Targeted therapies and adverse drug reactions in oncology: the role of clinical pharmacist in pharmacovigilance

In recent years, anticancer treatments have seen an enormous evolution. Targeted therapies are a new generation of anticancer drugs which interfere with specific molecules that are involved in the growth, progression, and spread of cancer, and are expressed by specific cancer types. These drugs have introduced the concept of individually-tailored cancer treatment. The specific mechanism of action of target therapies should cause less toxic effects than conventional chemotherapy drugs [1]. The specific safety profile of each new drug, which is the information known about its safety at the time of marketing, has always been based on pivotal clinical trials. For this reason, the adverse drug reactions (ADRs) reported in the Summary of Product Characteristics (SPC) cannot be exhaustive [2‐4], because the potential new drugs are tested under controlled conditions, with a small sample of selected patients, and often with a short follow-up time. The differences between selected patients enrolled in clinical trials and the real-world patients regard the characteristics of the latter [2]. Often, the real-world patients in oncology are represented by elderly patients which may be considered as a “special population”. Elderly patients are at a high risk of ADRs, medical errors, and drug interactions, because of comorbidities, polypharmacy, greater vulnerability, and age-related changes in pharmacokinetics and pharmacodynamics [4].

In everyday clinical practice, there is a significant list of side-effects that can be ascribed to targeted drugs; indeed, although they are different from the well-known side effects caused by chemotherapy, they can severely compromise patients’ quality of life, and can even cause discontinuation of therapy or changes in the therapeutic strategy [5].

Pharmacovigilance aims to improve patients’ safety through the detection of ADRs. Spontaneous reporting is the best method for highlighting adverse drug reactions outside clinical trials [6].

In oncology, under-reporting of adverse reactions is a common phenomenon, because ADRs are generally considered inevitable [7]. In addition, there is a relevant decrease of patient’s satisfaction during anticancer treatment as a consequence of ADRs. A shift in the trend of reporting ADRs by health professionals and patients is considered to be an important element to improve patient’s safety and adherence to targeted therapies. The involvement of patients in Pharmacovigilance reporting systems (PVRS) is a potential strategy to increase the knowledge of oncological ADRs, increase patient’s satisfaction, and reduce the phenomenon of under-reporting [8‐10].

The real conditions of clinical daily practice are needed to detect all of the possible “real” toxicities imputable to drugs, because ADRs reported in SPCs are essentially based on clinical trials. Patients often present comorbidities, polypharmacy, a greater vulnerability, and age-related changes in pharmacokinetics and pharmacodynamics. Indeed, the self-administration of oral drugs increases the risk of ADRs because of the improper use of drugs [22]; consequently, patients often suspend or self-regulate the dose of the drug when they experienced an important adverse drug reaction, with a possible decrease of therapy’s effectiveness. Furthermore, ADRs are the major problem of pharmacovigilance, especially in the oncology setting, as the anticancer drug toxicity is considered common, and a normal consequence of these therapies [23]. Health professionals do not report ADRs because they generally think that there could be negative consequences for the patients’ therapy if they fill out PV reports or complaints by the pharmaceutical industry [7, 24]. Moreover, they often have several doubts about how to appropriately complete the PV report. Often, patients are not informed about the existence of the PV report and about the possibility of directly completing this report. Motivating health professionals and patients to report ADRs to improve the knowledge of pharmacovigilance activities is an effective approach against under-reporting [4].

In this study, we showed the importance of pro-active pharmacovigilance in order to efficiently highlight adverse drug reactions, and the fundamental role of the pharmacist in ensuring patient’s safety. Most patients (71%) enrolled in the study presented comorbidities, and were therefore more vulnerable. The median age of patients enrolled in our study was 61 years old and the majority (54%) were female; in clinical trials, patients enrolled are young, male, and with no comorbidities.

Furthermore, it is also worth noting that even with a small number of patients, it has been possible to observe a difference in the incidence of some ADRs and to identify unknown ADRs. 28.6% of patients in monotherapy with bevacizumab had headaches but none had high blood pressure. Indeed, 42.9% of patients being treated with bevacizumab reported myalgia/arthralgia without disease progression. In patients treated with sunitinib, the collected data showed a significant difference in the incidence between ADRs observed in patients and those reported in SPC. All patients taking sunitinib followed the drug’s therapeutic scheme: 4 consecutive weeks, followed by a 2 week rest period. Thus, we considered the rest period to be a de-challenge and the drug re-intake as a re-challenge. We observed ADRs only during the drug intake period. Applying the PV principles, the correlation between ADRs reported and sunitinib was certain [12]. In particular, 96% of patients showed hypothyroidism during the treatment with sunitinib and 56% patients showed musculoskeletal pain without progression of the disease. We also observed 44% of patients with hypercholesterolaemia and hypertriglyceridemia, which improved during the interruption of sunitinib’s administration. In total, 8 of the 20 patients who took sorafenib showed neuropathy, so the drug had to be suspended because of this toxicity. Imatinib caused eyes toxicity; in particular, 67% of patients presented eyelid oedema, and 42% showed increased lacrimation. We observed unknown ADRs and searched for them in the Eudravigilance and AIFA databases to verify whether there were other reported cases other than ADRs [20, 21]. The results from our study showed that 12% of patients being treated with bevacizumab developed hypomagnesaemia and this adverse reaction was also reported in the Eudravigilance database. In the literature, this adverse effect is linked to anti-epidermal growth factor receptor (EGFR) monoclonal antibodies or to chemotherapy, but it is not linked to bevacizumab [25, 26]. Patients that used lenalidomide presented hyperglycaemia and hypercholesterolaemia as unknown adverse reactions. Those adverse effects have also been reported in the Eudravigilance database, but they could be associated with the concomitant use of dexamethasone. The unknown ADRs observed with sorafenib are also reported in the Eudravigilance database and we observed an improvement in adverse reactions with the suspension of sorafenib. Finally, although we observed neutropenia with cetuximab and there are some cases in the Eudravigilance and AIFA databases, the concomitant use of chemotherapy could affect this adverse effect. We also observed uncommon adverse effects with these ten targeted-therapies. These adverse events are not generally associated with the drugs and are consequently not reported to the regulatory agencies, causing a non-revised therapeutic administration of drugs. This can lead to serious health risks for the patient. It is important to report unknown and uncommon ADRs to the regulatory agency, in order to improve safety information about these new generations of drugs [2].

The results of the present study are also important for clinical practice. The monthly semi-structured interview allowed to understand if the drug had been taken correctly by the patient and intervened if there was any case of non-adherence. The review of Lam and Fresco [27] highlights that patient interviews and pill count are indirect measures used in routine clinical practice to verify patient’s non-adherence. Indeed, the monitoring of patients and the information gave them about the management of ADRs increase the satisfaction of patients and the dialogue between patients, health professionals, and pharmacists. Patients contacted the pharmacist if ADRs were present; if patients contacted their pharmacist before taking other substances (supplementations, herb, medical devices, etc.) or to understand how to take the drugs, the risk of interactions and adverse effects could decrease. Finally, the involvement of pharmacists in this study increased the pharmacovigilance reports from the beginning to the end of the study (37 vs. 83 individual case reports) [28].

During the study, we observed a difference of ADRs between the SPC and patients enrolled in the study as well as some unknown ADRs. This observational study also highlighted that there was an increase in pharmacovigilance reports, and therefore a decrease in the under-reporting phenomenon. This improved the information about ADRs of these ten targeted-therapies. Patient’s monitoring improved their satisfaction and decreased the autonomous suspension of drugs or self-regulation, and consequently adverse effects. Indeed, patients immediately contacted the pharmacist if there were changes in the treatment or ADRs. These results have given a high value to pharmacovigilance studies and the presence of clinical pharmacists in the treatment team to reduce the phenomenon of under-reporting. Results from the present study might be a starting point for developing a randomised trial which aims to confirm the impact of the pharmacist on improving patient’s adherence and in measuring the difference in ADRs reports with the intervention of the pharmacist.