Abstract
Objectives:
To define the profile of patients with prostate cancer (PCa) receiving a 3-month or 6-month formulation of luteinizing hormone-releasing hormone (LHRH) agonist in France and the reasons for choosing between formulations.
Methods:
This prospective 1-year observational study included patients with PCa starting LHRH agonist therapy in everyday practice. Reasons for prescription and patient preference were recorded at inclusion, 3 or 6 months, and 12 months. The percentage of patients with a renewed initial prescription was recorded during follow up.
Results:
A total of 1438 patients with PCa were included. Hormonotherapy was initiated more frequently with a 6-month (n = 903; 62.8%) than with a 3-month formulation (n = 535; 37.2%). The initial prescription was renewed in most patients after 3 or 6 months (86.1%) and 12 months (71%); 170 patients switched from a 3-month to a 6-month formulation during follow up. Presence of metastases influenced initial prescription (odds ratio 0.439; 95% confidence interval 1.095–1.892), with a 3-month formulation more often prescribed than a 6-month formulation to men with metastatic PCa at diagnosis (21.3% versus 15.8%, respectively). The most frequent reasons given by physicians for choosing the 6-month formulation were ‘simplification of therapeutic regimen’ (86.9%) or ‘fewer unnecessary visits’ (46.8%). Similar reasons were given for switching from a 3-month to a 6-month formulation during follow up. The most frequent reasons given by physicians to initiate therapy with a 3-month formulation were ‘usual practice/habit’ (55.5%) or ‘closer patient management’ (46.2%). ‘Closer patient management’ and ‘reassuring effect upon patient’ were the main reasons for switching from a 6-month to a 3-month formulation during follow up. Approximately 80% of patients were satisfied with the formulation they were prescribed and patients’ reasons for preferring one formulation over another were similar to the physicians’ reasons for prescribing these formulations.
Conclusions:
Slow-release formulations of LHRH agonists are useful therapies for physicians treating patients with PCa and there may be a preference for the 6-month formulation.
Keywords
Background
Prostate cancer (PCa), the most common cancer in France with an estimate of more than 71,000 new cases in 2012 [Haute Autorité De Santé, 2012], is a serious issue of public health. The incidence of PCa has increased in recent years (by 8.5% between 2000 and 2005) [Haute Autorité De Santé, 2012] due to the combined effect of population ageing, improvement in sensitivity of diagnostic procedures and wider use of prostate-specific antigen (PSA) screening tests. However, a concurrent decrease in the disease-specific mortality rate (2.5% per year) has occurred due to improved treatment management [Haute Autorité De Santé, 2012]. PCa has a relatively good prognosis with a 5-year relative survival rate estimated at around 80% [Haute Autorité De Santé, 2012].
Testosterone suppression remains the standard palliative treatment for patients with advanced PCa. Androgen deprivation therapy (ADT) can be achieved by either surgical or medical castration, or the use of antiandrogens, and both methods can be combined to achieve complete androgen blockade (CAB). The European Association of Urology (EAU) recommends initiating ADT as follows: as adjuvant therapy when nodal involvement is detected after surgery in patients with high-risk localized disease; for the long-term treatment of high-risk patients before and during radiotherapy and as short-term therapy before and during radiotherapy in selective cases; as an add on to external-beam radiation therapy in patients with locally advanced disease; as first-line hormone therapy in patients with metastatic disease; and for management of PSA relapse after radical prostatectomy or radiotherapy [Heidenreich et al. 2014].
Long-acting, luteinizing hormone-releasing hormone (LHRH) agonists are currently the main forms of ADT in advanced PCa and play a major role in the management of patients with locally advanced PCa (T2c–T4), lymph node metastases (N1) or with presence of metastases (M1). In the absence of metastases, LHRH agonists are generally reserved for patients who have symptomatic disease (T3–T4). They are generally delivered as depot injections on a 1-, 3- or 6-monthly basis. LHRH agonists have the potential for reversibility and enable the use of intermittent ADT. A meta-analysis evaluating single-therapy ADT for advanced PCa showed that LHRH agonists have similar efficacy to orchiectomy, regardless of the formulation of LHRH agonist [Seidenfeld et al. 2000]. Unlike surgery, LHRH agonist use avoids the physical and psychological discomfort associated with orchiectomy. The use of LHRH agonists to treat PCa may be associated with increased muscle and bone loss leading to osteoporosis and to an increased risk of bone fracture, which may be increased as a result of longer duration of ADT due to either improved survival or earlier initiation of hormonal therapy [Johnson and Buyyounouski, 2012; Heidenreich et al. 2014].
Since March 2008, the indications for 3-month or 6-month sustained release formulations of LHRH agonists in France are: ‘Treatment of patients with locally advanced, non-metastatic PCa, as an alternative to surgical castration’; ‘Treatment of metastatic PCa’; and ‘As adjuvant treatment to radiotherapy in patients with high-risk localized or locally advanced PCa’. However, the reasons physicians choose to prescribe LHRH agonists or choose a particular formulation are not well understood.
This observational study aimed to define the profile of patients with PCa receiving 3-month or 6-month formulations of LHRH agonists and to describe the reasons for choosing between these formulations. In addition, the study evaluated the proportion of patients whose initial prescription of LHRH agonist was renewed at the first 3-month or 6-month follow-up visit and at the second follow-up visit at 12 months.
Methods
Study design and participants
The study was a 1-year multicenter, prospective, longitudinal, observational study of patients recruited in France between 1 March 2010 and 16 December 2011. The study was approved by the Advisory Committee on Information Processing Research in the Field of Health and the Commission on Information Technology and Liberties, and was conducted in accordance with the Professional Standards and Good Practices in Epidemiology (ADELF 2003 revised recommendations).
The study included patients with PCa who were initiating hormonal therapy in a random sample of urology, oncology and radiotherapy practices in France. In total, 1600 physicians were approached (including all urologists practicing in France and a random sample of 400 oncologists/radiotherapists). Each participating physician had to consecutively include the first five patients consulting them for PCa and satisfying all selection criteria. Oral informed consent was obtained from each patient at the initial visit before proceeding with the study.
Patients were eligible if they presented with PCa and initiated LHRH agonist treatment at inclusion. The decision to start LHRH agonist therapy was made as part of routine clinical practice and was not influenced by inclusion in this study. Patients were not included if they had been previously treated with LHRH agonists or if they were participating in a clinical trial.
Data collection
Data were collected on all participants for 12 months; at inclusion and at two more visits that were conducted according to the patient’s usual disease management. The first follow-up visit was conducted after 3 or 6 months and the second follow-up visit was after 12 months. Physicians carried out the study without any additional intervention or change in their usual daily practice.
At inclusion, information was collected on age; date and circumstances of PCa diagnosis; comorbidities; estimated life expectancy according to the physicians’ local criteria or guidelines; PCa staging; PSA level at diagnosis and at inclusion; and total serum testosterone level at inclusion. Physicians had to specify in a multiple-choice questionnaire the reason(s) why they had chosen a 3-month or a 6-month formulation of LHRH agonist, and the reason(s) why they had prescribed an antiandrogen if they did so. Physicians also asked patients about the reasons for their own preference for injections every 3 months or every 6 months.
At follow up, information was collected on reason for any unscheduled visits; PSA level; total serum testosterone level; and the physician’s global satisfaction assessment. Physicians also recorded whether LHRH agonist treatment was continued and if there was any modification of the treatment regimen. Any change in LHRH agonist treatment between the 3-month and 6-month visit and the 12-month visit was documented. Any associated treatment was recorded (antiandrogens, treatment to prevent bone loss, chemotherapy, and others). As at inclusion, physicians specified the reasons why they had chosen a 3-month or 6-month LHRH agonist formulation.
After the follow-up visits, patients completed a self-administered questionnaire at home. This questionnaire aimed to elicit information on patients’ global satisfaction with the treatment prescribed at the previous visit (on a five-point scale from ‘very dissatisfied’ to ‘very satisfied’), and the degree of pain they felt at injection (on a four-point scale from ‘not painful at all’ to ‘very painful’). They were also asked about the reasons for their preference for LHRH formulations.
Statistical analyses
Assuming that the expected proportion of patients with renewal of LHRH agonist prescription was 60%, with a precision of 2.6%, a total of 1364 patients was required. Considering that approximately 10% of patients may not attend the first follow-up visit, it was planned for 1515 patients to be included. The primary target was that at least 20% of the 1600 physicians would agree to participate in the study. Sample representativeness was verified according to usual criteria (sex, age, workplace in France). Assuming that around 15% of physicians would recruit no patients, it was anticipated that approximately 300 centers would be involved in the study.
Evaluable patients were patients for whom LHRH agonist treatment was well documented at the first follow-up visit. Quantitative data were summarized as mean, standard deviation (SD), median, quartiles and range. Qualitative data were summarized as frequency counts and percentages. No missing data were replaced.
The percentage of patients renewing the initial prescription of LHRH agonist at the first follow-up visit (main outcome measure) and the second follow-up visit (secondary outcome measure) and 95% confidence intervals (CIs) were calculated.
In order to identify the determinants of LHRH agonist treatment selection at inclusion, a logistic regression model was carried out using the significant factors resulting from a univariate analysis. The following factors have been analyzed: patient characteristics (age, time from diagnosis, circumstances of diagnosis, comorbidities and life expectancy) and disease characteristics (PCa stage and Gleason score at inclusion, and PSA level at diagnosis and at inclusion).
The correlation between physician/patient satisfaction and the changes in PSA levels was analyzed using descriptive statistics and 95% CI.
The SAS System for Windows (SAS, Cary, NC, USA) version 9.3 was used for the analyses. All statistical tests were performed as two-sided tests with a significance level set at 0.05; p values were not adjusted for multiple comparisons.
Results
Physicians and patients
In total, 295 physicians (mean age 46.6 ± 9.1 years; men 98.3%) participated in the study and recruited 1438 patients (Table 1). Around half of these physicians (48.8%) exercised private practice, one-third (33.7%) worked in a hospital and the remaining 17.4% had mixed activity. All patients satisfied selection criteria requested by the protocol and no major deviations were identified during data review. Baseline patient and disease characteristics can be seen in Table 1.
Baseline patient and disease characteristics at inclusion according to luteinizing hormone-releasing hormone (LHRH) agonist formulation.
Comparisons between 3-month formulation and 6-month formulation. Data are presented as mean (standard deviation) with Student’s t test, or as absolute and relative frequencies with χ2 test.
PCa, prostate cancer; PSA, prostate-specific antigen; TURP, transurethral resection of the prostate.
The only significant differences in baseline characteristics detected between the group of patients prescribed the LHRH agonist 3-month formulation and the group prescribed a 6-month formulation were a longer time since diagnosis in the group receiving a 6-month formulation; a higher percentage of patients with recurrent PCa after local treatment in the group receiving a 6-month formulation; and a lower percentage of patients with metastatic PCa at diagnosis in the group receiving a 6-month formulation (Table 1). Logistic regression revealed that the presence of metastases was the only predictor that influenced the clinician’s initial prescription [odds ratio (OR) 0.439; 95% CI 1.095–1.892], with a 3-month formulation more often prescribed than a 6-month formulation to men with metastatic PCa at diagnosis (21.3% versus 15.8% respectively).
LHRH agonist therapy
Among the 1138 patients who completed the first follow-up visit (at 3 or 6 months), the initial prescription was renewed in 980 patients (86.1%; Table 2). Among the 1018 patients who attended the second follow-up visit (at 12 months), the initial prescription was renewed in 723 patients (71.0%; Table 2). The initial prescription was modified in 201 patients during follow up; 170 patients (84.6%) receiving initial prescriptions of a 3-month formulation switched over to a 6-month formulation and 31 patients (15.4%) switched from a 6-month to a 3-month formulation.
Luteinizing hormone-releasing hormone (LHRH) agonist therapy: prescriptions throughout the study.
The most frequent reasons for physicians to initiate LHRH agonist therapy with a 3-month formulation or a 6-month formulation are outlined in Table 3. During follow up, the reasons given for choosing a 3-month or 6-month formulation were similar to the reasons at treatment initiation (Table 3).
Reason for physician choice for luteinizing hormone-releasing hormone (LHRH) agonist formulation at baseline and follow up.
The reasons given for switching from a 3-month formulation to a 6-month formulation were the simplification of therapeutic regimen (89.0% of those who switched at 3–6 months and 80.7% at 12 months) or the avoidance of unnecessary visits (50.0% of those who switched at 3–6 months and 47.7% at 12 months). Reasons for switching from a 6-month formulation to a 3-month formulation were closer management of the patient (45.5% of those who switched at 3–6 months and 45.0% at 12 months), patient reassurance (36.4% of those who switched at 3–6 months and 30.0% at 12 months) or improved compliance (30.0% of those who switched at 12 months).
Associated treatments
At initiation of LHRH agonist therapy, physicians prescribed antiandrogens in 66.7% of the study population; this was to avoid ‘flare up’ in 47.6% of patients or to induce a CAB in 23.6% of patients. An antiandrogen was prescribed significantly more frequently in patients prescribed a 3-month formulation than in patients prescribed a 6-month formulation (392/527, 74.4% versus 555/893, 62.2%; p < 0.0001).
At LHRH agonist therapy initiation, 133 patients (9.4%) were given a treatment to prevent bone loss. In most cases (115/133, 86.5%), this treatment was a bisphosphonate. In the remaining patients, bone protection was provided by calcium and vitamin D supplementation. The frequency with which a treatment to protect bone mass was prescribed was similar in both groups (43/529, 8.1% and 90/883, 10.2% of those receiving a 3-month or 6-month formulation respectively; p = 0.199).
At follow-up visits, prescriptions of additional treatments were similar in the two groups of patients. At the 3-month or 6-month visit, among those receiving the 3-month formulation or 6-month formulation respectively, who had additional treatments, 42/79 (53.2%) and 76/117 (65.0%; p = 0.098) received antiandrogen therapy, 21/79 (26.6%) and 31/117 (26.5%; p = 0.989) received treatment to prevent bone loss, and 2/79 (2.5%) and 3/117 (2.6%; p = 0.989) received chemotherapy. At the 12-month visit, among those receiving the 3-month formulation or 6-month formulation respectively who had additional treatments, 29/40 (72.5%) and 76/111 (68.5%; p = 0.635) received antiandrogen therapy, 8/40 (20.0%) and 30/111 (27.0%; p = 0.380) received treatment to prevent bone loss, and 4/40 (10.0%) and 10/111 (9.0%; p = 0.853) received chemotherapy.
Patient preference
Among the 146 patients (27.3%) receiving a 3-month formulation at inclusion who were asked about their preference, 99 (67.8%) preferred this formulation because they visited their physician more often, 34 (23.3%) thought that it is more effective than the 6-month formulation, and 20 (13.7%) preferred to see their nurse every 3 months. At follow up, in patients for whom the initial prescription of a 3-month formulation was renewed, perceived effectiveness versus the 6-month formulation and seeing the nurse every 3 months were more frequently cited as reasons for preference compared with the initiation visit.
Among the 395 patients (43.7%) receiving a 6-month formulation at inclusion who were asked about their preference, 249 (63.0%) preferred this formulation because they thought this formulation was more convenient than the 3-month formulation, 226 (57.2%) preferred this formulation because it required fewer injections, and 207 (52.4%) thought the formulation was less stringent. For 67 (17.0%) patients, a 6-monthly frequency of injections allows them to forget their disease. At follow up, in patients for whom the initial prescription of a 6-month formulation was renewed, a similar answer profile was found at both visits.
Patient satisfaction
Self-administered questionnaires showed that, at follow up, approximately 80% of patients were satisfied or very satisfied with the LHRH agonist treatment prescribed by their physician, whether it was a 3-month or a 6-month formulation (Table 4). For both formulations, more than 90% of patients experienced either mild pain or no pain (Table 4).
Patient satisfaction assessed by self-administered questionnaire.
Physician satisfaction
Most physicians were satisfied over the follow-up period with a 3-month formulation [96.9% (n = 405) after 3 or 6 months and 95.6% (n = 282) after 12 months] and a 6-month formulation [95.8% (n = 682) after 3 or 6 months and 96.4% (n = 620) after 12 months]. Pain associated with treatment and insufficient efficacy were the most frequent reasons given in the few cases of dissatisfaction reported in the study. The correlation between physician satisfaction and the changes in PSA levels could not be analyzed because a large proportion of physicians were satisfied with LHRH agonist therapy.
Discussion
LHRH agonists offer a reversible alternative to surgical castration and display a better safety profile than estrogens and antiandrogens, and for these reasons they have become the mainstay of ADT for advanced PCa [Lepor and Shore, 2012]. LHRH agonist long-term delivery systems offer patients flexibility, improve quality of life and eventually reduce cost [De Jong et al. 2007]. These sustained-release depot formulations have gained wide acceptance from both patients and physicians and have contributed towards LHRH agonists being the treatment of choice for hormonotherapy.
This study involved 1438 patients diagnosed with PCa. Hormonotherapy was initiated with LHRH agonists for the treatment of locally advanced (44.2%) or metastatic (25.2%) PCa, or as adjuvant treatment to radiotherapy in patients with high-risk localized PCa (17.0%) or for biochemical recurrence after previous radical prostatectomy or radiotherapy (19.9%). The initial prescription was renewed in most patients (86.1%) 3 or 6 months later and at the end of the 1-year follow-up period (71.0%). In order to enhance patient adherence to LHRH agonist treatment, the choice of formulation should be largely dependent on patient preference. In this study, the reasons given by those patients asked about their preference at initiation of hormonotherapy were similar to those given by physicians. For example, patients’ reasons for preferring a 6-month formulation (more convenience, fewer injections and less stringent) are reflected by the reasons given by prescribers (simplified therapeutic regimen and fewer visits). Likewise, the main reason for patients preferring a 3-month formulation (they can visit their physician more often) is consistent with the main reasons given by physicians (closer patient management and reassurance for the patient). This reassuring effect was also observed in a recent survey carried out in France by 125 urologists and radiotherapists that showed that patient anxiety was one major reason for prescribing a 3-month formulation [Ouzaid and Roupret, 2011].
It seems interesting to compare these findings with those from a consensus opinion of experts published in 2007 [De Jong et al. 2007]. At that time, a review of the evidence underlying hormone treatment decisions suggested that a 3-month formulation was favored by many clinicians and patients as it coincides with the visit frequencies for PSA testing. This frequency of patient monitoring was considered to have psychological benefits in terms of providing patients with reassurance that their condition is being controlled. By contrast, some reservations were expressed about longer-lasting formulations. Indeed, if such formulations seemed useful in patients with specific lifestyle demands (e.g. those who are frequent travelers), many clinicians felt that they would have greater difficulty in convincing patients that the amount of delivered drug was adequate to be effective over periods as long as 6 or 12 months. Clinicians also had some concerns about measures to be taken in the event of local reactions, other adverse effects or if treatment was no longer working (as evidenced by increasing PSA levels). The authors concluded that ‘the 3-month depot formulation provided optimal convenience and flexibility for both healthcare professionals and patients’ [De Jong et al. 2007]. In contrast, the present study shows that 6-month formulations of LHRH agonists are currently favored by clinicians in France when initiating hormonotherapy in patients with PCa and over the 1-year follow-up period. During this follow up, a switch from a 3-month to a 6-month formulation was 5.5-fold more frequent than the reverse switch.
These depot formulations of LHRH agonists provide patients with a convenient treatment modality by reducing the number of physician visits and injections required, and their use could be considered for intermittent ADT. They also could have a positive impact on quality of life, an issue of paramount importance in patients with cancer; 17.0% of participants in this study reported that biannual injections allow them to forget their disease. These results are in line with the data recorded by face-to-face interviews of 200 European men showing that most patients would prefer fewer injections, with 68% preferring 6-monthly injections over 3- or 1-monthly depot formulations [Schulman, 2007]. Perceived advantages of 6-monthly injections included less discomfort/pain, better quality of life, fewer reminders of the disease, and greater ability to undertake activities without restriction [Schulman, 2007]. The findings of our study also support recent published data showing that 6-month formulations can increase patient convenience, comfort and compliance by reducing the number of physician visits and injections required [Crawford and Phillips, 2011].
LHRH agonists avoid the adverse psychological effects and irreversibility of surgical castration and the excess risk of cardiotoxicity reported with estrogens (but the existing literature on the relationship between ADT and cardiovascular morbidity is somewhat mixed) [Efstathiou et al. 2009; Bolla et al. 2010; Levine et al. 2010; Nguyen et al. 2011; Johnson and Buyyounouski, 2012]. To date, clinical trials have shown that LHRH agonists are generally well tolerated, with generally mild side effects stemming from testosterone suppression, and a very low rate of withdrawal due to adverse events [De Jong et al. 2007; Crawford and Phillips, 2011]. The high proportion of patients renewing prescriptions at 3 or 6 months and 12 months in our study may confirm this low withdrawal rate. The main concerns associated with LHRH agonist therapy are the potentially detrimental effects associated with ‘flare up’ in advanced disease. Concomitant therapy with an antiandrogen decreases the incidence of ‘clinical flare’, and it is recommended that administration of antiandrogens should be started on the same day as the depot injection and treatment should be continued for a 2-week period [Heidenreich et al. 2014]. In our study, at initiation of LHRH agonist treatment, physicians prescribed antiandrogens in order to avoid ‘flare up’ in nearly 50% of patients; the other reason for such prescription was to induce a CAB.
The use of LHRH agonists may be associated with increased bone loss leading to low bone density and enhanced risk of osteoporotic fractures. Additional measures to counteract loss of bone mineral density are thus recommended [Heidenreich et al. 2014]. In the whole study population, 8.0% of patients were given bisphosphonates. In EAU guidelines 2012, the routine use of bisphosphonates to prevent skeletal complications in patients undergoing ADT is not recommended unless there is a documented risk for fracture or castration-resistant PCa with skeletal metastasis [Heidenreich et al. 2014]. This study showed that urologists do not always wait for the emergence of a castration-resistant PCa to prescribe bisphosphonates.
For more than 95% of their patients, physicians were satisfied over the follow-up period with both LHRH agonist formulations, and around 80% of patients were satisfied or very satisfied with the treatment prescribed by their physician. LHRH agonist injections were locally well tolerated, being responsible for mild pain only in approximately 30% of patients.
This study has a number of limitations. Because the study was observational and participating physicians and patients were volunteers, there is likely to be a nonresponse selection bias that is typical of this type of study. Furthermore, inherent to observational studies, the numbers of participants responding at baseline and follow up were different and the effect of missing follow-up data could not be assessed. The number of patients with asymptomatic nonmetastatic disease was not recorded; therefore, the influence this may have had on the choice of a 6-monthversus a 3-month formulation (a 6-month formulation may have been preferred in this group) could not be assessed. In addition, other details such as the reasons for patients stopping LHRH therapy were not recorded. Despite these limitations, our study significantly adds to the information regarding the reasons underlying change to prescriptions. In addition, observational studies may better represent everyday clinical practice than randomized controlled trials.
Conclusion
This study demonstrates that slow-release formulations of LHRH agonists are a particularly attractive option for physicians in treating patients with PCa needing hormonotherapy, and that there may be a preference for a 6-month formulation. These findings support published data stating that longer-acting depot formulations have considerable advantages for patient comfort and convenience, and may expend fewer healthcare resources.
Footnotes
Acknowledgements
The authors thank all physicians who contributed to the study. The authors take full responsibility for the content of the paper. Martin Gilmour of ESP Bioscience, Crowthorne, UK (supported by Ipsen) provided editorial assistance in the preparation of the manuscript.
Funding
This study was funded by Ipsen Pharma.
Conflict of interest statement
TL has acted as a consultant for Ipsen, Astellas, Amgen and Novartis, and has been a Principal Investigator in trials funded by Ipsen. J-LD has received funding from Ipsen, Ferring, Sanofi, Astellas and Janssen. CH has provided consultancy for Ipsen, Astellas, Takeda, Janssen, Sanofi, Amgen and Roche. IL has participated in advisory boards for Ipsen, Sanofi, Takeda, Ferring, Amgen and Astellas. J-PM has no conflict of interest to declare. J-LM has served on advisory boards for Ipsen, Sanofi Pasteur, Ferring and Lilly. DR has received funding from Ipsen, Astra Zeneca, Lilly, Bouchara recordati, Sanofi and Takeda. AR received funding for participation in clinical trials or for training from AMS, CL-Medical, Allergan, Ipsen, Takeda, Astra Zeneca, Astellas, Medtronic, Coloplast, CL Medical, Steba, and Janssen. MZ has received funding from Ipsen, Ferring, Sanofi, Janssen, Abbott and Recordati. SC has acted as a Principal Investigator in trials or contributed to trials funded by Amgen, Janssen, Merck, Pierre Fabre and Sanofi, and as a speaker for Astellas, Bayer, Ferring, Ipsen, Janssen, Pfizer and Sanofi.