Proposed brachytherapy recommendations (practical implementation, indications, and dose fractionation) during COVID-19 pandemic

Abstract

The ongoing COVID-19 pandemic has impacted the availability of health care resources (personnel and material) for all patients ([1], [2], [3], [4]). This has especially impacted patients with cancer who are at a higher risk of contracting and suffering serious complications from COVID-19 infection ([5], [6], [7], [8], [9]). Nationwide, there have also been limitations placed on procedures including biopsies and cancer surgeries (10). Given the unclear duration for the resource limitations might last, it is imperative to promote clinical efficiencies while maintaining optimal efficacy and safety. Brachytherapy is an integral part of radiotherapeutic management for a variety of clinical indications. Many brachytherapy procedures are carried out with anesthesia support and with utilization of operating room resources. As such, there is considerable pressure on providers to judiciously select patients in need of brachytherapy. After applicator/catheter placement, there is also substantial variability in planning (CT vs. MRI simulation), isotope selection for low-dose-rate brachytherapy, and dose and fractionation for high-dose-rate brachytherapy. To maximize resources, there is an urgent need to propose efficient dose/fractionation recommendations that are supported by evidence-based medicine. Guidance is additionally needed regarding brachytherapy utilization in patients who develop influenza-like illness, persons under investigation, or those who test positive for COVID-19 (COVID-19 +). A number of guidelines are now published providing external beam radiation recommendations, but none have focused specifically on brachytherapy ([11], [12], [13]). We fully appreciate that access to brachytherapy is contingent on the impact of COVID-19+ patients on each specific hospital system and that clinical judgment needs to be used when considering the appropriateness of a treatment plan. Because of the critical role of brachytherapy in the management of a variety of cancers, it is important for institutions to consider offering brachytherapy if appropriate staff and personal protective equipment are available for the protection of patients and staff. Institutions are encouraged to follow guidelines set by their local policy with regard to personal protective equipment use during different surgical procedures. Through data shown in the table as follows, we suggest practical implementation considerations when using brachytherapy for a variety of clinical indications (Table 1). We also summarize available data supporting the use of higher dose-per-fraction high-dose-rate regimens to allow treatment completion in a shorter course thereby limiting resource utilization and exposure risk. It is strongly recommended that for all modified fractionations being considered, strict respect for normal tissue dosimetric constraints be met using available published data. We also recognize that our understanding of COVID-19 infections is rapidly evolving and that suggestions regarding appropriate time to wait for re-initiating therapy after a patient recovers from COVID-19 could change and may be institution specific. These suggestions are not meant to replace appropriate clinical judgment. Table 1 Proposed brachytherapy recommendations (practical implementation, indications, and dose fractionation) during COVID-19 pandemic Disease site Indication Practical implementation considerations during pandemic Common dose/fractionation Suggested dose/fractionation during pandemic References Gynecological cancers Intact cervix—Definitive 1. Effort should be made to complete treatment within 7–8 weeks for non-COVID-19 +/PUI/ILI patients (14). 2. Consider using MRI for first fraction only instead of all fractions especially if 1st MRI shows a minimal residual disease (15). 3. When using brachytherapy consider spinal/epidural anesthesia, oral analgesia or intravenous conscious sedation over general endo-tracheal anesthesia. 4. If patient is COVID-19 +/PUI/ILI then: a. If resources available continue brachytherapy boost with PPE precautions, or b. Delay till 10–14 days post-recovery from infection and try to increase dose of brachytherapy by 5 Gy cumulative dose for each week delay provided OAR constraints can be met (14). HDR intracavitary ± hybrid interstitial boost after 45–50.4 Gy:5–6 Gy × 5 fractions, or7 Gy × 4 fractions (16) HDR intracavitary ± hybrid interstitial boost after 45 Gy:7 Gy × 4 fractions (16), or 8 Gy × 3 fractions (16,17)9 Gy × 2 fractions showed inferior outcomes to 7 Gy × 4 and is not preferred (18) 1. retroEMBRACE, Tanderup et al. PMID: 27350396 (14) 2. University of Pittsburgh, Beriwal et al. PMID 21908180 (15) 3. ABS consensus guidelines, Viswanathan et al. PMID: 22265437 (16) 4. Compendium of fractionation choices for gynecologic HDR brachy. Albuquerque K et al. 2019. PIMD 30979631 (17) 5. Multi-institutional trial, Hendry J et al. ASTRO Annual Meeting 2017 (18). Inoperable endometrial—Definitive 1. Consider using MRI for first fraction only instead of all fractions especially in good responders. 2. When using brachytherapy consider spinal/epidural anesthesia, oral analgesia or intravenous conscious sedation over general endo-tracheal anesthesia. 3. If patient is COVID-19 +/PUI/ILI then: a. Consider hormonal therapy alone (19) and wait 10–14 days after recovery from infection before initiating brachytherapy, or b. In symptomatic cases may consider EBRT alone (20). HDR intracavitary monotherapy (Stage I):7–7.5 Gy × 5 fractions (21)HDR intracavitary boost after 45 Gy:8.5 Gy × 2 fractions, or 6.3–6.5 Gy × 3 fractions, or 5.2 Gy × 4 fractions (22)HDR intracavitary boost after 50.4 Gy:6 Gy × 2 fractions, or 3.75 Gy × 6 fractions (22) HDR intracavitary monotherapy (Stage I):8.5 Gy × 4 fractions (17), or 8–10 Gy × 3 fractions (23)HDR intracavitary boost after 45 Gy:8.5 Gy × 2 fractions, or 6.3–6.5 Gy × 3 fractions (22)HDR intracavitary boost after 50.4 Gy:6 Gy × 2 fractions(22) 1. University of Virginia, Staples et al. PMID: 29977988 (19) 2. SEER analysis. Yoo et al. PMID: 26083557 (20) 3. University of Pittsburgh, Gebhardt et al. PMID: 28923412 (21) 4. ABS consensus guidelines, Schwarz et al. PMID: 26186975 (22) 5. Compendium of fractionation choices for gynecologic HDR brachy. Albuquerque K et al. 2019. PIMD 30979631 (17) 6. McGill University, Canada Niazi et al. PMID: 16099598 (23) Interstitial (template)—Definitive 1. If patient COVID-19 +/PUI/ILI during EBRT then: a. Delay till 10–14 days after recovery from infection. For patients with cervical cancer consider increasing dose of brachytherapy by 5 Gy cumulative dose for each week delay provided OAR constraints can be met (14). Similar data not available for vaginal or recurrent endometrial cancer. Practitioners can individualize decision in each case. HDR boost after 45–50.4 Gy:4–6 Gy × 5 fractions (16,24)No consensus recommendation for re-irradiation. HDR boost after 45 Gy:7–8 Gy × 3 fractions (24,25)6 Gy × 4 fraction, twice daily (26) 1. retroEMBRACE, Tanderup et al. PMID: 27350396 (14) 2. ABS Consensus Guidelines, Beriwal et al. PMID: 22265440 (24) 3. ABS consensus guidelines, Viswanathan et al. PMID: 22265437 (16) 4. Canadian experience, Taggar et al., PMID: 27914911 (25) 5. London Health Sciences Center, Canada, D'Souza et al. PMID: 24613570 (26) Postoperative vaginal cuff 1. Can avoid brachytherapy boost after EBRT if no adverse factor like positive/close margin, cervical involvement/LVSI, possibly using 50.4 Gy instead. 2. Avoid placement of gold seeds. Instead consider CT for confirming placement. 3. If patient is COVID-19 +/PUI/ILI, a. For patients receiving systemic therapy delay brachytherapy until pandemic resolves/resources become available, or a. For brachytherapy alone patients, could delay treatment to 8 to 9 weeks from date of surgery (27,28), or b. For brachytherapy boost patients, could delay treatment by 2–3 weeks after EBRT, or c. If status changes after 1 or 2 fractions, then delay till 10–14 days after recovery from infection. HDR cylinder monotherapy:7 Gy × 3 fractions to 5 mm, or 5–5.5 Gy × 4–5 Fractions to surface, or 6–7.5 Gy × 5 fractions to surface, or 4 Gy × 6 fractions to surface (17,29)HDR cylinder boost after 45–50.4 Gy:5–6 Gy × 2–3 fractions to surface, or 4–5.5 Gy × 3 fractions to 5 mm (17,29) HDR cylinder monotherapy:3 cm cylinder: 7 Gy × 3 fractions to 5 mm (PORTEC-2) (30)2.5 cm cylinder: 7 Gy × 3 fractions to surface (30,31)HDR cylinder boost after 45 Gy (adverse factors):5 Gy × 2 fractions at 5 mm (32,33)5 Gy × 1 fraction to surface (34), orHDR Cylinder Boost after 50/50.4 Gy (adverse factors):6 Gy × 2 fractions to surface (29)Add more fractions if positive margin 1. Henry Ford Hospital, Michigan, Cattaneo et al. PMID: 24444758 (27) 2. University of Pisa, Fabrini et al. PMID: 22213303 (28) 3. ABS consensus guidelines, Small et al., PMID: 22265439 (29) 4. Compendium of fractionation choices for gynecologic HDR brachy. Albuquerque K et al. 2019. PIMD 30979631 (17) 5. PORTEC-2, Nout et al. PMID: 20206777 (30) 6. Dana-Farber Cancer Institute/Brigham and Women's Hospital, Alban et al. ABS Annual Meeting 2019 (31). 7. University of Pittsburgh, He et al. PMID: 2752789732 8. PORTEC-3, de Boer et al. PMID: 31345626 (33) 9. BC Canada, Bachand et al. ABS Annual Meeting 2013 (34) Prostate cancer Monotherapy, boost or salvage 1. All monotherapy should be deferred until pandemic resolves/resources become available. 2. Defer initiating EBRT and continue hormone therapy for unfavorable and high-risk prostate. 3. If already on EBRT, then consider brachytherapy boost If resources available with PPE precautions, else consider EBRT boost. 4. For salvage cases delay brachytherapy and consider hormone therapy until pandemic resolves/resources become available. 5. When using brachytherapy consider spinal/epidural anesthesia, or intravenous conscious sedation over general endo-tracheal anesthesia. 6. For patients considered for HDR boost, may start with EBRT first. 7. If patient is COVID-19 +/PUI/ILI during EBRT, then: a. Consider interrupting treatment to allow 10–14 days after recovery from infection before re-initiating EBRT/plan for brachytherapy. 8. If patient is COVID-19 +/PUI/ILI, after 1st fraction HDR, then: a. Consider delaying 2nd fraction to allow 10–14 days after recovery from infection. Interstitial monotherapy:HDR 13.5 Gy × 2 (19 Gy × 1 is not appropriate) (35)LDR dose per isotope used.HDR interstitial boost:45 Gy in 25 fraction pelvic RT or 37.5 Gy in 15 fraction (prostate/seminal vesicles) with HDR boost 15 Gy in one fraction (36,37)Salvage HDR brachytherapy:8 Gy × 4 fractions, single implant, twice daily (38), or6 Gy × 6 fractions, two separate implantsperformed 1 week apart (39) Interstitial monotherapy:No change in fractionation needed.Interstitial boost after EBRT:No change in fractionation needed. 1. Sunnybrook Odette Cancer Center, Toronto, Morton G et al. Green Journal. 2020. PIMD 32146259 (35) 2. Sunnybrook Odette Cancer Center, Toronto, Martell K et al. Green Journal. PIMD 31522882 (36) 3. Sunnybrook Odette Cancer Center, Toronto, Shahid N et al. Clin Oncol. 2017. PIMD 28190638 (37) 4. Memorial Sloan Kettering Cancer Center, Yamada et al. PMID: 24373762 (38) 5. University of California-San Francisco, Chen et al. reference PMID: 23474112 (39) Breast cancer Adjuvant 1. Delay adjuvant EBRT or interstitial brachytherapy for low risk breast cancer pts as no detrimental effect in outcome up until 16–20 weeks for ER + invasive breast cancer (40,41) or 12 weeks for DCIS (42) 2. Balloon/Catheter-based intracavitary brachytherapy is dependent on presence of cavity and hence, needs to be done sooner Balloon/catheter-based HDR:3.4 Gy × 10 fractions, single implant, twice daily over 5 days (43)IORT: single fraction Balloon/catheter-based HDR: 7–7.5 Gy × 3 fractions, single implant, twice daily over 1.5 days (44,45) or 7 Gy × 4 fractions, single implant, twice daily over 2 days (46)IORT:No change in fractionation needed 1. Sahlgrenska University Hospital, Gothenburg, Sweden, Karlsson et al. PMID: 20729007 (40) 2. British Columbia, Canada, Olivotto et al. PMID: 19018080 (41) 3. Memorial Sloan Kettering Cancer Center, Shurell et al. PMID: 28960259 (42) 4. ABS recommendations, Shah et al. PMID: 29074088 (43) 5. Mayo Clinic Rochester, Jethwa et al. PIMD 30583041 (44) 6. Triumph-T trial, Khan et al. PMID:30611839 (45) 7. Phase 1/2 trial, Wilkinson et al. PMID 28787281 (46) Skin cancer Definitive Delay brachytherapy until pandemic resolves/resources become available. Surface applicators (dose to 3–5 mm below surface) ([47], [48], [49]): Sensitive area (over very thin skin or with underlying cartilage/bone or cosmetically important areas) 3 Gy × 17–18 fractions, or 40–50 Gy in 8–10 fractions Nonsensitive area 7 Gy × 6 fractions, or 6 Gy × 7 fractions, or 5 Gy × 8 fractions, or 10 Gy × 3 fractions Molds/flaps (dose to 3–5 mm below surface) ([47], [48], [49]): Sensitive area 3 Gy × 17–18 fractions, or 4 Gy × 10 fractions Nonsensitive area 40–50 Gy in 10–12 fractions, or 7 Gy × 6 fractions, or 6 Gy × 7 fractions, or 5 Gy × 8 fractions Interstitial ([47], [48], [49]):36–55 Gy in 8–10 fractions 1. Spanish brachytherapy group recommendations, Rodriquez et al. PMID: 28808925 (47) 2. GEC-ESTRO ACROP Recommendations, Guinot et al. PMID: 29455924 (48) 3. ABS working group report, Ouhib et al. PMID: 26319367 (49) 4. ABS Consensus Statement, Shah et al. Brachytherapy. Accepted for publication Esophageal cancer Palliative Avoid brachytherapy until pandemic resolves/resources become available due to increased risk of staff exposure from droplets. Consider short-course EBRT Intraluminal HDR monotherapy:12 Gy × 1 fraction, prescribed to 5–10 mm from source axis (50,51), or7–7.5 Gy at 10 mm from source axis × 3 fractions (50)Intraluminal HDR with EBRT:8 Gy at 10 mm × 2 fractions, once weekly combined with EBRT (52), or10 Gy at 10 mm × 1 fraction or 7 Gy at 10 mm × 2 fractions, combined with EBRT (53) 1. Netherlands multicenter, Homs et al. PMID 15500894 (50) 2. Systematic review, Fuccio et al. PMID 28104297 (51) 3. IAEA, Rosenblatt et al. PMID: 20950882 (52) 4. ABS Guidelines, Gaspar et al. PMID: 9212013 (53) Re-irradiation Avoid brachytherapy until pandemic resolves/resources become available due to increased risk of staff exposure from droplets. Consider conformal EBRT. Intraluminal HDR monotherapy:5–7 Gy at 5 mm × 5–6 fractions (54), or10–17.5 Gy at tumor depth in 3 fractions (limit mucosa to ≤ 12 Gy per fraction) (55) 1. Saint Louis Hospital, Paris, Wong Hee Kam et al. PMID 25906950 (54) 2. Memorial Sloan Kettering Cancer Center, New York, Taggar et al. PMID 29496425 (55) Hepato-biliary cancers Hilar Cholangiocarcinoma (bridge to transplant) Definitive 1. Avoid brachytherapy until pandemic resolves/resources become available due to increased risk of staff exposure from droplets. Consider conformal EBRT. 2. If patient is COVID-19 +/PUI/ILI, then consider continuing EBRT instead of brachytherapy boost Intraluminal boost after EBRT:Mayo Clinic Protocol:45 Gy/30 fractions EBRT with concurrent 5FU and 20–30 Gy intraluminal brachytherapy (56) If brachytherapy needs to be used, then consider a single fraction regimen Boost after EBRT:9.3 Gy × 1 (1.0 cm radially beyond the catheter) (57) 1. Mayo Clinic, Rochester, Rea et al. PMID 16135931 (56)2. Mayo Clinic, Rochester, Deufel et al. PMID: 29776892 (57) Palliative unresectable malignant biliary obstruction or hepatocellular carcinoma (not for transplant) and metastatic lesions Avoid brachytherapy until pandemic resolves/resources become available due to increased risk of staff exposure from droplets. Consider conformal EBRT ([58], [59], [60]) Interstitial LDR malignant biliary obstruction:I-125 impregnated stents, 30–60 Gy at 15 mm (61,62)Interstitial HDR hepatocellular carcinoma:15–25 Gy 1 fraction (63)Interstitial HDR liver metastases:15 Gy × 1 for breast cancer metastases20 Gy × 1 for nonbreast secondary liver cancers (64) 1. Multicenter phase II study, Hong et al. PMID 26668346 (58) 2. Univ of Rochester, Stereotactic Hypofractionated RT. Katz et al. PMID 22172906 (59) 3. Systematic review. Rim et al. PMID 29233562 (60) 4. Systematic review, Xu et al. PMID 29075881 (61) 5. Multicenter study, China, Zhu et al. PMID: 29331343 (62) 6. Otto von Guericke University, Germany. Mohnike et al. PMID: 20056348 (63) 7. University Hospital Magdeburg, Magdeburg, Germany, Hass et al. PMID 31522972 (64) Rectal cancer Preoperative or definitive 1. Avoid brachytherapy until pandemic resolves/resources become available due to increased risk of staff exposure from possible fecal spread. Consider conformal hypofractionated EBRT. 2. If patient is COVID-19 +/PUI/ILI, then consider change to hypofractionated EBRT instead of brachytherapy boost. Intraluminal HDR monotherapy (pre-op):26 Gy in 4 fractions prescribed to target volume (65,66)Intraluminal HDR boost after chemoradiation (inoperable) (67):40 Gy in 16 fractions EBRT + 10 Gy at 10 mm depth × 3 fractions(68), or 39 Gy in 13 fractions EBRT+ 7 Gy to volume × 3 fractions (69,70), or 60 Gy in 30 fractions + 5 Gy at 10 mm from applicator surface x 1 fraction(71) 1. McGill University Health Center, Canada, Hesselager et al. PMID: 23461819 (65) 2. McGill University Health Center, Canada, Te Vuong et al. PMID 17714925 (66) 3. Systematic review. Buckley et al. PMID 28816137 (67) 4. McGill University Health Center, Canada, Garant et al. PMID: 31476417 (68) 5. HERBERT study, Rijkmans et al. PMID: 28366579 (69) 6. HERBERT study, Rijkmans et al. PMID: 30935576 (70) 7. Danish Colorectal Cancer Center South, Denmark, Appelt et al. PMID: 26156652 (71) Sarcoma BRT monotherapy or boost 1. Delay brachytherapy until pandemic resolves/resources become available. Consider EBRT. 2. If patient is COVID-19 +/PUI/ILI during EBRT, then consider continuing EBRT instead of brachytherapy boost. Interstitial HDR monotherapy (post-op, high-grade < 10 cm, negative margins):30–50 Gy/8–14 fractions/4–7 days twice daily (72)Interstitial HDR monotherapy (Post-op, high-grade, close or positive margins margins):36 Gy/6 fractions/3 days BID (73)Interstitial HDR boost (Post-op, low-grade deep > 5 cm or high-grade > 10 cm, negative margins):12–20 Gy/2–3 days + EBRT 45–50 Gy EBRTTotal Dose≥ 60 Gy (72)Interstitial HDR boost (Post-op, positive surgical margins):12–20 Gy/2–3 days + EBRT 45–50 Gy EBRTTotal dose ≥ 65–70 Gy (72,74)BRT 16 Gy/2 days + EBRT 45 Gy EBRT (75) 1. ABS STS recommendation, Naghavi et al. PMID: 28342738 (72) 2. National Cancer Center Hospital, Japan, Itami et al., PMID: 20692211 (73) 3. Martínez-Monge et al. Univ. Navarre, Spain PMID: 21353160 (74) 4. AIIMS, India, Sharma et al., PMID: 25861894 (75) Head and neck definitive reirradiation Definitive/boost oral cavity/oropharynx, Boost nasopharynx or any re-irradiation 1. Avoid brachytherapy until pandemic resolves/resources become available due to increased risk of staff exposure from droplets. Consider conformal EBRT 2. If patient is COVID-19 +/PUI/ILI, then consider continuing EBRT instead of brachytherapy boost Interstitial HDR monotherapy oral cavity/oropharynx:35–44 Gy/10–11 fractions/5–5.5 days/twice daily ([76], [77], [78])Interstitial HDR boost oral cavity/oropharynx:21–30 Gy/7–10 fractions/3–5 days + EBRT 40–50 Gy ([76], [77], [78])Interstitial HDR boost nasopharynx:12–18/4–6 fractions/2–3 days + EBRT 60–70 Gy ([76], [77], [78])Interstitial HDR monotherapy re-irradiation:30–40 Gy/10 fractions/5 days/twice daily (79,80) 1. ABS Task Group Report, Takácsi-Nagy et al. PMID: 27592129 (76) 2. GEC-ESTRO- ACROP recommendations, Kovacs et al. PMID: 27889184 (77) 3. GEC-ESTRO recommendations, Mazeron et al. PMID: 19329209 (78) 4. Jupiter Hospital, India, Bhalavat et al., PMID: 30479619 (79) 5. Sana Klinikum Offenbach GmbH, Germany, Tselis et al., PMID: 21129799 (80) Brain tumors Primary brain tumors or brain metastases Adjuvant Avoid brachytherapy until pandemic resolves/resources become available. Consider fractionated EBRT (glioma) or preoperative or postoperative SRS/SRT (brain metastases) Interstitial LDR (gliomas):50–65 Gy (81,82)Interstitial LDR (brain metastases):60–70 Gy (83) 1. Review, Barbarite et al. PMID: 27180560 (81) 2. Review, Nachbichler et al. PMID: 29393178 (82) 3. Review, Mahase et al. PMID: 30850332 (83) Lung cancers Palliative Avoid brachytherapy until pandemic resolves/resources become available due to increased risk of staff exposure from droplets. Consider short-course EBRT. Endobronchial HDR:10 Gy at 10 mm/1 fraction, or 30 Gy at 1 cm/6 fractions (84) 1. ABS recommendations Stewart et al. PMID: 26561277 (84) Post-transplant stenosis Avoid brachytherapy until pandemic resolves/resources become available due to increased risk of staff exposure from droplets. Endobronchial HDR:7–10 Gy at 10 mm/1–2 fractions/2 weeks (85) 1. Rabin Medical Center, Israel. Allen et al., PMID: 22381651 (85) Uveal Melanoma Definitive 70 to 100 Gy to the tumor apex over 5–7 days (86) No change 1. ABS recommendations, Simpson et al. PMID: 24373763 (86) HDR = high-dose-rate; LDR = low-dose-rate; BRT = brachytherapy; EBRT = external beam radiotherapy; PMID = Pubmed identifier; SRS/SRT = stereotactic radiosurgery/stereotactic radiotherapy; COVID-19 +/PUI/ILI = influenza-like illness (ILI), persons under investigations (PUI) for COVID-19 with test results pending, and patients who may have tested positive for COVID-19 (COVID-19 +). Disclosures Conflicts of Interest: None of the authors have any conflicts of interest to disclose. Funding: No funding was received for this article.