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.     

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.     

Management of single pulmonary metastases from colorectal cancer: State of the art

Colorectal cancer (CRC) is one of the most common causes of death from cancer. Lung seeding occurs in approximately 10% of patients surgically treated for primary CRC with radical intent: the lung is the most common site of metastases after the liver. While surgical treatment of liver metastases is widely accepted to affect long-term outcomes, more controversial and not standardized is the therapy for CRC patients developing lung metastases. Experience suggests the potential curative role of pulmonary metastasectomy, especially in oligometastatic disease. However, the optimal strategy of care and the definition of prognostic factors after treatment still need to be defined. This review focused on the uncommon scenario of single pulmonary metastases from CRC. We explored pertinent literature and provide an overview of the epidemiology, clinical characteristics and imaging of single pulmonary metastases from CRC. Additionally, we identified the best available evidence for overall management. In particular, we analyzed the role and results of locoregional approaches (surgery, radiotherapy or ablative procedures) and their integration with systemic therapy.     

Curative strategies for liver metastases from colorectal cancer: a review

Colorectal cancer is a very common malignancy and frequently manifests with liver metastases, often without other systemic disease. Margin-negative (R0) resection of limited metastatic disease, in conjunction with systemic antineoplastic agents, is the primary treatment strategy, leading to long survival times for appropriately selected patients. There is debate over whether the primary tumor and secondaries should be removed at the same time or in a staged manner. Chemotherapy is effective in converting some unresectable liver metastases into resectable disease, with a correspondingly better survival outcome. However, the ideal chemotherapy with or without biological agents and when it should be administered in the course of treatment are uncertain. The role of neoadjuvant chemotherapy in initially resectable liver metastases is controversial. Local delivery of chemotherapy, with and without surgery, can lead to longer disease-free survival times, but it is not routinely used with curative intent. This review focuses on methods to maximize the disease-free survival interval using chemotherapy, surgery, and local methods.     

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.     

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.     

Impact of BRAF mutations on clinical outcomes following liver surgery for colorectal liver metastases: An updated meta-analysis

BackgroundData regarding clinical outcomes of patients undergoing hepatic resection for BRAF-mutated colorectal liver metastases (CRLM) are scarce. Most of the studies report an impaired median overall survival (OS) in BRAF-mutated patients, but controversial Results regarding both recurrence-free survival (RFS) and recurrence patterns. The purpose of this updated meta-analysis was to better precise the impact of BRAF mutations on clinical outcomes following liver surgery for CRLM study, especially on recurrence.MethodsA systematic literature review was performed to identify articles reporting clinical outcomes including both OS and RFS, recurrence patterns, and clinicopathological details of patients who underwent complete liver resection for CRLM, stratified according to BRAF mutational status.ResultsThirteen retrospective studies, including 5192 patients, met the inclusion criteria. The analysis revealed that both OS (OR = 1.981; 95% CI = [1.613–2.432]) and RFS (OR = 1.49; 95% CI [1.01–2.21]) were impaired following liver surgery for CRLM in BRAF-mutated patients. Risks of both hepatic (OR = 0.42; 95% CI [0.18–0.98]) and extrahepatic recurrences (OR = 0.53; 95% CI [0.33–0.83] were significantly higher in BRAF-mutated patients. These patients tended to have higher rates of right-sided colon primary tumors, primary positive lymph nodes, and multiple CRLM.ConclusionsThis meta-analysis confirms that BRAF mutations impair both OS and RFS following liver surgery. Therefore, BRAF mutational status should probably be included in further prognostic scores for the assessment of the expected clinical outcomes following surgery for CRLM.     

Guidelines for the detection and treatment of liver metastases of colorectal cancer

The spread of the surgical treatment for hepatic metastases have been crucial in the improvement of treatment and survival of metastatic colorectal cancer. The early and accurate diagnosis of metastases and the assessment of their size are essential factors to reach the optimal results with this treatment strategy. The precise indication of the surgical technique with or without the previous administration of neoadjuvant chemotherapy is of significant importance for the choice of R0 surgery and the timing of intervention. Although there is an agreement regarding some parameters related to diagnosis techniques and surgical criteria such as the bilobar extension, the size of the remaining liver post-surgical removal and the indication of pre-operatory chemotherapy, it is necessary to consider all these factors to set up standard criteria and optimize the results. In this article we review all these parameters, from disease follow up to detect metastatic dissemination to the basic criteria for use of neoadjuvant chemotherapy, in order to suggest some general recommendations of evidence level II and recommendation grade A.     

Prognostic models for outcome following liver resection for colorectal cancer metastases: A systematic review

Background

Liver resection provides the best chance for cure in colorectal cancer (CRC) liver metastases. A variety of factors that might influence survival and recurrence have been identified. Predictive models can help in risk stratification, to determine multidisciplinary treatment and follow-up for individual patients.

Aims

To systematically review available prognostic models described for outcome following resection of CRC liver metastases and to assess their differences and applicability.

Methods

The Pubmed, Embase and Cochrane Library databases were searched for articles proposing a prognostic model or risk stratification system for resection of CRC liver metastases. Search terms included ‘colorectal’, ‘liver’, ‘metastasis’, ‘resection’, ‘prognosis’ and ‘prediction’. The articles were systematically reviewed.

Results

Fifteen prognostic systems were identified, published between 1996 and 2009. The median study population was 305 patients and the median follow-up was 32 months. All studies used Cox proportional hazards for multi-variable analysis. No prognostic factor was common in all models, though there was a tendency towards the number of metastases, CRC spread to lymph nodes, maximum size of metastases, preoperative CEA level and extrahepatic spread as representing independent risk factors. Seven models assigned more weight to selected factors considered of higher predictive value.

Conclusion

The existing predictive models are diverse and their prognostic factors are often not weighed according to their impact. For the development of future predictive models, the complex relations within datasets and differences in relevance of individual factors should be taken into account, for example by using artificial neural networks.     

Nationwide oncological networks for resection of colorectal liver metastases in the Netherlands: Differences and postoperative outcomes

IntroductionWidespread differences in patient demographics and disease burden between hospitals for resection of colorectal liver metastases (CRLM) have been described. In the Netherlands, networks consisting of at least one tertiary referral centre and several regional hospitals have been established to optimize treatment and outcomes. The aim of this study was to assess variation in case-mix, and outcomes between these networks.MethodsThis was a population-based study including all patients who underwent CRLM resection in the Netherlands between 2014 and 2019. Variation in case-mix and outcomes between seven networks covering the whole country was evaluated. Differences in case-mix, expected 30-day major morbidity (Clavien-Dindo ≥3a) and 30-day mortality between networks were assessed.ResultsIn total 5383 patients were included. Thirty-day major morbidity was 5.7% and 30-day mortality was 1.5%. Significant differences between networks were observed for Charlson Comorbidity Index, ASA 3+, previous liver resection, liver disease, preoperative MRI, preoperative chemotherapy, ≥3 CRLM, diameter of largest CRLM ≥55 mm, major resection, combined resection and ablation, rectal primary tumour, bilobar and extrahepatic disease. Uncorrected 30-day major morbidity ranged between 3.3% and 13.1% for hospitals, 30-day mortality ranged between 0.0% and 4.5%. Uncorrected 30-day major morbidity ranged between 4.4% and 6.0% for networks, 30-day mortality ranged between 0.0% and 2.5%. No negative outliers were observed after case-mix correction.ConclusionVariation in case-mix and outcomes are considerably smaller on a network level as compared to a hospital level. Therefore, auditing is more meaningful at a network level and collaboration of hospitals within networks should be pursued.     

Effectiveness and cost-effectiveness of peri-operative versus post-operative chemotherapy for resectable colorectal liver metastases

Background

The role of neo-adjuvant chemotherapy prior to hepatectomy in patients with resectable colorectal liver metastases is currently a matter of debate. The aim of the present study was to analyse life-expectancy, quality adjusted life-expectancy and cost-effectiveness of the two chemotherapeutic strategies.

Methods

A Markov decision model was developed, on the basis of parameters derived from an extensive literature search of the last ten years, to compare outcomes of peri-operative versus post-operative chemotherapy.

Results

Life-expectancy observed for peri-operative chemotherapy was 54.56 months and 52.62 months with post-operative chemotherapy only; the quality-adjusted life-expectancy with peri-operative chemotherapy was 39.33 quality-adjusted life-months (QALMs) and 37.84 QALMs with post-operative chemotherapy. Peri-operative chemotherapy results in an increase in total costs of 1180 € over ten years and in an incremental cost-effectiveness ratio (ICER) of 791.9 €/QALM. The model was more sensitive to the expected 3-year recurrence-free survival (RFS) and cost of hepatic resection: with respect to an expected 3-year RFS ? 25% the peri-operative approach was more cost-effective than post-operative strategy but differences in average cost-effectiveness were small. The relationship between ICER and cost of hepatic resection was inverse because the higher the cost of hepatic resection, the higher the cost saving due to patients becoming unresectable during neo-adjuvant therapy.

Conclusions

In the treatment of resectable colorectal liver metastases, the addition of neo-adjuvant chemotherapy could be cost-effective because it makes it possible to avoid hepatic resection in patients who do not respond to the neo-adjuvant approach; however, the life-expectancy of the two strategies is very similar.     

Regional lymph node involvement in patients undergoing liver resection for colorectal cancer metastases

Background

While the indications for surgery among patients with colorectal cancer liver metastases (CRCLM) are expanding, the role of surgery in patients with hepatic lymph node involvement remains controversial. We report management and outcomes in a population-based cohort of patients undergoing hepatectomy with concomitant hepatic lymphadenectomy for CRCLM.

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.     

结直肠癌同时性肝转移同期切除切口与近期预后探讨

目的：结直肠癌同时性肝转移（synchronous colorectal liver metastases ,sCRLM ）同期切除时,切口是外科医生需要考虑的技术问题。本研究旨在探讨切口对同期切除近期预后的影响。方法：回顾性分析2009年1 月至2014年12月北京大学肿瘤医院肝胆胰外Ⅱ科37例同期切除的sCRLM 患者的临床数据。结果：Mercedes 切口（Mer）组19例,正中切口（Mid）组18例。2 组间患者一般情况、大体积肝切除比例、手术时间、术中出血量、术中第一肝门阻断时间无显著性差异。正中切口组中直肠患者更多（P < 0.001）。 2 组共发生并发症11例（32.4%）,其中Mer组9 例（47.4%）,Mid组3 例（16.7%）,两组比较无显著性差异（P = 0.08）。 术后住院时间 Mer组（22.1 ± 9.5）d,Mid组（17.2 ± 6.7）d,两组比较无显著性差异（P = 0.08）。当患者 BMI（bodymassindex）< 25时,并发症Mer组5 例（38.5%）,Mid组0 例（0%）,两组比较有显著性差异（P = 0.046）。 术后住院时间Mer 组（22.1 ± 10.5）d,Mid组（15.7 ± 5.3）d,P = 0.051。结论：sCRLM 患者进行同期切除时,正中切口可以满足术野暴露要求,相比Mercedes 切口,对直肠术野的暴露更有优势;当BMI<25时,正中切口可能会有更好的近期预后。     

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.     

Laparoscopic liver resection for colorectal liver metastases — short- and long-term outcomes: A systematic review

BACKGROUNDFor well-selected patients and procedures, laparoscopic liver resection (LLR) has become the gold standard for the treatment of colorectal liver metastases (CRLM) when performed in specialized centers. However, little is currently known concerning patient-related and peri-operative factors that could play a role in survival outcomes associated with LLR for CRLM.AIMTo provide an extensive summary of reported outcomes and prognostic factors associated with LLR for CRLM.METHODSA systematic search was performed in PubMed, EMBASE, Web of Science and the Cochrane Library using the keywords “colorectal liver metastases”, “laparoscopy”, “liver resection”, “prognostic factors”, “outcomes” and “survival”. Only publications written in English and published until December 2019 were included. Furthermore, abstracts of which no accompanying full text was published, reviews, case reports, letters, protocols, comments, surveys and animal studies were excluded. All search results were saved to Endnote Online and imported in Rayyan for systematic selection. Data of interest were extracted from the included publications and tabulated for qualitative analysis.RESULTSOut of 1064 articles retrieved by means of a systematic and grey literature search, 77 were included for qualitative analysis. Seventy-two research papers provided data concerning outcomes of LLR for CRLM. Fourteen papers were eligible for extraction of data concerning prognostic factors affecting survival outcomes. Qualitative analysis of the collected data showed that LLR for CRLM is safe, feasible and provides oncological efficiency. Multiple research groups have reported on the short-term advantages of LLR compared to open procedures. The obtained results accounted for minor LLR, as well as major LLR, simultaneous laparoscopic colorectal and liver resection, LLR of posterosuperior segments, two-stage hepatectomy and repeat LLR for CRLM. Few research groups so far have studied prognostic factors affecting long-term outcomes of LLR for CRLM.CONCLUSIONIn experienced hands, LLR for CRLM provides good short- and long-term outcomes, independent of the complexity of the procedure.     

Role of liver transplantation in the management of colorectal liver metastases: Challenges and opportunities

The liver is the most common site of colorectal cancer metastasis. Complete resection of the metastatic tumor is currently the only treatment modality available with a potential for cure. However, only 20% of colorectal liver metastases (CRLM) are considered resectable at the time of presentation. Liver transplantation (LT) has been proposed as an alternative oncologic treatment for patients with unresectable CRLM. This review summarizes the published experiences of LT in the setting of unresectable CRLM from the previous decades and discusses the challenges and future horizons in the field. Contemporary experiences that come mostly from countries with broader access to liver grafts are also explored and their promising findings in terms of overall survival (OS) and disease-free survival (DFS) are outlined along with their study design and methods. The rationale of establishing specific patient selection criteria and the dilemmas around immunosuppressive regimens in patients undergoing LT for CRLM are also highlighted. Additionally, this review describes the findings of studies comparing LT vs chemotherapy alone and LT vs portal vein embolization plus resection for CRLM in terms of OS and DFS. Last but not least, we present current perspectives and ongoing prospective trials that try to elucidate the role of LT for CRLM.     

Evaluating distant metastases in breast cancer: from biology to outcomes

There is an urgent need to understand distant metastases in breast cancer as they are the most lethal form of recurrence and a major cause of mortality in patients. Some predictors for distant metastases, including nodal status, tumor grade, and hormonal status, are useful in identifying patients at increased risk for distant metastases. Adjuvant endocrine therapy has been the treatment of choice for postmenopausal women with hormone-sensitive breast cancer, and some therapies have shown significant reductions in the risk of distant metastases. Skeletal metastases in breast cancer are treated with bisphosphonates with a certain level of success. With more new agents undergoing clinical trials, a thorough review of the specific and long-term safety of these agents is essential, as is a better understanding of the deterioration in the quality of life and cost concerns of patients who develop distant metastases. Gene-expression profiling is a new entrant in the field of distant metastases diagnosis, which is largely successful in defining gene signatures that predict the development of distant metastases. This review will discuss the biology and the impact of distant metastases on outcomes for patients with breast cancer; it also encompasses the current status, emerging focus, and future perspectives in treatment of skeletal metastases in patients with breast cancer.