Impact of chemotherapy schedule modification on breast cancer patients: a single-centre retrospective study

Background Nonconformity to chemotherapy schedules is common in clinical practice. Multiple clinical studies have established the negative prognostic impact of dose delay on survival outcome. Objective This study investigated the prevalence and reason for chemotherapy schedule modifications of breast cancer patients. This study also investigated the impact of schedule modifications on overall survival (OS). Setting This retrospective cohort study was done among breast cancer patient receiving chemotherapy from 2013 to 2017 and patients were followed until 31 Dec 2018. Methods Medical records of patients with cancer were reviewed. Female patients over eighteen years old were included, with primary carcinoma of the breast, who received anthracycline or taxane based chemotherapy regime and completed more than two cycles of chemotherapy. Patients were categorized into three groups of (1) no schedule modification, (2) with schedule modification and (3) incomplete schedule. The Kaplan–Meier was used to test for survival differences in the univariate setting and Cox regression model was used in the multivariate setting. Main outcome measure Prevalence, overall survival rates and hazard ratio of three schedule group Results Among 171 patient who were included in the final analysis, 28 (16.4%) had no schedule modification, 118 (69.0%) with schedule modification and 25 (14.6%) had incomplete schedule with OS of 75.0%, 59.3% and 52.0% respectively. 94% (189) of all cycle rescheduling happened because of constitutional symptoms (70), for non-medical reasons (61) and blood/bone marrow toxicity (58). When compared to patients with no schedule modification, patients with schedule modification had a 2.34-times higher risk of death (HR 2.34, 95% CI 1.03–5.32; p = 0.043). Conclusion Nonconformity to the chemotherapy schedule is common in clinical practice because of treatment complications, patients’ social schedule conflicts, and facility administrative reasons. Cumulative delays of ≥ 14 days are likely to have negative prognostic effect on patient survival. Thus, the duration of the delays between cycles should be reduced whenever possible to achieve the maximum chemotherapeutic benefit.


Impact on practice statements
• Patients should be counselled to expect more visits to the hospital in the event of treatment toxicity because the chemotherapy cycle will be rescheduled until the patient's investigational value are satisfactory for subsequent chemotherapy administration • While rescheduling chemotherapy is warranted the physician should consider continuing the subsequent chemotherapy session within 5-7 days if the patient is clinically well to reduce the cumulative duration of the delay • Pharmacists should log the duration between the chemotherapy cycle and advise physicians on subsequently

Introduction
Over the last three decades, treatment paradigms for breast cancer have evolved, and the introduction of new cytotoxic agents have made chemotherapy a main treatment modality for breast cancer along with surgery and radiotherapy [1][2][3]. The superior survival benefit of chemotherapy for female breast cancer patients was demonstrated by a metaanalysis of 123 studies that reported a 21% reduction in mortality (Relative risk (RR) 0.79, 95% confidence interval [CI] 0.72-0.85) with an absolute 10-year gain of 6.5% among 100,000 patients [2]. However, the aforementioned benefit of chemotherapy was evaluated from randomised clinical trials where strict adherence to the chemotherapy schedule was required. In clinical practice, chemotherapy schedule modifications occur routinely for medical-related complications or non-medical reasons such as a patient's social schedule or a facility administrative reason. A large multicentre study compromising 1243 oncology centres in the USA reported that 24.9% of patients receiving chemotherapy experienced schedule modification of ≥ 7 days [4] while Wu et al. reported that 8.2% of 47,159 patients from a community oncology database had their chemotherapy duration extended by 17 ± 8 days [5]. Schedule modification contributes to nonconformity to the clinical trial protocol, which established the survival benefit of a particular chemotherapy regimen [6][7][8][9][10][11]. Consequently, several studies have reported a lower survival rate among chemotherapy-sensitive tumour patients who experienced dose delay and schedule modification [12][13][14]. For example, Liutkauskiene et al. reported that patients who experienced a chemotherapy schedule modification had a 3.3-times higher risk of death compared with patients who did not experience any chemotherapy schedule modifications (Hazard ratio (HR) 3.3, 95% CI 1.2-8.5, p = 0.016) [13].
However, the above studies associated a negative prognostic effect of schedule modification with survival for early stage breast cancer where chemotherapy is given with curative intent. The impact of schedule modification on overall survival (OS) and traditional prognostic factors for a neoadjuvant or palliative modality are relatively unknown. Understanding chemotherapy schedule modification is one research area that may help to improve breast cancer survival.

Aim of the study
This study aims to investigate the prevalence of chemotherapy schedule modification and to analyse the reason for schedule modification and duration of the delay (in days). This study also aims to investigate the impact of schedule modification on OS and the hazard of death among breast cancer patients.

Ethics approval
Ethics approval to conduct the study was obtained from the Medical Ethical Review Committee [MERC KKM. NIH-SEC. P18-1872(6)], Ministry of Health, Malaysia.

Study setting
This retrospective cohort study was conducted among female breast cancer patients receiving chemotherapy for cancer treatment in Hospital Seri Manjung, Malaysia from January 2013 to December 2017, and patients were followed until 31 December 2018. Data for this study were obtained from the patient medical documentation and chemotherapy registry.

Inclusion and exclusion
Inclusion criteria for this study were female patient's ≥ 18 year's old, primary neoplasia of the breast, received anthracycline-based or taxane-based therapy, and completed ≥ 2 cycles of chemotherapy. Exclusion criteria for this study were patients with recurrent cancer, patients with the non-complete medical record, referral for treatment between facilities, changes of chemotherapy regimen during treatment, and death before completion of a chemotherapy regimen.

Data variables
Individual subject data were collected retrospectively from patient medical records and a chemotherapy registry. The following data were collected: patient's age, ethnicity, tumour histology and molecular subtype, treatment modality, chemotherapy regimen, scheduled and administered date of chemotherapy, the reason for schedule modification, and date of death or date of last follow up. Age was grouped into categories (< 50 years old and ≥ 50 years old), while patient ethnicity was categorised into Malay and non-Malay to reflect the population distribution. Tumours (Stage I-IV) were staged according to the 6th edition of TNM classification by American Joint Committee on Cancer (AJCC) [15], while the molecular subtype of the tumour was categorised according to the presence of the oestrogen receptor (ER; positive or negative) and human epidermal growth factor receptor 2 (HER2; positive or negative). Information regarding treatment data consisted of treatment modality (adjuvant/neo-adjuvant/palliative) and type of chemotherapy used (anthracycline-based/taxane-based/anthracycline + taxane). The duration of the delay was the difference from the scheduled chemotherapy date to the administered date. The total length of the chemotherapy regimen was calculated from the first date to the last date of chemotherapy administration. Patients who completed chemotherapy during the expected chemotherapy timeline were categorised as 'no schedule modification', patients who had a longer-than-expected chemotherapy duration were categorised as 'with schedule modification', and patients who did not complete the expected number of cycles were categorised as 'incomplete schedule'. The reason for schedule modification was categorised as medical or non-medical reasons and the respective length of the delay for either reason was also calculated. The medical reason was defined as rescheduling by a physician with clinical evidence, while a non-medical reason was defined as rescheduling without an underlying medical cause such as a request by the patient or an administrative cause. The cumulative duration of the delay was categorised into < 14 days or ≥ 14 days. Data on mortality were obtained from the national registry database by matching the patient's identification number.

Statistical analysis
All categorical variables were presented as the number (n) and percentage (%). Survival analysis was performed using Kaplan-Meier analyses to estimate OS and the difference in the survival rate was compared using the Breslow test (Generalized Wilcoxon). Univariate analysis of a simple Cox regression was conducted to screen for all independent variables. The variable selection for the multivariate Cox proportional hazard regression model was obtained using backward selection and the stepwise method. The final model was presented with the adjusted HR with the 95% CI and its corresponding p value. For all tests, a two-tailed p-value of < 0.05 was considered to be statistically significant. All statistical analyses were performed using SPSS for Windows version 22.0 (SPSS Inc., Chicago, IL, USA).

Results
Among 171 patients who were included in the final analysis, 16.4% [28] of patients had no schedule modification, 69% (118) of patients had a schedule modification, and the remaining 14.6% [25] of patients had an incomplete schedule. As shown in Table 1, 143 (83.6%) patients had at least one schedule modification while 123 (71.9%) patients had at least one schedule modification for a medical reason. Most patients had a schedule modification for a combination of medical and non-medical reasons including 59 (50%) patients with a schedule modification and ten (40%) patients with an incomplete schedule.
Patients included in the analysis were expected to receive 1002 chemotherapy cycles but only 931 cycles were observed ( Table 2). Among the 931 observed cycles, 201 cycles were postponed, which corresponded to a delay of 1554 days. As shown in Table 3, 69.6% (140) of cycle schedule modifications occurred for medical reasons while non-medical reason contributed to the remaining 30.4% (61) of schedule modifications. When the duration of the delay (in days) was compared, medical reasons contributed to 1320 (84.9%) of days delayed, with a median delay of 7 days (range, 7-14 days), while non-medical reasons contributed to the remaining 234 days delay, with a median delay of 2 days (range, 1-6 days). This study shows that there were multiple reasons for modifying the chemotherapy schedule, but 94% (189) of all cycle rescheduling happened because of constitutional symptoms (70), for nonmedical reasons (61) and blood/bone marrow toxicity (58). Similarly, the combination of these three reasons contributed to 93.8% (1458) of days delayed. The most frequent reason for schedule modification was because of constitutional symptoms, which accounted for 70 (34.8%) cycles and 724 (46.6%) days delay. In this study, the criteria for constitutional symptoms included temperature ≥ 38.0 °C or absolute neutrophil count < 1.5 × 10 9 /l or fatigue (either reported by the patient or diagnosed by a physician).
The impact of the chemotherapy schedule modification on survival outcome was investigated using a Kaplan-Meyer analysis. The overall unadjusted survival was statistically significant (χ2 [2] = 6.136, p = 0.047; Fig. 1). The OS was 75.0% for patients with no schedule modification, 59.3% for patients with a schedule modification, and 52.0% for patients with an incomplete schedule (Table 4). A pairwise comparison between the schedule groups indicated that there was a significant difference in survival between the no schedule modification and incomplete schedule groups (Table 4). When the impact of a 14-day delay on survival outcome was analysed, the overall unadjusted survival was also statistically significant (χ2 [3] = 9.243, p = 0.026; Fig. 2). While OS for patient with no schedule modification and an incomplete schedule remained identical, OS for patients with a schedule modification < 14 days was 67.3% and that of patients with schedule modification ≥ 14 days was 52.4% (Table 4). An additional pairwise comparison indicated a statistically significant difference in survival between no schedule modification, incomplete schedule, and schedule modification ≥ 14 days (Table 4).
A final multivariate Cox proportional hazard regression model for OS that was adjusted for cancer stage, molecular subtype, type of chemotherapy, treatment modality, and schedule modification was performed (Table 5). When compared to patients with no schedule modification, patients with schedule modification had a 2.34-times higher risk of death (HR 2.34, 95% CI 1.03-5.32; p = 0.043) while patients with an incomplete schedule had a 3.47-times higher risk of death (HR 3.47; 95% CI 1.33-9.08; p = 0.011). When the length of schedule modification was categorised into < 14 days and ≥ 14 days, and the risk of death was 2.56times higher for patients with a schedule modification that had a ≥ 14-day delay (HR 2.56, 95% CI 1.10-5.99; p = 0.030), while patients with an incomplete schedule had a 3.44-times higher risk of death (HR 3.44; 95% CI 1.32-9.03; p = 0.012) compared to patients without a schedule modification.

Discussion
The chemotherapy schedule is commonly modified in clinical practice by delaying a chemotherapy dose to treat treatment-related complications because both the patient and physician anticipate a greater survival benefit by continuing the anti-cancer treatment given the treatment's curative intent. Less than one-quarter of the patients received chemotherapy within the optimal time frame as recommended by the clinical trial protocol. Chemotherapy regimen protocols recommend that the chemotherapy cycles be delayed until patients' investigational values are acceptable for administration of chemotherapeutic agents [16][17][18][19][20][21][22]. Thus, chemotherapy sessions are frequently rescheduled by 7 days, such as at our facility along with other leading oncology facilities [23][24][25][26], to allow for enough time to recover from treatment toxicity and for administrative convenience. Schedule modifications are widely acceptable because only 0.4% of treatment-related deaths [27] have been recorded, even with a prevalence of up to 42-64.5% of schedule modification for medical reasons [4,[28][29][30][31][32][33][34].
The high of proportion schedule modification (83.6%) in our study was anticipated because non-medical schedule modification criterion were included. Generally, non-medical reasons are not reported because the duration (1-6 days) is considered to be too short to have any significant clinical impact [24,26]. Similarly, even when the non-medical schedule modifications in our study group were higher compared to the European Organisation for Research and Treatment of Cancer (EORTC) Soft Tissue and Bone Sarcoma group audit report (30.3% vs. 21%) [33], non-medical reasons were not a significant predictor of OS (p = 0.227) in this study. A higher prevalence of schedule modification in our study may result from patients' sociodemographic characteristics because several studies have documented patients originating from a low socioeconomic neighbourhood or a household without a vehicle who required repeat visits for chemotherapy, which was an important issue that could have caused schedule modification [27,[35][36][37][38]. Additionally, a higher percentage of medical and non-medical reasons for schedule modifications was likely because strict adherence to the treatment protocol, such as during a clinical trial, is not required in daily clinical practice.
One of the main aims of this study was to evaluate the impact of the chemotherapy schedule modification on survival outcome. The clinical practice of modifying the chemotherapy schedule to treat chemotherapy complications has been reported to result in suboptimal outcomes, including suboptimal antitumor efficacy and reduced survival rates [39][40][41][42][43]. Chemotherapy schedule modification increased the duration between chemotherapy cycles, which consequently reduced the treatment's dose intensity. Henderson et al. proposed that the anti-tumour activity of cytotoxic agents depends on the drug used and on the schedule of drug administration [44]. This observation was further demonstrated in a study by Bonadonna et al., which analysed 20 years of follow-up data for the relationship between the delivered dose and survival outcome [41]. The study reported a 52% OS rate in patients who received the full dose intensity compared to a 25% OS rate among patients who received sub-optimal dose intensity. Moreover, the 25% OS rate was identical in the control group that received no chemotherapy. Although there was no control group in our study, there was an almost identical OS of 52.4% for patients who completed chemotherapy with a schedule modification of ≥ 14 days compared with 52.0% for patients who did not finish chemotherapy. The above result suggested that administration of chemotherapy with a prolonged schedule does not provide a superior survival outcome compared with patients who did not finish chemotherapy treatment or who received no treatment. In clinical practice, prolonged delays to restrict toxicity should be weighed against the benefit of completing chemotherapy according to the schedule.
The Cox analysis of schedule modification showed that the negative prognosis impact of schedule modification was affected by the different lengths of the delay. We analysed delays < 7 days and did not find a statistically significant impact on patient outcome in our study. Similarly, Motzer et al. reported that a delay of < 7 day had no influence on event-free survival [24] and another study by Denduluri et al. showed that the same duration of delay among advanced breast cancer patients was not associated with mortality [26]. A delay duration that is < 7 days was too short to have any negative prognostic effect on the survival outcome. With an increased length of delay, we found statistically significant evidence that a delay of ≥ 14 days increased the hazard for death by 2.56-times (HR 2.56; 95% CI 1.10-5.99; p = 0.030). Our results are consistent with findings by Seebacher et al., who reported that patients with a delay between 9 and 19 days had a 2.6-times higher hazard of death (HR 2.6; 95% CI 1.3-5.4; p = 0.0008) [45]. Similarly another study by Chirivella et al. reported a 1.41times higher hazard of death among patients with a delay ≥ 15 days (HR 1.41, 95% CI 1.04-1.90, p = 0.027) [46]. This finding suggests that short delays (< 7 days) may be acceptable because they may prevent serious toxicity for patients. Delays ≥ 7 days were strongly discouraged except in extraordinary life-threatening circumstances. Conversely, our results suggest that patients who had schedule modification of ≥ 14 days were more likely to have poorer survival.
Our clinical findings of a lower OS among patients with schedule modification were anticipated. The negative prognostic effect of schedule modification could be explained by the dose intensity (total amount of drug delivered over the total time course of treatment) that was received by the patient. Several studies have shown superior OS among  [49]. The above findings suggest that the established survival benefit of chemotherapy Despite the important results in this retrospective analysis, it seems that the mortality rate is affected by factors other than just the chemotherapy schedule. Although schedule modification was a statistically significant prognostic factor, cancer stage (Stage III and IV), molecular subtype (ER + HER2 + and ER − HER2 −), and treatment modality (neo-adjuvant and palliative) were also statistically significant confounding factors (Table 5). To verify our results, prospective studies that adjust for cancer stage, molecular subtype, and treatment modality when evaluating the impact of the chemotherapy schedule on long-term outcomes are required.

Conclusion
Nonconformity to the chemotherapy schedule is common in clinical practice because of treatment complications, patients' social schedule conflicts, and facility administrative  Adj. β, Adjusted regression coefficient; Adj. HR, Adjusted hazard ratio; CI, Confidence Interval; proportional hazard assumption by hazard function plot, log-minus-log plot and LOESS line for Schoenfeld partial residual plot were checked and assumption were met *No death was recorded for stage I cancer, hence to prevent non-convergence of coefficients, stage I and II was categorised together reasons. Cumulative delays of ≥ 14 days are likely to have negative prognostic effect on patient survival. Thus, the duration of the delays between cycles should be reduced whenever possible to achieve the maximum chemotherapeutic benefit.