Hepatic arterial infusion chemotherapy for colorectal liver metastases revisited

BackgroundRecent reports indicate improved survival in patients undergoing surgical treatment for colorectal liver metastases (CRLM) with hepatic arterial infusion (HAI) pump chemotherapy compared to surgery alone.MethodsPatients who underwent resection and/or ablation of CRLM between 1996 and 2016 were included from a single-institution prospectively maintained database. Proportional hazards regression analysis was performed to determine predictors of overall survival (OS) and 3:1 propensity score analysis (PSA).ResultsOf 349 patients included, 36 had HAI pumps placed (HAI group) and 313 did not (no-HAI group). There was no difference in primary tumor grade (p = 0.24), ECOG status (p = 0.44), tumor number (p = 0.1), tumor size (p = 0.56), margin status (p = 0.76) between the two groups.Median overall survival was 44.7months vs 37.1months for the HAI versus no-HAI group (p = 0.01). Cox proportional hazards regression analysis demonstrated positive margin status (HR:2.47,p < 0.0001), HAI therapy (HR:0.56,p = 0.02), preoperative chemotherapy (HR:0.69,p = 0.02) and tumor diameter (HR:1.07,p = 0.005) as predictors of OS. In 3:1 PSA, 32 HAI subjects were matched with 87 non-HAI subjects balancing all covariates. Median OS was 42.4 months versus 35.6 months for the HAI versus no-HAI group (p = 0.03).ConclusionSurgical treatment of CRLM combined with HAI chemotherapy is associated with improved OS compared to surgery alone. Further study of this treatment approach is indicated.     

Hepatic arterial infusion alternating with systemic chemotherapy in patients with non-resectable hepatic metastases from colorectal cancer

BACKGROUND AND AIM: Hepatic arterial infusion (HAI) chemotherapy has a number of limitations, including a low rate of complete response and frequent extrahepatic recurrence, in colorectal cancer patients with non-resectable hepatic metastases. METHODS: Twenty-nine colorectal cancer patients with non-resectable hepatic metastases were consecutively enrolled for HAI alternating with systemic chemotherapy (HA + SC group). The protocol comprised six cycles of alternating HAI (5-FU + leucovorin for 14 days, and mitomycin C on the first day) and systemic chemotherapy (5-FU + leucovorin). Colorectal cancer patients with two or more hepatic metastases treated using hepatic resection and systemic chemotherapy (HR + SC group) were selected as a comparative group. RESULTS: Within the HA + SC group, complete response was achieved in eight patients (28%), whereas 13 patients (45%) showed progressive disease. Six of the eight patients with complete response lived for more than 38 months. Extrahepatic recurrences were more frequent in the HR + SC group than the HA + SC group (47 vs 21%, P = 0.024). The two groups did not differ with respect to overall and hepatic progression-free survival (P = 0.947 and 0.444, respectively), displaying median +/- SE values of 38 +/- 7 and 20 +/- 3 months in the HA + SC group, and 39 +/- 9 and 33 +/- 14 months in the HR + SC group, respectively. One patient in each group experienced toxic hepatitis, and sclerosing cholangitis occurred in one patient of the HA + SC group. Other complications were mostly grade 1 or 2. CONCLUSIONS: HAI alternating with systemic chemotherapy led to a promising response and hepatic progression-free survival, possibly reducing extrahepatic recurrence in colorectal cancer patients with non-resectable liver metastases.     

The effect of hepatic steatosis on survival following resection of colorectal liver metastases in patients without preoperative chemotherapy

Background Hepatic steatosis, a common condition associated with insulin resistance and excess body weight, is reported to be associated with an increased risk for perioperative mortality in patients undergoing resection of colorectal liver metastases (CLM), but its impact upon longterm survival is less well documented.Methods The effects of background liver pathology, categorized as ‘normal’, ‘with steatosis’ and ‘other’, on perioperative mortality, overall survival (OS) and cancer-specific survival (CSS) were assessed in patients undergoing resection for CLM according to data maintained in the LiverMetSurvey database. As preoperative chemotherapy may confound the effects of steatosis, patients who had been given preoperative chemotherapy were excluded. Survival analyses included log-rank tests for comparisons, and multivariate Cox models, including well-established prognosticators.Results Of 5853 patients who underwent first-time liver resection without preoperative chemotherapy, 1793 (30.6%) had background steatosis. Rates of 90-day perioperative mortality in patients with normal, steatosis and other pathologies were 2.8%, 2.1% and 4.9%, respectively. Steatosis was associated with improved 5-year OS (47.4% versus 43.0%; log rank, P = 0.0017) and CSS (56.1% versus 50.3%; P = 0.002) compared with normal background liver. After adjustments, the survival advantage associated with steatosis remained (hazard ratio = 0.806, 95% confidence interval 0.717–0.905 for CSS).Discussion The paradoxical survival advantage observed in patients with steatosis undergoing liver resection for CLM generates a hypothesis that peri-diagnosis of excess body adiposity has a survival protective effect that warrants further research.     

大肠癌肝转移介入治疗与静脉化疗的对比研究

目的　探讨结直肠癌肝转移的有效治疗方法。方法　肝动脉化疗灌注及栓塞治疗（ ＨＡＩＣＥ）２５ 例,第一次ＨＡＩＣＥ 后４ 周重复一次,以后每间隔３ － ６ 月行一次ＨＡＩＣＥ。静脉化疗（ＶＣ） 采用静脉给药,４ 周为１ 周期,２ 周期后间隔３－ ６ 月化疗一次。结果　ＨＡＩＣＥ 一疗程后上腹疼痛减轻或消失者占８８ ％ ,肝内肿块缩小占６８ ％ ,ＣＥＡ 降低病例占９２ ％ ;ＶＣ 一疗程后肝区疼痛减轻或消失者占１８ ％ ,肝内肿块缩小占８－３ ％ ;两组病例１ 、２ 、３ 年生存率分别为７２ ％ 、５２ ％ 、２４ ％ 和４１－７ ％ 、１６－７ ％ 、０ ％ （ Ｐ＜ ０－０１） 。结论　对于不能手术的结直肠癌肝转移,ＨＡＩＣＥ 在改善临床症状及延长生存期上较ＶＣ更有效,是一个较好的姑息性治疗方法     

肝动脉介入联合全身静脉化疗预防大肠癌术后肝转移的临床研究

目的探讨肝动脉介入联合全身静脉化疗预防大肠癌术后肝转移的疗效及毒副反应。方法治疗组48例大肠癌术后病人,术后3周行肝动脉介入联合全身静脉化疗6个周期,药物奥沙利铂130 mg/m2,亚叶酸钙300 mg/m2,氟脲苷(FUDR)500/m2,羟基喜树碱15～20 mg/m2,对照组38例病人则仅予以同样药物全身静脉化疗6个疗程。所有病例术前、术后、化疗前后均行影像学检查以评价疗效,随访48个月,评价肝转移及毒副反应。结果肝转移率:治疗组4.17%(2/48)、对照组28.95%(11/38),近期疗效显著,两组均未发生化疗引起的造血系统、肝肾功能的损害,无化疗相关死亡,两组之间呈显著性差异(P<0.01)。结论肝动脉介入联合全身静脉化疗近期可有效预防大肠癌术后肝转移的发生,毒副反应小,安全有效。     

Hepatic arterial chemotherapy for colorectal liver metastases

The management of hepatic metastasis from colorectal cancer represents a significant clinical problem. For the majority of patients with colorectal liver metastases, chemotherapy will be the mainstay of treatment. Considerable data now exists to support hepatic arterial chemotherapy as being effective over systemic chemotherapy both in terms of quality of life and response rates. Morbidity and mortality rates are reduced when catheters are placed by skilled dedicated surgeons using rigorous protocols.     

Transbrachial hepatic arterial chemotherapy using an implanted infusion pump

Two patients with hepatic metastases from colonic cancer were treated with hepatic arterial FUDR using an innovative drug infusion system. The two patients reported underwent transbrachial hepatic artery catheterization with a 5 French polyethylene catheter. This catheter was amputated just distal to its exit from the brachial artery and attached to a totally implantable, percutaneously refillable drug infusion pump placed in the infraclavicular position. The patients received FUDR at flow rates of 3–4 ml/day. The pumps were refilled weekly by percutaneous injection. One patient was treated for seven weeks, and another for ten weeks without technical difficulties. This innovative approach offers marked improvement in comfort and convenience for patients who are candidates for long-term hepatic artery chemotherapy, and avoids the morbidity of laparotomy for direct hepatic arterial catheterization.     

Adjuvant intra-arterial chemotherapy for patients with resected colorectal liver metastases: a systematic review and meta-analysis

BackgroundThe practice of adjuvant hepatic arterial infusion chemotherapy (HAIC) for colorectal liver metastasis (CRLM) varies widely. This meta-analysis investigates the effectiveness of adjuvant HAIC and the influence of variations in HAIC treatment in patients with resected CRLM.MethodsPRISMA guidelines were followed for this study. The search was limited to comparative studies (HAIC vs non-HAIC) for overall survival. Subgroup meta-analyses using random-effects were performed for type of intra-arterial drug, method of catheter insertion, use of concomitant adjuvant systemic chemotherapy, and study design.ResultsEighteen eligible studies were identified. After excluding overlapping cohorts, fifteen studies were included in the quantitative analysis, corresponding to 3584 patients. HAIC was associated with an improved overall survival (pooled hazard ratio (HR) 0.77; 95%CI 0.64–0.93). Survival benefit of HAIC was most pronounced in studies using floxuridine (HR 0.76; 95%CI: 0.62–0.94), surgical catheter insertion with subcutaneous pump (HR 0.71; 95%CI: 0.61–0.84), and concomitant adjuvant systemic chemotherapy (HR 0.75; 95%CI: 0.59–0.96). The pooled HR of RCTs was 0.91 (95%CI 0.72–1.14), of which only 3 used floxuridine.ConclusionAdjuvant HAIC is a promising treatment for patients with resectable CRLM, in particular HAIC with floxuridine using a surgically placed catheter and a subcutaneous pump, and concomitant systemic chemotherapy.     

Repeat hepatic resection in patients with colorectal liver metastases

AIM:To investigate the survival outcomes of secondaryhepatectomy for recurrent colorectal liver metastases(CRLM).METHODS:From October 1994 to December 2009,patients with CRLM who underwent surgical treatment with curative intent were investigated.Patients were divided into two groups:patients who underwent primary hepatectomy(Group 1)and those who underwent secondary hepatectomy for recurrent CRLM(Group 2).RESULTS:Survival and prognostic factors were analyzed.A total of 461 patients were included:406patients in Group 1 and 55 patients in Group 2.After a median 39-mo(range,3-195 mo)follow-up,there was a significant difference between Groups 1 and 2in terms of disease-free survival(P=0.029)although there was no significant difference in overall survival(P=0.206).Secondary hepatectomy was less effective in patients with multiple recurrent CRLM than primary hepatectomy for initial CRLM(P=0.008).Multiple CRLM and radiofrequency ablation therapy were poor prognostic factors of secondary hepatectomy in multivariate Cox regression analysis(P=0.006,P=0.004,respectively).CONCLUSION:Secondary hepatectomy for single recurrent CRLM is as effective as primary surgical treatment for single recurrent CRLM.However,secondary hepatectomy for multiple recurrent CRLM is less effective than that for single recurrent CRLM.     

Impact of peri-operative bevacizumab on survival in patients with resected colorectal liver metastases: an analysis of the LiverMetSurvey

Background

Peri-operative chemotherapy is recommended for the management of colorectal liver metastases (CRLM). The aim of this study was to examine the impact of peri-operative bevacizumab on survival in patients with resected CRLM.

Methods

A multicentre retrospective cohort of patients with resected CRLM was analysed from the LiverMetSurvey Registry. Patients who received peri-operative FOLFOX (group A) were compared with those who received peri-operative FOLFOX and bevacizumab (group B).

Results

In total, 501 patients were compared (A, n = 384; B, n = 117). Group A was older (68.3 versus 62.5 years, P < 0.01), had more rectal cancers (30.7 versus 18.8%, P < 0.01) and higher carcinoembryonic antigen (CEA) levels at diagnosis (17.0 versus 9.7 ng/ml, P = 0.043). No difference was observed regarding primary tumour stage, synchronicity and the number or size of metastases. Post-operative infections were more frequent in group B (4.7% versus 12.8%, P < 0.01). Peri-operative bevacizumab had no effect on 3-year overall survival (OS) (76.4% versus 79.8%, P = 0.334), or disease-free survival (DFS) (7.4% versus 7.9%, P = 0.082). DFS was negatively associated with primary tumour node positivity (P = 0.011) and synchronicity (P = 0.041).

Conclusions

The addition of bevacizumab to standard peri-operative chemotherapy does not appear to be associated with improved OS or DFS in patients with resected CRLM.     

The impact of neoadjuvant chemotherapy on skeletal muscle depletion and preoperative sarcopenia in patients with resectable colorectal liver metastases

Background

Preoperative skeletal muscle depletion or sarcopenia has been suggested to predict worse outcome after resection of colorectal liver metastases. The aim of the present study was to investigate the impact of neoadjuvant chemotherapy on preoperative skeletal muscle mass prior to liver resection.

Metastatic recurrence after complete resection of colorectal liver metastases: impact of surgery and chemotherapy on survival

Purpose

Surgery is the standard of care for resectable colorectal liver metastases (CRC-LM). Unfortunately, 60 % of patients develop secondary metastatic recurrence (SMR) after R0-resection of CRC-LM. We investigated the impact of surgical re-intervention and chemotherapy (Ctx) on survival in a consecutive series of patients with SMR.

Methods

From 01/2001 to 11/2011, 104 out of 178 consecutive patients with R0-resection of CRC-LM developed SMR and were evaluated. The impact of surgical and Ctx re-interventions on recurrence free (RFS) and cancer-specific survival (CSS) was analyzed. Median follow-up was 28.0 (95 %CI: 19.4–37.4) months.

Results

SMR occurred in 81 patients at a single site (49× liver, 18× lung, 14× other) and in 23 patients at multiple sites. Forty-two patients were scheduled for primary surgery. Fifty-three patients were classified as non-resectable and treated with median 5.0 [IQR, 3.0–10.0] cycles of Ctx, combined with an EGFR/VEGF-antibody in 27 patients. Nine patients received best supportive care only. R0/R1 resection could be achieved in 35 patients primarily and even in 8 patients secondarily after Ctx. Surgical morbidity and mortality were 16 and 0 %, respectively. The 5-year RFS rates for patients with R0 versus R1-resection were 22 and 24 % (p?=?0.948). The 5-year CSS rate for R0/R1-resected patients was 38 % versus 10 % for those patients treated by Ctx alone (p?<?0.001).

Conclusion

In SMR, surgical re-intervention is feasible and safe in a remarkable number of patients and offers significantly longer CSS compared to patients without resection.     

Meta-analysis: Perioperative regional liver chemotherapy for improving survival and preventing liver metastases in patients with colorectal carcinoma

OBJECTIVE: To evaluate the effect of prophylactic regional liver chemotherapy during the perioperative period on improving survival and preventing liver metastases in patients with colorectal cancer (CRC). METHODS: A comprehensive retrieval of the relevant literature was performed by searching major biomedical database, mainly from Medline and Embase. Studies reported in the selected literature were categorized into two subgroups according to the type of therapy: a perioperative hepatic artery infusion subgroup and a perioperative portal vein infusion subgroup. Mortality and liver metastasis were analyzed using a fixed-effects model. Statistical analysis was performed using Review Manager software. RESULTS: The results of this meta-analysis illustrated that survival and the rate of liver metastasis in patients receiving perioperative hepatic artery infusion (HAI) chemotherapy were significantly better than for those receiving surgery alone (pooled relative risk 0.46 [95% CI: 0.31–0.69] and 0.44 [95% CI: 0.28–0.68], respectively, P= 0.0002), while survival and the rate of liver metastasis in patients receiving perioperative portal vein infusion (PVI) chemotherapy were not significantly different from those receiving surgery alone (pooled relative risk 0.98 [95% CI: 0.89–1.09], P= 0.73 and 0.86 [95% CI: 0.72–1.02], respectively. P= 0.08). CONCLUSION: As a method of regional liver chemotherapy, HAI might be able to improve survival and reduce the rate of liver metastasis in patients with advanced CRC.     

Perioperative chemotherapy and liver resection for hepatic metastases of colorectal cancer

Surgical resection has played a major role in the treatment for colorectal liver metastases. The safety and efficacy of surgery for liver metastasis are obvious, although there are some differences between the western countries and Japan concerning the surgical indication, procedures, timing of chemotherapies in a perioperative period, and treatment of a primary disease. In future, long-term outcomes after surgical resection for colorectal liver metastases would be expected to be prolonged by combination of surgery and chemotherapies.     

Carcinoembryonic antigen as an independent prognostic factor of recurrence and survival in patients resected for colorectal liver metastases

PURPOSE: We attempted to answer the question of whether serum levels of carcinoembryonic antigen provide prognostic information, in terms of survival, in patients resected for colorectal liver metastases, independently of that provided by other commonly used radioclinical and pathologic factors. METHOD: We performed a systematic review, without meta-analysis, of the biomedical literature using the methodology recommended by the Committee on Evidence-Based Laboratory Medicine of the International Federation of Clinical Chemistry and Laboratory Medicine. RESULTS: Despite the absence of sufficient details about the methods used to measure serum carcinoembryonic antigen in the 14 studies reviewed, strong arguments exist to include preoperative carcinoembryonic antigen measurements in future trials on the subject. In particular, preoperative carcinoembryonic antigen was found to be significant in the two studies with the greatest number of patients having a preoperative carcinoembryonic antigen assay, in the four studies with the most recent series of patients, in the study in which preoperative carcinoembryonic antigen was used as a continuous variable, and in the study in which preoperative carcinoembryonic antigen was used in terms of doubling time. Postoperative carcinoembryonic antigen was found to have a prognostic significance in the only two studies that evaluated this variable. CONCLUSION: Taking into account the possible reasons for disagreements regarding carcinoembryonic antigen prognostic value between the 14 studies reviewed, we propose some recommendations to improve the reproducibility and the quality of future studies in this field. In particular, we stress the need for a higher degree of multidisciplinary collaboration in clinical trials.     

A study of liver metastasis from colorectal cancer in which hepatic resection was performed after hepatic arterial infusion chemotherapy]

We experienced 5 cases of liver metastases from colorectal cancer, in which hepatic resection was carried out after down sizing by hepatic arterial infusion chemotherapy. In addition, a histological study about the effect of chemotherapy on the liver tumor was performed. Primary lesions were located at the sigmoid colon (2), cecum (1), descending colon (1) and rectum (1). We carried out hepatic arterial infusion chemotherapy using mainly 5-FU. The total amount of 5-FU was 10-81 g. Tumor volumes were reduced by 12.5-24%, and they were judged PR. However, surgery was indicated due to obstruction of the proper hepatic artery or other side effects. Postoperative courses were uneventful and the hospital stays were from 17-61 days, and all patients were still alive in tumor-free condition at writing. By the histological study of the excised specimen, we recognized not only remarkable fibrous changes or calcifications but also overt viable cancerous cells. We conclude that the option of hepatic resection after controlling the development of the cancer by hepatic arterial infusion chemotherapy is a rational strategy of treatment for liver metastasis from colorectal cancer.