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 chemotherapy-related 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.

OBJECTIVE: The treatment experience for patients undergoing surgical treatment of colorectal cancer (CRC) liver metastasis is understudied. This study sought to identify common themes in this experience in order to identify factors of importance in treatment decision making. METHODS: The study utilized the phenomenological qualitative research approach. In-depth patient interviews conducted by a nurse researcher were tape-recorded and analyzed using the Colaizzi procedural steps. RESULTS: All participants were interviewed and included 7 men and 5 women, ages 43-75, each with treatment experience with both chemotherapy and major surgery. Participants did not recall their decision to undergo liver surgery as a single event, rather as another in a series of health care choices during the long continuum of their CRC cancer disease experience. Seven common themes that emerged from the analyses of interviews as having significant impact on their treatment experience were communication with the health care provider, support from others, the patient's own attitude, cure uncertainty, coping strategies, hospital care concerns, and Internet information. SIGNIFICANCE OF RESULTS: This study identified factors of importance to patients that may serve to enhance communication, education, treatment satisfaction, and access to surgery for patients with CRC liver metastases. Further validation of our findings with a broader patient population is necessary.

INTRODUCTION: Over the past decade, the emergence of surgical adjuncts such as portal vein embolization, two-stage hepatectomy, and ablative therapies not only decreases mortality and morbidity after an extended hepatectomy but also broadens the indication for surgical treatment of liver metastasis from colorectal cancer. Combination chemotherapeutic regimens, namely 5-fluorouracil/folinic acid with irinotecan or oxaliplatin, and targeted monochromal antibodies can downsize the tumor burden to the extent that formerly unresectable metastases can sometimes be excised. DISCUSSION: The 5-year survival rate following liver resection ranges between 25% and 58%. During the 5-fluorouracil/folinic acid with oxaliplatin and 5-fluorouracil/folinic acid with irinotecan treatment period, the patients who were deemed to be resectable should be considered as surgical candidates regardless of the associated adverse predictive factors. The emergence of epidermal growth factor receptor antibody agents, which act effectively in patients with Kras wild-type tumor, fosters treatment individualization. CONCLUSION: The efficacy of the perioperative chemotherapy on survival benefit for resectable liver metastases has not been justified. However, the timing and indication of surgical treatment paradigm in colorectal liver metastasis, including for synchronous disease and extrahepatic disease, are dramatically changing with the development of chemotherapeutic agents.

ABSTRACT:[Background] The treatment of the primary tumor in advanced metastatic colorectal cancer (CRC) is still a matter of discussion. Little attention has thus far been paid to the endoscopically observable changes of the primary in non-curatively resectable stage IV disease.[Methods] 20 patients [14 men, 6 women, median age 67 (39-82) years] were observed after initial diagnosis of non-curatively resectable metastasized symptomatic (83 %) or asymptomatic (17 %) CRC, from June 2002 to April 2009. If necessary, endoscopic tumor debulking was performed. 5-FU based chemotherapy was given immediately thereafter. In 10 patients, chemotherapy was combined with antibody therapy.[Results] Response of the primary was observed in all patients. Local symptoms were treated endoscopically whenever necessary (obstruction or bleeding), and further improved after chemotherapy was started: Four patients showed initial complete endoscopic disappearance of the primary. In an additional 6 patients, only adenomatous tissue was histologically detected. In both these groups, two patients revealed local tumor relapse after interruption of therapy. Local tumor regression or stable disease was achieved in the remaining 10 patients. 15 patients died during the observation time. In 13 cases, death was related to metastatic disease progression. The mean overall survival time was 19.6 (3-71) months. No complications due to the primary were observed.[Conclusions] This study shows that modern anti-cancer drugs combined with endoscopic therapy are an effective and safe treatment of the symptomatic primary and ameliorate local complaints without the need for surgical intervention in advanced UICC stage IV CRC.

BACKGROUND: Liver resection is the only curative treatment offering a chance of long-term survival in patients with colorectal liver metastases (CRM). Recent data indicated that liver resection in patients with tumor progression while receiving chemotherapy was associated with poor outcome. The aim of the study was to identify risk factors for poor outcome in patients with pre-operative chemotherapy of CRM. METHODS: We analyzed 160 patients after liver resection for CRM with preoperative systemic. chemotherapy. Three groups of patients were identified: 44 patients (27.5%) had a tumor response, 20 (12.5%) showed stable disease, and 96 (60%) patients had tumor progression while on chemotherapy. Median follow-up was 2.4 years (range, 6 days-11.1 years). All available clinicopathologic variables possibly associated with outcome were evaluated. RESULTS: Survival was 88%, 53%, and 37% at 1, 3, and 5 years. Noncurative resection, carcinoembryonic antigen levels >200 ng/ml, tumor grading, size of the largest tumor >5 cm, and number of metastases were associated with poor patient outcome. In the multivariate analysis, tumor free margin and tumor grading correlated with the outcome. Tumor progression while on chemotherapy had no influence on the long-term survival. CONCLUSION: Liver resection offers a long-term survival benefit for patients with CRM, even when tumor growth proceeds during pre-operative chemotherapy.

AIM: To analyze the prognostic factors involved in survival and cancer recurrence in patients undergoing surgical treatment for colorectal liver metastases (CLM) and to describe the effects of time-related changes on survival and recurrence in these patients. METHODS: From January 1994 to January 2006, 236 patients with CLM underwent surgery with the aim of performing curative resection of neoplastic disease at our institution and 189 (80%) of these patients underwent resection of CLM with curative intention. Preoperative, intraoperative and postoperative data, including primary tumor and CLM pathology results, were retrospectively reviewed. Patients were divided into two time periods: a first period from January 1994 to January 2000 (n = 93), and a second period from February 2000 to January 2006 (n = 143). RESULTS: Global survival at 1, 3 and 5 years in patients undergoing hepatic resection was 91%, 54% and 47%, respectively. Patients with preoperative extrahepatic disease, carcinoembryonic antigen (CEA) levels over 20 ng/dL, more than four nodules or extrahepatic invasion at pathological analysis had worse survival. Tumor recurrence rate at 1 year was 48.3%, being more frequent in patients with preoperative and pathological extrahepatic disease and CEA levels over 20 ng/dL. Although patients in the second time period had more adverse prognostic factors, no differences in overall survival and recurrence were observed between the two periods. CONCLUSION: Despite advances in surgical technique and better adjuvant treatments and preoperative imaging, careful patient staging and selection is crucial to continue offering a chance of cure to patients with CLM.

PURPOSE: To assess the added prognostic value for overall survival (OS) of baseline health-related quality of life (HRQOL) and of early changes in HRQOL among patients with localized head and neck cancer (HNC) treated with radiation therapy. PATIENTS AND METHODS: All 540 patients with HNC who participated in a randomized trial completed two HRQOL instruments before radiation therapy: the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30) and the Head and Neck Radiotherapy Questionnaire. Six months after the end of radiation therapy, 497 trial participants again completed the two HRQOL instruments. During the follow-up, 179 deaths were observed. Multivariate Cox proportional hazards models were used to test whether HRQOL variables, baseline and change, provided additional prognostic value beyond recognized prognostic factors. RESULTS: The baseline EORTC QLQ-C30 physical functioning (PF) score was an independent predictor of OS. The hazard ratio (HR) associated with a 10-point increment in baseline PF was 0.87 (95% CI, 0.81 to 0.94). In multivariate models, the change in HRQOL was significantly associated with OS for most HRQOL dimensions. Among these, PF change was the strongest predictor. The magnitude of the association between PF change and survival decreased over time. At 1 year, the HR associated with a positive PF change of 10 points was 0.75 (95% CI, 0.68 to 0.83). After PF is taken into account, no other HRQOL variable was associated with survival. CONCLUSION: Our findings indicate that both baseline PF and PF change provide added prognostic value for OS beyond established predictors in patients with HNC. Assessing HRQOL could help better predict survival of cancer patients.

PURPOSE: In 1998, the American Society of Clinical Oncology (ASCO) published a special article regarding palliative care and companion recommendations. Herein we summarize the major accomplishments of ASCO regarding palliative cancer and highlight current needs and make recommendations to realize the Society's vision of comprehensive cancer care by 2020. METHODS: ASCO convened a task force of palliative care experts to assess the state of palliative cancer care in the Society's programs. We reviewed accomplishments, assessed current needs, and developed a definition of palliative cancer. Senior ASCO members and the Board of Directors reviewed and endorsed this article for submission to Journal of Clinical Oncology. RESULTS: Palliative cancer care is the integration into cancer care of therapies that address the multiple issues that cause suffering for patients and their families and impact their life quality. Effective provision of palliative cancer care requires an interdisciplinary team that can provide care in all patient settings, including outpatient clinics, acute and long-term care facilities, and private homes. Changes in current policy, drug availability, and education are necessary for the integration of palliative care throughout the experience of cancer, for the achievement of quality improvement initiatives, and for effective palliative cancer care research. CONCLUSION: The need for palliative cancer care is greater than ever notwithstanding the strides made over the last decade. Further efforts are needed to realize the integration of palliative care in the model and vision of comprehensive cancer care by 2020.

The triple drug combination consisting of irinotecan, oxaliplatin and 5-fluorouracil (FOLFOXIRI) has demonstrated higher activity and efficacy compared to the doublet FOLFIRI. 5-Fluorouracil could be substituted in FOLFOXIRI regimen by capecitabine, an oral fluoropyrimidine with similar efficacy. Recently, a dose-finding trial has demonstrated the feasibility of the combination of irinotecan, oxaliplatin and capecitabine (XELOXIRI) and established their recommended doses. The aim of this study was to evaluate the activity of XELOXIRI. A total of 36 patients with unresectable metastatic colorectal cancer received irinotecan 165 mg m(-2) and oxaliplatin 85 mg m(-2) on day 1 plus capecitabine 2000 mg m(-2) per day orally in two doses from day 1 to day 7, every 2 weeks. Grade 3-4 toxicities were infrequent, expect for neutropenia and diarrhoea, which were each observed in 30% of patients. Two complete and twenty-two partial responses were obtained, corresponding to an overall response rate of 67%(95% CI 51.4-82%). After a median follow-up of 17.7 months, the median progression-free and overall survival were 10.1 and 17.9 months, respectively.The substitution of 5-fluorouracil with capecitabine, in combination with irinotecan and oxaliplatin, is feasible and does not impair the activity of the regimen. However, the XELOXIRI combination is associated with a high incidence of diarrhoea and, therefore, should be considered as a not preferable alternative to FOLFOXIRI.British Journal of Cancer advance online publication, 12 May 2009; doi:10.1038/sj.bjc.6605075 www.bjcancer.com.

BACKGROUND: To investigate the safety/tolerability of the EGFR-antibody cetuximab when added to irinotecan/5-fluorouracil (5-FU)/folinic acid (FA) for first-line treatment in patients with metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: Twenty-one patients with untreated, metastatic, EGFR-expressing CRC received cetuximab 400 mg/m(2) as an initial dose, and thereafter 250 mg/m(2) weekly. In addition, patients received infusional 5-FU (24 h) in two dose levels (1500 mg/m(2), low 5-FU group, n = 6 or 2000 mg/m(2), high 5-FU group, n = 15), plus FA at 500 mg/m(2) and irinotecan at 80 mg/m(2), weekly x6 q50d. RESULTS: Twenty patients were assessable for tolerability after the first cycle. There were no dose limiting toxicities (DLTs) in the low 5-FU group and three DLTs (20%) in the high 5-FU group (two patients with diarrhea grade 3 and one patient with diarrhea grade 4). In the low 5-FU group all six patients received >80% of the planned dose. In the high 5-FU group, seven of 14 patients (50%) received </=80% of the planned chemotherapy dose during the first cycle due to dosage reductions whilst treatment delays occurred in 10/14 patients. During the whole study period, the common grade 3/4 adverse events were acne-like rash (38%) and diarrhea (29%). Chemotherapy did not affect the pharmacokinetics of cetuximab determined at weeks 1 and 4. Fourteen patients (67%, 95% CI 47% to 87%) had a confirmed response, and six (29%) had stable disease. Median time to progression was 9.9 months [lower 95% confidence limit (CL) 7.9, upper 95% CL not reached]. Median survival time was 33 months (lower CL 20, upper CL not reached). Four patients received secondary surgery with curative intent, and a fifth was potentially eligible for surgery but declined. CONCLUSIONS: Addition of cetuximab to weekly infusional 5-FU/FA plus irinotecan is safe and first data suggest a promising activity. The 5-FU dose of 1500 mg/m(2) is recommended for further studies.

BACKGROUND: Recently published population-based investigations showed elderly patients to be underrepresented in clinical trials and less often treated according to the standard therapy. Although there is evidence that elderly patients benefit from adjuvant (radio-) chemotherapy to the same extent as younger patients, no large series describes the influence of age on efficacy of chemotherapy in metastatic colorectal cancer. PATIENTS AND METHODS: We carried out a retrospective analysis using source data of 3825 patients who received 5-fluorouracil (5-FU)-containing treatment in 22 European trials and identified 629 patients with an age of > or = 70 years. RESULTS: We found an equal overall survival in elderly patients [10.8 months, 95% confidence interval (CI) 9.7-11.8] and in younger patients (11.3 months, 95% CI 10.9-11.7; P = 0.31). Response rate did not differ between age groups > or = 70 and <70 years (23.9% and 21.1%; respectively; P = 0.14). Progression-free survival was marginally prolonged in elderly patients (5.5 months, 95% CI 5.2-5.8; compared with 5.3 months, 95% CI 5.1-5.5; P = 0.01). In both age groups, infusional 5-FU resulted in significantly increased response rates, overall survival and progression-free survival compared with bolus 5-FU. CONCLUSIONS:'Fit' elderly patients benefit at least to the same extent from palliative chemotherapy with 5-FU as younger patients. Infusional 5-FU was shown to be more effective than bolus 5-FU in both age groups. Therefore, standardized palliative chemotherapy should generally be offered to elderly patients and they should not be excluded from clinical trials.

In stage II (T3-4N0) and III (TxN1-2) rectal cancer, adjuvant radiochemotherapy improves overall survival and decreases the rate of local failure compared to only surgical therapy and is regarded as standard for patients with carcinoma of the lower and intermediate rectum.(Preoperative) radiotherapy also decreases the local failure rate following total mesorectal excision. Postoperative radiotherapy has no proven influence on distant metastasis rates or on overall survival. In adjuvant therapy, continuous infusion of 5-flourouracil compared to bolus application increases long-term survival. However, additional administration of leucovorin or levamisole results in increased toxicity and not improved survival. Results of randomized trials of adjuvant therapy with new drugs such as capecitabine, UFT, irinotecan, or oxaliplatin are not yet available. These drugs should not be used outside clinical trials. Elderly patients benefit from adjuvant therapy to the same extent as younger patients and should receive adjuvant radiochemotherapy, if no contraindication exists.

Background:Cetuximab enhances the efficacy of chemotherapy in several cancer types. This trial assessed the activity of cetuximab and chemotherapy in advanced gastric cancer.Methods:Patients with previously untreated, metastatic, gastric cancer received cetuximab 400 mg m(-2) at first infusion followed by weekly infusions of 250 mg m(-2) combined with FUFOX (oxaliplatin 50 mg m(-2), 5-FU 2000 mg m(-2), and DL-folinic acid 200 mg m(-2) d1, 8, 15 and 22 qd36). The primary endpoint was tumour response.Results:Overall, 52 patients were enrolled. The most common grade 3/4 toxicities were diarrhoea (33%), and skin toxicity (24%). Efficacy was evaluable in 46 patients who showed a response rate of 65%(CI 95%: 50-79%) including four complete responses. Time to progression (TTP) was 7.6 months (CI 95%: 5.0-10.1 months) and overall survival (OS) was 9.5 months (CI 95%: 7.9-11.1 months). Epidermal growth factor receptor (EGFR) was detectable in 60% of tumours but showed no correlation with treatment outcome. A KRAS mutation was found in only 1 of 32 (3%) tumour samples analysed.Conclusion:Cetuximab plus FUFOX showed an interesting high response rate in metastatic gastric cancer. Cetuximab plus platinum-fluoropyrimidine chemotherapy is at present being investigated in a phase III randomised controlled trial.British Journal of Cancer advance online publication, 12 January 2010; doi:10.1038/sj.bjc.6605521 www.bjcancer.com.

Background:Recombinant tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) induces tumour-selective apoptosis in various pre-clinical models by binding its specific receptors expressed on cancer cells. Mapatumumab is a fully human monoclonal antibody that is agonistic to the TRAIL Receptor 1 (TRAIL-R1).Methods:This phase II multicentre study was designed to evaluate the efficacy and safety of mapatumumab in patients with colorectal cancer (CRC) who had failed to respond to, were intolerant to, or not candidates for fluoropyrimidine, oxaliplatin, and irinotecan-based regimens. All patients received two loading doses of mapatumumab (20 mg kg(-1) every 14 days), followed by maintenance therapy with 10 mg kg(-1) infused every 14 days.Results:A total of 38 patients, who had progressive disease after a median of three earlier chemotherapy lines, were enrolled. No response according to the Response Evaluation Criteria in Solid Tumors was observed. A total of 12 patients (32%) achieved stable disease for a median of 2.6 months. The median progression-free survival was 1.2 months. The most common adverse events reported, regardless of relationship, were fatigue, nausea, anorexia, and abdominal pain. Plasma mapatumumab concentrations were within the range of exposures predicted by the results of phase I studies of mapatumumab.Conclusion:No clinical activity of single-agent mapatumumab was observed in patients with advanced refractory CRC. However, on the basis of its favourable safety profile and pre-clinical evidence of potential synergy in combination with agents commonly used in the treatment of colorectal cancer, further evaluation of mapatumumab in combination with chemotherapy is warranted.British Journal of Cancer advance online publication, 12 January 2010; doi:10.1038/sj.bjc.6605507 www.bjcancer.com.

Overview of the Disease IncidencePrognosisCurrent General Therapy Standards StagingLymph Node ExcisionStage III DiseaseStage II DiseaseMolecular MarkersAccomplishments During the Year Therapy Cytotoxic ChemotherapyChemotherapy Plus Targeted TherapySpecial PopulationsBasic Science-BiomarkersMethodologyWhat Needs to Be Done Application of the AccomplishmentsControversies and DisagreementsFuture Directions Comments on ResearchObstacles to Progress.

As a result of an increasing life expectancy, the incidence of colon cancer in the older population is rising. As a consequence oncologists and their older patients commonly face the dilemma of whether or not to give/receive treatment for colon cancer. However, the paucity of large, well conducted prospective trials makes it difficult to provide evidence-based clinical recommendations for these patients. The current evidence supports the safety and efficacy of treatment for colon cancer in fit older patients and demonstrates that treatment outcome can be similar to that of their younger counterparts. However, it should be noted that these data are derived from retrospective studies which are likely to suffer from selection bias. Despite a growing body of data, further work is still needed to establish optimal strategies to care for this special population and prospective specific trials for older colon cancer patients are clearly needed.

Five percent of cancer cases present as metastases. If the primary tumor cannot be identified after diagnostic workup, the disease is referred to as cancer of unknown primary (CUP) and is classified as C80.9 according to ICD-10. In Germany, CUP is among the ten most common causes of tumor-related death, with mortality similar to mortality in gastric or pancreatic cancer. Biopsies of the tumor manifestation are generally examined histopathologically and by immunohistochemistry (IHC). Gene expression profiling (GEP) is a new diagnostic technique that might further contribute to tumor specification.In a retrospective study, 43 CUP cases underwent central immunohistochemical review and centrally performed GEP using a classifier based on 495 genes. There was concordance between IHC, GEP and clinical picture in 54% of cases. In four cases, the combination of methods led to an unequivocal identification of the primary tumor.In conclusion, we regard detailed IHC workup and complementary GEP advisable for the purposes of targeted therapy, as well as to identify or exclude specific tumors in a CUP situation.

Nowadays, the advancements of systemic chemotherapy for colorectal carcinoma improve a clinical response rate, and expand the possibility of resection which couldn't operable at the initial visit. In addition, the prognoses of the patients, who had a radical operation for metastasis, are clearly longer than the non-operable patients. Bevacizumab, anti-human VEGF monoclonal antibody, is significantly effective when used in combination with one of the systemic multi-agent chemotherapy such as FOLFOX regimen or FOLFIRI regimen. We report here two cases with colon carcinoma, which had initially unresectable liver metastases, were respond to the treatment of systemic multi-agent chemotherapy with bevacizumab. Then, both cases were able to undergo radical resections of primary tumor and liver metastases safely.

The aim of this study is to investigate the safety and efficacy of neoadjuvant chemotherapy for patients with hepatic colorectal cancer metastases who underwent hepatic resection. Surgical complications and survival rates of the patients with/without neoadjuvant chemotherapy were analyzed. Neoadjuvant chemotherapy was not associated with sever surgical complications after hepatic resection. Postoperative survival rate of the patients with neoadjuvant chemotherapy was not superior to that of patients without neoadjuvant chemotherapy. Neoadjuvant chemotherapy for patients with hepatic colorectal cancer metastases who underwent hepatic resection is safe, but further studies are required to clarify its efficacy.

Background: Recently, an increased number of reports have been published on liver resection following neoadjuvant chemotherapy( NAC)in patients with initially unresectable colorectal liver metastases(IUCLM). However, the definition of unresectable liver metastases differs among institutions. The size of liver tumor B5 cm and number of tumors B5 is commonly a contraindication for resection of liver metastases. The present study was performed to compare the short and longterm results between patients who underwent liver resection following NAC for IUCLM and those with multiple bilobar metastases for initially resectable liver metastases. Methods: Twenty-seven patients with multiple bilobar liver metastases between 1994 and 2007 were divided into two groups, i. e. 11 patients who underwent liver resection following NAC for IUCLM and 16 patients who initially underwent liver resection. NAC was used in three in J-IFL and eight cases in mFOLFOX6. Results: All eleven patients with IUCLM were H3/grade C. The median course of NAC was 6(4-6 courses, Mean+/-SD: 6+/-2 courses). The objective overall response rate was 100%(11/11). H3 of eleven patients was changed to two in H1 and nine in H2 after chemotherapy. Grade C of 11 patients was down-staged in 4 in grade Band 2 in grade A. The H factors and grade of 16 patients who initially underwent liver resection were H16H28H32 and grade A4/B6/C6, respectively. The disease-free and overall survival after resection of colorectal liver metastases between patients with initially unresectable and resectable liver metastases were not significantly different. Conclusions: NAC enables liver resection in some patients with IUCLM. It should be performed not only preoperatively but also postoperatively for IUCLM because of better survival after surgery.

The majority of patients with advanced colorectal cancer die from hepatic metastases caused by disease progression; therefore, several novel technologies are in clinical development to potentially improve local control of liver disease. Radioembolization is a technique for administering radiotherapy internally to unresectable primary or secondary hepatic malignancies in a single procedure. This technique involves the injection of resin or glass microspheres that contain (90)Y into the arterial supply of the liver. Clinical trials of radioembolization used with concomitant radiosensitizing chemotherapy have shown promising results in patients with metastatic colorectal cancer. Several reports suggest that radioembolization is associated with significant downsizing of liver metastases to permit subsequent surgical resection. In this article, the rationale for combining radioembolization with the cytotoxic and molecularly targeted agents licensed for the systemic treatment of colorectal cancer is outlined. Clinical data from trials of radioembolization with concomitant systemic treatment are reviewed, with an emphasis on the appropriateness of primary end points in large-scale trials and the practical aspects of surgical resection in patients whose tumors are successfully downsized by this chemoradiation approach.

Colorectal cancer patients with isolated liver metastasis are potentially cured with surgical resection. Recent advances in systemic chemotherapy have increased the ability to convert unresectable metastatic liver lesions to resectable lesions. The cost in toxicity of these therapeutic advances is increasingly being recognized. Numerous reports have demonstrated an association between irinotecan and steatohepatitis as well as between oxaliplatin and sinusoidal dilation. In this review, we summarize the current clinical experience with these hepatic toxicities and discuss the role they play in determining postoperative morbidity. We also review emerging safety data regarding the use of bevacizumab and cetuximab. Finally, we give specific clinical examples of how multidisciplinary teams can best manage patients receiving preoperative chemotherapy for potentially resectable liver metastases.

BACKGROUND: Neoadjuvant chemotherapy prior to hepatectomy in patients with resectable colorectal liver metastases (CLM) may facilitate the resectability of the liver lesions and treat occult metastasis but may also lead to hepatic parenchyma damage. There is argument over the oncologic benefit of this practice in patients who would already be suitable for a curative hepatectomy. METHODS: Extensive literature search of databases (MEDLINE and PubMed) to identify published studies of preoperative systemic chemotherapy for resectable CLM was undertaken with clinical response to treatment and survival outcomes as the endpoints. RESULTS: Twenty-three studies were reviewed: 1 phase III randomized control trial, 3 phase II studies, and 19 observational studies, comprising 3,278 patients. Objective (complete/partial) radiological response was observed in 64%(range 44-100%)[complete 4%(range 0-38%), partial 52%(range 10-90%)] of patients after neoadjuvant chemotherapy. Pathologically, a median of 9%(range 2-24%) and 36%(range 20-60%) had complete and partial response, respectively. Of patients, 41%(range 0-65%) had stable or progressive disease whilst on neoadjuvant chemotherapy. Median disease-free survival (DFS) was 21 (range 11-40) months. Median overall survival (OS) was 46 (range 20-67) months. CONCLUSION: Current evidence suggests that objective response to neoadjuvant chemotherapy may be achieved with improvement in DFS in patients with resectable CLM. A prospective randomized trial of neoadjuvant therapy versus adjuvant therapy after liver resection is required to determine the optimal perisurgical treatment regimen.

Although resection is the standard of care for liver metastasis, 80-90% of patients are not resectable at diagnosis. Advances in combination chemotherapy, particularly with targeted agents, have increased tumour response and survival in patients with unresectable metastatic colorectal cancer, but these techniques have limitations and may be associated with high recurrence rates. Some autopsy series have shown that as many as 40% of patients with metastatic colorectal cancer have disease confined to the liver; aggressive local therapy may improve overall survival in such patients. Local control of liver metastases can also ease hepatic capsular pain to improve quality of life. Stereotactic body radiation therapy (SBRT) offers an alternative, non-invasive approach to the treatment of liver metastasis through precisely targeted delivery of radiation to the tumours while minimising normal tissue toxicity. Early applications of SBRT to liver metastases have been promising with the reports of 2-year local control rates of 71-86% and other studies reporting 18-month local control rates of 71-93%. While these data establish the safety of SBRT for liver metastases, more rigorous phase II clinical studies are needed to fully evaluate long-term efficacy and toxicity results. In the interim, this review stresses that SBRT of liver must be performed cautiously given the challenges of organ motion and the low toxicity tolerance of the surrounding hepatic parenchyma.