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RATIONAL USE OF 5-FLUOROURACIL IN CHEMOTHERAPY AND BREAST Cancer.

Byline: K. T. Mehmood, K. Kiran - Email: Kiran_syed_777@hotmail.com and R. Rana

ABSTRACT: 5-Fluorouracil (5-FU) is one of the most commonly used chemotherapeutic agents for the systemic treatment of cancers of the gastrointestinal tract, breast, head, and neck. The aim of our study was to determine the rational use of 5-FU on breast cancer patients and in chemotherapy, and to observe rational measures like individualized dose adjustment, use of approved chemotherapy protocols, drug utilization review and better system for chemotherapy waste disposal. The results provide some evidence of the lack of awareness on the part of patients and the staff members of the health care team. Public awareness should be promoted.

Key words: Chemotherapy, 5-flourouracil, breast cancer, rational use.

INTRODUCTION

5-Fluorouracil (5-FU) is one of the most commonly used chemotherapeutic agents since 1970s for the systemic and palliative treatment of patients with cancers arising from the gastrointestinal tract, breast, head and neck. (Watne and Covey, 1972), (Van-Kuilenburg et al., 2003).

5-Fluorouracil acts by three main mechanisms. Principally, the intermediate metabolite fluorodeoxj uridine monophosphate inhibits a key enzyme in pyrimidine biosynthesis, namely thymidylate synthase (TS). Additionally, 5FU is metabolized to ribo- and deoxy-ribonucleotides, which act as false bases for incorporation into RNA and DNA. (Thomas et al, 1998). Bioavailability is less than75%, erratic and undependable.

Half-life elimination is Biphasic: Initial: 6-20 minutes; two metabolites, FdUMP and FUTP, have prolonged half-lives depending on the type of tissue. Excretion is by Lungs (large amounts as CO2) and urine (5% as unchanged drug) in 6 hours. I.V. bolus dose of 5-FU is 500-600 mg/m2 every 3-4 weeks or 425 mg/m2 on days 1-5 every 4 weeks and Continuous I.V. infusion dose of 5-FU is 1000 mg/m2/day for 4-5 days every 3-4 weeks.

Dihydropyrimidine dehydrogenase (DPD) is the initial and rate-limiting enzyme in the catabolism of 5-FU; a DPD deficiency is increasingly being recognized as an important pharmacogenetic disorder in the etiology of severe 5-FU-associated toxicity. (Van-Kuilenburg et al., 2003).

Adverse reactions and side effects of 5-FU are more likely to occur with systemic use. Recent developments include orally bioavailable formulations, such as ftorafur, capecitabine and the combination of 5FU with the dihydropyrimidine phosphate dehydrogenase inhibitor ethynyluracil.

Recognition of diurnal variation in the activity of such key enzymes as DPD has led to the administration of 5FU at regulated, variable infusion rates (chronomodulation). These promising pharmacological approaches may further improve clinical outcomes in common cancers.

Adjuvant chemotherapy including combination regimens of 5-FU is beneficial after surgery for premenopausal women with stage I (node-negative) breast cancer and for postmenopausal women with stage I (node-negative) breast cancer adjuvant tamoxifen is beneficial either alone for 5 years or in combination with chemotherapy. (Bonadonna et al., 1995), (Benz, 1983), (Smalley et al., 1983).

Women with node positive breast cancer are more prone to local and systemic reccurance so, postoperative administration of systemic chemotherapy with six cycles of fluorouracil, doxorubicin and cyclophosphamide (FAC) combination regimen or fluorouracil, cyclophosphamide and methotrexate (CMF) combination regimen can significantly reduce reccurance and also prolongs survival (Zambetti et al., 1996) (Goldhirsch et al., 1998) Symptoms reported on the SDS generally improved in responding patients. Continuous infusion 5-FU as a first-line therapy for metastatic breast cancer has moderate activity and low toxicity. Its use should be considered in the first-line setting when toxicity needs to be minimized (Chu et al., 1996).

According to the rules of rational use of drugs (RUD), patients should receive medications appropriate to their specific clinical needs, in doses that meet their own individual requirements for a sufficient length of time, with the lowest cost to them and their community. The

above requirements will be fulfilled if the 6-step process of rational prescribing is appropriately followed by (i) defining patient's problem(s) (ii) specifying therapeutic objectives; (iii) choosing the suitable drug(s), correct dosage and optimum duration of use, among the effective and safe treatment alternatives; (iv) starting the treatment by writing a 'good' prescription; (v) giving adequate information to the patient, and (vi) monitoring the therapeutic outcome (Akici et al., 2004).

The aims of this retrospective study included exploring the rational measures necessary to reduce the 5-Fluorouracil associated toxicity and related adverse reactions in cancer patients in order to ensure better quality of life for cancer patients and the measures which could ensure the cost effective chemotherapy.

MATERIALS AND METHODS

The study group consisted of 55 patients (12 male and 43 female; age 11-80 years) with the inclusion criteria that chemotherapy treatment regimens included 5-FU. The patients were categorized into three groups. The first group included 28 cancer patients (7 male and 21 female), selected from the Cancer Chemotherapy ward of Mayo Hospital Lahore. The second group included 22 cancer patients (3 male and 19 female), selected from the General Chemotherapy ward and Female Chemotherapy ward of Inmol Hospital Lahore.

The third study group included 5 cancer patients (2 male and 3 female), selected from the Chemotherapy Administration Room of Ganga Ram Hospital Lahore. Data collection modes included questionnaire and case studies. A detailed randomized Proforma was developed using standard methods. In all patients we recorded data on the identity of the patient, socio-demographic characteristics such as age, sex, family history of cancer patients, type of cancer and its possible causes. It also included medication pro ocols and investigational records of the patients, the clinical outcomes of the therapy, monitoring parameters of the therapy (also including Lab. test reports, drug interactions or any adverse reactions reported), chemotherapy administration procedures and chemotherapy cost related concerns of the patient. Results were simply calculated as percentages on the basis of answers of the Proforma

RESULTS AND DISCUSSION

Cancer patients of any age and sex were included in this study with treatment plan including 5-Fluorouracil chemotherapy regimens.

In most of the cases of breast cancer the prescribed chemotherapy regimen was six cycles of FAC (Fluorouracil + Adriamycin + Cyclophosphamide) administered every three weeks. Pre-medications were administered before chemotherapy to reduce the side effects in each and every case but not at least half hour before the chemotherapy. In all cases 5-FU dose was calculated according to individual body surface area (B.S.A). In all the cases no drug interaction was observed because approved protocols and regimens were used for chemotherapy in all hospitals. Usually in all the cases CBC, LFT'S and RFT'S were performed before administered of each cycle (day 1-5) of 5-FU. Concomitant diseases observed in cancer patients were mostly the hepatic impairment and anemia. Dose adjustment was done in all the cases for any concomitant diseases if present.

Site of infusion was usually rotated in all the cases as there were the chances of pain at the same site if used each time for infusion administration.

Table-1. Age and Sex Distribution of Cancer Patients (n = 55)

Age(years)###Sex###

###Male###Female

11-20###1###0

21-30###1###4

31-40###2###13

41-50###2###11

51-60###4###8

61-70###1###5

71-80###1###2

Total###12###43

Fig. 1: Cancer incidence by Site and Sex in Cancer Patients (n= 55)

The duty nurses were not fully aware of the SOPs of chemotherapy administration in all hospitals. Chemotherapy administration supervision by the Pharmacist was done only in Mayo hospital Lahore and in

Ganga Ram and Inmol hospital Pharmacists were not present at the site or there were no clinical Pharmacist present in the wards. Regular ward rounds by the clinical Pharmacist, drug utilization review and adverse drug reactions reporting system were only present in Mayo hospital Lahore. Attitude of patients towards chemotherapy was always complied because they had to come to the outdoor of chemotherapy room and drug administration was done by the nurses. The expenses of chemotherapy were borne by the Hospital's charity organization mostly. In Inmol and Mayo hospital charity organizations were active to bear the expenses of chemotherapy but in Ganga Ram hospital there was no charity organization to bear these expenses.

Table-2. Prescribed 5-FU Combination

Chemotherapy Regimens for Cancer

Patients (n = 55)

Chemotherapy###Diagnosis###No. of

regimen###patients

###Ca-Oral cavity###1

###Ca-Esophagus###2

###Ca-Neck###2

###Ca-Cervix###1

###Ca-Nasophyrnx###1

CF (cisplatin+ 5-Fu Day###SCC-Arm###1

1-5) 6cycles, 3weekly###Ca-Larynx###1

###Ca-Tongue###2

###Ca-Ethmoidal###1###

###Ca-Tonsils###1

###Ca-Leg###1

###Ca-###1

###Hypophyrnx

ECF (epirubicin+###

cyclophosphamide+ 5-###Ca-Stomach###1

Fu)###

CF/Folinic acid###Ca-Colon###2

###Ca-Rectum###1

5-Fu/Folinic acid###Ca-Colon###2

5-Fu/leucovorin###Ca-Colon###5

###Ca-Liver###1

###Ca-Liver###1

5-Fu alone###Ca-Gall###1

bladder

FAC 6 cycles###Ca-Breast###20

FAC 8 cycles###Ca-Breast###3

FAC 9 cycles###Ca-Breast###1

FEC 6 cycles###Ca-Breast###1

FAC 6 cycles and###Ca-Breast###1

carboplatin + taxol

Ca = cancer, FAC = Fluorouracil + cyclophosphamide + Adriamycin, FEC = 5-FU + epirubicin + cyclophosphamide, SCC= Squamous cell carcinoma.

CONCLUSION: The current study substantiates the potential relationship and role of the rational use of cytotoxic agents like 5-FU as the key to success and ensure better quality of life of cancer patients. 5-FU is one of the most commonly used chemotherapeutic agents now-a-days for the systemic treatment of cancers of the gastrointestinal tract, breast, head, and neck in Pakistan. The concept of rational use of drugs is still under-defined in Pakistan. The irrational use practices remain a big challenge. Strategies should be developed as per WHO guidelines on RUD. Indicator-based monitoring is effective and sustainability is important.

Health care professionals should play their role to promote rational use of drugs to ensure better quality of life for cancer patients. Public awareness programs should be organized for patient as well as for Health Care Provider

REFERENCES

Akici, A., S. Kalaca, M. Ugurlu, A. Karaalp, S. Cali, and S. Oktay. Impact of a short postgraduate course in rational pharmacotherapy for general practitioners. Br. J. Clin. Pharmacol., 57(3): 310-321 (2004).

Bonadonna, G., P. Valagussa, A. Moliterni, M. Zambetti and C. Brambilla. Adjuvant Cyclophosphamide, Methotrexate, and Fluorouracil in Node-Positive Breast Cancer. N. Engl. J. Med., 332:901-906 (1995).

Benz, C., E. D. Cadman, J. Gwin, T. Wu, J. Amara, A. Eisenfeld and P. Dannies. Tamoxifen and 5-Fluorouracil in Breast Cancer. C.R., 43:5298-5303 (1983).

Chu, L., L. M. Sutton, B. L. Peterson, K. A. Havlin and E. P. Winer. Continuous infusion 5-fluorouracil as first-line therapy for metastatic breast cancer. J. Infus. Chemother., 6(4):211-6 (1996).

Goldhirsch, A., A. S. Coates, M. Colleoni and M. Castiglione-Gertsch. Adjuvant chemoendocrine therapy in postmenopausal breast cancer. J.C.O., 16:1358-1362 (1998).

Smalley, R. V., J. Lefante, A. Bartolucci, J. Carpenter, C. Vogel and S. Krauss. A comparison of cyclophosphamide, Adriamycin, and 5-fluorouracil (CAF) and cyclophosphamide, methotrexate, 5-fluorouracil, vincristine, and prednisone (CMFVP) in patients with advanced breast cancer. Breast Cancer Res. Treat., 3(2):209-20 (1983).

Thomas, D.M. and J. R. Zalcberg. 5- Fluorouracil: A pharmacological paradigm in the use of cytotoxics. Clinical and Experimental Pharmacology and Physiology, 25(11):887-895 (1998).

Van-Kuilenburg, A. B. P., J. W. Baars, R. Meinsma and A. H. Van-Gennip. Lethal 5-fluorouracil toxicity associated with a novel mutation in the dihydropyrimidine dehydrogenase gene. Annals of Oncology, 14:341-342, (2003).

Watne, A.L. and T.H. Covey. Hormones, Chemotherapy and the Breast Cancer Patient. Oncology, 26:317-326 (1972).

Zambetti, M., P. Valagussa and G. Bonadonna. Adjuvant cyclophosphamide, methotrexate and fluorouracil in node- negative and estrogen receptor-negative breast cancer. Annals of Oncology, 7:481-485 (1996).
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Publication:Pakistan Journal of Science
Article Type:Report
Geographic Code:9PAKI
Date:Sep 30, 2010
Words:1866
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