Discussion

The elective WPRT including pelvic lymph node irradiation is regarded as a standard treatment regimen for intermediate or high-risk rectal and gynecological cancers. Although the benefits of WPRT has been controversial for the locally advanced prostate cancer patients (43), its role and gain have been reexamined with consideration of interaction between RT and adjuvant androgen deprivation therapy (ADT) according to the duration and timing of the hormone therapy and the field sizes of RT. Long-term outcomes were suggested in terms of improved free from progression and biochemical failure in ADT plus RT. In addition, recent results as per a new protocol were reported treatment gains in short-term ADT plus pelvic lymph node irradiation using IMRT (44, 45).

WPRT can bring out clinical merits with other treatment modalities, or clever radiation dose delivery techniques such as simultaneously integrated boost using a different dose scheme can be useful (46-48). However, acute and late radiation-induced complications have been significant concerns due to the use of a large size of the field (16-18). When large and irregular irradiated field is required to cover target volumes and regional lymph nodes, the radiation exposure of normal organ is inevitable. To achieve the target dose coverage with normal organ sparing in large and irregular anatomical geometries, VMAT is one of the useful dose delivery methods (21-23). Optimal fluence, which is created by MLC segments at individual numerous beam angles going through the arc trajectories in VMAT, can effectively reduce the radiation doses of normal organs.

The present study was conducted to overcome the limitation of MLC motion in wide field VMAT plan. In order to compensate for MLC leakage and non-blocking phenomena, HF-VMAT and MVMAT plans were designed and compared with conventional FF-VMAT. Anal cancer and vaginal cancer patients were enrolled due the benefit of HF-VMAT plan was expected to be more pronounced in WPRT patients with inguinal field.

Studies about HF-VMAT plan were already published, however they were very rare. Lai et al. reported that HF-VMAT plan was more effective for normal organ saving and dose distribution than FF-VMAT plan in breast cancer irradiation. HF-VMAT plan showed

improved dosimetry in ipsilateral lung and heart than FF-VMAT plan (27). There is also a study that the HF-VMAT plan showed an improved dose distribution in radiotherapy of scalp and lower neck node (49, 50). Previous studies have shown that RT field is large and irregular, like breast cancer or head and neck cancer. In present study, we analyzed the effect of VMAT plan in patients undergoing WPRT with inguinal node, and the HF-VMAT plan showed some dosimetric benefit compared to FF-HF-VMAT plan. We also compared MFF-VMAT plan with HF-VMAT and FF-VMAT plan in present study. The MFF-VMAT plan is a plan that X field size is fixed at the maximum equipment size (14 cm), in order to optimize the MLC modulation. Most of the parameters were not as good as HF-VMAT plan, but showed better results than FF-VMAT plan. This means that the adjustment of irradiation field size is possible to improve the dose distribution by the increasing of MLC modulation.

The small bowel requires careful treatment planning, because it is an organ that can cause fatal side effects, such as perforation, even at low radiation dose (51, 52). Especially, for gynecologic malignancies, the possibility of side effects may be increased because the small bowel can come down to the empty space after hysterectomy. Even in older patients, there is a high possibility that the small bowel may become deformed due to the elasticity of the abdominal wall or muscle weakness. Ahamad et al. analyzed the effect of IMRT in cervical cancer patient undergoing postoperative radiotherapy, and significantly less small bowel was irradiated by IMRT than conformal radiotherapy for doses greater than 25 Gy (53). For this reason, we focused on small bowel and compared various dosimetric factors according to various plans. As a result, we were able to confirm the advantages of HF-VMAT plan in several parameters. The bladder and colon also showed improved dosimetry and was statistically significant. The dosimetry of rectum did not show any difference. It is probably due to the inclusion of anal cancer patients in enrolled patients. Rectum is included in PTV of anal cancer. Except anal cancer patients, the analysis showed improved dosimetry in HF-VMAT plan.

HF-VMAT plan is effective in reducing the radiation dose of normal organ. However it is possible to impair the dose homogeneity of PTV. We evaluated this through CN and HI, and there was no difference between the three plans. On the contrary, CN showed

improved PTV homogeneity in HF-VMAT plan than FF-VMAT plan and it was statistically significant. Finally, HF-VMAT plan successfully reduced the normal organ dose without compromising the PTV dose homogeneity compared to FF-VMAT plan. We anticipated that the optimization of MLC movement enabled it, and MI was analyzed to access it. The concept of MI has already been applied to evaluate mechanical uncertainty in several previous studies on the VMAT plan (54, 55). In present study, we tried to analyze the values of MI using MCS model, which reflects MLC motion and PTV shape.

HF-VMAT plan showed improved MI than FF-VMAT plan, and MFF-VMAT plan also showed about 20% improved MI value than FF-VMAT plan. This implies that the optimization of MLC modulation affects the dose distribution of VMAT plan.

This study was conducted to improve the dose distribution when the irradiated field is large. However, not only the size of the irradiated field but also the shape is important factors. We conducted a preliminary study on WPRT without inguinal lymph node chain and obtained unsatisfactory results. In the WPRT without the inguinal lymph node, there was no effect of HF-VMAT plan. Like the WPRT containing the inguinal lymph node chain, the more irregular the irradiated field, the more effective HF-VMAT plan is.

Although there are rare studies about HF-VMAT plan, the studies were conducted on head and neck cancer and breast cancer with supraclavicular lymph node (27, 28). This implies that the shape of the irradiated field is an important factor.

HF-VMAT plan showed the improved dosimetric impact of normal organ, and the homogeneity of target volume was comparable with FF-VMAT plan. HF-VMAT plan can be more useful option than conventional FF-VMAT plan in patient with large and irregular irradiation field, such as WPRT with inguinal lymph node chains. The shape of irradiated field as well as size is considered as an important factor, therefore the further study about suitable cases for HF-VMAT plan are required.

References

1. Eifel PJ, Winter K, Morris M, Levenback C, Grigsby PW, Cooper J, et al. Pelvic irradiation with concurrent chemotherapy versus pelvic and para-aortic irradiation for high-risk cervical cancer: an update of radiation therapy oncology group trial (RTOG) 90-01. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2004;22(5):872-80.

2. Castaneda SA, Romak LB. Radiotherapy for Anal Cancer: Intensity-Modulated Radiotherapy and Future Directions. Surgical oncology clinics of North America. 2017;26(3):467-75.

3. Chang JH, Jang WI, Kim YB, Kim JH, Kim YS, Kim YS, et al. Definitive treatment of primary vaginal cancer with radiotherapy: multi-institutional retrospective study of the Korean Radiation Oncology Group (KROG 12-09). Journal of gynecologic oncology. 2016;27(2):e17.

4. Nicholas S, Chen L, Choflet A, Fader A, Guss Z, Hazell S, et al. Pelvic Radiation and Normal Tissue Toxicity. Semin Radiat Oncol. 2017;27(4):358-69.

5. Ray A, Sarkar B. Small bowel toxicity in pelvic radiotherapy for postoperative gynecological cancer: comparison between conformal radiotherapy and intensity modulated radiotherapy. Asia Pac J Clin Oncol. 2013;9(3):280-4.

6. Cheung CP, Chiu HS, Chung CH. Small bowel perforation after radiotherapy for cervical carcinoma. Hong Kong Med J. 2003;9(6):461-3.

7. Matsuura S, Royba E, Akutsu SN, Yanagihara H, Ochiai H, Kudo Y, et al. Analysis of individual differences in radiosensitivity using genome editing. Annals of the ICRP. 2016;45(1 Suppl):290-6.

8. Schuster B, Ellmann A, Mayo T, Auer J, Haas M, Hecht M, et al. Rate of individuals with clearly increased radiosensitivity rise with age both in healthy individuals and in cancer patients.

BMC geriatrics. 2018;18(1):105.

9. Hong TS, Moughan J, Garofalo MC, Bendell J, Berger AC, Oldenburg NBE, et al. NRG Oncology Radiation Therapy Oncology Group 0822: A Phase 2 Study of Preoperative Chemoradiation Therapy Using Intensity Modulated Radiation Therapy in Combination With Capecitabine and Oxaliplatin for Patients With Locally Advanced Rectal Cancer. Int J Radiat Oncol.

2015;93(1):29-36.

10. Jhingran A, Winter K, Portelance L, Miller B, Salehpour M, Gaur R, et al. A Phase II

Endometrial Carcinoma: Radiation Therapy Oncology Group Trial 0418. Int J Radiat Oncol.

2012;84(1):E23-E8.

11. Mabuchi S, Isohashi F, Yokoi T, Takemura M, Yoshino K, Shiki Y, et al. A phase II study of postoperative concurrent carboplatin and paclitaxel combined with intensity-modulated pelvic radiotherapy followed by consolidation chemotherapy in surgically treated cervical cancer patients with positive pelvic lymph nodes. Gynecol Oncol. 2016;141(2):240-6.

12. Holliday EB, Lester SC, Harmsen WS, Eng C, Haddock MG, Krishnan S, et al. Extended-Field Chemoradiation Therapy for Definitive Treatment of Anal Canal Squamous Cell Carcinoma Involving the Para-Aortic Lymph Nodes. Int J Radiat Oncol. 2018;102(1):102-8.

13. Lestrade L, Zilli T, Kountouri M, Jumeau R, Matzinger O, Bourhis J, et al. Early-stage Favourable Anal Cancer: A Retrospective Analysis of Clinical Outcomes of a Moderately Low Dose Elective Nodal Intensity-modulated Radiotherapy Schedule. Clin Oncol-Uk. 2017;29(7):E105-E9.

14. Magli A, Moretti E, Tullio A, Giannarini G, Tonetto F, Urpis M, et al. Hypofractionated simultaneous integrated boost (IMRT-SIB) with pelvic nodal irradiation and concurrent androgen deprivation therapy for high-risk prostate cancer: results of a prospective phase II trial. Prostate Cancer P D. 2018;21(2):269-76.

15. Lin YW, Lin LC, Lin KL. The early result of whole pelvic radiotherapy and stereotactic body radiotherapy boost for high-risk localized prostate cancer. Frontiers in oncology. 2014;4:278.

16. Roach M, 3rd, DeSilvio M, Valicenti R, Grignon D, Asbell SO, Lawton C, et al. Whole-pelvis, "mini-Whole-pelvis," or prostate-only external beam radiotherapy after neoadjuvant and concurrent hormonal therapy in patients treated in the Radiation Therapy Oncology Group 9413 trial.

International journal of radiation oncology, biology, physics. 2006;66(3):647-53.

17. Roeske JC, Bonta D, Mell LK, Lujan AE, Mundt AJ. A dosimetric analysis of acute gastrointestinal toxicity in women receiving intensity-modulated whole-pelvic radiation therapy.

Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology. 2003;69(2):201-7.

18. Yang TJ, Oh JH, Son CH, Apte A, Deasy JO, Wu A, et al. Predictors of acute gastrointestinal toxicity during pelvic chemoradiotherapy in patients with rectal cancer.

Gastrointestinal cancer research : GCR. 2013;6(5-6):129-36.

19. Kang HJ, Kay CS, Son SH, Kim M, Jo IY, Lee SJ, et al. Hypofractionated intensity-modulated radiotherapy in patients with localized prostate cancer: a preliminary study. Radiat Oncol J. 2016;34(1):45-51.

20. Yang R, Wang J, Xu F, Li H, Zhang X. Feasibility study of volumetric modulated arc therapy with constant dose rate for endometrial cancer. Med Dosim. 2013;38(3):351-5.

21. Ishii K, Ogino R, Hosokawa Y, Fujioka C, Okada W, Nakahara R, et al. Whole-pelvic volumetric-modulated arc therapy for high-risk prostate cancer: treatment planning and acute toxicity. Journal of radiation research. 2015;56(1):141-50.

22. Wong E, D'Souza DP, Chen JZ, Lock M, Rodrigues G, Coad T, et al. Intensity-modulated arc therapy for treatment of high-risk endometrial malignancies. International journal of radiation oncology, biology, physics. 2005;61(3):830-41.

23. Ishii K, Ogino R, Hosokawa Y, Fujioka C, Okada W, Nakahara R, et al. Comparison of dosimetric parameters and acute toxicity after whole-pelvic vs prostate-only volumetric-modulated arc therapy with daily image guidance for prostate cancer. The British journal of radiology.

2016;89(1062):20150930.

24. Huang B, Fang Z, Huang Y, Lin P, Chen Z. A dosimetric analysis of volumetric-modulated arc radiotherapy with jaw width restriction vs 7 field intensity-modulated radiotherapy for definitive treatment of cervical cancer. The British journal of radiology. 2014;87(1039):20140183.

25. Rossi M, Boman E, Skytta T, Kapanen M. A novel arc geometry setting for pelvic radiotherapy with extensive nodal involvement. Journal of applied clinical medical physics.

2016;17(4):73-85.

26. Zhang WZ, Lu JY, Chen JZ, Zhai TT, Huang BT, Li DR, et al. A Dosimetric Study of Using Fixed-Jaw Volumetric Modulated Arc Therapy for the Treatment of Nasopharyngeal Carcinoma with Cervical Lymph Node Metastasis. Plos One. 2016;11(5).

27. Lai Y, Chen Y, Wu S, Shi L, Fu L, Ha H, et al. Modified Volumetric Modulated Arc Therapy in Left Sided Breast Cancer After Radical Mastectomy With Flattening Filter Free Versus Flattened Beams. Medicine. 2016;95(14):e3295.

28. Casey KE, Wong PF, Tung SS. Effect of interfractional shoulder motion on low neck nodal targets for patients treated using volumetric-modulated arc therapy (VMAT). Journal of applied clinical medical physics. 2015;16(4):40-51.

29. Benson AB, 3rd, Venook AP, Al-Hawary MM, Cederquist L, Chen YJ, Ciombor KK, et al.

Anal Carcinoma, Version 2.2018, NCCN Clinical Practice Guidelines in Oncology. Journal of the National Comprehensive Cancer Network : JNCCN. 2018;16(7):852-71.

30. Koh WJ, Abu-Rustum NR, Bean S, Bradley K, Campos SM, Cho KR, et al. Cervical Cancer, Version 3.2019, NCCN Clinical Practice Guidelines in Oncology. Journal of the National Comprehensive Cancer Network : JNCCN. 2019;17(1):64-84.

31. Small W, Mell LK, Anderson P, Creutzberg C, De Los Santos J, Gaffney D, et al.

Consensus guidelines for delineation of clinical target volume for intensity-modulated pelvic

2008;71(2):428-34.

32. Gay HA, Barthold HJ, O'Meara E, Bosch WR, El Naqa I, Al-Lozi R, et al. Pelvic normal tissue contouring guidelines for radiation therapy: a Radiation Therapy Oncology Group consensus panel atlas. International journal of radiation oncology, biology, physics. 2012;83(3):e353-62.

33. Myerson RJ, Garofalo MC, El Naqa I, Abrams RA, Apte A, Bosch WR, et al. Elective clinical target volumes for conformal therapy in anorectal cancer: a radiation therapy oncology group consensus panel contouring atlas. International journal of radiation oncology, biology, physics.

2009;74(3):824-30.

34. McNiven AL, Sharpe MB, Purdie TG. A new metric for assessing IMRT modulation complexity and plan deliverability. Medical physics. 2010;37(2):505-15.

35. Moiseenko V, Song WY, Mell LK, Bhandare N. A comparison of dose-response characteristics of four NTCP models using outcomes of radiation-induced optic neuropathy and retinopathy. Radiat Oncol. 2011;6.

36. Dasu A, Toma-Dasu I, Olofsson J, Karlsson M. The use of risk estimation models for the induction of secondary cancers following radiotherapy. Acta Oncol. 2005;44(4):339-47.

37. Fowler JF. The radiobiology of prostate cancer including new aspects of fractionatedradiotherapy. Acta Oncol. 2005;44(3):265-76.

38. Brenner DJ. Fractionation and late rectal toxicity. Int J Radiat Oncol. 2004;60(4):1013-5.

39. Michalski JM, Gay H, Jackson A, Tucker SL, Deasy JO. Radiation Dose-Volume Effects in Radiation-Induced Rectal Injury. Int J Radiat Oncol. 2010;76(3):S123-S9.

40. Luxton G, Keall PJ, King CR. A new formula for normal tissue complication probability (NTCP) as a function of equivalent uniform dose (EUD). Phys Med Biol. 2008;53(1):23-36.

41. Feuvret L, Noel G, Mazeron JJ, Bey P. Conformity index: a review. International journal of radiation oncology, biology, physics. 2006;64(2):333-42.

42. Yoon M, Park SY, Shin D, Lee SB, Pyo HR, Kim DY, et al. A new homogeneity index based on statistical analysis of the dose-volume histogram. Journal of applied clinical medical physics. 2007;8(2):9-17.

43. Dirix P, Haustermans K, Junius S, Withers R, Oyen R, Van Poppel H. The role of whole pelvic radiotherapy in locally advanced prostate cancer. Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology. 2006;79(1):1-14.

44. Lawton CA, DeSilvio M, Roach M, 3rd, Uhl V, Kirsch R, Seider M, et al. An update of the phase III trial comparing whole pelvic to prostate only radiotherapy and neoadjuvant to adjuvant total androgen suppression: updated analysis of RTOG 94-13, with emphasis on unexpected hormone/radiation interactions. International journal of radiation oncology, biology, physics.

2007;69(3):646-55.

45. Roach M, Moughan J, Lawton CAF, Dicker AP, Zeitzer KL, Gore EM, et al. Sequence of hormonal therapy and radiotherapy field size in unfavourable, localised prostate cancer (NRG/RTOG 9413): long-term results of a randomised, phase 3 trial. The Lancet Oncology.

2018;19(11):1504-15.

46. Mabuchi S, Isohashi F, Yokoi T, Takemura M, Yoshino K, Shiki Y, et al. A phase II study of postoperative concurrent carboplatin and paclitaxel combined with intensity-modulated pelvic radiotherapy followed by consolidation chemotherapy in surgically treated cervical cancer patients with positive pelvic lymph nodes. Gynecologic oncology. 2016;141(2):240-6.

47. Holliday EB, Lester SC, Harmsen WS, Eng C, Haddock MG, Krishnan S, et al. Extended-Field Chemoradiation Therapy for Definitive Treatment of Anal Canal Squamous Cell Carcinoma Involving the Para-Aortic Lymph Nodes. International journal of radiation oncology, biology, physics. 2018;102(1):102-8.

48. Lestrade L, Zilli T, Kountouri M, Jumeau R, Matzinger O, Bourhis J, et al. Early-stage Favourable Anal Cancer: A Retrospective Analysis of Clinical Outcomes of a Moderately Low Dose Elective Nodal Intensity-modulated Radiotherapy Schedule. Clinical oncology. 2017;29(7):e105-e9.

49. Lai Y, Shi L, Lin Q, Fu L, Ha H. Planning study of flattening filter free beams for volumetric modulated arc therapy in squamous cell carcinoma of the scalp. Plos One.

2014;9(12):e114953.

50. Casey KE, Wong PF, Tung SS. Effect of interfractional shoulder motion on low neck nodal targets for patients treated using volumetric-modulated arc therapy (VMAT). Journal of applied clinical medical physics. 2015;16(4):40-51.

51. Yamashita H, Nakagawa K, Tago M, Igaki H, Shiraishi K, Nakamura N, et al. Small bowel perforation without tumor recurrence after radiotherapy for cervical carcinoma: report of seven cases. J Obstet Gynaecol Res. 2006;32(2):235-42.

52. Pietrzak L, Sopylo R, Bujko K. Acute small bowel perforation following preoperative radiotherapy and abdominoperineal resection: a case report. Acta Oncol. 2006;45(3):344-5.

53. Ahamad A, D'Souza W, Salehpour M, Iyer R, Tucker SL, Jhingran A, et al. Intensity-modulated radiation therapy after hysterectomy: comparison with conventional treatment and sensitivity of the normal-tissue-sparing effect to margin size. International journal of radiation oncology, biology, physics. 2005;62(4):1117-24.

54. Park JM, Park SY, Kim H. Modulation index for VMAT considering both mechanical and dose calculation uncertainties. Phys Med Biol. 2015;60(18):7101-25.

evaluate the degree of modulation for volumetric modulated arc therapy. Medical physics.

2014;41(11).

-국문요약- VMAT (HF-VMAT), full-field VMAT (FF-VMAT), modified full-field VMAT (MFF-VMAT) 기법을 비교 분석 하였다. 서혜부 임파선을 치료 범위 로 포함하는 자궁경부암, 항문암, 질암 환자들을 대상으로 하였고 처방선량은 50Gy (25 x 2Gy) 이었다. 치료 기법에 따라 직장, 방광, 소장과 같은 정상 장 기의 선량 분포를 획득하였다. 또한 Normal tissue complication probability (NTCP), conformity number (CN), homogeneity index (HI), modulation index (MI)를 계산하여 기법에 따른 차이를 분석하였다.

결과: HF-VMAT 기법의 평균 소장 선량은 MFF-VMAT와 FF-VMAT 기법 에 비해 낮았고 (29.57 vs 30.68 vs 29.57, p<0.05), V15부터 V45까지의 값 역시 유의하게 감소되었다. HF-VMAT 기법의 방광 평균 선량은 MFF-VMAT와 FF-VMAT 기법에 비해 낮았고 (33.64 vs 37.21 vs 38.63,

p<0.05), V35부터 V45까지의 값도 유의하게 감소되었다. 대장과 직장에서도 HF-VMAT 기법에 따른 향상된 DVH를 관찰할 수 있었다. 기법에 따른 NTCP값을 분석한 결과, HF-VMAT 기법의 소장 독성은 8 – 9%로 12 – 13%

의 FF-VMAT 기법에 비해 유의하게 향상된 값을 보여주었다. MLC 움직임의 불확실성을 반영하는 MI을 비교한 결과, HF-VMAT과 MFF-VMAT 기법에 서 FF-VMAT 기법에 비해 향상된 값을 보여주었다 (306.31 vs 307.88 vs 366.95, p<0.05).

결론: 넓고 불규칙한 모양의 방사선치료 타겟에서 HF-VMAT 기법은

결론: 넓고 불규칙한 모양의 방사선치료 타겟에서 HF-VMAT 기법은