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.     

Heterogeneous radiological response to neoadjuvant therapy is associated with poor prognosis after resection of colorectal liver metastases

IntroductionSurgery combined with perioperative chemotherapy has become standard of care in patients with resectable colorectal liver metastases. However, poor outcome is expected for a significant subgroup. The clinical implications of inter-metastatic heterogeneity remain largely unknown. In a prospective, population-based series of patients undergoing resection of multiple colorectal liver metastases, the aim was to investigate the prevalence and prognostic impact of heterogeneous response to neoadjuvant chemotherapy.Materials and MethodsRadiological response to treatment was evaluated in a lesion-specific manner in 2–5 metastases per patient. Change of lesion diameter was evaluated and response/progression was classified according to three different size thresholds; 3, 4 and 5 mm. A heterogeneous response was defined as progression and response of different metastases in the same patient.ResultsIn total, 142 patients with 585 liver metastases were examined with the same radiological method (MRI or CT) before and after neoadjuvant treatment. Heterogeneous response to treatment was seen in 16 patients (11%) using the 3 mm size change threshold, and this group had a 5-year cancer-specific survival of 19% compared to 49% for patients with response in all lesions (p = 0.003). Cut-off values of 4–5 mm were less sensitive for detecting a heterogeneous response, but the survival difference was similar and significant.ConclusionA subgroup of patients with multiple colorectal liver metastases had heterogeneous radiological response to neoadjuvant chemotherapy and poor prognosis. The evaluation of response pattern is easy to perform, feasible in clinical practice and, if validated, a promising biomarker for treatment decisions.     

Prognostic impact of inter-metastatic heterogeneity of viable tumour cells in colorectal liver metastases

BackgroundHeterogenous response to neoadjuvant chemotherapy in patients with multiple colorectal liver metastases (CRLM) has been associated with an acquired resistance to systemic therapy. This study evaluated the occurrence of a heterogenous inter-metastatic tumour response with regards to the proportion of viable tumour cells, and its prognostic impact.MethodsA retrospective cohort study was conducted, including all patients with CRLM surgically treated at Karolinska University Hospital, Stockholm, Sweden, from 2013 to 2018. Factors associated with the proportion of viable tumour cells and inter-metastatic heterogeneity were analysed with regression and survival analyses.ResultsOut of 640 surgically treated patients, 405 patients (1357 CRLM), received neoadjuvant chemotherapy. Multiple CRLM were present in 314 patients (78%), out of whom 72 patients (23%) presented with a heterogenous tumour response. The median overall survival (OS) for patients with a heterogenous inter-metastatic tumour response was 36 months, compared to 57 months for patients with a homogenous inter-metastatic tumour response (p < .001). Poor OS in patients receiving preoperative chemotherapy was significantly associated with a heterogenous inter-metastatic tumour response (hazard ratio (HR) 1.68 (1.02–2.78)), right-sided primary tumour (HR 2.01 (1.29–3.43)) and CRLM diameter >5 cm (HR 1.83 (1.06–3.17)).ConclusionOutcome in patients with a heterogenous inter-metastatic tumour response, illustrated by the proportion of viable tumour cells, is inferior to that of patients with a homogenous response. These results suggest that heterogeneity in treatment response is an important marker of aggressive disease and could be of clinical value for decisions on post-operative therapy.     

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.     

Radiological response of leptomeningeal metastases according to revised RANO criteria is associated with overall survival in breast cancer patients

Assessment of treatment response in patients (pts) with leptomeningeal metastases (LM) represents a significant challenge and standardized criteria are needed. In 2017, the RANO LM Working Group proposed a standardized scorecard to evaluate MRI findings (further simplified in 2019). Here, we aim to validate the prognostic impact of response to treatment assessed using this tool in a multicentric cohort of breast cancer (BC) pts. Pts with BC-related LM diagnosed at two institutions between 2005 and 2018 were identified. Baseline and follow-up MRI scans were centrally reviewed and response assessment was evaluated using 2019 revised RANO LM criteria. A total of 142 pts with BC-related LM and available baseline brain MRI imaging were identified; 60 of them had at least one follow-up MRI. In this subgroup, median overall survival (OS) was 15.2 months (95%CI 9.5-21.0). At first re-evaluation, radiological response by RANO criteria was: complete response (CR) in 2 pts (3%), partial response (PR) in 12 (20%), stable disease (SD) in 33 (55%) and progression of disease (PD) in 13 (22%). Median OS was 31.1 months (HR 0.10, 95%CI 0.01-0.78) in pts with CR, 16.1 months (HR 0.41, 95%CI 0.17-0.97) in pts with PR, 17.9 months (HR 0.45, 95%CI 0.22-0.91) in pts with SD and 9.5 months in pts with PD (P = .029). A second blinded evaluation showed a moderate interobserver agreement (K = 0.562). Radiological response according to 2019 RANO criteria is significantly associated with OS in pts with BC-related LM, thus supporting the use of this evaluation tool both in trials and clinical practice.     

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.     

The value of a dedicated multidisciplinary expert panel to assess treatment strategy in patients suffering from colorectal cancer liver metastases

BackgroundFor patients with colorectal cancer liver metastases (CRLM), local treatment is the only treatment with curative intent. The majority of patients with CRLM are however evaluated in multidisciplinary teams of colorectal cancer specialists often lacking expertise in local treatment of liver tumors. The aim of this study was therefore to assess the value of a dedicated multidisciplinary panel consisting of hepatobiliary surgeons and interventional radiologists for patients suffering from liver-only CRLM.MethodsPatients diagnosed with liver-only CRLM in 2016 were identified in a tertiary referral hospital, and two of the referring hospitals in the Netherlands. Diagnostic imaging was independently reviewed by a panel of four hepatobiliary surgeons and two interventional radiologists to re-evaluate treatment strategy retrospectively. If two or more panelists assessed all lesions eligible for resection and/or ablation, patients were deemed eligible for local treatment with curative intent. Interrater reliability between hepatobiliary surgeons was assessed through intraclass correlation coefficient (ICC) and weighted Cohen's kappa.ResultsDiagnostic imaging of 61 patients with liver-only metastases were reviewed. Local treatment strategies appeared feasible in 40/61 (65.6%) patients. Five out of 25 patients (20.0%) initially assigned to systemic therapy were deemed eligible for upfront local treatment with curative intent (p = 0.015). In this subgroup, interrater reliability between hepatobiliary surgeons was substantial (ICC: 0.704, 95% CI: 0.536–0.838, n = 25).ConclusionAssessment of treatment strategy by a dedicated multidisciplinary panel including liver experts may result in an increased number of patients eligible for potentially curative treatment and reduce undertreatment of patients suffering from liver-only CRLM.     

Efficacy of perioperative chemotherapy in resected colorectal liver metastasis: A systematic review and meta-analysis

BackgroundNearly half of patients with colorectal cancer develop liver metastases. Radical resection of colorectal liver metastases (CRLM) offers the best chance of cure, significantly improving 5-year survival. Recurrence of metastatic disease is common, occurring in 60 % or more of patients. Clinical equipoise exists regarding the role of perioperative chemotherapy in patients with resected CRLM. This investigation sought to clarify the efficacy of perioperative chemotherapy in patients that have undergone curative-intent resection of CRLM.MethodsA systematic review and meta-analysis was completed of randomized controlled trials (RCTs) comparing perioperative chemotherapy to surgery alone in patients with resected CRLM. MEDLINE (Ovid), EMBASE and Cochrane Central Register of Controlled Trials (CENTRAL) databases were searched, as well as abstracts from recent oncology conferences. A meta-analysis was performed pooling the hazard ratios for disease-free survival (DFS) and overall survival (OS), using a random-effects model.ResultsA total of five, phase 3, open-label, RCTs were included resulting in a pooled analysis of 1119 of the total 1146 enrolled patients. 559 patients were randomized to perioperative chemotherapy and 560 to surgery alone. Pooled estimates demonstrated a statistically significant improvement in DFS (HR 0.71, 95 % CI: 0.61–0.82; p < 0.001) but not OS (HR 0.87, 95 % CI: 0.73–1.04; p = 0.136).ConclusionPerioperative chemotherapy in the setting of resected CRLM resulted in an improvement in DFS, however this did not translate into an OS benefit. Poor compliance to post-hepatectomy oxaliplatin-based chemotherapy regimens was identified. Further investigation into the optimal regimen and sequencing of perioperative chemotherapy is justified.     

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.     

Development of a model to predict pathologic response to chemotherapy in patients with colorectal liver metastases

BackgroundPreoperative chemotherapy has widely been used in colorectal cancer liver metastasis (CRLM). Pathological response to chemotherapy is very important in evaluating tumor biology. However, there is still a lack of a non-invasive and accurate method to evaluate pathological response before surgery.MethodsWe retrospectively analyzed the clinicopathologic data of patients with CRLM who underwent liver resection after preoperative chemotherapy between January 2006 and December 2018. Pathological responses were defined as minor when there are ≥50% remnant viable cells and as major when 0–49% remnant viable cells exist.ResultsA total of 482 patients were included and randomly divided into training (n=241) and validation (n=241) cohorts. The proportion of major pathologic response was similar between the two groups (51.5% and 48.5%). Multivariate analysis determined the disease-free interval (DFI), tumor size, tumor number, and RAS status as independent predictors of major pathologic response to preoperative chemotherapy. The nomogram incorporating these variables showed good concordance statistics in the training cohort (0.746, 95% CI: 0.685–0.807) and validation cohort (0.764, 95% CI: 0.704–0.823). In addition, the nomogram showed good applicability in patients with different characteristics.ConclusionsThe established nomogram model performed well in predicting pathological response in patients with CRLM.     

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。     

Neutrophil-to-lymphocyte ratio as a prognostic factor for survival in patients with colorectal liver metastases: A systematic review

BACKGROUNDThe inflammatory response to tumor has been proven to be closely related to the prognosis of colorectal cancer. Neutrophil to lymphocyte ratio (NLR) is a widely available inflammatory biomarker that may have prognostic value for patients with colorectal liver metastasis (CRLM).AIMTo assess the role of NLR as a prognostic factor of survival and tumor recurrence in patients with CRLM.METHODSA systematic literature search of PubMed, Cochrane Library and clinicaltrials.gov was conducted by two independent researchers in order to minimize potential errors and bias. Conflicts were discussed and settled between three researchers. Studies including patients undergoing different types of medical interventions for the treatment of CRLM and evaluating the correlation between pretreatment NLR and disease-free survival (DFS) and overall survival (OS) were included in the review. Nineteen studies, involving 3283 patients matched our inclusion criteria.RESULTSIn the studies included, NLR was measured before the intervention and the NLR thresholds ranged between 1.9 and 7.26. Most studies used 5 as the cut-off value. Liver metastases were treated with hepatectomy with or without chemotherapy regimens in 13 studies and with radiofrequency ablation, radioembolization, chemoembolization or solely with chemotherapy in 6 studies. High NLR was associated with decreased OS and DFS after liver resection or other medical intervention. Moreover, high NLR was associated with poor chemosensitivity. On the contrary, CRLM patients with low pretreatment NLR demonstrated improved OS and DFS. NLR could potentially be used as a predictive factor of survival and tumor recurrence in patients with CRLM treated with interventions of any modality, including surgery, chemotherapy and ablative techniques.CONCLUSIONNLR is an inflammatory biomarker that demonstrates considerable prognostic value. Elevated pretreatment NLR is associated with poor OS and DFS in patients with CRLM who are submitted to different treatments.     

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.     

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.     

Nomogram predicted disease free survival for colorectal liver metastasis patients with preoperative chemotherapy followed by hepatic resection

BackgroundHepatic resection is regarded to as a potentially curative option for colorectal cancer liver metastases (CRLM), but it is associated with a high rate of recurrence. The present study intended to establish an effective nomogram to predict disease free survival (DFS) and select candidates of hepatic resection.MethodsThe nomogram was based on a retrospective study on 447 CRLM patients treated with preoperative chemotherapy followed by hepatic resection using a multicentric database between January 1st, 2010 and December 31st, 2017. Results were validated using bootstrap resampling on 117 patients. The predictive accuracy and discriminative ability of the nomogram were determined by concordance index (C-index) and calibration curve. Overall survival, disease free survival, and local recurrence rate for patients with colorectal cancer were measured.ResultsBased on multivariate analysis of the primary cohort, independent factors for DFS included tumor size larger than 5 cm, multiple liver metastases(>1), RAS mutation, primary lymph node metastasis and tumor size increase after preoperative chemotherapy. These five factors were all considered in the nomogram. The C-index of the nomogram for predicting survival was 0.675. With external validation, the C-index of the nomogram for the prediction of the DFS was 0.77, which demonstrated that this model has a good level of discriminative ability. For the 382 patients (66.7%) who developed recurrence, the optimal cutoff point for early recurrence was determined to be 12 months after hepatic resection.ConclusionsThe proposed nomogram demonstrated accurate prognostic prediction of DFS for CRLM patients with preoperative chemotherapy followed by hepatic resection.     

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.