Update on the prevention of local recurrence and peritoneal metastases in patients with colorectal cancer

The prevention of a disease process has always been superior to the treatment of the same disease throughout the history of medicine and surgery. Local recurrence and peritoneal metastases occur in approximately 8% of colon cancer patients and 25% of rectal cancer patients and should be prevented. Strategies to prevent colon or rectal cancer local recurrence and peritoneal metastases include cytoreductive surgery and hyperthermic perioperative chemotherapy (HIPEC). These strategies can be used at the time of primary colon or rectal cancer resection if the HIPEC is available. At institutions where HIPEC is not available with the treatment of primary malignancy, a proactive second-look surgery is recommended. Several phase II studies strongly support the proactive approach. If peritoneal metastases were treated along with the primary colon resection, 5-year survival was seen and these results were superior to the results of treatment after peritoneal metastases had developed as recurrence. Also, prophylactic HIPEC improved survival with T3/T4 mucinous or signet ring colon cancers. A second-look has been shown to be effective in two published manuscripts. Unpublished data from MedStar Washington Cancer Institute also produced favorable date. Rectal cancer with peritoneal metastases may not be so effectively treated. There are both credits and debits of this proactive approach. Selection factors should be reviewed by the multidisciplinary team for individualized management of patients with or at high risk for peritoneal metastases.

Cytoreductive surgery and intraperitoneal chemotherapy for colorectal peritoneal metastases

AIM: To systematically review the available evidence regarding cytoreductive surgery (CRS) and intraperitoneal chemotherapy (IPC) for colorectal peritoneal metastases (CPM).

Colorectal peritoneal metastases:Optimal management review

The peritoneum is a common site of dissemination for colorrectal cancer, with a poorer prognosis than other sites of metastases. In the last two decades, it has been considered as a locoregional disease progression and treated as such with curative intention treatments. Cytoreductive surgery(CRS) and hyperthermic intraperitoneal chemotherapy(HIPEC) is the actual reference treatment for these patients as better survival results have been reached as compared to systemic chemotherapy alone, but its therapeutic efficacy is still under debate. Actual guidelines recommend that the management of colorectal cancer with peritoneal metastases should be led by a multidisciplinary team carried out in experienced centers and consider CRS + HIPEC for selected patients. Accumulative evidence in the last three years suggests that this is a curative treatment that may improve patients disease-free survival, decrease the risk of recurrence, and does not increase the risk of treatment-related mortality. In this review we aim to gather the latest results from referral centers and opinions from experts about the effectiveness and feasibility of CRS + HIPEC for treating peritoneal disease from colorectal malignancies.

Diagnostic value of whole-body MRI with diffusion-weighted sequence for detection of peritoneal metastases in colorectal malignancy

Objective：To assess the diagnostic accuracy of whole-body MRI using diffusion-weighted sequence（WB-DWI）to determine the peritoneal cancer index（PCI）in correlation with surgical and histopathological findings.Methods：Twenty-seven patients underwent preoperative WB-MRI,followed by cytoreductive surgery for primary tumors of the appendix（n=15）,colorectum（n=12）,and associated peritoneal disease.A total of 351 regions were retrospectively reviewed.The sensitivity,specificity,and accuracy were calculated at 13 anatomical sites.The WB-DWI PCI and PCI type were compared with surgical and histopathological findings.Results：No statistical difference was found between the WB-DWI PCI and surgical PCI（P=0.574）.WB-DWI correctly predicted the PCI type in 24 of 27 patients with high accuracy（88.9%）,including 10 of 10 patients with small-volume tumor,12 of 14 with moderate-volume tumor,and 2 of 3 with large-volume tumor.WB-DWI correctly depicted tumors in 163 of 203 regions,with 40false-negative and 23 false-positive regions.The overall sensitivity,specificity,and accuracy of WB-DWI for the detection of peritoneal tumors were 80.3%,84.5%,and 82.1%,respectively.For lesions＆lt;0.5 cm in diameter,WB-DWI demonstrated good sensitivity（69.4%）.Conclusions：WB-DWI accurately predicted PCI before surgery in patients undergoing evaluation for cytoreductive surgery.

Immune response activation following hyperthermic intraperitoneal chemotherapy for peritoneal metastases:A pilot study

BACKGROUND Hyperthermic intraperitoneal chemotherapy(HIPEC)for peritoneal metastases(PM)is considered to be feasible,safe and to improve survival.AIM To investigate whether an immune response is activated following HIPEC for PM.METHODS Six patients were enrolled in this study.Peripheral blood samples were obtained from each patient prior to(day 0)and post-procedure(day 30),and used to evaluate the number of CD3+total,CD3+/CD4+T-Helper,CD3+/CD8+cytotoxic T,CD3+/CD56+natural killer and CD19+B lymphocyte numbers,and CD4+:CD8+T lymphocyte ratios.RESULTS The total numbers of CD3+,CD3+/CD4+T-Helper,CD3+/CD8+cytotoxic T,CD3+/CD56+natural killer and CD19+B lymphocytes,and CD4+:CD8+lymphocyte ratios were increased in all but one patient 30 d following the cytoreductive surgery-HIPEC procedure,and these increases were significant(P≤0.05)for CD3+/CD4+T Helper and CD3+/CD8+cytotoxic T lymphocyte numbers.CONCLUSION This report provides the first evidence that HIPEC exhibits immunomodulating activity in PM patients,resulting in generalized activation of the adaptive immune response.Moreover,the majority of lymphocyte populations increased following HIPEC and continued to be elevated several weeks following the procedure,consistent with a potential authentic immunomodulating effect rather than a normal inflammatory response,to be fully characterised in future studies.

Treatment of peritoneal metastases from colorectal cancer

Peritoneal seedings of a colorectal tumor represent the second most frequent site of metastasis(after the liver).In the era of 5-fluorouracil(5-FU)-only chemotherapy,the prognosis was poor for colorectal cancer with peritoneal metastases.Within the last few years,new chemotherapeutic and targeted agents have improved the prognosis;however,the response to these treatments seems to be lower than that for liver metastases.The combination of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy have further improved both disease-free survival and overall survival.Keeping this in mind,every patient presenting with peritoneal metastases from colorectal cancer should be evaluated and receive adequate treatment,if possible in the above-mentioned combination.This paper reviews recent advancements in the therapy of peritoneal carcinomatosis.

Comparison of hyperthermic intraperitoneal chemotherapy regimens for treatment of peritoneal-metastasized colorectal cancer

BACKGROUND Cytoreductive surgery(CRS)in combination with hyperthermic intraperitoneal chemotherapy(HIPEC)improves patient survival in colorectal cancer(CRC)with peritoneal carcinomatosis(PC).Commonly used cytotoxic agents include mitomycin C(MMC)and oxaliplatin.Studies have reported varying results,and the evidence for the choice of the HIPEC agent and uniform procedure protocols is limited.AIM To evaluate therapeutic benefits and complications of CRS+MMC vs oxaliplatin HIPEC in patients with peritoneal metastasized CRC as well as prognostic factors.METHODS One hundred and two consecutive patients who had undergone CRS and HIPEC for CRC PC between 2007 and 2019 at the Medical Center of the University Freiburg regarding interdisciplinary cancer conference decision were retrospectively analysed.Oxaliplatin and MMC were used in 68 and 34 patients,respectively.Each patient’s demographics and tumour characteristics,operative details,postoperative complications and survival were noted.Complications were stratified and graded using Clavien/Dindo analysis.Prognostic outcome factors were identified using univariate and multivariate analysis of survival.RESULTS The two groups did not differ significantly regarding baseline characteristics.We found no difference in median overall survival between MMC and oxaliplatin HIPEC.Regarding postoperative complications,patients treated with oxaliplatin HIPEC suffered increased complications(66.2%vs 35.3%;P=0.003),particularly intestinal atony,intraabdominal infections and urinary tract infection,and had a prolonged intensive care unit stay compared to the MMC group(7.2 d vs 4.4 d;P=0.035).Regarding univariate analysis of survival,we found primary tumour factors,nodal positivity and resection margins to be of prognostic value as well as peritoneal cancer index(PCI)-score and the completeness of cytoreduction regarding peritoneal carcinomatosis.Multivariate analysis of survival confirmed primary distant metastasis and primary tumour resection status to have a significant impact on survival and likewise peritoneal cancer index-scoring regarding peritoneal carcinomatosis.CONCLUSION In this single-institution retrospective review of patients undergoing CRS with either oxaliplatin or MMC HIPEC,overall survival was not different,though oxaliplatin was associated with a higher postoperative complication rate,indicating treatment favourably with MMC.Further studies comparing HIPEC regimens would improve evidence-based decision-making.

Prognostic significance of peritoneal metastasis from colorectal cancer treated with first-line triplet chemotherapy

BACKGROUND Peritoneal metastasis from colorectal cancer(CRC)carries a poor prognosis in most studies.The majority of those studies used either a single-agent or doublet chemotherapy regimen in the first-line setting.AIM To investigate the prognostic significance of peritoneal metastasis in a cohort of patients treated with triplet chemotherapy in the first-line setting.METHODS We retrospectively evaluated progression-free survival(PFS)and overall survival(OS)in 51 patients with metastatic CRC treated in a prospective clinical trial with capecitabine,oxaliplatin,irinotecan,and bevacizumab in the first-line setting according to the presence and absence of peritoneal metastasis.Furthermore,univariate and multivariate analyses for PFS and OS were performed to assess the prognostic significance of peritoneal metastasis at the multivariate level.RESULTS Fifty-one patients were treated with the above triplet therapy.Fifteen had peritoneal metastasis.The patient characteristics of both groups showed a significant difference in the sidedness of the primary tumor(left-sided primary tumor in 60%of the peritoneal group vs 86%in the nonperitoneal group,P=0.03)and the presence of liver metastasis(40%for the peritoneal group vs 75%for the nonperitoneal group,P=0.01).Univariate analysis for PFS showed a statistically significant difference for age less than 65 years(P=0.034),presence of liver metastasis(P=0.046),lung metastasis(P=0.011),and those who underwent metastasectomy(P=0.001).Only liver metastasis and metastasectomy were statistically significant for OS,with P values of 0.001 and 0.002,respectively.Multivariate analysis showed that age(less than 65 years)and metastasectomy were statistically significant for PFS,with P values of 0.002 and 0.001,respectively.On the other hand,the absence of liver metastasis and metastasectomy were statistically significant for OS,with P values of 0.003 and 0.005,respectively.CONCLUSION Peritoneal metastasis in patients with metastatic CRC treated with first-line triple chemotherapy does not carry prognostic significance at univariate and multivariate levels.Confirmatory larger studies are warranted.

Neutropenia in colorectal cancer treated with oxaliplatin-based hyperthermic intraperitoneal chemotherapy: An observational cohort study

BACKGROUND The implications of neutropenia after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy(HIPEC)treatment have never been investigated.AIM To evaluate the occurrence of neutropenia and its effect on the risk of increased Clavien-Dindo morbidity as well as its effect on overall or disease-free survival.METHODS All patients with colorectal peritoneal metastases(1996-2015)completing cytoreductive surgery and oxaliplatin-based HIPEC treatment from a biinstitutional database(Uppsala and Sydney)were included in the study.Clavien-Dindo grade 3-4 morbidity differences between the neutropenia group vs nonneutropenia group were calculated and Kaplan-Meier curves with log rank test were rendered.Univariate and multivariable Cox regression models for diseasefree survival were implemented.RESULTS Two hundred and forty-six patients were identified–32 postoperative any-grade neutropenia patients and 214 non-neutropenia patients.The neutropenia group had more combination oxaliplatin+irinotecan treatment than the nonneutropenia group(66%vs 13%,P=0.0001).The neutropenia group was not associated with increased Clavien-Dindo grade 3-4 morbidity.Median overall survival was 53 mo vs 37 mo for the neutropenia and non-neutropenia group,P=0.07.Median disease-free survival was 16 mo vs 11 mo,respectively,P=0.02.Neutropenia was an independent prognostic factor for disease-free survival with hazard ratio:0.58,95%confidence interval:0.36-0.95,P=0.03.CONCLUSION 13%of patients developed neutropenia which was not associated with increased Clavien-Dindo grade 3-4 morbidity.Neutropenia was an independent positive prognostic factor for disease-free survival and was associated with more intense HIPEC treatment.This is in direct contrast to the current paradigm of decreasing the treatment intensity.

Adjuvant chemotherapy for resected colorectal cancermetastases:literature review and meta-analysis

Surgical resection is the only option of cure for patients with metastatic colorectal cancer(CRC). However, the risk of recurrence within 18 mo after metastasectomy is around 75% and the liver is the most frequent site of relapse. The current international guidelines recommend an adjuvant therapy after surgical resection of CRC metastases despite the lower level of evidence(based on the quality of studies in this setting). However, there is still no standard treatment and the effective role of an adjuvant therapy remains controversial. The aim of this review is to report the state-of-art of systemic chemotherapy and regional chemotherapy with hepatic arterial infusion in the management of patients after resection of metastases from CRC, with a literature review and meta-analysis of the relevant randomized controlled trials.

Colorectal cancer with liver metastases:Neoadjuvant chemotherapy,surgical resection first or palliation alone?

Colorectal cancer (CRC) is one of the commonest cancers with 1.2 million new cases diagnosed each year in the world. It remains the fourth most common cause of cancer-related mortality in the world and accounts for > 600000 cancer-related deaths each year. There have been significant advances in treatment of metastatic CRC in last decade or so, due to availability of new active targeted agents and more aggressive approach towards the management of CRC, particularly with liver-only-metastases; however, these drugs work best when combined with conventional chemotherapy agents. Despite these advances, there is a lack of biomarkers to inform us about the accurate management of the patients with metastatic CRC. It is therefore imperative to carefully select the patients with comprehensive multi-disciplinary team input in order to optimise the management of these patients. In this review we will discuss various treatment options available in management of colorectal liver metastases with potential guidance on how and when to choose these options along with consideration on future directions in management of this disease.

Therapeutic options for peritoneal metastasis arising from colorectal cancer

Peritoneal metastasis is a common sign of advanced tumor stage, tumor progression or tumor recurrence in patients with colorectal cancer. Due to the improvement of systemic chemotherapy, the development of targeted therapy and the introduction of additive treatment options such as cytoreductive surgery(CRS) and hyperthermic intraperitoneal chemotherapy(HIPEC), the therapeutic approach to peritoneal metastatic colorectal cancer(pm CRC) has changed over recent decades, and patient survival has improved. Moreover, in contrast to palliative systemic chemotherapy or best supportive care, the inclusion of CRS and HIPEC as inherent components of a multidisciplinary treatment regimen provides a therapeutic approach with curative intent. Although CRS and HIPEC are increasingly accepted as the standard of care for selected patients and have become part of numerous national and international guidelines, the individual role, optimal timing and ideal sequence of the different systemic, local and surgical treatment options remains a matter of debate. Ongoing and future randomized controlled clinical trials may help clarify the impact of the different components, allow for further improvement of patient selection and support the standar-dization of oncologic treatment regimens for pm CRC. The addition of further therapeutic options such as neo-adjuvant intraperitoneal chemotherapy or pressurized intraperitoneal aerosol chemotherapy, should be investig-ated to optimize therapeutic regimens and further improve the oncological outcome.

Gastric cancer: prevention and treatment of peritoneal metastases

Gastric cancer is an aggressive malignancy that may metastasize through the bloodstream to the liver,through lymphatics to regi onal lymph n odes,or by pen etratio n of the perit on eal lining of the stomach to result in seed ing of the abdom inal and pelvis surfaces.Peritoneal metastases are the most common mode of cancer dissemination.Technologies to prevent or treat perit on eal metastases from adva need gastric can cer are prese nted in this manu script.The world's literature,both recent and over the past three decades,was reviewed in order to identify publications that present information regarding gastric cancer peritoneal metastases.Over one dozen randomized controlled trials to test perioperative chemotherapy for prevention of peritoneal metastases were reviewed.All of the trials performed with regional chemotherapy during or shortly after gastrectomy were positive.The clinical data regarding the treatment of peritoneal metastases diagnosed at the time of primary can cer resecti on or in follow-up were reviewed.Neoadjuva nt in traperit on eal and systemic chemotherapy shows that some long-term survivors occur after these treatments were combined with cytoreductive surgery and gastrectomy.Similar treatments are advocated for primary gastric cancer with cytology positive for gastric cancer but no visible implants.Surgery for gastric cancer should be combined with perioperative systemic and regional chemotherapy in order to maximally benefit patients with this disease by reducing the negative impact of peritoneal metastases on survival.

An update on chemotherapy of colorectal liver metastases

Surgical resection of liver metastases of colorectal cancer greatly improves the clinical outcome of patients with advanced disease. Developments in chemotherapeutic agents and strategies bring hope of a cure to patients with initially unresectable colorectal liver metastases (CLM). Perioperative chemotherapy signif icantly improves the survival time of patients who receive curative-intent hepatectomy. Even for unresectable CLM, recent studies demonstrated that active preoperative chemotherapy could achieve shrinkage of liver metastasis and thus render some for resection. Furthermore, an increase in tumor resection rate and prolonged survival time among patients with CLM has been observed following the application of monoclonal antibodies in recent years. However, the value of chemotherapy via hepatic arterial infusion is still unclear. More trials should be conducted in patients with CLM in order to improve survival.

Oncological outcome of unresectable lung metastases without extrapulmonary metastases in colorectal cancer

AIM: To explore the oncological outcomes of unresectable lung metastases without extrapulmonary metastases in colorectal cancer. METHODS: Patients with unresectable isolated lung metastases from colorectal cancer were prospectively collected in a single institution during a 5-year period. All patients received either the fluorouracil/leucovorin plus oxaliplatin, fluorouracil/leucovorin plus irinotecan or capecitabine plus oxaliplatin regimen as first-line treatment. The resectability after preoperative chemotherapy was evaluated. Patients' outcome and predictive factors for overall survival were also investigated by univariate and multivariate analysis.RESULTS: A total of 70 patients were included in the study. After standardized fi rst-line chemotherapy, only 4 patients (5.7%) were converted to resectable disease. The median overall survival time in all patients was 19 mo (95% CI: 12.6-25.4), with a 2-year overall survival rate of 38.8%. No survival difference was found among different fi rst-line chemotherapeutic regimens. Prognostic analysis demonstrated that only the fi rst response assessment for fi rst-line treatment was the independent factor for predicting overall survival. The median survival time in partial response, stable disease and progressive disease patients were 27 mo, 16 mo and 8 mo (P = 0.00001). CONCLUSION: Pulmonary metastasectomy can only be performed in a small part of unresectable lung metastases patients after chemotherapy. Patients' first response assessment is an important prognostic factor.

Treatment strategy for colorectal cancer with resectable synchronous liver metastases:Is any evidence-based strategy possible?

Fifteen percent to twenty-five percent of patients affected by colorectal cancer presents with liver metastases at diagnosis. In resectable cases, surgery is the only potentially curative treatment and achieves survival rates up to 50% at 5 years. Management is complex, as colorectal resection, liver resection, chemotherapy, and, in locally advanced mid/low rectal tumors, radiotherapy have to be integrated. Modern medical practice usually relies on evidence-based protocols. Levels of evidence for synchronous metastases are poor:published studies include few recent prospective series and several retrospective analyses collecting a limited number of patients across long periods of time. Data are difficult to be generalized and are mainly representative of single centre's experience, biased by local recruitment, indications and surgical technique. In this context, surgeons have to renounce to "evidence-based medicine" and to adopt a sort of "experience-based medicine". Anyway, some suggestions are possible. Simultaneous colorectal and liver resection can be safely performed whenever minor hepatectomies are planned, while a case-by-case evaluation is mandatory in case of more complex procedures. Neoadjuvant chemotherapy is preferentially scheduled for patients with advanced metastatic tumors to assess disease biology and to control lesions. It can be safely performed with primarytumor in situ , even planning simultaneous resection at its end. Locally advanced mid/low rectal tumor represents a further indication to neoadjuvant therapies, even if treatment's schedule is not yet standardized. In summary, several issues have to be solved, but every single HPB centre should define its proper strategy to optimize patient's selection, disease control and safety and completeness of surgery.

Current state of surgical treatment of liver metastases from colorectal cancer

Hepatic resection is the procedure of choice for curative treatment of colorectal liver metastases(CLM).Objectives of surgical strategy are low intraoperative blood loss,short liver ischemic times and minor postoperative morbidity and mortality.Blood loss is an independent predictor of mortality and compromises,in common with postoperative complications,long-term outcome after hepatectomy for CLM.The type of liver resection has no impact on the outcome of patients with CLM;wedge resections are not inferior to anatomical resections in terms of tumor clearance,pattern of recurrence or survival.Despite the lack of proof of survival benef it,routine lymphadenectomy has been advocated,allowing the detection of microscopic lymph node metastases and with prognostic value.In experienced hands,minimally invasive liver surgery is safe with acceptable morbidity and mortality and oncological results comparable to open hepatic surgery,but with reduced blood loss and earlier recovery.The European Colorectal Metastases Treatment Group recommended treating up front with chemotherapy for patients with both resectable and unresectable CLM.However,neoadjuvant chemotherapy can induce damage to the remnant liver,dependent on the number of chemotherapy cycles.Therefore,in our opinion,preoperative chemotherapy should be reserved for patients whose CLM are marginally resectable or unresectable.A meta analysis of randomized trials dealing with perioperative chemotherapy for the treatment of resectable CLM demonstrated a benefit of systemic chemotherapy but did not answer the question of whether a neoadjuvant or adjuvant approach should be preferred.Analysis of the literature demonstrates that the results of specialized centers cannot be attained in the reality of comprehensive patient care.Reasons behind the commonly poorer results seen in cancer networks as compared with literature-based data are,on the one hand,geographical disparities in access to specialized surgical and medical care.On the other hand,a selection bias in the reports of the literature may be assumed.Studies of surgical resection for CLM derive almost exclusively from case series generally drawn from large academic centers where patient selection or surgical expertise is superior to what is found in many communities.Therefore,we may conclude that the comprehensive propagation of the standards outlined in this paper constitutes a major task in the near future to reduce the variations in survival of patients with CLM.

Pathologic response after preoperative therapy predicts prognosis of Chinese colorectal cancer patients with liver metastases

Background: Pathologic response is evaluated according to the extent of tumor regression and is used to estimate the efficacy of preoperative treatment. Several studies have reported the association between the pathologic response and clinical outcomes of colorecal cancer patients with liver metastases who underwent hepatectomy.However, to date, no data from Chinese patients have been reported. In this study, we aimed to evaluate the association between the pathologic response to pre-hepatectomy chemotherapy and prognosis in a cohort of Chinese patients.Patients and methods: In this retrospective study, we analyzed the data of 380 liver metastases in 159 patients.The pathologic response was evaluated according to the tumor regression grade(TRG).The prognostic role of pathologic response in recurrence-free survival(RFS) and overall survival(OS) was assessed using Kaplan-Meier curves with the log-rank test and multivariate Cox models. Factors that had potential influence on pathologic response were also analyzed using multivariate logistic regression and Kruskal-Wallis/Mann-Whitney U tests.Results: Patients whose tumors achieved pathologic response after preoperative chemotherapy had significant longer RFS and OS than patients whose tumor had no pathologic response to chemotherapy(median RFS: 9.9 vs.6.5 months, P = 0.009; median OS: 40.7 vs. 28.1 months, P = 0.040). Multivariate logistic regression and Kruskal-Wallis/Mann-Whitney U tests showed that metastases with small diameter, metastases from the left-side primary tumors,and metastases from patients receiving long-duration chemotherapy had higher pathologic response rates than their control metastases(all P < 0.05). A decrease in the serum carcinoembryonic antigen(CEA) level after preoperative chemotherapy predicted an increased pathologic response rate(P < 0.05). Although the application of targeted therapy did not significantly influence TRG scores of all cases of metastases, the addition of cetuximab to chemotherapy resulted in a higher pathologic response rate when combined with irinotecan-based regimens rather than with oxaliplatin-based regimens.Conclusions: We found that the evaluation of pathologic response may predict the prognosis of Chinese colorectal cancer patients with liver metastases after preoperative chemotherapy. Small tumor diameter, long-duration chemotherapy, left primary tumor, and decreased serum CEA level after chemotherapy are associated with increased pathologic response rates.

Management of potentially resectable colorectal cancer liver metastases

Colorectal cancer is a very common malignancy worldwide and development of liver metastases,both synchronous or metachronous,is a common event.Of all patients with metastatic colorectal cancer,up to 77% have a liver-only disease and approximately 10%-20% of patients with colorectal liver metastases are considered resectable at the time of diagnosis.Surgical resection of liver metastases remains the best treatment option and it is associated with a survival plateau and a 20%-25% of long-term survivors.Perioperative chemotherapy for resectable liver metastases may improve resecability of liver metastases and disease free survival,but its impact on overall survival is still unclear and more studies are needed.Moreover,preoperative chemotherapy can increase postoperative complications.Further studies are needed to define the role of adjuvant chemotherapy after a R0 resection of liver metastases and to define the criteria for a better selection of patients candidate to hepatectomy.New strategies such as targeted therapies are emerging with promising results.Optimal management requires a multidisciplinary approach,local and systemic,but it is a still pending question.Colorectal liver metastases represent a major challenge for oncologists and surgeons.In this review will be analyzed available data about assessment and management of the patients with potentially resectable colorectal liver metastases.

Pharmacologic rationale for treatments of peritoneal surface malignancy from colorectal cancer

The peritoneal surfaces of the abdomen and pelvis are important sites for the dissemination of gastrointestinal and gynecologic malignancy. Transcoelomic dissemination of cancer cells gives rise to carcinomatosis, which, without special treatment, is a fatal manifestation of these diseases. To treat peritoneal carcinomatosis, cytoreductive surgery removes gross disease plus perioperative intraperitoneal and perioperative intravenous chemotherapy eradicates microscopic residual disease and chemical compatibilities. Chemotherapy agents are administered either by the intraperitoneal or intravenous route, based on their pharmacologic properties. A peritoneal-plasma barrier, which retards the clearance of high molecular weight chemotherapy from the peritoneal cavity, results in a large exposure of small cancer nodules on abdominal and pelvic surfaces. Tissue penetration of the intraperitoneal chemotherapy is facilitated by moderate hyperthermia (41-42℃). Targeting of intravenous chemotherapy to the peritoneal surface is facilitated by the intraperitoneal heat. A constant dose of chemotherapy agent and volume of carrier solution, based on body surface area, allows prediction of systemic drug exposure and systemic toxicity. Timing of the hyperthermic chemotherapy as a scheduled part of the surgical procedure to uniformly expose all peritoneal surfaces is crucial to success.