食管癌新辅助放化疗中放疗累及野照射的初步研究

doi:10.19401/j.cnki.1007-3639.2023.03.010

摘要/Abstract

摘要：

背景与目的：局部晚期食管癌患者的标准治疗方案是新辅助放化疗（neoadjuvant chemoradiotherapy，NCRT）联合根治性切除术，但临床上实施这一综合性治疗策略的技术环节存在一定差异性，特别是NCRT中放疗靶区范围的定义一直存在争议。本研究旨在分析局部晚期食管癌NCRT采用累及野照射（involving field irradiation，IFI）的可行性。方法：回顾性分析2016年7月—2017年5月在上海交通大学医学院附属胸科医院接受NCRT联合手术的局部晚期食管鳞癌患者，所有患者的放疗靶区均为我们推荐的IFI，再分别按照选择性淋巴引流区预防照射（elective node irradiation，ENI）和原发灶亚临床病灶照射（subclinical lesion irradiation，SLI）两种传统靶区勾画方式对入组患者重新制订放疗计划。比较3组计划的剂量学参数以及双肺、心脏、脊髓等危及器官（organ at risk，OAR）受照剂量差异，并分析IFI失败模式与靶区的关系。结果：共入组26例患者。IFI的靶区平均体积为（277±77）cm³，明显低于ENI和SLI（P<0.05）。剂量学分析发现，IFI能显著降低双肺受到5、20 Gy以上剂量照射的相对体积分数（V₅、V₂₀）、双肺平均受照剂量（D_mean）、心脏V₃₀、心脏D_mean和脊髓最大受照剂量（D_max）（P<0.05），双肺V₂₀、双肺D_mean、心脏D_mean和脊髓D_max较ENI分别下降27.1%、22.5%、27.4%和6.4%，较SLI分别下降24.1%、22.0%、24.8%和5.7%。经过28~69个月的随访，13例患者发生复发转移，其中7例患者为单纯远处转移，4例患者为照射野内复发，1例患者为照射野外局部复发，3年总生存（overall survival，OS）率和无病生存（disease-free survival，DFS）率分别为50.0%和42.3%。结论：本中心建议的IFI在保证临床疗效的同时显著降低了肺、心脏和脊髓等器官的辐射受量，具有一定的可行性。

关键词: 食管鳞癌, 新辅助放化疗, 放疗靶区, 危及器官, 剂量学, 失败模式

Abstract:

Background and purpose: The standard treatment for patients with locally advanced esophageal cancer is neoadjuvant chemoradiotherapy (NCRT) plus radical resection. However, the technical aspects for implementing this comprehensive treatment strategy differ, especially in the controversial definition of the radiotherapy target area in NCRT. This study aimed to analyze the feasibility of involving field irradiation (IFI) in NCRT for locally advanced esophageal cancer. Methods: Retrospective analysis of locally advanced esophageal squamous cell carcinoma patients receiving NCRT in Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine from July 2016 to May 2017 showed that the radiotherapy target of all patients was our recommended IFI. The radiotherapy plan was redesigned for the enrolled patients according to the two traditional target delineation of elective node irradiation (ENI) and primary subclinical lesion irradiation (SLI). The dosimetric parameters of the three groups and the dose differences of organ at risk (OAR), such as lungs, heart and spinal cord, were compared, and the relationship between IFI Recurrence pattern and radiation target volumes was analyzed. Results: A total of 26 patients were enrolled. The average target volume of IFI was (277±77) cm³, which was significantly lower compared with ENI and SLI (P<0.05). IFI could significantly reduce relative volume fraction of lungs irradiated more than 5 and 20 Gy (V₅ and V₂₀), lungs average dose (D_mean), heart V₃₀, heart D_mean and spinal cord maximum dose (D_max) (P<0.05), compared with ENI. Lungs V₂₀, lungs D_mean, heart D_mean and spinal cord D_max decreased by 27.1%, 22.5%, 27.4% and 6.4% compared with ENI, and 24.1%, 22.0%, 24.8% and 5.7% compared with SLI, respectively. After 28 to 69 months of follow-up, 13 patients had recurrence and metastasis, of whom 7 patients had distant metastasis, 4 patients had recurrence in the irradiation field, and 1 patient had local recurrence in the irradiation field. The 3-year overall survival (OS) rate and disease-free survival (DFS) rate were 50.0% and 42.3%, respectively. Conclusion: IFI recommended by our institution is feasible to ensure clinical efficacy while significantly reducing the radiation dose of lungs, heart and spinal cord.

Key words: Esophageal squamous carcinoma, Neoadjuvant chemoradiotherapy, Target volume, Organ at risk, Dosimetry, Recurrence pattern

中图分类号:

R735.1

董晓欢, 刘俊, 李洪选, 程妍, 李玥, 余雯, 蔡旭伟, 傅小龙. 食管癌新辅助放化疗中放疗累及野照射的初步研究[J]. 中国癌症杂志, 2023, 33(3): 267-273.

DONG Xiaohuan, LIU Jun, LI Hongxuan, CHENG Yan, LI Yue, YU Wen, CAI Xuwei, FU Xiaolong. Preliminary study on involving field irradiation radiotherapy in neoadjuvant chemoradiotherapy for esophageal cancer[J]. China Oncology, 2023, 33(3): 267-273.

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参考文献 24

[1]	CHEN W Q, ZHENG R S, BAADE P D, et al. Cancer statistics in China, 2015[J]. CA Cancer J Clin, 2016, 66(2): 115-132. doi: 10.3322/caac.21338
[2]	AJANI J A, D’AMICO T A, BENTREM D J, et al. Esophageal and esophagogastric junction cancers, version 2.2019, NCCN clinical practice guidelines in oncology[J]. J Natl Compr Canc Netw, 2019, 17(7): 855-883. doi: 10.6004/jnccn.2019.0033
[3]	HAGEN P V, HULSHOF M C C M, LANSCHOT J J B V, et al. Preoperative chemoradiotherapy for esophageal or junctional cancer[J]. N Engl J Med, 2012, 366(22): 2074-2084. doi: 10.1056/NEJMoa1112088
[4]	YANG H, LIU H, CHEN Y P, et al. Neoadjuvant chemoradiotherapy followed by surgery versus surgery alone for locally advanced squamous cell carcinoma of the esophagus (NEOCRTEC5010): a phase Ⅲ multicenter, randomized, open-label clinical trial[J]. J Clin Oncol, 2018, 36(27): 2796-2803. doi: 10.1200/JCO.2018.79.1483
[5]	LV J, CAO X F, ZHU B, et al. Long-term efficacy of perioperative chemoradiotherapy on esophageal squamous cell carcinoma[J]. World J Gastroenterol, 2010, 16(13): 1649-1654. doi: 10.3748/wjg.v16.i13.1649
[6]	OPPEDIJK V, VAN DER GAAST A, VAN LANSCHOT J J, et al. Patterns of recurrence after surgery alone versus preoperative chemoradiotherapy and surgery in the CROSS trials[J]. J Clin Oncol, 2014, 32(5): 385-391. doi: 10.1200/JCO.2013.51.2186 pmid: 24419108
[7]	LIU S L, WEN J, YANG H, et al. Recurrence patterns after neoadjuvant chemoradiotherapy compared with surgery alone in oesophageal squamous cell carcinoma: results from the multicenter phase Ⅲ trial NEOCRTEC5010[J]. Eur J Cancer, 2020, 138: 113-121. doi: 10.1016/j.ejca.2020.08.002
[8]	KUMAGAI K, ROUVELAS I, TSAI J A, et al. Meta-analysis of postoperative morbidity and perioperative mortality in patients receiving neoadjuvant chemotherapy or chemoradiotherapy for resectable oesophageal and gastro-oesophageal junctional cancers[J]. Br J Surg, 2014, 101(4): 321-338. doi: 10.1002/bjs.9418 pmid: 24493117
[9]	LIU T T, DING S L, DANG J, et al. Elective nodal irradiation versus involved-field irradiation in patients with esophageal cancer receiving neoadjuvant chemoradiotherapy: a network meta-analysis[J]. Radiat Oncol, 2019, 14(1): 176. doi: 10.1186/s13014-019-1388-8
[10]	YAMASHITA H, TAKENAKA R, OMORI M, et al. Involved-field radiotherapy (IFRT) versus elective nodal irradiation (ENI) in combination with concurrent chemotherapy for 239 esophageal cancers: a single institutional retrospective study[J]. Radiat Oncol, 2015, 10: 171. doi: 10.1186/s13014-015-0482-9 pmid: 26269033
[11]	JING W, ZHU H, GUO H B, et al. Feasibility of elective nodal irradiation (ENI) and involved field irradiation (IFI) in radiotherapy for the elderly patients (aged ≥ 70 years) with esophageal squamous cell cancer: a retrospective analysis from a single institute[J]. PLoS One, 2015, 10(12): e0143007.
[12]	GAO X S, QIAO X Y, WU F P, et al. Pathological analysis of clinical target volume margin for radiotherapy in patients with esophageal and gastroesophageal junction carcinoma[J]. Int J Radiat Oncol Biol Phys, 2007, 67(2): 389-396. doi: 10.1016/j.ijrobp.2006.09.015
[13]	HAGENS E R C, VAN BERGE HENEGOUWEN M I, GISBERTZ S S. Distribution of lymph node metastases in esophageal carcinoma patients undergoing upfront surgery: a systematic review[J]. Cancers (Basel), 2020, 12(6): E1592.
[14]	JI K, ZHAO L J, YANG C W, et al. Three-dimensional conformal radiation for esophageal squamous cell carcinoma with involved-field irradiation may deliver considerable doses of incidental nodal irradiation[J]. Radiat Oncol, 2012, 7: 200. doi: 10.1186/1748-717X-7-200 pmid: 23186308
[15]	LAMBIN P, LIEVERSE R I Y, ECKERT F, et al. Lymphocyte-sparing radiotherapy: the rationale for protecting lymphocyte-rich organs when combining radiotherapy with immunotherapy[J]. Semin Radiat Oncol, 2020, 30(2): 187-193. doi: S1053-4296(19)30078-5 pmid: 32381298
[16]	LADBURY C J, RUSTHOVEN C G, CAMIDGE D R, et al. Impact of radiation dose to the host immune system on tumor control and survival for stage Ⅲ non-small cell lung cancer treated with definitive radiation therapy[J]. Int J Radiat Oncol Biol Phys, 2019, 105(2): 346-355. doi: 10.1016/j.ijrobp.2019.05.064
[17]	VAN ROSSUM P S N, DENG W, ROUTMAN D M, et al. Prediction of severe lymphopenia during chemoradiation therapy for esophageal cancer: development and validation of a pretreatment nomogram[J]. Pract Radiat Oncol, 2020, 10(1): e16-e26. doi: 10.1016/j.prro.2019.07.010 pmid: 31369887
[18]	GRAHAM M V, PURDY J A, EMAMI B, et al. Clinical dose-volume histogram analysis for pneumonitis after 3D treatment for non-small cell lung cancer (NSCLC)[J]. Int J Radiat Oncol Biol Phys, 1999, 45(2): 323-329.
[19]	JIANG Z Q, YANG K Y, KOMAKI R, et al. Long-term clinical outcome of intensity-modulated radiotherapy for inoperable non-small cell lung cancer: the MD Anderson experience[J]. Int J Radiat Oncol, 2012, 83(1): 332-339. doi: 10.1016/j.ijrobp.2011.06.1963
[20]	FRANDSEN J, BOOTHE D, GAFFNEY D K, et al. Increased risk of death due to heart disease after radiotherapy for esophageal cancer[J]. J Gastrointest Oncol, 2015, 6(5): 516-523. doi: 10.3978/j.issn.2078-6891.2015.040 pmid: 26487946
[21]	WEI X, LIU H H, TUCKER S L, et al. Risk factors for pericardial effusion in inoperable esophageal cancer patients treated with definitive chemoradiation therapy[J]. Int J Radiat Oncol Biol Phys, 2008, 70(3): 707-714. doi: 10.1016/j.ijrobp.2007.10.056
[22]	SCHULTHEISS T E. The radiation dose-response of the human spinal cord[J]. Int J Radiat Oncol Biol Phys, 2008, 71(5): 1455-1459. doi: 10.1016/j.ijrobp.2007.11.075
[23]	HASHIMOTO J, KATO K, ITO Y, et al. Phase Ⅱ feasibility study of preoperative concurrent chemoradiotherapy with cisplatin plus 5-fluorouracil and elective lymph node irradiation for clinical stage Ⅱ/Ⅲ esophageal squamous cell carcinoma[J]. Int J Clin Oncol, 2019, 24(1): 60-67. doi: 10.1007/s10147-018-1336-x
[24]	KLEVEBRO F, VON DÖBELN G A, WANG N, et al. A randomized clinical trial of neoadjuvant chemotherapy versus neoadjuvant chemoradiotherapy for cancer of the oesophagus or gastro-oesophageal junction[J]. Ann Oncol, 2016, 27(4): 660-667. doi: 10.1093/annonc/mdw010 pmid: 26782957

Characteristic	Value
Age/year median (range)	61 (45-72)
Gender n
Male	22
Female	4
Length/cm median (range)	6 (2-17)
Location n
Upper thoracic	3
Middle thoracic	10
Lower thoracic	13
T stage n
cT₂	1
cT₃	20
cT_4a	5
N stage n
cN₀	5
cN₁	18
cN₂	2
cN₊	1
TNM stage _n
ⅡA	1
ⅡB	2
ⅢA	18
ⅣA	5

Variable	ENI	SLI	IFI	t value		P value
Variable	ENI	SLI	IFI	IFI vs ENI	IFI vs SLI	IFI vs ENI	IFI vs SLI
PTV/cm³	501±128	435±111	277±77	-11.120	-16.934	0.000	0.000
Lung
V₅/%	49±5	48±6	39±5	-13.433	-11.716	0.000	0.000
V₂₀/%	21±3	20±4	15±3	-14.667	-11.012	0.000	0.000
D_mean/cGy	1 042±122	1 038±139	808±126	-13.579	-12.786	0.000	0.000
Heart
V₃₀/%	46±14	42±13	30±16	-10.862	-9.434	0.000	0.000
D_mean/cGy	2 531±489	2 434±427	1 895±735	-8.293	-7.291	0.000	0.000
Spinal cord
D_max/cGy	3 989±342	3 958±326	3 727±313	-6.297	-5.266	0.000	0.000

Variable	IFI-ENI		IFI-SLI		P value
Variable	Media (range)	%	Media (range)	%	P value
Lung
V₅/%	11 (1-18)	-20.8	9 (0-19)	-19.7	0.544
V₂₀/%	6 (1-10)	-27.1	5 (0-12)	-24.1	0.231
D_mean/cGy	260 (7-378)	-22.5	241 (7-441)	-22.0	0.522
Heart
V₃₀/%	15 (0-30)	-36.9	12 (0-29)	-31.9	0.071
D_mean/cGy	624 (27-1 404)	-27.4	484 (3-1 244)	-24.8	0.442
Spinal cord					0.470
D_max/cGy	220 (2-826)	-6.4	154 (4-869)	-5.7

Recurrence	Infield	Outfield	Infield plus outfield	Total
LRR only	2	1	0	3
Distant only	0	7	0	7
LRR plus distant	2	0	1	3
Total	4	8	1	13