The safe use of drugs placed on the market is assured by pharmacovigilance. Through pharmacovigilance, adverse drug reactions can be continuously monitored so that possible risks in medicinal products can be promptly identified.
The aim of pharmacovigilance is to assure a favourable risk–benefit ratio for the population exposed to post-marketed medicinal products. Activities include detection, evaluation, validation, and prevention of adverse drug reactions. Data are gathered from various sources. These include spontaneous reporting system, trials, scientific research, company data, and intensive monitoring systems [1-5].
Spontaneous reporting is a crucial means of pharmacovigilance, as it prevents harm to the population and defines the safety and efficacy profile of medicinal products. In Italy, pharmacovigilance has improved during the past few years owing to the national pharmacovigilance network of suspected adverse drug reactions, and the promotion of educational and cultural activities. Nevertheless, spontaneous reporting by healthcare providers is still below the average recommended by WHO .
Antitumour drug reports, in particular, have increased, and still need improvement. The paucity of reports may be due, in some cases, to the difficulties in finding an unequivocal relationship between toxicity, reaction and drugs used [7-10].
In oncology, the difficulties of associating adverse reactions and drugs are even more pronounced. Reasons for this include the severity of the disease, the polychemotherapies used, complex protocols used—of which component drugs can produce toxicity even at therapeutic dosages, and worsening conditions of patients with other clinical conditions and in those who are immunocompromised [11-14].
In some cases, this scenario could be exacerbated by the use of non-conventional treatments, of which physicians may be unaware .
Concerned with these problems, we considered how best to manage pharmacovigilance in oncology but still improve the appropriate use of drugs during a patient’s common care pathway and maintain their quality of life. We decided that, from time of admission to hospital for oncological treatment, patients should be carefully monitored for the occurrence of potential toxicities that could result from their drug regimens .
In the Piedmont Region of Italy, pharmacovigilance activities are being encouraged in clinical practice. We were offered the opportunity, along with other local pharmacists of healthcare systems, to present our project, a collaborative study between oncologists and pharmacists.
Below we describe the oncology project presented and results obtained, focusing particularly on breast cancer.
Design and primary objectives
The study was multicentred and observational in design. The primary objectives were to: 1) observe and report toxicity developed in people receiving parenteral, neoadjuvant, adjuvant and first-line treatments for breast cancer and colorectal cancer in clinical practice; and 2) observe and record the consequences of toxicity resulting from oncological treatment. Secondary objectives were to: 1) note and collect the type of protocols used in the various centres for both the diseases; 2) report possible actions taken to control any toxicity observed; and 3) register patient’s outcome, such as progressive disease or mortality [17-21].
Materials and methods
The centres involved were Molinette Hospital, Turin; Gradenigo Hospital, Turin; Institute for Cancer Research and Treatment, Candiolo, Turin; General Hospital, Ivrea, Turin; together with the help of Consorzio Mario Negri Sud, Santa Maria Imbaro; for its research skills. We had planned to involve five centres, but one was not given Ethics Committee authorisation because it was felt that the pharmacists lacked the skills and resources to do this.
The study was funded by the Piedmont region within a wider project of pharmacovigilance promoted by pharmacists. The study population included people affected by breast cancer or colorectal cancer admitted to day wards of the centres involved. The study took place between 2007 and 2010 as stipulated by the Ethics Committee. Participants were enrolled when they first commenced treatment (first cycle) until the end of their treatment. Individuals affected by colorectal cancer receiving radiotherapy were excluded.
WHO criteria  for registering toxicity were used on the basis of simplicity. Data were collected by each centre and sent on paper to the reference centre for processing. A specific software was devised for processing.
Multivariate statistical analysis was used to assess the data. Participants were also followed for co-morbidities at the time of recruitment and thereafter for co-morbidities that could have occurred according to the cumulative illness rating scale . This scale is used to indicate the health status of frail, institutionalised older adults. Physicians rated the pathology and impairment of major organs, psychological, metabolic, neuro logical and musculoskeletal conditions of the participants from one to five—one signifying no impairment to the organ or system, and five signifying extremely severe impairment.
We used the Eastern Cooperative Oncology Group (ECOG) performance status scale to assess patients’ physical status and ability. The first assessment took place at recruitment (baseline), and recorded patient data such as demographics, physical description, tumour diagnosis, and planned oncology treatment. The second assessment took place at subsequent hospital admissions, reporting any toxicity that may have occurred, any reduction in drug dosages, and any specific treatment used to control toxicity. Data related to toxicity or treatment referred to those occurring between the courses.
A total of 340 participants were recruited; 257 (75.6%) were women. One hundred and eighty-two women (53.5%) were affected by breast cancer; 158 people (46.5%) were affected by colorectal cancer. The median age of our sample was 45–64 years (54%). Scores on the ECOG scale varied from Grade 0 (244 participants) to Grade 1 (17 participants). Most participants received adjuvant chemotherapy for both groups.
One hundred and fifty-three (84%) of the women enrolled in the breast cancer group received adjuvant chemotherapy. One-hundred and six (67%) participants in the colorectal cancer group received adjuvant chemotherapy.
One hundred and twenty-five participants (37%) received at least one reduced dose, owing to toxicity; 224 participants (66%) completed their treatment; 116 (34%) discontinued or delayed the treatment, 67 (58%) because of toxicity. Thirty-eight (11%) participants had progressive disease, and 11 (3%) discontinued treatment because of toxicity. No deaths occurred.
For women with breast cancer with co-morbid conditions, we observed that hypertension was one of the most common co-morbidities, followed by metabolic, psychiatric and respiratory dysfunctions, see Figure 1. Ages ranged from 40–70 years, see Figure 2. The most commonly prescribed chemotherapies are presented in Table 1.
*Figures 1 and 2, and Table 1 pending to upload.
One of our aims was to monitor prescribing activity. Surprisingly, different treatments were offered by the various centres. We noticed that one centre nearly always used the 5FU, epirubicin and cyclophosphamide (FEC) regimen followed by docetaxel, which is a sequential administration of three cycles of FEC and three cycles of docetaxel every three weeks.
Sixty-five percent of participants received an FEC-based regimen (all dosages of epirubicin included), whereas 59 participants received the combination FEC and docetaxel administered sequentially. For toxicity related to docetaxel administration (100 mg/m2 days, 1–21), we recorded haematologic impairment followed by hair loss. Gastrointestinal toxicity was one of the most frequent toxicities observed, see Figure 3.
*Figure 3 pending to upload.
With FEC regimens, toxicities observed (any grade) were gastrointestinal, hair loss, and haematologic toxicity, see Figure 4.
*Figure 4 pending to upload.
Grade 3 toxicity occurred in all women with breast cancer receiving adjuvant treatment. Toxicities included hair (76%), haematologic (37%), gastrointestinal (12%), and others (5%). Grade 4 toxicity was reported among 14% of all women receiving adjuvant treatment, of which 95% was haematologic toxicity. Thirty-two per cent of those women received granulocyte colony-stimulating factor-based therapy.
Data collected were as expected, and the toxicities observed were similar to those previously reported. The most surprising finding was the difference in protocols used by the different centres. We also found different sensitivity to toxicity reports among the various centres: the smaller centres being more attentive, with a higher percentage of reports, whereas the larger centres seemed to be more used to managing toxicity.
This study was a positive experience for us. It was a good opportunity to attend physician consultations. We talked to the patients, which is uncommon in Italy. The study was complex and time consuming but, despite scarce resources, we obtained interesting results. We believe that pharmacists encounter difficulties carrying out such projects because they are not considered to be researchers. Research needs more time and institutional recognition, together with space dedicated to it; pharmacists have the skills, and they should have the opportunity to participate in it.
This project forms the basis of future investigations. In order to obtain specific and more detailed information in suspected adverse drug reactions in oncology medicines, the monitoring and recording of hospitalisation, or any access to those departments requiring healthcare interventions owing to suspected drug toxicity, would be more useful [24-28].
Author for correspondence
Franca Goffredo, PharmD
Institute for Cancer Research and Treatment FPO
142 km 3.95 Strada Provinciale
IT-10060 Candiolo (TO), Italy
Marco Bellero, PharmD
Elena Giubellino, PharmD
Alessandro Comandone, MD
Sergio Bretti, MD
Libero Ciuffreda, MD
Oscar Bertetto, MD
Marilena Romero, PharmD
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