Impact of Clinicopathological Parameters in Chemo-Induced Adverse Drug Reaction in Treatment Strategy of Colorectal Cancer: A Hospital Based Prospective Study from Eastern India

Keywords

Adverse Drug Reactions, clinicopathological, Causality assessment, pharmacovigilance

Abstract

Adverse Drug Reactions (ADRs) are a prime cause and a major concern especially for chemotherapy receiving patients due to their suppressed immunity to combat other subsidiary malfunctions of the body. The findings of the study include accumulation of ADRs induced by chemotherapy in colorectal cancer patients ranging between 19 to above 70 years. One hundred eighty CRC patients were included in this study. Mild to moderate ADRs were observed in all age groups with the maximum being observed in the elderly. Mild reactions were observed in 35.3% males and 37.1% females while 16.8% males and 10.8% females showed moderate reactions. Higher tumor stage and grade (p<0.05) play a crucial role in ADR. Among CRC patients most commonly found ADRs were Nausea and vomiting (16.17%) followed by anorexia (14.97%), blurred vision (13.77%) etc. Results provide an insight that DNA modifying agents and topoisomerase inhibitors have an impact on mortality rate and moderate ADR (p<0.01). Both WHO causality assessment scale and Naranjo’s algorithm revealed similar grade in ADR, except for nausea & vomiting and stool incontinence due to non-specific reaction. This study helps to correlate the mutual association of clinicopathological parameters and chemo-induced ADR and also emphasized on the need of pharmacovigilance to increase the quality life of cancer patients.

Citation

Roy R and Banerjee K. Impact of Clinicopathological Parameters in Chemo Induced Adverse Drug Reaction in Treatment Strategy of Colorectal Cancer: A Hospital Based Prospective Study from Eastern India. J Gastroenterol. 2018; 4(1): 1013s.

Introduction

Adverse Drug Reactions (ADRs) may be defined as any unintended, unexpected response resulting from consumption of pharmaceutical product(s). According to the World Health Organisation (WHO), ADR is defined as “noxious and unintended” response to any drug. Patient safety, being the salient parameter of treatment strategy especially in case of oncology practice, ADRs stands a major concern of patient care. ADR was reported to increase the treatment expenditure moreover causing morbidity & mortality [1] and has stood a major challenge in the establishment of a pharmaceutical agent. When a new investigational drug moiety or an existing pharmaceutical with newer application (New Drug Application) approves itself of preclinical tests, Phase I clinical trial sets in on healthy volunteers where fewer commonly occurring adverse effects are mostly observed at this stage. ADRs (existing or absolutely unfamiliar ones) are specifically visualized on patients due to variable physiology of the receiving patients. In present day’s treatment algorithm in oncology practice, chemotherapy has stood as an indispensible strategy [2] , while administration of chemotherapeutics incurred common ADRs like vomiting, nausea, dizziness to severe like renal dysfunction, deep vein thrombosis to impaired renal dysfunction [3].

Colorectal cancer (CRC) contributes to a major portion of cancer related death worldwide [4], ranking fourth in men and third amongst female [5]. Patients with CRC are prescribed conventional chemotherapeutic drugs like 5-FU, Oxaliplatin, Irinotecan etc, and exposure to these drugs induce unintended effects as they interfere with the normal functioning of actively dividing healthy cells of the body resulting in ADRs to Serious Adverse events (SAE). A recent meta-analysis from USA showed that angiogenesis inhibitor Bevacizumab in combination with other chemotherapeutic agents resulted in increased mortality than Bevacizumab as monotherapy [6].

Different clinicopathological parameters such as tumor grade, size, lymph node status and metastatic condition have impact on choice of chemotherapeutic drugs and associated ADR [7]. Thus, aim of the present study was to correlate the mutual association of clinicopathological parameters and chemo-induced ADEs/SAEs in CRC patients in a tertiary care hospital of Eastern India.

Materials and Methods

This is an analytical, observational study. One hundred eighty (N=180) CRC patients (aged between 15 years to above 70 years) were included in this study. A detailed clinical history was taken during the last three years i.e. from May 2013 to May 2016.

Signs and symptoms of these patients were observed and demographic details along with clinicopathological factors were recorded. ADRs, nature of ADRs and other co-morbidity factors were noted for this study. These were performed at an interval of two weeks through routine check-up. The causality was assessed by both WHO-UMC causality assessment scale and Naranjo scale [8,9]. The entire study was approved by the ethical committee of Netaji Subhas Chandra Bose Cancer Research Institute, Kolkata, following the guidelines given by Indian council of Medical Research. Consents were obtained from the patients/parents before including them in the study.

Inclusion and/ Exclusion criteria

CRC patients devoid of any other ailments who underwent only chemotherapy as a treatment to CRC during the above mentioned study period were included in our study. Alopecia happens to be a common issue associated with most chemotherapeutic agent as the hair follicles are sensitive to these agents, so it was excluded from consideration as ADR associated symptom in our observational study. A specially designed data collection form including socio demographic status, habits, blood reports, drug for other ailments, hospital stay, comorbid factors, ADRs, nature of ADRs and sign and symptoms were used to collect inpatient’s data.

Drug regimen under study

Based on available data on CRC patients, four distinct classes of drugs were considered in our study: DNA modifying agents (5-FU+Cisplatin+Paclitaxel, Oxaliplatin and cisplatin), microtubule inhibitors (eg: Paclitaxel), topoisomerase inhibitor (Irinotecan), antimetabolite (5FU, Capecitabine).

Statistical Analysis

Descriptive statistical analyses were done by chi-square using SPSS (version 16). For all comparisons, p<0.05 was considered as level of significance. Overall survival (OS) was measured from the date of admission to the date of most recent follow-up or death (up to 3 years) by using Kaplan-Meier survival analysis.

Result

Patient Demography

180 patients were included in this study of which stage I comprised of 33 patients (18.33%), while stage II, III and IV constituted 86 (47.78%), 45 (25%) and 16 (8.89%) patients respectively. The study population consisted of 94 males (52.22%) and 86 females (47.8%) where 13 patients (7.22%) did not develop any ADR (Table 1). Out of the 167 ADR reported CRC patients, 59 male patients (35.3%) and 62 female patients (37.1%) showed mild reactions whereas 28 male (16.8%) and 18 female (10.8%) showed moderate reactions (Table 2). The age distribution of patients ranging between 15 to above 70 years where majority of moderate ADR cases were noticeable in the age group of 50-59 years (12%) (Figure 1).

Table 1: TNM and Duke staging among CRC patients.

Table 2: Comparison between the patients (N=167) with mild and moderate ADR at different stage, grade, habit (smoking, alcohol), sex with p-Value.

Figure 1: Age profile of colorectal cancer patients (N=167).

Association of ADR with Tumor stage, grade, habit (smoking, alcohol) and sex

A significant association found between ADR with higher tumor stage and grade (p<0.05) while no association was observed with sex and habits (smoking, alcohol) (p>0.05) (Table 2).

Pattern of ADR among CRC patients

167 CRC patients had reported ADR after receiving a single or multiple course of chemotherapy. Nausea & Vomiting, Anorexia, Blurred vision, Peripheral Neuropathy and Neutropenia were noted among maximum number of patients irrespective of their tumor stage and grade (Table 3).

Table 3: ADR profile of CRC patients (N=167).

Association of chemotherapeutic Drug regimen with common ADR

Among the different types of chemotherapeutic regimen, 46.1% patients of CRC received DNA modifying agents while 17.22%, 21.67% and 15% of patients were prescribed with microtubule inhibitor, topoisomerase inhibitor and antimetabolites respectively. Figure 2 illustrates different drug regime and common ADR.

Figure 2: Illustrates different drug regime and common ADR.

Causality assessment of ADR

In accordance to the WHO-UMC causality assessment scale [8], ADRs related with DNA modifying agents were “35.17% probable” and “44.3% possible”; with microtubule inhibitor it was “22.22% probable” and “44.45% possible”; “55.56% probable” and “33.33% possible with topoisomerase inhibitors; with antimetabolites “32% probable” and “44% possible” (Table 4).

Table 4: Causality assessment of ADR by Naranjo’s algorithm and WHO-UMC system.

Observation regarding ADRs collected from patient’s corner and following Naranjo’s Algorithm (according to Naranjo Causality Scale, score ranging between 5-8 are classified as Probable and 1-4 are classified as Possible) [9] we have categorized that DNA modifying agents were “35.17% probable” and “44.3% possible”, microtubule inhibitors were found “25.93% probable and “40.74% possible”; “58.53% probable” and 33.33% possible with topoisomerase inhibitors”; with antimetabolites 32% probable” and “44% possible” (Table 4).

Survival analysis

The Kaplan-Meier (K–M) survival analysis revealed (p value <0.01) that mortality rate and moderate ADR cases were distinctly observed higher in patients undergoing treatment with DNA modifying agents and topoisomerase inhibitors (Figure 3) in comparison to microtubule inhibitors and antimetabolites (Data not shown)

Figure 3: Kaplan-Meier analysis of survival of CRC patients (upto 3 years) with A: DNA modifying agent and B: Topoisomerase Inhibitor with Mild/ Moderate ADR.

Discussion

Over the past few decades, with the advent of newer chemotherapeutic regimen and novel drug delivery systems (NDDS) amendment in the scenario of cancer treatment correspondingly incidence of ADR has increased. ADRs are mainly studied during clinical trials but can be more appropriately discovered when used in larger population. New abnormalities that concurrently emerge with previous happenings should be reported immediately as resistance or shift in drug-receptor interaction or other metabolic dysfunctions do occur with repeated/single administration of pharmacologically active agents. There might be a pattern shift of ADR over time. ADRs may vary between patients depending on their different clinicopathological and other co-morbidity factors [10]. Thus, it is essential to be aware of these factors while opting for chemo regimen in oncology practice.

In the present study, 180 cases of colorectal cancer patients were taken as the studied population of which 13 did not show any ADR. Previous reports [11,12] showed that TNM staging and Dukes classification is the most powerful tool while opting for chemo drug. Thus, in the present study, we have classified our study population according to aforesaid classification (Table 1).

To the best of our knowledge, our report of ADR in CRC patients is the first work from Eastern India which encompasses different clinicopathological factors like stage, grade of CRC in relation to ADRs of different chemotherapeutic agents. In the present study, a strong correlation was found between different stages and grades of CRC with ADRs (<0.05).This may be the cause of reduced immune efficiency [13,14]. Alcohol, smoking and tobacco were reported to have an impact in drug metabolism. Previous reports established that smoking induces hepatic cytochrome P-450 isoenzymes 1A1, 1A2, while alcohol may sometimes facilitate and enhance the occurrence of ADRs [13]. Contrary to earlier observations, our present study showed no significant association of smoking, alcohol, tobacco consumption in the development of ADRs (p>0.05).

On the contrary to a study of Blacker et al., [15]out of 167 ADR reported CRC patients, majority of the male patients (52.09%) developed ADR followed by females (47.9%) which complies with other conducted studies as well as in present study (Table 2) [16,17]. The reason behind this fact lies on the dependence of pharmacodynamics and pharmacokinetic property of a particular drug on the physiological factors i.e. bodyweight, organ size, different gastric motility, glomerular filtration rate etc. which are comparatively lower in females than male [10].

Previous studies [18,19] highlight on higher frequency of ADR in elderly patients which also corresponds to our present observation, where majority of ADRs were reported in the age group 50-59 years with mean SD age 53.4 ± 1.57 years (Figure 1). Accumulation of drugs in the body due to reduced excretory and metabolizing function provides an answer for increased occurrence of ADRs in elderly patients [20]. Fluorouracil can get incorporated into nucleic acids which can be a cause of toxicity. This affects both the resting and rapidly multiplying cells. Major toxicity caused by paclitaxel is reversible myelosuppression or depression in immune system. Irinotecan inhibits acetylcholineesterase thereby producing cholinergic effects in some patients [21].

In our present study with 180 CRC patients, 167 of them had developed ADR of which Nausea & Vomiting (16.17%), Anorexia (14.97%), Blurred vision (13.77%), Peripheral Neuropathy (12.57%) and Neutropenia (11.98%) were observed more or less in all the patients. Data reflects nausea & vomiting to be the most popular ADR.There may be various reasons for these adverse drug events (ADEs) such as vomiting can be triggered by chemotherapeutic regimen Oxaliplatin as a non specific effect of the drug on the profusely dividing GI cells [22]. The chemoreceptor trigger zone in the medulla oblongata receives a signal from these chemotherapeutic agents and communication with the brain induces vomiting [19]. Chemotherapy undergoing patients who are simultaneously ultrarapid metabolizers of the isoenzyme CYP2D6 tend to experience vomiting more frequently [20]. Anorexia can be attributed as a symptom of cancer as it emerges owing to the increased release of tumor necrosis factor (TNF) and interleukin-1 (IL-1) to destroy cancer cells and when patient receives radiation or chemotherapy these cytokines’ release rate exceeds causing increased aversion to food [21]. Nausea & vomiting and anorexia are thus observed in majority of patients exposed to chemotherapy and radiation therapy.

White blood cells, platelets, red blood cells are affected by chemotherapy because the rapidly dividing cells of bone marrow are destroyed leading to reduced activity of immune system (or myelosuppression) [23]. Chemotherapy also pounces on nerve cells as they are more sensitive than other cells rendering them to become numb. Sensory nerves of the hands, feet and the nerve endings are damaged as they are more susceptible to Chemotherapy Induced Peripheral Neuropathy (CIPN) [24].

Alkylating agents and platinum drugs like cisplatin, oxaliplatin are highly emetogenic compounds though oxaliplatin can be considered to be less potent in triggering emesis. Oxaliplatin faces obstruction in being compatible with normal saline. This platinum analogue when administered as i.v. infusion was responsible for cold sensitivity in patients (6.59%). Axon part of the nerve cells is destroyed by chemotherapy which can be a cause of cold sensitivity [25]. Oxaliplatin has a 1,2-diaminocyclohexane (DACH) ring and upon administration it results in the formation of highly cytotoxic platinum-DNA adducts blocking DNA replication [26].

In our present study, most of the ADRs assumed similar grade in both WHO causality assessment scale and Naranjo’s algorithm except for nausea & vomiting and stool incontinence. Nausea & vomiting was assessed to be “probable” in Naranjo’s scale with microtubule inhibitor but “possible” in WHO-UMC scale. Stool incontinence was similarly judged as “probable” in Naranjo’s scale with topoisomerase inhibitor but “possible” in WHO-UMC scale. Physiologic factors and non specific effect of the drug can be a contributing reason in the fluctuation of calculated high and low values of Naranjo’s scale and WHO-UMC scale which is also similar to the previous study [22]. ADRs that did not acquire a satisfactory response from patients were grouped in the category “doubtful” (according to Naranjo’s scale) and “unclassified” (according to WHO-UMC scale). ADR for most of the patients receiving microtubule inhibitors was mild and thus was ranked as “doubtful” or “unclassified”. There were no “certain” or “definite” cases as re-challenge was not at all attempted because most patients who survived were either cured of cancer or had recurrence or metastatic cases which were prescribed with other antineoplastics [19].

In the present study, DNA modifying agents (oxaliplatin) and topoisomerase inhibitors (Irinotecan) indicated higher mortality (p<0.01) (figure 3) than the other aforesaid group of drugs (Data not shown for negligible mortality rate). Owing to their desirable therapeutic approach, these drugs have been administered in recurrence and metastatic conditioned patients. It can thus be assumed that physiologic factors and organ dysfunctioning can contribute to high mortality rate for the above mentioned cases.

Though ADRs develop as a consequence of being exposed to chemotherapy, often we have perceived that most patients recover and begin a new chapter of their life. But exceptions occur leading to the death of individuals which can be attributed to the physical conditions and inability to respond to any kind of medications.

Conclusion

Chemotherapeutic agents are mainly responsible for ADRs ranging from nausea, vomiting to neutropenia or peripheral neuropathy. It can be minimized by changing the chemo agent or modifying the dose depending on the clinicopathological and other factors of patients. This study emphasized on the need of pharmacovigilance awareness to reduce economic burden, ameliorate toxicity and increase the quality life of patients.

Acknowledgment

We are thankful to all the patients and other staffs of Netaji Subhas Chandra Bose Cancer Research Institute for their continuous support.

References

1. Nerurkar RP, Nadkar MY, Bichile SK. Need for monitoring adverse drug reactions. J Assoc Physicians India. 1998; 46: 673-674.

2. Chabner BA, Amrein PC, Druker BJ. Antineoplastic agents. In: Goodman and Gilman’s The Pharmacological Basis of Therapeutics, McGraw-Hill Companies, Inc., 11th edn: USA. 2006; 1315.

3. Beers MH and Berko R. The Merk manual. 17th edn: USA. 1999; 990-993.

4. Beyer KM, Zhou Y, Matthews K, Hoormann K, Bemanian A, Laud PW, et al. Breast and Colorectal Cancer Survival Disparities in Southeastern Wisconsin. WMJ. 2016; 115: 17-21.

5. Parkin DM. International variation. Oncogene. 2004; 23: 6329-6340.

6. Ranpura V, Hapani S, Wu S. Treatment-related mortality with bevacizumab in cancer patients: a meta-analysis. JAMA. 2011; 305: 487-494.

7. MacDonald V. Chemotherapy: Managing side effects and safe handling. Can Vet J. 2009; 50: 665-668.

8. The use of the WHO-UMC system for standardised case causality assessment. 2011.

9. Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther. 1981; 30: 239-245.

10. Alomar MJ. Factors affecting the development of adverse drug reactions (Review article). Saudi Pharm J. 2014; 22: 83-94.

11. Akkoca AN, Yanık S, Ozdemir ZT, Cihan FG, Sayar S, Cincin TG, et al. TNM and Modified Dukes staging along with the demographic characteristics of patients with colorectal carcinoma. Int J Clin Exp Med. 2014; 7: 2828-2835.

12. Compton CC. Colorectal carcinoma: diagnostic, prognostic, and molecular features. Mod Pathol. 2003; 16: 376-388.

13. Sharma A, Kumari KM, Manohar HD, Bairy KL, Thomas J. Pattern of adverse drug reactions due to cancer chemotherapy in a tertiary care hospital in South India. Perspect Clin Res. 2015; 6: 109-115.

14. Steele ML, Axtner J, Happe A, Kröz M, Matthes H, Schad F. Adverse Drug Reactions and Expected Effects to Therapy with Subcutaneous Mistletoe Extracts (Viscum album L.) in Cancer Patients. Evid Based Complement Alternat Med. 2014; 724258.

15. Blacker K, Stern R, Wintroub BU. Cutaneous reactions to drugs, Dermatology in General. McGraw-Hill, New York. 1993; 1783-1794.

16. Mallik S, Palaian S, Ojha P, Mishra P. Pattern of adverse drug reactions due to cancer chemotherapy in a tertiary care teaching hospital in Nepal. Pak J Pharm Sci. 2007; 20: 214-218.

17. Prasad A, Datta PP, Bhattacharya J, Chaitali Pattanayak , Ashok Singh Chauhan and Parbaty Panda, et al. Pattern of adverse drug reactions due to cancer chemotherapy in a tertiary care teaching hospital in Eastern India. J Pharmacovigilance. 2013; 1:107.

18. Jose J, Rao PG. Pattern of adverse drug reactions notified by spontaneous reporting in an Indian tertiary care teaching hospital. Pharmacol Res. 2006; 54: 226-233.

19. Poddar S, Sultana R, Sultana R, Akbor MM, Azad MAK, Hasnat A. Pattern of adverse drug reactions due to cancer chemotherapy in tertiary care teaching hospital in Bangladesh. Dhaka Univ J Pharm Sci. 2009; 8: 11-16.

20. Belachew SA, Erku AW, Mekuria AB, Gebresillassie BM. Pattern of chemotherapy-related adverse effects among adult cancer patients treated at Gondar University Referral Hospital, Ethiopia: a cross-sectional study. Drug Healthc Patient Saf. 2016; 8: 83-90.

21. Tripathy KD. Essentials of Medical Pharmacology, Sixth ed. Jaypee Bothers Medical Publishers (P) Ltd. 2008; 819-834.

22. Alcindor T, Beauger N. Oxaliplatin: a review in the era of molecularly targeted therapy. Curr Oncol. 2011; 18: 18-25.

23. Schnell FM. Chemotherapy-Induced Nausea and Vomiting: The Importance of Acute Antiemetic Control. Oncologist. 2003; 8: 187-198.

24. Dewys WD, Begg C, Lavin PT, Band PR, Bennett JM, Bertino JR, et al. Prognostic effect of weight loss prior to chemotherapy in cancer patients. Eastern Cooperative Oncology Group. Am J Med. 1980; 69: 491-497.

25. Banach M, Juranek JK, Zygulska AL. Chemotherapy-induced neuropathies-a growing problem for patients and health care providers. Brain Behav. 2016; 7: e00558.

26. Raymond E, Faivre S, Woynarowski JM, Chaney SG. Oxaliplatin: mechanism of action and antineoplastic activity. Semin Oncol. 1998; 25: 4-12.