Time Toxicity of Endocrine-based Oral CDK4/6 Inhibitor Therapies

Abstract

Adjuvant endocrine therapy with CDK4/6 inhibitors necessitates regular visits, lab assessments and side effect management, currently conducted primarily at breast cancer centers in Germany. This retrospective analysis estimates the potential travel distances, times and CO₂ emissions associated with centralized therapy management of adjuvant CDK 4/6 inhibitor application.
Eligible patients for ribociclib or abemaciclib therapy were retrospectively identified from 5053 early breast cancer cases at the university hospitals of Ulm, Lübeck and Tübingen, using the monarchE and NATALEE criteria. Travel times were calculated assuming 24 visits over three years for ribociclib and 18 visits over two years for abemaciclib.
Of the HR+/HER2− cohort, 1432 (38%) were potentially eligible for adjuvant CDK4/6 inhibitors, with 1080 patients included, based on available postal codes. Median travel distances and times for Ribociclib (3 years) were 1200 km (24.0 hours driving; 176.0 kg CO₂ emissions; 50.4 hours by public transport; 72.0 kg CO₂ emissions) and 900 km (18.0 hours driving; 132.3 kg CO₂ emissions; 37.8 hours by public transport; 54.0 kg CO₂ emissions) for abemaciclib (2 years).
Despite its retrospective limitations, this analysis provides valuable insight into the impact of centralized care on travel time and CO₂ emissions for oral cancer therapies in Germany. As the use of oral therapies increases, clinicians, patients, policymakers and the pharmaceutical industry should jointly develop strategies to optimize the safety, feasibility, and efficacy of oral therapies.

Zusammenfassung

Die kombinierte adjuvante endokrine Therapie mit einem CDK4/6-Inhibitor erfordert regelmäßige Klinikbesuche und Laboruntersuchungen zur Therapiekontrolle und zum Nebenwirkungsmanagement. Derzeit wird das Therapiemonitoring in Deutschland überwiegend „zentralisiert“ an Brustkrebszentren durchgeführt. Diese Arbeit analysiert retrospektiv die potenziellen Fahrtstrecken, Fahrzeiten und CO₂-Emissionen, die mit einem zentralisierten Therapiemanagement der oralen adjuvanten CDK4/6-Inhibitor-Therapien verbunden sind.
Zu diesem Zweck wurden 5053 Fälle mit primärem frühem Mammakarzinom aus den Brustkrebszentren Ulm, Tübingen und Lübeck retrospektiv hinsichtlich einer potenziellen Indikation für Ribociclib oder Abemaciclib gemäß den Einschlusskriterien der monarchE- und NATALEE-Studien analysiert. Die mit der Therapie verbundenen Fahrtstrecken, Fahrzeiten und CO₂-Emissionen wurden anschließend kalkuliert.
Insgesamt erfüllten 1432 Patientinnen (37,9% der HR+/HER2− Kohorte) anhand klinisch-pathologischer Risikofaktoren die Kriterien für eine adjuvante CDK4/6-Inhibitor-Therapie. Für 1080 Patientinnen lagen Adressdaten vor, sodass sie in die Analyse eingeschlossen werden konnten. Die kumulative mediane Fahrtstrecke und -zeit betrug für die 3-jährige Ribociclib-Therapie 1200 km mit 24,0 Stunden Fahrzeit per Pkw (176,0 kg CO₂-Emissionen) beziehungsweise 50,4 Stunden mit öffentlichen Verkehrsmitteln (72,0 kg CO₂-Emissionen). Für die 2-jährige Abemaciclib-Therapie ergaben sich 900 km Fahrstrecke mit 18,0 Stunden Fahrzeit per Pkw (132,3 kg CO₂) beziehungsweise 37,8 Stunden mit öffentlichen Verkehrsmitteln (54,0 kg CO₂).
Trotz der Limitationen einer retrospektiven Auswertung liefert diese Analyse wertvolle Einblicke in die zeitliche Belastung und die ökologischen Auswirkungen einer zentralisierten Versorgung bei oralen Krebstherapien in Deutschland. Angesichts der zunehmenden Bedeutung oraler Therapien sollten Ärztinnen und Ärzte, Patientinnen und Patienten, politische Entscheidungsträger und die pharmazeutische Industrie gemeinsam Strategien entwickeln, um Machbarkeit und Praktikabilität dieser Behandlungsformen weiter zu optimieren.

Keywords

oncology - breast cancer - systemic therapy - CDK 4/6 inhibitors - oral cancer therapy - time toxicity

Schlüsselwörter

Onkologie - Brustkrebs - systemische Therapie - CDK4/6-Inhibitoren - orale Krebstherapie - zeitliche Belastungen

Introduction

With 8.2 million cases diagnosed in the past five years, breast cancer remains the most common malignancy among women worldwide [1]. The continuous refinement of personalized treatment strategies has led to substantial improvements in prognosis [1] [2] [3]. Advances in risk stratification aim to further refine treatment indications, enabling tailored escalation or de-escalation of breast cancer therapy based on individual risk profiles [4]. Approximately 70% of early breast cancer (eBC) cases are classified as hormone receptor-positive and human epidermal growth factor receptor 2-negative (HR+/HER2−), making this the most prevalent subtype [5]. Despite therapeutic progress, HR+/HER2− eBC remains biologically heterogeneous, with recurrence risks varying widely [6] [7]. Accurate and individualized risk assessment is therefore essential to prevent both over- and undertreatment. For patients at intermediate or high risk of recurrence, oral endocrine-based maintenance therapy with cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i)—namely abemaciclib and ribociclib—has become a standard of care [8] [9] [10] [11].

Abemaciclib was approved for eBC based on the monarchE trial, which focused on high-risk patients with ≥ 4 positive nodes or 1–3 nodes plus additional risk factors (tumor size ≥ 5 cm, grade 3, or Ki-67 ≥ 20%) [12] [13] [14]. In March 2023, the FDA removed the Ki-67 ≥ 20% cohort from the adjuvant abemaciclib indication. The current FDA and EMA approvals no longer include Ki-67 status as a criterion for patient selection [15] [16]. Unlike monarchE, the NATALEE trial also included intermediate-risk patients. Eligibility required node-positive disease or stage IIB/III eBC, while stage IIA node-negative patients qualified if they had grade 3 tumors or grade 2 with high Ki-67 (≥ 20%) or genomic high risk. Overall, 28% of participants were node-negative at diagnosis [17] [18] [19] ([Fig. 1]).

Fig. 1 The most important characteristics of the two CDK4/6 Inhibitors for HR+/HER2− eBC. Abbreviations: AI = aromatase inhibitor; gBRCA1/2mt = germline breast cancer 1/2 mutation; GnRHa = gonadotropin-releasing hormone agonist; RS = recurrence score; TAM = tamoxifen.

Two German, retrospective, real-world analyses estimated the proportion of patients with HR+/HER2− eBC who have an indication for combined endocrine therapy with abemaciclib and/or ribociclib to be 34–43% [20] [21] [22]. In a retrospective analysis of male patients, 21.2% of HR+/HER2− eBC cases met the monarchE criteria, and 47.6% fulfilled the NATALEE criteria [20] [21] [22]. Based on this, Tauber et al. calculated an increased workload for physicians and determined that, depending on the number of additional patients, further physician positions would be required to adequately care for this patient cohort in the clinical setting [20].

Another important aspect concerns not only the additional time investment for physicians but also for patients, as therapy monitoring of CDK 4/6 inhibitors typically takes place in oncology clinics rather than in the often more locally accessible outpatient settings. A study from the field of rheumatology has already shown that longer travel distances significantly increase the risk of treatment discontinuation [23]. Another point concerns the CO₂ emissions generated by long travel distances, whether by car or public transport. Several analyses have already demonstrated high CO₂ emissions associated with the conduct of clinical trials [24] [25].

The aim of this retrospective study is to determine the so-called time toxicity for patients, due to travel distances to therapy monitoring in the respective outpatient clinics and the resulting CO₂ emissions, based on candidates for oral combined endocrine therapy with CDK 4/6 inhibitors from the breast cancer centers in Ulm, Tübingen and Lübeck.

Methods

This retrospective analysis included all patients who underwent complete surgical treatment for eBC at the Department of Gynecology and Obstetrics, Ulm University Hospital, and the Department of Women’s Health, Tübingen University Hospital, between 2018 and 2020, as well as between 2014 and 2023 at the Department of Gynecology and Obstetrics, University Hospital Schleswig-Holstein, Campus Lübeck. The study was conducted in compliance with the guidelines of the Declaration of Helsinki and approved by the Ethics Committee of Ulm University Hospital (protocol code 405/24), Tübingen University Hospital (protocol code 189/2025BO2) and Lübeck University Hospital (protocol code 2025–007).

Patient selection and retrospective data monitoring

Details on patient selection and retrospective data monitoring have already been described [20] [21]. Briefly, this retrospective analysis included male and female patients who underwent complete (R0) surgical resection for eBC. HR and HER2 status were assessed by certified pathologists using local standards as described earlier [20] [21]. Eligibility for ribociclib was based on the NATALEE trial criteria, consistent with its approval for adjuvant therapy: HR+/HER2− primary invasive eBC (Stage III, IIB, or IIA), with either N1 or N0 disease and high-risk features (Grade 3 or Grade 2 with Ki-67 ≥ 20% or high genomic risk). Eligibility for abemaciclib was based on its approval for eBC: HR+/HER2−, node-positive eBC with at least one high-risk feature (≥ 4 positive nodes, Grade 3, or tumor size ≥ 50 mm).

Analysis on time toxicity was conducted only for patients who potentially met the eligibility criteria for ribociclib and/or abemaciclib as adjuvant therapy for eBC based on their individual characteristics, and for whom all necessary clinical data and the residential postal code were available.

Time toxicity calculation

Travel distances to the respective breast centers were calculated using Google Maps, based on the center’s address and the patient’s residential postal code. The shortest route and estimated round trip travel time without traffic were used. Travel times by public transport were calculated when available. The shortest possible connection and its corresponding duration were included. All calculated times and distances refer to the round trip. Only net travel time was considered; waiting times at the point of departure were excluded. The estimated number of patient contacts was used to determine the frequency of visits required for endocrine-based maintenance therapies. For abemaciclib, which is administered over a treatment duration of two years, we calculated a total of 18 visits by adding the scheduled patient contacts over the corresponding time intervals: four visits in weeks 1–8, eight visits in weeks 9–52, and six visits in weeks 53–104 [20]. Similarly, for ribociclib, which is typically prescribed over a three-year period, we extended this visit schedule by incorporating an additional six contacts for weeks 105–156, resulting in a total of 24 visits. These visit counts directly reflect the structured monitoring intervals outlined in the table—ranging from biweekly to every 8–12 weeks—, ensuring that patient contact patterns in our model align with clinical practice recommendations for these therapies. The time estimates were made under the assumption of regular treatment visits; additional visits due to severe adverse events (SAE) were not considered, given the retrospective nature of the study ([Table 1]).

Table 1 Overview of monitoring intervals during CDK4/6 inhibitor therapy: Monitoring intervals and the number of physician–patient contacts over a maximum period of 3 years were assumed based on routine clinical practice and on the analysis by Tauber et al., 2025 [20]. Potential additional visits required for complications were not considered.

Therapy week	Control interval	Total number of patient visits for ribociclib	Total number of patient visits for abemaciclib
1–8	2 weeks	4	4
9–52	4–8 weeks	8	8
53–104	8–12 weeks	6	6
105–156	8–12 weeks	6	–
Total		24 (156 weeks)	18 (104 weeks)

CO₂ emissions from car travel were estimated, based on travel distance and average emission factors, in accordance with German and European standards. Emission values were calculated using data from the German Environment Agency, which provides standardized CO₂ emission factors for passenger cars, based on average fuel consumption and vehicle type. Specifically, an average emission factor of 147 g CO₂ per vehicle-kilometer was applied, as recommended for mixed urban and interurban traffic in Germany (Umweltbundesamt, 2023) [26]. For public transport an average emission factor of 72 g CO₂ per kilometer was applied [26].

Data processing and statistical analysis were conducted using Jupyter Notebook (Version 6.3.0, Project Jupyter, open-access and community-developed) on Anaconda (Version 3.0, Anaconda Inc., Austin, TX, USA) with the Python extension packages pandas (Version 1.4.1, open-access and community-developed). Excel, PowerPoint, and Power BI (Microsoft 365, Microsoft Redmond, Washington, USA) were utilized for creating flow charts and visualizing the data.

Results

Patient cohort and baseline characteristics

The overall retrospective cohort comprised 5053 patients with eBC who underwent complete surgical resection. 3776 were HR+/HER2−, 1432 (37.9% of HR+/HER2− cohort) were potentially eligible for adjuvant CDK4/6i therapy with abemaciclib and/or ribociclib ([Fig. 2]). Of these, 1080 patients with HR+/HER2− eBC, a potential indication for abemaciclib or ribociclib, and an available residential postal code, were included in the analysis. Patient characteristics are shown in [Table 2]. Mean age was 59.1 years (± 13), with 47% of patients being postmenopausal. The most common histological type was no special type (NST; 847/1080; 78.4%), followed by invasive lobular carcinoma (ILC; 192/1080; 17.8%). Most patients had a tumor size between 2 and 5 cm and 1–3 involved lymph nodes.

Fig. 2 Selection of patients with invasive early breast cancer. [Fig. 2] shows the flow chart of patient selection and final inclusion. A total of 5053 patients with early breast cancer were screened. Of these, 3776 had a hormone receptor-positive, HER2-negative breast cancer subtype. An indication for treatment with a CDK4/6 inhibitor was present in 1432 patients. For 1080 of these patients, all relevant clinical data and postal codes were available. TNBC: triple-negative early breast cancer; HER2+: HER2-positive early breast cancer (irrespective of HR-status); HR+/HER2−: hormone receptor positive, HER2-negative early breast cancer; CDK4/6i: Cyclin-dependent kinase 4 and 6 inhibitor.

Table 2 Patient characteristics.

	Number of patients	Percentage
* T and N stages were assessed after surgery. ER = estrogen receptor; HER2 = human epidermal growth factor receptor 2; ILC = invasive lobular carcinoma; n/a = not available; NST = non-special type; PR = progesterone receptor; TNBC = triple-negative breast cancer.
	1080	100%
Menopausal status
Premenopausal	464	43.0%
Postmenopausal	508	47.0%
Male	8	0.7%
n/a	7	0.6%
Histology
NST	847	78.4%
ILC	192	17.8%
Other	39	3.6%
n/a	2	0.2%
Grading
1	44	4.1%
2	726	67.2%
3	297	27.5%
n/a	13	1.2%
T-stage*
0	41	3.8%
1	218	20.2%
2	481	44.5%
3	234	21.7%
4	83	7.7%
N-stage*
0	304	28.1%
1	591	54.7%
2	126	11.7%
3	59	5.5%
n/a	0	0.0%
ER status
+	1048	97.0%
−	15	1.4%
PR status
+	874	80.9%
−	188	17.4%
n/a	18	1.7%
HER2 status
+	0	0.0%
−	1080	100.0%
Ki-67
≥ 20%	556	51.5%
< 20%	502	46.5%
n/a	22	2.0%

Travel distances, times, and environmental impact of therapy monitoring

For the total cohort of 1080 patients, median round trip travel distances and times for the entire three-year duration of ribociclib therapy were 1200 km (24.0 hours driving; 176.0 kg CO₂ emissions; 50.4 hours by public transport; 72.0 kg CO₂ emissions) and 900 km (18.0 hours driving; 132.3 kg CO₂ emissions; 37.8 hours by public transport; 54.0 kg CO₂ emissions) for the entire duration of two-year abemaciclib therapy.

The frequency distribution by one-way distance to the center for the total cohort (n = 1080) is shown in [Fig. 3].

Fig. 3 One-way distance to the assigned breast center (in kilometers). [Fig. 3] shows the distribution of one-way driving distances (in kilometers) from patients’ residential addresses to the breast cancer center. The distribution shows that the majority of patients (913; 85%) of the total cohort reside within a radius of 60 km by car. However, a relevant proportion of patients (167; 15%) live more than 60 km one way and were therefore excluded from further analysis, as it is unlikely that these patients would continue follow-up at the center after surgery.

In the following analysis, a cut-off ≤ 60 km one-way travel distance (n = 913) was applied, based on the assumption that patients beyond a certain distance are more likely to seek closer outpatient options for therapy monitoring rather than traveling to the university hospital. This approach is intended to avoid overestimating travel distances. Therefore, with the set cut-off of ≤ 60 kilometers one way travel distance by car, median travel distances and times for ribociclib (3 years) were 1008 km (21.6 hours driving; 148.2 kg CO₂ emissions; 48.0 hours by public transport; 60.5 kg CO₂ emissions) and for abemaciclib (2 years) 756 km (16.2 hours driving; 111.1 kg CO₂ emissions; 36.0 hours by public transport; 45.4 kg CO₂ emissions).

[Fig. 4] illustrates the catchment areas of all patients at the three study sites on a map of Germany. [Fig. 5] a displays the frequency distribution of patients with a one-way distance to the breast cancer center in Lübeck of ≤ 60 km, color-coded by frequency. [Fig. 5] b shows the mean round trip travel time by car per visit, while [Fig. 5] c presents the mean round trip travel time by public transport per visit. Corresponding figures for the Ulm and Tübingen centers are provided in the Supplement (Suppl. Fig. S1 and S2).

Fig. 4 Catchment areas of potential CDK 4/6 candidates: The catchment areas of the included patients from the total cohort (n = 1080) at the certified breast centers of the university hospitals Ulm, Tübingen, and Lübeck are shown on the map of Germany. As illustrated in [Fig. 3], some patients reside at considerable distances from the centers. Patients with one-way travel distances greater than 60 km by car were excluded from further time calculation analyses (see Methods).

Fig. 5 Map-based visualization University Clinic Lübeck (≤ 60 km one way). Graphical illustration of the catchment area (a) and travel time per visit by car (b) or public transport (c) is shown for the University Hospital Lübeck, including all patients residing ≤ 60 km by car. Panel a depicts the frequency distribution of patients by postal code, from dark blue (high) to light blue (low) as indicated in the legend. Panel b shows the mean duration per visit by car (round trip), with color coding according to the legend. Panel c shows the mean duration per visit by public transport. Corresponding figures for the Breast Cancer Centers of Tübingen and Ulm are provided in the Supplement.

For every 10 km of one-way travel distance by car, this corresponds to a median, cumulative travel time of 22.4 minutes per visit, resulting in 8.9 hours of additional, cumulative travel time per 10 km distance from the treatment center over the three-year duration of ribociclib therapy, and 6.7 hours over the two-year duration of abemaciclib therapy, respectively. When using public transport, the median travel time per visit per 10 km distance is 61.2 minutes, leading to a total of 24 hours per 10 km distance for the full course of ribociclib therapy (3 years) and 18.6 hours for abemaciclib therapy (2 years).

Accessibility and public transport limitations

Among patients with a travel distance by car of ≤ 60 km one way, 15.8% (144/913) would have no access, or only limited access, to the breast cancer center via public transport, with unreasonable round trip travel times exceeding 5 hours. Among patients with a travel distance by car of ≤ 30 km, 11.2% (67/599) would have no access to the breast cancer center via public transport. For patients within a car travel distance of ≤ 60 km, travel time by public transport was increased by a factor of 2.4. Among those living ≤ 30 km away, travel time by public transport was prolonged by a factor of 3.1. By using public transport, patients with a car travel distance of ≤ 60 km could save approximately 40.8 % of CO₂ emissions.

Real-world analyses estimate that approximately one in three patients with HR+/HER2− eBC is a potential candidate for ribociclib. Based on this analysis—regardless of receptor status and treatment setting—approximately one in five breast cancer patients overall would be eligible for ribociclib in the eBC setting [20]. With around 70000 breast cancer cases per year in Germany, this would correspond to 14000 eBC patients eligible for ribociclib annually. Accordingly, the CO₂ burden for 14000 ribociclib candidates is estimated at a maximum of 2000 tonnes per year. This amount of CO₂ is equivalent to the annual electricity consumption of 6500 people or the yearly carbon sequestration capacity of 200000 trees.

Discussion

In 10/2021, abemaciclib was FDA, and in 03/2023 EMA, approved for the treatment of HR+/HER2− eBC with high recurrence risk, demonstrating an IDFS benefit of 6.0% (HR 0.68, 95% CI 0.60–0.77) after four years compared to endocrine therapy alone. Recently, ribociclib was FDA (09/24) and EMA (11/24) approved for adjuvant therapy of early HR+/HER2− breast cancer with intermediate or high risk, based on positive data from the NATALEE trial, showing a four-year iDFS by 4.9% (HR 0.72, 95% CI 0.61–0.84) in the overall cohort and 5.1% in the node-negative cohort [27]. Previous studies have demonstrated the high relevance of these trials for clinical practice, as between 15.3% and 19.4 % of our patients with early HR+/HER2− breast cancer qualify for abemaciclib [20] [28], and between 33.6% and 43.0 % qualify for ribociclib therapy [20] [21].

While initial studies in internal medicine have already shown that a longer driving distance to the clinic significantly negatively impacts adherence to intravenous or subcutaneous alpha-tumor necrosis factor therapy with adalimumab, it can be assumed that this also applies to other therapies requiring clinical monitoring, even though this could not be assessed in the present study due to the focus on evaluating potential CDK4/6 inhibitor candidates [23]. In the present analysis, the oral CDK4/6i are taken independently by the patients themselves. Since both therapeutic agents (ribociclib and abemaciclib) can cause not only vegetative and generalized symptomatic side effects (e.g., diarrhea, emesis, vomiting) but also laboratory abnormalities (e.g., neutropenia and hepatotoxicity with elevated transaminases), regular clinical and laboratory monitoring is necessary. In the case of ribociclib, ECG monitoring is additionally required at the beginning of treatment due to the risk of QTc interval prolongation [9].

To date, these monitoring appointments take place in the oncology outpatient clinics of university hospitals or other oncology outpatient facilities, but not in the outpatient practices, which typically have the shortest distance to the patients’ homes. Structures such as certified oncology centers or mammography screening programs already provide examples of decentralized and quality-assured patient care. Integrating CDK4/6 inhibitor monitoring into similar established care networks could facilitate broader accessibility while ensuring adherence to high medical standards.

Potential solutions within the German healthcare system could include involving outpatient practitioners — who are located closest to the patients — in the monitoring and management of oral oncologic therapies. A positive example is the adjuvant endocrine therapy in early breast cancer with positive hormone receptors, which is typically prescribed and monitored over 5–8 years by outpatient practitioners [8] [29]. For this to be successful, a closer network between outpatient practitioners and hospitals would be essential to ensure optimal care for patients with moderate to severe side effects under CDK4/6i therapy, allowing early and timely referrals to the clinics. However, it must be acknowledged that outpatient gynecologists with specialized oncology expertise are unevenly distributed, and a shortage of adequately trained specialists could limit the feasibility of such a model. Strengthening oncology-specific training within gynecology and internal medicine residency programs could be a sustainable strategy to expand the pool of qualified physicians able to supervise oral tumor therapies. This would not only reduce the burden on university hospitals but also improve continuity of care in the outpatient setting.

The ongoing management of patients receiving CDK4/6 inhibitors does not require continuous in-person supervision. In clinical practice, several breast cancer centers have already adopted remote strategies, including scheduled telephone consultations, to ensure patient monitoring while reducing the need for physical visits. Laboratory results are transmitted directly to the breast center, where they are reviewed by oncologists or specialist medical staff. Subsequently, patients are contacted by phone to assess current symptoms and potential side effects. If no abnormalities are identified, prescriptions are issued and dispatched by mail.

The digitalization of this process presents significant potential for optimization. An app-based solution could allow for the direct integration of laboratory results into a secure, digital platform, enabling real-time evaluation by clinicians. Patient-reported outcomes, particularly the occurrence and severity of side effects, could be captured via structured, digital questionnaires. In addition, patients could be prompted to indicate whether they feel the need for a specialist consultation. The feasibility and acceptance of digital follow-up concepts in breast cancer care have already been demonstrated, for example in the Pro-B study, which showed that structured digital monitoring can improve both patient satisfaction and the early detection of adverse events. Building on such evidence, the integration of app-based CDK4/6i monitoring could be a promising approach to enhance adherence while minimizing unnecessary clinic visits [30]. In addition to reducing time spent on travel, the integration of digital solutions may also help to close further gaps in the care of breast cancer patients [31].

If the digital assessment does not reveal any clinical concerns, and the patient does not request contact, further interaction might be deemed unnecessary, particularly in cases of stable disease and after successful treatment implementation. In such scenarios, prescriptions could be generated automatically and transmitted via ePrescription systems. For patients wishing direct consultation, an appointment—either virtual or in-person—could be arranged within a short time frame. Importantly, the development and deployment of such digital solutions in Germany must comply with national data protection and data security regulations, as well as the European General Data Protection Regulation (GDPR). Implementation should occur only with the fully informed consent of participating patients.

For the benefit of our patients, it is important to consider time toxicity in treatment planning. Collaboration with local practitioners, or smaller centers closer to patients’ homes, should be encouraged to minimize travel time and treatment burden. Despite considerable differences in population density between metropolitan regions such as Stuttgart and more rural areas such as Schleswig-Holstein and Swabia, similar patterns of accessibility to care can be observed. High-quality oncological care also appears to remain relatively available in less densely populated regions. Nevertheless, regional differences in infrastructure and transportation may influence the individual burden of travel time as well as the continuity of care. In the current socio-political context, a more nuanced discussion of these aspects would further strengthen healthcare planning and highlight opportunities for system-level improvements.

Strengths and limitations

Real-world data represent an important complement to randomized controlled trials, both to confirm effectiveness in the broader population and to address structural and healthcare delivery questions [32] [33] [34], but they have their limitations. An important limitation of this study is its retrospective nature. The patients included in the time toxicity analysis were not necessarily treated with a CDK4/6i but were identified as potential candidates, based on their clinical and pathological characteristics. Since not all patients would have actually received a CDK4/6i, the number of patients who would have been treated with one is likely smaller. However, this does not impact the travel times. By conducting the study at three major German breast centers, an attempt was made to capture a consistent and representative real-world cohort. Since the data analysis was based on existing datasets that had been monitored and supplemented for this study, the observation periods differ between the Tübingen and Ulm cohorts and the Lübeck cohort; however, this is of limited relevance given the hypothetical nature of the analysis. We believe our analysis represents a relevant cohort of patients from German university hospitals receiving oral cancer therapy. The main limitation, however, is that it is unclear at what distance a patient would choose a center closer to their home. We set a threshold of 60 km, based on clinical experience, but this distance might vary depending on the location of residence. In urban areas with a higher density of specialized centers, distances are generally shorter. Nonetheless, the min/km distance estimates are widely applicable and highly valuable for clinical counseling.

Conclusion

This retrospective analysis provides valuable insights into the so-called time toxicity of oral adjuvant therapies. In addition to detailed information on efficacy and side effects, thorough counseling regarding the treatment process and associated time commitment is of great value to patients, particularly in the curative, adjuvant setting. The data collected here aims to increase awareness of time toxicity as a key factor for patients and to improve healthcare structures to further reduce the time burden imposed by therapy. Prospective data on time toxicity, therapy adherence and treatment discontinuation due to increased time burden need to be investigated in future real-world evidence analyses. For optimal patient outcomes and improved healthcare economics, clinicians, patients, policymakers and the pharmaceutical industry should jointly develop strategies to optimize the safety, feasibility, and efficacy of oral therapies.

Supplementary Material

• Suppl. Fig. S1: Map-based visualization University Clinic Ulm (≤ 60 km one way).

• Suppl. Fig. S2: Map-based visualization University Clinic Tübingen (≤ 60 km one way).

Conflict of Interest

H. Schäffler: honoraria from: AstraZeneca, Daiichi Sankyo, Gilead, Lilly, Novartis, Pfizer. S. Heublein: recieved honoraria for lectures or participation in advisory boards: Clovis Oncology, GlaxoSmithKline, Novartis, Pfizer, Merck Sharp & Dohme. J. Lichtblau: no. L. Wisniewski: no. B. Rack: honoraria from: AstraZeneca, Daiichi Sankyo, Eisai, ExactScience, Gilead, GSK, Guardant Health, Lilly, Menarini Stemline, MSD, NeoGenomics, Novartis, Pfizer, Roche. W. Janni: Research Grants and/or honoraria from: AstraZeneca, Cellgene, Chugai, Daiichi Sankyo, Eisai, ExactScience, Gilead, GSK, Guardant Health, Janssen, Lilly, Menarini Stemline, MSD, NeoGenomics, Novartis, Pfizer, Roche, Sanofi-Aventis, Seagen. A. Englisch: no. J. Englisch: Honoraria: AstraZeneca. T. Engler: Honoraria from AstraZeneca, Eli Lilly, Daiichi Sankyo, Gilead, GSK, MDS, Novartis, Pierre Fabre, Pfizer, Roche, Stemline. A. Hartkopf: Honoraria from Roche, Novartis, Lilly, MSD, AstraZeneca, Agendia, Seagen, GSK, ExactScience, Riemser, Teva, Onkowissen.TV, Gilead, Menarini Stemline, Pfizer, Amgen, Pierre Fabre, Eisai, Daiichi Sankyo, Thieme, Veracyte, Springer. S. Brucker: Advisory Boards: AstraZeneca, Lilly, MSD, Hologic. L. Hilmer: no. F. Fick: Lecture honoraria from Novartis, Travel grants from AstraZeneca and Novartis. F. Kohls: Honoraria Merck/Pfizer, Lilly, AstraZeneca. M. Banys-Paluchowski: Honoraria for lectures and advisory boards: Roche, Novartis, Pfizer, pfm, Eli Lilly, Onkowissen, Seagen, AstraZeneca, Eisai, Amgen, Samsung, Canon, MSD, GSK, Daiichi Sankyo, Gilead, Sirius Medical, Syantra, resitu, Pierre Fabre, ExactSciences, Aurikamed; Study support: Korean Breast Cancer Society, Eugen & Irmgard Hahn Stiftung, EndoMag, Mammotome, MeritMedical, Sirius Medical, Gilead, Hologic, ExactSciences, Claudia von Schilling Stiftung, Damp Stiftung, Ehmann Stiftung Savognin; Travel expenses: Eli Lilly, ExactSciences, Pierre Fabre, Pfizer, Daiichi Sankyo, Roche, Stemline. A. Rody: Lecture and consulting honoraria from Roche, Pfizer, Novartis, Celgen, Novartis, ExactSciences, Pierre Fabre, Lilly, Seagen, AstraZeneca, Eisai, MSD, Hexal, Amgen. D. Dannehl: received honoraria for lectures and participation in advisory boards: AstraZeneca, Gilead, Novartis, Daiichi Sankyo, Onkowissen, Oncologics. Travel expenses: Gilead and Daiichi Sankyo. N. Tauber: Honoraria for lectures and participation in advisory boards: Novartis, ExactSciences, Thieme, if-kongress, Deltamed. Travel grants from AstraZeneca, Thieme, Novartis, DGGG e.V., if-kongress, Aurikamed.

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Publication History

Received: 12 July 2025

Accepted after revision: 05 October 2025

Article published online:
03 November 2025