高龄与Ⅱ期结直肠癌患者预后不良的相关性研究

doi:10.19401/j.cnki.1007-3639.2024.05.005

摘要/Abstract

摘要：

背景与目的： 随着人口老龄化，老年结直肠癌（colorectal cancer，CRC）患者日益增加。目前高龄Ⅱ期CRC患者在接受根治术后通常接受减弱的化疗方案或不化疗，而这是否会引起不良的肿瘤学结局目前仍不明确。本研究旨在通过多因素COX回归分析方法探究去除偏倚后，高龄对于Ⅱ期CRC患者预后的影响。方法： 回顾性收集3 314例2008—2019年在复旦大学附属肿瘤医院接受过手术治疗且术后病理学检查结果为Ⅱ期、无既往肿瘤史、术后5年内无第二原发肿瘤且术前未接受新辅助治疗的CRC患者。本研究通过复旦大学附属肿瘤医院医学伦理委员会的审查（伦理编号：050432-4-2108*）。使用R软件（version 3.0）的survminer包（surv_cutpoint算法）计算年龄相对于生存的最佳临界值为73岁。比较高龄组（年龄>73岁）和非高龄组（年龄≤73岁）的临床病理学特征、总生存期（overall survival，OS）和无病生存期（disease-free survival，DFS），并使用survival包和rms包绘制列线图预测模型。结果： 高龄组和非高龄组在性别、肿瘤位置、分化、脉管侵犯、神经侵犯和pT分期等方面均衡可比。多因素COX回归分析显示，高龄是OS[风险比（hazard ratio，HR）=3.667（2.946~4.565），P <0.001]和DFS[HR=2.368（1.953~2.872），P<0.001]的独立预后危险因素。根据多因素COX回归分析构建的列线图预测模型可以有效地评估Ⅱ期CRC患者的预后。结论： 在Ⅱ期CRC患者中，高龄与较短的OS及DFS相关。足够强度的辅助化疗或许是必要的。治疗决策可根据患者列线图预测模型得分进行调整。

关键词: 结直肠癌, 高龄, 预后, 化疗方案, 预测模型

Abstract:

Background and purpose: With the aging population, the number of elderly patients with colorectal cancer (CRC) is increasing. To date, elderly patients with stage Ⅱ CRC often receive a weakened chemotherapy regimen or even no chemotherapy after radical surgery, and It is still unclear whether this will lead to adverse oncological outcomes. This study aimed to explore the prognostic impact of advanced age on stage Ⅱ CRC patients after removing bias through a multivariate COX regression approach. Methods: We retrospectively collected data of 3314 colorectal cancer patients with postoperative pathology of stage Ⅱ, no history of previous tumors, no secondary primary tumors within 5 years after surgery and no preoperative neoadjuvant therapy. This study was reviewed by the medical ethics committee of Fudan University Shanghai Cancer Center (ethics number: 050432-4-2108*). The optimal threshold for calculating age relative to survival using survminer package of R software (version 3.0) (surv_cutpoint algorithm) was 73 years. We compared the clinical and pathological characteristics, overall survival (OS) and disease-free survival (DFS) between the older group (age>73 years) and the younger group (age≤73 years). The alignment diagram prediction model was drawn using the survival package and RMS package. Results: The elderly and non-elderly groups were evenly comparable in terms of gender, tumor location, differentiation, vascular invasion, perineural invasion and pT stage. Multivariate COX regression showed that advanced age was an independent prognostic risk factor for OS [hazard ratio (HR)=3.725 (3.051-4.549), P<0.001] and DFS [HR=2.431 (2.029-2.912), P<0.001]. The nomogram (alignment diagram) prediction model constructed based on multivariate COX regression could effectively evaluate the prognosis of stage Ⅱ CRC patients and provide guidance for practical clinical work. Conclusion: In stage Ⅱ CRC patients, older age is associated with shorter OS and DFS. Adequate intensity of adjuvant chemotherapy may be necessary. Treatment decisions can be adjusted based on the predicted model scores of the patient’s alignment diagram.

Key words: Colorectal cancer, Advanced age, Prognosis, Chemotherapy regimen, Prediction model

中图分类号:

R735.3

张若昕, 叶紫岚, 翁俊勇, 李心翔. 高龄与Ⅱ期结直肠癌患者预后不良的相关性研究[J]. 中国癌症杂志, 2024, 34(5): 485-492.

ZHANG Ruoxin, YE Zilan, WENG Junyong, LI Xinxiang. Correlation study between advanced age and inferior prognosis in stage Ⅱ colorectal cancer patients[J]. China Oncology, 2024, 34(5): 485-492.

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参考文献 36

[1]	MILLER K D, NOGUEIRA L, DEVASIA T, et al. Cancer treatment and survivorship statistics, 2022[J]. CA Cancer J Clin, 2022, 72(5): 409-436.
[2]	SUNG H, FERLAY J, SIEGEL R L, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin, 2021, 71(3): 209-249.
[3]	KIM J H. Chemotherapy for colorectal cancer in the elderly[J]. World J Gastroenterol, 2015, 21(17): 5158-5166.
[4]	ZHANG H, HU H Q, HUANG R, et al. Natural orifice specimen extraction surgery versus conventional laparoscopic-assisted resection for colorectal cancer in elderly patients: a propensity-score matching study[J]. Updates Surg, 2022, 74(2): 599-607.
[5]	BETESH A L, SCHNOLL-SUSSMAN F H. Colorectal cancer screening in the elderly[J]. Clin Geriatr Med, 2021, 37(1): 173-183. doi: 10.1016/j.cger.2020.08.012 pmid: 33213771
[6]	KANNARKATT J, JOSEPH J, KURNIALI P C, et al. Adjuvant chemotherapy for stage Ⅱ colon cancer: a clinical dilemma[J]. J Oncol Pract, 2017, 13(4): 233-241.
[7]	SCHRAG D, RIFAS-SHIMAN S, SALTZ L, et al. Adjuvant chemotherapy use for medicare beneficiaries with stage Ⅱ colon cancer[J]. J Clin Oncol, 2002, 20(19): 3999-4005.
[8]	FONTANA E, MEYERS J, SOBRERO A, et al. Early-onset colorectal adenocarcinoma in the IDEA database: treatment adherence, toxicities, and outcomes with 3 and 6 months of adjuvant fluoropyrimidine and oxaliplatin[J]. J Clin Oncol, 2021, 39(36): 4009-4019.
[9]	ANDRÉ T, MEYERHARDT J, IVESON T, et al. Effect of duration of adjuvant chemotherapy for patients with stage Ⅲ colon cancer (IDEA collaboration): final results from a prospective, pooled analysis of six randomised, phase 3 trials[J]. Lancet Oncol, 2020, 21(12): 1620-1629.
[10]	PETRELLI F, LABIANCA R, ZANIBONI A, et al. Assessment of duration and effects of 3 vs 6 months of adjuvant chemotherapy in high-risk stage Ⅱ colorectal cancer: a subgroup analysis of the TOSCA randomized clinical trial[J]. JAMA Oncol, 2020, 6(4): 547-551.
[11]	IVESON T J, KERR R S, SAUNDERS M P, et al. 3 versus 6 months of adjuvant oxaliplatin-fluoropyrimidine combination therapy for colorectal cancer (SCOT): an international, randomised, phase 3, non-inferiority trial[J]. Lancet Oncol, 2018, 19(4): 562-578. doi: S1470-2045(18)30093-7 pmid: 29611518
[12]	MIMA K, KURASHIGE J, MIYANARI N, et al. Advanced age is a risk factor for recurrence after resection in stage Ⅱ colorectal cancer[J]. In Vivo, 2020, 34(1): 339-346.
[13]	NAGTEGAAL I D. Never too old to fight cancer? What do we know about colorectal cancer in the elderly?[J]. Colorectal Dis, 2017, 19(3): 223.
[14]	NITSCHE U, SPÄTH C, MÜLLER T C, et al. Colorectal cancer surgery remains effective with rising patient age[J]. Int J Colorectal Dis, 2014, 29(8): 971-979. doi: 10.1007/s00384-014-1914-y pmid: 24924447
[15]	HE J N, BIAN X H, SONG C X, et al. High neutrophil to lymphocyte ratio with type 2 diabetes mellitus predicts poor prognosis in patients undergoing percutaneous coronary intervention: a large-scale cohort study[J]. Cardiovasc Diabetol, 2022, 21(1): 156.
[16]	SHI Q, ANDRE T, GROTHEY A, et al. Comparison of outcomes after fluorouracil-based adjuvant therapy for stages Ⅱ and Ⅲ colon cancer between 1978 to 1995 and 1996 to 2007: evidence of stage migration from the ACCENT database[J]. J Clin Oncol, 2013, 31(29): 3656-3663.
[17]	HOSHINO N, HASEGAWA S, HIDA K, et al. Nomogram for predicting recurrence in stage Ⅱ colorectal cancer[J]. Acta Oncol, 2016, 55(12): 1414-1417.
[18]	BENSON A B 3rd, SCHRAG D, SOMERFIELD M R, et al. American Society of Clinical Oncology recommendations on adjuvant chemotherapy for stage Ⅱ colon cancer[J]. J Clin Oncol, 2004, 22(16): 3408-3419.
[19]	BENSON A B, VENOOK A P, AL-HAWARY M M, et al. NCCN guidelines insights: colon cancer, version 2.2018[J]. J Natl Compr Canc Netw, 2018, 16(4): 359-369.
[20]	BENSON A B 3rd, VENOOK A P, CEDERQUIST L, et al. Colon cancer, version 1.2017, NCCN clinical practice guidelines in oncology[J]. J Natl Compr Canc Netw, 2017, 15(3): 370-398.
[21]	CASTLE S C. Clinical relevance of age-related immune dysfunction[J]. Clin Infect Dis, 2000, 31(2): 578-585. doi: 10.1086/313947 pmid: 10987724
[22]	UHRLAUB J L, SMITHEY M J, NIKOLICH-ŽUGICH J. Cutting edge: the aging immune system reveals the biological impact of direct antigen presentation on CD8 T cell responses[J]. J Immunol, 2017, 199(2): 403-407. doi: 10.4049/jimmunol.1700625 pmid: 28615415
[23]	LI G, SMITHEY M J, RUDD B D, et al. Age-associated alterations in CD8α⁺ dendritic cells impair CD8 T-cell expansion in response to an intracellular bacterium[J]. Aging Cell, 2012, 11(6): 968-977.
[24]	CASTLE S, UYEMURA K, WONG W, et al. Evidence of enhanced type 2 immune response and impaired upregulation of a type 1 response in frail elderly nursing home residents[J]. Mech Ageing Dev, 1997, 94(1/2/3): 7-16.
[25]	WANG C, YUAN Y, ZHENG M Y, et al. Association of age of onset of hypertension with cardiovascular diseases and mortality[J]. J Am Coll Cardiol, 2020, 75(23): 2921-2930.
[26]	SORRENTINO M F, KIM J, FODERARO A E, et al. 5-fluorouracil induced cardiotoxicity: review of the literature[J]. Cardiol J, 2012, 19(5): 453-458. pmid: 23042307
[27]	JENSEN S A, SØRENSEN J B. 5-fluorouracil-based therapy induces endovascular injury having potential significance to development of clinically overt cardiotoxicity[J]. Cancer Chemother Pharmacol, 2012, 69(1): 57-64.
[28]	VAN CUTSEM E, HOFF P M, BLUM J L, et al. Incidence of cardiotoxicity with the oral fluoropyrimidine capecitabine is typical of that reported with 5-fluorouracil[J]. Ann Oncol, 2002, 13(3): 484-485. doi: 10.1093/annonc/mdf108 pmid: 11996484
[29]	Surgery for colorectal cancer in elderly patients: a systematic review. Colorectal Cancer Collaborative Group[J]. Lancet, 2000, 356(9234): 968-974.
[30]	FORMICA V, ZANIBONI A, LOUPAKIS F, et al. Noninferiority of three months versus six months of oxaliplatin-based adjuvant chemotherapy for resected colon cancer. how should IDEA findings affect clinical practice?[J]. Int J Cancer, 2018, 143(10): 2342-2350. doi: 10.1002/ijc.31616 pmid: 29873066
[31]	FELIU J, SERENO M, CASTRO J D, et al. Chemotherapy for colorectal cancer in the elderly: whom to treat and what to use[J]. Cancer Treat Rev, 2009, 35(3): 246-254. doi: 10.1016/j.ctrv.2008.11.004 pmid: 19345021
[32]	BRAGA M, GIANOTTI L, VIGNALI A, et al. Preoperative oral arginine and n-3 fatty acid supplementation improves the immunometabolic host response and outcome after colorectal resection for cancer[J]. Surgery, 2002, 132(5): 805-814.
[33]	GIANOTTI L, BRAGA M, NESPOLI L, et al. A randomized controlled trial of preoperative oral supplementation with a specialized diet in patients with gastrointestinal cancer[J]. Gastroenterology, 2002, 122(7): 1763-1770. doi: 10.1053/gast.2002.33587 pmid: 12055582
[34]	CHEN Y, LIU B L, SHANG B, et al. Nutrition support in surgical patients with colorectal cancer[J]. World J Gastroenterol, 2011, 17(13): 1779-1786.
[35]	MIYATA H, YANO M, YASUDA T, et al. Randomized study of clinical effect of enteral nutrition support during neoadjuvant chemotherapy on chemotherapy-related toxicity in patients with esophageal cancer[J]. Clin Nutr, 2012, 31(3): 330-336. doi: 10.1016/j.clnu.2011.11.002 pmid: 22169459
[36]	MIYATA H, YANO M, YASUDA T, et al. Randomized study of the clinical effects of ω-3 fatty acid-containing enteral nutrition support during neoadjuvant chemotherapy on chemotherapy-related toxicity in patients with esophageal cancer[J]. Nutrition, 2017, 33: 204-210. doi: S0899-9007(16)30124-1 pmid: 27644137

Characteristic	Age≤73 years old (n=2 820)	Age>73 years old (n=494)	P value
Age/year $\bar{x} \pm s$	57.36±9.995	78.22±3.570
Gender			0.545
Male	1 777 (63.0)	304 (61.5)
Female	1 043 (37.0)	190 (38.5)
Location			0.061
Rectum	1 196 (42.4)	192 (38.9)
Left colon	699 (24.8)	131 (26.5)
Right colon	916 (32.5)	170 (34.4)
Unknown	9 (0.3)	1 (0.2)
Differentiation			0.359
Poor	547 (19.4)	113 (22.9)
Moderate	2 183 (77.4)	366 (74.1)
Well	32 (1.1)	5 (1.0)
Unknown	58 (2.1)	10 (2.0)
Intravascular invasion			0.791
-	2 586 (91.7)	455 (92.1)
+	234 (8.3)	39 (7.9)
Neural invasion			0.087
-	2 388 (84.7)	433 (87.7)
+	432 (15.3)	61 (12.3)
pT stage			0.456
3	1 147 (40.7)	192 (38.9)
4	1 673 (59.3)	302 (61.1)

	OS				DFS
	Univariate P value	Multivariate analysis			Univariate P value	Multivariate analysis
	Univariate P value	HR	95% CI	P value	Univariate P value	HR	95% CI	P value
Age/year
≤73	<0.001	—			<0.001	—
>73	<0.001	3.667	2.946-4.565	<0.001	<0.001	2.368	1.953-2.872	<0.001
Gender
Female	0.026	—			0.028	—
Male	0.026	1.272	1.018-1.591	0.035	0.028	1.200	1.001-1.440	0.049
Location
Rectum	0.513	—			0.128	—
Left colon		0.824	0.626-1.085	0.167		0.809	0.648-1.011	0.062
Right colon		0.894	0.701-1.140	0.365		0.831	0.679-1.017	0.073
Differentiation
Well	0.45	—			0.04	—
Median		1.046	0.418-2.613	0.924		1.181	0.517-2.698	0.692
Poor		0.945	0.387-2.306	0.901		0.952	0.679-1.017	0.073
pT stage
3	0.217	—			0.562	—
4	0.217	1.127	0.849-1.495	0.408	0.562	1.047	0.856-1.279	0.655
Lymphovasclular invasion
No	0.029	—			0.001	—
Yes	0.029	1.360	0.963-1.922	0.081	0.001	1.455	1.108-1.911	0.007
Neural invasion
No	0.019	—			<0.001	—
Yes	0.019	1.504	1.132-1.999	0.005	<0.001	1.599	1.279-1.999	<0.001