HealthiiED - Volume 5/ Number 3/2011 Neutropenia induction by vinorelbine alone and in combination with doxorubicin and cisplatin in cancer patients Taha Nocir!, Habib-Ur- Rehman’, Owais Omar, Tahir Aztz MughaP * Department of pharmacy, University of Sargodha, Pakistan, 2 University of Veterinary & Animal Sciences, Pakistan, > Shaukat Khanum Memorial Cancer Hospital & Research Centre, Pakistan Abstract ‘Neutropenia is a kind of leukopenia associa- ted with shortage of neutrophils. It is included by myelotoxic drugs, acute infectious stress and le- ukemia. The anticancer drugs beside cancer trea- tment have the deleterious effects on the metabo- lism and vital organs. These drugs could damage the blood producing cells of bone marrow and re- ‘duce the neutrophils counts resulting in increased ‘chance of infection. This study aimed to investi- gate the alterations in neutrophilic count in can- ‘cer patients and was administered vinorelbine as part of their chemotherapy. A total 60 adult cancer patients were randomly divided in to two groups; Group-I received the treatment of Vinorelbine alone and group 2 patients on Vinorelbine base ‘combinations. Results showed significantly lower potential of neutropenia induction in the patients ‘on vinorelbine alone (p value <0,001) as compare ‘with the patient received vinorelbine based combi- nations (p value 0.021). The comparison of mean values of these two groups at every week indica- ted higher chance of neutropenia at week-3 in the patients receiving vinorelbine based combinations (Mean +SEM: 1.8180+0,3018, p value 0.118). The ‘mean neutrophils counts before therapy were si- sgnificantly lower than that of after therapy in both. of the groups (p values during weeks 0-4: 0.742, 0.208, 0.425, 0.048, and 0.791). However, among the groups, the potential for induction of neutro- ppenia is similar, Thus; in conclusion, there is no significant difference in the overall neutropenia in. both of the chemotherapy protocols. The clinical ‘oncologist, consultant physician and pharmacist, ‘can select either ofthe treatment plan. 486 Key words: Neutropenia, Vinorelbine, Cispla- tin, Doxorubicin, breast cancer and NSCLC Introduction ‘Neutropenia is a hematological disorder cha- racterized by an abnormally low number of ne- utrophils. Neutrophils usually make up 50-70% of circulating white blood cells and serve as the primary defense against infections. The causes of neutropenia are either problems in the production by the bone marrow or destruction elsewhere in the body. It affects as many as one in three patients receiving chemotherapy for cancer. Neutropenia can be a serious crisis requiring quick attention. Without proper medical care, patients may find it hard to lead normal lives especially neutropenic sepsis can be life threatening (Neutropenia Sup- port Assoc. Inc. 2010). ‘Moreover; there are several types of neutrope- nia: the eyclic neutropenia is an autosomal domi- nant disorder of unknown etiology in which 3-6 days of neutropenia occur every 21-30 days in a periodic pattem. During the periods of neutrope- nia the patient may develop fever and infections such as stomatitis, cellulitis, and vaginitis. There appears to be some abnormality of feedback mec- hhanisms. Chronic idiopathic neutropenia is a dis- order in which the neutrophil count is less than 1.0 x 10"/L, but results in few infections (Pathology, 2010) In addition to that; the drug-induced neutrope- nia also is caused by four mechanisms: a) drugs induce cytolysis cause marrow depression and aplastic anemia (alkylating agents, inhibitors of “Journal of Society for development in new net environment in BSH.HealthilED - Volume § / Number 3/2011 mitosis, DNA depolymerizors, ionizing radiation), 'b) impairment of DNA synthesis (phenothazines, chloramphenicol, methotrexate, hydroxyurea, azothioprine, cytosine arabinoside, and 6-mercap- topurine). c) Meiosyneratic reactions (chloramp- hhenicol, gold salts, phenylbutazone, thiazides, ‘sulfonamides, quinine, procanamide). d) immuno- logic neutropenia, the drug and neutrophil surfa- ce protein form an antigenic complex. Antibody is produced against this complex. and remains inactive in the plasma. When this drug is given it interacts with neutrophil surface protein and com- plexes antibody. This causes leukoagglutiation or activation of complement (Pathology, 2010). The initial symptoms of neutropenia begin after 1-3 days with malaise, chills, sore throat, fever. Later ‘easy fatigability and weakness are seen. Infection is the most serious consequence of neutropenia ‘Neutropenia less than 1.0 x 10° seriously com- promises the ability to fight infection. Agranulo- ‘eytosis (= 0.5 x 10° /L) may lead to death within days due to overwhelming infection. ‘Cancer is treated stereoscopically in certain sta- ‘ges with abundant agents (Perry, 1996). Vinorelbi ne, cisplatine and doxorubicin are major drugs gi ‘ven for breast, cervix and non-small cell lung can- cer. Vinorelbine is semi-synthetic vinca alkaloid ‘obtained from the rosy periwinkle, Catharanthus roseus. Cisplatin’ cisplatinum’ cis-diamminedic- hloroplatinum is a platinum-based drug employ for sarcomas, carcinomas, lymphomas and germ cell tumors. Platinum complexes react in vivo, binding to and causing crosslinking of DNA whi- ch ultimately triggers apoptosis (programmed cell death). Doxorubicin is an anthracycline antibiotic and works by intercalating DNA. It was originally isolated from bacteria found in soil samples taken from Castel del Monte, an Italian castle in 1950's, Tris used in the treatment of wide range of cancers, ‘many types of carcinoma and soft tissue sarcomas. ‘Thus; we have aimed this project, to evaluate the neutropenia induced by vinorelbine alone and in combinations with these three widely used anti- ‘cancer drugs. This may help to evaluate the thera- peutical credibility of treatment plans Journal of Society for development in new net environment in B&H ‘Materials and methods ‘The study was conducted at Shaukat Khanum ‘Memorial Cancer Hospital & Research Center (SKMCH&RO), M.A Johar town, Lahore, Pakistan to investigate the changes in neutrophil count of ‘adult cancer patients with Non small cell lung can- cer, metastatic breast cancer, and of cervix, treated ‘with Vinorelbine alone, Vinorelbine/ Doxorubicin and Vinorelbine/Cisplatin treatment protocols Study Design These patients were selected from outpatient department (OPD) of SKMCH&RC who were di- agnoses as breast cancer, NSCLC and cancer of cervix belong to any age group, had ether sex and ‘consented for this study. An exclusion criterion is involvement of patient in any other study. A total (60 cancer patients were divided into two groups; Group-1 comprising of patient received vinorelbi- ne as single therapy and Group-2 having the can- ‘cer patients on treatment protocol of vinorelbine ‘based combinations ie. Vinorelbine/ Cisplatin or ‘vinorelbine/ Doxorubicin (Table!). Preparations of Standard Regimen of ‘Chemotherapeutical Agents ‘The standard treatment regimen for vinorelbine, cisplatin and doxorubicin is reported by Nazir etal, 2009. The vinorelbine was administered 25 mg‘ml ‘on day 1, weekly 4, iv, with 045% sodium chlori- de of 5% glucose solution as diluents and delivered ‘over intravenous push (IVP) (Kubota K., 2000), The injected dose infused over a short period -15 0 20 minutes (Reynald, etal 1996). In combination therapy the dose of Vinorelbine was decreased and ‘administer as 20 mg/ml on day 1, 8 VV with dilu- cent day 5 ¥% normal saline and delivered over IVP. ‘The Doxorubicin was given as 50 mgm? on day 1 only (Fauzia 2000), Doxorubicin was administe- red slowly in to tubing of freely running infusion ‘of Sodium Chloride 0.9% or Glucose 5%. (USPDI, 1997). The Cisplatin was administered intra-veno- uly as 40mg/ml on day 1 only, with the diluent of day 5 NS and delivered over IVP. 487Heatt\c0 - Volume §/ Number 3/2011 Table 1. The chemotherapy protocols follow up schedule and cancer site of experimental patients ‘Sample ‘Chemotherapy | Follow up Group) “size | Chemotherapy protocol | Patient neoplasm Pe | schedule (days) | schedule (days) Metastatic breast cancer [1,7,14,21 _|6,13,20,28 SH] S| Nawetine /NSCL Cancer 17.1421 [6,13,20,28 Vinorebine’ Doxurubicin | Metastatic breast cancer | 1,8 71S Gu] is NSCL Cmoer Ls 7.18 fnorelbine! Cisplatine’ Cervix Cancer LS 7.18 ‘Sample Collection and Neutrophils Count: ‘The 3ml of blood samples were drawn from brachial veins in S ce disposal syringes and tran- sferred to appropriately labeled (complete blood count (C.B.C) vials containing 20 wiv of EDTA. ‘Theneutrophils count was performed using acom- puterized auto-analyzer (Technicon 113, Bayer Laboratories USA) at the Pathology laboratory, ‘SKMCH&RC. Data Analysis ‘The means of two groups were compared by student Test to avoid the consistent deviation of analytical results or systematic errors inthe proce- dure. ANOVA used to identify any factor influen- cing the test results, Result and discussion ‘The effect of different treatment on neutrophils is given in Table 1. On week 1, 2nd 4 of the trea- ‘ment no significant difference in neutropenia was observed. However as shown by the neutrophils ‘count on week 3, significant potential for neutro- penia was observed in the patients on treatment protocol of vinorelbine alone and vinorelbine ba- sed combinations. When the mean neutrophils co- ‘unt before therapy (Week 0) were compared with that of after therapy (week 4), there a significant decrease was noted in the patients on treatment protocol of vinorelbine alone only. ‘The finding of this study are in line with the ‘work of Dorr etal (1994), who reported the neu- tropenia, which have the dose limiting toxic effect ‘of oral Vinorelbine, Kondo etal, (1999) reported neutropenia as a major adverse effect of cancer chemotherapy and sometimes causes life-thre- atening events. The present study was therefore ‘conducted to identify risk factors for such neutro- penia, Forty patients who had received chemothe- apy at 3- of 4-week intervals for advanced lung cancer analyzed retrospectively. Thirty-seven of the patients had received cisplatin-based chemot- hherapy. The mean monocyte counts on days 6 to 8 in the 32 patients with grade 3 or 4 neutropenia (5.181 +/- 1,830\microl and 87 +/- $4/micro, res- pectively) were significantly lower than those in the eight patients with grade 1 or 2 neutropenia (7175 += 1671/microl and 248 += 127/microl, respectively: p = 0,008 and p = 0.0001). Moreo- ver, all 30 patients with a monocyte count of less than 1SOmicrol on days 6 to 8 had grade 3 or 4 neutropenia and 8 of 10 patients with a monocyte count of 150/microl or higher on days 6 to 8 had ‘grade 1 or 2 neutropenia, despite the absence of a correlation between the leukocyte count on days 6 to 8 and the neutrophil nadir. We conclude that a ‘monocyte count of less than 150microl on days 6 to &may be a predictor of grade 3 or 4 neutropenia during cancer chemotherapy at 3- or 4-week inter- vals (Sensitivity 94%, specificity 100%). Figure 1. Mean Newsrophils count (in 000) Vs time (in weeks) Journal of Society for development in new net environment in BAHLHealthVleD - Volume 5 / Number 3/2011 Table 2. The mean SEM Neutrophils count (10!) per ul, Pre and post chemotherapy of cancer pati- ‘ents on the treatment protocol of vinorelbine (Group 1), vinorelbine based combinations (Group ID) and ‘overall total (60) patients caetky | Minoretbine Group-D | eoaujinaton tCreep-1}) ‘Overall Pvalue Mem | SEM | Mem | SEM | Mean | SEM Weeko | 43361 | 032614 | 413133 | 048079 | 2802 | 27076 | 072 Week 1 | 2.68003 | 0208617 | 213 | 042035 | 25379 | o190063 | 0208 Week2 | 187195 | 0304722 | 2344 | 0497071 | 19983 | 0258908 | 0.495 Week3 | 28 0258624 | 1818083 | 0301872 | 25577 | o21e248 | 0088 Week 4 | 201666 | 030368 | 217777 | 0.420667 | 205388 | 0250712 | 0.791 Pralue™ | 0.001 0021 0.001 Pvalue? | <0.001 ous ee” Oveal comparizn of ean vies over Tie P value? Independent comparison of mean values for two groups at every week P value’ Comparison of mean values observed before therapy with that of at week 4 The study under discussion also supported by the work of Marty etal. (1989), who concluded the leucopenia as noncumulative and of short duration (€7 days). Shamseddine etal, (1999), reported the acceptable hematological toxicities of Cisplatin and Vinorelbine in combination therapy having, Tn conclusion, there were insignificant diffe ences observed in the overall hematological toxi- cities of both of the chemotherapy protocols. The clinical oncologist, consultant phy’ician and phar- ‘macist therefore can select either of the protocol to provide maximum relief to patients. Moreover the therapeutical efficacy should probably constitute the overall consideration while treating the parti- ccular neoplasm. Journal of Society for development in new net environment in BSE References 1. Bruce A. Chabner, Thomas J. Lynch, Dan L. 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Box 243, 971 Corydon Ave. Winnipeg, MB, Canada R3M 357 Toll Free (Canada & U'S)1-800-6 NEU- TRO hinp:/svvewneutropenia.ca/HealthivED - Volume 5 / Number 3/2011 8. Pathology, (2010), University of Virgenia, College of Medicine, University of Virginia School of Me- divine PO Box 800793, Charlottesville, VA 22908, 434-924-5118. hnnp:/svwwmed-ed virginia.edulco- uurses/parh inuessved/leukopenta.cfin 9. Perry C. M. (1996), the Chemotherapy Source Book, 2 Edition, William & Wilkins. Awaverly Company, USA p3-4, 19-20 10. Reynold P, Parfitt FJ, Parsolf.C, Martindal VN (1996), Martindale, the extra pharmacopoeia, 31° Ea, Royal Pharmaceutical Society, London, UK pp 607 IL. Romero Acu-na, Langhi L., Pere: M,, Romero J., Machiavelli J, and Lacava J. (1999), Vinorelbine ‘and Paclitaxal as first line chemotherapy in me= tastatie breast cancer; Clin Oncol, 17(1): 74-81 12. Shamseddin AL, Taher A, Dabaja8 B., Dandashi A, Salem Z and Saghir EL. (1999), Combination Cisplatine — Vinorelbine for relapse and chemot- herapy ~ pretreament metastatic breast cancer, AMI Clin Oncol, 22(3): 298-302 413. Subramanyan S, Abeloff M.D., Bond S.E., David- son N-E,, Fetting IH, Gordon GB. and Kennedy MJ. (1999), A phase I/ It study of vinorelbine, doxorubicin and methotrexate with leucovorin, rescue as first line reatment for metastatic breast ‘cancer, cancer chemother Phyarmacolo, 43(6) 497-502 14, USPDI (United State Pharmacopoeia & Drug Information) (1997), advice for patient drug in- formation in lay language (Part I & I), 17% Edi- ‘tion, (1997), 12601 Tein Book Parkway; Rockville Maryland, 20852 p. 719-21, 1281-1287 Corresponding author Habib-Ur-Rehaman, Dept. of Physiology; University of Veterinary & Animal Sciences, Pakistan, E-mail: habibrehman@uvas.edu pk Journal of Society for development in new net eavironment in B&H