Early follow-up of outpatients with oral anticancer therapy in the ONCORAL multidisciplinary community-hospital program.

Implications for practice

- Early follow-up of outpatients receiving oral anticancer therapy is crucial to assure safety and efficacy of treatment.

- Drug–drug interactions between oral anticancer agents and over-the-counter drugs or complementary medicine are frequent and potentially dangerous, highlighting the importance to realize medication review at initiation of cancer treatment.

- Multidisciplinary follow-up of patients treated with oral anticancer drugs is needed, by including community health professionals.

Introduction

Oral anticancer therapy (OAT) is now an integral part of hematology and oncology practice in a wide range of treatment regimens, either as monotherapy or in combination with other anticancer medications. Oral intake of OAT is effective, convenient, and preferred by patients, 1 who can manage their treatment in an outpatient setting, enabling a better quality of life by maintaining their family and social lifestyle. However, OAT raises other questions for patients, for whom managing their own treatment is a paradigm shift compared to intravenous chemotherapy courses administered in hospitals. Healthcare professionals are therefore faced with the new challenges of preventing and managing drug-related problems (DRP): side-effects, drug–drug interactions (DDIs), non-adherence, or even medication errors.

Side effects are the main issue, especially during the first months of treatment, leading to clinical consequences impairing quality of life or even threatening survival. 2 , 3 Most patients are polymedicated, increasing the risk of DDI, and potentially impairing the efficacy and tolerance of the OAT when taken concomitantly with other medications, over-the-counter (OTC) drugs, or complementary and alternative medicine (CAM). 4 , 5 In addition, adherence to OAT remains insufficient, 4 , 5 leading to decreased survival. 6

In this context, educational programs are being developed to secure cancer care. Most are now based on multidisciplinary follow-up associated with coordinated intervention of hospital and community health professionals. 7 , 8 Kinnaer et al suggested that the care processes for patients treated by OAT open up opportunities for optimization of management and multidisciplinary coordination of the care pathway. 9 These programs increasingly include telemonitoring and follow-up of patient-reported outcomes (PROs) to enable early treatment of symptoms as soon as they are reported by the patient. As well as enabling anticipatory management of iatrogenic events, PROs can also improve patient–physician communication and clinical decision-making. 10 , 11 Significant improvements in survival and tolerance have already been demonstrated compared to standard care. 12 , 13

The ONCORAL program (for ONCological care for outpatients with ORAL anticancer drugs) was set up in 2014 to ensure the safety of outpatients treated with OAT. This real-life multidisciplinary care plan for patients with cancer is based on educational interviews and follow-up performed by the hospital team (oncologist, clinical pharmacist, and nurse), coordinated with the community health professionals (general practitioner, community pharmacy, and nurse). 14-16 The present study aims to assess the impact of ONCORAL on the first OAT cycle.

Materials and methods

Patients

A prospective cohort study was conducted between October 1, 2021 and October 1, 2022 in a 1038-bed university hospital at Hospices Civils de Lyon (France). Outpatients starting OAT treatment under ONCORAL community-hospital follow-up were enrolled. Patients treated by OAT in combination with an intravenous anticancer drug, and/or adjuvant hormone therapy and patients with experimental drugs were not eligible. Patients with “hospital-at-home” management or home nursing care to take their medications, having difficulties of communication, or living in institutions were also not included.

All patients provided written informed consent to the processing of their personal data, in accordance with the provisions of the French Act n°78-17 of January 6, 1978 (as modified by Act 2018-473 of June 20, 2018). The study was registered in the National Data Protection Commission registry for Hospices Civils de Lyon (n° 15-122).

ONCORAL program

During the first OAT cycle, the program consists of 6 weekly scheduled face-to-face or phone consultations to prevent and manage DRPs ( Figure 1 ). Nurse and pharmacist interventions (NPI) to optimize treatments are shared via secure messaging with the community general practitioner, pharmacist and, as appropriate, community nurse. Follow-up according to individual needs and management of DRPs continues during the subsequent cycles. Patients are able to contact hospital pharmacists or nurses by phone or email at any time to clarify doubts about treatment and to report PRO. These spontaneous PROs can be followed by NPI. As appropriate, the pharmacist and the nurse intervene, with the patient for problems of adherence, for example, or with the prescriber, for example in the case of DDI.

Patients and community health professionals may seek a green light from the hospital to initiate a new kind of treatment, whether prescribed or advised, or to resort to CAM. Approval is given only after checking that the new treatment will not interact with the OAT of other drugs the patient is taking. When the oncologist changes the OAT at the end of the first course, a new full cycle of follow-up is triggered as soon as the new OAT is prescribed. Thus, a given patient may have several consecutive ONCORAL follow-ups.

Outcomes

Baseline data for age, gender, cancer type, and OAT were identified at the first prescription appointment and were also collected from medical records.

Primary end points comprised number of nurse and pharmacist interventions (NPIs), classified according to the validated tool of the French Society of Clinical Pharmacy (SFPC) for PharmaceuticaI Intervention (PI), 17 adapted to outpatient management of patients with cancer by adding items: identification of DRPs (11 categories: contraindication/non-conformity to guidelines; dosage problem; drug interaction; adverse drug reaction; drug omission; drug or medical device not received; unjustified drug prescription; therapeutic redundancy; improper prescription; pharmacodependence; and monitoring), and identification of NPIs (dose adjustment; choice of administration route; optimization of dispensing/administration mode; drug monitoring; addition of a new drug; drug switch; discontinuation or refusal to deliver; pharmaceutical greenlight for a drug according to known interactions).

NPIs were motivated 3 distinct types of problems over and above scheduled patient’s interviews: DRPs detected by the nurse and pharmacist, symptoms or adverse effects declared as PROs by the patient or family, and problems of coordination in the community-hospital care pathway, leading to information relay, referral to specialist consultation, or pharmaceutical advice.

Secondary outcomes included the relative dose intensity (RDI) of the first cycle of OAT, defined as the ratio of the prescribed dose to the approved dose throughout the first course of treatment. Treatment termination or interruption, with duration and cause, were extracted from medical files.

Medication adherence was also measured at the end of cycle 1, on a 6-item scale. A score of 0 indicated good adherence, 1 or 2 a minor or moderate problem, and ≥3 poor adherence.

Statistics

Summary statistics were used to describe patient characteristics: gender, age, cancer, and OAT. Continuous variables were reported as mean ± SD (range), and categorical variables as number and percentage.

Results

Population characteristics

Between October 1, 2021 and October 1, 2022, 209 patients were included in the analysis; 8 completed the first cycle twice because of a treatment switch, and thus 217 first cycles were analyzed ( Figure 2 ).

Mean age was 69 ± 14 years ( Table 1 ). In all, 51 different OATs were prescribed, the most frequent being lenalidomide ( n = 35), ibrutinib ( n = 26) and imatinib ( n = 9) in hematological malignancies, and enzalutamide ( n = 9), capecitabine ( n = 8), apalutamide ( n = 7), cabozantinib ( n = 7), and abemaciclib ( n = 7). Other OATs were prescribed for 1- 6 patients.

Fifty-two percent of patients were polymedicated (≥5 daily drugs). The most commonly used drugs were antiacids for 33.9% patients, and anti-thrombotics for 28.2%, followed by cardiovascular drugs as calcium channel blockers, β-blocking agents, or statins for respectively 15.3%, 14.8%, or 17.2%.

Forty-five of the 209 patients had treatment interruptions, of a mean of 7.2 ± 6.1 days, and in 10 (4.8%) OAT was terminated ( Figure 1 ).

ONCORAL NPIs

During the first OAT cycle, 562 NPIs were performed by the ONCORAL team for 182 patients: that is, 87.1% of patients, for a mean 3.1 ± 2.2 NPIs/patient ( Table 2 ). A total of 340 interventions (60.5%) addressed to the patient or caregiver, 149 (26.5%) the oncologist, 21 (3.7%) the community pharmacist, and 52 (9.3%) other healthcare workers (home nurse, general practitioner, specialists, etc.). Totally 15% followed a call by the patient to the ONCORAL team.

The 562 NPI mainly concerned DRPs detected by the nurse and pharmacist (346, 61.6%), symptoms and/or adverse effects reported as PROs by the patient or family (138, 24.6%), or problems of coordination in the community-hospital care pathway, such as the anticipation of the OAT order by the community pharmacy (78, 13.9%) ( Table 2 ). The 346 DRPs were mainly requests for a green light to add a drug or CAM addressed to the ONCORAL pharmacist by the patient, caregiver, or other health professional (139, 24.7%); others were drug–drug interactions (DDIs) (73, 13.0%), adherence issues (39, 6.9%), or others concerning dosage, indications, or monitoring (95, 27.5%) ( Table 3 ).

Drug–drug interactions

DDIs detected at medication review

Seventy-three DDIs were detected and managed during medication review, in a quarter of patients ( n = 54/209), leading to the discontinuation of daily concomitant medication in 30 cases (41%), therapeutic monitoring of a clinical or biological parameter in 29 (39.7%), OAT switch in 6 (8.2%), optimization of OAT intake (eg, time with respect to meal) in 6 (8.2%), and dose adjustment of the patient’s usual treatment in 2 (2.7%). More than half of the DDIs (53.4%) could have increased OAT toxicity if not detected, directly in 12% of cases ( n = 9) or by increasing the risk of adverse effects such as increased QT interval in 41% ( n = 30). Risk of reduced efficacy was reported for OAT in 26% of DDIs ( n = 19) and for daily concomitant treatment (antihypertensive or antidiabetic drugs) in 21% ( n = 15). Almost 70% of DDIs would have impacted OAT, by increasing toxicity or reducing efficacy ( Table 4 ).

DDI concerned OAT and concomitant medication in 45 (61.6%) and CAM in 17 (23.2%), interaction between concomitants medications in 7 cases (9.6%) or between concomitant medication and CAM in 2 (2.7%). Sixty-eight percent of DDIs involved prescribed digestive or metabolic drugs according to the ATC classification, particularly proton pump inhibitors, and cardiovascular drugs such as amiodarone, a strong inhibitor of P450 3A4. OTC drugs, CAM such as dietary supplements and probiotics, or herbal products used for self-medication were responsible for 32% of DDIs.

Prevention of DDIs in requests for pharmaceutical green lights for drugs or CAM

DDI screenings (139) were made by the ONCORAL pharmacist on request by patients, caregivers, or community pharmacists following prescription or advice by a community professional for a new medication or the patient’s wish to use some new phytotherapy. Thirty-three potential drug interactions were proactively detected and avoided before the patient started taking the new substance: 17 herbal medicines, 12 dietary supplements and 4 drugs (aspirin (1), antiemetic (2), and antidiarrheal (1)).

Non-adherence

Thirty-nine NPIs (69.4%) concerned adherence issues, for which the ONCORAL team designed a personalized plan in addition to the treatment plan drawn up at the interview for the first prescription. In 173 OAT cycles (82%), patients were adherent, in 28 (13%) minor adherence issues were reported, and only 1 patient was non-adherent. Data were missing for 5 patients.

PROs

NPIs (138, 24.6%) were in relation to a PRO ( Table 5 ). Nurses and pharmacists were both involved, but nurses initiated the intervention. PROs leading to NPI mainly concerned with digestive problems (21.7%), pain (14.5%), impaired general health (14.5%), or signs of infection (11.6%) ( Table 5 ).

NPIs related to symptoms or adverse effects were conducted without first seeking the oncologist’s approval in 44% of cases ( n = 61). In 49% of cases, interventions were relayed to the oncologist ( n = 68), who then intervened in three-quarters of cases, for example by teleconsultation with the patient ( n = 11), prescription of additional support drugs such as anti-emetics ( n = 17), discontinuation of the OAT ( n = 7), or dose reduction ( n = 1). Seven patients were referred to another professional, such as the general practitioner. In 7 other cases, the patient was hospitalized ( n = 5) or admitted to an emergency department ( n = 2).

Coordination of the patient’s care pathway

Seventy-eight NPIs concerned with coordination of the patient’s care pathway, including the community-hospital link, and enabling relay of information: for example, transferring an anti-emetic prescription to the community pharmacy, informing the community pharmacist of treatment suspension due to digestive toxicity, informing the oncologist that the patient has contracted coronavirus disease (COVID) ( Table 2 ). In one case, the hospital team received an early alert from the community pharmacist about the severe deterioration in the patient’s health, resulting in prompt hospital admission.

Community pharmacists (162) agreed to follow patients on the ONCORAL program, ensuring a strong hospital-community link for these patients. Nineteen pharmacists followed at least 2 patients. Thirty-two general practitioners agreed to take part (15%).

Relative dose intensity (RDI)

Mean RDI at the end of the first cycle, calculated for 209 patients, was 83.1 ± 23.9% (range, 17.56-144.23). The mean RDI in patients with hematologic malignancies and with solid tumors was respectively 81.7 ± 26.6% and 84.5 ± 21.8%.

The prescribed starting dose matched the approved dose for 71.1% of patients ( n = 148) and remained correct throughout the first course for 51.4% ( n = 107). It was high from the outset for 1 patient and low for 64 (30.7%). In 4 of these low-dosed patients, the dose was increased during the first course, illustrating progressive determination of treatment.

Forty-five patients (48 first courses), or about 1 in 5, had treatment interruption during the first course. The cause was an adverse event, related to OAT or not, in 39 cases (74.7% of interruptions), suspension for surgery in 1 case (2.1%), and on the patient’s request in 1 case (2.1%). In 5 cases, interruption was due to insufficient cover between 2 consultations. Mean duration of interruption was 7.2 ± 6.1 days (range, 1-22).

During the first course, the prescribed dose was reduced without interrupting treatment in 3.6% of courses ( n = 8; 3.8% of patients, n = 8). This followed an adverse event in all cases. There was only 1 such reduction for each patient. As well as these dose changes during the first course, changes were made at renewal for 10 patients (4.8%), with interruption or dose reduction for 8, and increase for 2 patients whose starting dose had been below the approved dose.

Discussion

This study provides detailed information on early follow-up during the first month of OAT cycle. These results are essential to provide data for clinicians and decision-makers in a context in which experiences are increasingly developed in oncology to prevent and manage iatrogenic DRPs and their possible impact on OAT efficacy and tolerance and hence on unscheduled admissions, emergency presentations and life-threatening situations. 18

As well as the scheduled follow-up, the pharmacist and nurse conducted interventions with the oncologist for almost 9 in 10 patients, averaging more than 3 interventions per patient. Mostly NPIs were addressed to the patient and family, and secondly to the oncologist, as previously described. 2 , 19 These interventions mainly concerned management of DRPs, and PROs for symptoms and/or adverse events or problems of coordination in the community-hospital care pathway. One of the strongest points of the ONCORAL program is the deal with all such needs simultaneously, based on coordination with the multidisciplinary hospital team of oncologists, pharmacists and nurses and the link with the community physicians, pharmacists and nurses. Compared to previous nurse-led pathways, 20-22 including a hospital pharmacist optimized multidisciplinary management, with exhaustive management of DRPs concerning side-effects, DDI and adherence and an effective community-hospital link, shown to have positive medico-economic impact. 12 , 23

Management of DDIs is a major aspect of resolving DRPs, with an average of 1 significant DDI requiring corrective action during the first month of treatment for half of the patients. In the present study, 7 in 10 DDIs that were dealt with could have increased OAT toxicity or impaired efficacy. DDIs are especially frequent in case of polypharmacy (≥ 5 daily drugs), 18 as in more than half (52%) of the patients in the present study. In ONCORAL series, 68% of DDIs involved prescribed drugs: usually anti-ulcer drugs such as proton pump inhibitors (22%), antithrombotics (17%), or cardiovascular drugs (14%), followed by antidepressants (8%), and anti-infective drugs. Other studies also reported interactions with anticonvulsants, corticosteroids, opioids, and even dietary supplements and minerals. 24-27 In the AMBORA study, the most frequent interactions involved CYP450, reduced absorption due to elevated gastric pH, and QT segment elevation. 28

The present study also highlights DDIs with OTC drugs and CAM, as reported by other studies in which patients were responsible for almost 30% of errors and interactions. 18 , 28 , 29 The proportion of DDIs involving self-medication was 1 in 3, similar to that reported by Solomon et al 30 but higher than reported elsewhere. 31 The ONCORAL program includes very thorough screening for DDIs on a face-to-face questionnaire and search of the literature and of several databases dedicated to phytotherapy, which may account for the higher rate of DDIs than reported elsewhere. DDIs involving phytotherapy were managed for 12% of patients in the present study, leading to discontinuations of phytotherapy in case of risk for OAT efficacy or tolerance or of general health impairment. Other studies found interactions with phytotherapy for 8% of patients, and that these are difficult to manage because poorly explored, 32 with a real risk of loss of chance. 33

In addition, the hospital-community link generates pharmaceutical green lights, asking the ONCORAL team whether a new drug or CAM, prescribed or self-medicated, can be associated with the OAT and existing medication. For the patient, caregiver, or health professional making the request, it is a matter of ensuring in advance that there will be no interaction. It is a relevant question of prevention and tele-expertise that had not been planned for when the ONCORAL program was originally designed. These green light requests are very time-consuming for the ONCORAL pharmacist but testify to all parties’ adoption of the pathway and highlight the success of the community-hospital link.

About 80% of patients experience adverse events during the first month of OAT, 2 and follow-up should be close in this early stage. Weekly follow-up may ensure long-term management of adverse events. In light of these experiences, during the first months of treatment, the ONCORAL program includes reinforced follow-up and repeated intervention by the clinical pharmacist and hospital nurse. PROs concerning symptoms or adverse events led to almost a quarter of the NPIs. Patients need to be able to identify potential events and alert health professionals, leading, if needed, to an emergency consultation or even hospitalization. In the present study, interventions by the ONCORAL team led to the early hospitalization of 2 patients with severe adverse effects. In addition, interviews conducted within the pathway should enable patients to manage some of the adverse effects at home, with associated support drugs. Medication information transfer is a crucial element in the patient’s discharge process from hospital to home. Adherence is a major issue for patients treated with OAT. 6 , 34 Pharmaceutical monitoring is a key to improving adherence. 30 , 35-40 Oncoral achieved good adherence in 82% of patients at the end of the first course of treatment. This is an encouraging result, and the challenge is to make it sustainable.

Although the present study demonstrated the benefit of weekly phone monitoring, digital applications are now known to improve outcomes. Basch et al showed a significant increase in overall survival with electronic PROs (e-PROs) in patients with metastatic cancer, compared to usual care. 11 More recently, Mir et al reported decreased treatment-related grade≥3 toxicity with a navigator-led follow-up system and a web portal-smartphone application on top of usual care. 41 Digital follow-up combined with nurse or pharmacist consultation could also help balance medical resource utilization. An assessment of the additional costs and burden on healthcare professionals recently demonstrated the cost-benefit of this type of remote patient monitoring. 42

Strong collaboration between the community and hospital pharmacists could help limit iatrogenic events. The community-hospital link set up under ONCORAL attracted the active involvement of 78% of community pharmacists who were contacted, whereas a previous study reported that more than half of community pharmacists rarely provided feedback to hospitals, and 14.3% rarely performed tasks such as continuous side-effect monitoring and patient guidance, including supportive care. 8 It is essential to define the role of the community pharmacist in the management of patients treated with OAT, and this is lacking in the literature.

This study further reported the first results for relative dose intensity (RDI) after 1 month’s OAT. RDI was determined directly by dose reduction, course spacing, and temporary interruptions or terminations due to adverse effects, and is thus a robust endpoint for assessing patient exposure to oral therapy. Several studies correlated the onset of severe grades 3-4 adverse events with dose reduction and treatment interruption or termination, all of which reduce RDI, with correlation to survival. 43 , 44

The mean RDI in the ONCORAL series was 83.1%: that is, within the 80%-85% recommended target range for OAT efficacy in hematologic or solid malignancy. 6 , 45 , 46 This assessment was made only for the first month of treatment and needs to be extended to 6 months for comparison with other reports 41 ; it is nevertheless promising. Analysis of RDI also provides crucial information on OAT in real life. Over the first course (30-35 days), 1 in 5 patients experienced interruption, for a mean of 7.2 days.

As this was a real-life study, the main limitation was that it was not comparative. In addition, it was a single-center study. However, ONCORAL has more than 10 years of experience, enabling integration in daily practice and assessment on robust criteria such as RDI. ONCORAL is recognized as a model for many other educational programs for patients with cancer and, more recently, for the French national Onco’Link program, with a 33 month assessment of the deployment of an innovative community-hospital follow-up for 15 000 outpatients enrolled by 45 health centers. 47 Further studies are necessary to confirm benefits over a longer term.

Conclusion

The results from the multidisciplinary community-hospital ONCORAL program were very encouraging for the first OAT cycle. ONCORAL succeeded in the early detection and management of DRPs. The community-hospital link is well-structured in real life, with the active involvement of community health professionals.

Contributor Information

Claire Lattard, Hospices Civils de Lyon, Groupement Hospitalier Sud, Unité de Pharmacie Clinique Oncologique, 69495 Pierre-Bénite, France.

Chloé Herledan, Hospices Civils de Lyon, Groupement Hospitalier Sud, Unité de Pharmacie Clinique Oncologique, 69495 Pierre-Bénite, France; Université Lyon 1, EA 3738, CICLY, Lyon, 69921 OULLINS Cedex, France.

Thibaut Reverdy, Hospices Civils de Lyon, Groupement Hospitalier Sud, Unité d’Oncologie médicale, 69495 Pierre-Bénite, France.

Gabriel Antherieu, Hospices Civils de Lyon, Groupement Hospitalier Sud, Unité d’hématologie, 69495 Pierre-Bénite, France.

Anne-Gaelle Caffin, Hospices Civils de Lyon, Groupement Hospitalier Sud, Unité de Pharmacie Clinique Oncologique, 69495 Pierre-Bénite, France.

Marie-Anne Cerfon, Hospices Civils de Lyon, Groupement Hospitalier Sud, Unité de Pharmacie Clinique Oncologique, 69495 Pierre-Bénite, France.

Magali Maire, Hospices Civils de Lyon, Groupement Hospitalier Sud, Unité de Pharmacie Clinique Oncologique, 69495 Pierre-Bénite, France.

Marine Rivat, Hospices Civils de Lyon, Groupement Hospitalier Sud, Unité de Pharmacie Clinique Oncologique, 69495 Pierre-Bénite, France.

Stéphanie France, Hospices Civils de Lyon, Groupement Hospitalier Sud, Unité de Pharmacie Clinique Oncologique, 69495 Pierre-Bénite, France.

Hervé Ghesquières, Hospices Civils de Lyon, Groupement Hospitalier Sud, Unité d’hématologie, 69495 Pierre-Bénite, France.

Benoit You, Université Lyon 1, EA 3738, CICLY, Lyon, 69921 OULLINS Cedex, France; Hospices Civils de Lyon, Groupement Hospitalier Sud, Unité d’Oncologie médicale, 69495 Pierre-Bénite, France.

Gilles Freyer, Université Lyon 1, EA 3738, CICLY, Lyon, 69921 OULLINS Cedex, France; Hospices Civils de Lyon, Groupement Hospitalier Sud, Unité d’Oncologie médicale, 69495 Pierre-Bénite, France.

Florence Ranchon, Hospices Civils de Lyon, Groupement Hospitalier Sud, Unité de Pharmacie Clinique Oncologique, 69495 Pierre-Bénite, France; Université Lyon 1, EA 3738, CICLY, Lyon, 69921 OULLINS Cedex, France.

Catherine Rioufol, Hospices Civils de Lyon, Groupement Hospitalier Sud, Unité de Pharmacie Clinique Oncologique, 69495 Pierre-Bénite, France; Université Lyon 1, EA 3738, CICLY, Lyon, 69921 OULLINS Cedex, France.

Author contributions

Conception and design: Claire Lattard, Chloé Herledan, Magali Maire, Stéphanie France, Anne-Gaelle Caffin, Florence Ranchon, and Catherine Rioufol. Data collection: Claire Lattard, Marine Rivat, Stéphanie France, Magali Maire, Anne-Gaelle Caffin. Analysis and interpretation of data: all authors. Manuscript writing: Claire Lattard, Magali Maire, Marine Rivat, Florence Ranchon, and Catherine Rioufol. Approval of final article: All authors.

Funding

None declared.

Conflicts of interest

Authors declare no competing interest

Data availability

The data underlying this article will be shared on reasonable request to the corresponding author.

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Associated Data

Data Availability Statement

The data underlying this article will be shared on reasonable request to the corresponding author.