Surgical treatment of synchronous colorectal liver and lung metastases：the usefulness of thoracophrenolaparotomy for single stage resection

When suitable, surgery still remains the therapeu-tic option to be preferred for patients carrier of colorectal liver and lung metastases. Since thoracophrenolaparotomy should be helpful during liver resection for some of these patients, si-multaneous removal of right lung metastases can be proposed through this approach. Eleven consecutive patients (median age of 53 years) carrier of colorectal liver and lung metastases, underwent single session surgical resection of both liver and right lung lesions by means of J-shaped thoracophrenolapa-rotomy. The median number of liver metastases removed was 5 (range 2-30) and of lung metastases removed was 2 (range 1-3). Lung metastases were located in the upper lobe in 1 pa-tient, in the middle lobe in 2, in the lower lobe in 6, and in the upper and lower lobe in 2. Mortality and major morbidity were nil. Two patients had a minor morbidity: one had wound infection and bile leakage treated conservatively and the other had transient fever. Mean overall survival was 24.4 months. An aggressive surgical approach should be undertaken for colorectal metastases: in case of multifocal liver disease with complex presentations, J-shaped thoracophrenolaparotomy could be considered as safe approach for combined liver and right lung metastasectomies.     

Role of cetuximab in first-line treatment of metastatic colorectal cancer

The treatment of metastatic colorectal cancer(mCRC)has evolved considerably in the last decade,currently allowing most mCRC patients to live more than two years.Monoclonal antibodies targeting the epidermal growth factor receptor(EGFR)and vascular endothelial growth factor play an important role in the current treatment of these patients.However,only antibodies directed against EGFR have a predictive marker of response,which is the mutation status of v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog(KRAS).Cetuximab has been shown to be effective in patients with KRAS wild-type mCRC.The CRYSTAL study showed that adding cetuximab to FOLFIRI(regimen of irinotecan,infusional fluorouracil and leucovorin)significantly improved results in the first-line treatment of KRAS wildtype mCRC.However,results that evaluate the efficacy of cetuximab in combination with oxaliplatin-based chemotherapy in this setting are contradictory.On the other hand,recent advances in the management of colorectal liver metastases have improved survival in these patients.Adding cetuximab to standard chemotherapy increases the response rate in patients with wild-type KRAS and can thus increase the resectability rate of liver metastases in this group of patients.In this paper we review the different studies assessing the efficacy of cetuximab in the first-line treatment of mCRC.     

Treatment strategies for colorectal carcinoma with synchronous liver metastases: Which way to go?

AIM: To offer an up-to-date review of all availabletreatment strategies for patients with synchronous colorectal liver metastases(CLM).METHODS: A comprehensive literature search was performed to identify articles related to the management of patients with synchronous CLM. A search of the electronic databases PubMed, MEDLINE, and Google Scholar was conducted in September 2014.The following search terms were used: synchronous colorectal liver metastases, surgery, stage Ⅳ colorectal cancer, liver-first approach, and up-front hepatectomy.These terms were employed in various combinations to maximize the search. Only articles written in English were included. Particular attention was devoted to studies and review articles that were published within the last six years(2009-2014). Additional searches of the cited references from primary articles were performed to further improve the review. The full texts of all relevant articles were accessed by two independent reviewers.RESULTS: Poor long-term outcomes of patients with synchronous CLM managed by a traditional treatment strategy have led to questions about the timing and sequence of possible therapeutic interventions. Thus,alternative paradigms called reverse strategies have been proposed. Presently, there are four treatment strategies available:(1) primary first approach(or traditional approach) comprises resection of the primary colorectal tumor followed by chemotherapy;subsequent liver resection is performed 3-6 mo after colorectal resection(provided that CLM are still resectable);(2) simultaneous resection of the primary colorectal tumor and CLM during a single operation presents intriguing options for a highly select group of patients, which can be associated with significant postoperative morbidity;(3) liver-first(or chemotherapy-first) approach comprises preoperative chemotherapy(3-6 cycles) followed by liver resection,adjuvant chemotherapy, and resection of the primary colorectal tumor(it is best suited for patients withasymptomatic primary tumors and initially unresectable or marginally resectable CLM); and(4) up-front hepatectomy(or "true" liver-first approach) includes liver resection followed by adjuvant chemotherapy,colorectal resection, and adjuvant chemotherapy(strategy can be offered to patients with asymptomatic primary tumors and initially resectable CLM).CONCLUSION: None of the aforementioned strategies appears inferior. It is necessary to establish individual treatment plans in multidisciplinary team meetings through careful appraisal of all strategies.     

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.     

Preoperative evaluation of colorectal cancer using CT colonography,MRI, and PET/CT

Imaging studies are a major component in the evaluation of patients for the screening,staging and surveillance of colorectal cancer.This review presents commonly encountered findings in the diagnosis and staging of patients with colorectal cancer using computed tomography(CT)colonography,magnetic resonance imaging(MRI),and positron emission tomography(PET)/CT colonography.CT colonography provides important information for the preoperative assessment of T staging.Wall deformities are associated with muscular or subserosal invasion.Lymph node metastases from colorectal cancer often present with calcifications.CT is superior to detect calcified metastases.Three-dimensional CT to image the vascular anatomy facilitates laparoscopic surgery.T staging of rectal cancer by MRI is an established modality because MRI can diagnose rectal wall laminar structure.N staging in patients with colorectal cancer is still challenging using any imaging modality.MRI is more accurate than CT for the evaluation of liver metastases.PET/CT colonography isvaluable in the evaluation of extra-colonic and hepatic disease.PET/CT colonography is useful for obstructing colorectal cancers that cannot be traversed colonoscopically.PET/CT colonography is able to localize synchronous colon cancers proximal to the obstruction precisely.However,there is no definite evidence to support the routine clinical use of PET/CT colonography.     

Surgical approaches of resectable synchronous colorectal liver metastases： Timing considerations

AIM: To compare the safety and efficacy of simultaneous versus two stage resection of primary colorectal tumors and liver metastases. METHODS: From January 1996 to May 2004, 103 colorectal tumor patients presented with synchronous liver metastases. Twenty five underwent simultaneous colorectal and liver surgery and 78 underwent liver surgery 1-3 mo after primary colorectal tumor resection. Data were retrospectively analyzed to assess and compare the morbidity and mortality between the surgical strategies. The two groups were comparable regarding the age and sex distribution, the types of liver resection and stage of primary tumors, as well as the number and size of liver metastases. RESULTS: In two-stage procedures more transfusions were required (4 ± 1.5 vs 2 ± 1.8, pRBCs, P < 0.05). Chest infection was increased after the two-stage approach (26% vs 17%, P < 0.05). The two-stage procedure was also associated with longer hospitalization (20 ± 8 vs 12 ± 6 d, P < 0.05). Five year survival in both groups was similar (28% vs 31%). No hospital mortality occurred in our series. CONCLUSION: Synchronous colorectal liver metastases can be safely treated simultaneously with the primary tumor. Liver resection should be prioritized over colon resection. It is advisable that complex liver resections with marginal liver residual volume should be dealt with at a later stage.     

Hepatic artery infusion chemotherapy for advanced hepatocellular carcinoma

Hepatocellular carcinoma(HCC) is one of the most common cancers worldwide. Surgery, percutaneous ablation and liver transplantation are the only curative treatment modalities for HCC. However, the majority of patients have unresectable disease at diagnosis. Therefore, effective treatment options for patients with advanced HCC are required. In advanced HCC, according to current international guidelines, sorafenib, a molecular targeted agent, is the standard treatment. However, alternative treatment modalities are required because of the low response rates and unsuitability of molecular agents in real practice. In various treatment modalities, mostly in Asia, hepatic arterial infusion chemotherapy(HAIC) has been applied to advanced HCC with a view to increasing the therapeutic efficacy. HAIC provides direct drug delivery into the tumor feeding vessels and also minimizes systemic toxicities through a greater first-pass effect in the liver. However, the sample sizes of studies on HAIC have been small and large randomized trials are still lacking. In this article, we describe the treatment efficacy of HAIC for advanced stage HCC and discuss future therapeutic possibilities.     

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.     

Management of locally advanced and metastatic colon cancer in elderly patients

Colon cancer is the second leading cause of cancer mortality in the United States with a median age at diagnosis of 69 years.Sixty percent are diagnosed over the age of 65 years and 36%are 75 years or older.At diagnosis,approximately 58% of patients will have locally advanced and metastatic disease,for which systemic chemotherapy has been shown to improve survival.Treatment of cancer in elderly patients is more challenging due to multiple factors,including disabling co-morbidities as well as a decline in organ function.Cancer treatment of elderly patients is often associated with more toxicities that may lead to frequent hospitalizations.In locally advanced disease,fewer older patients receive adjuvant chemotherapy despite survival benefit and similar toxicity when compared to their younger counterparts.A survival benefit is also observed in the palliative chemotherapy setting for elderly patients with metastatic disease.When treating elderly patients with colon cancer,one has to consider drug pharmacokinetics and pharmacodynamics.Since chronological age is a poor marker of a patient’s functional status,several methods of functional assessment including performance status and activities of daily living(ADL)or instrumental ADL,or even a comprehensive geriatric assessment,may be used.There is no ideal chemotherapy regimen that fits all elderly patients and so a regimen needs to be tailored for each individual.Important considerations when treating elderly patients include convenience and tolerability.This review will discuss approaches to the management of elderly patients with locally advanced and metastatic colon cancer.     

Early rehabilitation programs after laparoscopic colorectal surgery:Evidence and criticism

During the past several decades,early rehabilitation programs for the care of patients with colorectal surgery have gained popularity.Several randomized controlled trials and meta-analyses have confirmed that the implementation of these evidence-based detailed perioperative care protocols is useful for early recovery of patients after colorectal resection.Patients cared for based on these protocols had a rapid recovery of bowel movement,shortened length of hospital stay,and fewer complications compared with traditional care programs.However,most of the previous evidence was obtained from studies of early rehabilitation programs adapted to open colonic resection.Currently,limited evidence exists on the effects of early rehabilitation after laparoscopic rectal resection,although this procedure seems to be associated with a higher morbidity than that reported with traditional care.In this article,we review previous studies and guidelines on early rehabilitation programs in patients undergoing rectal surgery.We investigated the status of early rehabilitation programs in rectal surgery and analyzed the limitations of these studies.We also summarized indications and detailed protocol components of current early rehabilitation programs after rectal surgery,focusing on laparoscopic resection.     

Neoadjuvant radiotherapy for rectal cancer management

Thirty per cent of all colorectal tumours develop in the rectum.The location of the rectum within the bony pelvis and its proximity to vital structures presents significant therapeutic challenges when considering neoadjuvant options and surgical interventions.Most patients with early rectal cancer can be adequately managed by surgery alone.However,a significant proportion of patients with rectal cancer present with locally advanced disease and will potentially benefit from down staging prior to surgery.Neoadjuvant therapy involves a variety of options including radiotherapy,chemotherapy used alone or in combination.Neoadjuvant radiotherapy in rectal cancer has been shown to be effective in reducing tumour burden in advance of curative surgery.The gold standard surgical rectal cancer management aims to achieve surgical removal of the tumour and all draining lymph nodes,within an intact mesorectal package,in order to minimise local recurrence.It is critically important that all rectal cancer cases are discussed at a multidisciplinary meeting represented by all relevant specialties.Pre-operative staging including CT thorax,abdomen,pelvis to assess for distal disease and magnetic resonance imaging to assess local involvement is essential.Staging radiology and MDT discussion are integral in identifying patients who require neoadjuvant radiotherapy.While Neoadjuvant radiotherapy is potentially beneficial it may also result in morbidity and thus should be reserved for those patients who are at a high risk of local failure,which includes patients with nodal involvement,extramural venous invasion and threatened circumferential margin.The aim of this review is to discuss the role of neoadjuvant radiotherapy in the management of rectal cancer.     

Evolution in the treatment of metastatic colorectal carcinoma of the liver

Metastatic colorectal cancer to the liver is associated with a uniform poor prognosis without treatment. Advances in therapy over the past decades have now allowed surgical resections of the liver to occur with a low morbidity and mortality. Improvements in chemotherapy regimes have paralleled technical improvements and now allow a new group of patients to become eligible for surgical resection. This chapter will review the recent advances in surgical and chemotherapeutic regimes in metastatic colorectal cancer to the liver.     

Neuroendocrine carcinomas arising in ulcerative colitis： Coincidences or possible correlations？

Patients with inflammatory bowel disease （IBD） are at increased risk of colorectal malignancies. Adenocarcinoma is the commonest type of colorectal neoplasm associated with ulcerative colitis （UC） and Crohn＇s disease, but other types of epithelial and non-epithelial tumors have also been described in inflamed bowel. With regards to non-epithelial malignancies, lymphomas and sarcomas represent the largest group of tumors reported in association with IBD, especially in immunosuppressed patients. Carcinoids and in particular neuroendocrine neoplasms other than carcinoids （NENs） are rare tumors and are infrequently described in the setting of IBD. Thus, this association requires further investigation. We report two cases of neoplasms arising in mild left-sided UC with immuno- histochemical staining for neuroendocrine markers： a large cell and a small cell neuroendocrine carcinoma of the rectum. The two patients were different in age （35 years vs 77 years） and disease duration （11 years vs 27 years）, and both had never received immunosuppressant drugs. Although the patients underwent regular endoscopic and histological follow-up, the two neoplasms were locally advanced at diagnosis. One of the two patients developed multiple liver metastases and died 15 mo after diagnosis. These findings confirm the aggressiveness and the poor prognosis of NENs compared to colorectal adenocarcinoma. While carcinoids seem to be coincidentally associated with IBD, NENs may also arise in this setting. In fact, long-standing inflammation could be directly responsible for the development of pancellular dysplasia involving epithelial, goblet, Paneth and neuroendocrine cells. It has yet to be established which IBD patients have a higher risk of developing NENs.     

Role of a liver-first approach for synchronous colorectal liver metastases

AIM: To evaluate the feasibility and survival outcomes of a liver-first approach.METHODS: Between January 2009 and April 2013, 18 synchronous colorectal liver metastases(s CRLMs) patients with a planned liver-first approach in the Hepatopancreatobiliary Surgery Department Ⅰ of the Beijing Cancer Hospital were enrolled in this study. Clinical data, surgical outcomes, morbidity and mortality rates were collected. The feasibility and long-term outcomes of the approach were retrospectively analyzed.RESULTS: Sixteen patients(88.9%) completed the treatment protocol for primary and liver tumors. The main reason for treatment failure was liver disease recurrence. The 1 and 3 year overall survival rates were 94.4% and 44.8%, respectively. The median survival time was 30 mo. The postoperative morbidity and mortality were 22.2% and 0%, respectively, following a hepatic resection, and were 18.8% and 0%, respectively, after a colorectal surgery.CONCLUSION: The liver-first approach appeared to be feasible and safe. It can be performed with a comparable mortality and morbidity to the traditional treatment paradigm. This approach might offer a curative opportunity for s CRLM patients with a high liver disease burden.     

Liver transplantation for hepatic tumors:a systematic review

Improvements in the medical and pharmacological management of liver transplantation(LT)recipients have led to a better long-term outcome and extension of the indications for this procedure.Liver tumors are relevant to LT;however,the use of LT to treat malignancies remains a debated issue because the high risk of recurrence.In this review we considered LT for hepatocellular carcinoma(HCC),cholangiocarcinoma(CCA),liver metastases(LM)and other rare tumors.We reviewed the literature,focusing on the past 10 years.The highly selected Milan criteria of LT for HCC(single nodule<5 cm or up to 3 nodules<3cm)have been recently extended by a group from the University of S.Francisco(1 lesion<6.5 cm or up to3 lesions<4.5 cm)with satisfying results in terms of recurrence-free survival and the"up-to-seven criteria".Moreover,using these criteria,other transplant groups have recently developed downstaging protocols,including surgical or loco-regional treatments of HCC,which have increased the post-operative survival of recipients.CCA may be treated by LT in patients who cannot undergo liver resection because of underlying liver disease or for anatomical technical challenges.A well-defined protocol of chemoirradiation and staging laparotomy before LT has been developed by the Mayo Clinic,which has resulted in long term diseasefree survival comparable to other indications.LT for LM has also been investigated by multicenter studies.It offers a real benefit for metastases from neuroendocrine tumors that are well differentiated and when a major extrahepatic resection is not required.If LT is an option in these selected cases,liver metastases from colorectal cancer is still a borderline indication because data concerning the disease-free survival are still lacking.Hepatoblastoma and hemangioendothelioma represent rare primary tumors for which LT is often the only possible and effective cure because of the frequent multifocal,intrahepatic nature of the disease.LT is a very promising procedure for both primary and secondary liver malignancies;however,it needs an accurate evaluation of the costs and benefits for each indication to balance the chances of cure with actual organ availability.     

Radiofrequency ablation or percutaneous ethanol injection for the treatment of liver tumors

The liver is a common location of both primary and secondary malignancies. For unresectable liver cancer, many local ablative therapies have been developed. These include e.g., percutaneous ethanol injection (PEI), percutaneous acetic acid injection, radiofrequency ablation (RFA), cryoablation, microwave ablation, laserinduced thermotherapy, and high-intensity focused ultrasound. RFA has recently gained interest and is the most widely applied thermoablative technique. RFA allows more effective tumor control in fewer treatment sessions compared with PEI, but with a higher rate of complications. However, there are certain circumstances where PEI therapy represents a better strategy to control liver tumors than RFA, especially in situations where RFA is difficult, for example when large vessels surround the tumor. In the context of hepatocellular carcinoma (HCC), both RFA and PEI are feasible and of benefit in non-operable patients. RFA seems superior to PEI in HCC 2 cm, and the combination of interventions may be of benefit in selected patients. Liver resection is superior to RFA for patients with HCC meeting the Milan criteria, but RFA can be employed in tumors ≤ 3 cm and where there is an increased expected operative mortality. In addition, some lines of evidence indicate that RFA and PEI can be employed as a bridge to liver transplantation. The use of RFA in colorectal liver metastases is currently limited to unresectable disease and for patients unfit for surgery. The aim of this article is to summarize the current status of RFA in the management of liver tumors and compare it to the cheap and readily available technique of PEI.     

Neutron-induced apoptosis of HR8348 cells in vitro

INTRODUCTIONTo date,the major therapy for rectal carcinoma isextensive abdomino-perineal resection.Unfortunately,after resection of rectal carcinoma,many patients still die of blood-borne metastases,usually in the liver or lungs,or local pelvicrecurrence,which is the major cause ofmorbidity and mortality in patients with rectalcarcinoma.Pre-or postoperative radiotherapy canreduce the incidence of local recurrence,buteven with moderately high radiation doses,manypatients are not locally controlled and have distantmetastases.The reason for this may be low     

Massive hepatic necrosis with toxic liver syndrome following portal vein ligation

Right portal vein ligation (PVL) is a safe and widespread procedure to induce controlateral liver hypertrophy for the treatment of bilobar colorectal liver metastases. We report a case of a 60-year-old man treated by both right PVL and ligation of the glissonian branches of segment 4 for colorectal liver metastases surrounding the right and median hepatic veins. After surgery, the patient developed massive hepatic necrosis with secondary pulmonary and renal insufficiency requiring transfer to the intensive care unit. This so-called toxic liver syndrome finally regressed after hemofiltration and positive oxygen therapy. Diagnosis of acute congestion of the ligated lobe was suspected. The mechanism suspected was an increase in arterial inflow secondary to portal vein ligation concomitant with a decrease in venous outflow due to liver metastases encircling the right and median hepatic vein. This is the first documented case of toxic liver syndrome in a non-cirrhotic patient with favorable issue, and a rare complication of PVL.     

Neoadjuvant and adjuvant treatment strategies for hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the most common liver malignancy worldwide and a major cause of cancer-related mortality for which liver resection is an important curative-intent treatment option. However, many patients present with advanced disease and with underlying chronic liver disease and/or cirrhosis, limiting the proportion of patients who are surgical candidates. In addition, the development of recurrent or de novo cancers following surgical resection is common. These issues have led investigators to evaluate the benefit of neoadjuvant and adjuvant treatment strategies aimed at improving resectability rates and decreasing recurrence rates. While high-level evidence to guide treatment decision making is lacking, recent advances in locoregional and systemic therapies, including antiviral treatment and immunotherapy, raise the prospect of novel approaches that may improve the outcomes of patients with HCC. In this review, we evaluate the evidence for various neoadjuvant and adjuvant therapies and discuss opportunities for future clinical and translational research.