Acceptance of oral chemotherapy in breast cancer patients - a survey study

Breast cancer is the leading neoplastic malignancy among women worldwide affecting one in 8 women [1]. Its incidence is steady and so is the number of patients under therapy with a chronic metastatic disease [2, 3]. Therefore, the search for new innovative chemotherapeutic standards is ongoing. On the one hand, facing the demand to develop new drugs with higher antitumor activity and lower systemic toxicity [3]. On the other hand aiming to find drugs that control cancer as a chronic process and match requirements of a convenient long term application with high quality of life [4‐6]. Conventional anticancer chemotherapy is dominated by complex intravenous (i.v.) regimes which affect patients' life considerably [7‐9]. Not only the substantial amount of time spent for the treatment as such places a major burden on patients but also the frequent placement of indwelling catheters and its associated fears or severe complications [10‐12]. Thus, the development of an oral (p.o.) anticancer therapy has been in focus over the past few years [13‐17] and has also been evaluated in all-oral combination regimes [18]. Oral chemotherapy offers several benefits in terms of convenience, ease of administration, improved quality of live and economic aspects [9, 19‐23].

Previous surveys and studies have addressed the acceptance of oral chemotherapy among patients and health care professionals [24, 25]. These results revealed that most patients, who had experienced p.o. therapy, favor p.o. over i.v. chemotherapy [8, 19, 24‐30]. Since these data have been published an increasing number of oral chemotherapeutics have been licensed and approved and will find their way in adjuvant therapies. Our survey study investigates breast cancer patients' personal concerns, doubts and general feelings towards p.o. application as well as the patient's reasons for preferring a p.o. or an i.v. treatment in the adjuvant as well as palliative setting. The assessment of the study provides insights for health care professionals on patient orientated education as well as guidelines to obtain a high compliance under oral treatment. In addition, the study offers important information on patient desires as well as on prejudices that have to be taken into account when establishing oral chemotherapy as an alternative standard to i.v. treatment in palliative as well as adjuvant setting.

Breast cancer - with its high incidence worldwide - requires effective treatment options with high practicability, selectivity and tolerability. At present most therapy options are complex i.v. treatments, being usually connected with traveling efforts, time-consuming hospital-procedures and high costs [23, 31‐33]. In contrast, p.o. chemotherapy can easily be applied in an out-patient setting, e.g. in cooperation with the patient's general practitioner, thus reducing hospital visits and burdensome invasive medical procedures, such as placements of catheters. It was already demonstrated that, with oral treatment, the time spend in hospital as well as the overall costs of chemotherapy can be reduced considerably [13].

However, patients' and health care professionals' skepticism towards p.o. treatment has been observed [9, 11, 19, 24, 26, 34‐36]. Hesitations towards p.o. drug prescriptions mainly resulting from apprehensions regarding bioavailability, doubts about efficacy, and concerns about compliance initially hampered the development of p.o. anticancer drugs [26, 37]. In addition, patients sometimes believed that p.o. drugs are prescribed as last resort [24]. In the meanwhile, results from various studies contributed to the resolution of such prejudices and led to considerable progress in the development of oral treatment options [13, 14, 16, 17] as well as of all-oral chemotherapy combinations [9, 26, 38‐40].

When talking about oral chemotherapy, the therapy course and the therapeutically success first of all depend on patient-independent factors such as bioavailability, side effect profile (e.g. gastrointestinal toxicity) and optimal dosing schedules. Oral treatments face additional pathways such as gastrointestinal passage and first-pass effects in comparison to i.v. treatments and thus require specific knowledge of healthcare professionals [26]. The development of modern oral chemotherapies led to oral treatment options with adequate pharmacokinetic properties, acceptable side effect profiles and high efficacy [16, 38, 40‐44].

Since 2005, when Catania et al. assessed patients' perceptions on efficacy of p.o. therapy, several oral agents have been licensed for breast cancer treatment and gained acceptance in this indication [30]. Based on the above mentioned efforts in oral drug development, initial reservation is increasingly obsolete and usage of p.o. treatment has grown. Among our interviewed patients, 9 out of 10 being treated orally and 7 out of 10 being treated intravenously would prefer p.o. over i.v. treatment if same efficacy is ensured. This is in agreement with the data of Liu et al, who also reported a high patient preference (89%) for p.o. treatment [19]. Other studies involving patients having experienced p.o. and i.v. treatment within the respective trial revealed patient preferences of 39% [45], 64% [20], 74% [25], 84% [46] and 90% [47]. Moreover, our survey revealed that the majority of patients in the p.o. and the i.v. group believed in equal efficacy of both routes of administration. However, p.o. treated patients trusted more in oral therapy than those under i.v. treatment, leading to a significant difference between both groups; in the i.v. group approximately 1/3 of patients still were of the opinion that i.v. drugs generally provide higher efficacy. Presumably, unfamiliarity with p.o. treatment led to these hesitations.

Commercial availability of active p.o. drugs will not directly ensure their use [26]. It is known that patients' compliance may still to some extent be hampered by general prejudices and incertitude con-cerning correct usage of the medication. Thus, oral chemotherapy will only be effective if compliance is optimized. For that reason, the ability of patients to understand the treatment in general, the specifics of an oral chemotherapy and the treatment schedule are key issues for a successful p.o. therapy. Our survey showed that the treating physicians still represent the main source for such treatment information, emphasizing their role for a correct therapy run. Data have shown that patients with p.o. chemotherapy treatments are generally motivated to ensure intake of their treatment [48, 49]. Comparing recent studies (2000 - 2009) to those from the early 90's clear improvements in patient compliance have been observed [49]. An understandable treatment regimen and the use of patient dairies can reduce misunderstandings or wrong intakes [50, 51]. Detailed information on side effect profiles (e.g. using patient information leaflets) and on requirements for treatment adaptations enable patients to contribute to the treatment and give them a greater sense of personal responsibility [26].

The impact of i.v.-treatment-related hospital visits on everyday life has been mentioned to be a major factor influencing quality of life [24]. In both treatment groups investigated in our survey the majority of patients agreed that oral treatment contributes to a better quality of life; especially those women who had experienced p.o. treatment confirmed a clear benefit (i.v.: 43%; p.o.: 63%). We assumed that especially younger women with young children would prefer p.o. therapy, however - consistent with the results of Catania et al. - no significant age-depended differences could be observed [24].

It is interesting to see that most of the questions analyzed with our survey revealed significant differences between the p.o. and i.v. group, indicating that prior treatment experience guides the acceptance of oral vs. intravenous therapy. This is also true with regard to the coping and handling of the disease. Approximately 50% of the women with p.o. treatment saw a clear benefit due to personal freedom and the possibility of self-management by p.o. application. Some women stated that a p.o. treatment gives them the feeling of a chronic instead of a life-threatening disease and allows them a better coping with the disease. The i.v. treated population was more skeptic. Some of the patients who had not yet experienced p.o. chemotherapy stated that they would miss the personal contact to other patients, the peer group benefit as well as the frequent interaction with the medical team. Most patients appreciated however, the possibility to reduce the daily presence of their disease by using oral treatment combined with a close connection to the centre and the availability of supporting staff via phone or out-patient clinic if required. The importance of this infrastructural setting was emphasized before [24]. It is important to mention that especially patients under adjuvant or neoadjuvant treatment stated that confrontation with other patients in a more progressed status of disease causes high emotional involvement; therefore such patients often prefer a home-based treatment. Also to mention the institutional triggered side effects such as psychogenic nausea along with institution-induced vomiting that considerably reduces quality of life and often seems to get worse with longer duration of palliative i.v. chemotherapy. Those negative issues are not relevant when using p.o. chemotherapy.

In general, the major benefit of oral versus i.v. chemotherapy can be described with a broader flexibility enabling a more individualized therapy and a higher quality of life. However, the amount of tablets or capsules needed to be swallowed has to be taken into account. Compliance can be lower if patients have to swallow numerous tablets every day [34, 35] and studies have shown that a daily intake of maximum 6-8 tablets is acceptable [9]. This finding should be taken into account in the future development of oral drugs. One example of such development are so called duplex drugs, establishing a chemical link between two highly active anticancer compounds and resulting in a new, mono-molecule'[52].

Oral chemotherapy plays an increasing role in breast cancer therapy. So far, it has mainly be-en used in palliative setting, however it will gain its place additionally in adjuvant settings as the PARPi inhibitors will show. High efficacy, adequate tolerability, acceptable bioavailability with low inter- and intra-individual variability and a limited number of tablets/capsules per day are basic prerequisites and have been limiting factors for oral drug development. When fulfilling these requirements, oral treatment can contribute to an improvement of the patients' quality of life, which remains high priority especially in metastatic disease. Nevertheless, successful oral therapy requires compliance. Thus, a differentiated indication as well as a detailed patient-oriented education and explanation of the p.o. treatment schedule, including information on potential side effects, are key factors for a successful treatment.