Literature

Peer-reviewed evidence on surgical margins, cancer recurrence, and intra-operative brachytherapy

1. The incidence of "high risk" surgical margins after gross tu…2. The association of high-risk surgical margins and the risk o…3. The use of intra-operative brachytherapy for high-risk surgi…
1

The incidence of "high risk" surgical margins after gross tumor resection

Head & Neck

  1. Zanoni DK, Migliacci JC, Xu B, et al. A proposal to redefine close surgical margins in squamous cell carcinoma of the oral tongue. JAMA Otolaryngol Head Neck Surg. 2017;143(6):555-560.

    PMID: 28278337

Lung

  1. Predina JD, Kunkala MR, Aliperti LA, et al. Clinical implications of positive margins following non-small cell lung cancer surgery. J Thorac Cardiovasc Surg. 2016.

    PMID: 26719121

  2. Wong LY, et al. Impacts of positive margins and surgical extent on outcomes after resection of clinical stage I NSCLC. Ann Thorac Surg. 2024.

    PMID: 38866199

Breast

  1. Hotsinpiller WJ, et al. Rates of margin positive resection with breast conservation for invasive breast cancer: a modern national database analysis. 2021.

    PMC8441089

  2. Alblowi TM, et al. Trends and predictors of re-excision following breast-conserving surgery (includes positive and close margins <2 mm rates). 2025.

    PMC12445626

Esophagus

  1. Pultrum BB, et al. A critical appraisal of circumferential resection margins in esophageal carcinoma. Ann Surg Oncol. 2010;17:812-820.

    PMID: 19924487

Stomach

  1. Gaspar-Figueiredo S, et al. Impact of positive microscopic resection margins (R1) after oncologic gastrectomy on survival and tumour recurrence in diffuse-type gastric cancer. 2023.

    PMID: 37344606

  2. Hirata Y, et al. Clinical impact of positive surgical margins in gastric adenocarcinoma in the era of preoperative therapy. Ann Surg Oncol. 2023.

    PMID: 37106276

Duodenum / Small Bowel / Large Bowel

  1. Baril JA, et al. Treatment and outcomes for resected stage II small bowel adenocarcinoma (positive margin reported as high-risk feature). 2025.

    PMC12863234

Biliary Tree (Perihilar & Distal Bile Duct)

  1. Shinohara K, et al. A study on radial margin status in resected perihilar cholangiocarcinoma. 2021.

    PMID: 30946074

  2. Tjaden C, et al. Distal bile duct cancer: radical (R0 >1 mm) resection achieves favorable survival after pancreaticoduodenectomy. 2021/2023.

    PMID: 34171863

  3. Umino R, et al. Impact of surgical margin status on survival and recurrence after pancreaticoduodenectomy for distal cholangiocarcinoma. Ann Surg Oncol. 2024.

    PMID: 38679686

  4. D'Amico FE, et al. Impact of positive radial margin on recurrence and survival after resection for perihilar cholangiocarcinoma. Cancers (Basel). 2022.

    PMC8996964

Pancreas (PDAC)

  1. Verbeke CS. Redefining resection margin status in pancreatic cancer. HPB (Oxford). 2009.

    PMID: 19718354

  2. Verbeke CS, et al. Redefining the R1 resection in pancreatic cancer (standardized pathology; R1 incidence shifts markedly). 2006.

    PMID: 16804874

  3. van Roessel S, et al. Pathological margin clearance and survival after pancreaticoduodenectomy for pancreatic adenocarcinoma. 2018.

    PMID: 29651577

  4. Hank T, et al. Validation of at least 1 mm as cut-off for resection margins in resected pancreatic adenocarcinoma involving body and tail. 2018.

    PMID: 29738626

Colon / Rectum / Large Bowel

Rectum (CRM positivity incidence and predictors)

  1. Birbeck KF, Macklin CP, Tiffin NJ, et al. Rates of circumferential resection margin involvement vary between surgeons and predict outcomes in rectal cancer surgery. Ann Surg. 2002;235(4):449-457.

    PMID: 11923599

  2. Rickles AS, Dietz DW, Chang GJ, et al. High rate of positive circumferential resection margins following rectal cancer surgery: a call to action. Ann Surg. 2015.

    PMID: 26473651

  3. Simon HL, et al. Predictors of positive circumferential resection margin in rectal cancer: contemporary national data. Dis Colon Rectum. 2021.

    PMID: 33951688

Colon (CRM positivity incidence)

  1. Healy MA, et al. High rate of positive circumferential resection margin in US colon cancer cases. 2022.

    PMID: 33630474

  2. Goffredo P, et al. Positive circumferential resection margins following locally advanced colon cancer resections: national incidence and predictors. 2020.

    PMID: 31853986

Kidney (Partial Nephrectomy)

  1. Yossepowitch O, Thompson RH, Leibovich BC, et al. Positive surgical margins at partial nephrectomy: predictors and oncological outcomes. J Urol. 2008.

    PMID: 18423758

Ureter / Upper Tract Urothelial Carcinoma

  1. Colin P, Ouzzane A, Yates DR, et al. Influence of positive surgical margin status after radical nephroureterectomy on upper urinary tract urothelial carcinoma survival. Ann Surg Oncol. 2012;19(11):3613-3620.

    PMID: 22843187

Bladder (Radical Cystectomy)

  1. Novara G, Svatek RS, Karakiewicz PI, et al. Soft tissue surgical margin status is a powerful predictor of outcomes after radical cystectomy: a multicenter study of more than 4,400 patients. J Urol. 2010.

    PMID: 20399473

  2. Xylinas E, et al. Risk stratification after radical cystectomy (defines and reports positive soft tissue surgical margin frequency). Br J Cancer. 2012.

    PMC3504939

Prostate (Radical Prostatectomy)

  1. Yossepowitch O, Bjartell A, Eastham JA, et al. Positive surgical margins in radical prostatectomy: outlining the problem and its long-term consequences. Eur Urol. 2009;55:87-99.

    PMID: 18838211

Uterine Cervix (Radical Hysterectomy)

  1. McCann GA, Taege SK, Boutsicaris CE, et al. The impact of close surgical margins after radical hysterectomy for early-stage cervical cancer. Gynecol Oncol. 2013.

    PMID: 23138134

Retroperitoneum (Retroperitoneal Sarcoma / RPS)

  1. Paik B, et al. A systematic review of margin status in retroperitoneal liposarcoma. Front Oncol. 2022.

    PMID: 36033535

  2. Buja A, et al. Epidemiology, pathological characteristics and survival of retroperitoneal sarcomas. 2023.

    PMC10265397
2

The association of high-risk surgical margins and the risk of loco-regional cancer recurrence

Head & Neck

  1. Tasche KK, Buchakjian MR, Pagedar NA, et al. Definition of "Close Margin" in Oral Cancer Surgery and Association of Margin Distance With Local Recurrence Rate. JAMA Otolaryngol Head Neck Surg. 2017.

    PMID: 28445581

  2. Wu SS, Kim Y, Chen AM, et al. Margin Assessment Methods in Oral Cavity Squamous Cell Carcinoma Resection and Association With Local Recurrence. JAMA Otolaryngol Head Neck Surg. 2023.

    PMID: 37278321

Lung

  1. Predina JD, Kunkala MR, Aliperti LA, et al. Clinical implications of positive margins following non-small cell lung cancer surgery. J Thorac Cardiovasc Surg. 2016.

    PMID: 26719121

Breast

  1. Tyler S, Graham R, Broadwater G, et al. Close Margins Less Than 2 mm Are Not Associated With Higher Risks of 10-Year Local Recurrence and Breast Cancer Mortality Compared With Negative Margins in Women Treated With Breast-Conserving Therapy. Int J Radiat Oncol Biol Phys. 2018.

    PMID: 29678525

  2. Moran MS, Schnitt SJ, Giuliano AE, et al. Society of Surgical Oncology–American Society for Radiation Oncology Consensus Guideline on Margins for Breast-Conserving Surgery With Whole-Breast Irradiation in Stages I and II Invasive Breast Cancer. Ann Surg Oncol. 2014.

    PMID: 24515565

  3. Dunne C, Burke JP, Morrow M, Kell MR. Effect of margin status on local recurrence after breast conservation and radiation therapy for ductal carcinoma in situ: a meta-analysis. J Clin Oncol. 2009.

    PMID: 19255332

  4. Marinovich ML, Azizi L, Macaskill P, et al. The Association of Surgical Margins and Local Recurrence in Women With Ductal Carcinoma In Situ Treated With Breast-Conserving Surgery: A Meta-analysis. Ann Surg Oncol. 2016.

    PMID: 27527715

Esophagus

  1. Dexter SP, Sue-Ling H, McMahon MJ, Quirke P, Mapstone N, Martin IG. Circumferential resection margin involvement: an independent predictor of survival following surgery for oesophageal cancer. Br J Surg. 2001.

    PMID: 11302966

  2. Salih T, Jose P, Mehta S, et al. Prognostic significance of cancer within 1 mm of the circumferential resection margin in oesophageal cancer following neoadjuvant chemotherapy. Eur J Cardiothorac Surg. 2013.

    PMID: 22665383

Stomach

  1. Juez LD, Pera M, Millán M, et al. Influence of positive margins on tumour recurrence and survival after curative gastrectomy for gastric cancer. 2021.

    PMID: 34013576

  2. Gaspar-Figueiredo S, Oliveira AF, Pimentel-Nunes P, et al. Impact of positive microscopic resection margins (R1) after oncologic gastrectomy on survival and tumour recurrence in diffuse-type gastric cancer. 2023.

    PMID: 37344606

Duodenum / Small Bowel

  1. Colina A, et al. Prognostic factors and recurrence outcomes in localized small bowel adenocarcinoma. 2020.

    PMC7668374

  2. Wonglhow J, et al. Adjuvant therapy outcomes in resected small bowel adenocarcinoma with high-risk features including positive margin status. 2025.

    PMC12608280

Biliary Tree (Perihilar / Distal Cholangiocarcinoma)

  1. Umino R, et al. Impact of Surgical Margin Status on Survival and Recurrence After Pancreaticoduodenectomy for Distal Cholangiocarcinoma. 2024.

    PMID: 38679686

  2. Zhang XF, Squires MH, Bagante F, et al. The Impact of Intraoperative Re-Resection of a Positive Frozen-Section Bile Duct Margin to Achieve R0 Resection in Hilar Cholangiocarcinoma. 2018.

    PMID: 29470820

  3. Nooijen LE, et al. Impact of Positive Lymph Nodes and Resection Margin Status on Recurrence-Free Survival and Survival After Resection for Perihilar Cholangiocarcinoma. 2022.

    PMID: 35625993

  4. D'Amico FE, et al. Impact of Positive Radial Margin on Recurrence and Outcomes After Resection for Perihilar Cholangiocarcinoma. Cancers (Basel). 2022.

    PMID: 35327074

Pancreas (PDAC)

  1. McIntyre CA, et al. Detailed Analysis of Margin Positivity and the Site of Local Recurrence Following Pancreaticoduodenectomy for Pancreatic Ductal Adenocarcinoma. 2020.

    PMC7918294

  2. Kaltenmeier C, et al. Impact of Resection Margin Status in Patients With Pancreatic Cancer. 2020.

    PMC8169716

  3. Obonyo D, et al. The impact of resection margin distance on survival and prediction of recurrence following pancreatic head ductal adenocarcinoma. PLoS One. 2023.

    PMID: 36854861

Colon / Rectum / Large Bowel

  1. Agger EA, et al. Risk of local recurrence of rectal cancer and circumferential resection margin distance. Br J Surg. 2020.

    PMID: 32133651

  2. Hwang MR, et al. Prognostic impact of circumferential resection margin distance and recurrence after preoperative chemoradiotherapy for locally advanced rectal cancer. 2014.

    PMID: 24468928

  3. Trakarnsanga A, et al. What is the Significance of the Circumferential Margin in Rectal Cancer in the Modern Era? 2013.

    PMC4067458

  4. Amri R, Bordeianou LG, Berger DL. Association of radial margin positivity with colon cancer recurrence and survival. JAMA Surg. 2015.

    PMID: 26132363

  5. Makazu M, et al. Relationship between indeterminate or positive lateral margin and local recurrence after endoscopic resection of intramucosal colorectal neoplasms. 2015.

    PMC4486031

Kidney

  1. Yossepowitch O, et al. Positive surgical margins at partial nephrectomy: predictors and oncological outcomes. J Urol. 2008.

    PMID: 18423758

  2. García-Perdomo HA, et al. Effect of Positive Surgical Margins in Patients Who Underwent Partial Nephrectomy: Systematic Review. Clin Genitourin Cancer. 2022.

    PMID: 35840533

  3. Omrani MA, et al. Impact of Positive Surgical Margins on Recurrence and Local Recurrence After Partial Nephrectomy: Systematic Review and Meta-analysis. 2025.

    PMID: 39741400

Ureter / Upper-Tract Urothelial Carcinoma

  1. Colin P, Ouzzane A, Yates DR, et al. Influence of positive surgical margin status after radical nephroureterectomy on upper urinary tract urothelial carcinoma survival. Ann Surg Oncol. 2012.

    PMID: 22843187

  2. Katims AB, et al. Risk Factors for Intravesical Recurrence after Minimally Invasive Radical Nephroureterectomy for Upper Tract Urothelial Carcinoma. 2021.

    PMID: 33881931

Bladder (Radical Cystectomy)

  1. Novara G, Svatek RS, Karakiewicz PI, et al. Soft tissue surgical margin status is a powerful predictor of outcomes after radical cystectomy: a multicenter study of more than 4400 patients. J Urol. 2010.

    PMID: 20399473

  2. Xylinas E, et al. Predictors of survival in patients with positive soft tissue surgical margins at radical cystectomy. 2013.

    PMID: 23099729

Prostate

  1. Pfitzenmaier J, Pahernik S, Tremmel T, et al. Positive surgical margins after radical prostatectomy: association with PSA recurrence and local recurrence. 2008.

    PMID: 18537951

  2. Yossepowitch O, Bjartell A, Eastham JA, et al. Positive surgical margins in radical prostatectomy: outlining the problem and its long-term consequences. Eur Urol. 2009.

    PMID: 18838211

Uterine Cervix

  1. McCann GA, Taege S, Boutsicaris CE, et al. The impact of close surgical margins after radical hysterectomy for early-stage cervical cancer. Gynecol Oncol. 2013.

    PMID: 23138134

Uterus (Endometrium)

  1. Chu CS, et al. Vaginal cuff recurrence of endometrial cancer after hysterectomy. Gynecol Oncol. 2003.

    PMID: 12504629

Retroperitoneum (Retroperitoneal Sarcoma)

  1. Singer S, Corson JM, Demetri GD, et al. Histologic subtype and margin of resection predict local recurrence and survival in retroperitoneal liposarcoma. Ann Surg. 2003.

    PMC1422708

  2. Novais EN, Demiralp B, Alderete J, et al. Do surgical margin and local recurrence influence survival in soft tissue sarcomas? Clin Orthop Relat Res. 2010.

    PMC2947688
3

The use of intra-operative brachytherapy for high-risk surgical margins after gross tumor resection

Cross-Cutting Guidance / Technique (Multi-Site)

  1. Lloyd S, Chang BW, Amdur RJ, Smith GL, Morris CG, Kirwan J, et al. Intraoperative high-dose-rate brachytherapy: An American Brachytherapy Society consensus report. Brachytherapy. 2017 May-Jun;16(3):446-465.

    PMID: 28173994

  2. Verrijssen ASE, et al. Narrowing the difference in dose delivery for IOERT and intraoperative brachytherapy (IOBT): technical/physics considerations. 2022.

    PMID: 36199944

  3. Morikawa LK, et al. Intraoperative high-dose-rate brachytherapy using dose painting (HDR-IORT-DP): first clinical report. Brachytherapy. 2013;12.

    PMID: 23167979

Head & Neck

  1. Teckie S, Scala LM, Ho F, Wolden S, Chiu J, Cohen GN, et al. High-dose-rate intraoperative brachytherapy and radical surgical resection in the management of recurrent head-and-neck cancer. Brachytherapy. 2013 May-Jun;12(3):228-234.

    PMID: 23466361

  2. Nag S, Koc M, Schuller DE, Tippin D, Grecula JC. Intraoperative single fraction high-dose-rate brachytherapy for head and neck cancers. Brachytherapy. 2005;4(3):217-223.

    PMID: 16182222

  3. Nag S, et al. Pilot study of intraoperative high dose rate brachytherapy (IOHDR) for head and neck tumors at skull base/inaccessible sites. Int J Radiat Oncol Biol Phys. 1996.

    PMID: 9004354

  4. Nag S, et al. Intraoperative high dose rate brachytherapy can be used to treat previously irradiated head and neck cancers. 1999.

    PMID: 11256004

  5. Geiger EJ, Basques BA, Chang CC, Alcon AW, Narayan D. Wound healing complications with intraoperative brachytherapy for head and neck cancer. Ann Plast Surg. 2014 Oct;73(4):378-384.

    PMID: 25003401

  6. Luginbuhl A, Calder A, Kutler D, Zender C, Wise-Draper T, Patel J, et al. Multi-institutional study validates safety of intraoperative cesium-131 brachytherapy combined with salvage resection for recurrent head and neck cancer. Front Oncol. 2021;11:786216.

    PMID: 34900741

Lung

  1. Fernando HC, Landreneau RJ, Mandrekar SJ, Nichols FC, Hillman SL, Heron DE, et al. Impact of brachytherapy on local recurrence rates after sublobar resection: results from ACOSOG Z4032 (Alliance), a phase III randomized trial. J Clin Oncol. 2014;32(23):2456-2462.

    PMID: 24982457

  2. Colonias A, Betler J, Trombetta M, Bigdeli G, Gayou O, Keenan R, et al. Mature follow-up for high-risk stage I NSCLC treated with sublobar resection and intraoperative iodine-125 brachytherapy. Int J Radiat Oncol Biol Phys. 2011;79(1):105-109.

    PMID: 20382483

  3. Johnson M, Colonias A, Parda D, Trombetta M, Gayou O, Reitz B, et al. Dosimetric and technical aspects of intraoperative I-125 brachytherapy for stage I non-small cell lung cancer. Phys Med Biol. 2007 Mar 7;52(5):1237-1245.

    PMID: 17301451

  4. Blasberg JD, Belsley SJ, Schwartz GS, Evans A, Wernick I, Ashton RC Jr, et al. Robotic brachytherapy and sublobar resection for T1 NSCLC in high-risk patients. Ann Thorac Surg. 2010 Feb;89(2):360-367.

    PMID: 20103299

  5. d'Amato TA, et al. Intraoperative brachytherapy following thoracoscopic wedge resection for stage I lung cancer. Chest. 1998.

    PMID: 9792585

Breast

  1. Dutta SW, Showalter SL, Czito BG, et al. Implementation of an HDR brachytherapy-based breast intraoperative radiation therapy program (PB-IORT; CT-on-rails). 2019.

    PMID: 30846329

  2. Turkheimer LM, et al. Precision breast intraoperative radiation therapy (PB-IORT) using CT-based plans and HDR brachytherapy: interim results of a prospective phase II trial. 2024.

    PMID: 37870228

  3. Dutta SW, et al. Normal tissue dose and risk estimates comparing CT-guided HDR brachy PB-IORT vs external beam approaches. 2020.

    PMID: 31876106

  4. Wickberg Å, et al. Intraoperative high dose rate brachytherapy during breast-conserving surgery: a prospective pilot study. Scand J Surg. 2021 Sep;110(3):312-321.

    PMID: 32228155

Esophagus

  1. Wilson LD, Chung JY, Haffty BG, Cahow EC, Sasaki CT, Son YH. Intraoperative brachytherapy with laryngopharyngoesophagectomy and gastric transposition for recurrent hypopharyngeal and cervical esophageal carcinoma. Laryngoscope. 1998;108(10):1504-1508.

    PMID: 9778290

Biliary Tree

  1. Stein DE, Heron DE, Rosato EL, Anne PR, Topham AK, Shafiq J, et al. Positive microscopic margins alter outcome in lymph node-negative hilar cholangiocarcinoma patients treated with resection and adjuvant radiotherapy. Int J Radiat Oncol Biol Phys. 2005.

    PMID: 15685030

  2. Mattiucci GC, et al. Chemoradiation and brachytherapy in extrahepatic bile duct cancer. 2014.

    PMID: 24289902

Pancreas

  1. Taylor RJ, Todor D, Kaplan BJ, Stover W, Fields EC. CivaSheet intraoperative radiation therapy for pancreatic cancer. Brachytherapy. 2022 Mar-Apr;21(2):255-259.

    PMID: 35031255

Large Bowel / Colon / Rectum

  1. Alektiar KM, Zelefsky MJ, Paty PB, Guillem JG, Saltz LB, Cohen AM, et al. High-dose-rate intraoperative brachytherapy for recurrent colorectal cancer. Int J Radiat Oncol Biol Phys. 2000.

    PMID: 10924992

  2. Harrison LB, et al. High dose rate intraoperative radiation therapy (HDR-IORT) as part of the management strategy for locally advanced primary and recurrent rectal cancer. Int J Radiat Oncol Biol Phys. 1998 Sep 1;42(2):325-330.

    PMID: 9788411

  3. Tan J, et al. Prospective single-arm study of intraoperative radiotherapy using high-dose-rate brachytherapy for locally advanced or recurrent rectal cancers. Ann Surg Oncol. 2013.

    PMID: 24119279

  4. Turley RS, et al. Intraoperative pelvic brachytherapy for treatment of locally advanced or recurrent colorectal cancer. Tech Coloproctol. 2013.

    PMID: 22986843

  5. Gierej P, et al. Surgery and intraoperative HDR brachytherapy for locally advanced/recurrent rectal cancer: morbidity and preliminary outcomes. 2009.

    PMID: 27799949

  6. Monbailliu T, et al. HDR-IORT in multimodality treatment of LARC/LRRC. 2019.

    PMID: 29745309

  7. Stoian R, et al. Outcome of intraoperative brachytherapy as a salvage treatment for locally recurrent rectal cancer. Strahlenther Onkol. 2025;201(1):27-35.

    PMID: 39115680

  8. Voogt ELK, et al. Intraoperative electron beam radiotherapy (IOERT) versus HDR-IORT in rectal cancer with R1 resection. 2021.

    PMID: 33567303

Bladder

  1. Bosschieter J, et al. Robot-assisted laparoscopic implantation of brachytherapy catheters in bladder cancer. 2018.

    PMID: 28619396

  2. Han X, et al. Efficacy of brachytherapy (particle implantation) plus neoadjuvant chemotherapy in locally advanced urothelial bladder carcinoma undergoing radical cystectomy. 2025.

    PMID: 40405409

Uterine Cervix / Uterus

  1. Martínez-Monge R, Jurado M, Cambeiro M, Valero J, Villafranca E, Alcázar JL. Perioperative high-dose-rate brachytherapy in locally advanced and recurrent gynecologic cancer: initial results of a phase II trial. Brachytherapy. 2006 Oct-Dec;5(4):203-210.

    PMID: 17118310

Retroperitoneum (Retroperitoneal Sarcoma)

  1. Dziewirski W, Rutkowski P, Nowecki ZI, Sałamacha M, Morysiński T, Kulik A, et al. Surgery combined with intraoperative brachytherapy in the treatment of retroperitoneal sarcomas. Ann Surg Oncol. 2006 Feb;13(2):245-252.

    PMID: 16411144

  2. Dziewirski W, et al. Surgery combined with brachytherapy in patients with recurrent sarcomas. 2010.

    PMID: 28031738

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