Supplementary Material for: Temozolomide Alone or Combined with Capecitabine for the Treatment of Advanced Pancreatic Neuroendocrine Tumor

Background: The combination of capecitabine (CAP) with temozolomide (TEM) chemotherapy in advanced pancreatic neuroendocrine tumors (PanNET) relies on limited evidence. We compared TEM-CAP to TEM alone in patients with advanced PanNET. Methods: Consecutive patients with advanced PanNET treated with TEM or TEM-CAP between 2004 and 2017 in three expert centers were included. Progression-free survival (PFS), tolerance, tumor response, and overall survival were compared between the two groups. Propensity-based analyses were performed to reduce confounding bias due to the nonrandomized setting. Results: TEM and TEM-CAP were administered to 38 patients and 100 patients, respectively, with a median age of 58 years. The patients in the TEM group more often had hormonal syndromes (p = 0.03), a longer median delay to diagnosis (p = 0.001), and a higher number of pretreatment lines (p < 0.001). The performance status was 0 in 58% versus 65% of the patients, and tumor’s median Ki-67 index was 8% versus 11%, respectively. Tolerance was similar, except that there were more cases of asthenia in the TEM group (p = 0.017) and more cases of hand-foot syndrome in the TEM-CAP group (p = 0.025). The objective response rate was 34% versus 51% (p = 0.088). The raw median PFS was similar with TEM and with TEM-CAP (21.4 vs. 19.8 months, p = 0.84). Although CAP tended to decrease the risk of progression in Cox multivariate analysis (HR 0.65, p = 0.12), it had no effect after adjustment for the propensity score (HR 1.06, p = 0.80). Conclusions: TEM-CAP might not prolong PFS but might achieve a higher response rate than TEM alone. Hence, TEM-CAP might be preferred when tumor shrinkage is the main therapeutic objective. Otherwise, TEM might be adequate for patients with an impaired performance status or in case of extrahepatic metastases.

背景：晚期胰腺神经内分泌肿瘤（pancreatic neuroendocrine tumors, PanNET）中采用卡培他滨（capecitabine, CAP）联合替莫唑胺（temozolomide, TEM）的化疗方案，目前相关循证医学证据较为有限。本研究针对晚期PanNET患者，对比了TEM-CAP联合方案与单药TEM方案的疗效。
方法：本研究纳入2004年至2017年间，于三家专业诊疗中心接受单药TEM或TEM-CAP联合方案治疗的晚期PanNET连续入组患者。对两组患者的无进展生存期（progression-free survival, PFS）、药物耐受性、肿瘤应答情况及总生存期进行对比。鉴于本研究为非随机对照设计，我们采用基于倾向得分的分析方法以降低混杂偏倚。
结果：本研究共纳入138例患者，其中38例接受单药TEM治疗，100例接受TEM-CAP联合治疗，患者中位年龄为58岁。单药TEM组患者更常出现激素综合征（p=0.03），确诊中位延迟时间更长（p=0.001），且既往治疗线数更多（p<0.001）。两组患者体力状态评分为0的占比分别为58%与65%，肿瘤中位Ki-67指数分别为8%与11%。两组药物耐受性整体相似，但单药TEM组乏力发生率更高（p=0.017），TEM-CAP联合组手足综合征发生率更高（p=0.025）。客观缓解率分别为34%与51%（p=0.088）。两组原始中位无进展生存期相近，单药TEM组为21.4个月，TEM-CAP联合组为19.8个月（p=0.84）。在Cox多因素分析中，CAP联合治疗虽有降低疾病进展风险的趋势（风险比HR=0.65，p=0.12），但经倾向得分调整后，该效应不再显著（HR=1.06，p=0.80）。
结论：TEM-CAP联合方案虽未显著延长无进展生存期，但相较单药TEM可获得更高的肿瘤应答率。因此，当以肿瘤缩小为主要治疗目标时，可优先选择TEM-CAP联合方案；反之，对于体力状态受损或存在肝外转移的患者，单药TEM治疗即可满足需求。