Chinese experts' consensus on the application of pegylated recombinant human granulocyte colony-stimulating factor during concurrent chemoradiotherapy （2023 version）

doi:10.3760/cma.j.cn371439-20230227-00039

Abstract

Abstract:

Neutropenia is the most common hematologic toxicity of concurrent chemoradiotherapy for malignant tumor patients， which can lead to follow-up treatment delay and/or dose reduction， induce febrile neutropenia and severe infection easily， thus affecting prognosis and safety of patients. It is important to prevent and manage neutropenia in patients with malignant tumors during concurrent chemoradiotherapy reasonably. As a long-acting preparation of recombinant human granulocyte colony-stimulating factor， pegylated recombinant human granulocyte colony-stimulating factor （PEG-rhG-CSF） can prevent and treat neutropenia， which is more convenient for clinical practice. In order to promote clinical rational administration of drugs， Radiation Oncology Treatment Physician Branch of Chinese Medical Doctor Association， Radiation Oncology Therapy Branch of Chinese Medical Association， Chinese Association of Radiation Therapy of China Anti-Cancer Association consulted guidelines and the latest evidence-based evidences related to PEG-rhG-CSF， evaluated the effectiveness and safety of the application of PEG-rhG-CSF during concurrent chemoradiotherapy， clarified the clinical pathway and administration route of prevention and treatment and then formed a Chinese experts' consensus on the application of PEG-rhG-CSF during concurrent chemoradiotherapy.

Key words: Chemoradiotherapy, Neutropenia, PEG-rhG-CSF, Clinical consensus

Radiation Oncology Treatment Physician Branch, Chinese Medical Doctor Association, Radiation Oncology Therapy Branch, Chinese Medical Association, Chinese Association of Radiation Therapy, China Anti-Cancer Association. Chinese experts' consensus on the application of pegylated recombinant human granulocyte colony-stimulating factor during concurrent chemoradiotherapy （2023 version）[J]. Journal of International Oncology, 2023, 50(4): 193-201.

Figures/Tables 4

肿瘤类型	放化疗方案	放化疗剂量				FN发生风险	3~4级中性粒细胞减少症发生率
头颈部肿瘤	顺铂+同步放疗^[16]	顺铂		100 mg/m²，d1，q3w		低危	—
		同步放疗		72 Gy，1.8或1.5 Gy/次
小细胞肺癌^a	依托泊苷+顺铂+同步放疗^[17-18]	依托泊苷		100 mg/（m²·d），d1~3		高危	75%~95%
		顺铂		75~80 mg/m²，d1或25 mg/（m²·d），d1~3，q3w
		同步放疗		45 Gy，1.5 Gy/次，bid/3w
	依托泊苷+顺铂+同步放疗^[17]	依托泊苷		100 mg/（m²·d），d1~3		中危	64%
		顺铂		75 mg/m²，d1或25 mg/（m²·d），d1~3，q3w
		同步放疗		60~70 Gy，1.8~2.0 Gy/次
非小细胞肺癌	顺铂+多西他赛+同步放疗^[19]	顺铂		40 mg/m²，d1、8、29、36		高危	62%
		多西他赛		40 mg/m²，d1、8、29、36
		同步放疗		60 Gy/30次
	顺铂+长春瑞滨+同步放疗^[10,20]	顺铂		80 mg/m²，d1		中危	52%~77%
		长春瑞滨		20 mg/m²，d1、8，q4w
		同步放疗		60~72 Gy/30次
	顺铂+依托泊苷+同步放疗^[21]	顺铂		50 mg/m²，d1、8、29、36		低危	28.7%
		依托泊苷		50 mg/m²，d1~5，d29~33
		同步放疗		60~66 Gy/30~33次
	顺铂+培美曲塞+同步放疗^[21]	顺铂		75 mg/m²，d1		低危	18.4%
		培美曲塞		500 mg/m²，d1，q3w
		同步放疗		60~66 Gy/30~33次
食管癌	多西他赛+顺铂+氟尿嘧啶+同步放疗^[22]	多西他赛		35 mg/m²，d1		高危	56.6%
		顺铂		40 mg/m²，d1
		氟尿嘧啶		400 mg/（m²·d），d1~5，q2w
		同步放疗		50.4 Gy/28次
	顺铂+氟尿嘧啶+同步放疗^[12]	顺铂		75 mg/m²，d1、29		中危	41%
		氟尿嘧啶		1 000 mg/m²，d1~4，d29~33
		同步放疗		50.4 Gy/28次
	卡铂+紫杉醇+同步放疗^[23]b	卡铂		AUC=2，d1，qw		中危	27%
		紫杉醇		50 mg/m²，d1，qw
		同步放疗		50 Gy/25次
	卡铂+紫杉醇+同步放疗^[24]b	卡铂		AUC=2，d1，qw		低危	9%
		紫杉醇		50 mg/m²，d1，qw
		同步放疗		41.4 Gy/23次
	顺铂+替吉奥+同步放疗^[25]	替吉奥		80~100 mg/（m²·d），d1~14		低危	37.9%
		顺铂		70 mg/m²，d8，q3w
		同步放疗		30 Gy/15次
	顺铂+长春瑞滨+同步放疗^[26]	长春瑞滨		25 mg/m²，d1、8		未报道	45.7%
		顺铂		75 mg/m²，d1或25 mg/（m²·d），d1~4，q3w
		同步放疗		40 Gy/20次
	顺铂+紫杉醇+同步放疗^[27]	紫杉醇		50 mg/m²，d1、8、15、22、29		未报道	29%
		顺铂		30 mg/m²，d1、8、15、22、29
		同步放疗		45 Gy/25次
结直肠癌	卡培他滨+伊立替康+同步放疗^[28]		卡培他滨		625 mg/m²，bid，每周5天	低危		20%
			伊立替康		80或65 mg/（m²·w）
			同步放疗		50 Gy/25次
	卡培他滨+同步放疗^[28]		卡培他滨		825 mg/m²，bid，每周5天	低危		2%
			同步放疗		50 Gy/25次
宫颈癌	顺铂+紫杉醇+同步放疗^[29]		紫杉醇		150 mg/m²，d1	中危		77.78%
			顺铂		35 mg/（m²·d），d1~2，q3w
			同步放疗		45 Gy/25次
	顺铂+同步放疗^[30]		顺铂		40 mg/m²，d1，qw	低危		3.80%
			同步放疗		1.8 Gy/（次·d），25~28次

References 46

[1]	Tang LL, Guo R, Zhang N, et al. Effect of radiotherapy alone vs radiotherapy with concurrent chemoradiotherapy on survival without disease relapse in patients with low-risk nasopharyngeal carcinoma:a randomized clinical trial[J]. JAMA, 2022, 328(8): 728-736. DOI: 10.1001/jama.2022.13997. doi: 10.1001/jama.2022.13997
[2]	Li Y, Wang J, Ma X, et al. A review of neoadjuvant chemoradiotherapy for locally advanced rectal cancer[J]. Int J Biol Sci, 2016, 12(8): 1022-1031. DOI: 10.7150/ijbs.15438. doi: 10.7150/ijbs.15438 pmid: 27489505
[3]	Donadieu J, Fenneteau O, Beaupain B, et al. Congenital neutropenia: diagnosis, molecular bases and patient management[J]. Orphanet J Rare Dis, 2011, 6: 26. DOI: 10.1186/1750-1172-6-26. doi: 10.1186/1750-1172-6-26 pmid: 21595885
[4]	Klastersky J, de Naurois J, Rolston K, et al. Management of febrile neutropaenia:ESMO Clinical Practice Guidelines[J]. Ann Oncol, 2016, 27(Suppl 5): v111-v118. DOI: 10.1093/annonc/mdw325. doi: 10.1093/annonc/mdw325
[5]	Kuderer NM, Dale DC, Crawford J, et al. Mortality, morbidity, and cost associated with febrile neutropenia in adult cancer patients[J]. Cancer, 2006, 106(10): 2258-2266. DOI: 10.1002/cncr.21847. doi: 10.1002/cncr.21847 pmid: 16575919
[6]	石远凯, 许建萍, 吴昌平, 等. 聚乙二醇化重组人粒细胞刺激因子预防化疗后中性粒细胞减少症的多中心上市后临床研究[J]. 中国肿瘤临床, 2017, 44(14): 679-684. DOI: 10.3969/j.issn.1000-8179.2017.14.291. doi: 10.3969/j.issn.1000-8179.2017.14.291
[7]	Griffiths EA, Roy V, Alwan L, et al. NCCN Guidelines Insights: Hematopoietic Growth Factors, Version 1.2023[J/OL]. J Natl Compr Canc Netw, 2022: 12-02. https://www.nccn.org/guidelines/guidelines-detail?category=3&id=1493.
[8]	O'Rourke N, Roqué I Figuls M, Farré Bernadó N, et al. Concurrent chemoradiotherapy in non-small cell lung cancer[J]. Cochrane Database Syst Rev, 2010(6): CD002140. DOI: 10.1002/14651858.CD002140.pub3. doi: 10.1002/14651858.CD002140.pub3
[9]	Mac Manus M, Lamborn K, Khan W, et al. Radiotherapy-associated neutropenia and thrombocytopenia: analysis of risk factors and development of a predictive model[J]. Blood, 1997, 89(7): 2303-2310. pmid: 9116273
[10]	Sekine I, Sumi M, Ito Y, et al. Phase Ⅰ study of concurrent high-dose three-dimensional conformal radiotherapy with chemotherapy using cisplatin and vinorelbine for unresectable stage Ⅲ non-small-cell lung cancer[J]. Int J Radiat Oncol Biol Phys, 2012, 82(2): 953-959. DOI: 10.1016/j.ijrobp.2011.01.008. doi: 10.1016/j.ijrobp.2011.01.008
[11]	Christodoulou M, Blackhall F, Mistry H, et al. Compliance and outcome of elderly patients treated in the concurrent once-daily versus twice-daily radiotherapy (CONVERT) trial[J]. J Thorac Oncol, 2019, 14(1): 63-71. DOI: 10.1016/j.jtho.2018.09.027. doi: S1556-0864(18)33182-4 pmid: 30391573
[12]	Sugimura K, Miyata H, Tanaka K, et al. Multicenter randomized phase 2 trial comparing chemoradiotherapy and docetaxel plus 5-fluorouracil and cisplatin chemotherapy as initial induction therapy for subsequent conversion surgery in patients with clinical T_4b esophageal cancer: short-term results[J/OL]. Ann Surg, 2021, 274(6): e465-e472. DOI: 10.1097/SLA.0000000000004564. doi: 10.1097/SLA.0000000000004564
[13]	Videtic GM, Fung K, Tomiak AT, et al. Using treatment interruptions to palliate the toxicity from concurrent chemoradiation for limited small cell lung cancer decreases survival and disease control[J]. Lung Cancer, 2001, 33(2/3): 249-258. DOI: 10.1016/s0169-5002(00)00240-3. doi: 10.1016/s0169-5002(00)00240-3
[14]	Ohira M, Kubo N, Yamashita Y, et al. Impact of chemoradiation-induced myelosuppression on prognosis of patients with locally advanced esophageal cancer after chemoradiotherapy followed by esophagectomy[J]. Anticancer Res, 2015, 35(9): 4889-4895. pmid: 26254384
[15]	Xu C, Yang SP, Zhang Y, et al. Neutropenia during the first cycle of induction chemotherapy is prognostic for poor survival in locoregionally advanced nasopharyngeal carcinoma: a real-world study in an endemic area[J]. Cancer Res Treat, 2018, 50(3): 777-790. DOI: 10.4143/crt.2017.255. doi: 10.4143/crt.2017.255 pmid: 28745036
[16]	Haddad R, O'Neill A, Rabinowits G, et al. Induction chemotherapy followed by concurrent chemoradiotherapy (sequential chemoradiotherapy) versus concurrent chemoradiotherapy alone in locally advanced head and neck cancer (PARADIGM): a randomised phase 3 trial[J]. Lancet Oncol, 2013, 14(3): 257-264. DOI: 10.1016/S1470-2045(13)70011-1. doi: 10.1016/S1470-2045(13)70011-1 pmid: 23414589
[17]	Faivre-Finn C, Snee M, Ashcroft L, et al. Concurrent once-daily versus twice-daily chemoradiotherapy in patients with limited-stage small-cell lung cancer (CONVERT): an open-label, phase 3, randomised, superiority trial[J]. Lancet Oncol, 2017, 18(8): 1116-1125. DOI: 10.1016/S1470-2045(17)30318-2. doi: S1470-2045(17)30318-2 pmid: 28642008
[18]	Kubota K, Hida T, Ishikura S, et al. Etoposide and cisplatin versus irinotecan and cisplatin in patients with limited-stage small-cell lung cancer treated with etoposide and cisplatin plus concurrent accelerated hyperfractionated thoracic radiotherapy (JCOG0202): a randomised phase 3 study[J]. Lancet Oncol, 2014, 15(1): 106-113. DOI: 10.1016/S1470-2045(13)70511-4. doi: 10.1016/S1470-2045(13)70511-4 pmid: 24309370
[19]	Segawa Y, Kiura K, Takigawa N, et al. Phase Ⅲ trial comparing docetaxel and cisplatin combination chemotherapy with mitomycin, vindesine, and cisplatin combination chemotherapy with concurrent thoracic radiotherapy in locally advanced non-small-cell lung cancer: OLCSG 0007[J]. J Clin Oncol, 2010, 28(20): 3299-3306. DOI: 10.1200/JCO.2009.24.7577. doi: 10.1200/JCO.2009.24.7577
[20]	Naito Y, Kubota K, Nihei K, et al. Concurrent chemoradiotherapy with cisplatin and vinorelbine for stage Ⅲ non-small cell lung cancer[J]. J Thorac Oncol, 2008, 3(6): 617-622. DOI: 10.1097/JTO.0b013e3181753b38. doi: 10.1097/JTO.0b013e3181753b38
[21]	Senan S, Brade A, Wang LH, et al. PROCLAIM: randomized phase Ⅲ Trial of pemetrexed-cisplatin or etoposide-cisplatin plus thoracic radiation therapy followed by consolidation chemotherapy in locally advanced nonsquamous non-small-cell lung cancer[J]. J Clin Oncol, 2016, 34(9): 953-962. DOI: 10.1200/JCO.2015.64.8824. doi: 10.1200/JCO.2015.64.8824
[22]	Higuchi K, Komori S, Tanabe S, et al. Definitive chemoradiation therapy with docetaxel, cisplatin, and 5-fluorouracil (DCF-R) in advanced esophageal cancer: a phase 2 trial (KDOG 0501-P2)[J]. Int J Radiat Oncol Biol Phys, 2014, 89(4): 872-879. DOI: 10.1016/j.ijrobp.2014.03.030. doi: 10.1016/j.ijrobp.2014.03.030
[23]	Noronha V, Prabhash K, Joshi A, et al. Clinical outcome in definitive concurrent chemoradiation with weekly paclitaxel and carboplatin for locally advanced esophageal and junctional cancer[J]. Oncol Res, 2016, 23(4): 183-195. DOI: 10.3727/096504016X14537290676865. doi: 10.3727/096504016X14537290676865 pmid: 27053347
[24]	van Hagen P, Hulshof MC, van Lanschot JJ, et al. Preoperative chemoradiotherapy for esophageal or junctional cancer[J]. N Engl J Med, 2012, 366(22): 2074-2084. DOI: 10.1056/NEJMoa1112088. doi: 10.1056/NEJMoa1112088
[25]	Iwase H, Shimada M, Tsuzuki T, et al. Concurrent chemoradiotherapy with a novel fluoropyrimidine, S-1, and cisplatin for locally advanced esophageal cancer: long-term results of a phase Ⅱ trial[J]. Oncology, 2013, 84(6): 342-349. DOI: 10.1159/000348383. doi: 10.1159/000348383
[26]	Yang H, Liu H, Chen Y, 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. doi: 10.1200/JCO.2018.79.1483
[27]	Kleinberg LR, Catalano PJ, Forastiere AA, et al. Eastern Cooperative Oncology Group and American College of Radiology Imaging Network randomized phase 2 trial of neoadjuvant preoperative paclitaxel/cisplatin/radiation therapy (RT) or irinotecan/cisplatin/RT in esophageal adenocarcinoma: long-term outcome and implications for trial design[J]. Int J Radiat Oncol Biol Phys, 2016, 94(4): 738-746. DOI: 10.1016/j.ijrobp.2015.12.009. doi: 10.1016/j.ijrobp.2015.12.009
[28]	Zhu J, Liu A, Sun X, et al. Multicenter, randomized, phase Ⅲ trial of neoadjuvant chemoradiation with capecitabine and irinotecan guided by UGT1A1 status in patients with locally advanced rectal cancer[J]. J Clin Oncol, 2020, 38(36): 4231-4239. DOI: 10.1200/JCO.20.01932. doi: 10.1200/JCO.20.01932 pmid: 33119477
[29]	Zou D, Guo M, Zhou Q. A clinical study of pegylated recombinant human granulocyte colony stimulating factor (PEG-rhG-CSF) in preventing neutropenia during concurrent chemoradiotherapy of cervical cancer[J]. BMC Cancer, 2021, 21(1): 661. DOI: 10.1186/s12885-021-08364-9. doi: 10.1186/s12885-021-08364-9 pmid: 34078317
[30]	Yang X, Ren H, Li Z, et al. A phase Ⅲ randomized, controlled trial of nedaplatin versus cisplatin concurrent chemoradiotherapy in patients with cervical cancer[J]. ESMO Open, 2022, 7(5): 100565. DOI: 10.1016/j.esmoop.2022.100565. doi: 10.1016/j.esmoop.2022.100565
[31]	Gomes F, Faivre-Finn C, Mistry H, et al. Safety of G-CSF with concurrent chemo-radiotherapy in limited-stage small cell lung cancer—secondary analysis of the randomised phase 3 CONVERT trial[J]. Lung Cancer, 2021, 153: 165-170. DOI: 10.1016/j.lungcan.2021.01.025. doi: 10.1016/j.lungcan.2021.01.025
[32]	中国临床肿瘤学会指南工作委员会. 中国临床肿瘤学会(CSCO)肿瘤放化疗相关中性粒细胞减少症规范化管理指南(2021)[J]. 临床肿瘤学杂志, 2021, 26(7): 638-648. DOI: 1009-0460(2021)07-0638-11. doi: 1009-0460(2021)07-0638-11
[33]	Wang C, Zhu S, Miao C, et al. Safety and efficacy of pegylated recombinant human granulocyte colony-stimulating factor during concurrent chemoradiotherapy for small-cell lung cancer: a retrospective, cohort-controlled trial[J]. BMC Cancer, 2022, 22(1): 542. DOI: 10.1186/s12885-022-09644-8. doi: 10.1186/s12885-022-09644-8 pmid: 35562713
[34]	Li W, Dong M, Huang S, et al. Efficacy and safety of PEG-rhG-CSF in preventing chemoradiotherapy-induced neutropenia in patients with locally advanced cervical cancer[J]. Biomol Biomed, 2023, 23(2): 310-316. DOI: 10.17305/bjbms.2022.7859. doi: 10.17305/bjbms.2022.7859 pmid: 36300280
[35]	Liu F, Du Y, Cai B, et al. A clinical study of polyethylene glycol recombinant human granulocyte colony-stimulating factor prevention neutropenia syndrome in patients with esophageal carcinoma and lung cancer after concurrent chemoradiotherapy[J]. J Cancer Res Ther, 2017, 13(5): 790-795. DOI: 10.4103/jcrt.JCRT_320_17. doi: 10.4103/jcrt.JCRT_320_17 pmid: 29237905
[36]	杨晟, 何小慧, 刘鹏, 等. 聚乙二醇化重组人粒细胞集落刺激因子预防化疗后中性粒细胞减少的有效性分析[J]. 中国肿瘤临床, 2015, 42(12): 626-631. DOI: 10.3969/j.issn.1000-8179.20150577. doi: 10.3969/j.issn.1000-8179.20150577
[37]	Smith TJ, Khatcheressian J, Lyman GH, et al. 2006 update of recommendations for the use of white blood cell growth factors: an evidence-based clinical practice guideline[J]. J Clin Oncol, 2006, 24(19): 3187-3205. DOI: 10.1200/JCO.2006.06.4451. doi: 10.1200/JCO.2006.06.4451 pmid: 16682719
[38]	Wu FP, Wang J, Wang H, et al. Clinical observation of the therapeutic effects of pegylated recombinant human granulocyte colony-stimulating factor in patients with concurrent chemoradiotherapy-induced grade Ⅳ neutropenia[J]. Exp Ther Med, 2015, 9(3): 761-765. DOI: 10.3892/etm.2014.2160. doi: 10.3892/etm.2014.2160
[39]	刘青, 关嵩, 曹峰, 等. PEG-rhG-CSF对同步放化疗中性粒细胞缺乏挽救性治疗临床分析[J]. 中华肿瘤防治杂志, 2017, 24(7): 481-485. DOI: 10.16073/j.cnki.cjcpt.2017.07.010. doi: 10.16073/j.cnki.cjcpt.2017.07.010
[40]	杜艳芳, 范艳玲, 胡兵, 等. 乳腺癌术后放疗预防性使用聚乙二醇化重组人粒细胞刺激因子的临床观察[J]. 国际肿瘤学杂志, 2020, 47(3): 141-145. DOI: 10.3760/cma.j.issn.1673-422X. 2020.03.003. doi: 10.3760/cma.j.issn.1673-422X. 2020.03.003
[41]	Baden LR, Swaminathan S, Almyroudis NG, et al. NCCN Guidelines Insights: Prevention and Treatment of Cancer-Related Infections, Version 3.2022[J]. J Natl Compr Canc Netw, 2022: 10-28. https://www.nccn.org/guidelines/guidelines-detail?category=3&id=1457.
[42]	Curigliano G, Banerjee S, Cervantes A, et al. Managing cancer patients during the COVID-19 pandemic: an ESMO multidisciplinary expert consensus[J]. Ann Oncol, 2020, 31(10): 1320-1335. DOI: 10.1016/j.annonc.2020.07.010. doi: S0923-7534(20)39948-8 pmid: 32745693
[43]	中国抗癌协会肿瘤支持治疗专业委员会, 中国抗癌协会肿瘤临床化疗专业委员会. 新型冠状病毒肺炎疫情期间实体肿瘤患者防护和诊治管理相关问题中国专家共识(2022版)[J]. 中华肿瘤杂志, 2022, 44(10): 1083-1090. DOI: 10.3760/cma.j.cn112152-20220505-00309. doi: 10.3760/cma.j.cn112152-20220505-00309
[44]	Shi YK, Chen Q, Zhu YZ, et al. Pegylated filgrastim is comparable with filgrastim as support for commonly used chemotherapy regimens: a multicenter, randomized, crossover phase 3 study[J]. Anticancer Drugs, 2013, 24(6): 641-647. DOI: 10.1097/CAD.0b013e3283610b5d. doi: 10.1097/CAD.0b013e3283610b5d
[45]	Pfeil AM, Allcott K, Pettengell R, et al. Efficacy, effectiveness and safety of long-acting granulocyte colony-stimulating factors for prophylaxis of chemotherapy-induced neutropenia in patients with cancer: a systematic review[J]. Support Care Cancer, 2015, 23(2): 525-524. DOI: 10.1007/s00520-014-2457-z. doi: 10.1007/s00520-014-2457-z pmid: 25284721
[46]	Kirshner JJ, Heckler CE, Janelsins MC, et al. Prevention of pegfilgrastim-induced bone pain: a phase Ⅲ double-blind placebo-controlled randomized clinical trial of the university of rochester cancer center clinical community oncology program research base[J]. J Clin Oncol, 2012, 30(16): 1974-1979. DOI: 10.1200/JCO.2011.37.8364. doi: 10.1200/JCO.2011.37.8364 pmid: 22508813

推荐级别	代表意义
1类	基于高级别临床研究证据，专家意见高度一致
2A类	基于低级别临床研究证据，专家意见高度一致；或基于高级别证据，专家意见基本一致
2B类	基于低级别临床研究证据，专家意见基本一致
3类	不论基于何种级别临床证据，专家意见明显分歧