TAW0010.1177/2042098616672572Therapeutic Advances in Drug SafetyJB Wahlang, P Devi
Therapeutic Advances in Drug Safety
Adverse drug reactions due to cancer chemotherapy in a tertiary care teaching hospital
Ther Adv Drug Saf 2017, Vol. 8(2) 61–66 DOI: 10.1177/ 2042098616672572 © The Author(s), 2016. Reprints and permissions: http://www.sagepub.co.uk/ journalsPermissions.nav
Julie Birdie Wahlang, Purnima Devi Laishram, Dhriti Kumar Brahma, Chayna Sarkar, Joonmoni Lahon and Banylla Shisha Nongkynrih
Abstract Background: An adverse drug reaction (ADR) is defined by World Health Organization (WHO) as ‘Any response to a drug which is noxious, unintended and occurs at doses used in man for prophylaxis, diagnosis or therapy’. ADRs associated with cancer chemotherapy warrant analysis on their severity and preventability. The outcome would create awareness among health care providers and prevent their recurrence. We have performed a hospital-based prospective observational study designed to analyze the pattern of ADRs to chemotherapeutic agents in cancer patients of a tertiary care hospital. Methods: A total of 119 cancer patients were monitored for suspected ADRs during the course of chemotherapy from November 2014 to December 2015. Clinical events were recorded and analyzed with regard to the demographics and drug details of the patients. Results: A total of 106 ADRs were recorded from 119 cases. The ADRs commonly encountered included constipation, nausea, vomiting, alopecia and hematological changes. Cisplatin, cyclophosphamide, paclitaxel and 5-FU were used for the treatment of commonly found cancers in this region affecting the lungs, esophagus and lymphomas. Naranjo’s causality assessment showed 86.7% possible (score 4) and 13.2% probable (score 5–6). Severity of adverse reactions showed 77.4% mild, 18.9% moderate and 3.8% severe. A total of 45.3% of ADRs were preventable reactions such as nausea, vomiting and constipation. Conclusions: This study highlights the role of active monitoring as an important tool for early detection, assessment and timely management of ADRs in patients undergoing cancer chemotherapy. The observed ADRs were preventable although ADRs such as hiccough, anemia, neutropenia and alopecia were not preventable.
Keywords: adverse drug reactions, cancer chemotherapy, premedications
Introduction The development and use of drugs in various types of diseases has brought wonders to the human race but it has also set new threats in the form of adverse drug reactions (ADRs). An ADR is defined as ‘Any response to a drug which is noxious, unintended and occurs at doses used in man for prophylaxis, diagnosis or therapy’ [The Uppsala Monitoring Centre, 2002]. Worldwide, ADRs accounted for 10% of hospital admissions [Farcas and Bojita, 2009] and 6% of hospitalized patients suffer from ADRs [Asawari et al. 2012]. With the introduction of pharmacovigilance in recent times, more
ADRs are reported and documented in various parts of the world. The administration of cancer chemotherapy is one approach to the management of cancer patients and this ensures an improved quality of life, especially with the development of new drugs for the cure of various neoplasms. However, this has also brought out various adverse events that are often neglected by the treating physicians because of the goal of therapy. Documentations of ADRs associated with cancer chemotherapy warrant proper analysis of their severity and preventability. The outcome would create awareness
Correspondence to: Julie Birdie Wahlang, MD North Eastern Indira Gandhi Regional Institute of Health and Medical Sciences, Mawdiangdiang, Shillong, Meghalaya, 793001, India [email protected]
Purnima Devi Laishram, MD Dhriti Kumar Brahma, MD Chayna Sarkar, MD Joonmoni Lahon, MD Banylla Shisha Nongkynrih, MD North Eastern Indira Gandhi Regional Institute of Health and Medical Sciences, India
Therapeutic Advances in Drug Safety 8(2) among health care providers and prevent their recurrence in subsequent chemotherapeutic cycles; hence, the objective of this evaluation. Materials and methods Study design The study was a hospital-based prospective observational study conducted from 14 November 2014 to December 2015 in patients who received chemotherapy in the oncology ward of a tertiary care hospital after obtaining due approval from the Institute Ethics Committee (NEIGR/IEC/2013/58). A total of 119 patients gave written informed consent to participate in the study. Consent forms were in a predesigned format approved by the Institute. All 119 patients were interviewed and monitored during the course of chemotherapy for any possible ADR. Data collection Appropriate proforma forms developed in accordance with the ADR reporting form of the Central Drugs Standard Control Organization (CDSCO), Government of India, were used for collecting data regarding the patients’ demographic profile, the details of drugs received during chemotherapy session and also any pre-existing medical condition which may lead to any ADR. All of the suspected cases of ADRs were then reported to the ADR Monitoring Centre and also in Vigiflow to the national coordinating center. Data analysis The pattern of ADRs thus obtained was analyzed. The suspected drugs were identified and their causal associations were analyzed by using the Naranjo scale. The severity and preventability of ADRs were analyzed by using the modified Hartwig Siegel’s severity assessment scale and the modified Schumock and Thornton scale, respectively [Naranjo et al. 1981; Hartwig et al. 1992; Schumock and Thornton, 1992].
were female. The mean age group of the study population was 48.71 ± 15.94 years. Analysis of ADRs with suspected drugs In our study, ADRs were found in 70 patients out of the 119 participants and a total of 106 ADRs were recorded and analyzed. The ADRs were seen more in male participants which accounted for 61.43% (n = 43) than in female participants which accounted for 38.57% (n = 27). Among the ADRs encountered, the most common were gastrointestinal adverse reactions such as breakthrough and delayed onset vomiting (15.09%), constipation (12.26%) and anorexia (11.3%). Anemia (2.8%), neutropenia (1.9%) and leucopenia (3.8%) were the most common hematological reactions that were recorded. Alopecia was reported in 20.75% of patients, followed by symptoms of weakness in 10.37%, giddiness in 7.55% and hiccough in 7.55% (Figure 1). Analysis of types of cancer and chemotherapeutic agents The commonly used drugs for chemotherapy in our patients were the combination regimen using cisplatin, cyclophosphamide, paclitaxel and 5-FU for the treatment of cancers common in this region such as those that affect the lungs, esophagus and lymphomas. Carboplatin, oxaliplatin, docetaxel and doxorubicin were the other drugs used for the treatment of cancers of the breast, cervix, ovary, uterus, stomach, rectum and colon; see Table 1.
Causality and severity assessment The ADRs were analyzed for causality assessment with the Naranjo scale which showed 13.2% probable (score 5–6) and 86.7% possible (score 4) association with the suspected drugs. The assessment of the severity of adverse reactions by using the Hartwig scale showed that 77.4% were mild (level 1), 18.9% were moderate (level 3–4) and 3.8% were severe (level 5). Preventability was assessed by using the Modified Schumock and Thornton scale which showed that 45.3% of reactions seen in our study were mostly preventable, while 54.7% were not preventable (Figures 2–4).
Patient’s demographic pattern A total of 119 patients who were receiving cancer chemotherapy participated in our study, among which 67 (56.3%) were male and 52 (43.69%)
Emetogenic drugs Assessment High-risk emetogenic drugs used in our setting were cisplatin and cyclophosphamide. The
JB Wahlang, P Devi et al.
Figure 2. Naranjo causality assessment scale. Figure 1. Pattern of ADR. Table 1. Types of cancer and suspected chemotherapeutic agents. Suspected medications
Types of cancer
Cyclophosphamide + Doxorubicin + Vincristine + Prednisone Paclitaxel + Cisplatin Cisplatin + Cyclophosphamide, Liposomal doxorubicin Paclitaxel + Carboplatin Capecitabine + Oxaliplatin + 5-FU + Leucovorin Oxaliplatin + 5-FU + Leucovorin Etoposide + Actinomycin-D + Methotrexate Cyclophosphamide+ Vincristine Cisplatin + 5-FU Paclitaxel + Cisplatin Paclitaxel + Cisplatin Gemcitabine + Cisplatin Capacitabine docetaxel + Cisplatin + 5-FU docetaxel + Carboplatin Cyclophosphamide + Adriamycin + 5-FU
Cyclophosphamide + Adriamycin + Vincristine
Ca Cervix Ca Ovary
Figure 3. Hartwig severity scale.
Ca Rectum Ca Colon Choriocarcinoma Figure 4. Schumock and Thornton scale. Ca Esophagus Ca Lung Ca Stomach Ca Breast
Ca, Cancer; NHL, non-Hodgkin’s lymphoma.
premedication drugs most commonly prescribed along with these regimens were granisetron 3 mg, ranitidine 50 mg and dexamethasone 8 mg. Patients receiving moderate emetogenic drugs such as paclitaxel, carboplatin, doxorubicin and oxaliplatin were given premedications with ondansetron 16 mg, dexamethasone 4 mg and pantoprazole 40 mg.
Discussion After the ADRs were collected and analyzed, we observed that the population belonging to the mean age group of 48.71 ± 15.94 years were more prone to the development of ADRs during cancer chemotherapy which can be compared with one study that was conducted in Bangladesh [Poddar et al. 2009]. The incidence of ADRs was greater in male participants (61.43%) as compared with female participants (38.57%) which can be explained from the higher incidence of lung cancer (22.86%) seen in our setting as also reported from western and eastern parts of India [Goyale et al. 2014; Prasad et al. 2013]. However, studies from other parts of India and Bangladesh showed a higher preponderance of ADRs in cases affecting female patients. [Sharma et al. 2015; Poddar et al. 2009]. Cisplatin, cyclophosphamide, paclitaxel and 5-FU containing regimens were commonly used and
Therapeutic Advances in Drug Safety 8(2) were found to be associated with most of the ADRs in our setting which is comparable with other study reports [De, 2010; Sharma et al. 2015]. The system that was most frequently affected by ADRs was the gastrointestinal tract (GIT), a feature which is similar to another study reported by Guo and colleagues [Guo et al. 2012] and Chopra and colleagues [Chopra et al. 2016]. A total of 15.09% cases of nausea and vomiting, including breakthrough vomiting (within 24 h) and delayed onset vomiting cases, is reported in our setting which is significantly lower as compared with 31.5% and 48.1% that was reported in two other studies [Kirthi et al. 2014; De, 2010]. The lower incidence of this adverse reaction in our patients is attributed to the prompt premedication with antiemetic drugs such as granisetron as well as to the judicious administration of ranitidine, pantoprazole, dexamethasone and aprepitant. The most common mechanism of chemotherapyinduced nausea and vomiting is the activation of the chemoreceptor trigger zone (CTZ). The management plan in our setting for most of these reactions was the administration of a higher dose of granisetron which is consistent with the findings of other studies where patients received higher doses of antiemetic drugs to treat chemotherapy-induced nausea and vomiting [Poddar et al. 2009]. There is documented evidence of occurrence of constipation with anticancer regimens containing vincristine and cisplatin. Constipation was seen in 12.26% of our patients which was higher than other reported studies [De, 2010; Sharma et al. 2015]. Concomitant administration of premedication drug such as pheniramine maleate for lowgrade emetogenic drugs (Taxanes) may be one of the causes of constipation [Gibson and Keefe, 2006; Mancini and Bruera, 1998]. It is noteworthy to mention that the presentation of constipation observed in our patients was of grade 1 type [US Department of Health and Human Services, 2010] and was managed with laxatives and proper counsel on dietary modification. However, three of our patients presented with persistent grade 2 type constipation where regular use of laxatives was indicated. The incidence of hiccough was found to be higher (7.55%) in our setting as compared with 0.5% in a study conducted by Chopra and colleagues [Chopra et al. 2016]. There are reports of cisplatin-based-regimen-induced hiccough, especially
in patients who had received dexamethasone as premedication during chemotherapy [Liaw et al. 2005] and this is consistent with 4.77% of our patients who received cisplatin- or carboplatinbased regimen and dexamethasone premedication and presented with hiccough. Drugs used in cancer chemotherapy can alter an individual’s metabolism through changes in taste and this itself will lead to weight loss. Therefore, symptoms of anorexia and weakness seen in 11.3% and 10.37% of our patients were noteworthy in cancer therapy, as response to treatment diminishes with subsequent decrease in weight [Dewys et al. 1980]. We have seen from the present evaluation that the drug regimen comprising doxorubicin, vincristine and cyclophosphamide, administered especially for the treatment of lymphomas, was associated with hematological disorders (8.4%) namely anemia (mild anemia to anemia of grade 2 level), neutropenia and leucopenia [US Department of Health and Human Services, 2010]. Another prospective study among the patients with non-Hodgkin’s lymphoma treated with the same regimen had reported lifethreatening neutropenia [Intragumtornchai et al. 2000]. In contrast to our evaluation, two other reports suggested hematological disorders as the most common ADR [Mallik et al. 2007; Sharma et al. 2015]. An important measure taken to overcome anemia and neutropenia in these patients was the administration of blood transfusions and filgrastim (granulocyte colony-stimulating factor), respectively. In our study, a total of 20.75% patients suffered from alopecia, a figure which is less as compared with 51% and 58% that were reported in previous studies [Surendiran et al. 2010; Poddar et al. 2009]. On analyzing the causality assessment of the ADRs by the Naranjo score, we found that 13.2% of cases showed probable and 86.7% showed possible association whereas Khandelwal and colleagues reported 100% and Goyal and colleagues reported 61% of probable scores using the same scale [Khandelwal et al. 2015; Goyal et al. 2014]. The reason for this can be attributed to the observed occurrence of ADRs which were mostly breakthrough vomiting, anorexia and hiccough. Analyses of the severity of these adverse reactions using Hartwig’s severity scale revealed that majority of the ADRs (77.4%) were mild followed by moderate (18.9%) and severe (3.8%), a finding which was comparable with the above two studies conducted in western and southern India.
JB Wahlang, P Devi et al. Assessment of the preventability by the Schumock and Thornton scale showed that only 45.3% of the ADRs could have probably been prevented in patients who had symptoms of vomiting, general weakness, constipation and hiccough where appropriate premedication was given and proper dietary counsel was ensured before the start of chemotherapy. All 106 reported ADR cases in our study were managed symptomatically and all of these patients had recovered fully with no further untoward reactions. Conclusion The analysis of ADRs associated with the cancer chemotherapy in a hospital setup gives an insight regarding the causality, severity and preventability of the identified ADRs. It may also create awareness among the treating physicians that can prevent further occurrence of similar ADRs in the same patient. Pharmacovigilance is of utmost importance to ensure safe and effective medications, more so in palliative health care services. Proper evaluation of ADRs helps in preventing their recurrence in subsequent chemotherapeutic cycles. Our study highlighted the common ADRs of anticancer drugs as well as their causality, severity and preventability. The intensive surveillance from our end has led to early detection of some common but important ADRs and to some extent contributed towards achieving the goal of pharmacovigilance in this part of the country. Acknowledgements The authors are immensely grateful to the Institute Ethical Committee for approval of the study. We wish to thank the patients and staff of the oncology department, both technical and administrative for their cooperation in this study. We also extend our gratitude to Professor Tonny C. L. Kharmujai, Department of English, St. Anthony’s College, Shillong. This study was accepted for poster presentation at the Drug Discovery and Therapy World Congress 2016, Boston, MA, USA. Funding The author(s) received no financial support for the research, authorship, and/or publication of this article. Conflict of interest statement The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
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