J Natl Cancer Inst. 1997 Apr 2;89(7):497-505.
Systemic delivery of cytotoxic drugs yields relatively low doses in the liver, a major site of recurrence for colorectal cancer. Giving chemotherapy by means of continuous portal vein infusion (PVI) into the liver during the immediate postoperative period may improve therapeutic efficacy.
We undertook a meta-analysis to assess the effects on recurrence and survival of administering fluorouracil (5-FU)-based chemotherapy by PVI after colorectal cancer surgery.
Data on mortality and recurrence were sought for all patients enrolled in randomized trials initiated before 1987 in which a few days (range, 5-7 days) of continuous postoperative PVI of cytotoxic drugs was compared with no further treatment. Data from 10 trials (a promising initial study and nine hypothesis-testing trials) involving about 4000 patients were available for analysis. The main cytotoxic drug in each trial was 5-FU (given with heparin); however, mitomycin C was co-administered in two of the trials. Four trials included an additional control group of patients treated with continuous noncytotoxic PVI of either heparin or urokinase alone; one trial included a second control group of patients treated with continuous systemic infusion of 5-FU. Reported P values are two-sided.
Among the 3499 patients randomly assigned to receive either cytotoxic PVI or no further treatment, 1557 deaths are known to have occurred. Survival with and without PVI appeared to be the same for the first 2 years; thereafter, it diverged significantly, with the absolute survival difference (i.e., improvement) associated with PVI at 5 years being 4.7 % (standard deviation [SD] = 1.2 %) (P = .006). When just the nine hypothesis-testing trials were considered, the absolute survival difference was 3.6% (SD = 1.2%) (P = .04). If, ignoring any potential for bias in stage assignment, attention was restricted to patients with Dukes' stage A, B, or C disease (88.3% of the total), the absolute effect on 5-year survival for all 10 trials increased to 6.0% (SD = 1.8%) (P = .001); this estimate remained statistically significant when the initial study was excluded (absolute survival difference = 4.8%; SD = 1.8%; P = .01). In contrast to the highly significant reduction in liver metastases seen in the initial study (79% reduction; SD = 15%; P = .00000007), the reduction found in the nine hypothesis-testing trials was not significant (14% reduction; SD = 10%; P = .2). In the trials with additional control groups, survival appeared to be better with cytotoxic PVI than with noncytotoxic PVI or with systemic cytotoxic drug infusion.
PVI of 5-FU (with or without other cytotoxic drugs) for about 1 week after surgery in patients with colorectal cancer may produce an absolute improvement in 5-year survival of a few percent. Although encouraging, this finding is not statistically secure, and additional evidence from randomized trials involving several thousand more patients is needed.
细胞毒性药物的全身给药在肝脏（结直肠癌复发的主要部位）产生的剂量相对较低。在术后即刻通过持续门静脉输注（PVI）将化疗药物注入肝脏可能会提高治疗效果。
我们进行了一项荟萃分析，以评估结直肠癌手术后通过PVI给予基于氟尿嘧啶（5-FU）的化疗对复发和生存的影响。
我们查找了1987年之前启动的随机试验中所有患者的死亡率和复发数据，这些试验将术后连续几天（范围为5 - 7天）的细胞毒性药物PVI与不进行进一步治疗进行了比较。来自10项试验（1项有前景的初始研究和9项假设检验试验）、涉及约4000名患者的数据可供分析。每项试验中的主要细胞毒性药物为5-FU（与肝素联合使用）；然而，两项试验中同时使用了丝裂霉素C。4项试验纳入了另外的对照组，这些患者接受单独的肝素或尿激酶持续非细胞毒性PVI治疗；1项试验纳入了第二个对照组，这些患者接受5-FU持续全身输注治疗。报告的P值为双侧。
在随机分配接受细胞毒性PVI或不进行进一步治疗的3499例患者中，已知有1557例死亡。接受PVI和未接受PVI的患者在前2年的生存率似乎相同；此后，两者出现显著差异，PVI在5年时的绝对生存差异（即改善）为4.7%（标准差[SD]=1.2%）（P = 0.006）。仅考虑9项假设检验试验时，绝对生存差异为3.6%（SD = 1.2%）（P = 0.04）。如果忽略分期分配中任何潜在的偏倚，将注意力仅集中在Dukes A、B或C期疾病患者（占总数的88.3%）上，所有10项试验对5年生存的绝对影响增加到了6.0%（SD = 1.8%）（P = 0.001）；排除初始研究后，这一估计仍具有统计学意义（绝对生存差异 = 4.8%；SD = 1.8%；P = 0.01）。与初始研究中观察到的肝转移显著减少（减少79%；SD = 15%；P = 0.00000007）相反，9项假设检验试验中发现的减少并不显著（减少14%；SD = 10%；P = 0.2）。在有额外对照组的试验中，细胞毒性PVI组的生存率似乎优于非细胞毒性PVI组或全身细胞毒性药物输注组。
结直肠癌患者术后约1周进行5-FU（有或无其他细胞毒性药物）的PVI可能会使5年生存率绝对提高几个百分点。尽管这一发现令人鼓舞，但在统计学上并不确凿，还需要来自涉及数千名更多患者的随机试验的额外证据。
