Cancer Res Treat.  2024 Jan;56(1):1-17. 10.4143/crt.2023.562.

Intensity-Modulated Radiation Therapy for Uterine Cervical Cancer to Reduce Toxicity and Enhance Efficacy – an Option or a Must?: A Narrative Review

• Lee SW
• Kim A
• Lee SJ
• Kim SH
• Lee JH

• KMID: 2550318
• DOI: http://doi.org/10.4143/crt.2023.562

Abstract

Radiotherapy (RT) is a fundamental modality in treatment of cervical cancer. With advancement of technology, conventional RT used for external beam radiotherapy (EBRT) for over half a century has been rapidly replaced with intensity-modulated radiation therapy (IMRT) especially during the last decade. This newer technique is able to differentiate the intensity of radiation within the same field, thus reduces the inevitable exposure of radiation to normal organs and enables better dose delivery to tumors. Recently, the American Society for Radiation Oncology has released a guideline for RT in cervical cancer. Although a section of the guideline recommends IMRT for the purpose of toxicity reduction, a thorough review of the literature is necessary to understand the current status of IMRT in cervical cancer. This narrative review updates the recent high-level evidences regarding the efficacy and toxicity of IMRT and provides a better understanding of the most innovative techniques currently available for EBRT enabled by IMRT.

Keyword

Uterine cervical neoplasms; Intensity-modulated radiation therapy; External beam radiotherapy; Definitive; Postoperative

Figure

• 

  Fig. 1. Conceptual image of 2-dimensional (2D), 3-dimensional conformal (3D), and intensity-modulated radiotherapy (IMRT) showing the differences in high dose irradiated area (red solid line) and radiation intensities (black arrows). CT, computed tomography; MRI, magnetic resonance imaging; OAR, organs at risk; PET, positron emission tomography.

• 

  Fig. 2. Adaptive intensity-modulated radiotherapy shows significant reduction of both cervical mass and bulky lymph nodes at initiation of radiotherapy (A) compared to adaptive replanning at 40 Gy (B).

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  Fig. 3. 18F-Fluorodeoxyglucose–positron emission tomography/computed tomography (A) adoptive intensity-modulated radiotherapy (B) in oligometastatic cervical cancer treated with salvage stereotactic ablative body radiotherapy.

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  Fig. 4. Compared to intensity-modulated radiotherapy (IMRT) without ovary sparing (A), the ovary sparing IMRT (B) saves ovaries (yellow outline) from high dose irradiation.

Reference

References

1. Arbyn M, Weiderpass E, Bruni L, de Sanjose S, Saraiya M, Ferlay J, et al. Estimates of incidence and mortality of cervical cancer in 2018: a worldwide analysis. Lancet Glob Health. 2020; 8:e191–203.

2. National Comprehensive Cancer Network. Cervical cancer (version 1.2023) [Internet]. Plymouth Meeting, PA: National Comprehensive Cancer Network;2023. [cited 2023 Feb 1]. Available from: https://www.nccn.org/professionals/physician_gls/pdf/cervical.pdf.

3. Aronowitz JN, Aronowitz SV, Robison RF. Classics in brachytherapy: Margaret Cleaves introduces gynecologic brachytherapy. Brachytherapy. 2007; 6:293–7.

4. Huh HD, Kim S. History of radiation therapy technology. Prog Med Phys. 2020; 31:124–34.

5. Gerstner N, Wachter S, Knocke TH, Fellner C, Wambersie A, Potter R. The benefit of Beam’s eye view based 3D treatment planning for cervical cancer. Radiother Oncol. 1999; 51:71–8.

6. Brahme A, Roos JE, Lax I. Solution of an integral equation encountered in rotation therapy. Phys Med Biol. 1982; 27:1221–9.

7. Mundt AJ, Lujan AE, Rotmensch J, Waggoner SE, Yamada SD, Fleming G, et al. Intensity-modulated whole pelvic radiotherapy in women with gynecologic malignancies. Int J Radiat Oncol Biol Phys. 2002; 52:1330–7.

8. Gill BS, Lin JF, Krivak TC, Sukumvanich P, Laskey RA, Ross MS, et al. National Cancer Data Base analysis of radiation therapy consolidation modality for cervical cancer: the impact of new technological advancements. Int J Radiat Oncol Biol Phys. 2014; 90:1083–90.

9. Portelance L, Chao KS, Grigsby PW, Bennet H, Low D. Intensity-modulated radiation therapy (IMRT) reduces small bowel, rectum, and bladder doses in patients with cervical cancer receiving pelvic and para-aortic irradiation. Int J Radiat Oncol Biol Phys. 2001; 51:261–6.

10. Du XL, Tao J, Sheng XG, Lu CH, Yu H, Wang C, et al. Intensity-modulated radiation therapy for advanced cervical cancer: a comparison of dosimetric and clinical outcomes with conventional radiotherapy. Gynecol Oncol. 2012; 125:151–7.

11. Simpson DR, Song WY, Moiseenko V, Rose BS, Yashar CM, Mundt AJ, et al. 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. 2012; 83:e81–6.

12. Verma J, Sulman EP, Jhingran A, Tucker SL, Rauch GM, Eifel PJ, et al. Dosimetric predictors of duodenal toxicity after intensity modulated radiation therapy for treatment of the para-aortic nodes in gynecologic cancer. Int J Radiat Oncol Biol Phys. 2014; 88:357–62.

13. Luo HC, Lin GS, Liao SG, Wang FM, Cheng HH, Feng J, et al. Cervical cancer treated with reduced-volume intensity-modulated radiation therapy base on Sedlis criteria (NCCN VS RTOG). Br J Radiol. 2018; 91:20170398.

14. Shih KK, Hajj C, Kollmeier M, Frey MK, Sonoda Y, Abu-Rustum NR, et al. Impact of postoperative intensity-modulated radiation therapy (IMRT) on the rate of bowel obstruction in gynecologic malignancy. Gynecol Oncol. 2016; 143:18–21.

15. Chen MF, Tseng CJ, Tseng CC, Kuo YC, Yu CY, Chen WC. Clinical outcome in posthysterectomy cervical cancer patients treated with concurrent cisplatin and intensity-modulated pelvic radiotherapy: comparison with conventional radiotherapy. Int J Radiat Oncol Biol Phys. 2007; 67:1438–44.

16. Lin AJ, Kidd E, Dehdashti F, Siegel BA, Mutic S, Thaker PH, et al. Intensity modulated radiation therapy and image-guided adapted brachytherapy for cervix cancer. Int J Radiat Oncol Biol Phys. 2019; 103:1088–97.

17. Chang Y, Yang ZY, Li GL, Li Q, Yang Q, Fan JQ, et al. Correlations between radiation dose in bone marrow and hematological toxicity in patients with cervical cancer: a comparison of 3DCRT, IMRT, and RapidARC. Int J Gynecol Cancer. 2016; 26:770–6.

18. Kidd EA, Siegel BA, Dehdashti F, Rader JS, Mutic S, Mutch DG, et al. Clinical outcomes of definitive intensity-modulated radiation therapy with fluorodeoxyglucose-positron emission tomography simulation in patients with locally advanced cervical cancer. Int J Radiat Oncol Biol Phys. 2010; 77:1085–91.

19. Gandhi AK, Sharma DN, Rath GK, Julka PK, Subramani V, Sharma S, et al. Early clinical outcomes and toxicity of intensity modulated versus conventional pelvic radiation therapy for locally advanced cervix carcinoma: a prospective randomized study. Int J Radiat Oncol Biol Phys. 2013; 87:542–8.

20. Yu C, Zhu W, Ji Y, Guo J, Pan P, Han J, et al. A comparative study of intensity-modulated radiotherapy and standard radiation field with concurrent chemotherapy for local advanced cervical cancer. Eur J Gynaecol Oncol. 2015; 36:278–82.

21. Naik A, Gurjar OP, Gupta KL, Singh K, Nag P, Bhandari V. Comparison of dosimetric parameters and acute toxicity of intensity-modulated and three-dimensional radiotherapy in patients with cervix carcinoma: a randomized prospective study. Cancer Radiother. 2016; 20:370–6.

22. Lin Y, Chen K, Lu Z, Zhao L, Tao Y, Ouyang Y, et al. Intensity-modulated radiation therapy for definitive treatment of cervical cancer: a meta-analysis. Radiat Oncol. 2018; 13:177.

23. Wang X, Shen Y, Zhao Y, Li Z, Gou H, Cao D, et al. Adjuvant intensity-modulated radiotherapy (IMRT) with concurrent paclitaxel and cisplatin in cervical cancer patients with high risk factors: a phase II trial. Eur J Surg Oncol. 2015; 41:1082–8.

24. Lou H, Ni J. A prospective study of IMRT versus 3D-CRT for post-operative cervical cancer patients. Int J Radiat Oncol Biol Phys. 2018; 102(3 Suppl):S85.

25. Schwarz JK, Wahab S, Grigsby PW. Prospective phase I-II trial of helical tomotherapy with or without chemotherapy for postoperative cervical cancer patients. Int J Radiat Oncol Biol Phys. 2011; 81:1258–63.

26. Chopra S, Dora T, Chinnachamy AN, Thomas B, Kannan S, Engineer R, et al. Predictors of grade 3 or higher late bowel toxicity in patients undergoing pelvic radiation for cervical cancer: results from a prospective study. Int J Radiat Oncol Biol Phys. 2014; 88:630–5.

27. Klopp AH, Yeung AR, Deshmukh S, Gil KM, Wenzel L, Westin SN, et al. Patient-reported toxicity during pelvic intensity-modulated radiation therapy: NRG Oncology-RTOG 1203. J Clin Oncol. 2018; 36:2538–44.

28. Chopra S, Gupta S, Kannan S, Dora T, Engineer R, Mangaj A, et al. Late toxicity after adjuvant conventional radiation versus image-guided intensity-modulated radiotherapy for cervical cancer (PARCER): a randomized controlled trial. J Clin Oncol. 2021; 39:3682–92.

29. Yeung AR, Pugh SL, Klopp AH, Gil KM, Wenzel L, Westin SN, et al. Improvement in patient-reported outcomes with intensity-modulated radiotherapy (RT) compared with standard RT: a report from the NRG Oncology RTOG 1203 Study. J Clin Oncol. 2020; 38:1685–92.

30. Supriya C, Nilesh R, Mayuri C, Sadhana K, Reena E, Tapas D, et al. Late toxicity within a Phase III clinical trial of IG-IMRT in cervix cancer (PARCER): reanalysis with time weighted adverse event reporting (MOSES). Radiother Oncol. 2022; 177:16–20.

31. Brixey CJ, Roeske JC, Lujan AE, Yamada SD, Rotmensch J, Mundt AJ. Impact of intensity-modulated radiotherapy on acute hematologic toxicity in women with gynecologic malignancies. Int J Radiat Oncol Biol Phys. 2002; 54:1388–96.

32. Mell LK, Kochanski JD, Roeske JC, Haslam JJ, Mehta N, Yamada SD, et al. Dosimetric predictors of acute hematologic toxicity in cervical cancer patients treated with concurrent cisplatin and intensity-modulated pelvic radiotherapy. Int J Radiat Oncol Biol Phys. 2006; 66:1356–65.

33. Rose BS, Aydogan B, Liang Y, Yeginer M, Hasselle MD, Dandekar V, et al. Normal tissue complication probability modeling of acute hematologic toxicity in cervical cancer patients treated with chemoradiotherapy. Int J Radiat Oncol Biol Phys. 2011; 79:800–7.

34. Rose BS, Liang Y, Lau SK, Jensen LG, Yashar CM, Hoh CK, et al. Correlation between radiation dose to ¹⁸F-FDG-PET defined active bone marrow subregions and acute hematologic toxicity in cervical cancer patients treated with chemoradiotherapy. Int J Radiat Oncol Biol Phys. 2012; 83:1185–91.

35. Noticewala SS, Li N, Williamson CW, Hoh CK, Shen H, McHale MT, et al. Longitudinal changes in active bone marrow for cervical cancer patients treated with concurrent chemoradiation therapy. Int J Radiat Oncol Biol Phys. 2017; 97:797–805.

36. Huang J, Gu F, Ji T, Zhao J, Li G. Pelvic bone marrow sparing intensity modulated radiotherapy reduces the incidence of the hematologic toxicity of patients with cervical cancer receiving concurrent chemoradiotherapy: a single-center prospective randomized controlled trial. Radiat Oncol. 2020; 15:180.

37. Klopp AH, Moughan J, Portelance L, Miller BE, Salehpour MR, Hildebrandt E, et al. Hematologic toxicity in RTOG 0418: a phase 2 study of postoperative IMRT for gynecologic cancer. Int J Radiat Oncol Biol Phys. 2013; 86:83–90.

38. Williamson CW, Sirak I, Xu R, Portelance L, Wei L, Tarnawski R, et al. Positron emission tomography-guided bone marrow-sparing radiation therapy for locoregionally advanced cervix cancer: final results from the INTERTECC phase II/III trial. Int J Radiat Oncol Biol Phys. 2022; 112:169–78.

39. Mell LK, Sirak I, Wei L, Tarnawski R, Mahantshetty U, Yashar CM, et al. Bone marrow-sparing intensity modulated radiation therapy with concurrent cisplatin for stage IB-IVA cervical cancer: an International Multicenter Phase II Clinical Trial (INTERTECC-2). Int J Radiat Oncol Biol Phys. 2017; 97:536–45.

40. Chino J, Annunziata CM, Beriwal S, Bradfield L, Erickson BA, Fields EC, et al. Radiation therapy for cervical cancer: executive summary of an ASTRO Clinical Practice Guideline. Pract Radiat Oncol. 2020; 10:220–34.

41. Chino J, Annunziata CM, Beriwal S, Bradfield L, Erickson BA, Fields EC, et al. Radiation therapy for cervical cancer: an ASTRO Clinical Practice Guideline [Internet]. Philadelphia, PA: Elsevier;2020. [cited 2023 Feb 1]. Available from: https://www.practicalradonc.org/cms/10.1016/j.prro.2020.04.002/attachment/b3495c02-3020-4944-9248-122057abef3b/mmc1.pdf.

42. Mileshkin LR, Moore KN, Barnes E, Gebski V, Narayan K, Bradshaw N, et al. Adjuvant chemotherapy following chemoradiation as primary treatment for locally advanced cervical cancer compared to chemoradiation alone: the randomized phase III OUTBACK trial (ANZGOG 0902, RTOG 1174, NRG 0274). J Clin Oncol. 2021; 39(18 Suppl):LBA3.

43. Holschneider CH, Petereit DG, Chu C, Hsu IC, Ioffe YJ, Klopp AH, et al. Brachytherapy: A critical component of primary radiation therapy for cervical cancer: from the Society of Gynecologic Oncology (SGO) and the American Brachytherapy Society (ABS). Brachytherapy. 2019; 18:123–32.

44. Potter R, Tanderup K, Schmid MP, Jurgenliemk-Schulz I, Haie-Meder C, Fokdal LU, et al. MRI-guided adaptive brachytherapy in locally advanced cervical cancer (EMBRACE-I): a multicentre prospective cohort study. Lancet Oncol. 2021; 22:538–47.

45. Potter R, Tanderup K, Kirisits C, de Leeuw A, Kirchheiner K, Nout R, et al. The EMBRACE II study: the outcome and prospect of two decades of evolution within the GEC-ESTRO GYN working group and the EMBRACE studies. Clin Transl Radiat Oncol. 2018; 9:48–60.

46. Ito K, Kito S, Shimizuguchi T, Ogawa H, Tanaka H, Nihei K, et al. Phase I dose-escalation study of stereotactic body radiotherapy boost for cervical cancer unsuitable for intracavitary brachytherapy. Int J Radiat Oncol Biol Phys. 2019; 105(1 Suppl):E323.

47. Jullian N, Benkhaled S, Bellal S, Nguyen P, Louis C, Bogdal Z, et al. 2022-RA-932-ESGO: Stereotactic body radiotherapy boost as an alternative for locally advanced cervical cancer when brachytherapy is not available, a prospective monocentric phase II. Int J Gynecol Cancer. 2022; 32(Suppl 2):A34.

48. Bacorro W, Baldivia K, Dumago M, Bojador M, Milo A, Trinidad CM, et al. Phase 1/2 trial evaluating the effectiveness and safety of dose-adapted Hypofractionated pelvic radiotherapy for Advanced Cervical cancers INeligible for ChemoTherapy (HYACINCT). Acta Oncol. 2022; 61:688–97.

49. Chino JP, Dorth JA, Suneja G, Rodrigues A, Light K, Craciunescu OI. IDEAL-GYN (Integrated Dose Escalation for Advanced Localized Gynecologic Cancers): a dose escalation trial of bowel sparing simultaneous integrated boosts for node positive cervical and vulvar cancers. Int J Radiat Oncol Biol Phys. 2017; 99(2 Suppl):E286.

50. Cho WK, Kim H, Park W, Kim SW, Kim J, Lee KK, et al. A dummy-run evaluation of postoperative hypofractionated intensity-modulated radiation therapy (POHIM-RT) trials for cervical cancer. J Radiat Res. 2021; 62:149–54.

51. Hypofractionated external-beam radiOtherapy for intact cervical cancer (HEROICC-Trial): a feasibility study [Internet]. Bethesda, MD: ClinicalTrials.gov;2020. [2023 Jun 30]. Available from: https://classic.clinicaltrials.gov/ct2/show/NCT04583254.

52. Sturdza A, Potter R, Fokdal LU, Haie-Meder C, Tan LT, Mazeron R, et al. Image guided brachytherapy in locally advanced cervical cancer: improved pelvic control and survival in RetroEMBRACE, a multicenter cohort study. Radiother Oncol. 2016; 120:428–33.

53. Arnesen MR, Rekstad BL, Stokke C, Bruheim K, Londalen AM, Hellebust TP, et al. Short-course PET based simultaneous integrated boost for locally advanced cervical cancer. Radiat Oncol. 2016; 11:39.

54. Duan J, Kim RY, Elassal S, Lin HY, Shen S. Conventional high-dose-rate brachytherapy with concomitant complementary IMRT boost: a novel approach for improving cervical tumor dose coverage. Int J Radiat Oncol Biol Phys. 2008; 71:765–71.

55. Assenholt MS, Vestergaard A, Kallehauge JF, Mohamed S, Nielsen SK, Petersen JB, et al. Proof of principle: applicatorguided stereotactic IMRT boost in combination with 3D MRI-based brachytherapy in locally advanced cervical cancer. Brachytherapy. 2014; 13:361–8.

56. Klepczyk L, Shen S, Duan J, Kim RY. Image-based intracavitary brachytherapy with concurrent applicator-guided IMRT boost for cervical cancer. Brachytherapy. 2013; 12(Suppl 1):S56–7.

57. Wang X, Li J, Wang P, Yuan K, Yin G, Wan B. Image guided radiation therapy boost in combination with high-dose-rate intracavitary brachytherapy for the treatment of cervical cancer. J Contemp Brachytherapy. 2016; 8:122–7.

58. Lee TH, Song C, Kim IA, Kim JS, Kim YB, Kim K, et al. Stereotactic ablative body radiotherapy boost for cervical cancer when brachytherapy boost is not feasible. Radiat Oncol. 2021; 16:148.

59. Albuquerque K, Tumati V, Lea J, Ahn C, Richardson D, Miller D, et al. A phase II trial of stereotactic ablative radiation therapy as a boost for locally advanced cervical cancer. Int J Radiat Oncol Biol Phys. 2020; 106:464–71.

60. Kim H, Kim YS, Joo JH, Eom KY, Park W, Kim JH, et al. Tumor boost using external beam radiation in cervical cancer patients unable to receive intracavitary brachytherapy: outcome from a multicenter retrospective study (Korean Radiation Oncology Group 1419). Int J Gynecol Cancer. 2018; 28:371–8.

61. Gultekin M, Yilmaz MT, Sari SY, Yildiz D, Ozyigit G, Yildiz F. Stereotactic body radiotherapy as a boost in cervical cancer: a single-center experience. Int J Radiat Oncol Biol Phys. 2020; 108(3 Suppl):E476.

62. Rose PG, Bundy BN, Watkins EB, Thigpen JT, Deppe G, Maiman MA, et al. Concurrent cisplatin-based radiotherapy and chemotherapy for locally advanced cervical cancer. N Engl J Med. 1999; 340:1144–53.

63. Keys HM, Bundy BN, Stehman FB, Muderspach LI, Chafe WE, Suggs CL 3rd, et al. Cisplatin, radiation, and adjuvant hysterectomy compared with radiation and adjuvant hysterectomy for bulky stage IB cervical carcinoma. N Engl J Med. 1999; 340:1154–61.

64. Mendez LC, Raziee H, Davidson M, Velker V, D’Souza D, Barnes E, et al. Should we embrace hypofractionated radiotherapy for cervical cancer? A technical note on management during the COVID-19 pandemic. Radiother Oncol. 2020; 148:270–3.

65. Komen A. A retrospective study of advanced carcinoma of the cervix treated with a hypofractionated radiation therapy protocol at the department of radiation oncology [Dissertation]. Johannesburg: University of the Witwatersrand, Johannesburg;2014.

66. Muckaden MA, Budrukkar AN, Tongaonkar HB, Dinshaw KA. Hypofractionated radiotherapy in carcinoma cervix IIIB: Tata Memorial Hospital experience. Indian J Cancer. 2002; 39:127–34.

67. Viegas CM, Araujo CM, Dantas MA, Froimtchuk M, Oliveira JA, Marchiori E, et al. Concurrent chemotherapy and hypofractionated twice-daily radiotherapy in cervical cancer patients with stage IIIB disease and bilateral parametrial involvement: a phase I-II study. Int J Radiat Oncol Biol Phys. 2004; 60:1154–9.

68. Figueredo Negron CI, Gamboa Garay O, Pabon Giron A, Esguerra Cantillo JA, Guerrero Lizcano E. A comparison of intensity-modulated radiotherapy with simultaneous integrated boost with three-dimensional conformal radiotherapy with sequential boost for locally advanced cervical cancer: a dosimetric study. Cureus. 2022; 14:e32940.

69. Ramlov A, Assenholt MS, Jensen MF, Gronborg C, Nout R, Alber M, et al. Clinical implementation of coverage probability planning for nodal boosting in locally advanced cervical cancer. Radiother Oncol. 2017; 123:158–63.

70. Boyle J, Craciunescu O, Steffey B, Cai J, Chino J. Methods, safety, and early clinical outcomes of dose escalation using simultaneous integrated and sequential boosts in patients with locally advanced gynecologic malignancies. Gynecol Oncol. 2014; 135:239–43.

71. Jethwa KR, Jang S, Gonuguntla K, Garda AE, Evans JD, Whitaker TJ, et al. Lymph node–directed simultaneous integrated boost in patients with clinically lymph node–positive cervical cancer treated with definitive chemoradiotherapy: clinical outcomes and toxicity. J Radiat Oncol. 2020; 9:103–11.

72. Jiang P, Deng X, Qu A, Jiang W, Guo F, Han Q, et al. Image guidance volume-modulated arc radiation therapy concurrently with nab-paclitaxel plus cisplatin for patients with locally advanced cervical cancer: a single-arm dose escalation trial. Int J Radiat Oncol Biol Phys. 2023; 115:1197–204.

73. Gouy S, Morice P, Narducci F, Uzan C, Gilmore J, Kolesnikov-Gauthier H, et al. Nodal-staging surgery for locally advanced cervical cancer in the era of PET. Lancet Oncol. 2012; 13:e212–20.

74. Ramirez PT, Jhingran A, Macapinlac HA, Euscher ED, Munsell MF, Coleman RL, et al. Laparoscopic extraperitoneal para-aortic lymphadenectomy in locally advanced cervical cancer: a prospective correlation of surgical findings with positron emission tomography/computed tomography findings. Cancer. 2011; 117:1928–34.

75. Vargo JA, Kim H, Choi S, Sukumvanich P, Olawaiye AB, Kelley JL, et al. Extended field intensity modulated radiation therapy with concomitant boost for lymph node-positive cervical cancer: analysis of regional control and recurrence patterns in the positron emission tomography/computed tomography era. Int J Radiat Oncol Biol Phys. 2014; 90:1091–8.

76. Bacorro W, Dumas I, Escande A, Gouy S, Bentivegna E, Morice P, et al. Dose-volume effects in pathologic lymph nodes in locally advanced cervical cancer. Gynecol Oncol. 2018; 148:461–7.

77. Kim JY, Kim JY, Kim JH, Yoon MS, Kim J, Kim YS. Curative chemoradiotherapy in patients with stage IVB cervical cancer presenting with paraortic and left supraclavicular lymph node metastases. Int J Radiat Oncol Biol Phys. 2012; 84:741–7.

78. Kim HS, Kim T, Lee ES, Kim HJ, Chung HH, Kim JW, et al. Impact of chemoradiation on prognosis in stage IVB cervical cancer with distant lymphatic metastasis. Cancer Res Treat. 2013; 45:193–201.

79. Ning MS, Ahobila V, Jhingran A, Stecklein SR, Frumovitz M, Schmeler KM, et al. Outcomes and patterns of relapse after definitive radiation therapy for oligometastatic cervical cancer. Gynecol Oncol. 2018; 148:132–8.

80. Macchia G, Nardangeli A, Laliscia C, Fodor A, Draghini L, Gentile PC, et al. Stereotactic body radiotherapy in oligometastatic cervical cancer (MITO-RT2/RAD study): a collaboration of MITO, AIRO GYN, and MaNGO groups. Int J Gynecol Cancer. 2022; 32:732–9.

81. Pirasteh A, Lovrec P, Pedrosa I. Imaging and its impact on defining the oligometastatic state. Semin Radiat Oncol. 2021; 31:186–99.

82. Olson R, Mathews L, Liu M, Schellenberg D, Mou B, Berrang T, et al. Stereotactic ablative radiotherapy for the comprehensive treatment of 1-3 Oligometastatic tumors (SABR-COMET-3): study protocol for a randomized phase III trial. BMC Cancer. 2020; 20:380.

83. Palma DA, Olson R, Harrow S, Correa RJ, Schneiders F, Haasbeek CJA, et al. Stereotactic ablative radiotherapy for the comprehensive treatment of 4-10 oligometastatic tumors (SABR-COMET-10): study protocol for a randomized phase III trial. BMC Cancer. 2019; 19:816.

84. Sapienza LG, Salcedo MP, Ning MS, Jhingran A, Klopp AH, Calsavara VF, et al. Pelvic insufficiency fractures after external beam radiation therapy for gynecologic cancers: a meta-analysis and meta-regression of 3929 patients. Int J Radiat Oncol Biol Phys. 2020; 106:475–84.

85. Ioffe YJ, Hillen TJ, Zhou G, Schwarz JK, Massad LS, Powell MA, et al. Postradiation damage to the pelvic girdle in cervical cancer patients: is intensity-modulated radiation therapy safer than conventional radiation? Int J Gynecol Cancer. 2014; 24:806–12.

86. Ramlov A, Pedersen EM, Rohl L, Worm E, Fokdal L, Lindegaard JC, et al. Risk factors for pelvic insufficiency fractures in locally advanced cervical cancer following intensity modulated radiation therapy. Int J Radiat Oncol Biol Phys. 2017; 97:1032–9.

87. Vitzthum LK, Park H, Zakeri K, Heide ES, Nalawade V, Mundt AJ, et al. Risk of pelvic fracture with radiation therapy in older patients. Int J Radiat Oncol Biol Phys. 2020; 106:485–92.

88. Levine JM, Kelvin JF, Quinn GP, Gracia CR. Infertility in reproductive-age female cancer survivors. Cancer. 2015; 121:1532–9.

89. Ghadjar P, Budach V, Kohler C, Jantke A, Marnitz S. Modern radiation therapy and potential fertility preservation strategies in patients with cervical cancer undergoing chemoradiation. Radiat Oncol. 2015; 10:50.

90. Kovtun KA, Yeo WP, Phillips CH, Viswanathan A, Baldini EH. Ovary-sparing radiation planning techniques can achieve ovarian dose reduction for soft tissue sarcoma of the buttock and thigh. Sarcoma. 2017; 2017:2796925.

91. Wallace WH, Thomson AB, Saran F, Kelsey TW. Predicting age of ovarian failure after radiation to a field that includes the ovaries. Int J Radiat Oncol Biol Phys. 2005; 62:738–44.

92. Charo LM, Eskander RN, Okamura R, Patel SP, Nikanjam M, Lanman RB, et al. Clinical implications of plasma circulating tumor DNA in gynecologic cancer patients. Mol Oncol. 2021; 15:67–79.

93. Ferrandina G, Palluzzi E, Gallotta V, Gambacorta MA, Autorino R, Turco LC, et al. Neo-adjuvant platinum-based chemotherapy followed by chemoradiation and radical surgery in locally advanced cervical cancer (Lacc) patients: a phase II study. Eur J Surg Oncol. 2018; 44:1062–8.

94. Lesnock JL, Farris C, Beriwal S, Krivak TC. Upfront treatment of locally advanced cervical cancer with intensity modulated radiation therapy compared to four-field radiation therapy: a cost-effectiveness analysis. Gynecol Oncol. 2013; 129:574–9.

95. Chen LA, Kim J, Boucher K, Terakedis B, Williams B, Nickman NA, et al. Toxicity and cost-effectiveness analysis of intensity modulated radiation therapy versus 3-dimensional conformal radiation therapy for postoperative treatment of gynecologic cancers. Gynecol Oncol. 2015; 136:521–8.

96. Chan P, Dinniwell R, Haider MA, Cho YB, Jaffray D, Lockwood G, et al. Inter- and intrafractional tumor and organ movement in patients with cervical cancer undergoing radiotherapy: a cinematic-MRI point-of-interest study. Int J Radiat Oncol Biol Phys. 2008; 70:1507–15.

97. Beadle BM, Jhingran A, Salehpour M, Sam M, Iyer RB, Eifel PJ. Cervix regression and motion during the course of external beam chemoradiation for cervical cancer. Int J Radiat Oncol Biol Phys. 2009; 73:235–41.

98. Jadon R, Pembroke CA, Hanna CL, Palaniappan N, Evans M, Cleves AE, et al. A systematic review of organ motion and image-guided strategies in external beam radiotherapy for cervical cancer. Clin Oncol (R Coll Radiol). 2014; 26:185–96.

99. Heijkoop ST, Langerak TR, Quint S, Mens JW, Zolnay AG, Heijmen BJ, et al. Quantification of intra-fraction changes during radiotherapy of cervical cancer assessed with preand post-fraction Cone Beam CT scans. Radiother Oncol. 2015; 117:536–41.

100. Chopra S, Patidar A, Dora T, Moirangthem N, Paul SN, Engineer R, et al. Vaginal displacement during course of adjuvant radiation for cervical cancer: results from a prospective IG-IMRT study. Br J Radiol. 2014; 87:20140428.

101. Adli M, Mayr NA, Kaiser HS, Skwarchuk MW, Meeks SL, Mardirossian G, et al. Does prone positioning reduce small bowel dose in pelvic radiation with intensity-modulated radiotherapy for gynecologic cancer? Int J Radiat Oncol Biol Phys. 2003; 57:230–8.

102. Chen VE, Gillespie EF, Manger RP, Skerritt LA, Tran JH, Proudfoot JA, et al. The impact of daily bladder filling on small bowel dose for intensity modulated radiation therapy for cervical cancer. Med Dosim. 2019; 44:102–6.

103. Rios I, Vasquez I, Cuervo E, Garzon O, Burbano J. Problems and solutions in IGRT for cervical cancer. Rep Pract Oncol Radiother. 2018; 23:517–27.

104. Mens JM. Tumor tracking in cervical cancer patients based on implanted polymeric markers. Int J Radiat Oncol Biol Phys. 2011; 81(2 Suppl):S460.

105. Heijkoop ST, Langerak TR, Quint S, Bondar L, Mens JW, Heijmen BJ, et al. Clinical implementation of an online adaptive plan-of-the-day protocol for nonrigid motion management in locally advanced cervical cancer IMRT. Int J Radiat Oncol Biol Phys. 2014; 90:673–9.

106. Shelley CE, Barraclough LH, Nelder CL, Otter SJ, Stewart AJ. Adaptive radiotherapy in the management of cervical cancer: review of strategies and clinical implementation. Clin Oncol (R Coll Radiol). 2021; 33:579–90.

107. Ahmad R, Hoogeman MS, Bondar M, Dhawtal V, Quint S, De Pree I, et al. Increasing treatment accuracy for cervical cancer patients using correlations between bladder-filling change and cervix-uterus displacements: proof of principle. Radiother Oncol. 2011; 98:340–6.

108. Stewart J, Lim K, Kelly V, Xie J, Brock KK, Moseley J, et al. Automated weekly replanning for intensity-modulated radiotherapy of cervix cancer. Int J Radiat Oncol Biol Phys. 2010; 78:350–8.

109. Bondar ML, Hoogeman MS, Mens JW, Quint S, Ahmad R, Dhawtal G, et al. Individualized nonadaptive and online-adaptive intensity-modulated radiotherapy treatment strategies for cervical cancer patients based on pretreatment acquired variable bladder filling computed tomography scans. Int J Radiat Oncol Biol Phys. 2012; 83:1617–23.

110. Novakova E, Heijkoop ST, Quint S, Zolnay AG, Mens JW, Godart J, et al. What is the optimal number of library plans in ART for locally advanced cervical cancer? Radiother Oncol. 2017; 125:470–7.

111. Ahmad R, Bondar L, Voet P, Mens JW, Quint S, Dhawtal G, et al. A margin-of-the-day online adaptive intensity-modulated radiotherapy strategy for cervical cancer provides superior treatment accuracy compared to clinically recommended margins: a dosimetric evaluation. Acta Oncol. 2013; 52:1430–6.

112. Buschmann M, Majercakova K, Sturdza A, Smet S, Najjari D, Daniel M, et al. Image guided adaptive external beam radiation therapy for cervix cancer: evaluation of a clinically implemented plan-of-the-day technique. Z Med Phys. 2018; 28:184–95.

113. Hunt A, Hansen VN, Oelfke U, Nill S, Hafeez S. Adaptive radiotherapy enabled by MRI guidance. Clin Oncol (R Coll Radiol). 2018; 30:711–9.

114. Khan AA, Vijay A, Wani SQ, Haq MM. Dosimetric analysis of intracavitary brachytherapy applicators: a practical study. Radiat Oncol J. 2022; 40:180–91.

115. A trial comparing intensity modulated radiation therapy (IMRT) with conventional radiation therapy in stage IIB carcinoma cervix [Internet]. Bethesda, MD: ClinicalTrials.gov;2019 [cited 2023 Jun 30]. Available from: https://classic.clinicaltrials.gov/ct2/show/NCT00193804.

116. Leath CA, Deng W, Mell LK, Richardson DL, Walker JL, Holman LL, et al. Incorporation of triapine (T) with cisplatin chemoradiation (CRT) for locally advanced cervical and vaginal cancer: results from NRG-GY006, a phase III randomized trial. J Clin Oncol. 2023; 41(16 Suppl):5502.

117. Monk B, Toita T, Wu X, Limon JC, Zhou Q, Tarnawski R, et al. O001/#504 Durvalumab, in combination with and following chemoradiotherapy, in locally advanced cervical cancer: results from the phase 3 international, randomized, doubleblind, placebo-controlled calla trial. Int J Gynecol Cancer. 2022; 32:A2–3.

118. Mayadev J, Zamarin D, Deng W, Lankes H, O’Cearbhaill R, Aghajanian CA, et al. Anti-PD-L1 (atezolizumab) as an immune primer and concurrently with extended-field chemoradiotherapy for node-positive locally advanced cervical cancer. Int J Gynecol Cancer. 2020; 30:701–4.

119. Frumovitz M, Querleu D, Gil-Moreno A, Morice P, Jhingran A, Munsell MF, et al. Lymphadenectomy in locally advanced cervical cancer study (LiLACS): phase III clinical trial comparing surgical with radiologic staging in patients with stages IB2-IVA cervical cancer. J Minim Invasive Gynecol. 2014; 21:3–8.

120. Marnitz S, Tsunoda AT, Martus P, Vieira M, Affonso Junior RJ, Nunes J, et al. Surgical versus clinical staging prior to primary chemoradiation in patients with cervical cancer FIGO stages IIB-IVA: oncologic results of a prospective randomized international multicenter (Uterus-11) intergroup study. Int J Gynecol Cancer. 2020; 30:1855–61.