical analysis software (StatView-J Version 5.0, Macintosh) was used for the analyses.
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RESULTS |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Incidence of Venous Irritation
A total of 928 infusions of VNR were administered to the 201 patients. The median number of infusions per patient was four (range, 1–14). Venous irritation occurred in 63 of the 201 patients (31%) infused with VNR and after 74 of the 928 infusions (8%), with 17% of the venous irritation events (11/63) occurring after the first VNR infusion. Five of 18 high BMI patients who developed venous irritation experienced two or more episodes of venous irritation (27%). In contrast, three of 45 normal BMI patients who developed venous irritation experienced two or more episodes of venous irritation (7%). A significant difference was observed between the two groups (P = 0.036). Grade 1 venous irritation was observed in 15% (n = 11), grade 2 in 81% (n = 60) and grade 3 in 4% (n = 3). The relationship between venous irritation and the clinical variables is summarized in Table 2. The incidence of venous irritation was 28% in the normal BMI (<25) group and 45% in the high BMI (
25) group and the difference between the two groups was statistically significant (P = 0.037). On the other hand, there were no significant correlations between the incidence of venous irritation and the clinical variables except BMI.
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Multivariate Analysis
The results of the multivariate analysis of six variables (gender, age, BMI, chemotherapeutic regimen, dose of VNR and prior chemotherapy) are shown in Table 3. BMI (normal versus high) turned out to be a significant independent variable correlated with increased risk of venous irritation (P = 0.017).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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We examined the clinical risk factors related to the incidence of venous irritation caused by peripheral infusion of vinorelbine. The results showed that high BMI was associated with a significantly increased risk of venous irritation over normal BMI (P = 0.017). The reasons for this are considered to be as follows. One is the relationship between obesity and venous thrombotic disease. Obesity, as indicated by an elevated BMI, is clearly associated with cardiovascular disease and diabetes worldwide and is also a detectable risk marker of venous thrombotic disease including superficial vein thrombosis and phlebitis (15). In our study, the incidences of history of cardiovascular diseases and venous thrombosis were 55% (22/40) in the high BMI group and 20% (32/161) in low BMI group, the difference being statistically highly significant (P < 0.0001). Patients with high BMI would therefore be expected to have impaired venous valve functions and be prone to superficial vein thrombosis and thus tend to have stagnant venous return as a result. Because of this, vinorelbine may adhere to the peripheral vein in the injection site and cause venous irritation and phlebitis. Another is that for patients with high BMI there may be technical difficulties with injection. The peripheral vein of patients with high BMI is often difficult to locate compared with that of patients with normal BMI and therefore there may be practically no reasonable venous access for peripheral infusion. Consequently, patients with high BMI may tend to develop minor leakage that might be a cause of venous irritation owing to failure of peripheral infusion. Moreover, as another possible risk factor related to the incidence of venous irritation, the infusion site of VNR such as the difference in the diameter of the vein may also be considered to be a risk factor. However, unfortunately, we could not clarify the relationship between infusion site of VNR and venous irritation, because this study was a retrospective analysis.
Vinorelbine is generally well tolerated and can be administered safely in outpatient settings. However, it is a moderate vesicant with the potential to cause venous irritation and phlebitis (16). Our results suggest that care is required, especially with regard to the development of venous irritation, if vinorelbine is administered through a peripheral vein to patients with a high BMI.
The use of drugs with anti-thrombotic and protective endothelial cell activity, such as heparin and defibrotide, has been investigated in an attempt to reduce the incidence of venous irritation by vinorelbine. Lozano et al. (13) administered heparin with vinorelbine. In their study, a population of 23 patients was randomized to arm A, in which vinorelbine plus 5000 U of heparin was diluted in 500 ml of normal saline and infused over 2 h, or arm B, in which vinorelbine was diluted in 50 ml of normal saline and infused over 10 min. However, arm A, with heparin, was found to be inferior to arm B in terms of pain control at the injection site (13). In another study, defibrotide was used to prevent venous irritation. A total of 360 infusions were delivered and the incidence of venous irritation was 5%. Maisano et al. reported that defibrotide could be used to prevent venous irritation by vinorelbine (12). Incidentally, vinorelbine has been shown to be a mast cell activator and to induce histamine release in rats (17,18). On the basis of these findings, cimetidine, which inhibits histamine actions in endothelial cells, was administered prior to vinorelbine infusion and an incidence of phlebitis of only 6% among a total of 127 vinorelbine infusions was reported (11). Recently, a retrospective study reported the incidence of phlebitis with administration of vinorelbine by intravenous bolus injection (19). The results indicated that the incidence of phlebitis by bolus injection was lower than that with drip infusion but other toxicities were equivalent. Although these methods of preventing venous irritation may show promise, there have been no randomized controlled trials to verify the benefit of these methods, hence a randomized controlled study is needed to draw definite conclusions about their efficacy.
In conclusion, our study is the first to statistically investigate clinical risk factors related to the incidence of venous irritation caused by peripheral infusion of vinorelbine. Our findings indicated that high BMI is associated with a significantly increased risk of venous irritation by vinorelbine. Care is required especially in regard to the development of venous irritation when vinorelbine is administered through a peripheral vein to patients with a high BMI. We suggest that BMI (high or normal) should be considered as a stratification factor in randomized controlled trials to compare the incidence of venous irritation caused by peripheral infusion of vinorelbine. Currently in our department, a randomized controlled study of 1 min bolus injection versus 6 min drip infusion is being conducted in order to investigate the best intravenous administration of vinorelbine.
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FOOTNOTES |
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+ For reprints and all correspondence: Kiyotaka Yoh, Division of Thoracic Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba 277-8577, Japan. E-mail: kyoh{at}east.ncc.go.jp
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REFERENCES |
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Received November 1, 2003; accepted January 22, 2004
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