Prediction of mucositis risk secondary to cancer therapy: a systematic review of current evidence and call to action

Abstract

Purpose

Despite advances in personalizing the efficacy of cancer therapy, our ability to identify patients at risk of severe treatment side effects and provide individualized supportive care is limited. This is particularly the case for mucositis (oral and gastrointestinal), with no comprehensive risk evaluation strategies to identify high-risk patients. We, the Multinational Association for Supportive Care in Cancer/International Society for Oral Oncology (MASCC/ISOO) Mucositis Study Group, therefore aimed to systematically review current evidence on that factors that influence mucositis risk to provide a foundation upon which future risk prediction studies can be based.

Methods

We identified 11,018 papers from PubMed and Web of Science, with 197 records extracted for full review and 113 meeting final eligibility criteria. Data were then synthesized into tables to highlight the level of evidence for each risk predictor.

Results

The strongest level of evidence supported dosimetric parameters as key predictors of mucositis risk. Genetic variants in drug-metabolizing pathways, immune signaling, and cell injury/repair mechanisms were also identified to impact mucositis risk. Factors relating to the individual were variably linked to mucositis outcomes, although female sex and smoking status showed some association with mucositis risk.

Conclusion

Mucositis risk reflects the complex interplay between the host, tumor microenvironment, and treatment specifications, yet the large majority of studies rely on hypothesis-driven, single-candidate approaches. For significant advances in the provision of personalized supportive care, coordinated research efforts with robust multiplexed approaches are strongly advised.

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References

  1. 1.

    Bode AM, Dong Z (2018) Recent advances in precision oncology research. NPJ Precis Oncol 2:11. https://doi.org/10.1038/s41698-018-0055-0

    Article  PubMed  PubMed Central  Google Scholar 

  2. 2.

    Bode AM, Dong Z (2017) Precision oncology-the future of personalized cancer medicine? NPJ Precis Oncol 1(1):2. https://doi.org/10.1038/s41698-017-0010-5

    Article  PubMed  PubMed Central  Google Scholar 

  3. 3.

    Bowen J, Al-Dasooqi N, Bossi P, Wardill H, Van Sebille Y, Al-Azri A, Bateman E, Correa ME, Raber-Durlacher J, Kandwal A, Mayo B, Nair RG, Stringer A, Ten Bohmer K, Thorpe D, Lalla RV, Sonis S, Cheng K, Elad S, Mucositis Study Group of the Multinational Association of Supportive Care in Cancer/International Society of Oral O (2019) The pathogenesis of mucositis: updated perspectives and emerging targets. Supportive care in cancer: official journal of the Multinational Association of Supportive Care in Cancer 27(10):4023–4033. https://doi.org/10.1007/s00520-019-04893-z

    CAS  Article  Google Scholar 

  4. 4.

    Bachour PC, Sonis ST (2018) Predicting mucositis risk associated with cytotoxic cancer treatment regimens: rationale, complexity, and challenges. Current opinion in supportive and palliative care 12(2):198–210. https://doi.org/10.1097/SPC.0000000000000339

    Article  PubMed  Google Scholar 

  5. 5.

    Ariyawardana A, Cheng KKF, Kandwal A, Tilly V, Al-Azri AR, Galiti D, Chiang K, Vaddi A, Ranna V, Nicolatou-Galitis O, Lalla RV, Bossi P, Elad S, Mucositis Study Group of the Multinational Association of Supportive Care in Cancer/International Society for Oral O (2019) Systematic review of anti-inflammatory agents for the management of oral mucositis in cancer patients and clinical practice guidelines. Supportive care in cancer: official journal of the Multinational Association of Supportive Care in Cancer 27(10):3985–3995. https://doi.org/10.1007/s00520-019-04888-w

    Article  Google Scholar 

  6. 6.

    Correa MEP, Cheng KKF, Chiang K, Kandwal A, Loprinzi CL, Mori T, Potting C, Rouleau T, Toro JJ, Ranna V, Vaddi A, Peterson DE, Bossi P, Lalla RV, Elad S (2019) Systematic review of oral cryotherapy for the management of oral mucositis in cancer patients and clinical practice guidelines. Supportive care in cancer: official journal of the Multinational Association of Supportive Care in Cancer. 28:2449–2456. https://doi.org/10.1007/s00520-019-05217-x

    Article  Google Scholar 

  7. 7.

    Hong CHL, Gueiros LA, Fulton JS, Cheng KKF, Kandwal A, Galiti D, Fall-Dickson JM, Johansen J, Ameringer S, Kataoka T, Weikel D, Eilers J, Ranna V, Vaddi A, Lalla RV, Bossi P, Elad S, Mucositis Study Group of the Multinational Association of Supportive Care in Cancer/International Society for Oral O (2019) Systematic review of basic oral care for the management of oral mucositis in cancer patients and clinical practice guidelines. Supportive care in cancer: official journal of the Multinational Association of Supportive Care in Cancer 27(10):3949–3967. https://doi.org/10.1007/s00520-019-04848-4

    Article  Google Scholar 

  8. 8.

    Yarom N, Hovan A, Bossi P, Ariyawardana A, Jensen SB, Gobbo M, Saca-Hazboun H, Kandwal A, Majorana A, Ottaviani G, Pentenero M, Nasr NM, Rouleau T, Lucas AS, Treister NS, Zur E, Ranna V, Vaddi A, Cheng KKF, Barasch A, Lalla RV, Elad S, Mucositis Study Group of the Multinational Association of Supportive Care in Cancer/International Society of Oral O (2019) Systematic review of natural and miscellaneous agents for the management of oral mucositis in cancer patients and clinical practice guidelines-part 1: vitamins, minerals, and nutritional supplements. Supportive care in cancer: official journal of the Multinational Association of Supportive Care in Cancer 27(10):3997–4010. https://doi.org/10.1007/s00520-019-04887-x

    Article  Google Scholar 

  9. 9.

    Zadik Y, Arany PR, Fregnani ER, Bossi P, Antunes HS, Bensadoun RJ, Gueiros LA, Majorana A, Nair RG, Ranna V, Tissing WJE, Vaddi A, Lubart R, Migliorati CA, Lalla RV, Cheng KKF, Elad S, Mucositis Study Group of the Multinational Association of Supportive Care in Cancer/International Society of Oral O (2019) Systematic review of photobiomodulation for the management of oral mucositis in cancer patients and clinical practice guidelines. Supportive care in cancer: official journal of the Multinational Association of Supportive Care in Cancer 27(10):3969–3983. https://doi.org/10.1007/s00520-019-04890-2

    Article  Google Scholar 

  10. 10.

    Bowen JM, Gibson RJ, Coller JK, Blijlevens N, Bossi P, Al-Dasooqi N, Bateman EH, Chiang K, de Mooij C, Mayo B, Stringer AM, Tissing W, Wardill HR, van Sebille YZA, Ranna V, Vaddi A, Keefe DM, Lalla RV, Cheng KKF, Elad S, Mucositis Study Group of the Multinational Association of Supportive Care in Cancer/International Society of Oral O (2019) Systematic review of agents for the management of cancer treatment-related gastrointestinal mucositis and clinical practice guidelines. Supportive care in cancer: official journal of the Multinational Association of Supportive Care in Cancer 27(10):4011–4022. https://doi.org/10.1007/s00520-019-04892-0

    Article  Google Scholar 

  11. 11.

    Rashidi A, Shanley R, Holtan SG, MacMillan ML, Blazar BR, Khoruts A, Weisdorf DJ (2018) Pretransplant serum citrulline predicts acute graft-versus-host disease. Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 24(11):2190–2196. https://doi.org/10.1016/j.bbmt.2018.06.036

    CAS  Article  Google Scholar 

  12. 12.

    Mizuno H, Miyai H, Yokoi A, Kobayashi T, Inabu C, Maruyama T, Ekuni D, Mizukawa N, Kariya S, Nishizaki K, Kimata Y, Morita M (2019) Relationship between renal dysfunction and oral mucositis in patients undergoing concurrent chemoradiotherapy for pharyngeal cancer: a retrospective cohort study. In vivo (Athens, Greece) 33 (1):183-189. Doi:https://doi.org/10.21873/invivo.11457

  13. 13.

    Jenq RR, Taur Y, Devlin SM, Ponce DM, Goldberg JD, Ahr KF, Littmann ER, Ling L, Gobourne AC, Miller LC, Docampo MD, Peled JU, Arpaia N, Cross JR, Peets TK, Lumish MA, Shono Y, Dudakov JA, Poeck H, Hanash AM, Barker JN, Perales MA, Giralt SA, Pamer EG, van den Brink MR (2015) Intestinal Blautia is associated with reduced death from graft-versus-host disease. Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 21(8):1373–1383. https://doi.org/10.1016/j.bbmt.2015.04.016

    Article  Google Scholar 

  14. 14.

    Ippolito E, Guido A, Macchia G, Deodato F, Giaccherini L, Farioli A, Arcelli A, Cuicchi D, Frazzoni L, Cilla S, Buwenge M, Mantini G, Alitto AR, Nuzzo M, Valentini V, Ingrosso M, Morganti AG, Fuccio L (2017) Predictive factors of late-onset rectal mucosal changes after radiotherapy of prostate cancer. In vivo (Athens, Greece) 31 (5):961-966. Doi:https://doi.org/10.21873/invivo.11154

  15. 15.

    Peach MS, Showalter TN, Ohri N (2015) Systematic review of the relationship between acute and late gastrointestinal toxicity after radiotherapy for prostate cancer. Prostate Cancer 2015:624736. doi:https://doi.org/10.1155/2015/624736

  16. 16.

    Shaw PJ, Nath CE, Lazarus HM (2014) Not too little, not too much-just right! (Better ways to give high dose melphalan). Bone Marrow Transplant 49(12):1457–1465. https://doi.org/10.1038/bmt.2014.186

    CAS  Article  PubMed  Google Scholar 

  17. 17.

    McCullough RW (2017) US oncology-wide incidence, duration, costs and deaths from chemoradiation mucositis and antimucositis therapy benefits. Future oncology (London, England) 13(30):2823–2852. https://doi.org/10.2217/fon-2017-0418

    CAS  Article  Google Scholar 

  18. 18.

    Heil SG (2019) Genetics of high-dose methotrexate-induced oral mucositis: current perspectives. Pharmacogenomics 20(9):621–623. https://doi.org/10.2217/pgs-2019-0062

    CAS  Article  PubMed  Google Scholar 

  19. 19.

    Oosterom N, Berrevoets M, den Hoed MAH, Zolk O, Hoerning S, Pluijm SMF, Pieters R, de Jonge R, Tissing WJE, van den Heuvel-Eibrink MM, Heil SG (2018) The role of genetic polymorphisms in the thymidylate synthase (TYMS) gene in methotrexate-induced oral mucositis in children with acute lymphoblastic leukemia. Pharmacogenet Genomics 28(10):223–229. https://doi.org/10.1097/fpc.0000000000000352

    CAS  Article  PubMed  Google Scholar 

  20. 20.

    van Erp NP, Eechoute K, van der Veldt AA, Haanen JB, Reyners AK, Mathijssen RH, Boven E, van der Straaten T, Baak-Pablo RF, Wessels JA, Guchelaar HJ, Gelderblom H (2009) Pharmacogenetic pathway analysis for determination of sunitinib-induced toxicity. Journal of clinical oncology: official journal of the American Society of Clinical Oncology 27(26):4406–4412. https://doi.org/10.1200/jco.2008.21.7679

    Article  Google Scholar 

  21. 21.

    Chen RC, Mamon HJ, Ancukiewicz M, Killoran JH, Crowley EM, Blaszkowsky LS, Wo JY, Ryan DP, Hong TS (2012) Dose--volume effects on patient-reported acute gastrointestinal symptoms during chemoradiation therapy for rectal cancer. Int J Radiat Oncol Biol Phys 83(4):e513–e517. https://doi.org/10.1016/j.ijrobp.2012.01.013

    Article  PubMed  Google Scholar 

  22. 22.

    Reyna-Figueroa J, Garcia-Beristain JC, Galindo-Delgado P, Limon-Rojas AE, Madrid-Marina V (2015) Antibiotic use before chemotherapy: a risk factor for developing neutropenic colitis in children with leukemia. J Pediatr Hematol Oncol 37(2):121–127. https://doi.org/10.1097/mph.0000000000000227

    CAS  Article  PubMed  Google Scholar 

  23. 23.

    Vokurka S, Steinerova K, Karas M, Koza V (2009) Characteristics and risk factors of oral mucositis after allogeneic stem cell transplantation with FLU/MEL conditioning regimen in context with BU/CY2. Bone Marrow Transplant 44(9):601–605. https://doi.org/10.1038/bmt.2009.66

    CAS  Article  PubMed  Google Scholar 

  24. 24.

    Blijlevens N, Schwenkglenks M, Bacon P, D’Addio A, Einsele H, Maertens J, Niederwieser D, Rabitsch W, Roosaar A, Ruutu T, Schouten H, Stone R, Vokurka S, Quinn B, McCann S (2008) Prospective oral mucositis audit: oral mucositis in patients receiving high-dose melphalan or BEAM conditioning chemotherapy--European Blood and Marrow Transplantation Mucositis Advisory Group. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 26(9):1519–1525. https://doi.org/10.1200/jco.2007.13.6028

    CAS  Article  Google Scholar 

  25. 25.

    Kashiwazaki H, Matsushita T, Sugita J, Shigematsu A, Kasashi K, Yamazaki Y, Kanehira T, Kondo T, Endo T, Tanaka J, Hashino S, Nishio M, Imamura M, Kitagawa Y, Inoue N (2012) A comparison of oral mucositis in allogeneic hematopoietic stem cell transplantation between conventional and reduced-intensity regimens. Support Care Cancer 20(5):933–939. https://doi.org/10.1007/s00520-011-1164-2

    Article  PubMed  Google Scholar 

  26. 26.

    Bhide SA, Gulliford S, Schick U, Miah A, Zaidi S, Newbold K, Nutting CM, Harrington KJ (2012) Dose-response analysis of acute oral mucositis and pharyngeal dysphagia in patients receiving induction chemotherapy followed by concomitant chemo-IMRT for head and neck cancer. Radiother Oncol 103(1):88–91. https://doi.org/10.1016/j.radonc.2011.12.027

    Article  PubMed  Google Scholar 

  27. 27.

    Werbrouck J, De Ruyck K, Duprez F, Veldeman L, Claes K, Van Eijkeren M, Boterberg T, Willems P, Vral A, De Neve W, Thierens H (2009) Acute normal tissue reactions in head-and-neck cancer patients treated with IMRT: influence of dose and association with genetic polymorphisms in DNA DSB repair genes. Int J Radiat Oncol Biol Phys 73(4):1187–1195. https://doi.org/10.1016/j.ijrobp.2008.08.073

    CAS  Article  PubMed  Google Scholar 

  28. 28.

    Barnett GC, De Meerleer G, Gulliford SL, Sydes MR, Elliott RM, Dearnaley DP (2011) The impact of clinical factors on the development of late radiation toxicity: results from the Medical Research Council RT01 trial (ISRCTN47772397). Clinical oncology (Royal College of Radiologists (Great Britain)) 23(9):613–624. https://doi.org/10.1016/j.clon.2011.03.001

    CAS  Article  Google Scholar 

  29. 29.

    Orlandi E, Iacovelli NA, Rancati T, Cicchetti A, Bossi P, Pignoli E, Bergamini C, Licitra L, Fallai C, Valdagni R, Cavallo A (2018) Multivariable model for predicting acute oral mucositis during combined IMRT and chemotherapy for locally advanced nasopharyngeal cancer patients. Oral Oncol 86:266–272. https://doi.org/10.1016/j.oraloncology.2018.10.006

    Article  PubMed  Google Scholar 

  30. 30.

    Mazeron R, Fokdal LU, Kirchheiner K, Georg P, Jastaniyah N, Segedin B, Mahantshetty U, Hoskin P, Jurgenliemk-Schulz I, Kirisits C, Lindegaard JC, Dorr W, Haie-Meder C, Tanderup K, Potter R (2016) Dose-volume effect relationships for late rectal morbidity in patients treated with chemoradiation and MRI-guided adaptive brachytherapy for locally advanced cervical cancer: results from the prospective multicenter EMBRACE study. Radiother Oncol 120(3):412–419. https://doi.org/10.1016/j.radonc.2016.06.006

    Article  PubMed  Google Scholar 

  31. 31.

    Simpson DR, Song WY, Moiseenko V, Rose BS, Yashar CM, Mundt AJ, Mell LK (2012) Normal tissue complication probability analysis of acute gastrointestinal toxicity in cervical cancer patients undergoing intensity modulated radiation therapy and concurrent cisplatin. Int J Radiat Oncol Biol Phys 83(1):e81–e86. https://doi.org/10.1016/j.ijrobp.2011.12.012

    Article  PubMed  Google Scholar 

  32. 32.

    Nakamura A, Shibuya K, Matsuo Y, Nakamura M, Shiinoki T, Mizowaki T, Hiraoka M (2012) Analysis of dosimetric parameters associated with acute gastrointestinal toxicity and upper gastrointestinal bleeding in locally advanced pancreatic cancer patients treated with gemcitabine-based concurrent chemoradiotherapy. Int J Radiat Oncol Biol Phys 84(2):369–375. https://doi.org/10.1016/j.ijrobp.2011.12.026

    Article  PubMed  Google Scholar 

  33. 33.

    Arcadipane F, Olimpio E, Ragona R, Martini S, Iorio GC, Gallio E, Di Muzio J, Franco P, Ricardi U (2019) Clinical and dosimetric predictors of oral mucositis in the treatment of head and neck cancer. Radiother Oncol 132:71–71. https://doi.org/10.1016/s0167-8140(19)30300-7

    Article  Google Scholar 

  34. 34.

    Cattaneo GM, Passoni P, Longobardi B, Slim N, Reni M, Cereda S, di Muzio N, Calandrino R (2013) Dosimetric and clinical predictors of toxicity following combined chemotherapy and moderately hypofractionated rotational radiotherapy of locally advanced pancreatic adenocarcinoma. Radiother Oncol 108(1):66–71. https://doi.org/10.1016/j.radonc.2013.05.011

    Article  PubMed  Google Scholar 

  35. 35.

    Sanguineti G, Endres EJ, Sormani MP, Parker BC (2009) Dosimetric predictors of diarrhea during radiotherapy for prostate cancer. Strahlentherapie und Onkologie: Organ der Deutschen Rontgengesellschaft [et al] 185(6):390–396. https://doi.org/10.1007/s00066-009-1953-4

    Article  Google Scholar 

  36. 36.

    Han K, Cummings BJ, Lindsay P, Skliarenko J, Craig T, Le LW, Brierley J, Wong R, Dinniwell R, Bayley AJ, Dawson LA, Ringash J, Krzyzanowska MK, Moore MJ, Chen EX, Easson AM, Kassam Z, Cho C, Kim J (2014) Prospective evaluation of acute toxicity and quality of life after IMRT and concurrent chemotherapy for anal canal and perianal cancer. Int J Radiat Oncol Biol Phys 90(3):587–594. https://doi.org/10.1016/j.ijrobp.2014.06.061

    Article  PubMed  Google Scholar 

  37. 37.

    Gunnlaugsson A, Nilsson P, Kjellen E, Johnsson A (2009) The effect on the small bowel of 5-FU and oxaliplatin in combination with radiation using a microcolony survival assay. Radiation oncology (London, England) 4:61. https://doi.org/10.1186/1748-717X-4-61

    CAS  Article  Google Scholar 

  38. 38.

    Julie DA, Oh JH, Apte AP, Deasy JO, Tom A, Wu AJ, Goodman KA (2016) Predictors of acute toxicities during definitive chemoradiation using intensity-modulated radiotherapy for anal squamous cell carcinoma. Acta oncologica (Stockholm, Sweden) 55(2):208–216. https://doi.org/10.3109/0284186x.2015.1043396

    Article  Google Scholar 

  39. 39.

    Tho LM, Glegg M, Paterson J, Yap C, MacLeod A, McCabe M, McDonald AC (2006) Acute small bowel toxicity and preoperative chemoradiotherapy for rectal cancer: investigating dose-volume relationships and role for inverse planning. Int J Radiat Oncol Biol Phys 66(2):505–513. https://doi.org/10.1016/j.ijrobp.2006.05.005

    Article  PubMed  Google Scholar 

  40. 40.

    Olsen JR, Moughan J, Myerson R, Abitbol A, Doncals DE, Johnson D, Schefter TE, Chen Y, Fisher B, Michalski J, Narayan S, Chang A, Crane CH, Kachnic L (2017) Predictors of radiation therapy-related gastrointestinal toxicity from anal cancer dose-painted intensity modulated radiation therapy: secondary analysis of NRG oncology RTOG 0529. Int J Radiat Oncol Biol Phys 98(2):400–408. https://doi.org/10.1016/j.ijrobp.2017.02.005

    Article  PubMed  PubMed Central  Google Scholar 

  41. 41.

    Yang TJ, Oh JH, Son CH, Apte A, Deasy JO, Wu A, Goodman KA (2013) Predictors of acute gastrointestinal toxicity during pelvic chemoradiotherapy in patients with rectal cancer. Gastrointestinal cancer research : GCR 6(5–6):129–136

    PubMed  Google Scholar 

  42. 42.

    Nishii M, Soutome S, Kawakita A, Yutori H, Iwata E, Akashi M, Hasegawa T, Kojima Y, Funahara M, Umeda M, Komori T (2019) Factors associated with severe oral mucositis and candidiasis in patients undergoing radiotherapy for oral and oropharyngeal carcinomas: a retrospective multicenter study of 326 patients. Supportive care in cancer: official journal of the Multinational Association of Supportive Care in Cancer 28:1069–1075. https://doi.org/10.1007/s00520-019-04885-z

    Article  Google Scholar 

  43. 43.

    Hildebrandt MA, Komaki R, Liao Z, Gu J, Chang JY, Ye Y, Lu C, Stewart DJ, Minna JD, Roth JA, Lippman SM, Cox JD, Hong WK, Spitz MR, Wu X (2010) Genetic variants in inflammation-related genes are associated with radiation-induced toxicity following treatment for non-small cell lung cancer. PLoS One 5(8):e12402. https://doi.org/10.1371/journal.pone.0012402

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  44. 44.

    Huang CM, Huang MY, Tsai HL, Huang CW, Ma CJ, Lin CH, Huang CJ, Wang JY (2017) A retrospective comparison of outcome and toxicity of preoperative image-guided intensity-modulated radiotherapy versus conventional pelvic radiotherapy for locally advanced rectal carcinoma. J Radiat Res 58(2):247–259. https://doi.org/10.1093/jrr/rrw098

    Article  PubMed  Google Scholar 

  45. 45.

    Prasad S, Cambridge L, Huguet F, Chou JF, Zhang Z, Wu AJ, O’Reilly EM, Allen PJ, Goodman KA (2016) Intensity modulated radiation therapy reduces gastrointestinal toxicity in locally advanced pancreas cancer. Practical radiation oncology 6(2):78–85. https://doi.org/10.1016/j.prro.2015.09.006

    Article  PubMed  Google Scholar 

  46. 46.

    Bonner J, Giralt J, Harari P, Spencer S, Schulten J, Hossain A, Chang SC, Chin S, Baselga J (2016) Cetuximab and radiotherapy in laryngeal preservation for cancers of the larynx and hypopharynx: a secondary analysis of a randomized clinical trial. JAMA Otolaryngol Head Neck Surg 142(9):842–849. https://doi.org/10.1001/jamaoto.2016.1228

    Article  PubMed  PubMed Central  Google Scholar 

  47. 47.

    Bolwell BJ, Kalaycio M, Sobecks R, Andresen S, Kuczkowski E, Bernhard L, Lomax R, Kohuth J, Mendiola S, Rybicki L, Pohlman B (2002) A multivariable analysis of factors influencing mucositis after autologous progenitor cell transplantation. Bone Marrow Transplant 30(9):587–591. https://doi.org/10.1038/sj.bmt.1703694

    CAS  Article  PubMed  Google Scholar 

  48. 48.

    Grazziutti ML, Dong L, Miceli MH, Krishna SG, Kiwan E, Syed N, Fassas A, van Rhee F, Klaus H, Barlogie B, Anaissie EJ (2006) Oral mucositis in myeloma patients undergoing melphalan-based autologous stem cell transplantation: incidence, risk factors and a severity predictive model. Bone Marrow Transplant 38(7):501–506. https://doi.org/10.1038/sj.bmt.1705471

    CAS  Article  PubMed  Google Scholar 

  49. 49.

    Wardley AM, Jayson GC, Swindell R, Morgenstern GR, Chang J, Bloor R, Fraser CJ, Scarffe JH (2000) Prospective evaluation of oral mucositis in patients receiving myeloablative conditioning regimens and haemopoietic progenitor rescue. Br J Haematol 110(2):292–299. https://doi.org/10.1046/j.1365-2141.2000.02202.x

    CAS  Article  PubMed  Google Scholar 

  50. 50.

    Fadda G, Campus G, Luglie P (2006) Risk factors for oral mucositis in paediatric oncology patients receiving alkylant chemotherapy. BMC oral health 6:13. https://doi.org/10.1186/1472-6831-6-13

    Article  PubMed  PubMed Central  Google Scholar 

  51. 51.

    Robien K, Schubert MM, Bruemmer B, Lloid ME, Potter JD, Ulrich CM (2004) Predictors of oral mucositis in patients receiving hematopoietic cell transplants for chronic myelogenous leukemia. J Clin Oncol 22(7):1268–1275. https://doi.org/10.1200/jco.2004.05.147

    Article  PubMed  Google Scholar 

  52. 52.

    Goyal M, Shukla P, Gupta D, Bisht SS, Dhawan A, Gupta S, Pant MC, Verma NS (2009) Oral mucositis in morning vs. evening irradiated patients: a randomised prospective study. Int J Radiat Biol 85(6):504–509. https://doi.org/10.1080/09553000902883802

    CAS  Article  PubMed  Google Scholar 

  53. 53.

    Bjarnason GA, Mackenzie RG, Nabid A, Hodson ID, El-Sayed S, Grimard L, Brundage M, Wright J, Hay J, Ganguly P, Leong C, Wilson J, Jordan RC, Walker M, Tu D, Parulekar W (2009) Comparison of toxicity associated with early morning versus late afternoon radiotherapy in patients with head-and-neck cancer: a prospective randomized trial of the National Cancer Institute of Canada Clinical Trials Group (HN3). International journal of radiation oncology, biology, physics 73(1):166–172. https://doi.org/10.1016/j.ijrobp.2008.07.009

    Article  PubMed  Google Scholar 

  54. 54.

    Shukla P, Gupta D, Bisht SS, Pant MC, Bhatt ML, Gupta R, Srivastava K, Gupta S, Dhawan A, Mishra D, Negi MP (2010) Circadian variation in radiation-induced intestinal mucositis in patients with cervical carcinoma. Cancer 116(8):2031–2035. https://doi.org/10.1002/cncr.24867

    Article  PubMed  Google Scholar 

  55. 55.

    Reyes-Gibby CC, Melkonian SC, Wang J, Yu RK, Shelburne SA, Lu C, Gunn GB, Chambers MS, Hanna EY, Yeung S-CJ, Shete S (2017) Identifying novel genes and biological processes relevant to the development of cancer therapy-induced mucositis: an informative gene network analysis. Figshare

  56. 56.

    Campbell JM, Bateman E, Peters M, Bowen JM, Keefe DM, Stephenson MD (2016) Fluoropyrimidine and platinum toxicity pharmacogenetics: an umbrella review of systematic reviews and meta-analyses. Pharmacogenomics 17(4):435–451. https://doi.org/10.2217/pgs.15.180

    CAS  Article  PubMed  Google Scholar 

  57. 57.

    Campbell JM, Bateman E, Stephenson MD, Bowen JM, Keefe DM, Peters MD (2016) Methotrexate-induced toxicity pharmacogenetics: an umbrella review of systematic reviews and meta-analyses. Cancer Chemother Pharmacol 78(1):27–39. https://doi.org/10.1007/s00280-016-3043-5

    CAS  Article  PubMed  Google Scholar 

  58. 58.

    Campbell JM, Stephenson MD, Bateman E, Peters MD, Keefe DM, Bowen JM (2017) Irinotecan-induced toxicity pharmacogenetics: an umbrella review of systematic reviews and meta-analyses. Pharmacogenomics J 17(1):21–28. https://doi.org/10.1038/tpj.2016.58

    CAS  Article  PubMed  Google Scholar 

  59. 59.

    Ulrich CM, Yasui Y, Storb R, Schubert MM, Wagner JL, Bigler J, Ariail KS, Keener CL, Li S, Liu H, Farin FM, Potter JD (2001) Pharmacogenetics of methotrexate: toxicity among marrow transplantation patients varies with the methylenetetrahydrofolate reductase C677T polymorphism. Blood 98(1):231–234

    CAS  Article  Google Scholar 

  60. 60.

    Tantawy AA, El-Bostany EA, Adly AA, Abou El Asrar M, El-Ghouroury EA, Abdulghaffar EE (2010) Methylene tetrahydrofolate reductase gene polymorphism in Egyptian children with acute lymphoblastic leukemia. Blood coagulation & fibrinolysis: an international journal in haemostasis and thrombosis 21(1):28–34. https://doi.org/10.1097/MBC.0b013e32833135e9

    CAS  Article  Google Scholar 

  61. 61.

    Venkatesh GH, Manjunath VB, Mumbrekar KD, Negi H, Fernandes DJ, Sharan K, Banerjee S, Bola Sadashiva SR (2014) Polymorphisms in radio-responsive genes and its association with acute toxicity among head and neck cancer patients. PLoS One 9(3):e89079. https://doi.org/10.1371/journal.pone.0089079

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  62. 62.

    Mlak R, Powrozek T, Brzozowska A, Homa-Mlak I, Mazurek M, Malecka-Massalska T (2018) RRM1 gene expression evaluated in the liquid biopsy (blood cfRNA) as a non-invasive, predictive factor for radiotherapy-induced oral mucositis and potential prognostic biomarker in head and neck cancer patients. Cancer biomarkers: section A of Disease markers 22(4):657–667. https://doi.org/10.3233/cbm-171082

    CAS  Article  PubMed  Google Scholar 

  63. 63.

    Borchiellini D, Etienne-Grimaldi MC, Bensadoun RJ, Benezery K, Dassonville O, Poissonnet G, Llorca L, Ebran N, Formento P, Chateau Y, Thariat J, Milano G (2017) Candidate apoptotic and DNA repair gene approach confirms involvement of ERCC1, ERCC5, TP53 and MDM2 in radiation-induced toxicity in head and neck cancer. Oral Oncol 67:70–76. https://doi.org/10.1016/j.oraloncology.2017.02.003

    CAS  Article  PubMed  Google Scholar 

  64. 64.

    Smith JJ, Wasserman I, Milgrom SA, Chow OS, Chen CT, Patil S, Goodman KA, Garcia-Aguilar J (2017) Single nucleotide polymorphism TGFbeta1 R25P correlates with acute toxicity during neoadjuvant chemoradiotherapy in rectal cancer patients. Int J Radiat Oncol Biol Phys 97(5):924–930. https://doi.org/10.1016/j.ijrobp.2016.12.015

    CAS  Article  PubMed  Google Scholar 

  65. 65.

    Osti MF, Nicosia L, Agolli L, Gentile G, Falco T, Bracci S, Di Nardo F, Minniti G, De Sanctis V, Valeriani M, Maglio M, Borro M, Simmaco M, Enrici RM (2017) Potential role of single nucleotide polymorphisms of XRCC1, XRCC3, and RAD51 in predicting acute toxicity in rectal cancer patients treated with preoperative radiochemotherapy. Am J Clin Oncol 40(6):535–542. https://doi.org/10.1097/coc.0000000000000182

    CAS  Article  PubMed  Google Scholar 

  66. 66.

    Bohanes P, Rankin CJ, Blanke CD, Winder T, Ulrich CM, Smalley SR, Rich TA, Martensen JA, Benson AB 3rd, Mayer RJ, Cripps CM, Danenberg K, Makar KW, Zhang W, Benedetti JK, Lenz HJ (2015) Pharmacogenetic analysis of INT 0144 trial: association of polymorphisms with survival and toxicity in rectal cancer patients treated with 5-FU and radiation. Clin Cancer Res 21(7):1583–1590. https://doi.org/10.1158/1078-0432.Ccr-14-0857

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  67. 67.

    Soares S, Nogueira A, Coelho A, Assis J, Pereira D, Bravo I, Medeiros R (2018) Relationship between clinical toxicities and ERCC1 rs3212986 and XRCC3 rs861539 polymorphisms in cervical cancer patients. Int J Biol Markers 33(1):116–123. https://doi.org/10.5301/ijbm.5000279

    CAS  Article  PubMed  Google Scholar 

  68. 68.

    Zhao J, Zhi Z, Zhang M, Li Q, Li J, Wang X, Ma C (2018) Predictive value of single nucleotide polymorphisms in XRCC1 for radiation-induced normal tissue toxicity. OncoTargets and therapy 11:3901–3918. https://doi.org/10.2147/ott.S156175

    Article  PubMed  PubMed Central  Google Scholar 

  69. 69.

    Chen H, Wu M, Li G, Hua L, Chen S, Huang H (2017) Association between XRCC1 single-nucleotide polymorphism and acute radiation reaction in patients with nasopharyngeal carcinoma: a cohort study. Medicine 96(44):e8202. https://doi.org/10.1097/md.0000000000008202

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  70. 70.

    Nanda SS, Gandhi AK, Rastogi M, Khurana R, Hadi R, Sahni K, Mishra SP, Srivastava AK, Bhatt MLB, Parmar D (2018) Evaluation of XRCC1 gene polymorphism as a biomarker in head and neck cancer patients undergoing chemoradiation therapy. Int J Radiat Oncol Biol Phys 101(3):593–601. https://doi.org/10.1016/j.ijrobp.2018.03.039

    CAS  Article  PubMed  Google Scholar 

  71. 71.

    Coller JK, White IA, Logan RM, Tuke J, Richards AM, Mead KR, Karapetis CS, Bowen JM (2015) Predictive model for risk of severe gastrointestinal toxicity following chemotherapy using patient immune genetics and type of cancer: a pilot study. Supportive care in cancer: official journal of the Multinational Association of Supportive Care in Cancer 23(5):1233–1236. https://doi.org/10.1007/s00520-014-2481-z

    Article  Google Scholar 

  72. 72.

    Sakamoto K, Oka M, Yoshino S, Hazama S, Abe T, Okayama N, Hinoda Y (2006) Relation between cytokine promoter gene polymorphism and toxicity of 5-fluorouracil plus cisplatin chemotherapy. Oncol Rep 16(2):381–387

    CAS  PubMed  Google Scholar 

  73. 73.

    Bowen JM, White I, Smith L, Tsykin A, Kristaly K, Thompson SK, Karapetis CS, Tan H, Game PA, Irvine T, Hussey DJ, Watson DI, Keefe DM (2015) Pre-therapy mRNA expression of TNF is associated with regimen-related gastrointestinal toxicity in patients with esophageal cancer: a pilot study. Support Care Cancer 23(11):3165–3172. https://doi.org/10.1007/s00520-015-2696-7

    CAS  Article  PubMed  Google Scholar 

  74. 74.

    Brzozowska A, Powrozek T, Homa-Mlak I, Mlak R, Ciesielka M, Golebiowski P, Malecka-Massalska T (2018) Polymorphism of promoter region of TNFRSF1A gene (-610 T > G) as a novel predictive factor for radiotherapy induced oral mucositis in HNC patients. Pathology oncology research : POR 24(1):135–143. https://doi.org/10.1007/s12253-017-0227-1

    CAS  Article  PubMed  Google Scholar 

  75. 75.

    Brzozowska A, Mlak R, Homa-Mlak I, Golebiowski P, Mazurek M, Ciesielka M, Malecka-Massalska T (2018) Polymorphism of regulatory region of APEH gene (c.-521G>C, rs4855883) as a relevant predictive factor for radiotherapy induced oral mucositis and overall survival in head neck cancer patients. Oncotarget 9(51):29644–29653. https://doi.org/10.18632/oncotarget.25662

    Article  PubMed  PubMed Central  Google Scholar 

  76. 76.

    Brzozowska A, Homa-Mlak I, Mlak R, Golebiowski P, Mazurek M, Ciesielka M, Malecka-Massalska T (2018) Polymorphism of regulatory region of GHRL gene (-2531C>T) as a promising predictive factor for radiotherapy-induced oral mucositis in patients with head neck cancer. Head & neck 40(8):1799–1811. https://doi.org/10.1002/hed.25154

    Article  Google Scholar 

  77. 77.

    Ma WL, Liu R, Huang LH, Zou C, Huang J, Wang J, Chen SJ, Meng XG, Yang JK, Li H, Yang GP, Guo CX (2017) Impact of polymorphisms in angiogenesis-related genes on clinical outcomes of radiotherapy in patients with nasopharyngeal carcinoma. Clin Exp Pharmacol Physiol 44(5):539–548. https://doi.org/10.1111/1440-1681.12738

    CAS  Article  PubMed  Google Scholar 

  78. 78.

    Le Z, Niu X, Chen Y, Ou X, Zhao G, Liu Q, Tu W, Hu C, Kong L, Liu Y (2017) Predictive single nucleotide polymorphism markers for acute oral mucositis in patients with nasopharyngeal carcinoma treated with radiotherapy. Oncotarget 8(38):63026–63037. https://doi.org/10.18632/oncotarget.18450

    Article  PubMed  PubMed Central  Google Scholar 

  79. 79.

    Gutierrez-Camino A, Oosterom N, den Hoed MAH, Lopez-Lopez E, Martin-Guerrero I, Pluijm SMF, Pieters R, de Jonge R, Tissing WJE, Heil SG, Garcia-Orad A, van den Heuvel-Eibrink MM (2017) The miR-1206 microRNA variant is associated with methotrexate-induced oral mucositis in pediatric acute lymphoblastic leukemia. Pharmacogenet Genomics 27(8):303–306. https://doi.org/10.1097/fpc.0000000000000291

    CAS  Article  PubMed  Google Scholar 

  80. 80.

    Vokurka S, Bystricka E, Koza V, Scudlova J, Pavlicova V, Valentova D, Visokaiova M, Misaniova L (2006) Higher incidence of chemotherapy induced oral mucositis in females: a supplement of multivariate analysis to a randomized multicentre study. Supportive care in cancer: official journal of the Multinational Association of Supportive Care in Cancer 14(9):974–976. https://doi.org/10.1007/s00520-006-0031-z

    Article  Google Scholar 

  81. 81.

    Tebbutt NC, Norman AR, Cunningham D, Allen M, Chau I, Oates J, Hill M (2003) Analysis of the time course and prognostic factors determining toxicity due to infused fluorouracil. Br J Cancer 88(10):1510–1515. https://doi.org/10.1038/sj.bjc.6600917

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  82. 82.

    Schwab M, Zanger UM, Marx C, Schaeffeler E, Klein K, Dippon J, Kerb R, Blievernicht J, Fischer J, Hofmann U, Bokemeyer C, Eichelbaum M, German FUTSG (2008) Role of genetic and nongenetic factors for fluorouracil treatment-related severe toxicity: a prospective clinical trial by the German 5-FU Toxicity Study Group. Journal of clinical oncology: official journal of the American Society of Clinical Oncology 26(13):2131–2138. https://doi.org/10.1200/JCO.2006.10.4182

    CAS  Article  Google Scholar 

  83. 83.

    Valeh M, Kargar M, Mansouri A, Kamranzadeh H, Gholami K, Heidari K, Hajibabaei M (2018) Factors affecting the incidence and severity of oral mucositis following hematopoietic stem cell transplantation. International journal of hematology-oncology and stem cell research 12(2):142–152

    PubMed  PubMed Central  Google Scholar 

  84. 84.

    van den Broek GB, Balm AJ, van den Brekel MW, Hauptmann M, Schornagel JH, Rasch CR (2006) Relationship between clinical factors and the incidence of toxicity after intra-arterial chemoradiation for head and neck cancer. Radiother Oncol 81(2):143–150. https://doi.org/10.1016/j.radonc.2006.09.002

    Article  PubMed  Google Scholar 

  85. 85.

    Porock D, Nikoletti S, Cameron F (2004) The relationship between factors that impair wound healing and the severity of acute radiation skin and mucosal toxicities in head and neck cancer. Cancer Nurs 27(1):71–78

    Article  Google Scholar 

  86. 86.

    Cakmak S, Nural N (2019) Incidence of and risk factors for development of oral mucositis in outpatients undergoing cancer chemotherapy. Int J Nurs Pract 25(1):e12710. https://doi.org/10.1111/ijn.12710

    Article  PubMed  Google Scholar 

  87. 87.

    Carreon-Burciaga RG, Castaneda-Castaneira E, Gonzalez-Gonzalez R, Molina-Frechero N, Gaona E, Bologna-Molina R (2018) Severity of oral mucositis in children following chemotherapy and radiotherapy and its implications at a single oncology centre in Durango State, Mexico. Int J Pediatr 2018:3252765–3252765. https://doi.org/10.1155/2018/3252765

    Article  PubMed  PubMed Central  Google Scholar 

  88. 88.

    Shouval R, Kouniavski E, Fein J, Danylesko I, Shem-Tov N, Geva M, Yerushalmi R, Shimoni A, Nagler A (2019) Risk factors and implications of oral mucositis in recipients of allogeneic hematopoietic stem cell transplantation. Eur J Haematol 103:402–409. https://doi.org/10.1111/ejh.13299

    CAS  Article  PubMed  Google Scholar 

  89. 89.

    Tao Z, Gao J, Qian L, Huang Y, Zhou Y, Yang L, He J, Yang J, Wang R, Zhang Y (2017) Factors associated with acute oral mucosal reaction induced by radiotherapy in head and neck squamous cell carcinoma: a retrospective single-center experience. Medicine 96(50):e8446. https://doi.org/10.1097/md.0000000000008446

    Article  PubMed  PubMed Central  Google Scholar 

  90. 90.

    Vatca M, Lucas JT Jr, Laudadio J, D’Agostino RB, Waltonen JD, Sullivan CA, Rouchard-Plasser R, Matsangou M, Browne JD, Greven KM, Porosnicu M (2014) Retrospective analysis of the impact of HPV status and smoking on mucositis in patients with oropharyngeal squamous cell carcinoma treated with concurrent chemotherapy and radiotherapy. Oral Oncol 50(9):869–876. https://doi.org/10.1016/j.oraloncology.2014.06.010

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  91. 91.

    Santini D, Vincenzi B, Perrone G, Rabitti C, Borzomati D, Caricato M, La Cesa A, Grilli C, Verzi A, Coppola R, Tonini G (2004) Thymidylate synthase expression in normal colonic mucosa: a predictive marker of toxicity in colorectal cancer patients receiving 5-fluorouracil-based adjuvant chemotherapy. Oncology 67(2):135–142. https://doi.org/10.1159/000081000

    CAS  Article  PubMed  Google Scholar 

  92. 92.

    Xu B, Guo Y, Chen Y, Lu H, Tang T, Yue Z, Guan G, Chi P, Lin C (2015) Is the irradiated small bowel volume still a predictor for acute lower gastrointestinal toxicity during preoperative concurrent chemo-radiotherapy for rectal cancer when using intensity-modulated radiation therapy? Radiat Oncol 10:257. https://doi.org/10.1186/s13014-015-0566-6

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  93. 93.

    Goutham HV, Mumbrekar KD, Vadhiraja BM, Fernandes DJ, Sharan K, Kanive Parashiva G, Kapaettu S, Bola Sadashiva SR (2012) DNA double-strand break analysis by gamma-H2AX foci: a useful method for determining the overreactors to radiation-induced acute reactions among head-and-neck cancer patients. Int J Radiat Oncol Biol Phys 84(5):e607–e612. https://doi.org/10.1016/j.ijrobp.2012.06.041

    CAS  Article  PubMed  Google Scholar 

  94. 94.

    Allen G, Logan R, Revesz T, Keefe D, Gue S (2018) The prevalence and investigation of risk factors of oral mucositis in a pediatric oncology inpatient population; a prospective study. J Pediatr Hematol Oncol 40(1):15–21. https://doi.org/10.1097/mph.0000000000000970

    Article  PubMed  Google Scholar 

  95. 95.

    Ruiz-Arguelles GJ, Coconi-Linares LN, Garces-Eisele J, Reyes-Nunez V (2007) Methotrexate-induced mucositis in acute leukemia patients is not associated with the MTHFR 677T allele in Mexico. Hematology (Amsterdam, Netherlands) 12(5):387–391. https://doi.org/10.1080/10245330701448479

    CAS  Article  Google Scholar 

  96. 96.

    Agostini M, Pasetto LM, Pucciarelli S, Terrazzino S, Ambrosi A, Bedin C, Galdi F, Friso ML, Mescoli C, Urso E, Leon A, Lise M, Nitti D (2008) Glutathione S-transferase P1 Ile105Val polymorphism is associated with haematological toxicity in elderly rectal cancer patients receiving preoperative chemoradiotherapy. Drugs Aging 25(6):531–539. https://doi.org/10.2165/00002512-200825060-00006

    CAS  Article  PubMed  Google Scholar 

  97. 97.

    Liu SG, Gao C, Zhang RD, Zhao XX, Cui L, Li WJ, Chen ZP, Yue ZX, Zhang YY, Wu MY, Wang JX, Li ZG, Zheng HY (2017) Polymorphisms in methotrexate transporters and their relationship to plasma methotrexate levels, toxicity of high-dose methotrexate, and outcome of pediatric acute lymphoblastic leukemia. Oncotarget 8(23):37761–37772. https://doi.org/10.18632/oncotarget.17781

    Article  PubMed  PubMed Central  Google Scholar 

  98. 98.

    Lundberg M, Saarilahti K, Mäkitie AA, Mattila PS (2010) TGFbeta1 genetic polymorphism is associated with survival in head and neck squamous cell carcinoma independent of the severity of chemoradiotherapy induced mucositis. Oral Oncol 46(5):369–72. https://doi.org/10.1016/j.oraloncology.2010.02.012

  99. 99.

    Goutham HV, Mumbrekar KD, Hitendra N, Vadhiraja BM, Fernandes DJ, Satish Rao Dr BS (2017) Genotype-phenotype association of TGF-β1 and GST with chemo-radiotherapy induced toxicity. Int J Radiat Res 15(1):15–23 https://doi.org/10.18869/acadpub.ijrr.15.1.15

  100. 100.

    Gunnlaugsson A, Kjellen E, Nilsson P, Bendahl PO, Willner J, Johnsson A (2007) Dose-volume relationships between enteritis and irradiated bowel volumes during 5-fluorouracil and oxaliplatin based chemoradiotherapy in locally advanced rectal cancer. Acta oncologica (Stockholm, Sweden) 46(7):937–944. https://doi.org/10.1080/02841860701317873

    CAS  Article  Google Scholar 

  101. 101.

    Dodd MJ, Miaskowski C, Dibble SL, Paul SM, MacPhail L, Greenspan D, Shiba G (2000) Factors influencing oral mucositis in patients receiving chemotherapy. Cancer Pract 8(6):291–297

    CAS  Article  Google Scholar 

  102. 102.

    van Kuilenburg AB, Klumpen HJ, Westermann AM, Zoetekouw L, Van Lenthe H, Bakker PJ, Richel DJ, Guchelaar HJ (2007) Increased dihydropyrimidine dehydrogenase activity associated with mild toxicity in patients treated with 5-fluorouracil and leucovorin. European journal of cancer (Oxford, England : 1990) 43(2):459–465. https://doi.org/10.1016/j.ejca.2006.09.017

    CAS  Article  Google Scholar 

  103. 103.

    Figliolia SL, Oliveira DT, Pereira MC, Lauris JR, Mauricio AR, Oliveira DT, Mello de Andrea ML (2008) Oral mucositis in acute lymphoblastic leukaemia: analysis of 169 paediatric patients. Oral Dis 14(8):761–766. https://doi.org/10.1111/j.1601-0825.2008.01468.x

    CAS  Article  PubMed  Google Scholar 

  104. 104.

    Diaconescu R, Flowers CR, Storer B, Sorror ML, Maris MB, Maloney DG, Sandmaier BM, Storb R (2004) Morbidity and mortality with nonmyeloablative compared with myeloablative conditioning before hematopoietic cell transplantation from HLA-matched related donors. Blood 104(5):1550–1558. https://doi.org/10.1182/blood-2004-03-0804

    CAS  Article  PubMed  Google Scholar 

  105. 105.

    Anand A, Anandi P, Jain NA, Lu K, Dunavin N, Hourigan CS, Le RQ, Chokshi PD, Ito S, Stroncek DF, Sabatino M, Barrett AJ, Battiwalla M (2016) CD34+ selection and the severity of oropharyngeal mucositis in total body irradiation-based allogeneic stem cell transplantation. Supportive care in cancer: official journal of the Multinational Association of Supportive Care in Cancer 24(2):815–822. https://doi.org/10.1007/s00520-015-2848-9

    Article  Google Scholar 

  106. 106.

    Reinbolt RE, Sonis S, Timmers CD, Fernandez-Martinez JL, Cernea A, de Andres-Galiana EJ, Hashemi S, Miller K, Pilarski R, Lustberg MB (2018) Genomic risk prediction of aromatase inhibitor-related arthralgia in patients with breast cancer using a novel machine-learning algorithm. Cancer Med 7(1):240–253. https://doi.org/10.1002/cam4.1256

    CAS  Article  PubMed  Google Scholar 

  107. 107.

    Alterovitz G, Tuthill C, Rios I, Modelska K, Sonis S (2011) Personalized medicine for mucositis: Bayesian networks identify unique gene clusters which predict the response to gamma-D-glutamyl-L-tryptophan (SCV-07) for the attenuation of chemoradiation-induced oral mucositis. Oral Oncol 47(10):951–955. https://doi.org/10.1016/j.oraloncology.2011.07.006

    CAS  Article  PubMed  Google Scholar 

  108. 108.

    Sonis S, Antin J, Tedaldi M, Alterovitz G (2013) SNP-based Bayesian networks can predict oral mucositis risk in autologous stem cell transplant recipients. Oral Dis 19(7):721–727. https://doi.org/10.1111/odi.12146

    Article  PubMed  Google Scholar 

  109. 109.

    Suresh AV, Varma PP, Sinha S, Deepika S, Raman R, Srinivasan M, Mandapal T, Reddy CO, Anand BB (2010) Risk-scoring system for predicting mucositis in patients of head and neck cancer receiving concurrent chemoradiotherapy [rssm-hn]. J Cancer Res Ther 6(4):448–451. https://doi.org/10.4103/0973-1482.77100

    CAS  Article  PubMed  Google Scholar 

  110. 110.

    Hurria A, Cirrincione CT, Muss HB, Kornblith AB, Barry W, Artz AS, Schmieder L, Ansari R, Tew WP, Weckstein D, Kirshner J, Togawa K, Hansen K, Katheria V, Stone R, Galinsky I, Postiglione J, Cohen HJ (2011) Implementing a geriatric assessment in cooperative group clinical cancer trials: CALGB 360401. Journal of clinical oncology: official journal of the American Society of Clinical Oncology 29(10):1290–1296. https://doi.org/10.1200/JCO.2010.30.6985

    Article  Google Scholar 

  111. 111.

    Hurria A, Togawa K, Mohile SG, Owusu C, Klepin HD, Gross CP, Lichtman SM, Gajra A, Bhatia S, Katheria V, Klapper S, Hansen K, Ramani R, Lachs M, Wong FL, Tew WP (2011) Predicting chemotherapy toxicity in older adults with cancer: a prospective multicenter study. Journal of clinical oncology: official journal of the American Society of Clinical Oncology 29(25):3457–3465. https://doi.org/10.1200/JCO.2011.34.7625

    CAS  Article  Google Scholar 

  112. 112.

    Covington JA, Wedlake L, Andreyev J, Ouaret N, Thomas MG, Nwokolo CU, Bardhan KD, Arasaradnam RP (2012) The detection of patients at risk of gastrointestinal toxicity during pelvic radiotherapy by electronic nose and FAIMS: a pilot study. Sensors (Basel) 12(10):13002–13018. https://doi.org/10.3390/s121013002

    CAS  Article  Google Scholar 

  113. 113.

    Orlandi E, Iacovelli NA, De Cecco L, Rancati T, Cavallo A, Ferella L, Mancinelli E, Serafini MS, Devecchi A, Giandini T, Cicchetti A, Bossi P, Alfieri S, Locati L, Licitra L, Fallai C, Valdagni R (2019) Role of microbiota in predicting oral mucositis in head and neck cancer patients treated with IMRT. Radiother Oncol 132:57–57. https://doi.org/10.1016/s0167-8140(19)30278-6

    Article  Google Scholar 

  114. 114.

    Chua LL, Rajasuriar R, Azanan MS, Abdullah NK, Tang MS, Lee SC, Woo YL, Lim YA, Ariffin H, Loke P (2017) Reduced microbial diversity in adult survivors of childhood acute lymphoblastic leukemia and microbial associations with increased immune activation. Microbiome 5(1):35. https://doi.org/10.1186/s40168-017-0250-1

    Article  PubMed  PubMed Central  Google Scholar 

  115. 115.

    Friend AJ, Feltbower RG, Newton HL, Picton HM, Glaser AW (2018) Late effects of childhood cancer. Lancet (London, England) 391 (10132):1772. doi:https://doi.org/10.1016/S0140-6736(18)30572-5

  116. 116.

    Derrien M, Alvarez AS, de Vos WM (2019) The gut microbiota in the first decade of life. Trends Microbiol 27(12):997–1010. https://doi.org/10.1016/j.tim.2019.08.001

    CAS  Article  PubMed  Google Scholar 

  117. 117.

    Huang K, Liu Y, Tang H, Qiu M, Li C, Duan C, Wang C, Yang J, Zhou X (2019) Glabridin prevents doxorubicin-induced cardiotoxicity through gut microbiota modulation and colonic macrophage polarization in mice. Front Pharmacol 10:107. https://doi.org/10.3389/fphar.2019.00107

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  118. 118.

    Wang A, Ling Z, Yang Z, Kiela PR, Wang T, Wang C, Cao L, Geng F, Shen M, Ran X, Su Y, Cheng T, Wang J (2015) Gut microbial dysbiosis may predict diarrhea and fatigue in patients undergoing pelvic cancer radiotherapy: a pilot study. PLoS One 10(5):e0126312. https://doi.org/10.1371/journal.pone.0126312

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  119. 119.

    Wen Y, Jin R, Chen H (2019) Interactions between gut microbiota and acute childhood leukemia. Front Microbiol 10:1300. https://doi.org/10.3389/fmicb.2019.01300

    Article  PubMed  PubMed Central  Google Scholar 

  120. 120.

    Dong ST, Butow PN, Costa DS, Lovell MR, Agar M (2014) Symptom clusters in patients with advanced cancer: a systematic review of observational studies. J Pain Symptom Manag 48(3):411–450. https://doi.org/10.1016/j.jpainsymman.2013.10.027

    Article  Google Scholar 

  121. 121.

    Montassier E, Al-Ghalith GA, Ward T, Corvec S, Gastinne T, Potel G, Moreau P, De La Cochetiere MF, Batard E, Knights D (2016) Erratum to: pretreatment gut microbiome predicts chemotherapy-related bloodstream infection. Genome Med 8(1):61. https://doi.org/10.1186/s13073-016-0321-0

    Article  PubMed  PubMed Central  Google Scholar 

  122. 122.

    Wardill HR, Van Sebille YZ, Mander KA, Gibson RJ, Logan RM, Bowen JM, Sonis ST (2015) Toll-like receptor 4 signaling: a common biological mechanism of regimen-related toxicities: an emerging hypothesis for neuropathy and gastrointestinal toxicity. Cancer Treat Rev 41(2):122–128. https://doi.org/10.1016/j.ctrv.2014.11.005

    CAS  Article  PubMed  Google Scholar 

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Acknowledgments

Thanks are given to members of the Multinational Association of Supportive Care in Cancer and International Society for Oral Oncology Mucositis Study Group for supporting this initiative.

Funding

Hannah R Wardill is supported by an NHMRC CJ Martin Biomedical Research Fellowship.

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HRW/JMB/SE/PB/KKFC/STS: conceptualization and project initiation, DAC/LP/SE/HRW/JMB: search strategy and record retrieval, HRW/JMB: record triaging, HRW/JMB/NMAB/YZAVS/EAHL/MAC: record review and data extraction, HRW/JMB: data synthesis/writing, All authors: review and editing of final manuscript.

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Correspondence to H. R. Wardill.

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Dr. Sonis reports personal fees from Biomodels, LLC, personal fees from Primary Endpoint Solutions, LLC, outside of the submitted work. As an employee of Biomodels and PES, he is involved in assisting industry, government and academics in the study and enablement of drugs, biologicals and devices to treat patients for a broad range of indications including cancer and oral toxicities of cancer therapy. He does not have equity or receive payment from any of the companies’ clients.

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Wardill, H.R., Sonis, S.T., Blijlevens, N.M.A. et al. Prediction of mucositis risk secondary to cancer therapy: a systematic review of current evidence and call to action. Support Care Cancer (2020). https://doi.org/10.1007/s00520-020-05579-7

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Keywords

  • Mucositis
  • Diarrhea
  • Supportive oncology
  • Risk prediction
  • Precision medicine
  • Personalized care