Compliance and patient reported toxicity from oral adjuvant bisphosphonates in patients with early breast cancer. A cross sectional study.

BACKGROUND: Adjuvant bisphosphonates (BPs) are recommended as part of routine early breast cancer treatment for many postmenopausal (PM) women within the past year. There is a paucity of 'real world' data on compliance and patient satisfaction with oral BPs in this population. The aim of our study was to investigate patient reported compliance and toxicity of these drugs in a retrospective cohort study. PATIENTS AND METHODS: 413 patient were identified as receiving adjuvant oral BPs as part of their breast cancer treatment in the past 12 months from five NHS hospitals. The validated Osteoporosis Patient Treatment Satisfaction Questionnaire (OPSAT-Q) was sent to all suitable patients (n = 389).
RESULTS: 295 (76%) of patients responded. Average age was median (range) 67 (35-89). The majority of patients had T1 (52%), N0 (61%) grade 2 (58%) ER positive (87%), HER2 negative (84%) breast cancer and were PM at diagnosis of breast cancer (93%). All patients had been prescribed at least 1 month of oral ibandronate 50 mg daily. Review of items rated on the 7-point scale (1 = very dissatisfied to 7 = very satisfied), the mean item scores ranged from 5.0 (lowest) for time required to take oral BPs, to 6.1 (highest) for how easy it is to remember to take the medication. <10% of patients were extremely bothered by heartburn or stomach upset. 16% of responders stopped oral BPs with 10% of those converting onto IV BPs.
CONCLUSIONS: Prevalence of severe side effects in a 'real world' population of PM women receiving adjuvant BPs is low and these drugs are generally well accepted and tolerated by patients.

Introduction

A significant percentage of women diagnosed with breast cancer develop metastatic disease, with bone representing the first site of metastasis in approximately 50% of patients. Bisphosphonates (BPs), as potent inhibitors of osteoclast-mediated bone resorption, significantly reduce the risk of skeletal complications in metastatic bone disease and have been used in this treatment setting for many years.

A wealth of pre-clinical data reported that BPs may modify disease course and disrupt the metastatic process by preventing tumour cell homing to bone, inducing tumour cell apoptosis in bone, maintaining dormancy of tumour cells in bone, modifying the bone microenvironment and interrupting the vicious cycle of bone metastasis by inhibiting the release of growth factors rendering it less fertile for metastatic tumour growth [1], [2], [3], [4]. These data support the rationale for clinical metastasis-prevention studies. The first adjuvant study showing a benefit of clodronate in terms of bone-metastasis free survival and overall survival was published 20 years ago [5]. A larger oral clodronate trial initiated in the 1990s supported the findings from the Diel study [6] but a third trial reported a negative and potential harmful effect on disease outcome [7]. Over the last 10 years several further large adjuvant metastases prevention studies, including the use of oral ibandronate and intravenous zoledronic acid, have been conducted [8], [9], [10], [11]. Whilst results were from these trials were not consistent, two of these trials, including ABCSG-12 and AZURE/BIG 1-04, gave the first indication that the benefits of adjuvant bisphosphonates are restricted to women with a low oestrogen environment, achieved either through menopause or treatment with ovarian suppression.

Subsequently, these findings have been corroborated by results from the Early Breast Cancer Trials Collaborative Group (EBCTCG) meta-analysis, published in 2015 [12]. This included data on 18,766 women treated in trials with 2–5 years of bisphosphonates, including 11,767 post-menopausal women in which bisphosphonates reduced the risk of recurrence (RR 0.86, 95% CI 0.78–0.94, 2p = 0.002), distant recurrence (RR 0.82, 95% CI 0.74–0.92, 2p = 0.0003), bone recurrence (0.72, 0.60–0.86, 2p = 0.0002) and a reduction in 10 year breast cancer mortality by 3.3% (RR 0.82, 95% CI 0.73–0.93, 2p = 0.002) was observed. There was no beneficial survival outcome effect in pre-menopausal women. The benefits seen in post-menopausal women were similar irrespective of grade, ER status, axillary node status, receipt of chemotherapy or not. The meta-analysis was also not able to demonstrate any difference in terms of dosing regimen or type of bisphosphonate.

International consensus recommendations and guidelines have subsequently been published advocating the use adjuvant bisphosphonates in post-menopausal women with early breast cancer [13], [14] and have recommended oral clodronate or IV zoledronic acid as choice of agent. Although only published in abstract form so far, the SWOG S0307 included 6097 patients with stage I-III breast cancer receiving adjuvant systemic therapy randomized to receive 3 years of clodronate (1600 mg daily), ibandronate 50 mg po daily or zoledronic acid 4 mg IV monthly for 6 months, then 3-monthly for 2.5 years. There was no difference in 5-year disease-free survival between the 3 arms (88% in the clodronate and zoledronic acid arms, and 87% in the ibandronate arms) [15]. These data indicate ibandronate is an additional choice of agent in the adjuvant setting. Of interest, prior to randomisation, 76% of patients expressed a preference for oral medication versus 24% for intravenous if the drugs proved equal in efficacy. Clodronate (a non amino-BP) has slightly difference gastrointestinal toxicity than ibandronate (an amino BP) in that the main side effects reported with clodronate over placebo are diarrhoea (15% vs 7%) with less excess of upper GI toxicity over placebo (22% vs 19%). Ibandronate however is reported to double the incidence of GI toxicity including abdominal pain, dyspepsia, nausea and oesophagitis compared to placebo [16].

Locally in our practice, adjuvant bisphosphonates were commissioned by Sheffield Clinical Commissioning Group (CCG) in 2016, followed by other local CCGs shortly after, and came into routine clinical practice between November 2016 and February 2017. Post-menopausal patients, either naturally or rendered post-menopausal by ovarian suppression therapy with GnRH analogues, were selected for treatment and patients receiving adjuvant chemotherapy also received zoledronic acid 6-weekly for 3 infusions and then on completion of chemotherapy switched to oral ibandronate 50 mg daily to complete three years of bisphosphonate treatment. Patients not requiring chemotherapy received oral ibandronate 50 mg daily from the outset, intended for a 3-year treatment period. From the literature, concerns do exist regarding oral bisphosphonate compliance in the osteoporosis treatment settings, in which bisphosphonates are most commonly given as a weekly oral dose [17], but limited data is available on the compliance with the daily oral dosing recommended for prevention of recurrence of breast cancer. Now that oral ibandronate has been embedded into our local routine practice for over 12 months, we aimed to evaluate the compliance and tolerability of oral ibandronate within our early breast cancer population.

Patients and methods

The OPSAT-Q is a validated questionnaire to assess patient satisfaction with BP treatment [18]. Convenience, confidence and daily functioning whilst on oral BPs and overall satisfaction items are rated on a 7-point scale from “very dissatisfied” to “very satisfied”. Side effect evaluation includes ‘heartburn/acid reflux”, “stomach upset” and any “other side effects” and are rated on a 5 point scale from “not bothered at all “ to “extremely bothered”. In addition we collected data on whether patients have “considered” or “already” stopped their medication. We also included a free text box to facilitate patient comments. The OPSAT-Q questionnaire was modified for our patient population and was reviewed and approved by the Clinical Effectiveness Unit at Sheffield Teaching Hospitals Foundation NHS trust.

Patients were included in this study if they had a diagnosis of invasive breast cancer, which had been treated with curative intent and they had been prescribed at least 1 month of oral ibandronate (50 mg daily) between November 2016 and January 2018 from secondary care pharmacy records. Patients were excluded if they had developed metastatic disease since their ibandronate was first prescribed or if they were non-compliant with follow up oncology appointments. 413 patients were identified from pharmacy records at Weston Park Hospital Sheffield, Doncaster Royal Infirmary, Rotherham District General Hospital, Barnsley Hospital and Chesterfield Royal Hospital. 389 patients were identified as eligible to take part (see Fig. 1).

Fig. 1

Study consort diagram.

Statistical analysis was performed in graph pad PRISM v 7.0d and Excel v14.5.6. Average item scores were expressed as mean + 95% confidence interval. Other results were expressed as percentage of total study responders. Comparison of groups was evaluated using paired t-test for significance.

Results

Patient characteristics

Of 389 questionnaires sent out, 295 patients responded (76%). Mean (range) age was 67 years (35–89) and 273 (93%) were postmenopausal at the diagnosis of breast cancer. Those who were pre-menopausal were rendered chemically postmenopausal with goserelin prior to initiation of bisphosphonates. The majority of patients had T1 (52%), N0 (61%), grade 2 (58%) breast cancer giving a mean (range) Nottingham prognostic index of 4.3 (2.2–8.2)(see Table 1).

Table 1

Patient demographics.

Patient demographic	Number (% of responders)
Age (mean and range)	67 (35–89)
T stage
T1	152 (52%)
T2	127 (43%)
T3	17 (5%)
N stage
N0	181 (61%)
N1	77 (25%)
N2	28 (10%)
N3	13 (4%)
NPI (mean and range)	4.33 (2.2–8.2)
Tumour grade
1	17 (5%)
2	177 (58%)
3	113 (37%)
Menopausal status at diagnosis
Pre	14 (4%)
Peri	8 (3%)
Post	273 (93%)
ER Allred score
0–2	41 (13%)
3–5	7 (2%)
6–8	252 (85%)
Herceptin status
Positive	43 (15%)
Negative	257(84%)
Not tested	4 (1%)
Systemic treatment
Endocrine alone	137 (46%)
Chemotherapy	138 (47%)
Herceptin	37 (13%)

Patient satisfaction

The mean item scores for satisfaction where 1 reflects “very dissatisfied” and 7 reflects “very satisfied” were: 5.7 for how easy it is to take the medication, 6.1 for how easy it is to remember to take the medication, 5.5 for how well oral BPs fit into medication schedule, 5.0 for amount of time required to take oral BPs, 5.3 for overall satisfaction with the medication and 5.3 for how satisfied to continue taking the medication. We evaluated if there was any significant differences in satisfaction according to age, with the recognition that the majority of women ≤55years will still be in regular employment with caregiver responsibility [19]. There was no significant difference in mean item score for satisfaction with the exception of how well BPs fit into medication schedule with those ≤55 years scoring 5.3 and those >55years scoring 6.1 (p = 0.045) (see Fig. 2).

Fig. 2

Patient reported satisfaction stratified according to age. (1 represents “very dissatisfied”, 7 “very satisfied”). Bars represent mean + 95%CI. *P-value < 0.05 (paired t-test).

Patient reported side effects

The mean item scores for side effects where 1 reflects “not bothered at all” and 5 reflects “extremely bothered” were: 1.9 for heartburn/acid reflux, 1.7 for stomach upset other than heartburn/acid reflux and 1.8 for other side effects. Less than 10% of patients reported being extremely bothered by side effects (see Fig. 3). The predominant ‘other’ side effect reported by patients was aching muscles / joints / bones. 3 patients reported dental issues with no reports of osteonecrosis of the jaw, 4 reported skin irritation, 1 reported kidney problems.

Fig. 3

Patient reported side effects of oral ibandronate.

Discontinuation of oral BPs

22% of patients reported they had considered stopping their oral bisphosphonates but only 16% of responders (n = 47) had stopped. Of those that had stopped, 10% converted onto IV zoledronic acid but the remaining 6% did not continue with adjuvant bisphosphonates either due to advice from the General Practitioner, Oncology team or patient choice. In the 47 patients who had to stop oral BPs, the majority of those ceased the medication in the first 6 months of use (see Fig. 4).

Fig. 4

Time to cessation of oral ibandronate.

Discussion

Adjuvant BPs have now become standard of care to reduce breast cancer mortality in post-menopausal early breast cancer patients in Europe and America, supported by published guidelines on drug choice, duration and patient selection [13], [14]. Clinicians have the option to prescribe intravenous or oral BPs for 3–5 years duration after consideration of side effect profile and according to local commissioning agreements.

Patient satisfaction and compliance with BPs is important to optimise the benefit of a 17% relative reduction in breast cancer mortality as demonstrated in the recent meta-analysis of adjuvant BP clinical trials [12]. In the present study we investigated patient reported tolerability with daily ibandronate in women with early breast cancer. Patient satisfaction overall was good and less than 10% of patients were extremely bothered by side effects. This data reflects better tolerability than patient data from the metastatic setting where 24% of patients expressed dissatisfaction with the constraints, especially the time required to be upright after taking the tablet [20].This may be due to differences between the patient cohorts with the patients in our study receiving curative breast cancer treatment compared to the metastatic setting where polypharmacy is more likely to occur, patients may be symptomatic of their metastatic disease and a duration for compliance with the tablets is not defined, all of which can impact on resilience to comply with daily oral medication that requires such a stringent administration process. In addition, the potential to prevent metastatic disease and improve survival may be a stronger driver to comply with medication in the adjuvant setting than the prevention of skeletal related events in the metastatic setting.

In the adjuvant setting, there is currently no patient reported data on compliance and tolerability of oral BPs administered as a daily dose to reduce breast cancer mortality in a ‘real world’ setting. In the context of a randomised controlled trial of adjuvant clodronate, adherence to treatment at 3 years was 56% [10]. In the present study, rates of discontinuation from medication were low (16%) in the 295 patients who responded. This is lower than discontinuation rates seen in the metastatic studies of daily oral BP with clodronate (1600 mg/day) where rates of discontinuation were ∼35% due to GI side effects [21], [22], but similar to metastatic studies with daily ibandronate (5–50 mg/day) with a 10% discontinuation rate [23]. Compliance with weekly oral BPs in the metastatic breast cancer setting has also been evaluated and showed poor persistence with 45.6% of patients stopping after 1 year of therapy [24]. Previous studies have suggested oncologists tend to overestimate patient compliance with oral bisphosphonates and a third of surveyed oncologists anticipated that adherence would be >70% in the metastatic setting [25]. This has the potential to negatively impact on clinical outcomes and there is recognition amongst clinicians that strategies to improve compliance are needed [26].

In the osteoporosis setting, compliance is less with daily regimes compared to weekly regimes with a 40–60% higher discontinuation rate with daily compared to weekly regimes [27]. Compliance was evaluated in a systematic review of 27 studies in the osteoporotic setting and demonstrated persistence rates of 27.9–86.8% at 1 year with increased compliance in those patients who has experienced a fracture compared to those who were asymptomatic from their osteoporosis [28]. Compliance is higher in our population with a persistence rate of 84% at 1 year and may reflect patient perception of the importance of compliance with a medication that can improve survival after a breast cancer diagnosis.

Our adjuvant patient data is encouraging and can reassure clinicians that daily oral bisphosphonates in the early breast cancer setting are a viable option and adherence to the medication in the first year is 84%. If patients do stop, this is most likely to be in the first 6 months of treatment and is reflected in the reported early withdrawal from study rates (within 6 weeks of start) of 8% in the metastatic trials of ibandronate [16]. This is important clinical information that needs to be corresponded to primary care colleagues so that potential toxicities from this treatment are recognised and patients are referred back to secondary care for consideration of an intravenous BP regimen.

Our study does have limitations. We did not collect additional data on lifestyle factors that may have predisposed to poor compliance (including smoking, alcohol consumption, socioeconomic status, employment status). Additionally we did not record if the patient had pre-existing GI symptoms, which are not uncommon after adjuvant chemotherapy regimens containing oral steroids. We relied entirely on patient reported compliance with oral BPs and did not check primary care records of repeat prescriptions. The response rate to our questionnaire was 76% so it must be acknowledged that compliance rates may be lower than recorded. However, this is the first patient reported data to evaluate compliance with adjuvant daily oral BPs since they were introduced into routine clinical practice and provide useful data on which clinicians can base choice of drug and assess impact on local clinical practice.

In conclusion, prevalence of severe side effects in a ‘real world’ population of post-menopausal women receiving adjuvant oral BPs is low and these drugs are generally well accepted and tolerated by patients, but a proportion of patients will discontinue treatment. Further research is needed to understand if the compliance issues with oral BPs affect the clinical impact of adjuvant bisphosphonates on breast cancer mortality compared to an IV regimen.