DOI: https://doi.org/10.21203/rs.3.rs-1762559/v1
To evaluate progression free survival (PFS) in patients with advanced or metastatic, hormone receptor positive (HR+), HER2-negative (HER2-) breast cancer treated with palbociclib in combination with fulvestrant as second or later lines of treatment. Method: An observational, retrospective study with cohorts in 11 sites in Colombia, extracted from the medical records of women who began treatment between February 2018 and August 2019. Index date was first prescription, and patients were followed until they experienced disease progression, death, treatment discontinuation, were lost to follow-up, or until 12 months of follow-up, whichever occurred first. Kaplan Meier were used to estimate PFS.
Sixty-nine patients who received at least one dose of the drugs were included in the analysis. Median follow-up was 10.81 ± 3.18 months, mean age was 61.2 ± 11.14 years and 96.3% were postmenopausal. At the time of starting treatment, 52 were in stage IV, with 59 with > 2 sites of metastasis. All patients started on palbociclib 125 mg. 23 reported discontinuation, 10 of them permanently but none due to neutropenia. Clinical benefit rate was 69.35%, and median PFS was not achieved at 12 months. One death was reported due to disease progression.
Effectiveness of Palbociclib for patients with HR+/HER2- advanced or metastatic breast cancer treated with palbociclib in combination with fulvestrant as second or later lines of treatment in Colombia is consistent with the efficacy observed in clinical trials while maintaining a good safety profile. Implications for practice: Real-world data from Colombia for the first time indicates the combination of palbociclib + fulvestrant is associated with high levels of effectiveness in women with HR+/HER2- advanced or metastatic breast cancer, even in third or later lines of treatment. Although neutropenia was frequent and, in some cases, clinically significant, no patients required permanent treatment discontinuation due to this event. All of the adverse effects resolved without sequelae, and no deaths due to this cause were seen. This confirms an adequate safety profile for the drug combination.
Breast cancer is the most frequent cancer in women. It is estimated that every year 46 out of 100,000 women develop the disease1. According with World Health Organization, in 2020 over 2.3 million women were diagnosed with breast cancer with 3% of the mortality in women globally2. In the last decades, there has been an increasing tendency both in new cases and in survival. If current tendencies continue, it is estimated that breast cancer diagnoses in Latin America will increase by 34% by 20303. In Latin America breast cancer incidence was 51.9 per 100,000 women in 20181, with some variations among countries in the region4. In Colombia, figures from the Global Cancer Observatory (GCO) estimate an age-adjusted incidence of 44.1 cases per 100,000, and more than 3 700 women die from this cause each year1. The Instituto Colombiano Nacional de Cancerología registered 861 new cases of breast cancer in 2018, a > 10% increase from 778 in 2017. The “Cuenta de Alto Costo” reported in 2020 a total of 7047 new cases and 3009 deaths related to breast cancer, of which 81.5% had positive hormone receptors (HR+) and 17.8% had positive human epidermal growth factor receptor 2 (HER2)5. 30 to 40% of Latin-American patients with breast cancer are diagnosed in advanced stages (III/IV), which is primarily due to limitations in timely access to the health system (especially when population screening rates for the disease are low), and this results in a poorer prognosis and lower survival rates. Wide adoption of screening programs that promote early detection and the development and application of therapeutic strategies that extend survival for advanced stages are therefore warranted6.
For the management of advanced and metastatic hormone dependent breast cancer, clinical practice guidelines currently recommend the use of CDK 4/6 inhibitors in combination with endocrine therapy as first line of treatment or subsequent lines after the failure of the endocrine therapy7–10.
Palbociclib is an oral small-molecule inhibitor of CDK 4/6, which has been shown to be effective for treatment of advanced, HR + and HER2-negative breast cancer. It has a significant impact on progression free survival (PFS) when combined with hormone therapy, such as letrozole (and compared to the latter alone) or fulvestrant11–12.
PALOMA-2 trial evaluated the use of palbociclib in combination with letrozole as first line treatment for postmenopausal women, showing a 10-month improvement in PFS with a median of 24.8 months (95% confidence interval [CI] 22.1-not estimable) in the intervention group, compared to 14.5 months (95% CI 12.9–17.1) in the placebo group; the toxicity profile was considered acceptable11. PALOMA-3 evaluated the use of palbociclib in combination with fulvestrant in women who were non-responders to prior endocrine therapy, demonstrating after a median follow-up of 8.9 months a significant increase in median PFS, of 9.5 months (95% CI 9.2–11.0) compared to 4.6 months (95% CI 3.5–5.6) in the placebo group12, and an increase in overall survival in women treated with palbociclib and with prior sensitivity to endocrine therapy.
Palbociclib received market commercialization approval in Colombia in October 2018. Its use has been approved for postmenopausal patients with metastatic or advanced, hormone receptor positive, HER2-negative breast cancer in combination with endocrine treatment: letrozole as initial treatment, or fulvestrant in women with disease progression after endocrine therapy. Since then, palbociclib has been widely prescribed, especially as emerging data from real-world studies provide important information regarding clinical outcomes of patients treated in clinical practice. The Ibrance Real World Insights Study (IRIS), with results from Argentina, Canada, Germany, and United States, supports the effectiveness and tolerability of palbociclib13–15. RENATA, POLARIS, and PALPract are other real-world ongoing studies that provide additional data on palbociclib prescribing and treatment patterns in routine clinical practice16–19.
In the scenario of using targeted therapies, such as palbociclib, to treat metastatic breast cancer, real-world studies allow treating physicians to evaluate the results regarding effectiveness and safety of the treatment under the conditions of the local health system. Based on this, the primary objective of this study is to describe the real-life experience of the use of palbociclib in combination with fulvestrant as second or later lines of treatment in Colombia, taking into account clinical outcomes and treatment patterns after the initiation of the therapy. Secondary objectives are to describe demographic and clinical variables, mortality, persistence of the treatment, discontinuation and the reason of discontinuation or dosage reduction.
An observational, retrospective and descriptive study was carried out based on the review of medical records of women with advanced or metastatic, hormonal receptor positive and HER2-negative breast cancer, treated with palbociclib in combination with fulvestrant. This study was conducted in 11 outpatient care centers from different cities in Colombia. The study protocol was approved by the Institutional Review Board of each site.
The index date was defined as the date on which the first prescription of palbociclib in combination with fulvestrant as second line or greater line of treatment between February 2018 to August 2019 was made, and the follow-up time began at the index date and up to disease progression, death, loss, switch or discontinuation to follow-up or 12 months of follow up, whichever came first. Results are presented excluding missing data.
Eligible patients were women aged ≥ 18 years with a diagnosis of advanced or metastatic, hormonal receptor positive, HER2-negative breast cancer. Patients received palbociclib in combination with fulvestrant as second line or greater, in accordance with the Colombian drug label. The included patients initiated palbociclib in combination with fulvestrant up to 2 months after the index date in order to ensure the minimum follow-up for clinical outcomes data. Patients who had been exposed to other CDK inhibitors prior to index date were excluded.
Data were extracted from the patients’ medical records through case report forms. Data of interest included demographic characteristics, diagnostic processes, characteristics of the tumor, response to treatment and time to response, discontinuation, or death. Definitions of clinical response were provided to physicians based on their assessment of radiological evidence for change in burden of disease over the course of treatment. Clinical outcomes were defined as:
Complete response: complete resolution of all visible disease.
Partial response: partial reduction in size of visible disease in some or all areas without any areas of increase in visible disease.
Stable disease: no change in overall size of visible disease; also, if some lesions increased in size and others decreased in size.
Progressive disease: an increase in visible disease and/or presence of any new lesions; included cases where the clinician indicated progressive disease.
Death: Death of the patient that occurs from initiation of treatment of interest to study period.
Progression free survival: Time between the date the patient receives the first dose of study treatment to the date of disease progression or death from any cause. For the whole cohort it is presented as a median of time, if reached, or a percentage of patients without progression or death at a defined time point (12 months).
Persistence: Continuation of treatment from the index event to 12 months of follow-up with a time to delivery of drugs no greater than 60 days after prescription. Those patients who had to suspend treatment for a period of time under medical recommendation were not considered as non-persistent.
Loss to follow up: Patients who dropped out due to administrative reasons such as changes of health maintenance organization (HMO) or relocations, and those who did not return to the site for other reasons.
Analyses were mainly descriptive, and included estimates of the mean, standard deviation, 95% confidence intervals of the mean, median, interquartile ranges and frequency distributions for continuous scale variables and frequency distributions for categorical scale variables. Time-to-event outcomes were calculated using Kaplan-Meier estimates of the survival in function of time to disease progression, death, partial response, complete response, and treatment discontinuation. Subgroup analysis of progression by Age, ECOG, line of treatment, number and site of metastasis was conducted using Cox proportional Hazard Models. The results were presented as Hazard ratio (HR). Missing data were not imputed. The analyses were conducted on observed cases and the data were censored at the time of last known follow-up. The objective response rate was estimated from the proportion of patients achieving complete response or partial response. The clinical benefit rate corresponds to the proportion of patients with complete response, partial response, and stable response.
During 2020–2021, an analysis of medical records of patients with confirmed HR+/HER2- advanced breast cancer or metastatic breast cancer treated with palbociclib in combination with fulvestrant was performed. Data were collected from patients treated between February 2018 and August 2019 at 11 sites from Colombia.
Sixty-nine patients were included in the final cohort after exclusion of those with missing data and considering inclusion and exclusion criteria, such as those who did not receive at least one dose of the drugs. Mean age was 61.2 ± 11.14 (range 39.9–89.7), 53.3% had completed secondary school or other superior education and 91.3% lived in the urban area. The mean follow-up was 9.44 ± 2.84 months, 96.3% of the women were postmenopausal, 57.9% were patients with pre-existing comorbidity and 68.1% patients received the treatment as a second line, in 20.3% as a third lines, in 10.1% it was the fourth line and in 1.4% it was a further line of treatment.
Demographic, clinical, and therapeutic information at baseline for all patients, and the second line and other lines subgroups are presented in Table 1. The characteristics were similar between patients under a second line of treatment and other lines, with some slight differences. More patients in further lines had Eastern Cooperative Oncology Group Performance Status Scale (ECOG) of 1 or 2; however, this information was not reported in 25 patients. Ninety five percent of patients in further lines of treatment were positive for progesterone receptors, in contrast with those in a second line. About half of patients with this line of treatment (52.4%) had more than 4 sites of metastasis. The most frequent sites of metastasis were lung and visceral (57.1% in both sites). In second line of treatment, bone metastasis was identified in 65.2% of patients. 61/69 women had received hormonal treatment, mostly tamoxifen (28), anastrozole (13) and letrozole (11). Comparing by lines of treatment, a higher proportion of patients received tamoxifen in further lines (76.2%) compared with those in a second line of treatment (23.9%), while anastrozole and letrozole were more frequent in the latter (41.3%).
| Characteristic | All patients | Second line | Other lines |
|---|---|---|---|
| No of Patients | 69 | 46 | 23 |
| Age | |||
| Mean (SD) | 61.2 (11.15) | 61.0 (11.6) | 61.7 (10.5) |
| Family history of cancer n (%) | |||
| Yes | 11 (15.9) | 7 (15.2) | 4 (17.4) |
| No | 44 (63.8) | 29 (63.0) | 15 (65.2) |
| Unknow | 14 (20.1) | 10 (21.7) | 4 (17.4) |
| Charlson comorbidity index score, n (%) | |||
| 0–1 | 14 (20.3) | 10 (21.7) | 4 (17.4) |
| 2–3 | 21 (30.4) | 14 (30.4) | 7 (30.4) |
| 4+ | 14 (20.3) | 10 (21.7) | 4 (17.4) |
| Unknown | 20 (28.9) | 12 (26.1) | 8 (34.8) |
| Menopause status n (%) | |||
| Pre/peri menopausal | 2 (2.8) | 2 (4.4) | 0 (0.0) |
| Postmenopausal | 53 (76.8) | 34 (73.9) | 19 (82.6) |
| Unknown | 14 (20.3) | 10 (21.7) | 4 (17.4) |
| ECOG at Palbociclib initiation n (%) | |||
| 0 | 16 (23.2) | 10 (21.7) | 6 (26.1) |
| 1 | 25 (36.2) | 13 (28.3) | 12 (52.2) |
| 2 | 3 (4.3) | 3 (6.5) | 0 (0.0) |
| Unknown | 25 (36.2) | 20 (43.5) | 5 (21.7) |
| BRCA | |||
| Yes | 2 (2.9) | 1 (2.2) | 1 (4.4) |
| No | 8 (11.6) | 6 (13.0) | 2 (8.7) |
| Unknown | 59 (85.5) | 39 (84.8) | 20 (87) |
| Hormonal therapy (n%) | |||
| ER+/PR+ | 60 (86.9) | 38 (82.6) | 22 (95.7) |
| ER+/PR- | 8 (13.0) | 7 (15.2) | 1 (4.4) |
| ER-/PR+ | 1 (1.4) | 1 (2.2) | 0 |
| Stage at ABC/MBC at Palbociclib prescription n (%) | |||
| IIIA | 2 (2.9) | 2 (4.4) | 0 (0.0) |
| IIIB | 3 (4.3) | 3 (6.5) | 0 (0.0) |
| IIIC | 1 (1.4) | 1 (2.2) | 0 (0.0) |
| IV | 54 (78.3) | 34 (73.9) | 20 (87) |
| Unknown | 9 (13.0) | 6 (13.0) | 3 (13) |
| Recurrence, n (%) * | |||
| Loco-regional | 8 (24.2) | 2 (9.0) | 6 (66) |
| Local | 1 (3.0) | 1 (4.5) | 0 (0.0) |
| Distant | 24 (72.7) | 19 (86.4) | 5 (44) |
| Number of sites of metastasis n (%) | |||
| 1 | 1 (1.4) | 1 (2.2) | 0 (0.0) |
| 2 | 22 (31.9) | 16 (34.8) | 6 (26.1) |
| 3 | 25 (36.2) | 19 (41.3) | 6 (26.1) |
| 4+ | 21 (30.4) | 10 (21.7) | 11 (47.8) |
| Metastatic site n (%) | |||
| Visceral* | 33 (47.8) | 20 (43.5) | 13 (56.5) |
| Bone only | 42 (60.9) | 30 (65.2) | 12 (52.2) |
| Lung | 25 (36.2) | 12 (26.1) | 13 (56.5) |
| Lymph nodes | 18 (26.1) | 11 (23.9) | 7 (30.4) |
| Prior therapy for ABC/MBC n (%) | |||
| Endocrine | 61 (88.4) | 39 (84.8) | 22 (95.7) |
| Chemotherapy | 60 (86.9%) | 37 | 21 |
| Adjuvant | 28 (40.6) | 17 (37.0) | 11 (47.8) |
| Neoadjuvant | 19 (27.5) | 13 (28.3) | 6 (26.1) |
| Metastatic | 13 (18.8) | 7 (15.2) | 6 (26.1) |
| Radiotherapy | |||
| Adjuvant | 5 (7.2) | 4 (8.7) | 1 (4.4) |
| Neoadjuvant | 45 (65.2) | 29 (63.0) | 16 (69.6) |
| None | 19 (27.5) | 13 (28.3) | 6 (26.1) |
| † Percentage estimate from the number of patients with recurrence. *Visceral: It includes metastasis in brain, lungs, pancreas, liver and kidney. SD: Standard deviation, n: number of patients. ABC/MBC: advanced/ metastatic breast cancer | |||
While at 6 months, the estimated proportion of patients who not progressed or dead from any cause was 0.88 (95% CI 0.81–0.96) (Fig. 1). At 12 months, it was 0.69 (95% CI 0.58–0.82) (Fig. 2). Subgroup analysis showed HR was statistically significant in number of metastases, age older 60 years, and ECOG more than 2. Type of chemotherapy, and metastasis in lung and bone do not show to be significant with numerical difference in the HR (Fig. 3). However, small sample size by subgroups and the characteristics of the patients in each comparison could affect the results. Multivariable analysis were not conducted. Only one patient dead during the time of follow up, therefore, the overall survival was not possible to estimate.
After 12 months, the objective response rate was 7.2% in all participants, with a 59.4% of patients with stable disease, increasing the clinical benefit rate to 66.6%. There were no differences in the clinical outcomes for patients in second and third lines, but the clinical benefit rate in other lines was lower. However, there was a small number of patients in the latter group affecting the significance of the results (Table 2).
| All lines n (%) | Second line n (%) | Third line n (%) | Other lines n (%) | |
|---|---|---|---|---|
| Total patients | 69 | 46 | 13 | 10 |
| Follow up | ||||
| Complete response | 1 (1.4) | 0 (0.0) | 1 (7.7) | 0 (0.0) |
| Partial response | 4 (5.8) | 4 (8.7) | 0 (0.0) | 0 (0.0) |
| Stable diseases | 42 (60.7) | 27 (62.8) | 8 (61.5) | 7 (70) |
| Progression | 22 (31.9) | 15 (32.6) | 4 (30.8) | 3 (30) |
| Objective response rate | 5 (7.2) | 4 (8.7) | 1 (7.6) | 0 (0.0) |
| Clinical benefit rate | 46 (66.6) | 31 (67.4) | 9 (69.2) | 7 (70) |
Discontinuation of therapy was observed in 14 patients; ten patients discontinued therapy due to disease progression and rest discontinued because of adverse effects or other reasons. None of the permanent discontinuations were due to neutropenia of a grade that warranted definite interruption of the treatment. In 23 cases, transitory suspensions were required: 82% of the patients suspended treatment only once and 34.5% of the cases occurred in the first or second cycles. Treatment was temporarily stopped in 17 patients for transitory neutropenia. Dose reduction was necessary for 23 patients; 60.8%, only once; in 34.7%, twice, and 4.3% required reductions three times.
All patients started with 125 mg of palbociclib, in 21/25 (84%) of the patients it was necessary to reduce the dose to 100 mg, and in 4 (16%), to 75 mg. Treatment delay, defined when a patient does not get Palbociclib in the time in which it was supposed to be delivered, on a single occasion was evidenced in 12 patients (41.4%), in two occasions in 4 patients (13.8%), and 13 patients suffered 3 or more delays (44.8%). The average treatment delay was 62 (56.1) days. Figure 4 describes the causes of discontinuation, transitory suspensions, dose reductions and delays.
Sixty-four adverse events were reported in 24 subjects, 61 cases of them were blood and lymphatic system (2 episodes of anemia, 11 of leukopenia, 45 of neutropenia, 2 of thrombocytopenia and 1 of pancytopenia). Diarrhea, skin rash and mucositis were presented in 1 patient each. One neutropenia was considered severe and 29 moderate (Table 3).
| Tipo de adverse event | Number of events | Number of subjects | Severity | ||
|---|---|---|---|---|---|
| Mild | Moderate | Severe | |||
| Anemia | 2 | 2 | 1 | 1 | 0 |
| Diarrhea | 1 | 1 | 0 | 1 | 0 |
| Leukopenia | 11 | 5 | 1 | 10 | 0 |
| Mucositis | 1 | 1 | 0 | 1 | 0 |
| Neutropenia | 45 | 22 | 12 | 29 | 1 |
| Pancytopenia | 1 | 1 | 1 | 0 | 0 |
| Skin Rash | 1 | 1 | 0 | 1 | 0 |
| Thrombocytopenia | 2 | 2 | 0 | 2 | 0 |
The findings of this study suggest that patients receiving palbociclib in the combination with fulvestrant as second or later lines had good tolerance, with low rates of treatment discontinuation due to adverse effects (including neutropenia) and dose-adjustment. A clinical benefit rate of 66.6% was identified, and progression-free survival at 12 months was 0.69 (95% CI 0.58–0.82).
Results were similar to PALOMA-3 in terms of clinical benefit rate, with high levels of PFS at 12 months. However, the objective response rate was lower than that communicated in the pivotal trial, and better in terms of PFS. Whilst the median was not reached at the end of the follow up, Paloma-3 study reported a median of 9.5 months12. PFS at 12 months observed in this Colombian population were more favorable than other real-world studies, where the median of PFS was achieved before 12 months or the value was lower than 0.60 at this time point20,21. In terms of progression rate, similar results were obtained in other studies conducted in Europe and US, with a progression rate of approximately 21%22–24. Results were better in Argentina, with a 6% less progression rate than the Colombian population13. The overall survival reported in this study was favorable with only one death reported by progression during the 12 months of follow-up.
Early discontinuation leads to greater recurrence rates and negatively influences survival25. The discontinuation rate was variable in observational studies, which vary greatly in other studies. For instance, patients in Hungary treated with palbociclib had a discontinuation rate of 56.0% at 12 months while 49.6% of patients switched to other therapies26. In other studies, a 72.2% discontinuation rate was reported among patients in Spain19, while in the US this was 19.9% 24 and in Argentina, 2.0%13. In the case of Colombia, the health care system is obliged to guarantee the treatment after approval by the HMO, thus the present study shows that discontinuation was more associated with progression of the disease and safety causes than administrative issues related to insurance.
In the present study high levels of delays in the patients’ treatment were seen, with 89% reporting at least one delay during follow up. Other countries such as Argentina and the US reported rates of delays of 11% and 15%, respectively13,24. Therefore, local authorities need to continue working to guarantee adequate access to these treatments, particularly for time-sensitive disorders such as breast cancer.
Tolerability was consistent between the pivotal trial and other real-world studies, which reported discontinuation due to adverse events in 4% of the patients12,13,27. However, the number of serious adverse events were smaller in this study than other reports, including PALOMA-3. Similar to the other studies, neutropenia was the main adverse event19,23, and dose modifications or transitory suspension were required in some patients.
Strengths of this study include the definitions of outcomes, PFS and OS, which were obtained from routine clinical data, as they were reported in the medical records. The study is also bringing a wider perspective, providing evidence among different cancer care sites across the country. However, these findings may not be generalizable to the overall advanced breast cancer population in Colombia despite the representation of the different sites, since the sample size was small to the expected. There were limited number of patients available in the index period, mainly, for Palbociclib was recently commercialized in the index period having administrative issues with HMOs. Likewise, for the limited sample size, statistical analyses for some subgroups of patients were not conducted.
Immortal bias was not identified for the inclusion criterion of minimum time of treatment with two months due to none patient was excluded by this criterion. Other limitations include the observational nature of the study, and the lack of a control group. Although the assessment of disease progression was evaluated through imaging procedures, physical exams, assessment of symptoms, or other methods, according to definitions used in previous published studies, the measurement of PFS has a combination of subjective and objective variables, contrary to overall survival, reducing the reliability of the outcome.
The landscape of breast cancer continues to evolve, as implementation of novel strategies in health care delivery and new treatments for breast cancer emerge for the Colombian population. This new evidence for treatment patterns and outcomes provides critical information supporting clinician assessment of treatments for patients and provides further insight into local clinical practice. In the next few years, long-term data in clinical outcomes will be needed especially in different groups of patients, to recognize changes in disease patterns and access to treatments.
Effectiveness of Palbociclib for patients with HR+/HER2- advanced or metastatic breast cancer treated with palbociclib in combination with fulvestrant as second or later lines of treatment in Colombia is consistent with the efficacy observed in clinical trials while maintaining a good safety profile.
ACKNOWLEDGMENTS
We thank all Research Centers (Instituto Médico De Alta Tecnología Oncomédica S.A., Clínica del Occidente, Hemato Oncologos Asociados, Unicáncer, Instituto de Cancerología Las Américas, Sociedad De Oncologia Y Hematologia Del Cesar S A S, Clínica del Country, Clínica de Oncología Astorga, Hospital universitario Mayor Mederi, Fundación Hospital San Pedro and Instituto Nacional de Cancerología for allowing us to conduct the study and all the investigators who contributed their knowledge, expertise, and the integrity of the work. Sebastian Menazzi, Nicolas Palla, and Francisco Fernandez are employees of Content who provided operational support on the medical writing of the study.
DISCLOSURE
AUTHOR CONTRIBUTIONS
All authors contributed equally to the study conception and design. Material preparation was performed by JMR and AA. The data collection was conducted by the different site participants. The statistical analysis was executed by JMR and reviewed by all the authors. The first draft of the manuscript was written by JMR and NC and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
COMPETING INTERESTS
MG, AA, NC and JMR are paid employees of Pfizer. No other author has competing interest to declare
FUNDING
This work was funded by Pfizer S.A.S
ETHICS APPROVAL AND CONSENT TO PARTICIPATE
All experimental protocols were approved by licensing committee: Comité de Ética Independiente Instituto de Cancerología SAS, Comité de Ética en la Investigación Centro de Atención e Investigación Médica (CAIMED), Comité de Ética de la Investigación Riesgo de Fractura, Comité de ética para la Investigación (CEIC), Comité de Ética en Investigación de la Universidad del Rosario Sala de Ciencias de la Vida, Comité de Ética en investigación CEI COMETA, Comité de Ética e Investigaciones del Instituto Nacional de Cancerología ESE, Comité de Ética en Investigación de la Fundación Cardiovascular de Colombia. The study was conducted in accordance with the Declaration of Helsinki and the local regulation of the participant countries. Informed consent was obtained from all study participants/ their legal guardians
CONSENT FOR PUBLICATION
Not applicable.
AVAILABILITY OF DATA
The data are not publicly available; restrictions apply to the availability of these data. However, the datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
ACKNOWLEDGMENT
We thank all the following Research Centers for allowing us to conduct the study: Instituto Médico de Alta Tecnología Oncomédica SA, Clínica de Occidente, Hemato-oncologos Asociados, Unicancer, Fundación Cardiovascular de Colombia, Instituto de Cancerología Las Américas, Sociedad de Oncología y Hematología de Cesar Ltda (SOHEC), Clínica del Country, Clínica de Oncología Astorga, Hospital Universitario Mayor-Mederi, Fundación Hospital San Pedro, Instituto Nacional de Cancerologíaand all the investigators who contributed their knowledge, expertise and the integrity of the work as a whole. Likewise, we thank all the patients that accepted to participate in the study.