A total of 1110 records from database searches and 990 records from congresses and SLR bibliographies were screened. In total, 26 publications reporting on 21 unique studies were included in this SLR (Fig. 1).
Of the 21 included studies, 10 reported on the treatment of NETs [25,26,27,28,29,30,31,32,33], 10 reported the treatment of acromegaly [34,35,36,37,38,39,40,41,42,43], and one reported both . The included studies were conducted using a range of study designs, most commonly including open-label trials [25, 27, 34, 37], and prospective observational studies [25, 31, 39, 43] among others (Table 1). Group comparison studies compared experience between patients on parallel treatment arms [25, 26, 28, 29, 31, 32, 36, 41,42,43,44] whereas crossover studies reported the experience of patients who switched from one SSA to the other [34, 35, 37, 38, 40]. Patients switched from OCT LAR to LAN treatment in all crossover studies. Most studies (n = 19) were conducted in the USA and/or Europe (Table 1).
All but one of the studies included LAN [25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44]; 17 compared LAN with OCT [25, 26, 28, 29, 31,32,33,34,35,36,37,38, 40,41,42, 44], four studies investigated different formulations or administration methods of LAN exclusively [30, 33, 39, 43], and a single study exclusively investigated different formulations of OCT . Most studies did not specifically aim to investigate patient or HCP perspectives of SSA treatments; efficacy and tolerability of treatment were often the primary outcomes in these cases, and treatment perspective was collected as a secondary or exploratory outcome. The majority of studies (n = 12) used structured questionnaires or surveys to elicit patient or HCP treatment perspectives or preference [25, 26, 28, 30, 31, 36, 38,39,40,41, 43, 44], though these were not validated instruments, and informal patient questioning was also a common approach (n = 5) [27, 34, 35, 37, 42]. Methods less frequently employed included use of a patient–clinician shared decision-making framework [29, 33], and a Delphi panel . As such, where preference was not explicitly reported, the independent investigators reviewing the studies in this SLR assessed the statistical and numerical comparisons presented in each study. These comparisons were used to determine which, if any, of the two treatments was associated with the more favorable outcome, such as lowest level of anxiety or fewest technical problems, for example. Including preference, nine key outcomes in treatment experience were identified (Table 2). Here, we focus on studies in which respondents had direct experience of SSA treatment (rather than anticipated preference) and where statistical or numerical comparisons were provided (rather than qualitative comparisons).
Of the 21 studies included in this SLR, five crossover studies explicitly reported the preferences of patients who had direct experience of both LAN and OCT LAR treatment (Table 3) [34, 35, 37, 39, 40]. LAN was preferred in four of the five studies that reported patient preference as an outcome [34, 37, 39, 40]. All crossover studies included patients who switched from OCT LAR to LAN with the standard 28-day dosing interval for each treatment.
Salvatori et al. reported that 81.3% of patients preferred LAN in comparison with 12.5% for OCT LAR (n = 33, p = 0.0001), based on a structured questionnaire, though reasons for preference were not reported . Alexopoulou et al. reported that 17/25 (68%) patients with acromegaly chose LAN by informal opinion, whereas 2/25 (8%) preferred OCT LAR; 6/25 (24%) patients did not report treatment preference . Reduced pain at the injection site and fewer technical problems following LAN injection were deemed by investigators in this study to influence patient choice .
Neggers et al. included three study arms, whereby patients with acromegaly were switched from OCT LAR 4-week dosing interval to LAN with either a 4-week dosing interval or a 6- or 8-week extended dosing interval (EDI) . LAN was preferred over OCT LAR in all treatment regimens. At week 48, 53/68 (77.9%) patients in the 6-week EDI group preferred LAN, vs 10/68 (14.7%) who preferred OCT LAR; and 24/26 (92.3%) patients in the 8-week EDI group preferred LAN, vs 2/26 who preferred the OCT LAR 4-week interval . Although this study sought to investigate the impact of EDIs on treatment preference, notably, 10/13 (76.9%) patients chose LAN when administered with the same 4-week dosing interval used for their previous OCT LAR treatment; just 2/13 (15.3%) patients chose OCT LAR and 1/13 (7.7%) had no preference (reasons for preference were not reported) . Schopohl et al. conducted a similar study in which patients with acromegaly (n = 33) switched from OCT LAR with standard dosing interval to LAN with standard dosing interval and EDI groups . Preference for LAN was higher overall; LAN was preferred in both the 6- and 8-week EDI groups compared with OCT LAR (63.6% vs 18.2%, and 57.1% vs 28.6%, respectively) . However, preference was higher for OCT LAR over the standard LAN 4-week dosing interval group (41.2% vs 11.8%) .
OCT LAR was preferred overall in one crossover study, where 6/10 patients with acromegaly cited fewer adverse effects (such as nodules at the administration site) and greater perceived efficacy compared with LAN .
Just two studies specifically reported HCP preferences (Table 3) [36, 44]. A multicenter opinion study in patients with NETs or acromegaly reported HCP preference when HCPs had experience administering both SSAs . LAN was preferred in this study because of the attributes of a LAN injection syringe over OCT LAR, such as faster and smoother administration with lower risk of needle clogging, as well as the option for patients to self-inject using this syringe . Though direct experience with either SSA was unclear, in one study where endocrinologists (n = 196) completed an online survey, HCPs reported preference for OCT LAR (47.1%; n = 92) over LAN (32.2%; n = 63) as their postoperative adjunctive medical therapy of choice, deemed by the study’s authors to be based on the longer period of market authorization of OCT LAR compared with LAN, although this varies between continents .
Proximal Factors in Treatment Experience
Outcomes commonly emerging as aspects that influence preference or treatment experience may be divided into proximal and distal factors. Proximal factors refer to the practicalities and immediate aspects of treatment, such as those surrounding method of administration, while distal factors are more conceptual and include emotional aspects of treatment experience, and preference itself.
Injection-associated pain was reported as an outcome in three studies [34, 38, 41], all of which reported LAN as the favored treatment as a result of less injection-associated pain compared with OCT LAR injections. Of 33 patients with acromegaly who switched from OCT LAR to LAN treatment in the Salvatori et al. study, more patients reported that LAN injection was not painful at week 24 vs the OCT injection at week 0 (the final OCT injection prior to switching), compared using a McNemar’s test (50.0% vs 25.0% of patients, respectively; p = 0.0201) . Among those who did report pain, patients described the LAN and OCT LAR injections as “somewhat painful” (43.8% vs 59.4%; p = NR), “moderately painful” (6.3% vs 6.3%; p = NR), or “very painful” (0.0% vs 9.4%; p = NR) .
One group comparison study found that patients with acromegaly (n = 83 prescribed LAN; n = 112 prescribed OCT LAR) considered the overall injection burden to be similar for the two treatments . The authors found small but statistically significant differences in pain and other injection site reactions; OCT LAR injections were associated with slightly greater pain at the injection site hours and days after the injection (hours mean score [scale 0–3], 0.7 vs 0.6 for LAN, p = 0.05; days mean score [scale 0–3], 0.5 vs 0.3 for LAN, p = 0.0007). However, LAN injections were associated with the development of nodules, swelling, bruising, and dermatitis (mean score [scale 0–3], 0.8 vs 0.5 for OCT, p = 0.0008) . In one crossover study also in acromegaly, patients reported significantly superior immediate local tolerability at the injection site with LAN injections compared with OCT LAR ; 76% (n = 19) of patients reported mild-to-moderate pain at the injection site with OCT LAR, vs 12% (n = 3) reporting local pain after LAN injection.
Technical Problems with Injecting
Technical problems with injecting, such as needle clogging and difficulty in completing dose administration, were reported as an outcome in four studies [26, 28, 34, 43]. LAN injections were favorable in all four studies, with markedly fewer technical problems reported compared with OCT LAR injections. Alexopoulou et al. reported results from 25 patients with acromegaly who experienced treatment with LAN after switching from OCT LAR . Patients informally gave their opinion, with the majority recalling the occurrence of minor or major technical problems for at least one of their six most recent OCT LAR injections, despite injections being administered by experienced paramedical staff (60/150 injections reported by 19 patients) . By contrast, no technical problems were reported during any LAN injections (p < 0.001) . Geilvoet et al. carried out a survey designed for patients with NETs with satisfaction-related theorems with a five-point Likert scale, multiple choice, and free text . The survey revealed that 52% of patients treated with OCT LAR (n = 23) experienced injection problems, compared to 17% of patients treated with LAN (n = 28) .
Witek et al. used a crossover study for patients with acromegaly to assess technical problems related to treatment administration . Measured by a visual analog scale (VAS), whereby “no technical problems” was coded as 0, and “technical problems” was coded as 100, patients (n = 102) reported fewer technical problems related to the administration of LAN (final mean VAS 5.3) compared with OCT LAR (mean VAS 37.6) . Almquist et al. used a survey questionnaire to assess recent SSA injection experiences of patients with GEP-NETs, including technical problems with injecting . Twelve out of 66 (18%) patients treated with OCT LAR reported problems with their most recent injection, whereas none of the 53 patients receiving LAN treatment reported any problems with their most recent injection (p = 0.001) . From the HCP perspective, HCPs in one time and motion study involved with treatment administration indicated concerns over OCT LAR, due to longer time to prepare as well as increased risk of needle clogging (p = 0.034) and device failures (p = 0.057) .
Distal Factors in Treatment Experience
Emotional factors were a notable outcome reported among patients when examining SSA treatment perspectives. Two studies were identified reporting such outcomes, both of which reported group comparisons, with patients experiencing either LAN or OCT LAR treatment; both studies favored LAN [25, 26]. Adams et al. asked 120 patients to grade the “emotional quality” of their injection experience, where LAN injections were significantly associated with a positive injection experience vs OCT LAR injections (p < 0.001) . The questionnaire used by Almquist et al. also assessed levels of anxiety prior to injection . Fewer patients reported moderate-to-high anxiety with LAN injections vs OCT LAR (2% vs 11%, n = 119; p = NR) .
One time and motion study reported statistical comparisons for satisfaction between LAN and OCT LAR in terms of treatment delivery attributes from the perspective of both patients and HCPs . Of the 22 patients included for each treatment arm, 20 (90.9%) patients treated with LAN reported that all or most of their expectations had been met compared with 18 (81.8%) patients treated with OCT LAR (p = 0.25) . HCPs involved in preparing and delivering SSAs indicated significantly higher satisfaction with LAN vs OCT LAR (median satisfaction score 5 vs 4, p = 0.006) .
Three studies reported statistical comparisons between LAN and OCT regarding the time taken for treatment administration and patient waiting time in the clinic prior to their injection [28, 31, 44]. Geilvoet et al. concluded from a patient survey that visits by nurses administering LAN (n = 28) were significantly shorter than for OCT LAR (n = 23; p = 0.048) . Ryan et al., using a time and motion study comparing treatment delivery attributes between SSAs, reported that patient waiting times (from clinic check-in to check-out) were similar for LAN and OCT LAR. The median total waiting time per visit was 6.2 min shorter for patients receiving LAN than for those receiving OCT LAR (25.0 min vs 31.2 min, respectively), though this comparison did not reach statistical significance (p = 0.734; n = 43) .
From the HCP perspective, Ryan et al. also reported that there was a mean reduction of 3.7 min of treatment delivery time in favor of LAN (2.5 [95% confidence interval (CI) 2.0–3.1] min) vs OCT LAR (6.2 [95% CI 4.4–7.9] min, p = 0.001) . In an opinion study where syringe attributes were rated by 77 nurses via a questionnaire, Adelman et al. found that injection preparation and administration time were significantly shorter with the LAN syringe than OCT LAR (p < 0.01) . This study also reported a significant difference in mean score for ease/convenience of preparation and injection, ranked among the most important attributes by 70% of nurses, for the LAN syringe (rated 9.4/10) and OCT LAR (rated 3.8/10, p < 0.05) . In another study, comparing HCP-administered injections with LAN vs OCT LAR, LAN injections were judged by the study investigators to be “much easier” or “easier” for 57.1% of 37 patients, “the same” for 17.1%, “more difficult” for 22.9%, and “much more difficult” for 0.0% . The most frequently cited reasons for investigator preference for LAN were ease of injection (51.4%), being time-saving (45.7%) and patient preference (45.7%) .
Four studies reported that patients with acromegaly indicated a greater preference for longer dosing intervals vs shorter intervals [27, 37, 40, 42]. In two studies in patients with acromegaly initially treated with OCT LAR (dosing interval of 28 days) who then switched to LAN (42- or 56-day intervals), over 55% of patients in both studies expressed a preference for the EDIs of LAN (numerical comparisons only) [37, 40]. However, one of these studies also reported that a higher proportion of patients demonstrated a preference for a LAN dosing interval of 42 days compared with 56 days (63.6% vs 57.1%), although no statistical comparisons were performed . The preference for the 56-day interval was higher when investigator preference was also taken into account . The remaining two older studies compared short-acting with long-acting formulations; one study included patients switching from daily subcutaneous octreotide injections to monthly intramuscular octreotide LAR , and the other included patients switching from daily subcutaneous octreotide injections to a lanreotide sustained release microsphere formulation, administered by intramuscular injection every 7–14 days . The longer-acting formulations with longer intervals between doses were preferred in both studies [27, 42].
Self-/Partner-Injectable Treatment with LAN
Self- or partner-injection with LAN was investigated in two studies in patients with acromegaly and one in NETs [30, 38, 39]. Self- or partner-injectable treatment was generally favored compared with attending a medical site or receiving LAN injections administered by HCPs. Johanson et al. reported that reasons pertained to increased independence and convenience, especially for patients living in remote locations. Indirect costs associated with SSA treatments for patients or their caregivers were also estimated on the basis of patient/partner time for travel and injection; one HCP-administered LAN injection was estimated to cost €7.95, while one self-injection was estimated to cost €0.10, on account of patients not having to travel or take time off work to be treated .
A quality assessment was conducted for each study using the PREFs checklist (Table 4) . Just one of the included studies sufficiently answered all domains of the checklist , and six studies answered four out of the five domains [29, 31, 33, 41, 43, 45], most commonly not including statistical comparisons [29, 33, 43, 45]. Most of the included studies did not explicitly aim to investigate SSA preference and, as such, purpose in relation to preferences and significance was not a strong domain across studies. Methods of assessment in the context of treatment experience and preferences were reported inconsistently; some studies specifically stated their assessments as part of their methodology, while several did not, or assessment methods were unclear. Statistical comparisons were used to assess differences between the SSAs in only 8/21 studies, with the majority of studies making numerical comparisons. A minority of studies explicitly reported preference between SSAs, and the remainder often did not report sufficient information relevant to SSA treatment experience to clearly determine which SSA was favored.