Stage IA Patients With Pancreatic Ductal Adenocarcinoma Cannot Benefit From Chemotherapy: A Propensity Score Matching Study

Abstract

Purpose: Adjuvant chemotherapy following resection is recommended by clinical practice guidelines for all patients with pancreatic ductal adenocarcinoma (PDAC). This study aimed to evaluate the efficacy of adjuvant chemotherapy among the staging groups of the American Joint Committee on Cancer (AJCC) for PDAC. Patients and Methods: This retrospective cohort analysis was performed by the Surveillance Epidemiology and End Results (SEER) (2004-2015) database and multi-institutional dataset (2010-2018). Baseline clinicopathologic characteristics of PDAC patients, including age, gender, ethnicity, marital status, education level, county income level, county unemployed rate, insurance status, grade, stage, chemotherapy, and radiotherapy, were collected. Overall survival (OS) was analyzed using the Kaplan-Meier method. The SEER and multi-institutional data were adjusted with 1:1 ratio propensity score matching (PSM). Results: In total, 6,274 and 1,361 PDAC patients were included from the SEER database and multi-institutional dataset, respectively. Regardless of the count of resected lymph nodes, adjuvant chemotherapy prolonged the long-term OS time for stage IB, IIA, IIB, and III patients in both SEER and multi-institutional cohorts. Nevertheless, adjuvant chemotherapy did not provide additional clinical benefits even after a PSM adjustment for stage IA patients in both SEER and multi-institutional cohorts. Conclusion: Adjuvant chemotherapy improved the long-term survival of stage IB, IIA, IIB, and III PDAC patients; however, it demonstrated no survival benefit in stage IA PDAC patients. Thus, adjuvant chemotherapy should not be recommended for stage IA PDAC patients. These would significantly reduce the economic burden of society and improve the life quality of stage IA PDAC patients.

A novel risk-scoring system conducing to chemotherapy decision for patients with pancreatic ductal adenocarcinoma after pancreatectomy

“…In fact, the predictive effect of the AJCC staging system, detected by C-index (nomogram: 0.637, 95%CI: 0.630-0.645; vs. the AJCC staging system: 0.616, 95%CI: 0.608-0.624), calibration curves, ROC curves and DCA curves, was not as good as the nomogram in this study (Supplementary Figure 2). In fact, the results regarding the survival difference between chemotherapy and non-chemotherapy in each AJCC stage display that only stage IA PDAC cannot obtain survival benefit from chemotherapy (Supplementary Figure 3), which matches the previous study [8]. Furthermore, the early-stage PDAC patients defined by the AJCC staging system may be classified as intermediate or high-risk groups, as displayed by the Sankey diagrams.…”

“…Advanced surgical concepts may allow more resectable PDAC patients to avoid multi-drug chemotherapy or even chemotherapy. Moreover, a recent study reported that PDAC patients with stage IA cannot receive better survival from chemotherapy [8]. These evidences motivated us to identify low-risk PDAC patients after pancreatectomy who do not need chemotherapy.…”

“…A meta-analysis including five randomized controlled trials showed that adjuvant chemotherapy only provided an extra 3 months of median survival time for patients with resected PDAC [7]. A recent study confirmed that chemotherapy even cannot provide survival benefit for patients with early-stage PDAC [8]. Moreover, experiences from the treatment of other tumors, such as colorectal cancer, gastric cancer, are able to affirm that early-stage tumors can be completely cured by surgical resection.…”

Adjuvant chemotherapy in pancreatic cancer at different AJCC stages: a propensity score matching analysis

“…However, the potential benefits of adjuvant chemotherapy for patients with varying stages of pancreatic cancer remain unclear. A multicenter cohort study [ 4 ] has demonstrated that adjuvant chemotherapy enhances long-term survival among patients with stage IB, IIA, IIB, and III pancreatic cancer. However, adjuvant chemotherapy does not confer a survival benefit to patients with stage IA pancreatic cancer.…”

Whether early stage pancreatic ductal adenocarcinoma patients could benefit from the post-operation chemotherapy regimens: a SEER-based propensity score matching study

“…( surveillance，epidemiology, and end results，SEER) ；美国癌症联合委员会 (American Joint Committee on Cancer，AJCC) ；风险比(hazard ratio，HR)；可信区间(credibility interval，CI) 胰腺癌是世界范围内恶性程度最高的肿瘤之一，也是全球癌症相关死亡的主要原因 [1] ，位居中国恶性 肿瘤病死率第 6 位，其中 PDAC 患者占比超过 85% [2] 。超过 80%的 PDAC 患者在诊断时已处于不可切除 或远处转移的状态，这使得仅有 6%左右的 PDAC 患者存活超过 5 年 [3] 。目前，根治性手术治疗是治愈胰 腺癌的唯一方法，而对那些接受了手术治疗的患者， 66%~92%在 2 年内复发， 5 年存活率也仅仅 20% [4] 。由于胰腺癌患者术后复发率较高，NCCN 指南建议所有接受手术的胰腺癌患者都应该接受术后辅 助化疗(Folfirinox 方案、吉西他滨单药方案或吉西他滨联合卡培他滨方案)，以延长术后存活时间 [5] 。 而针对胰腺腺癌的化疗方案毒副作用较大，患者在接受化疗的过程中可能会经历严重的恶心呕吐、乏力、 疼痛、骨髓抑制等不良反应 [6] 。目前，已证实一些早期消化道肿瘤患者不能从术后辅助化疗中获益 [7][8] ，因 此部分学者对Ⅰ A 期胰腺癌患者术后是否需要化疗存疑。Walid 等 [9] 研究证实，肿瘤小于 1 cm 的 PDAC 患者不能从术后辅助治疗中获得生存收益；Zhang 等 [10] [13] ；以吉西他滨联合卡培他滨为主的辅助化疗方案可以显著延长胰腺癌患者的术后生存时间 [14] ；Folfirinox 方案常作为胰腺癌的一线化疗方案，Neoptolemos 等 [15] 证明以氟尿嘧啶为基础的术后化 疗可以显著提高胰腺癌患者的 年存活率；对氟尿嘧啶的剂量进行调整后的改良 Folfirinox 方案可以延长 PDAC 患者的术后生存时间 [16] 。但上述化疗方案都相对激进，化疗产生的毒副作用较大。 由于胰腺癌恶性程度高，生长较隐匿，疾病确诊时大多数病例处于局部晚期或已发生远处转移，只有 10%~20%的胰腺癌患者有机会接受手术治疗，而这其中归类至Ⅰ A 期的患者往往数量更少。目前大多数 临床试验中Ⅰ A 期胰腺癌患者数量只有几例或十几例，术后化疗对这部分胰腺癌患者的有效性及相关临床 试验结果的准确性存在争议。尽管 NCCN 指南推荐Ⅰ A 期 PDAC 患者需接受术后化疗，但部分学者提出 了不同的看法 [9][10] 。同时，目前开展的大多数关于胰腺癌化疗疗效的临床试验及前瞻性研究都聚焦于分子 靶向治疗、免疫治疗等新兴疗法与传统化疗方案之间的生存差异 [17][18][19] ，研究早期胰腺癌患者能否从化疗中 获益的临床试验缺乏。因此，本研究通过对 SEER 数据库Ⅰ A~ⅡB 期 PDAC 且接受过手术治疗的患者资料 进行回顾性分析，以探究术后辅助化疗能否改善早期 PDAC 患者的生存预后。 本文资料通过生存分析、多因素分析发现，目前常用的化疗方案并不能延长接受了手术治疗的Ⅰ A 期 PDAC 患者的术后生存时间，也不能提高患者的 3 年存活率。Zhang 等 [10] 通过回顾性分析也得到类似的 结论。本研究根据Ⅰ A 期患者肿瘤分化程度分析，结果低分化和未分化的Ⅰ A 期胰腺癌患者可以从术后化 疗中获得生存收益，而高分化、中分化的患者则不能从目前常用的化疗方案中获得生存收益。 由于胰腺位于后腹膜、腹腔深处，与周围器官的关系密切，客观来讲胰腺癌的手术难度较大。同时， 胰腺癌的侵袭性强，Vennin 等 [20] 证实，胰腺癌细胞能通过分泌基底膜蛋白多糖改变肿瘤微环境，同化周 围的成纤维细胞，从而增强肿瘤的局部侵袭性和转移能力。因此，胰腺癌患者整体术后复发率很高 ， 66%~92%的患者在两年内复发。术后化疗对延长患者术后生存时间显得尤为重要。胰腺癌患者术后化疗 的目的主要是通过化疗药物对细胞核内 DNA 合成、转录的干扰、拮抗来抑制肿瘤的生长，降低肿瘤术后 复发率，延长患者的无瘤生存时间。但化疗药物在杀伤肿瘤细胞的同时也会对杀伤正常细胞，产生毒副作 用。对于Ⅰ A 期胰腺癌患者来说，由于肿瘤体积较小(＜ 2 cm)，患者有很大的概率获得根治性切除 。 Matsumoto 等 [21] 研究证实肿瘤直径大于 3 cm 的胰腺癌患者术后可能更容易发生远处转移，说明肿瘤体 积小的患者远处转移的发生率更低，这解释了为什么Ⅰ A 期胰腺癌患者无法从术后化疗中生存获益。田景 媛等 [22]…”