Advertisement
Advances in Radiation Oncology
ASTRO
Advanced searchSave search
Brief Opinion| Volume 5, ISSUE 4, P687-689, July 2020

Management of Locally Advanced Rectal Cancer During The COVID-19 Pandemic: A Necessary Paradigm Change at Memorial Sloan Kettering Cancer Center

Open AccessPublished:April 22, 2020DOI:https://doi.org/10.1016/j.adro.2020.04.011
Management of Locally Advanced Rectal Cancer During The COVID-19 Pandemic: A Necessary Paradigm Change at Memorial Sloan Kettering Cancer Center
Previous ArticlePractice Considerations for Proton Beam Radiation Therapy of Uveal Melanoma During the Coronavirus Disease Pandemic: Particle Therapy Co-Operative Group Ocular Experience
Next ArticleImplementation of a Novel Remote Physician Stereotactic Body Radiation Therapy Coverage Process during the Coronavirus Pandemic

      Abstract

      The COVID-19 pandemic will consume significant health care resources. Given the concerns for rapidly increasing infection rates in the United States, impending staffing shortages, and the potential for resource reallocation, we rapidly reevaluated our rectal cancer practice policies during this public health emergency. Before the pandemic, we commonly used total neoadjuvant therapy with a strong preference for long-course chemoradiation. In the setting of the ongoing pandemic, we now mandate short-course radiation therapy (SCRT). Despite multiple randomized trials demonstrating no difference in locoregional recurrence, distant recurrence, or overall survival between SCRT and long-course chemoradiation, the adaptation of SCRT in the United States has been low given concerns for less tumor downstaging and increased toxicity. In the setting of the ongoing and likely prolonged COVID-19 pandemic, we feel that these concerns must be reevaluated, because SCRT presents a well-validated alternative that will allow us to meet the needs of a greater number of potentially curable patients at a time when resources are severely and acutely constrained.

      Perspective

      Early reports from China suggest that patients with cancer who are diagnosed with coronavirus disease 2019 (COVID-19) have an increased need for intensive care unit admission and ventilator use and a higher mortality compared with patients without cancer who are not infected.
      • Liang W.
      • Guan W.
      • Chen R.
      • et al.
      Cancer patients in SARS-CoV-2 infection: A nationwide analysis in China.
      Lancet Oncol. 2020; 21: 335-337
      The risk of severe complications was even greater for patients with cancer who underwent surgery or received cytotoxic chemotherapy within 1 month of documented severe acute respiratory syndrome coronavirus 2 infection.
      • Liang W.
      • Guan W.
      • Chen R.
      • et al.
      Cancer patients in SARS-CoV-2 infection: A nationwide analysis in China.
      Lancet Oncol. 2020; 21: 335-337
      Robust predictors of outcome are still being determined, but patients undergoing active oncologic therapy are likely at an elevated risk for morbidity and mortality from COVID-19.
      • Liang W.
      • Guan W.
      • Chen R.
      • et al.
      Cancer patients in SARS-CoV-2 infection: A nationwide analysis in China.
      Lancet Oncol. 2020; 21: 335-337
      ,
      • Yu J.
      • Ouyang W.
      • Chua M.L.K.
      • Xie C.
      SARS-CoV-2 transmission in patients with cancer at a tertiary care hospital in Wuhan, China [Epub ahead of print].
      JAMA Oncol. 2020; (Accessed March 25, 2020)https://doi.org/10.1001/jamaoncol.2020.0980
      The pandemic will consume significant health care resources, even with conservative estimates forecasting that COVID-19–related health needs will exceed the capacity of the US health care system and that of other developed countries.
      • Emanuel E.J.
      • Persad G.
      • Upshur R.
      • et al.
      Fair allocation of scarce medical resources in the time of Covid-19 [Epub ahead of print].
      N Engl J Med. 2020; (Accessed May 12, 2020)https://doi.org/10.1056/NEJMsb2005114
      Given the legitimate concerns for impending staffing shortages, resource reallocation, and rapidly increasing infection rates in the United States, we rapidly reevaluated our rectal cancer practice policies during this public health emergency. Multidisciplinary experts in rectal cancer at our high-volume comprehensive cancer center worked together (electronically, due to the need for social/physical distancing) to establish new institutional guidelines for rectal cancer treatment during the COVID-19 pandemic.
      Before March 2020, our standard approach for patients with locally advanced rectal cancer favored total neoadjuvant therapy (TNT), which incorporated preoperative long-course chemoradiation.
      • Cercek A.
      • Roxburgh C.S.D.
      • Strombom P.
      • et al.
      Adoption of total neoadjuvant therapy for locally advanced rectal cancer.
      JAMA Oncol. 2018; 4e180071
      ,
      • Smith J.J.
      • Strombom P.
      • Chow O.S.
      • et al.
      Assessment of a watch-and-wait strategy for rectal cancer in patients with a complete response after neoadjuvant therapy.
      JAMA Oncol. 2019; 5e185896
      Chemoradiation was delivered in 25 to 28 fractions using either 3-dimensional conformal radiation therapy (RT) or intensity modulated RT with concurrent capecitabine. The sequencing of chemoradiation and chemotherapy varied depending on the clinical scenario, but induction chemotherapy followed by consolidative chemoradiation was our most common approach.
      • Cercek A.
      • Roxburgh C.S.D.
      • Strombom P.
      • et al.
      Adoption of total neoadjuvant therapy for locally advanced rectal cancer.
      JAMA Oncol. 2018; 4e180071
      Given the pandemic conditions, the utility of long-course chemoradiation therapy (LCCRT) was questioned owing to concerns for increased infectivity rates of severe acute respiratory syndrome coronavirus 2 among our patients and staff, increased risk for infectivity with prolonged and frequent visits, and contingent planning if reallocation of institutional resources is required.
      The ability of preoperative RT to prevent locoregional recurrence for locally advanced rectal cancer has been well established for both short-course RT (SCRT)
      • Folkesson J.
      • Birgisson H.
      • Pahlman L.
      • Cedermark B.
      • Glimelius B.
      • Gunnarsson U.
      Swedish rectal cancer trial: Long lasting benefits from radiotherapy on survival and local recurrence rate.
      J Clin Oncol. 2005; 23: 5644-5650
      , 
      • van Gijn W.
      • Marijnen C.A.
      • Nagtegaal I.D.
      • et al.
      Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer: 12-year follow-up of the multicentre, randomised controlled TME trial.
      Lancet Oncol. 2011; 12: 575-582
      , 
      • Sebag-Montefiore D.
      • Stephens R.J.
      • Steele R.
      • et al.
      Preoperative radiotherapy versus selective postoperative chemoradiotherapy in patients with rectal cancer (MRC CR07 and NCIC-CTG C016): A multicentre, randomised trial.
      Lancet. 2009; 373: 811-820
      and LCCRT.
      • Sauer R.
      • Becker H.
      • Hohenberger W.
      • et al.
      Preoperative versus postoperative chemoradiotherapy for rectal cancer.
      N Engl J Med. 2004; 351: 1731-1740
      SCRT has been shown to be a noninferior alternative to LCCRT,
      • Erlandsson J.
      • Holm T.
      • Pettersson D.
      • et al.
      Optimal fractionation of preoperative radiotherapy and timing to surgery for rectal cancer (Stockholm III): A multicentre, randomised, non-blinded, phase 3, non-inferiority trial.
      Lancet Oncol. 2017; 18: 336-346
      with multiple randomized trials demonstrating no difference in locoregional recurrence, distant recurrence, or overall survival.
      • Erlandsson J.
      • Holm T.
      • Pettersson D.
      • et al.
      Optimal fractionation of preoperative radiotherapy and timing to surgery for rectal cancer (Stockholm III): A multicentre, randomised, non-blinded, phase 3, non-inferiority trial.
      Lancet Oncol. 2017; 18: 336-346
      , 
      • Bujko K.
      • Nowacki M.P.
      • Nasierowska-Guttmejer A.
      • et al.
      Sphincter preservation following preoperative radiotherapy for rectal cancer: Report of a randomised trial comparing short-term radiotherapy vs. conventionally fractionated radiochemotherapy.
      Radiother Oncol. 2004; 72: 15-24
      , 
      • Ngan S.Y.
      • Burmeister B.
      • Fisher R.J.
      • et al.
      Randomized trial of short-course radiotherapy versus long-course chemoradiation comparing rates of local recurrence in patients with T3 rectal cancer: Trans- Tasman Radiation Oncology Group trial 01.04.
      J Clin Oncol. 2012; 30: 3827-3833
      SCRT is delivered in 5 fractions using either 3-dimensional conformal or intensity modulated RT to protect adjacent normal tissue. Importantly, given the higher dose per fraction, no concurrent chemotherapy is used with SCRT. Concerns have been expressed, in the absence of randomized data, that SCRT may result in less tumor downstaging, especially for patients with low rectal tumors (ie, <5 cm from anal verge) and bulky tumors with a close or involved circumferential resection margin, and a higher rate of late toxicity (especially among patients with tumors abutting the anal canal).
      • Ngan S.Y.
      • Burmeister B.
      • Fisher R.J.
      • et al.
      Randomized trial of short-course radiotherapy versus long-course chemoradiation comparing rates of local recurrence in patients with T3 rectal cancer: Trans- Tasman Radiation Oncology Group trial 01.04.
      J Clin Oncol. 2012; 30: 3827-3833
      ,
      • Downing A.
      • Glaser A.W.
      • Finan P.J.
      • et al.
      Functional outcomes and health-related quality of life after curative treatment for rectal cancer: A population-level study in England.
      Int J Radiat Oncol Biol Phys. 2019; 103: 1132-1142
      However, the Stockholm III trial evaluated SCRT with immediate surgery, SCRT followed by delayed surgery, and LCCRT with delayed surgery and found no difference in locoregional recurrence, distant metastasis, and overall survival. SCRT with delayed surgery compared with SCRT with immediate surgery resulted in greater tumor downstaging and higher acute toxicity, but decreased surgical and postoperative complications.
      • Erlandsson J.
      • Holm T.
      • Pettersson D.
      • et al.
      Optimal fractionation of preoperative radiotherapy and timing to surgery for rectal cancer (Stockholm III): A multicentre, randomised, non-blinded, phase 3, non-inferiority trial.
      Lancet Oncol. 2017; 18: 336-346
      A longer interval from radiation to surgery results in greater tumor downstaging for both SCRT
      • Erlandsson J.
      • Holm T.
      • Pettersson D.
      • et al.
      Optimal fractionation of preoperative radiotherapy and timing to surgery for rectal cancer (Stockholm III): A multicentre, randomised, non-blinded, phase 3, non-inferiority trial.
      Lancet Oncol. 2017; 18: 336-346
      and LCCRT.
      • Garcia-Aguilar J.
      • Chow O.S.
      • Smith D.D.
      • et al.
      Effect of adding mFOLFOX6 after neoadjuvant chemoradiation in locally advanced rectal cancer: A multicentre, phase 2 trial.
      Lancet Oncol. 2015; 16: 957-966
      Furthermore, the incorporation of SCRT into TNT has been evaluated with promising results,
      • Myerson R.J.
      • Tan B.
      • Hunt S.
      • et al.
      Five fractions of radiation therapy followed by 4 cycles of FOLFOX chemotherapy as preoperative treatment for rectal cancer.
      Int J Radiat Oncol Biol Phys. 2014; 88: 829-836
      , 
      • Bujko K.
      • Wyrwicz L.
      • Rutkowski A.
      • et al.
      Long-course oxaliplatin-based preoperative chemoradiation versus 5 × 5 Gy and consolidation chemotherapy for cT4 or fixed cT3 rectal cancer: Results of a randomized phase III study.
      Ann Oncol. 2016; 27: 834-842
      , 
      • Jia A.Y.
      • Narang A.
      • Safar B.
      • et al.
      Sequential short-course radiation therapy and chemotherapy in the neoadjuvant treatment of rectal adenocarcinoma.
      Radiat Oncol. 2019; 14: 147
      , 
      • Markovina S.
      • Youssef F.
      • Roy A.
      • et al.
      Improved metastasis- and disease-free survival with preoperative sequential short-course radiation therapy and FOLFOX chemotherapy for rectal cancer compared with neoadjuvant long-course chemoradiotherapy: Results of a matched pair analysis.
      Int J Radiat Oncol Biol Phys. 2017; 99: 417-426
      , 
      • van der Valk M.J.M.
      • Marijnen C.A.M.
      • van Etten B.
      • et al.
      Compliance and tolerability of short-course radiotherapy followed by preoperative chemotherapy and surgery for high-risk rectal cancer - Results of the international randomized RAPIDO-trial.
      Radiother Oncol. 2020; 147: 75-83
      and although still under active investigation,
      • Nilsson P.J.
      • van Etten B.
      • Hospers G.A.
      • et al.
      Short-course radiotherapy followed by neo-adjuvant chemotherapy in locally advanced rectal cancer—the RAPIDO trial.
      BMC Cancer. 2013; 13: 279
      ,
      • Jin J.
      • Liu S.
      • Zhu Y.
      • et al.
      The updated results for the phase 3 study of 5 × 5 Gy followed by chemotherapy in locally advanced rectal cancer (STELLAR trial).
      Int J Radiat Oncol Biol Phys. 2017; 99: SE157
      our colorectal disease management team concluded that delivering TNT with SCRT off-trial is reasonable and necessary given the ongoing COVID-19 pandemic. Admittedly, other potential differences between SCRT and LCCRT have not yet been fully understood (eg, in the context of nonoperative management and long-term anal sphincter function).
      In the setting of an ongoing pandemic, SCRT has the potential to provide efficient and quality oncological care for patients; significantly decrease patient exposure with repeated RT appointments for LCCRT; decrease the likelihood of a patient being diagnosed with COVID-19 during treatment; decrease immunosuppression by omitting concurrent chemotherapy; decrease resource utilization in a setting where RT capacity may be sharply curtailed or reallocated; provide at least partial therapy in the event that surgery or chemotherapy need to be delayed; and reinforce federal, state, and city mandates to encourage social and physical distancing while still addressing the active cancer for each patient. After careful consideration of the risks and benefits, we have now mandated that at Memorial Sloan Kettering Cancer Center, all patients with locally advanced rectal cancer are to be treated with SCRT until the current COVID-19 epidemic passes. This mandate benefits patients by reducing the number of exposures to other potentially infected patients and health care workers and lowering the chances that treatment would be interrupted or terminated if they were diagnosed with COVID-19. This mandate is also in the best interest of our patient population as a whole given the decreased utilization of health care resources, allowing 5 patients to be treated instead of 1 patient in a setting where we expect to have substantial reductions in available staff to administer treatment owing to expected staff illness from the epidemic.
      Despite being shown to be more cost effective than LCCRT,
      • Raldow A.C.
      • Chen A.B.
      • Russell M.
      • et al.
      Cost-effectiveness of short-course radiation therapy vs long-course chemoradiation for locally advanced rectal cancer.
      JAMA Netw Open. 2019; 2e192249
      SCRT has been used in <1% of patients receiving neoadjuvant radiation for rectal cancer in the United States due, in part, to strong physician bias regarding diminished downstaging and increased toxicity.
      • Sineshaw H.M.
      • Jemal A.
      • Thomas Jr., C.R.
      • Mitin T.
      Changes in treatment patterns for patients with locally advanced rectal cancer in the United States over the past decade: An analysis from the National Cancer Data Base.
      Cancer. 2016; 122: 1996-2003
      ,
      • Mowery Y.M.
      • Salama J.K.
      • Zafar S.Y.
      • et al.
      Neoadjuvant long-course chemoradiation remains strongly favored over short-course radiotherapy by radiation oncologists in the United States.
      Cancer. 2017; 123: 1434-1441
      In the setting of the ongoing and likely prolonged COVID-19 pandemic, we feel that these concerns must be reevaluated because SCRT presents a well-validated alternative that has been shown in randomized studies to result in noninferior oncologic outcomes. Rectal cancer radiation is unique and presents 2 well-established and substantially equivalent options for locally advanced disease. Under COVID-19 pandemic conditions, SCRT has important nononcologic benefits that justify making SCRT the standard regimen for locally advanced rectal cancer, such as limiting the potential for patients with rectal cancer to contract COVID-19 and significantly reducing the utilization of health care resources, which allows us to meet the needs of a greater number of potentially curable patients at a time when resources are severely and acutely constrained.

      References

        • Liang W.
        • Guan W.
        • Chen R.
        • et al.
        Cancer patients in SARS-CoV-2 infection: A nationwide analysis in China.
        Lancet Oncol. 2020; 21: 335-337
        View in Article
        • Yu J.
        • Ouyang W.
        • Chua M.L.K.
        • Xie C.
        SARS-CoV-2 transmission in patients with cancer at a tertiary care hospital in Wuhan, China [Epub ahead of print].
        JAMA Oncol. 2020; (Accessed March 25, 2020)https://doi.org/10.1001/jamaoncol.2020.0980
        View in Article
        • Emanuel E.J.
        • Persad G.
        • Upshur R.
        • et al.
        Fair allocation of scarce medical resources in the time of Covid-19 [Epub ahead of print].
        N Engl J Med. 2020; (Accessed May 12, 2020)https://doi.org/10.1056/NEJMsb2005114
        View in Article
        • Cercek A.
        • Roxburgh C.S.D.
        • Strombom P.
        • et al.
        Adoption of total neoadjuvant therapy for locally advanced rectal cancer.
        JAMA Oncol. 2018; 4e180071
        View in Article
        • Smith J.J.
        • Strombom P.
        • Chow O.S.
        • et al.
        Assessment of a watch-and-wait strategy for rectal cancer in patients with a complete response after neoadjuvant therapy.
        JAMA Oncol. 2019; 5e185896
        View in Article
        • Folkesson J.
        • Birgisson H.
        • Pahlman L.
        • Cedermark B.
        • Glimelius B.
        • Gunnarsson U.
        Swedish rectal cancer trial: Long lasting benefits from radiotherapy on survival and local recurrence rate.
        J Clin Oncol. 2005; 23: 5644-5650
        View in Article
        • van Gijn W.
        • Marijnen C.A.
        • Nagtegaal I.D.
        • et al.
        Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer: 12-year follow-up of the multicentre, randomised controlled TME trial.
        Lancet Oncol. 2011; 12: 575-582
        View in Article
        • Sebag-Montefiore D.
        • Stephens R.J.
        • Steele R.
        • et al.
        Preoperative radiotherapy versus selective postoperative chemoradiotherapy in patients with rectal cancer (MRC CR07 and NCIC-CTG C016): A multicentre, randomised trial.
        Lancet. 2009; 373: 811-820
        View in Article
        • Sauer R.
        • Becker H.
        • Hohenberger W.
        • et al.
        Preoperative versus postoperative chemoradiotherapy for rectal cancer.
        N Engl J Med. 2004; 351: 1731-1740
        View in Article
        • Erlandsson J.
        • Holm T.
        • Pettersson D.
        • et al.
        Optimal fractionation of preoperative radiotherapy and timing to surgery for rectal cancer (Stockholm III): A multicentre, randomised, non-blinded, phase 3, non-inferiority trial.
        Lancet Oncol. 2017; 18: 336-346
        View in Article
        • Bujko K.
        • Nowacki M.P.
        • Nasierowska-Guttmejer A.
        • et al.
        Sphincter preservation following preoperative radiotherapy for rectal cancer: Report of a randomised trial comparing short-term radiotherapy vs. conventionally fractionated radiochemotherapy.
        Radiother Oncol. 2004; 72: 15-24
        View in Article
        • Ngan S.Y.
        • Burmeister B.
        • Fisher R.J.
        • et al.
        Randomized trial of short-course radiotherapy versus long-course chemoradiation comparing rates of local recurrence in patients with T3 rectal cancer: Trans- Tasman Radiation Oncology Group trial 01.04.
        J Clin Oncol. 2012; 30: 3827-3833
        View in Article
        • Downing A.
        • Glaser A.W.
        • Finan P.J.
        • et al.
        Functional outcomes and health-related quality of life after curative treatment for rectal cancer: A population-level study in England.
        Int J Radiat Oncol Biol Phys. 2019; 103: 1132-1142
        View in Article
        • Garcia-Aguilar J.
        • Chow O.S.
        • Smith D.D.
        • et al.
        Effect of adding mFOLFOX6 after neoadjuvant chemoradiation in locally advanced rectal cancer: A multicentre, phase 2 trial.
        Lancet Oncol. 2015; 16: 957-966
        View in Article
        • Myerson R.J.
        • Tan B.
        • Hunt S.
        • et al.
        Five fractions of radiation therapy followed by 4 cycles of FOLFOX chemotherapy as preoperative treatment for rectal cancer.
        Int J Radiat Oncol Biol Phys. 2014; 88: 829-836
        View in Article
        • Bujko K.
        • Wyrwicz L.
        • Rutkowski A.
        • et al.
        Long-course oxaliplatin-based preoperative chemoradiation versus 5 × 5 Gy and consolidation chemotherapy for cT4 or fixed cT3 rectal cancer: Results of a randomized phase III study.
        Ann Oncol. 2016; 27: 834-842
        View in Article
        • Jia A.Y.
        • Narang A.
        • Safar B.
        • et al.
        Sequential short-course radiation therapy and chemotherapy in the neoadjuvant treatment of rectal adenocarcinoma.
        Radiat Oncol. 2019; 14: 147
        View in Article
        • Markovina S.
        • Youssef F.
        • Roy A.
        • et al.
        Improved metastasis- and disease-free survival with preoperative sequential short-course radiation therapy and FOLFOX chemotherapy for rectal cancer compared with neoadjuvant long-course chemoradiotherapy: Results of a matched pair analysis.
        Int J Radiat Oncol Biol Phys. 2017; 99: 417-426
        View in Article
        • van der Valk M.J.M.
        • Marijnen C.A.M.
        • van Etten B.
        • et al.
        Compliance and tolerability of short-course radiotherapy followed by preoperative chemotherapy and surgery for high-risk rectal cancer - Results of the international randomized RAPIDO-trial.
        Radiother Oncol. 2020; 147: 75-83
        View in Article
        • Nilsson P.J.
        • van Etten B.
        • Hospers G.A.
        • et al.
        Short-course radiotherapy followed by neo-adjuvant chemotherapy in locally advanced rectal cancer—the RAPIDO trial.
        BMC Cancer. 2013; 13: 279
        View in Article
        • Jin J.
        • Liu S.
        • Zhu Y.
        • et al.
        The updated results for the phase 3 study of 5 × 5 Gy followed by chemotherapy in locally advanced rectal cancer (STELLAR trial).
        Int J Radiat Oncol Biol Phys. 2017; 99: SE157
        View in Article
        • Raldow A.C.
        • Chen A.B.
        • Russell M.
        • et al.
        Cost-effectiveness of short-course radiation therapy vs long-course chemoradiation for locally advanced rectal cancer.
        JAMA Netw Open. 2019; 2e192249
        View in Article
        • Sineshaw H.M.
        • Jemal A.
        • Thomas Jr., C.R.
        • Mitin T.
        Changes in treatment patterns for patients with locally advanced rectal cancer in the United States over the past decade: An analysis from the National Cancer Data Base.
        Cancer. 2016; 122: 1996-2003
        View in Article
        • Mowery Y.M.
        • Salama J.K.
        • Zafar S.Y.
        • et al.
        Neoadjuvant long-course chemoradiation remains strongly favored over short-course radiotherapy by radiation oncologists in the United States.
        Cancer. 2017; 123: 1434-1441
        View in Article

      Article info

      Publication history

      Published online: April 22, 2020
      Accepted: April 8, 2020
      Received: April 7, 2020

      Footnotes

      Sources of support: All authors are supported by Cancer Center Support Grant P30 CA008748.

      Discoslures: Dr Paul B. Romesser reports research funding from and is a consultant for EMD Serono and has received travel support from Elekta. Dr Abraham J. Wu reports research funding from CivaTech Oncology, personal fees from AstraZeneca, and nonfinancial support from AlphaTau Medical. Dr Andrea Cercek reports research funding from Tesaro/GSK, Seattle Genetics, and RGenix, and personal fees from Array Biopharma and Bayer. Dr Julio Garcia-Aguilar reports personal fees from Medtronic, Johnson and Johnson, and Intuitive Surgical.

      Identification

      DOI: https://doi.org/10.1016/j.adro.2020.04.011

      Copyright

      © 2020 The Author(s). Published by Elsevier Inc. on behalf of American Society for Radiation Oncology.

      User license

      Creative Commons Attribution – NonCommercial – NoDerivs (CC BY-NC-ND 4.0) |
      How you can reuse Information Icon
      Creative Commons Attribution – NonCommercial – NoDerivs (CC BY-NC-ND 4.0)

      Permitted

      For non-commercial purposes:

      • Read, print & download
      • Redistribute or republish the final article
      • Text & data mine
      • Translate the article (private use only, not for distribution)
      • Reuse portions or extracts from the article in other works

      Not Permitted

      • Sell or re-use for commercial purposes
      • Distribute translations or adaptations of the article

      Elsevier's open access license policy

      ScienceDirect

      Access this article on ScienceDirect

      The content on this site is intended for healthcare professionals.


      We use cookies to help provide and enhance our service and tailor content. To update your cookie settings, please visit the Cookie Preference Center for this site.
      Copyright © 2023 Elsevier Inc. except certain content provided by third parties.


      RELX