A survey on gastrointestinal adverse drug reactions of Doxorubicin and Cyclophosphamide combination therapy.
Adverse drug reactions (ADRs) are very common with anticancer drugs. The objectives of the survey are to evaluate ADRs of AC (Adriamycin (Doxorubicin) and Cyclophosphamide) combination therapy with special reference to GIT (Gastrointestinal system). It was a prospective, descriptive, observational study which included 90 female patients receiving AC combination therapy for their treatment through a purposive sampling and from 01-01-2016 to 31-12-2016 at Cancer Hospital Jamshoro Pakistan. Patients were interviewed during follow up session with a consultant, their response was recorded in a questionnaire and verified through British National formulary (BNF), Hartwig and Siegel scale (ADR severity assessment scale).
The survey results shows that AC anticancer combination therapy can result in various disturbances in gastrointestinal tract among which nausea, vomiting decreased appetite and hyperacidity were most common. These must be taken into account and managed with supportive treatment in order to maintain better quality of life during the cancer treatment.
Keywords: GIT, ADRs, Drugs, Cancer, Anticancer drugs, AC therapy Doxorubicin, Cyclophosphamide.
Gastrointestinal system (GIT), a vital organ system helps to process food, nutrients and to maintain the healthy lifestyle of an individual. GIT disorders are common in developed and developing countries and their development can affect the quality of life.1 These disorders of GIT can result from variety of the factors which include: unnecessary food intake which is unable to be digested by system, high stress which affect the secretions of GIT and can alter the environment of digestive system, improper exercise, in some individuals travelling and the drugs administered orally or by other route for systemic effect.1-3 Cancer patients treated with chemotherapeutic agents have high susceptibility to develop GIT disorders when administered as a single agent as a result of effect upon normal cells.4-6 The situation is prone to even more worse response when a multiple dosage regimen is used for improved efficacy especially when patient is suffering from Advance Disease level.
Breast cancer one of the most frequent cancer type among females and treatment involves various combination therapies in which AC is one of most frequent therapy prescribed by physicians especially for the treatment of breast cancer.7 AC stands for Adriamycin (doxorubicin) and Cyclophosphamide which is given in cycles which are repeated every 21 days and usually four cycles are given. Adriamycin/ Doxorubicin belongs to anthracycline anticancer antibiotic group, whereas Cyclophosphamide belongs to the class of alkylating agent. Both drugs have similar cytotoxic effect as both interfere with synthesis of DNA of the cells not only tumour cells but also normal cells especially those which divide rapidly and therefore affecting the organs with rapid cell division. One of the important systems affected is the gastrointestinal tract and therefore patients are at high risk to develop various gastrointestinal symptoms as a result of disturbance in their functioning of the cells by the Anticancer drugs.
Common adverse effects of these anticancer agents reported in standard literature include: nausea, emesis, mouth sores, dyspepsia, diarrhoea etc. Various clinical trial studies reports showed that the different anticancer agents cause various effects among which the gastrointestinal tract problems are more frequent as compared to other effects in patients of developed countries.6,8-11
A prospective observational survey was conducted on 90 breast cancer patients on AC (Adriamycin/Doxorubicin, Cyclophosphamide) therapy at the dose of 60/600mg/m2 with prophylactic anti-emetic treatment as per ESMO guidelines for moderately emetogenic therapy at Cancer Hospital Jamshoro Pakistan through a purposive sampling method from 01-01-2016 to 31-12-2016. All the patients were interviewed during follow up session with consultant and the response was recorded in a questionnaire. The results were compared with British National formulary (BNF)5 2012 and severity assessed via Modified Hartwig and Siegel Scale. The survey was conducted in accordance with the Principles of declaration of Helsinki. The inclusion criteria consisted of female patients receiving AC combination therapy for breast cancer treatment (Adjuvant curative protocol) aged above 18 years.
Exclusion Criteria: Any patient receiving another protocol for treating any other severe condition such as HIV, Tuberculosis, Hepatitis, any precondition associated with malignant disease or other related factor which could affect the accuracy of results, neurological diseases, unable to respond were excluded from study to avoid ambiguity of response.
Table-1: Age group distribution.
Age (in years)###Patients###Frequency (%)###Cumulative (%)
61 and above###7###7.778###100
Table-2: Frequency of gastrointestinal disturbances.
Sr. No###ADRs###No of Patients###Frequency (%)
The survey results included 90 patients, 80% having an invasive type of cancer. The age group of majority of population were above 40 and up to 50 years as shown in Table-1 with the mean age of 43.522+-9.922 Table-2 represents the occurrence of various adverse-effects related to GIT secondary to administration of AC protocol. Each patient responded differently towards the therapy and showed various combinations of these gastrointestinal disorders. All the ADRs reported by the patients were compared with standard reference BNF and severity assessed in modified Hartwig and Siegel scale and those severe enough as level 2 or greater were included in the survey. This helped to evaluate not only the ADRs associated but also the severity to develop a complete picture of local patients response towards the combination therapy (Table-2). Represents the percentage of gastrointestinal disorders from which patients suffered during the anticancer therapy.
The manner in which these ADRs reported by the patients are presented in Table-2. Nausea appeared to be the most common problem (70%) whereas vomiting was the 3rd most common problem, which either appeared as breakthrough symptoms and/or symptoms relapsed after few hours of chemotherapy and these persisted for more than 24hours in majority of the patients after every cycle. Decreased appetite appeared 2nd frequent problem and majority of the patients suffered for more than 24 hours even up to 72 hours. Hyperacidity, indigestion and pain in the abdominal also affected a large number of patients and persisted for 24-48 hours after each cycle. Mouth sores appeared in a small number of patients and majority of them showed a level of 2 ADR. Diarrhoea was also less frequently encountered. ADRs were included in the data if symptoms persisted for more than 24 hours. Majority of patients were of level 2 ADR in scale.12
Our study identified multiple ADRs associated with the digestive tract among the local population and by comparing them with the other studies was found to be 70% and 60% respectively. Similarly diarrhoea presented as an uncommon ADR in 6-20% patients and in our cases it was 13.333%. Mouth sores were reported by 20% of the patients and they were of a severe form requiring medical intervention. Present findings show that people from developed as well as developing countries can equally suffer from these ADRs of digestive tract with little difference.6 As per NCCN, ASCO, ESMO's updated guidelines (2016-17), which classified AC as highly emetogenic regimen with response rate >90% but present study subject's response was moderate.13-17 Present study results shows that in our population AC therapy can be considered as a moderately emetogenic regimen (response rate <90%) along with other gastrointestinal ADRs.
The health professionals can manage them with supportive therapy by following the guidelines that best suits the patient, to maintain a better quality of life during the cancer treatment as well as can reduce health and economic burdens associated with therapy.
Disclaimer: None to declare.
Conflict of Interest: None to declare.
Funding Disclosure: None to declare.
1. What are gastrointestinal problems. [Online] [Cited 2017 Jan 01] Available from: URL: http://www.nutricia.ie/articles/
2. American College of Gastroenterology, Patient education and resource centre home page. Common GIsymptoms. [Online] [Cited 2017 Jan 01]. Available from: URL: www. patients.gi.org.
3. Ritz MA, Fraser R, Tam W, Dent J. Impacts and patterns of disturbed gastrointestinal function in critically ill patients. Am J Gastroenterol 2000; 95: 3044-52.
4. Love RR, Leventhal H, Easterling DV, Nerenz DR Side effects and emotional distress during cancer chemotherapy. Cancer 1989; 63: 604-12.
5. British national formulary (BNF). British Medical Association and Royal Pharmaceutical Society 2012; 63: 540-57.
6. Partridge AH1, Burstein HJ, Winer EP. Side effects of chemotherapy and combined chemohormonal therapy in women with early-stage breast cancer. J Natl Cancer Inst Monogr 2001; 30: 135-42
7. Gilani GM, Kamal S, Akhter AS. A differential study of breast cancer patients in Punjab, Pakistan. J Pak Med Assoc 2003; 53: 478-81.
8. Chu E, DeVita Jr VT. Physician's cancer chemotherapy Drug Manual. 1st ed. United States: Jones and Bartlett Publishers; 2008, pp 92-6; 134-8; 177-82.
9. Martin M1, Lluch A, Segui MA, Ruiz A, Ramos M, Adrover E, et al. Toxicity and health-related quality of life in breast cancer patients receiving adjuvant docetaxel, doxorubicin, cyclophosphamide (TAC) or 5-fluorouracil, doxorubicin and cyclophosphamide (FAC): impact of adding primary prophylactic granulocyte-colony stimulating factor to the TAC regimen. Ann Oncol 2006; 17: 1205-12.
10. Kirthi C, Afzal A, Reddy M, Aamir Ali S, Yerramilli A, Sharma S. A study on the adverse effects of anticancer drugs in an oncology center of a tertiary care hospital. Int J Pharm Pharmaceut Sci 2014; 6: 580-3.
11. Khokher S1, Mahmood S, Qureshi MU, Khan SA, Chaudhry NA. "Initial clinical response" to neoadjuvant chemotherapy: In vivo chemo sensitivity test for efficacy in patients with advance breast cancer. Asian Pac J Cancer Prev 2011; 12: 939-46.
12. Hartwig S, Siegel J, Schneider P. Preventability and severity assessment in reporting adverse drug reactions. Am J Hosp Pharm 1992; 49: 2229-32.
13. Hesketh PJ, Kris MG, Basch E, Bohlke K, Barbour SY, Clark-Snow RA, et al, Antiemetics: American Society of Clinical Oncology Focused Guideline Update. J Clin Oncol 2016; 34: 381-6. DOI: 10.1200/JCO.2015.64.3635.
14. New Recommendations for Controlling Nausea and Vomiting Related to the Cancer Treatment. [Online] [Cited 2017 Sept 1]. Availabel from URL: https://www.asco.org.
15. NCCN Guidelines for Antiemesis V.1.2017. [Online] [Cited 2017 June 1]. Availabel from URL: https://www.nccn.org.
16. MASCC/ESMO Antiemetic Guidelines 2016. [Online] [Cited 2017 Jan 1]. Availabel from URL: https://www.mascc.org.
17. NCCN Guidelines Insights: Antiemesis, Version 2.2017. [Online] [Cited 2017 Jul 26]. Availabel from URL: https://www.jnccn.orgs.
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|Publication:||Journal of Pakistan Medical Association|
|Article Type:||Clinical report|
|Date:||Jun 30, 2018|
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