应用放射生物学模型比较早期鼻咽癌不同放疗剂量分割方案
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摘要
目的:通过放射生物学模型分析和剂量学比较为早期鼻咽癌放疗剂量分割方案的优化选择提供参考。方法:选取24个病例,采用3种剂量分割方案(总剂量均为70 Gy,分割数分别为30、33、35 Fr)分别制定3组容积弧形调强计划。采用考虑肿瘤克隆源性细胞再增殖与乏氧的Webb-Nahum模型预测肿瘤控制概率(TCP),使用Lyman-Kutcher-Burman模型预测危及器官正常组织并发症发生概率(NTCP)。然后结合TCP和NTCP计算无并发症肿瘤控制概率(UTCP)。比较并分析3种剂量分割方案的UTCP、TCP、NTCP值以及剂量学参数。结果:3种方案中,70 Gy/30 Fr方案的UTCP值(80.6%)最高,而70 Gy/35 Fr方案的UTCP值(78.0%)最低(P<0.05)。70 Gy/30 Fr方案能提高TCP值,最大幅度为7.3%(P<0.05),同时保持或略微增加了NTCP值,最大幅度仅为2.2%(P<0.05)。3种剂量分割方案的剂量学参数均无明显差异(P>0.05)。结论:通过放射生物学模型分析,早期鼻咽癌70 Gy/30 Fr方案的治疗增益比最大,能显著提高肿瘤局控率同时不显著增加正常组织毒性,本结论还需临床试验进一步确认。
Objective To provide a theoretical reference for selecting a preferable fractionation regimen(FR) for radiotherapy of early-stage nasopharyngeal carcinoma by comparing radiobiological and dosimetric responses of tumor to different FR. Methods A total of 24 patients were enrolled in this study, and 3 volumetric modulated arc therapy(VMAT) plans with different FR(70 Gy/30 Fr, 70 Gy/33 Fr and 70 Gy/35 Fr) were designed for each patient. Webb-Nahum radiobiological model considering the repopulation and hypoxia of tumor clonogenic cells was used to predict tumor control probability(TCP), and Lyman-KutcherBurman model was utilized to estimate the normal tissue complication probability(NTCP) for organs-at-risk. Subsequently, TCP was combined with NTCP to calculate uncomplicated TCP(UTCP). The UTCP, TCP, NTCP and dosimetric parameters of VMAT plans with different FR were compared and analyzed. Results Among 3 different VMAT plans, the VMAT plan with 70 Gy/30 Fr had the highest UTCP(80.6%), while the VMAT plan with 70 Gy/35 Fr had the lowest UTCP(78.0%)(P<0.05). The VMAT plan with 70 Gy/30 Fr increased TCP by up to 7.3%, and meanwhile maintained or slightly increased NTCP, only with a maximum increase of 2.2%(P<0.05). No significant dosimetric difference was found among 3 different FR. Conclusion Based on the radiobiological model analysis, the VMAT with 70 Gy/30 Fr for early-stage nasopharyngeal carcinoma provides the maximal therapeutic gain and improves improving local control rate of tumor, without significantly increasing the toxicity of normal tissues.However, more clinical trials are needed to validate the conclusion.
Objective To provide a theoretical reference for selecting a preferable fractionation regimen(FR) for radiotherapy of early-stage nasopharyngeal carcinoma by comparing radiobiological and dosimetric responses of tumor to different FR. Methods A total of 24 patients were enrolled in this study, and 3 volumetric modulated arc therapy(VMAT) plans with different FR(70 Gy/30 Fr, 70 Gy/33 Fr and 70 Gy/35 Fr) were designed for each patient. Webb-Nahum radiobiological model considering the repopulation and hypoxia of tumor clonogenic cells was used to predict tumor control probability(TCP), and Lyman-KutcherBurman model was utilized to estimate the normal tissue complication probability(NTCP) for organs-at-risk. Subsequently, TCP was combined with NTCP to calculate uncomplicated TCP(UTCP). The UTCP, TCP, NTCP and dosimetric parameters of VMAT plans with different FR were compared and analyzed. Results Among 3 different VMAT plans, the VMAT plan with 70 Gy/30 Fr had the highest UTCP(80.6%), while the VMAT plan with 70 Gy/35 Fr had the lowest UTCP(78.0%)(P<0.05). The VMAT plan with 70 Gy/30 Fr increased TCP by up to 7.3%, and meanwhile maintained or slightly increased NTCP, only with a maximum increase of 2.2%(P<0.05). No significant dosimetric difference was found among 3 different FR. Conclusion Based on the radiobiological model analysis, the VMAT with 70 Gy/30 Fr for early-stage nasopharyngeal carcinoma provides the maximal therapeutic gain and improves improving local control rate of tumor, without significantly increasing the toxicity of normal tissues.However, more clinical trials are needed to validate the conclusion.
引文
[1]LEE F K,YIP C W,CHEUNG F C,et al.Dosimetric difference amongst 3 techniques:TomoTherapy,sliding-window intensitymodulated radiotherapy(IMRT),and RapidArc radiotherapy in the treatment of late-stage nasopharyngeal carcinoma(NPC)[J].Med Dosim,2014,39(1):4-49.
[2]XUE W Q,QIN H D,RUAN H L,et al.Quantitative association of tobacco smoking with the risk of nasopharyngeal carcinoma:a comprehensive meta-analysis of studies conducted between 1979 and2011[J].Am J Epidemiol,2013,178(3):325-338.
[3]CO J,MEJIAM B,DIZON J M.Evidence on effectiveness of intensitymodulated radiotherapy versus 2-dimensional radiotherapy in the treatment of nasopharyngeal carcinoma:meta-analysis and a systematic review of the literature[J].Head Neck,2016,38(Suppl 1):2130-2142.
[4]CAPONIGRO F,LONGO F,IONNA F,et al.Treatment approaches to nasopharyngeal carcinoma:a review[J].Anticancer Drugs,2010,21(5):471-477.
[5]YAN H,CAO X,WANG J.Application of intensity-modulated radiation therapy in the treatment of nasopharyngeal carcinoma[J].Oncol Lett,2017,14(6):7773-7776.
[6]XU T,SHEN C,ZHU G,et al.Omission of chemotherapy in early stage nasopharyngeal carcinoma treated with IMRT:a paired cohort study[J].Medicine(Baltimore),2015,94(39):e1457.
[7]SONG C H,WU H G,HEO D S,et al.Treatment outcomes for radiotherapy alone are comparable with neoadjuvant chemotherapy followed by radiotherapy in early-stage nasopharyngeal carcinoma[J].Laryngoscope,2008,118(4):663-670.
[8]AU K H,NGAN R K,NG A W,et al.Treatment outcomes of nasopharyngeal carcinoma in modern era after intensity modulated radiotherapy(IMRT)in Hong Kong:a report of 3 328 patients(HKNPCSG 1 301 study)[J].Oral Oncol,2018,77:16-21.
[9]KAN M W,WONG W,LEUNG L H,et al.A comprehensive dosimetric evaluation of using RapidArc volumetric-modulated arc therapy for the treatment of early-stage nasopharyngeal carcinoma[J].J Appl Clin Med Phys,2012,13(6):3887.
[10]XIAO G,CAO Y,QIU X,et al.Influence of gender and age on the survival of patients with nasopharyngeal carcinoma[J].BMC Cancer,2013,13:226.
[11]王丽,杨智宁,彭逊,等.不同分割剂量治疗鼻咽癌的效果比较[J].广东医学,2015,36(8):1216-1219.WANG L,YANG Z N,PENG X,et al.Comparison of treatment effects of different fractionated dose on nasopharyngeal carcinoma[J].Guangdong Medical Journal,2015,36(8):1216-1219.
[12]SPIOTTO M T,KOSHY M.Impact of fraction size on locally advanced oropharyngeal and nasopharyngeal cancers treated with chemoradiation[J].Oral Oncol,2017,68:27-35.
[13]LE Q T,FU K K,KROLL S,et al.Influence of fraction size,total dose,and overall time on local control of T1-T2 glottic carcinoma[J].Int J Radiat Oncol Biol Phys,1997,39(1):115-126.
[14]BOUGHALIA A,MARCIE S,FELLAH M,et al.Assessment and quantification of patient set-up errors in nasopharyngeal cancer patients and their biological and dosimetric impact in terms of generalized equivalent uniform dose(gEUD),tumour control probability(TCP)and normal tissue complication probability(NTCP)[J].Br J Radiol,2015,88(1050):20140839.
[15]CHANG J H,GEHRKE C,PRABHAKAR R,et al.RADBIOMOD:a simple program for utilising biological modelling in radiotherapy plan evaluation[J].Phys Med,2016,32(1):248-254.
[16]AVANZO M,STANCANELLO J,FRANCHIN G,et al.Correlation of a hypoxia based tumor control model with observed local control rates in nasopharyngeal carcinoma treated with chemoradiotherapy[J].Med Phys,2010,37(4):1533-1544.
[17]LUXTON G,KEALL P J,KING C R.A new formula for normal tissue complication probability(NTCP)as a function of equivalent uniform dose(EUD)[J].Phys Med Biol,2008,53(1):23-36.
[18]BURMAN C,KUTCHER G J,EMAMI B,et al.Fitting of normal tissue tolerance data to an analytic function[J].Int J Radiat Oncol Biol Phys,1991,21(1):123-135.
[19]HUANG B T,LU J Y,LIN P X,et al.Radiobiological modeling analysis of the optimal fraction scheme in patients with peripheral nonsmall cell lung cancer undergoing stereotactic body radiotherapy[J].Sci Rep,2015,5:18010.
[20]HUANG B T,LIN Z,LIN P X,et al.Radiobiological modeling of two stereotactic body radiotherapy schedules in patients with stage Iperipheral non-small cell lung cancer[J].Oncotarget,2016,7(26):40746-40755.
[21]WARREN S,PARTRIDGE M,CARRINGTON R,et al.Radiobiological determination of dose escalation and normal tissue toxicity in definitive chemoradiation therapy for esophageal cancer[J].Int J Radiat Oncol Biol Phys,2014,90(2):423-429.
[22]KUANG Y,WU L,HIRATA E,et al.Volumetric modulated arc therapy planning for primary prostate cancer with selective intraprostatic boost determined by18F-choline PET/CT[J].Int J Radiat Oncol Biol Phys,2015,91(5):1017-1025.
[23]WEBB S,NAHUM A E.A model for calculating tumour control probability in radiotherapy including the effects of inhomogeneous distributions of dose and clonogenic cell density[J].Phys Med Biol,1993,38(6):653-666.
[24]LEE M,WYNNE C,WEBB S,et al.A comparison of proton and megavoltage X-ray treatment planning for prostate cancer[J].Radiother Oncol,1994,33(3):239-253.
[25]ISACSSON U,MONTELIUS A,JUNG B,et al.Comparative treatment planning between proton and X-ray therapy in locally advanced rectal cancer[J].Radiother Oncol,1996,41(3):263-272.
[26]FOWLER J F.Optimum overall times II:extended modelling for head and neck radiotherapy[J].Clin Oncol(R Coll Radiol),2008,20(2):113-126.
[27]FOWLER J F.How much radiation is the chemotherapy worth in advanced head and neck cancer?[J].Int J Radiat Oncol Biol Phys,2008,71(2):326-329.
[28]BUSSINK J,KAANDERS J H,VAN DER KOGEL A J.Tumor hypoxia at the micro-regional level:clinical relevance and predictive value of exogenous and endogenous hypoxic cell markers[J].Radiother Oncol,2003,67(1):3-15.
[29]MIFTEN M M,DAS S K,SU M,et al.A dose-volume-based tool for evaluating and ranking IMRT treatment plans[J].J Appl Clin Med Phys,2004,5(4):1-14.
[30]WARKENTIN B,STAVREV P,STAVREVA N,et al.A TCP-NTCPestimation module using DVHs and known radiobiological models and parameter sets[J].J Appl Clin Med Phys,2004,5(1):50-63.
[31]TAHERI H,TAVAKOLI M B,AKHAVAN A.Radiobiological evaluation of three common clinical radiotherapy techniques including combined photon-electron,tangential beams and electron therapy in left-sided mastectomy patients[J].Adv Biomed Res,2018,7:99.
[32]LIANG X,PENAGARICANO J,ZHENG D,et al.Radiobiological impact of dose calculation algorithms on biologically optimized IMRTlung stereotactic body radiation therapy plans[J].Radiat Oncol,2016,11:10.
[33]BASU K S,BAHL A,SUBRAMANI V,et al.Normal tissue complication probability:does simultaneous integrated boost intensitymodulated radiotherapy score over other techniques in treatment of prostate adenocarcinoma[J].J Cancer Res Ther,2009,5(2):78-84.
[34]MCGINN C J,TEN HAKEN R K,ENSMINGER W D,et al.Treatment of intrahepatic cancers with radiation doses based on a normal tissue complication probability model[J].J Clin Oncol,1998,16(6):2246-2252.
[35]ROSENZWEIG K E,FOX J L,YORKE E,et al.Results of a phase I dose-escalation study using three-dimensional conformal radiotherapy in the treatment of inoperable nonsmall cell lung carcinoma[J].Cancer,2005,103(10):2118-2127.
[36]SONG D Y,BENEDICT S H,CARDINALE R M,et al.Stereotactic body radiation therapy of lung tumors:preliminary experience using normal tissue complication probability-based dose limits[J].Am JClin Oncol,2005,28(6):591-596.
[37]YANG Y,XING L.Clinical knowledge-based inverse treatment planning[J].Phys Med Biol,2004,49(22):5101-5117.
[38]FENG Z,TAO C,ZHU J,et al.An integrated strategy of biological and physical constraints in biological optimization for cervical carcinoma[J].Radiat Oncol,2017,12(1):64.
[39]EMAMI B,LYMAN J,BROWN A,et al.Tolerance of normal tissue to therapeutic irradiation[J].Int J Radiat Oncol Biol Phys,1991,21(1):109-122.
[40]LYMAN J T.Complication probability as assessed from dose-volume histograms[J].Radiat Res Suppl,1985,8:S13-S19.
[41]KUTCHER G J,BURMAN C.Calculation of complication probability factors for non-uniform normal tissue irradiation:the effective volume method[J].Int J Radiat Oncol Biol Phys,1989,16(6):1623-1630.
[42]TSOUGOS I,MAVROIDIS P,THEODOROU K,et al.Clinical validation of the LKB model and parameter sets for predicting radiation-induced pneumonitis from breast cancer radiotherapy[J].Phys Med Biol,2006,51(3):L1-L9.
[43]RODRIGUEZ-CABALLERO A,TORRES-LAGARES D,ROBLES-GARCIA M,et al.Cancer treatment-induced oral mucositis:a critical review[J].Int J Oral Maxillofac Surg,2012,41(2):225-238.
[2]XUE W Q,QIN H D,RUAN H L,et al.Quantitative association of tobacco smoking with the risk of nasopharyngeal carcinoma:a comprehensive meta-analysis of studies conducted between 1979 and2011[J].Am J Epidemiol,2013,178(3):325-338.
[3]CO J,MEJIAM B,DIZON J M.Evidence on effectiveness of intensitymodulated radiotherapy versus 2-dimensional radiotherapy in the treatment of nasopharyngeal carcinoma:meta-analysis and a systematic review of the literature[J].Head Neck,2016,38(Suppl 1):2130-2142.
[4]CAPONIGRO F,LONGO F,IONNA F,et al.Treatment approaches to nasopharyngeal carcinoma:a review[J].Anticancer Drugs,2010,21(5):471-477.
[5]YAN H,CAO X,WANG J.Application of intensity-modulated radiation therapy in the treatment of nasopharyngeal carcinoma[J].Oncol Lett,2017,14(6):7773-7776.
[6]XU T,SHEN C,ZHU G,et al.Omission of chemotherapy in early stage nasopharyngeal carcinoma treated with IMRT:a paired cohort study[J].Medicine(Baltimore),2015,94(39):e1457.
[7]SONG C H,WU H G,HEO D S,et al.Treatment outcomes for radiotherapy alone are comparable with neoadjuvant chemotherapy followed by radiotherapy in early-stage nasopharyngeal carcinoma[J].Laryngoscope,2008,118(4):663-670.
[8]AU K H,NGAN R K,NG A W,et al.Treatment outcomes of nasopharyngeal carcinoma in modern era after intensity modulated radiotherapy(IMRT)in Hong Kong:a report of 3 328 patients(HKNPCSG 1 301 study)[J].Oral Oncol,2018,77:16-21.
[9]KAN M W,WONG W,LEUNG L H,et al.A comprehensive dosimetric evaluation of using RapidArc volumetric-modulated arc therapy for the treatment of early-stage nasopharyngeal carcinoma[J].J Appl Clin Med Phys,2012,13(6):3887.
[10]XIAO G,CAO Y,QIU X,et al.Influence of gender and age on the survival of patients with nasopharyngeal carcinoma[J].BMC Cancer,2013,13:226.
[11]王丽,杨智宁,彭逊,等.不同分割剂量治疗鼻咽癌的效果比较[J].广东医学,2015,36(8):1216-1219.WANG L,YANG Z N,PENG X,et al.Comparison of treatment effects of different fractionated dose on nasopharyngeal carcinoma[J].Guangdong Medical Journal,2015,36(8):1216-1219.
[12]SPIOTTO M T,KOSHY M.Impact of fraction size on locally advanced oropharyngeal and nasopharyngeal cancers treated with chemoradiation[J].Oral Oncol,2017,68:27-35.
[13]LE Q T,FU K K,KROLL S,et al.Influence of fraction size,total dose,and overall time on local control of T1-T2 glottic carcinoma[J].Int J Radiat Oncol Biol Phys,1997,39(1):115-126.
[14]BOUGHALIA A,MARCIE S,FELLAH M,et al.Assessment and quantification of patient set-up errors in nasopharyngeal cancer patients and their biological and dosimetric impact in terms of generalized equivalent uniform dose(gEUD),tumour control probability(TCP)and normal tissue complication probability(NTCP)[J].Br J Radiol,2015,88(1050):20140839.
[15]CHANG J H,GEHRKE C,PRABHAKAR R,et al.RADBIOMOD:a simple program for utilising biological modelling in radiotherapy plan evaluation[J].Phys Med,2016,32(1):248-254.
[16]AVANZO M,STANCANELLO J,FRANCHIN G,et al.Correlation of a hypoxia based tumor control model with observed local control rates in nasopharyngeal carcinoma treated with chemoradiotherapy[J].Med Phys,2010,37(4):1533-1544.
[17]LUXTON G,KEALL P J,KING C R.A new formula for normal tissue complication probability(NTCP)as a function of equivalent uniform dose(EUD)[J].Phys Med Biol,2008,53(1):23-36.
[18]BURMAN C,KUTCHER G J,EMAMI B,et al.Fitting of normal tissue tolerance data to an analytic function[J].Int J Radiat Oncol Biol Phys,1991,21(1):123-135.
[19]HUANG B T,LU J Y,LIN P X,et al.Radiobiological modeling analysis of the optimal fraction scheme in patients with peripheral nonsmall cell lung cancer undergoing stereotactic body radiotherapy[J].Sci Rep,2015,5:18010.
[20]HUANG B T,LIN Z,LIN P X,et al.Radiobiological modeling of two stereotactic body radiotherapy schedules in patients with stage Iperipheral non-small cell lung cancer[J].Oncotarget,2016,7(26):40746-40755.
[21]WARREN S,PARTRIDGE M,CARRINGTON R,et al.Radiobiological determination of dose escalation and normal tissue toxicity in definitive chemoradiation therapy for esophageal cancer[J].Int J Radiat Oncol Biol Phys,2014,90(2):423-429.
[22]KUANG Y,WU L,HIRATA E,et al.Volumetric modulated arc therapy planning for primary prostate cancer with selective intraprostatic boost determined by18F-choline PET/CT[J].Int J Radiat Oncol Biol Phys,2015,91(5):1017-1025.
[23]WEBB S,NAHUM A E.A model for calculating tumour control probability in radiotherapy including the effects of inhomogeneous distributions of dose and clonogenic cell density[J].Phys Med Biol,1993,38(6):653-666.
[24]LEE M,WYNNE C,WEBB S,et al.A comparison of proton and megavoltage X-ray treatment planning for prostate cancer[J].Radiother Oncol,1994,33(3):239-253.
[25]ISACSSON U,MONTELIUS A,JUNG B,et al.Comparative treatment planning between proton and X-ray therapy in locally advanced rectal cancer[J].Radiother Oncol,1996,41(3):263-272.
[26]FOWLER J F.Optimum overall times II:extended modelling for head and neck radiotherapy[J].Clin Oncol(R Coll Radiol),2008,20(2):113-126.
[27]FOWLER J F.How much radiation is the chemotherapy worth in advanced head and neck cancer?[J].Int J Radiat Oncol Biol Phys,2008,71(2):326-329.
[28]BUSSINK J,KAANDERS J H,VAN DER KOGEL A J.Tumor hypoxia at the micro-regional level:clinical relevance and predictive value of exogenous and endogenous hypoxic cell markers[J].Radiother Oncol,2003,67(1):3-15.
[29]MIFTEN M M,DAS S K,SU M,et al.A dose-volume-based tool for evaluating and ranking IMRT treatment plans[J].J Appl Clin Med Phys,2004,5(4):1-14.
[30]WARKENTIN B,STAVREV P,STAVREVA N,et al.A TCP-NTCPestimation module using DVHs and known radiobiological models and parameter sets[J].J Appl Clin Med Phys,2004,5(1):50-63.
[31]TAHERI H,TAVAKOLI M B,AKHAVAN A.Radiobiological evaluation of three common clinical radiotherapy techniques including combined photon-electron,tangential beams and electron therapy in left-sided mastectomy patients[J].Adv Biomed Res,2018,7:99.
[32]LIANG X,PENAGARICANO J,ZHENG D,et al.Radiobiological impact of dose calculation algorithms on biologically optimized IMRTlung stereotactic body radiation therapy plans[J].Radiat Oncol,2016,11:10.
[33]BASU K S,BAHL A,SUBRAMANI V,et al.Normal tissue complication probability:does simultaneous integrated boost intensitymodulated radiotherapy score over other techniques in treatment of prostate adenocarcinoma[J].J Cancer Res Ther,2009,5(2):78-84.
[34]MCGINN C J,TEN HAKEN R K,ENSMINGER W D,et al.Treatment of intrahepatic cancers with radiation doses based on a normal tissue complication probability model[J].J Clin Oncol,1998,16(6):2246-2252.
[35]ROSENZWEIG K E,FOX J L,YORKE E,et al.Results of a phase I dose-escalation study using three-dimensional conformal radiotherapy in the treatment of inoperable nonsmall cell lung carcinoma[J].Cancer,2005,103(10):2118-2127.
[36]SONG D Y,BENEDICT S H,CARDINALE R M,et al.Stereotactic body radiation therapy of lung tumors:preliminary experience using normal tissue complication probability-based dose limits[J].Am JClin Oncol,2005,28(6):591-596.
[37]YANG Y,XING L.Clinical knowledge-based inverse treatment planning[J].Phys Med Biol,2004,49(22):5101-5117.
[38]FENG Z,TAO C,ZHU J,et al.An integrated strategy of biological and physical constraints in biological optimization for cervical carcinoma[J].Radiat Oncol,2017,12(1):64.
[39]EMAMI B,LYMAN J,BROWN A,et al.Tolerance of normal tissue to therapeutic irradiation[J].Int J Radiat Oncol Biol Phys,1991,21(1):109-122.
[40]LYMAN J T.Complication probability as assessed from dose-volume histograms[J].Radiat Res Suppl,1985,8:S13-S19.
[41]KUTCHER G J,BURMAN C.Calculation of complication probability factors for non-uniform normal tissue irradiation:the effective volume method[J].Int J Radiat Oncol Biol Phys,1989,16(6):1623-1630.
[42]TSOUGOS I,MAVROIDIS P,THEODOROU K,et al.Clinical validation of the LKB model and parameter sets for predicting radiation-induced pneumonitis from breast cancer radiotherapy[J].Phys Med Biol,2006,51(3):L1-L9.
[43]RODRIGUEZ-CABALLERO A,TORRES-LAGARES D,ROBLES-GARCIA M,et al.Cancer treatment-induced oral mucositis:a critical review[J].Int J Oral Maxillofac Surg,2012,41(2):225-238.