Publications by authors named "Mauricio Burotto"

46 Publications

Results of a Dose-Finding Phase 1b Study of Subcutaneous Atezolizumab in Patients With Locally Advanced or Metastatic Non-Small Cell Lung Cancer.

Clin Pharmacol Drug Dev 2021 Mar 31. Epub 2021 Mar 31.

F. Hoffmann-La Roche, Ltd., Basel, Switzerland.

Intravenous (IV) atezolizumab is approved for non-small cell lung and other cancers. Subcutaneous (SC) atezolizumab coformulated with recombinant human hyaluronidase, a permeation enhancer for SC dispersion and absorption, is being developed to improve treatment options, reduce burden, and increase efficiency for patients and practitioners. IMscin001 (NCT03735121), a 2-part, open-label, global, multicenter, phase 1b/3 study, is evaluating the pharmacokinetics (PK), safety, and efficacy of SC atezolizumab. The part 1 (phase 1b) objective was determination of an SC atezolizumab dose yielding a serum trough concentration (C ) comparable with IV. Patients enrolled in 3 cohorts received SC atezolizumab 1800 mg (thigh) once (cohort 1), 1200 mg (thigh) every 2 weeks for 3 cycles (cohort 2), or 1800 mg (abdomen) every 3 weeks cycle 1, then cycles 2 and 3 (thigh) every 3 weeks (cohort 3). In subsequent cycles, IV atezolizumab 1200 mg every 3 weeks was administered until loss of clinical benefit. SC atezolizumab 1800 mg every 3 weeks and 1200 mg every 2 weeks provided similar C and area under the curve values in cycle 1 to the corresponding IV atezolizumab reference, was well tolerated, and exhibited a safety profile consistent with the established IV formulation. Exposure following SC injection in the abdomen was lower (20%, 28%, and 27% for C , maximum concentration, and area under the concentration-time curve from time 0 to day 21, respectively) than in the thigh. Part 1 SC and IV PK data were analyzed using a population PK modeling approach, followed by simulations. Part 2 (phase 3) will now be initiated to demonstrate that SC atezolizumab PK exposure is not lower than that of IV.
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http://dx.doi.org/10.1002/cpdd.936DOI Listing
March 2021

Nivolumab plus Cabozantinib versus Sunitinib for Advanced Renal-Cell Carcinoma.

N Engl J Med 2021 03;384(9):829-841

From the Department of Medical Oncology, Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Brigham and Women's Hospital, and Harvard Medical School, Boston (T.K.C.); the Department of Genitourinary Oncology, Barts Cancer Institute, Cancer Research UK Experimental Cancer Medicine Centre, Queen Mary University of London, Royal Free National Health Service Trust, London (T.P.); the Bradford Hill Clinical Research Center, Santiago, Chile (M.B.); the Department of Medical Oncology, Gustave Roussy, Villejuif, France (B.E.); the Department of Hemato-Oncology, Urologic Oncology Clinic, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City (M.T.B.), the Department of Medical Oncology, Centro Universitario contra el Cáncer, Hospital Universitario "Dr. José Eleuterio González," Universidad Autónoma de Nuevo León, Nuevo León (V.M.O.J.), and the Department of Medical Oncology, Hospital H+ Querétaro, Querétaro (J.P.F.) - all in Mexico; the Department of Outpatient Chemotherapy, Professor Franciszek Lukaszczyk Oncology Center, Bydgoszcz (B.Z.), and the Department of Clinical Oncology and Hematology, Regional Specialist Hospital, Biała Podlaska (J. Żołnierek) - both in Poland; the Division of Oncology, Department of Medicine, Siteman Cancer Center, Washington University School of Medicine, St. Louis (J.J.H.); Oncology Unit 1, Department of Oncology, Istituto Oncologico Veneto IRCCS, Padua (U.B.), the Department of Medical Oncology, Ospedale San Donato, Istituto Toscano i, Arezzo (A.H.), the Department of Internal Medicine, University of Pavia, Pavia (C.P.), and the University of Bari "A. Moro," Bari (C.P.) - all in Italy; the Department of Genitourinary Medical Oncology, M.D. Anderson Cancer Center, Houston (A.Y.S.); the Department of Medical Oncology, Vall d'Hebron Institute of Oncology, Hospital Universitari Vall d'Hebron, Vall d'Hebron Barcelona Hospital Campus, Barcelona (C.S.); the Department of Medical Oncology, Royal Brisbane and Women's Hospital, Herston, QLD (J.C.G.), and Cabrini Monash University Department of Medical Oncology, Cabrini Health, Malvern, VIC (D.P.) - both in Australia; the Oncology Research Center, Hospital São Lucas, Porto Alegre, Brazil (C.B.); Fundacion Richardet Longo, Instituto Oncologico de Cordoba, Cordoba (M.R.), and Instituto Multidisciplinario de Oncología, Clínica Viedma, Viedma (R.K.) - both in Argentina; the Division of Medical Oncology, Department of Internal Medicine, University of Colorado School of Medicine, Aurora (E.R.K.); the Departments of Urology and Molecular Oncology, Niigata University Graduate School of Medical and Dental Sciences, Niigata (Y.T.), and the Department of Urology, Keio University School of Medicine, Tokyo (R.M.) - both in Japan; the Department of Urology, Eberhard Karls University Tübingen, Tübingen, Germany (J.B.); the Departments of Clinical Research (J. Zhang.), Clinical Oncology (M.A.M.), Biostatistics (B.S.), and Health Economics and Outcomes Research (F.E.), Bristol Myers Squibb, Princeton, NJ; the Department of Clinical Oncology, Exelixis, Alameda, CA (G.M.S.); the Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD (A.B.A.); and the Department of Medicine, Memorial Sloan Kettering Cancer Center, New York (R.J.M.).

Background: The efficacy and safety of nivolumab plus cabozantinib as compared with those of sunitinib in the treatment of previously untreated advanced renal-cell carcinoma are not known.

Methods: In this phase 3, randomized, open-label trial, we randomly assigned adults with previously untreated clear-cell, advanced renal-cell carcinoma to receive either nivolumab (240 mg every 2 weeks) plus cabozantinib (40 mg once daily) or sunitinib (50 mg once daily for 4 weeks of each 6-week cycle). The primary end point was progression-free survival, as determined by blinded independent central review. Secondary end points included overall survival, objective response as determined by independent review, and safety. Health-related quality of life was an exploratory end point.

Results: Overall, 651 patients were assigned to receive nivolumab plus cabozantinib (323 patients) or sunitinib (328 patients). At a median follow-up of 18.1 months for overall survival, the median progression-free survival was 16.6 months (95% confidence interval [CI], 12.5 to 24.9) with nivolumab plus cabozantinib and 8.3 months (95% CI, 7.0 to 9.7) with sunitinib (hazard ratio for disease progression or death, 0.51; 95% CI, 0.41 to 0.64; P<0.001). The probability of overall survival at 12 months was 85.7% (95% CI, 81.3 to 89.1) with nivolumab plus cabozantinib and 75.6% (95% CI, 70.5 to 80.0) with sunitinib (hazard ratio for death, 0.60; 98.89% CI, 0.40 to 0.89; P = 0.001). An objective response occurred in 55.7% of the patients receiving nivolumab plus cabozantinib and in 27.1% of those receiving sunitinib (P<0.001). Efficacy benefits with nivolumab plus cabozantinib were consistent across subgroups. Adverse events of any cause of grade 3 or higher occurred in 75.3% of the 320 patients receiving nivolumab plus cabozantinib and in 70.6% of the 320 patients receiving sunitinib. Overall, 19.7% of the patients in the combination group discontinued at least one of the trial drugs owing to adverse events, and 5.6% discontinued both. Patients reported better health-related quality of life with nivolumab plus cabozantinib than with sunitinib.

Conclusions: Nivolumab plus cabozantinib had significant benefits over sunitinib with respect to progression-free survival, overall survival, and likelihood of response in patients with previously untreated advanced renal-cell carcinoma. (Funded by Bristol Myers Squibb and others; CheckMate 9ER ClinicalTrials.gov number, NCT03141177.).
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http://dx.doi.org/10.1056/NEJMoa2026982DOI Listing
March 2021

Nivolumab plus ipilimumab versus sunitinib for first-line treatment of advanced renal cell carcinoma: extended 4-year follow-up of the phase III CheckMate 214 trial.

ESMO Open 2020 11;5(6):e001079

Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

Purpose: To report updated analyses of the phase III CheckMate 214 trial with extended minimum follow-up assessing long-term outcomes with first-line nivolumab plus ipilimumab (NIVO+IPI) versus (vs) sunitinib (SUN) in patients with advanced renal cell carcinoma (aRCC).

Methods: Patients with aRCC with a clear cell component were stratified by International Metastatic Renal Cell Carcinoma Database Consortium risk and randomised to NIVO (3 mg/kg) plus IPI (1 mg/kg) every three weeks ×4 doses, followed by NIVO (3 mg/kg) every two weeks; or SUN (50 mg) once per day ×4 weeks (6-week cycle). Efficacy endpoints included overall survival (OS), progression-free survival (PFS) and objective response rate (ORR) per independent radiology review committee in patients with intermediate/poor-risk disease (I/P; primary), intent-to-treat patients (ITT; secondary) and in patients with favourable-risk disease (FAV; exploratory).

Results: Overall, 1096 patients were randomised (ITT: NIVO+IPI, n=550, SUN, n=546; I/P: NIVO+IPI, n=425, SUN, n=422; FAV: NIVO+IPI, n=125, SUN, n=124). After 4 years minimum follow-up, OS (HR; 95% CI) remained superior with NIVO+IPI vs SUN in ITT (0.69; 0.59 to 0.81) and I/P patients (0.65; 0.54 to 0.78). Four-year PFS probabilities were 31.0% vs 17.3% (ITT) and 32.7% vs 12.3% (I/P), with NIVO+IPI vs SUN. ORR remained higher with NIVO+IPI vs SUN in ITT (39.1% vs 32.4%) and I/P (41.9% vs 26.8%) patients. In FAV patients, the HRs (95% CI) for OS and PFS were 0.93 (0.62 to 1.40) and 1.84 (1.29 to 2.62); ORR was lower with NIVO+IPI vs SUN. However, more patients in all risk groups achieved complete responses with NIVO+IPI: ITT (10.7% vs 2.6%), I/P (10.4% vs 1.4%) and FAV (12.0% vs 6.5%). Probability (95% CI) of response ≥4 years was higher with NIVO+IPI vs SUN (ITT, 59% (0.51 to 0.66) vs 30% (0.21 to 0.39); I/P, 59% (0.50 to 0.67) vs 24% (0.14 to 0.36); and FAV, 60% (0.41 to 0.75) vs 38% (0.22 to 0.54)) regardless of risk category. Safety remained favourable with NIVO+IPI vs SUN.

Conclusion: After long-term follow-up, NIVO+IPI continues to demonstrate durable efficacy benefits vs SUN, with manageable safety.

Trial Registration Details: ClinicalTrials.gov identifier: NCT02231749.
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http://dx.doi.org/10.1136/esmoopen-2020-001079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7703447PMC
November 2020

Primary Adrenal Insufficiency due to Immune Checkpoint Inhibitors: More Common than We Thought.

Oncologist 2021 Jan 23;26(1):e191. Epub 2020 Nov 23.

Centro de Investigación Clínica Bradford Hill and Oncologia Medica, Clinica Universidad de los Andes, Santiago de Chile, Chile.

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http://dx.doi.org/10.1002/onco.13588DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7794173PMC
January 2021

Potential use of n-3 PUFAs to prevent oxidative stress-derived ototoxicity caused by platinum-based chemotherapy.

Free Radic Biol Med 2020 11 19;160:263-276. Epub 2020 Aug 19.

Faculty of Medicine, Universidad de Chile, Santiago, Chile. Electronic address:

Platinum-based compounds are widely used for the treatment of different malignancies due to their high effectiveness. Unfortunately, platinum-based treatment may lead to ototoxicity, an often-irreversible side effect without a known effective treatment and prevention plan. Platinum-based compound-related ototoxicity results mainly from the production of toxic levels of reactive oxygen species (ROS) rather than DNA-adduct formation, which has led to test strategies based on direct ROS scavengers to ameliorate hearing loss. However, favorable clinical results have been associated with several complications, including potential interactions with chemotherapy efficacy. To understand the contribution of the different cytotoxic mechanisms of platinum analogues on malignant cells and auditory cells, the particular susceptibility and response of both kinds of cells to molecules that potentially interfere with these mechanisms, is fundamental to develop innovative strategies to prevent ototoxicity without affecting antineoplastic effects. The n-3 long-chain polyunsaturated fatty acids (n-3 PUFAs) have been tried in different clinical settings, including with cancer patients. Nevertheless, their use to decrease cisplatin-induced ototoxicity has not been explored to date. In this hypothesis paper, we address the mechanisms of platinum compounds-derived ototoxicity, focusing on the differences between the effects of these compounds in neoplastic versus auditory cells. We discuss the basis for a strategic use of n-3 PUFAs to potentially protect auditory cells from platinum-derived injury without affecting neoplastic cells and chemotherapy efficacy.
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http://dx.doi.org/10.1016/j.freeradbiomed.2020.07.035DOI Listing
November 2020

Recommendations for detection, prioritization, and treatment of thoracic oncology patients during the COVID-19 pandemic: the THOCOoP cooperative group.

Crit Rev Oncol Hematol 2020 Sep 20;153:103033. Epub 2020 Jun 20.

Cancer Biology and Precision Medicine Program, Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Badalona, Barcelona, Spain.

The world currently faces a pandemic due to SARS-CoV-2. Relevant information has emerged regarding the higher risk of poor outcomes in lung cancer patients. As such, lung cancer patients must be prioritized in terms of prevention, detection and treatment. On May 7th, 45 experts in thoracic cancers from 11 different countries were invited to participate. A core panel of experts regarding thoracic oncology care amidst the pandemic gathered virtually, and a total of 60 initial recommendations were drafted based on available evidence, 2 questions were deleted due to conflicting evidence. By May 16th, 44 experts had agreed to participate, and voted on each of the 58 recommendation using a Delphi panel on a live voting event. Consensus was reached regarding the recommendations (>66 % strongly agree/agree) for 56 questions. Strong consensus (>80 % strongly agree/agree) was reached for 44 questions. Patients with lung cancer represent a particularly vulnerable population during this time. Special care must be taken to maintain treatment while avoiding exposure.
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http://dx.doi.org/10.1016/j.critrevonc.2020.103033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7305738PMC
September 2020

Primary Adrenal Insufficiency during Immune Checkpoint Inhibitor Treatment: Case Reports and Review of the Literature.

Case Rep Oncol 2020 May-Aug;13(2):621-626. Epub 2020 Jun 9.

Medical Oncology Service Bradford Hill, Santiago de Chile, Chile.

As the indications and clinical use of immune checkpoint inhibitors increase, it is expected that we will face some of their less frequently reported complications. Primary adrenal insufficiency is one of them, and given its unspecific symptoms and potentially serious consequences, it is important to have a high degree of clinical suspicion. We present 3 cases and a review of the literature concerning its main clinical characteristics, diagnostics, and management.
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http://dx.doi.org/10.1159/000507652DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7315192PMC
June 2020

Nephrectomy in metastatic renal cell carcinoma with venous thrombus: more thrombus equals less benefit?

Ann Transl Med 2019 Sep;7(Suppl 6):S186

Medical Oncology Department, University of Chile Clinical Hospital, Santiago, Chile.

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http://dx.doi.org/10.21037/atm.2019.07.67DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6789373PMC
September 2019

Clinical Experience With 75-mg Dose of Erlotinib for Mutated Metastatic EGFR Non-small Cell Lung Cancer.

Am J Ther 2019 Sep 9. Epub 2019 Sep 9.

Medical Oncology Department Bradford Hill Investigation Centre, Santiago, Chile.

Background: Non-small cell lung cancer (NSCLC) remains the leading cause of cancer death worldwide, although important advances in target therapy have been developed in the past few years. Erlotinib is a reversible epidermal growth factor receptor (EGFR) inhibitor, which was approved at its maximum tolerated dose of 150 mg/d determined from the initial phase I study. Studies suggest that the optimal biological dose of erlotinib should be lower and dependent on different variables.

Study Question: We aimed to evaluate the response rates and toxicity with 75 mg/d dose of erlotinib in South American patients.

Method: We performed a retrospective review of 18 patients with histologically proven (+) EGFR (+) mutation metastatic NSCLC (mNSCLC) treated with 75 mg/d erlotinib as starting dose.

Measures And Outcomes: Clinical information, including toxicity grade 1-4, drug discontinuation, clinical evolution and radiological evaluation, and overall survival (OS), was revised.

Results: Patients received 75 mg/d of erlotinib as starting dose. Sixteen (89%) patients were treated in first-line treatment and 2 (11%) in second-line treatment. Mean age was 62 years (range 36-89 years), and 50% patients were female. Sixteen percent of the patients had brain metastases at first diagnosis. All patients had mutation positive EGFR, 12 (66%) had Del19 and 6 (34%) exon 21 mutation. Median progression-free survival was 17 months and OS 23 months. The main grade 1-2 toxicities were rash (44%) and diarrhea (22%). No grade 3-4 toxicity and no cases of drug discontinuation were reported.

Conclusions: In South American population with mutated mNSCLC, a dose of 75 mg/d of erlotinib was well tolerated. This dose resulted in comparable benefits in progression-free survival and OS when compared to those reported in the literature with the standard dose. More studies are needed to explore the use of adjusted doses of biological agents in different ethnic backgrounds.
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http://dx.doi.org/10.1097/MJT.0000000000001074DOI Listing
September 2019

Developing a National Center of Excellence for Prostate Imaging.

Curr Urol Rep 2019 Sep 2;20(10):59. Epub 2019 Sep 2.

Centro de Estudios Clínicos Bradford Hill, Santiago, Chile.

Purpose Of Review: The purpose of this review is to summarize the most current literature regarding the most important aspects to consider when developing a center of excellence for prostate imaging and biopsy.

Recent Findings: Multiparametric MRI (mp-MRI) has changed the way we diagnose and treat prostate cancer. This imaging modality allows for more precise identification of areas suspicious in terms of harboring prostate cancer, enabling performance of targeted mp-MRI-guided biopsies that have been demonstrated to yield superior cancer detection rates. Centers worldwide are increasingly adopting this technology. However, obtaining results comparable with those findings published in the literature can be challenging. The imaging and biopsy process entails the need for a multidisciplinary team including a dedicated radiologist, urologist, and pathologist. Adequate mp-MRI interpretation for accurate lesion identification, acquaintance with the biopsy technique selected, and precise characterization of Gleason Score/Grade Groupings are equal determinants of accurate biopsy results. Furthermore, all specialists are required to attain appropriate learning curves to ensure optimal results. In this review, we characterize crucial aspects to consider when developing a center of excellence for prostate imaging and biopsy as well as insights regarding how to implement them.
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http://dx.doi.org/10.1007/s11934-019-0923-3DOI Listing
September 2019

Lung Cancer in Chile.

J Thorac Oncol 2019 09;14(9):1504-1509

Department of Public Health, Pontificia Universidad Católica de Chile, Santiago, Chile.

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http://dx.doi.org/10.1016/j.jtho.2019.02.024DOI Listing
September 2019

Immune Checkpoint Inhibitor Dosing: Can We Go Lower Without Compromising Clinical Efficacy?

J Glob Oncol 2019 07;5:1-5

Los Andes University, Santiago, Chile.

In just a few years, immune checkpoint inhibitors have dramatically changed the landscape in oncology, offering durable responses and improved survival for many patients across several tumor types. With more than 3,300 new agents in the immuno-oncology pipeline plus a wide array of combinations being studied, it seems this new era is just getting started. These advances come with a significant caveat: most of the world population does not have access to their benefits, because the yearly cost of a novel anticancer medication can routinely exceed $100,000. There is a large amount of data showing that checkpoint inhibitors have significant activity at doses much lower than those currently approved. We review the evidence for reduced drug dosing as a strategy to increase the number of patients who can be treated and what would be needed to further validate this approach.
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http://dx.doi.org/10.1200/JGO.19.00142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6690659PMC
July 2019

Is Cytoreductive Nephrectomy Still a Standard of Care in Metastatic Renal Cell Carcinoma?

J Kidney Cancer VHL 2019 5;6(1):1-7. Epub 2019 Mar 5.

Oncology Department, Los Andes University, Bradford Hill Clinical Research Center, Santiago, Chile.

Cytoreductive nephrectomy has been an integral part of management in metastatic renal cell carcinoma for patients with good performance status, based on the benefit shown by prospective trials in the interferon era and retrospective trials in the targeted therapies era. Clinical Trial to Assess the Importance of Nephrectomy (CARMENA), the first prospective phase III trial comparing a targeted agent alone (sunitinib) versus nephrectomy plus sunitinib, has been recently published, showing non-inferiority for the nephrectomy-sparing arm. In this article, we discuss the impact of nephrectomy including its immune-mediated effects, surgical morbidity and mortality, and the clinical data supporting the indications of nephrectomy in order to analyze the CARMENA trial in context, with the aim to identify optimal strategies for different patient populations in the metastatic setting.
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http://dx.doi.org/10.15586/jkcvhl.2019.114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6403966PMC
March 2019

Adjuvant and neoadjuvant cancer therapies: A historical review and a rational approach to understand outcomes.

Semin Oncol 2019 Feb 26;46(1):83-99. Epub 2019 Jan 26.

Columbia University / New York Presbyterian Hospital and James J. Peters VA Medical Center, New York, NY, USA. Electronic address:

Drug development in oncology usually establishes efficacy in metastatic disease before advancing a therapy to the adjuvant or neoadjuvant settings. Unfortunately, too often use in adjuvant or neoadjuvant settings fails to improve overall survival. Reasons for the modest benefits include the fact that in many cases surgery cures a majority of patients making it difficult to demonstrate gains. We begin by looking at the history of adjuvant and neoadjuvant therapies and the principles guiding their development. We summarize accepted adjuvant and neoadjuvant therapies in several cancers and tabulate their outcomes. Then, extending our work on the growth and regression rate constants of tumors and the fraction of cells killed we demonstrate that therapies developed in the metastatic setting primarily delay tumor growth rather than kill more cells and argue this is a likely explanation for poor outcomes in adjuvant or neoadjuvant settings. We suggest a rational approach for enhancing success.
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http://dx.doi.org/10.1053/j.seminoncol.2019.01.002DOI Listing
February 2019

Clinical decision making in postmastectomy radiotherapy in node negative breast cancer.

Ecancermedicalscience 2018 26;12:874. Epub 2018 Sep 26.

Centro de Investigación Clínica Bradfordhill, Santiago, Chile.

For decades, postmastectomy radiotherapy (PMRT) has been recommended for node positive [N(+)] breast cancer patients; nevertheless, the beneficial effect of PMRT for treatment of node negative [N(-)] disease remains under discussion. Nowadays, the biology of breast cancer and the risk factors (RFs) for locoregional failure (LRF) must be included in the decision on whether or not to carry out PMRT. For these reasons, the present review aims to evaluate the rationale use of PMRT in N(-) patients and discuss which subgroups may further benefit from the treatment in present times where the decision must be personalised, according to the RFs of locoregional recurrence (LRR). To perform the analysis, we ponder that LRR of over 10% should be considered unacceptable due to the fact that LRRs generate great morbidity in patients. For this purpose, we consider that routine RT in these patients is not recommended, although there are subgroups of patients with high LRR, in which PMRT could be beneficial.
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http://dx.doi.org/10.3332/ecancer.2018.874DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6214678PMC
September 2018

Viable Pregnancy in a patient with metastatic melanoma treated with double checkpoint immunotherapy.

Semin Oncol 2018 06 22;45(3):164-169. Epub 2018 Mar 22.

Departamento de Ginecología y Obstetricia, Clínica Las Condes, Santiago Chile.

Metastatic cancers during pregnancy have historically been associated with dismal outcomes, with greater rates of tumor progression in part because of diminished treatment alternatives. Immunotherapy with T-cell checkpoint inhibitors has significantly impacted the survival of several metastatic tumors. However, given their mechanism of action, immune-related adverse events can occur, especially with combined immunotherapy treatments. During pregnancy, checkpoint pathways have a major role, providing immune tolerance to the fetal allograft. Furthermore, evidence suggests that inhibition of this pathway may be associated with an increased risk of miscarriage. We describe, to our knowledge, the first case reported in the literature of a patient 7 weeks pregnant, diagnosed with metastatic melanoma and treated with nivolumab plus ipilimumab. We also present the associated immune-related side effects and their treatment, as well as the oncologic results that lead to favorable pregnancy outcome.
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http://dx.doi.org/10.1053/j.seminoncol.2018.03.003DOI Listing
June 2018

Breast Cancer Staging: Is TNM Ready to Evolve?

J Glob Oncol 2018 09 28;4:1-3. Epub 2017 Aug 28.

Fernando Cadiz, Juan G. Gormaz, and Mauricio Burotto, Clínica Alemana de Santiago; Mauricio Burotto, Universidad del Desarrollo, Santiago, Chile.

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http://dx.doi.org/10.1200/JGO.17.00004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6180749PMC
September 2018

Biomarkers for immune-related toxicities of checkpoint inhibitors: current progress and the road ahead.

Expert Rev Mol Diagn 2018 03 15;18(3):297-305. Epub 2018 Feb 15.

a Department of Hematology and Oncology , Taussig Cancer Institute, Cleveland Clinic , Cleveland , USA.

Introduction: Immune checkpoint pathways are key immune regulatory pathways that play a physiologic role in maintaining immune-homeostasis and are often co-opted by cancer cells to evade the host immune system. Recent developments in cancer immunotherapy, mainly drugs blocking the immune checkpoint pathways, have revolutionized the treatment paradigm for many solid tumors. A wide spectrum of immune-related adverse events (irAEs) have been described with the use of these agents which necessitate treatment with immunosuppression, lead to disruption of therapy and can on occasion be life-threatening. There are currently no clinically validated biomarkers to predict the risk of irAEs. Areas covered: In this review, the authors describe the current progress in identifying biomarkers for irAEs and potential future directions. Literature search was conducted using PubMed-MEDLINE, Embase and Scopus. In addition, abstracts from major conference proceedings were reviewed for relevant content. Expert commentary: The discovery of biomarkers for irAEs is currently in its infancy, however there are a lot of promising candidate biomarkers that are currently being investigated. Biomarkers that can identify patients at a higher risk of developing irAEs or lead to early detection of autoimmune toxicities are crucial to optimize patient selection for immune-oncology agents and to minimize toxicity with their use.
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http://dx.doi.org/10.1080/14737159.2018.1440209DOI Listing
March 2018

Neutral evolution of drug resistant colorectal cancer cell populations is independent of their KRAS status.

PLoS One 2017 5;12(10):e0175484. Epub 2017 Oct 5.

Division of Hematology and Oncology, Department of Medicine, Columbia University, New York and James J. Peters VA Medical Center, Bronx, New York, United States of America.

Emergence of tumor resistance to an anti-cancer therapy directed against a putative target raises several questions including: (1) do mutations in the target/pathway confer resistance? (2) Are these mutations pre-existing? (3) What is the relative fitness of cells with/without the mutation? We addressed these questions in patients with metastatic colorectal cancer (mCRC). We conducted an exhaustive review of published data to establish a median doubling time for CRCs and stained a cohort of CRCs to document mitotic indices. We analyzed published data and our own data to calculate rates of growth (g) and regression (d, decay) of tumors in patients with CRC correlating these results with the detection of circulating MT-KRAS DNA. Additionally we estimated mathematically the caloric burden of such tumors using data on mitotic and apoptotic indices. We conclude outgrowth of cells harboring intrinsic or acquired MT-KRAS cannot explain resistance to anti-EGFR (epidermal growth factor receptor) antibodies. Rates of tumor growth with panitumumab are unaffected by presence/absence of MT-KRAS. While MT-KRAS cells may be resistant to anti-EGFR antibodies, WT-KRAS cells also rapidly bypass this blockade suggesting inherent resistance mechanisms are responsible and a neutral evolution model is most appropriate. Using the above clinical data on tumor doubling times and mitotic and apoptotic indices we estimated the caloric intake required to support tumor growth and suggest it may explain in part cancer-associated cachexia.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0175484PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5628783PMC
October 2017

MABp1 for the treatment of colorectal cancer.

Expert Opin Biol Ther 2017 09 10;17(9):1155-1161. Epub 2017 Jul 10.

b Medical Oncology Service , Clinica Alemana De Santiago,universidad Del Desarrollo , Santiago , Chile.

Introduction: Inflammation is an established process in colorectal cancer development and a hallmark of progression, and pro-inflammatory cytokines have been implicated in the morbidity and functional compromise associated with malignancy. MABp1, described as a first-in-class true human antibody against interleukin-1α, has undergone clinical trial evaluation in a number of indications, recently completing late phase clinical trial testing under Fast Track designation for cancer anorexia-cachexia syndrome in colorectal cancer patients. To date, MABp1 has been evaluated as a novel therapeutic strategy to ameliorate phenotypic factors associated with poor prognosis in colorectal cancer patients. Areas covered: In this review, the authors discuss the clinical trial data available to date for this antibody in colorectal cancer, including novel clinical trial endpoints utilized to evaluate sarcopenia and inflammation, as well as the proposed role of interleukin-1α antagonism in leading to improved patient outcomes. Expert opinion: There is a multitude of antibodies in therapeutic development in oncology, and MABp1 is a novel class of antibody which has been safely tolerated to date. Clinical studies of this agent suggest a significant improvement in lean body mass, though additional results evaluating the impact of targeting inflammation as a strategy to delay disease progression in this population are awaited.
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http://dx.doi.org/10.1080/14712598.2017.1347631DOI Listing
September 2017

A Phase II Multi-Center Study of Bevacizumab in Combination with Ixabepilone in Subjects with Advanced Renal Cell Carcinoma.

Oncologist 2017 08 5;22(8):888-e84. Epub 2017 Jul 5.

Columbia University, New York, New York, USA.

Lessons Learned: Accrual to renal cell carcinoma trials remains a challenge despite the lack of prolonged response to the available treatments.The observation of three responses among the 30 patients with median progression-free survival and overall survival of 8.3 and 15 months, respectively, indicates the combination has some activity, but it is not sufficient for further development.

Background: Treatment of metastatic renal cell carcinoma (mRCC) remains suboptimal. Preclinical data have previously shown that ixabepilone, a microtubule-stabilizing agent approved for the treatment of breast cancer, is active in taxane-sensitive and -resistant cells. In this single-arm phase II trial, we investigated a combination of ixabepilone plus bevacizumab in patients with refractory mRCC.

Methods: We enrolled 30 patients with histologically confirmed mRCC, clear cell subtype, who had not been previously treated with ixabepilone or bevacizumab but had received at least one prior U.S. Food and Drug Administration (FDA)-approved treatment for renal cell carcinoma (RCC). The treatment regimen consisted of 6 mg/m ixabepilone per day for 5 days and 15 mg/kg bevacizumab every 21 days. After 6 cycles, the treatment interval could be extended to every 28 days. The primary endpoint was the objective response rate according to the Response Evaluation Criteria in Solid Tumors (RECIST). Secondary endpoints were progression-free survival (PFS), overall survival (OS), and the toxicity of the combination.

Results: The median number of prior therapies was two (range per patient one to five). Patients received a median of 8 cycles of ixabepilone plus bevacizumab (range 2-54). The median follow-up was 36.4 months (range 23.5-96.5). Nineteen patients (63.3%) had stable disease as a best response. Three patients (10%) had a partial response. The median PFS was 8.3 months (95% confidence interval [CI], 4.9-10.6) and the median OS was 15.0 months (95% CI, 11.3-28.8). The total number of cycle for safety evaluation was 289. Grade 3/4 adverse events (>5% incidence) included lymphopenia (16.7%), hypertension (6.7%), and leukopenia (6.7%).

Conclusion: The combination of ixabepilone and bevacizumab was well tolerated, with modest activity in second - or later-line mRCC, but it is not recommended as a therapy without further clinical development. Alternative combinations with these agents could be explored in future studies.
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http://dx.doi.org/10.1634/theoncologist.2017-0211DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5553966PMC
August 2017

Molecular Testing of EGFR, EGFR Resistance Mutation, ALK and ROS1 Achieved by EBUS-TBNA in Chile.

Arch Bronconeumol 2017 Mar 5;53(3):172-174. Epub 2016 Nov 5.

Servicio de Oncología, Clínica Alemana Universidad del Desarrollo, Santiago, Chile.

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http://dx.doi.org/10.1016/j.arbres.2016.08.013DOI Listing
March 2017

Double hit lymphoma: from biology to therapeutic implications.

Expert Rev Hematol 2016 Jul 21;9(7):669-78. Epub 2016 May 21.

b Lymphoid Malignancies Branch, Center for Cancer Research , National Cancer Institute , Bethesda , MD , USA.

Introduction: Diffuse large B-cell lymphoma (DLBCL) is a molecularly heterogeneous disease defined by different cellular origins and mechanisms of oncogenic activation. Approximately 10% of DLBCL cases harbor a MYC rearrangement and this has been associated with a more aggressive clinical course following standard therapy.

Areas Covered: So-called 'double-hit lymphomas' (DHL) or 'triple hit lymphomas' (THL) occur when MYC is concurrently rearranged with BCL2 and/or BCL6. These tumors are characterized by high proliferation rate and a very poor outcome following standard R-CHOP (rituximab, cyclophosphamide, doxorubicin vincristine and prednisone) therapy, in most (though not all) studies that have looked at this. Though there is a paucity of published experience with other chemotherapy regimens, there is emerging evidence that more intensive approaches may improve outcome. Recently, there has been a lot of focus in the literature on 'double-expresser lymphomas' (DEL) with high MYC, BCL2 and/or BCL6 expression but typically without rearrangements of these genes. These DEL cases, have a poor outcome with R-CHOP and there is little consensus on how they should be approached. Expert commentary: This review will focus on the biology and treatment of DHL and DEL, discuss the outcome of these diseases with current standard as well as promising new approaches and conclude with a section on novel agents that are in development for these diseases.
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http://dx.doi.org/10.1080/17474086.2016.1182858DOI Listing
July 2016

Reply to A. Wong et al.

J Clin Oncol 2016 05 29;34(13):1562-3. Epub 2016 Feb 29.

Clinica Alemana de Santiago, Universidad del Desarrollo, Santiago, Chile

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http://dx.doi.org/10.1200/JCO.2015.66.2031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5321100PMC
May 2016

Pseudoprogression and Immune-Related Response in Solid Tumors.

J Clin Oncol 2015 Nov 10;33(31):3541-3. Epub 2015 Aug 10.

Center for Cancer Research, National Cancer Institute, Bethesda, MD

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http://dx.doi.org/10.1200/JCO.2015.61.6870DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4622096PMC
November 2015

The Strength of Association Between Surrogate End Points and Survival in Oncology: A Systematic Review of Trial-Level Meta-analyses.

JAMA Intern Med 2015 Aug;175(8):1389-98

Division of Medical Oncology, University of California, Los Angeles.

Importance: The strength of association between surrogate end points and survival in oncology is important to understand because surrogate end points are frequently used in oncology clinical trials, supporting US Food and Drug Administration approvals and National Comprehensive Cancer Network guideline recommendations.

Objective: To identify and evaluate trial-level meta-analyses of randomized clinical trials quantifying the association between a surrogate end point and overall survival in medical oncology. Trial-level correlations test whether treatments that improve the surrogate end point also improve the final end point and are widely considered the strongest evidence to validate a surrogate end point.

Evidence Review: Our literature search was built on earlier reported data sets and updated with Google Scholar and MEDLINE searches conducted on December 26, 2014. For MEDLINE, search terms included ("regression" or "correlation") and "surrogate" and "end point [or endpoint]" and ("oncology" or "cancer"). For Google scholar, search terms included ("regression" or "correlation") and "surrogate end point [or endpoint]" and "overall survival" and "trial level." A total of 108 abstracts were retrieved, and 62 articles were read in full in addition to articles identified through prior reviews.

Findings: We found 36 articles in which 65 specific correlations between a surrogate end point and survival were identified. Surrogate end points were studied in the neoadjuvant, adjuvant, locally advanced, and metastatic settings. The most common sources for trials included in the 36 articles were systematic reviews of the published literature (10 of 36; 28%), and published literature and meeting abstracts (14 of 36; 39%). Four meta-analyses (11%) used a convenience sample, and only 5 studies (14%) attempted to include unpublished trials by surveying clinical trial registries. Among these 5 studies, only 352 of 684 eligible trials (51.1%) were included in the analyses. More than half of reported correlations (34 of 65; 52%) were of low strength (r ≤ 0.7). Approximately a quarter (16 of 65; 25%) were of medium strength (r > 0.7 to r < 0.85), and 15 of 65 (23%) were highly correlated (r ≥ 0.85) with survival.

Conclusions And Relevance: Most trial-level validation studies of surrogate end points in oncology find low correlations with survival. All validation studies use only a subset of available trials. The evidence supporting the use of surrogate end points in oncology is limited.
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http://dx.doi.org/10.1001/jamainternmed.2015.2829DOI Listing
August 2015

Phase II Clinical Trial of Ixabepilone in Metastatic Cervical Carcinoma.

Oncologist 2015 Jul 3;20(7):725-6. Epub 2015 Jun 3.

National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA;

Lessons Learned: Accrual to cervical cancer studies remains a puzzling challenge given the lack of options and the dismal prognosis of this disease. The majority of patients referred for a trial such as this have very advanced disease that is difficult to manage.The observation of 4 partial responses among the 41 patients indicates that ixabepilone has some activity but not sufficient for further development without greater understanding of mechanisms of sensitivity and resistance.

Background: Ixabepilone is a microtubule-stabilizing agent approved for metastatic breast cancer. Preclinical data have shown that ixabepilone is active in taxane-sensitive and -resistant cells. Metastatic cervical carcinoma (mCC) has a poor prognosis and no established second-line therapies. This study assessed the efficacy and safety of ixabepilone in previously treated mCC.

Methods: Patients with histologically confirmed mCC and at least one prior cisplatin-containing regimen were treated with ixabepilone [6 mg/m(2) per day for 5 days] every 21 days. The primary endpoint was progression-free survival (PFS) according to the Response Evaluation Criteria in Solid Tumors (RECIST). Secondary endpoints were response rate, rate of tumor growth, overall survival (OS), and safety. Levels of glu-terminated and acetylated tubulin, markers of microtubule stabilization, and surrogates for target engagement were assessed by Western blot.

Results: In total, 41 patients were enrolled; 34 had tumors with primarily squamous histology. The median number of prior therapies was 2 (range 1-6). Four patients (9.7%) had a partial response. Median PFS in months was 2.3 for all, 3.84 for taxane-naïve, and 2.03 for taxane-pretreated patients (p = .13). Consistent with this, we found statistically similar (p = 1) rates of growth in taxane-naive patients (0.0035 per day) and taxane pretreated patients (0.0053 per day). Median OS was 5.84 months. G1/2 toxicities included vomiting (43%), sensory neuropathy (21%), and fatigue (60%). Bowel fistulas were observed in 7% of patients. Glu and acetylated tubulin were assessed in tumor samples from 11 patients during the first cycle of treatment. Although there was clear evidence of "target engagement" and microtubule stabilization in all tumors, a correlation between the extent of tubulin stabilization and response to therapy could not be demonstrated.

Conclusion: Ixabepilone was well tolerated but showed very modest activity in second- or later-line mCC and cannot be recommended as a therapy. Target engagement was demonstrated but was not correlated with responses, suggesting that other factors mediate drug sensitivity. New strategies are needed for refractory mCC.
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http://dx.doi.org/10.1634/theoncologist.2015-0104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4492237PMC
July 2015

Emphasizing unique strengths and eliminating redundancy for research in low-income and middle-income countries: Lessons from a South American country.

Cancer 2015 Aug 22;121(16):2668-70. Epub 2015 Apr 22.

Medical Oncology Service, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.

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http://dx.doi.org/10.1002/cncr.29408DOI Listing
August 2015

Non-inferiority trials: why oncologists must remain wary.

Lancet Oncol 2015 Apr;16(4):364-6

Medical Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address:

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http://dx.doi.org/10.1016/S1470-2045(15)70129-4DOI Listing
April 2015