FDG-PET-CT is effective in selecting patients with poor long term survivals for colorectal liver metastases

Aims

Having incorporated PET-CT as part of the staging process for colorectal liver metastases (CRLM) in our unit since 2008, this study aims to evaluate the survival outcomes of all patients managed by our specialist multi-disciplinary team (MDT).

Methods

All patients with colorectal liver metastases referred to a single liver MDT between 2008 and 2011 were examined. Overall survival (OS) for palliative groups due to occult extrahepatic disease detected by PET-CT (A) and those upfront palliative patients with extensive multi-site disease as identified on baseline CT or disease progression during chemotherapy (B), and resected (C) groups were evaluated and compared. Different extents of occult extrahepatic disease as characterised by PET-CT were also compared.

Results

532 patients were included in the study. Median OS for group A (n = 80), B (n = 161) and C (n = 291) were 10.9, 12.0 and 46.7 months, with a 5-year OS approaching 6.5%, 6.1% and 43.0% respectively. There were significant differences in OS of C vs. A & B (p < 0.001). Single compartment metastases had a significant better survival outcomes than non-torso metastases (p = 0.04).

Conclusion

This is the first report of OS of patients with CRLM excluded from surgery on the basis of PET-CT. We have confirmed that PET-CT is effective in selecting patients with occult extrahepatic disease, which has poor survival outcomes. However, a subgroup with single compartment extrahepatic disease has a better than expected outcome.     

The differential response to chemotherapy of ovarian metastases from colorectal carcinoma

Patients and methods

All patients with metastatic (ovarian and extraovarian) CRC who underwent resection of ovarian metastases in our institution from April 1988 to August 2006 were analyzed and the response to preoperative chemotherapy was evaluated according to the RECIST criteria, and analyzed with respect to the sites of metastases (ovarian and extraovarian).

Results

The studied population consisted of 23 women. At presentation, 20 patients had symptoms. Preoperative chemotherapy resulted in tumor control of measurable extraovarian metastases in 65% of cases. In contrast, no objective tumor response of ovarian metastases was observed, disease stabilization was obtained in only 3 patients (13%), and progression or occurrence of new ovarian metastases were observed in 20 patients (87%) (p = 0.0005).With a median follow-up of 54 months [15–229], median overall survival was 30 months, and 3-year overall survival was 18%.

Conclusion

Ovarian metastases are less responsive to chemotherapy compared to other sites. As these “metastatic sanctuaries” often cause symptoms, surgical resection should always be considered for ovarian metastases, even in the case of associated extraovarian metastases.     

Hepatic vascular inflow occlusion is associated with reduced disease free survival following resection of colorectal liver metastases

Background

Hepatic vascular inflow occlusion (VIO) can be applied during resection of colorectal liver metastases (CRLM) to control intra-operative blood loss, but has been linked to accelerated growth of micrometastases in experimental models. This study aimed to investigate the effects of hepatic VIO on disease-free and overall survival (DFS and OS) in patients following resection for CRLM.

Patterns of hepatotoxicity after chemotherapy for colorectal cancer liver metastases

Aim

The aim of this study was to assess chemotherapy associated hepatotoxicity after 3 months' treatment and to correlate patterns of hepatotoxicity with perioperative morbidity.

Methods

Liver specimens of 50 patients with liver metastases from colorectal cancer receiving XELOX or FOLFOX4 for six cycles and 13 specimens of non-chemotherapy patients subjected to liver resection were analyzed. Different patterns of hepatotoxicity were evaluated according to widely accepted pathohistological scores. Furthermore, the histomorphological findings were correlated with perioperative morbidity.

Results

Steatosis grades did not differ among the chemotherapy treated groups and non-chemotherapy patients. Chemotherapy showed an independent effect on fibrosis stage. Age and chemotherapy were independently associated with sinusoidal dilatation. Centrilobular vein fibrosis correlated with administration of chemotherapy. Higher fibrosis stages were associated with increased transfusion requirements.

Conclusion

XELOX and FOLFOX4 do not correlate with the development of steatosis or steatohepatitis. We do not detect a difference in liver injury between the XELOX and FOLFOX4 group. Although 5-fluorouracil based chemotherapy may cause profound changes in liver parenchyma, it can be safely applied. However, age and oxaliplatin predispose for the development of sinusoidal dilatation; therefore caution must be taken in old patients treated with oxaliplatin.     

Chemotherapy plus percutaneous radiofrequency ablation in patients with inoperable colorectal liver metastases

AIM:To access the efficacy of chemotherapy plus radiofrequency ablation(RFA)as one line of treatment in inoperable colorectal liver metastases.METHODS:Eligible patients were included in three PhaseⅡstudies.In the first study percutaneous RFA was used first followed by 6 cycles of 5-fluorouracil,leucovorin and irinotecan combination(FOLFIRI)(adjunctive chemotherapy trial).In the other two,chemotherapy(FOLFIRI or 5-fluorouracil,leucovorin and oxaliplatin combination)up to 12 cycles was used first with percutaneous RFA offered to responding patients (primary chemotherapy trials).RESULTS:Thirteen patients were included in the adjunctive chemotherapy trial and 17 in the other two.At inclusion they had 1-4 liver metastases(up to 6.5 cm in size).Two patients died during chemotherapy.All patients in the adjunctive chemotherapy trial and 44%in the primary chemotherapy studies had their metastases ablated.Median PFS and overall survival in the adjunctive study were 13 and 24 mo respectively while in the primary chemotherapy studies they were 10 and 21 mo respectively.Eighty one percent of the patients had tumour relapse in at least one previously ablated lesion.CONCLUSION:Chemotherapy plus RFA in patients with low volume inoperable colorectal liver metastases seems safe and relatively effective.The high local recurrence rate is of concern.     

Impact of biological agents on the prevalence of chemotherapy associated liver injury (CALI): Multicentric study of patients operated for colorectal liver metastases

Background

The prevalence of chemotherapy associated liver injuries (CALI), especially SOS (sinusoidal obstruction syndrome) and NRH (nodular regenerative hyperplasia) might be reduced since the introduction of routine use of biological agents with chemotherapy in colorectal liver metastases (CRLM).

结直肠癌肝转移经肝动脉栓塞及持续灌注化疗的临床疗效

背景与目的：结直肠癌肝转移患者经肝动脉介入栓塞或静脉持续滴注化疗药物,治疗效果有所提高,但尚存肿瘤局部化疗药物浓度不够高,化疗药物对肿瘤细胞的杀伤力不够强,晚期结肠直肠癌的治疗效果仍然不够好的缺陷。本文将动脉介入与持续灌注化疗药物两种方法相结合,观察结直肠癌肝转移患者经肝动脉介入栓塞或持续灌注化疗的临床疗效。方法：对26例结直肠癌肝转移患者经肝动脉介入治疗93次,单用肝动脉持续灌注化疗42次,肝动脉介入栓塞联合持续灌注化疗51次。化疗药物选用阿霉素（ADM）、顺铂（DDP）、丝裂霉素（MMC）、醛氢叶酸（CF）和5-氟尿嘧啶（5-FU）。先将ADM30mg/m^2和MMC6mg/m^2加入超液化碘油10-30ml中进行肝动脉灌注栓塞,然后留置导管进行持续动脉滴注。方案为CF200mg/m^2,d1-3,静脉滴注;DDP80mg/m^2d1,如肾功能改变则改用Vp-1660mg/m^2,d1-3,应用电动输液泵动脉滴注;5-FU2500mg/m^2,采用便携式输液泵将5-FU持续动脉滴注72h。结果：近期疗效以实体瘤疗效评价标准评价,CR1例,CR率3.85%;PR14例,PR率53.84%,总有效率为57.69%。本组0.5、1、2、3和5年生存率分别为92.31%、76.92%、38.46%、23.07%和3.85%,肝转移后中位生存期为11.5个月。全组病人出现的不良反应主要有肝功能损害、胃肠道反应和骨髓抑制,经护肝、制酸、止呕、水化和应用升白细胞药物对症治疗后可缓解。结论：经肝动脉持续灌注化疗及栓塞是治疗结直肠癌肝转移瘤的较好方法,能提高治疗效果。     

Elevated preoperative neutrophil to lymphocyte ratio predicts survival following hepatic resection for colorectal liver metastases

Background

The neutrophil–lymphocyte ratio (NLR) provides an indicator of inflammatory status. An elevated NLR has been shown to be a prognostic indicator in primary colorectal malignancy. The aim of this study was to establish whether NLR predicts outcome in patients undergoing resection for colorectal liver metastasis.

Design

Retrospective analysis of the white cell and differential counts for 440 patients undergoing liver resections for colorectal liver metastasis between January 1996 and January 2006. An NLR ≥ 5 was considered to be elevated.

Results

Two hundred and eighty-nine males and 151 females were included. Seventy-eight patients (18%) had an elevated NLR, 55 of whom died, giving elevated NLR a positive predictive value (PPV) for death of 71%. Sixty of the 78 patients had recurrent disease giving raised NLR an PPV for recurrence of 78%. The 5-year survival for patients undergoing resection with high NLR was significantly worse than that for patients with normal NLR (22% vs. 43%, p < 0.0001). Univariate analysis of factors affecting survival revealed raised NLR, number of metastases >8, tumour size >5 cm and age >70 significantly affected outcome. All factors except tumour size remained significant predictors of term survival on multivariate analysis (NLR:HR = 2.261, CI = 1.654–3.129, p < 0.0001, metastases >8:HR = 1.611, CI = 1.006–2.579, p = 0.047, age >70:HR = 1.418, CI = 1.049–1.930, p = 0.027). Elevated NLR was found to be the sole positive predictor of recurrence on univariate analysis (HR = 4.521, CI = 2.475–8.257, p < 0.0001).

Conclusion

Elevated NLR increases both risk of death and the risk of recurrence in patients who undergo surgery for CRLM. Preoperative NLR measurement may therefore provide a simple method of identifying patients with a poorer prognosis.     

Prolonged portal triad clamping during liver surgery for colorectal liver metastases is associated with decreased time to hepatic tumour recurrence

Aims

The aim of this study was to evaluate the oncological outcome of portal triad clamping during hepatectomy in colorectal cancer patients.

Methods

160 patients with colorectal liver metastases underwent a partial hepatectomy with curative intent. Data were collected in a prospective database and were retrospectively analyzed for time to liver recurrence (TTLiR) and time to overall recurrence (TTR). The prognostic significance of portal triad clamping of any type and severe ischemia due to prolonged portal triad clamping was determined by Cox regression models.

Results

TTLiR was reduced after clamping of any type, although not statistically significant (p = 0.061). Severe ischemia due to prolonged portal triad clamping significantly decreased TTLiR (p = 0.022), but not TTR. Furthermore, severe ischemia independently predicted TTLiR in a multivariable analysis (p = 0.038).

Conclusions

Severe ischemia due to prolonged portal triad clamping during hepatic resection for colorectal liver metastases appears to be associated with decreased TTLiR. Further research remains necessary to determine the causative effect of prolonged vascular clamping on liver tumour recurrence.     

Primary tumor resection in colorectal cancer with unresectable synchronous metastases: A review

At the time of diagnosis, 25% of patients with colorectal cancer (CRC) present with synchronous metastases, which are unresectable in the majority of patients. Whether primary tumor resection (PTR) followed by chemotherapy or immediate chemotherapy without PTR is the best therapeutic option in patients with asymptomatic CRC and unresectable metastases is a major issue, although unanswered to date. The aim of this study was to review all published data on whether PTR should be performed in patients with CRC and unresectable synchronous metastases. All aspects of the management of CRC were taken into account, especially prognostic factors in patients with CRC and unresectable metastases. The impact of PTR on survival and quality of life were reviewed, in addition to the characteristics of patients that could benefit from PTR and the possible underlying mechanisms. The risks of both approaches are reported. As no randomized study has been performed to date, we finally discussed how a therapeutic strategy’s trial should be designed to provide answer to this issue.     

Selection for surgery and survival of synchronous colorectal liver metastases; a nationwide study

BackgroundResection of colorectal liver metastases (CRLM) is associated with improved survival but we currently have limited population-based data on selection for surgery.MethodsPatients in the Swedish Colorectal Cancer Register reported with liver metastases at diagnosis in 2007–2011 were identified. Clinical characteristics including American Society of Anesthesiologists classification, type of hospital and health care region were retrieved. Linkage to the National Patient Register and Statistics Sweden provided information on liver resection and socioeconomic variables.ResultsSynchronous CRLM was found in 4243/27,990 (15.2%) patients, of whom 1094 (25.8%) also had concurrent lung metastases. Of 3149 patients with liver-only metastases, 556 (17.8%) were subjected to liver resection. The resection rate varied by subsite; right-sided 11.7%, left-sided 19.7% and rectal cancer 22.7% (p = 0.001). It varied by type of hospital 14.1–23.6%, by region 11.5–22.7%, and was 19.8% in men and 14.9% in women (all p < 0.001).The adjusted odds were 0.74 (0.59–0.93) for females, 0.58 (0.46–0.74) for general district and 0.50 (0.37–0.68) for district hospital patients, and there were large regional differences. Patients >75 years were very unlikely to receive liver surgery 0.22 (0.15–0.32).In patients subjected to liver surgery, median survival was 57 months, 5-year survival rate was 45.4%, and those with left-sided colon cancer had the best outcome (48.8%; p = 0.02). Five-year hazard ratio for patients not subjected to liver surgery was 4.3 (3.7–5.0).ConclusionNationwide outcome after resection of synchronous CRLM was impressing but ambiguous selection mechanisms and inaccessibility need to be resolved. The implications of subsite deserve further attention.     

Impact of timing and cycles of systemic chemotherapy on survival outcome of colorectal liver metastases patients treated by percutaneous microwave ablation

Purpose: The aim of this retrospective study is to determine the optimal timing and number of cycles of systemic chemotherapy in patients with colorectal liver metastases (CLM) treated by ultrasound-guided percutaneous microwave ablation (PMWA).

Materials and methods: In total 199 patients with 318 CLM, median number of tumours one per patient and median maximum size of tumours 3.0?cm, treated by PMWA combined with or without systemic chemotherapy were included in our study. Chemotherapy was administered pre-ablatively in 148 of those patients (74.4%), and post-ablatively in 142 (73.6%). Chemotherapy regimens included FOLFOX/XELOX, FOLFIRI/XELIRI, and sequential monotherapy. Prognostic factors were evaluated by univariate and multivariate analyses, using log-rank test and Cox proportional hazards model, respectively.

Results: The estimated 5-year rates of progression free survival (PFS) and overall survival (OS) were 10.1% and 27.9%, respectively. The number of CLM (P?=?0.003), maximum size of CLM (P?<?0.001) and topography (P?=?0.030) were independent prognostic factors for PFS of patients with CLM while age (P?=?0.002), maximum size of CLM (P?=?0.006) and post-ablative chemotherapy (P?=?0.046) for OS. In further analysis, CLM patients receiving more than six cycles of post-ablative chemotherapy had significantly better OS (P?=?0.015) than those without post-ablative chemotherapy.

Conclusion: This study revealed chemotherapy administered after (more than six cycles) PMWA improved the OS of CLM patents. And, PMWA was a safe procedure in view of the absence of procedure-related death and low rate of major complications.     

Synchronous resection for colorectal liver metastases: The future

Colorectal Cancer is a common malignancy. Many patients have metastatic disease at presentation and a significant proportion subsequently go onto develop metastatic disease, following surgery for the primary disease.     

Laparoscopic liver resection compared to open approach in patients with colorectal liver metastases improves further resectability: Oncological outcomes of a case-control matched-pairs analysis

Aims

Liver resection is considered the standard treatment of colorectal metastases (CRLM). However, to date, no long term oncological results and data regarding repeat hepatectomy after laparoscopic approach are known. The aim of this study is to analyze single center long-term surgical and oncological outcomes after liver resection for CRLM.

Methods

A total of 57 open resections (OR) were matched with 57 laparoscopic resections (LR) for CRLM. Matching was based mainly on number of metastases, tumor size, segmental position of lesions, type of hepatectomy and type of resection.

Results

Morbidity rate was significantly less in the LR group (p = 0.002); the length of hospital stay was 6.5 ± 5 days for the LR group and 9.2 ± 4 days for the OR group (p = 0.005). After a median follow up of 53.7 months for the OR group and 40.9 months for the LR group, the 5-y overall survival rate was 65% and 60% respectively (p = 0.36) and the 5-y disease free survival rate was 38% and 29% respectively (p = 0.24). More patients in the LR group received a third hepatectomy for CRLM relapse than in the OR group (80% vs. 14.3% respectively; p = 0.015).

Conclusions

Laparoscopic resection for CRLM offers advantages in terms of reduced blood loss, morbidity rate and hospital stay. It provides comparable long-term oncological outcomes but can improve further resectability in patients with recurrent disease.     

Management of liver metastases in colorectal cancer patients: A retrospective case-control study of systemic therapy versus liver resection

ObjectiveTo evaluate and compare the overall survival (OS) in case-matched patient groups treated either with systemic therapy or surgery for colorectal liver metastases (CRLM).MethodsPatients with CRLM, without extra-hepatic disease, treated with chemotherapy with or without targeted therapy in two phase III studies (n = 480) were selected and case-matched to patients who underwent liver resection (n = 632). Matching criteria were sex, age, established prognostic factors for survival (clinical risk score). Available computed tomography (CT)-scans of patients treated with systemic therapies were reviewed by three independent liver surgeons for resectability. Survival was compared between patients with resectable CRLM (based on CT-scan review) who were treated with systemic therapy versus patients who underwent liver resection.ResultsA total of 96 patients treated with systemic therapy were included. Pre-treatment CT-scans of the liver were available for review in 56 of the systemically treated patients, and metastases were unanimously considered resectable in 36 patients (64.3%) (complex resectable: n = 25; 69%). These 36 patients were case-matched with 36 patients who underwent liver resection (wedge resection or segmentectomy: n = 26; 72%). Median OS in the patient group treated with systemic therapy was 26.5 months (range 0–81 months), which was significantly lower than that in case-matched patients who underwent liver resection (median OS 56 months; range 6–116) (p = 0.027).ConclusionsIn this case-matched control study, surgery provided superior OS rates compared to systemic therapy for CRLM. Resection of CRLM should always be considered, preferably in a dedicated liver centre, since not all patients that qualify for resection are identified as such.     

Nodular regenerative hyperplasia (NRH) complicating oxaliplatin chemotherapy in patients undergoing resection of colorectal liver metastases

Introduction

Sinusoidal obstructive syndrome (SOS) is well associated with the use oxaliplatin-based chemotherapy, and represents a spectrum of hepatotoxicity, with nodular regenerative hyperplasia (NRH) representing the most significant degree of injury. The aim of this study was to determine the prevalence of NRH in patients undergoing resection of colorectal liver metastases (CRLM) and to determine its impact on outcome.

Methods

From January 2000 to December 2010, some 978 first primary liver resections were performed for CRLM. A prospectively maintained database was analysed to identify all patients with evidence of NRH in the non-tumour portion of their histopathology specimens. Clinical data of these patients was reviewed and outcomes assessed.

Results

Five patients exhibited NRH (four males, one female) with a median age of 69 years (range: 35–74). Three patients presented with synchronous hepatic metastases, and two with metachronous lesions. All received at least 6 cycles of oxaliplatin as either adjuvant or neo-adjuvant chemotherapy. Only one patient developed a post-operative complication namely transient hepatic failure that required a 4-day stay in the intensive care unit. The median hospital stay was 6 days (range: 6–14 days). There were no 90-day mortalities. One patient is alive and disease free at 55 months, the remaining 4 died of recurrent disease between 37 and 70 months following diagnosis of their primary tumours.

Conclusions

NRH is not an uncommon finding amongst patients with SOS with all patients having received oxaliplatin-based chemotherapy. Data on outcome would suggest no increased morbidity and mortality associated with the presence of NRH.     

Effect of preoperative chemotherapy on liver resection for colorectal liver metastases

Aim

To compare the effects of preoperative chemotherapy on liver parenchyma morphology, as well as morbidity and mortality after liver resection for colorectal liver metastases.

Methods

Prospectively collected data on 173 patients undergoing liver resection for CLM between 1/2003 and 9/2005 was analysed in three groups: A: preoperative oxaliplatin (Ox, n = 70); B: other chemotherapeutic agents (OC, n = 60); and C: surgery alone without chemotherapy (SA, n = 43). Blood transfusion, hospital stay, operative procedure, peak postoperative bilirubin levels, complications and histopathology of the resected liver were compared.

Results

Intra-operative blood transfusion requirement (34%) and biliary complications (16%) was higher in patients receiving oxaliplatin-based chemotherapy (p = 0.01 and p = 0.06, respectively). Oxaliplatin-based chemotherapy was also associated with sinusoidal dilatation of mild grade in 52.8% vs. 26.6% and 23.3% patients (p = 0.007 and p = 0.004) in other groups, respectively. Steatosis was similarly distributed across the study group. Postoperative mortality was 2, 1 and 4 patients, respectively (p = ns).

Conclusion

Oxaliplatin-based preoperative chemotherapy is associated with vascular alterations in the liver parenchyma without significantly increasing the risk of steatosis, or postoperative morbidity and mortality.     

Chemotherapy for colorectal cancer liver metastases

Colorectal cancer (CRC) is a highly prevalent malignant disease in industrialized nations. The annual incidence of invasive CRC in the U.S. is among the highest in the world, and the liver is the only metastatic site in approximately one third of patients. Without treatment, patients with metastatic disease have a poor prognosis; however, long-term survival benefits and even cure have been reported in patients undergoing surgical resection of metastases. In addition, advances in chemotherapy, imaging, and surgical techniques have increased the proportion of patients who are eligible for resection. Combination therapy with fluorouracil and leucovorin has been the mainstay of treatment for metastatic CRC; however, the introduction of newer agents, such as oxaliplatin and irinotecan, and targeted agents, such as cetuximab and bevacizumab, has yielded improvements in response rates (RRs) and survival. Maximizing the exposure of hepatic metastases to high target concentrations of cytotoxic drugs using hepatic arterial infusion (HAI) increases RRs further than with systemic chemotherapy; however, the impact of HAI on survival is unclear. As the goals of chemotherapeutic treatment for metastatic CRC increasingly shift from palliation to prolongation of survival, improvement in RRs, and downsizing of tumors in order to enable or optimize resection, treatment in a multidisciplinary environment involving a medical oncologist, radiologist, and surgical oncologist with hepatobiliary expertise will become central to deciding the best course of therapy and timing of surgery.