Resectable colorectal liver metastases: pro neoadjuvant therapy - contra neoadjuvant therapy

Approximately one third of patients with colorectal cancer (CRC) present with metastases confined to the liver only. In 15 % of these patients the metastases are primarily resectable. After resection of colorectal liver metastases the 5-year survival rate is 25 - 40 %. The EORTC trial of Nordlinger et al. has examined the role of perioperative/neoadjuvant chemotherapy of resectable liver metastases and found in the subgroup of resected patients a significant improvement in disease-free survival through chemotherapy. The results were not significant in the intent-to-treat population. Possible arguments pro neoadjuvant therapy of resectable liver metastases are the early eradication of disseminated tumour cells, the identification of a worse prognosis tumour biology in the individual patient and the higher dose density which can be achieved preoperatively versus postoperatively. Arguments against preoperative chemotherapy are the chemotherapy-induced hepatotoxicity and related increase in perioperative morbidity, the risk of achieving a complete remission of lesions which then cannot be detected intraoperatively and the uncertain optimal duration of chemotherapy. Especially surgical oncologists in Germany do not consider the neoadjuvant treatment of resectable liver metastases as a standard of care. In summary, because of the lack of level 1 evidence, patients with resectable liver metastases of colorectal cancer should be discussed within interdisciplinary tumour boards together with surgeons, gastroenterologists and medical oncologists. Potentially, overall survival data of the EORTC trial which is expected for late 2010 could change the level of evidence.     

Current preventive treatment for recurrence after curative hepatectomy for liver metastases of colorectal carcinoma： A literature review of randomized control trials

To review the preventive approaches for recurrence after curative resection of hepatic metastases from colorectal carcinoma, we have summarized all available publications reporting randomized control trials (RCTs) covered in PubMed. The treatment approaches presented above include adjuvant intrahepatic arterial infusion chemotherapy, systemic chemotherapy, neoadjuvant chemotherapy, and immunotherapy. Although no standard treatment has been established, several approaches present promising results, which are both effective and tolerable in post-hepatectomy patients. Intrahepatic arterial infusion chemotherapy should be regarded as effective and tolerable and it increases overall survival (OS) and disease free survival (DFS) of patients, while 5-fluorouracil-based systemic chemotherapy has not shown any significant survival benefit. Fortunately chemotherapy combined with hepatic arterial infusion and intravenous infusion has shown OS and DFS benefit in many researches. Few neoadjuvant RCT studies have been conducted to evaluate its effect on prolonging survivals although many retrospective studies and case reports are published in which unresectable colorectal liver metastases are downstaged and made resectable with neoadjuvant chemotherapy. Liver resection supplemented with immunotherapy is associated with optimal results; however, it is also questioned by others. In conclusion, several adjuvant approaches have been studied for their efficacy on recurrence after hepatectomy for liver metastases from colorectal cancer (CRC), but multi-centric RCT is still needed for further evaluation on their efficacy and systemic or local toxicities. In addition, new adjuvant treatment should be investigated to provide more effective and tolerable methods for the patients with resectable hepatic metastases from CRC.     

Chemotherapy and molecular-targeted treatment for unresectable hepatic metastases: a Japanese perspective

Liver metastasis from colorectal cancer has become a common disease associated with the increase of primary colorectal cancer in Japan. The standard treatment for resectable liver metastases is still complete liver resection. Recent advances in systemic chemotherapy have introduced another strategy, i.e., conversion chemotherapy, for patients with initially diagnosed unresectable liver metastases. The conversion rate after neo-adjuvant chemotherapy is increasing with multidisciplinary approaches. Long-term clinical data have not been established yet. Indications for liver resection after neo-adjuvant chemotherapy; optimal chemotherapy regimens; and histological changes in the normal liver are important research issues for the future.     

Simultaneous surgery for primary colorectal cancer and metastatic lesions?

Approximately 20-25% of patients with colorectal cancer present with liver metastases at the time of diagnosis. Traditionally, resection of the primary tumor has been advocated in order to prevent complications of the primary tumor colorectal cancer in patients with synchronous liver metastases. The published data concerning long-term prognosis in this group of patients are discordant. Although some of the reports show survival benefits from resection of the primary tumor, these studies are retrospective with small number of patients and using single drug chemotherapy. For patients with resectable liver metastases, new studies indicate that progression-free survival is best in patients receiving perioperative chemotherapy. In patients with synchronous nonresectable liver metastases and colorectal cancer, there is no published prospective randomized study comparing initial surgery of the primary tumor with neoadjuvant chemotherapy. However, recent publications show that in patients receiving chemotherapy based on oxaliplatin or irinotecan combined with targeted treatments, the complications associated with the primary tumor are less than 10%. The conclusion should be that today prophylactic surgery of asymptomatic primary colorectal cancer in patients with liver metastases cannot be recommended.     

Secondary hepatic resection as a therapeutic goal in advanced colorectal cancer

Surgery is the only curative option for patients with liver metastases of colorectal cancer, but few patients present with resectable hepatic lesions. Chemotherapy is increasingly used to downstage initially unresectable disease and allow for potentially curative surgery. Standard chemotherapy regimens convert 10%-20% of cases to resectable disease in unselected populations and 30%-40% of those with disease confined to the liver. One strategy to further increase the number of candidates eligible for surgery is the addition of active targeted agents such as cetuximab and bevacizumab to standard chemotherapy. Data from a phase Ⅲ trial indicate that cetuximab increases the number of patients eligible for secondary hepatic resection, as well as the rate of complete resection when combined with first-line treatment with the FOLFIRI regimen. The safety profiles of preoperative cetuximab or bevacizumab have not been thoroughly assessed, but preliminary evidence indicates that these agents do not increase surgical mortality or exacerbate chemotherapyrelated hepatotoxicity, such as steatosis （5-fluorouracil）, steatohepatitis （irinotecan）, and sinusoidal obstruction （oxaliplatin）. Secondary resection is a valid treatment goal for certain patients with initially unresectable liver metastases and an important end point for future clinical trials.     

Portal thrombosis and steatosis after preoperative chemotherapy with FOLFIRI-bevacizumab for colorectal liver metastases

In order to discuss the role of preoperative chemotherapy for colorectal liver metastases, which is used frequently before hepatic resection, even in patients with resectable disease at presentation, we herein report the development of two complications, partial portal vein thrombosis and hepatic steatosis with lobular inflammation, during the course of preoperative chemotherapy with FOLFIRI plus bevacizumab for colorectal liver metastases, which recognition led to timely discontinuation of chemotherapy as well as a change in the surgical strategy to resect the tumors and the damaged liver through advanced techniques.We conclude that duration of treatment and drug doses and combinations may impact the development of chemotherapy-induced liver injury. Surgeons and medical oncologists must work together to devise safe, rational,and oncologically appropriate treatments for patients with multiple colorectal liver metastases, and to improve the understanding of the pathogenesis of chemotherapyinduced liver injury.     

Kurativer Ansatz für metastasierte kolorektale Karzinome

Synchronous or metachronous metastases of colorectal cancer (CRC), although being the expression of systemic disease, allow a curative approach for a selected group of patients. Mainly patients presenting with colorectal liver metastases (CLM) should be evaluated for multimodal management with curative intent. Preoperative and/or postoperative systemic chemotherapy show beneficial impact on progression-free and overall survival, without significantly increasing postoperative complication rates. Concerning the complex definition of resectability and the number of patients with ?borderline“ resectable CLM, preoperative chemotherapy plays an important role in both improvement of prognosis and ?conversion“ to a resectable status. Advances in hepatic surgery and the addition of either locally ablative procedures, such as radiofrequency and SIRT are extending resectability to a larger group of patients and have joined the armamentarium for cases of positive resection margins or technically unresectable disease or add to surgery with a large loss of liver parenchyma. Moreover, multimodal approaches should be considered in pulmonary and peritoneal metastases of CRC.     

Treatment of liver metastases from colorectal cancer

In recent years several new local as well as systemic treatment options have become available for patients with advanced colorectal cancer. A survey among Dutch hospitals revealed considerable differences in the use of diagnostic and therapeutic strategies. Radiofrequency ablation is a promising technique that is currently being investigated in a randomised trial. The role of adjuvant chemotherapy in patients with resectable liver metastases and of neoadjuvant chemotherapy in patients with nonresectable liver metastases has not been clearly established yet. The current status of local and systemic treatment options for colorectal cancer liver metastases is reviewed.     

Portal thrombosis and steatosis after preoperative chemotherapy with FOLFIRI-bevacizumab for colorectal liver metastases

INTRODUCTIONSurgical resection of colorectal liver metastases is nowadays a standard of care for resectable disease with5-year survival rate approaching60%[1-3].Because of several theoretical benefits,preoperative systemic chemotherapy has been frequently…     

Time to think: Selecting patients who may benefit from synchronous resection of primary pancreatic cancer and liver metastases

Pancreatic cancer remains a lethal disease and is associated with poor prognosis, particularly for patients with distant metastasis at diagnosis. Recently, Oweira reported a retrospective study that included 13233 metastatic pancreatic cancer patients from the Surveillance, Epidemiology and End Results database. They demonstrated that pancreatic cancer patients with isolated liver metastases had worse outcomes than patients with isolated lung metastases or distant nodal metastases. At present, the standard treatment for metastatic pancreatic cancer is chemotherapy. However, improvement in the safety of pancreatic surgery has led to the consideration of more aggressive surgical approaches. Schneitler reported two cases of hepatic metastatic pancreatic cancer in which negative margin(R0) resection and long survival were achieved after effective preoperative chemotherapy. In general, these two studies indicate that although pancreatic cancer patients with liver metastasis have a poor prognosis, surgical approaches may prolong survival for a few of these patients. A strategy to select hepatic metastatic pancreatic cancer patients who may benefit from surgical intervention is urgently needed.     

Resection and local therapy for liver metastases

In 30-50% of patients the liver is a preferred site of distant disease for many malignant tumours. Due to the high incidence, most of the available data relate to metastases arising from colorectal primaries. Surgical resection is at present the only treatment offering potential cure. The achievable 5-year survival rate is 30%. However, only 10-15% of patients with colorectal liver metastases can undergo potentially curative liver resection. Therefore, accurate staging is an important prerequisite in selecting patients who would benefit from surgery. Recurrence of hepatic metastases after potentially curative resection occurs in up to 60% of the cases. Results demonstrate that re-resection of liver metastases can provide long-term survival rates in a carefully selected group of patients without extrahepatic disease. Because of the high rate of recurrences following an apparently curative resection several authors investigated the use of adjuvant chemotherapy (systemic, intraportal, and hepatic arterial infusion). Until recently none had shown effectiveness. Pre-operative chemotherapy seems to be a promising approach in patients with liver metastases initially considered unsuitable for radical surgery. Recently, neoadjuvant chemotherapy has been proposed as an alternative approach to conventional surgery as initial management with the aim of improving the results in resectable liver metastases. Interventional strategies (ethanol injection, cryosurgery, laser-induced thermotherapy, radio-frequency ablation) and combined modalities (surgical/interventional) are additive methods which may help to improve treatment results in the future.     

Multimodale Therapie des kolorektalen Karzinoms

Adjuvant chemotherapy for resected stage III colon cancer is indicated for all patients, including elderly patients >70 years. In general, adjuvant oxaliplatin-fluoropyrimidine chemotherapy should be started within 6 weeks after tumor resection and should be given for a period of 6 months. However, patients aged >70 should receive fluoropyrimidine mono-chemotherapy. This mono-therapy, but not an oxaliplatin-based combination, can also be considered for patients with standard risk stage II tumors without microsatellite instability. In stage II patients with a high risk constellation adjuvant oxaliplatin-fluoropyrimidine combination therapy should be considered. Patients with stage II and III rectal cancer require neoadjuvant radiochemotherapy with fluoropyrimidine followed by adjuvant fluoropyrimidine treatment. There is no role for the use of VEGF- or EGFR-antibodies in the adjuvant therapy of colon cancer or in neoadjuvant therapy of rectal cancer. The prognosis of patients with primary resectable colorectal liver metastases may be improved by adjuvant or perioperative chemotherapy, while neoadjuvant systemic chemotherapy frequently facilitates potential curative resection of initially non-resectable liver metastases.     

Multi-modality treatment of colorectal liver metastases

Liver metastases synchronously or metachronously occur in approximately 50% of colorectal cancer patients. Multimodality comprehensive treatment is the best therapeutic strategy for these patients. However, the optimal pattern of multimodality therapy is still controversial, and it raises several significant concerns. Liver resection is the most important treatment for colorectal liver metastases. The definition of resectability has shifted to focus on the completion of R0 resection and normal liver function maintenance. The role of neoadjuvant and adjuvant chemotherapy still needs to be clarified. The management of either progression or complete remission during neoadjuvant chemotherapy is challenging. The optimal sequencing of surgery and chemotherapy in synchronous colorectal liver metastases patients is still unclear. Conversional chemotherapy, portal vein embolization, two-stage resection, and tumor ablation are effective approaches to improve resectability for initially unresectable patients. Several technical issues and concerns related to these methods need to be further explored. For patients with definitely unresectable liver disease, the necessity of resecting the primary tumor is still debatable, and evaluating and predicting the efficacy of targeted therapy deserve further investigation. This review discusses different patterns and important concerns of multidisciplinary treatment of colorectal liver metastases.     

Percutaneous vs. surgical placement of hepatic artery indwelling catheters for regional chemotherapy

BACKGROUND/AIMS: Intra-arterial hepatic chemotherapy based on floxuridine infusion is an effective treatment for hepatic metastases from colorectal cancer. The aim of the present study is the comparative analysis of surgical and percutaneous transaxillary approaches to implant a catheter into the hepatic artery for intra-arterial hepatic chemotherapy with floxuridine. METHODOLOGY: Fifty-six patients received an arterial device for intra-arterial hepatic chemotherapy. Twenty-eight patients (LPT group) underwent laparotomy to implant the catheter into the hepatic artery, the other 28 patients (PCT group) received a percutaneous catheter into the hepatic artery through a transaxillary percutaneous access. Safety and efficacy of surgical and percutaneous transaxillary approaches were comparatively analyzed in terms of number of intra-arterial hepatic chemotherapy cycles administered, device-related complications causing suppression of intra-arterial hepatic chemotherapy, and biological costs of the procedures. RESULTS: Mean postoperative hospitalization was 8.2 +/- 2.2 days in the LPT group and 1.8 +/- 0.7 days in the PCT group (P < 0.0001), while mean analgesic requirements were 9.7 +/- 3.2 doses in the LPT group and 2 +/- 0.9 doses in the PCT group (P < 0.0001). Mean number of intra-arterial hepatic chemotherapy cycles administered was 6.5 +/- 4.2 in the LPT group and 4.3 +/- 3.4 in the PCT group (P = 0.038). The overall incidence of device-related complications causing suppression of intra-arterial hepatic chemotherapy was 42.7% in the PCT group and 7.1% in the LPT group (P = 0.005). CONCLUSIONS: Surgical implantation is still recommended when laparotomy has to be performed for other contextual procedures, such as colorectal or hepatic resection, while percutaneous transaxillary catheter placement is indicated for palliative or neoadjuvant intra-arterial hepatic chemotherapy.     

Evaluating agreement regarding the resectability of colorectal liver metastases: a national case-based survey of hepatic surgeons

Background

The resectability of colorectal liver metastases is in part largely based on the surgeon''s assessment of cross-sectional imaging. This process, while guided by principles, is subjective. The objective of the present study was to assess agreement between hepatic surgeons regarding the resectability of colorectal liver metastases.

Methods

Forty-six hepatic surgeons across Canada were invited. A patient with biologically favourable disease was presented after having received neoadjuvant chemotherapy. The scenario was matched with 10 different scrollable abdominal CT scans representing a maximum response after six cycles of chemotherapy. Surgeons were asked to offer an opinion on resectability of liver metastases, and whether they would use adjunct modalities to hepatic resection.

Results

Twenty-six surgeons participated. Twenty responses were complete. The median number of scenarios deemed resectable was 6/10 (range 3–8). Two control scenarios demonstrated perfect agreement. Agreement on resectability was poor for 4/8 test scenarios, of which one scenario demonstrated complete disagreement. Among resectable cases, the pattern of use of adjunct modalities was variable. A median ratio of 0.87 adjunct modality per resectable scenario per surgeon was used (range 0.25–1.75).

Conclusion

A significant lack of agreement was identified among surgeons on the resectability and use of adjunct modalities in the treatment of colorectal liver metastases.     

Long-term complete response of unresectable liver metastases from colorectal cancer

Recent advances in chemotherapy for metastatic colorectal cancer, such as fluorouracil -leucovorin, irinotecan, oxliplatin, and bevacizumab, have been demonstrated to achieve a high response rate. For most patients with unresectable liver metastases, however, chemotherapy is still not considered to provide a sufficient long-term disease-free survival without a surgical resection. We herein report two cases of a complete response for more than 8 years after having received treatment consisting of hepatic arterial infusion of fluorouracil and oral chemotherapy for unresectable liver metastases. The clinicopathological characteristics of these two cases were as follows: the number of liver metastases, 20, 11; the maximum size, 1.2 cm, 2.8 cm; the serum carcinoembryonic antigen level, 1.2 ng/ ml, 2.4 ng/ml. The following computed tomography scan revealed the liver metastases to have completely disappeared 7 months and 22 months after the treatment, respectively. It is speculated that a small size and a low level carcinoembryonic antigen may predict a good response to chemotherapy for unresectable liver metastases from colorectal cancer.     

Impact of hepatic lymph node metastasis on survival of patients with synchronous resectable or unresectable liver metastases of colorectal cancer

Background

The goals of this retrospective study were to comprehensively evaluate the impact of hepatic lymph node (HLN) involvement on survival in patients with synchronous resectable or unresectable liver metastases from colorectal cancer and to highlight how to deal with such cases in the light of recent advances in chemotherapy.

Methods

The impact of HLN involvement on survival, along with various clinical, pathological, and therapeutic factors, was retrospectively evaluated in 61 patients with synchronous liver metastases from colorectal cancer (resectable, 26; unresectable, 35), undergoing resection of the primary tumor and histopathological evaluation between July 2000 and April 2008.

Results

The proportion with HLN metastasis was 11.5 % in resectable cases and 28.6 % in unresectable cases. On multivariate analysis using the Cox proportional hazards model, HLN metastasis (P < 0.001), along with non-resection of hepatic lesions (P < 0.001), larger metastatic tumor volume (P < 0.001), non-use of oxaliplatin-based chemotherapy (P < 0.001), involvement of 4 or more regional lymph nodes (P < 0.001), and excessive lymphatic invasion (P = 0.02), was identified as an independent risk factor for shorter survival.

Conclusions

To establish a new therapeutic strategy for synchronous liver metastasis of colorectal cancer, the HLNs should be examined histologically in patients undergoing resection of their primary colon and rectal cancer.     

Metastasized pancreatic carcinoma with neoadjuvant FOLFIRINOX therapy and R0 resection

Patients with metastasized carcinoma of the pancreas have a very poor prognosis, and long-term survival cannot be expected. This case report describes two patients with an initial diagnosis of metastatic pancreatic cancer, both with hepatic metastases and one with an additional peritoneal carcinomatosis. Initially, both patients were treated intravenously with the FOLFIRINOX chemotherapy regimen, consisting of 5-FU, folinic acid, irinotecan and oxaliplatin. Surprisingly, the FOLFIRINOX treatment resulted in complete resolution of the hepatic metastases in both patients, with no lesions detectable by computed tomography scan. Furthermore, treatment response included decreased diameter of the primary tumor in the tail of the pancreas and disappearance of the additional peritoneal carcinomatosis. Both patients were discussed by our multidisciplinary tumor board, which recommended surgical resections of the carcinoma. The R0 resection of the primary tumor was successful in both cases and, interestingly, the resected tissues showed no evidence of the hepatic metastases intraoperatively. In the first case, the patient received a postoperative 6-mo course of adjuvant chemotherapy with gemcitabine. In the second case, the patient continued to receive the FOLFIRINOX regimen for an additional 6 mo postoperatively. At 12 mo after the operation, a nonresectable retroperitoneal lymph node metastasis was detected in the first patient, whereas the second patient remained in complete remission at the time of this report (5 mo after the adjuvant therapy was discontinued). This case report is the first of its kind to describe two cases of hepatic metastatic pancreatic carcinoma that were resectable following treatment with FOLFIRINOX. Further studies are required to examine the role of FOLFIRINOX as a neoadjuvant treatment option in subgroups of patients with initially metastasized pancreatic carcinoma.