General overview of neo‐adjuvant therapy for hepatocellular carcinoma before liver transplantation: necessity or option?

Because of its increasing incidence of hepatocellular carcinoma, it is now recognized as a worldwide health problem affecting mostly patients with chronic liver disease. Liver transplantation is the optimal therapy and achieves its best results in patients with small tumour burden. In an effort to prevent tumour progression and patient dropout from the transplant wait list, the concept and utilization of neo-adjuvant locoregional therapies have gained relevance in the past few years. Moreover, good and maintained response to therapy is now considered a surrogate of favourable tumour biology, therefore aiding the patient transplant selection process. Herein, we review the current role of neo-adjuvant therapies and revise concepts of tumour 'downstaging' or 'bridging therapy' in the setting of liver transplantation. In addition, we explore the debate of implementing locoregional therapy for patients with small tumours and short waiting times to liver transplantation.     

New frontiers in the management of advanced hepatocellular carcinoma. "A new look to an old problem"

BACKGROUND/AIMS: To evaluate the benefits of two-stage liver surgery with main portal branch ligation and transection combined with transarterial targeting locoregional neo and adjuvant immunochemotherapy in patients suffering from hepatocellular carcinoma. METHODOLOGY: 43 consecutive patients underwent two-stage liver surgery for advanced hepatocellular carcinoma. First we performed ligation and transection of the main portal vein branch corresponding to the liver lobe occupied by the tumor. Subsequently we introduced an arterial jet port catheter towards the hepatic artery via the gastroduodenal artery. After locoregional transarterial targeting immunochemotherapy regimen the patient underwent a second laparotomy for hemihepatectomy. Following surgery, locoregional transarterial targeting immunochemotherapy was given to all patients via the arterial port of the gastroduodenal artery as an adjuvant treatment. RESULTS: Mean survival was 41 months. There were no operative deaths. CONCLUSIONS: Two-stage liver surgery and transarterial targeting locoregional immunochemotherapy is the favorable option of treatment for advanced hepatocellular carcinoma. It not only results in an increase in the overall survival of these patients, but also increases the rate of resectability of these tumors by the hepatobiliary surgeon.     

Radiological findings in non-surgical recurrent hepatocellular carcinoma: From locoregional treatments to immunotherapy

Since hepatocellular carcinoma(HCC) represents an important cause of mortality and morbidity all over the world. Currently, it is fundamental not only to achieve a curative treatment but also to manage in the best way any possible recurrence. Even if the latest update of the Barcelona Clinic Liver Cancer guidelines for HCC treatment has introduced new locoregional techniques and confirmed others as well-established clinical practices, there is still no consensus about the treatment of recurrent ...     

Anaplastic thyroid carcinoma

Anaplastic thyroid carcinoma may represent the ultimate dedifferentiation step of thyroid tumorigenesis and is one of the poorest cancers in human. It accounts for less than 2% of thyroid cancers and affects older patients in their sixth to eighth decade. Usual clinical presentation is a rapidly growing thyroid mass invading surrounding structures with compressive symptoms. Cervical lymph nodes enlargement and distant metastases occur frequently. Though cytological results obtained by fine needle aspiration may be suggestive of diagnosis, tissue biopsy for immunohistochemical study can be necessary to exclude lymphoma and to validate aggressive therapies. Patients developing anaplastic thyroid cancer must be referred urgently in cancer centers to plan multimodality therapeutic approach depending on their performance status. The treatment regimen combines surgery when feasible, hyperfractionated and accelerated external beam radiotherapy and doxorubicin based chemotherapy. Such treatment can provide control of locoregional disease but does not impact on overall survival in patients with distant metastases. The prognosis is dismal with a mean survival of four to nine months after diagnosis. Long survivors are patients with emerging disease presenting a resectable tumor and receiving adjuvant radiotherapy and/or chemotherapy. Therapeutic researches investigate redifferenciation strategies and targeted therapies to inhibit EGF receptors and neoplastic angiogenesis. Primary prevention of this lethal disease may consist of adequate treatment of differentiated thyroid cancers and goiters in elderly.     

Impact of lymph node staging on therapy of esophageal carcinoma

BACKGROUND & AIMS: Therapy of esophageal carcinoma is stage dependent. The role of EUS-guided fine-needle aspiration (EUS FNA) in this setting is unclear. The aims of this study were to compare the performance characteristics of CT, EUS, and EUS FNA for preoperative nodal staging of esophageal carcinoma and to measure the impact of each staging test on treatment decisions. METHODS: From December 1999 to March 2001, all patients with esophageal carcinoma seen at the Mayo Clinic Rochester were prospectively evaluated with CT, EUS, and EUS FNA. The impact of tumor stage on final therapy was assessed. RESULTS: A total of 125 patients with esophageal carcinoma were enrolled. EUS FNA was more sensitive (83% vs. 29%; P < 0.001) than CT and more accurate than CT (87% vs. 51%; P < 0.001) or EUS (87% vs. 74%; P = 0.012) for nodal staging. Direct surgical resection was contraindicated in 77% of patients evaluated due to advanced locoregional/metastatic disease. Tumor location, patient age, comorbidities, and tumor stage determined by CT, EUS, and EUS FNA were associated with treatment decisions (P < 0.05). EUS FNA resulting in a higher/worse stage than CT (41 patients) was associated with a greater rate of treatments that were not direct surgeries compared with cases in which the stage was the same or better. CONCLUSIONS: EUS FNA is more accurate for nodal staging and impacts on therapy of patients with esophageal carcinoma. EUS FNA should be included in the preoperative staging algorithm of these patients.     

肝癌根治术后肝内复发合并肝外转移积极手术治疗10例

目的:探讨对严格选择的肝癌根治术后肝内复发并肝外转移患者采取积极外科治疗策略的临床价值.方法:回顾性分析10例肝癌根治术后肝内复发伴肝外孤立转移灶病例的外科治疗情况.并与行保守治疗的肝癌根治术后肝内复发伴肝外转移的48例患者的生存情况进行比较.结果:Kaplan-Meier生存分析显示积极外科治疗组复发后中位生存时间为45.0mo±5.1mo,保守治疗组复发后中位生存时间仅为12.0mo±2.1mo.Log-rank检验对两组生存时间比较,发现积极手术治疗组生存时间显著长于保守治疗组(P<0.01)结论:对于严格选择的病例采取肝外孤立转移灶切除联合肝内复发灶切除或局部治疗的积极外科治疗策略能够显著提高患者生存时间.     

Chemoradiotherapy in tumours of the oesophagus and gastro-oesophageal junction

Oesophageal cancer remains a malignancy with a poor prognosis. However, in the recent 10–15 years relevant progress has been made by the introduction of chemoradiotherapy (CRT) for tumours of the oesophagus or gastro-oesophageal junction. The addition of neo-adjuvant CRT to surgery has significantly improved survival and locoregional control, for both adenocarcinoma and squamous cell carcinoma. For irresectable or medically inoperable patients, definitive CRT has changed the treatment intent from palliative to curative. Definitive CRT is a good alternative for radical surgery in responding patients with squamous cell carcinoma and those running a high risk of surgical morbidity and mortality. For patients with an out-of-field solitary locoregional recurrence after primary curative treatment, definitive CRT can lead to long term survival.     

Immunotherapy for hepatocellular carcinoma:Current and future

Hepatocellular carcinoma(HCC) arises on the background of chronic liver disease. Despite the development of effective anti-viral therapeutics HCC is continuing to rise, in part driven by the epidemic of non-alcoholic fatty liver disease. Many patients present with advanced disease out with the criteria for transplant, resection or even locoregional therapy. Currently available therapeutics for HCC are effective in a small minority of individuals. However,there has been a major global interest in immunotherapies for cancer and although HCC has lagged behind other cancers, great opportunities now exist for treating HCC with newer and more sophisticated agents. Whilst checkpoint inhibitors are at the forefront of this revolution, other therapeutics such as inhibitory cytokine blockade, oncolytic viruses, adoptive cellular therapies and vaccines are emerging. Broadly these may be categorized as either boosting existing immune response or stimulating de novo immune response. Although some of these agents have shown promising results as monotherapy in early phase trials it may well be that their future role will be as combination therapy,either in combination with one another or in combination with treatment modalities such as locoregional therapy. Together these agents are likely to generate new and exciting opportunities for treating HCC, which are summarized in this review.     

Transarterial embolization of metastatic mediastinal hepatocellular carcinoma

This paper introduces an innovative treatment for extrahepatic metastasis of hepatocellular carcinoma. A 71-yearold patient had a stable liver condition following treatment for hepatocellular carcinoma, but later developed symptomatic mediastinal metastasis. This rapidly growing mediastinal mass induced symptoms including cough and hoarseness. Serial sessions of transarterial embolization (TAE) successfully controlled this mediastinal mass with limited side effects. The patient’s survival time since the initial diagnosis of the mediastinal hepatocellular carcinoma was 32 mo, significantly longer than the 12 mo mean survival period of patients with similar diagnoses: metastatic hepatocellular carcinoma and a liver condition with a Child-Pugh class A score. Currently, oral sorafenib is the treatment of choice for metastatic hepatocellular carcinoma. Recentstudies indicate that locoregional treatment of extrahepatic metastasis of hepatocellular carcinomas might also significantly improve the prognosis in patients with their primary hepatic lesions under control. Many effective locoregional therapies for extrahepatic metastasis, including radiation and surgical resection, may provide palliative effects for hepatocellular carcinoma-associated mediastinal metastasis. This case report demonstrates that TAE of metastatic mediastinal hepatocellular carcinoma provided this patient with tumor control and increased survival time. This finding is important as it can potentially provide an alternative treatment option for patients with similar symptoms and diagnoses.     

Locoregional therapies for hepatocellular carcinoma: Which patients are most likely to gain a survival advantage?

Background and Aim: Locoregional therapies for hepatocellular carcinoma (HCC) are considered to confer a survival advantage, however, the patient group that should be targeted is not clearly defined. This study aimed to determine the impact on survival of locoregional therapies compared with supportive care, within prognostic categories as stratified by the Cancer of the Liver Italian Program (CLIP) scoring system. Methods: A prospective database was used to identify those patients who were treated with either locoregional therapy (n = 128) or supportive care (n = 92). Survival analysis was performed for groups matched by CLIP score at presentation. Comparison of important prognostic factors was undertaken and univariate and multivariate analysis was performed to assess determinants of survival. Results: Use of locoregional therapies was only associated with a survival benefit in patients with a CLIP score of 1 or 2. In this group, the median survival in patients who received locoregional therapies was 25.0 months (95% confidence interval 22.7–27.4) compared with 8.9 months (95% confidence interval 7.3–10.5) for supportive care (P = 0.001). For patients with CLIP scores of 3 or greater, no survival benefit of locoregional therapies was observed. Multivariate analysis revealed locoregional intervention, CLIP score, tumor symptoms, α‐fetoprotein level, bilirubin and alkaline phosphatase level as independent prognostic indicators. Conclusion: Locoregional therapies should be targeted specifically to patients with non‐advanced hepatocellular carcinoma as assessed by validated scoring systems. Use of these therapies in patients with advanced disease does not appear to be associated with a survival benefit and may expose patients to unnecessary harm.     

The rates and CT patterns of locoregional recurrence after resection surgery of lung cancer: correlation with histopathology and tumor staging

The purpose of our study was to assess the rates and CT patterns of locoregional recurrence after resection surgery of lung cancers according to histopathology and tumor staging. Three hundred and seventy nine patients who underwent lung resection surgery due to lung cancer in a recent 6 year period were followed up with CT (at 3, 6, 12, 18, 24 months, and then annually after surgery) for evaluation of locoregional tumor recurrence (analysis of hilar or mediastinal lymph nodes and surgical margin including bronchial stump, pleura, and chest wall). The recurrence rates and CT patterns were compared in terms of underlying histopathology and tumor staging. Of 379 patients, 75 (20%) patients had locoregional recurrences. The recurrence rates were higher in squamous cell carcinoma (39/190, 21%) than adenocarcinoma (24/140, 17%) (P = 0.012). The patterns of recurrence in 75 patients were hilar-mediastinal lymph node enlargement (n = 39, 52%), ipsilateral pleural lesion (n = 24, 32%), chest wall lesion (n = 13, 17%), bronchial stump lesion (n = 8, 11%), and bronchial extension including the trachea (n = 3, 4%). Bronchial stump recurrence was seen only in squamous cell carcinoma. Bronchioloalveolar carcinoma did not show any evidence of locoregional recurrence. Pleural (P = 0.0016) and mediastinal nodal (P = 0.001) recurrence, respectively, were more common in N2 than N0 cancers. Chest wall recurrence rates were higher with higher T staging (P < 0.001). The locoregional recurrence of lung cancer occurs in about one fifth of patients who undergo curative resection and is more common in squamous cell carcinoma than in adenocarcinoma. Recurrent patterns are diverse and different according to histopathologic type and pathologic staging of lung cancer.     

Hepatocellular carcinoma locoregional therapies: Outcomes and future horizons

Hepatocellular carcinoma (HCC) is the most common primary cancer of the liver and has an overall five-year survival rate of less than twenty percent. For patients with unresectable disease, evolving liver-directed locoregional therapies provide efficacious treatment across the spectrum of disease stages and via a variety of catheter-directed and percutaneous techniques. Goals of locoregional therapies in HCC may include curative intent in early-stage disease, bridging or downstaging to surgical resection or transplantation for early or intermediate-stage disease, and local disease control and palliation in advanced-stage disease. This review explores the outcomes of chemoembolization, bland embolization, radioembolization, and percutaneous ablative therapies. Attention is also given to prognostic factors related to each of the respective techniques, as well as future directions of locoregional therapies for HCC.     

Impact of surgeon's technique on outcome after treatment of rectal carcinoma

PURPOSE: The aim of this study was to analyze the impact of institutions and individual surgeons on long-term prognosis after curative resection of rectal carcinoma. METHODS: We used univariate and multivariate analysis of data from a German prospective, multicenter, patient-care evaluation study. RESULTS: The locoregional recurrence rates and the observed and cancer-related survival rates showed a considerable interinstitutional and intersurgeon variability. Multivariate analysis confirmed the institution and the individual surgeon as significant independent factors influencing locoregional recurrence and survival. There was a statistically highly significant correlation between the rate of locoregional recurrence and survival rate. CONCLUSIONS: The surgeon's technique and skill has to focus on prevention of locoregional recurrence to achieve good long-term outcome after curative resection for rectal carcinoma. New clinical trials on adjuvant treatment have to include quality assurance for surgery and pathology and documentation of the surgeon (as local code).Harry E Bacon Lectureship at the meeting of The American Society of Colon and Rectal Surgeons, San Antonio, Texas, May 2 to 7, 1998. No reprints are available.     

Diagnosis and non-surgical treatment of bile duct carcinoma: developments in the past decade

In the past decade, ultrasonography and magnetic resonance cholangiography have become useful modalities for the screening of bile duct cancer. Intraductal ultrasonography, using a thin-caliber (2.0 to 2.4 mm in diameter) and high-frequency (15 to 20 MHz) probe, has become a promising modality in assessing locoregional staging. For interventional therapy of unresectable bile duct carcinoma, metallic stents also became an excellent modality. However, tumor ingrowth and overgrowth into the mesh of stents are problems to be solved, and external radiation therapy is widely conducted to control the tumor. To improve the limitations of external radiation, brachytherapy, photodynamic therapy, and microwave coagulation therapy are conducted. However, these modalities are available in only a limited number of institutions even now. To predict the prognosis of the patients, approaches using molecular biology must be established. Received: October 26, 1999 / Accepted: November 26, 1999     

Radiation therapy alone for stage I (UICC T1N0M0) squamous cell carcinoma of the esophagus: indications for surgery or combined chemoradiotherapy

BACKGROUND AND AIM: The aim of this study was to clarify the efficacy and limitations of radiation therapy (RT) for superficial esophageal carcinoma, and to explore the indications for more aggressive therapy, such as combined chemo-radiotherapy. METHODS: Sixty-eight patients with stage I (UICC T1N0M0) esophageal squamous cell carcinoma treated by definitive RT alone were analyzed. Brachytherapy was administered in 36 patients as a boost, and the prescribed doses were 10 Gy (5 Gy x 2 times) at a low dose rate (19 patients) and 9 Gy (3 Gy x 3 times) at a high dose rate (17 patients). Recurrence patterns and survival rates were assessed and the factors predisposing to recurrences after RT were statistically investigated by univariate analysis. RESULTS: The 5-year cause-specific survival rate and the locoregional control rate were 79.9% and 82.1%, respectively. No case of recurrence or disease-related death was observed in any of the patients with mucosal cancer. Among the cases with the cancer invading the submucosa, there were 12 cases with locoregional recurrence and two cases with distant metastases. In cases of submucosal esophageal cancer, the tumor length was the only statistically significant factor predicting locoregional control. The 5-year locoregional control rate in cases with a short length of the tumor (5 cm in length was 57.8% (P = 0.036). Patients treated by additional brachytherapy exhibited better cause-specific survival and locoregional control rates than those receiving external RT alone, however, the addition had no statistically significant influence on the outcome. CONCLUSIONS: RT was a successful treatment for stage I esophageal cancer, and the treatment outcome using RT was nearly comparable to that of surgery. However, it is suggested that chemo-radiation should be considered in inoperable cases of submucosal cancer when the tumor is more than 5 cm in length.     

Extrapulmonary small-cell carcinoma: report of three cases and update of therapy and prognosis

Three male patients with extrapulmonary small-cell carcinoma originating from esophagus, pancreas and prostate are described. The patient with the esophagus tumor had a combined small-cell and undifferentiated carcinoma. The other two patients had a pure small-cell carcinoma. All patients were treated with primary combination chemotherapy consisting of etoposide and cisplatin followed in one patient by locoregional radiotherapy. The patients with the esophagus and the pancreas tumor showed a partial response; the patient with the prostate tumor achieved a complete remission but relapsed with brain metastasis. All patients are alive 7, 13 and 19 months, respectively after initiation of the therapy. As in pulmonary small-cell carcinoma, primary chemotherapy is the treatment of choice in extrapulmonary small-cell carcinoma.     

Effectiveness of cisplatin in the treatment of anal squamous cell carcinoma

The therapeutic activity of cisplatin was explored in three consecutive patients with locoregional squamous cell carcinoma of the anus who received no prior therapy. One complete response and two partial responses were achieved. These data, although preliminary, strongly suggest that this disease is sensitive to cisplatin, and further trials are indicated to assess the precise role of this drug in the overall management of anal carcinoma.     

Locoregional immunochemotherapy in hepatocellular carcinoma

Hepatocellular carcinoma remains a disease with a poor and dismal prognosis, and all forms of currently available conventional therapies are rarely beneficial. However, in recent years, combined targeting locoregional immunochemotherapy has been reported with very promising results. Adoptive immunotherapy with LAK cells (lymphokine-activated killer cells) and recombinant interleukin-2 is becoming one of the new modalities to reconstitute the depressed immune status of the tumor-bearing host. Interleukin-2, gamma-interferon, and interleukin-12 induce cytolytic activity of LAK and natural killer cells and are considered for cellular activation to locoregional immunotherapy before, after resection or even in unresectable hepatocellular carcinomas. Spleen is a suitable organ for LAK cell induction because it has densely packed lymphocytes. The strategy of administration of both interleukin-2 and gamma-interferon into the spleen for in vivo immunostimulation is based on the well-known synergism of the above cytokines. LAK cells have cytotoxic activity against a variety of tumor cells. In particular, LAK cells exhibit efficacy against lung and liver malignant lesions, as suggested by their trafficking pattern; activated killer cells injected i.v. into humans appeared in the lung early and were subsequently rapidly redistributed to the liver and spleen. Lipiodol-Urografin emulsion is probably an ideal cytokine/anti-cancer drug carrier suitable for the combined locoregional immunochemotherapy because during its preferential retention in the vascular network of the spleen and tumor, a gradual release of both immuno- and chemotherapeutical drugs bound to emulsion droplets is achieved ensuring a prolong half life for these drugs. Recent data point to the potential of considering intratumoral or intravascular use of adenovirus carrying interleukin-12 gene, and/or p53-based gene therapy as possible therapeutic strategies in patients with hepatocellular carcinoma.     

Rectal excision and colonic pouch-anal anastomosis for rectal cancer

PURPOSE: Preservation of the anal sphincter is now accepted as a primary aim in surgical treatment of rectal cancer. The use of colonic J-pouch-anal anastomosis after complete rectal excision is one method that permits retention of continence without compromising oncologic principles. This study aimed to assess carcinologic results of rectal excision followed by colonic J-pouch anal anastomosis, with particular reference to rate of locoregional recurrence. METHOD: From 1984 to 1990 complete rectal excision and colonic pouch-anal anastomosis were performed in 167 patients for cancer of the middle or low rectum. A total of 154 patients were followed for this study for a minimum of five years, with evaluation of the frequency of locoregional recurrence. RESULTS: Sixty-five patients died during the period of surveillance, giving a five-year survival rate of 68.8 percent. Twenty patients (13 percent) presented with locoregional recurrence at an average of 31 months after surgery. In 11 cases (7 percent) the local recurrence was not associated with metastatic disease, and six of these patients underwent further curative surgery. CONCLUSIONS: These results confirm that coloanal anastomosis after complete rectal excision is a valuable option in the surgical treatment of rectal cancer and is accompanied by a frequency of isolated locoregional recurrence of less than 7 percent, of which half underwent surgical resection with curative intent.Presented at Journées Francophones de Pathologie Digestive, Lille, France, March 23 to 27, 1996.     

Concurrent vs sequential chemoradiotherapy for patients with advanced non–small-cell lung cancer: A meta-analysis of randomized controlled trials

Background:Chemotherapy in combination with thoracic radiotherapy yields significant results in patients with advanced non–small-cell lung cancer (NSCLC) compared with thoracic radiotherapy alone. However, whether concurrent or sequential delivery of chemotherapy combined with thoracic radiotherapy is optimal remains unclear. Herein, we conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) to evaluate the efficacy and safety of concurrent vs sequential chemoradiotherapy in patients with NSCLC.Methods:PubMed, EmBase, and Cochrane Library were systematically searched for RCTs focusing on concurrent and sequential chemoradiotherapy for patients with NSCLC. The pooled-effect estimate was calculated using the random-effects model. Sensitivity, subgroup, and publication biases were also evaluated. A total of 14 RCTs (2634 patients with NSCLC) were selected for the final meta-analysis.Results:Compared with sequential chemoradiotherapy, concurrent chemoradiotherapy did not increase the 1-year survival rates; however, concurrent chemoradiotherapy significantly increased the 2-, 3-, 4-, and 5-year survival rates. Moreover, although there were no significant differences between concurrent and sequential chemoradiotherapy in terms of distant relapse and locoregional plus distant relapse, concurrent chemoradiotherapy significantly reduced the risk of locoregional relapse. Furthermore, concurrent chemoradiotherapy yielded positive results with respect to overall response rates. Unfortunately, concurrent chemoradiotherapy could result in esophagitis, nausea/vomiting, and reduced leukocyte and platelet counts in patients with NSCLC.Conclusion:Compared with sequential chemoradiotherapy, concurrent chemoradiotherapy may be significantly beneficial in terms of long-term survival and locoregional relapse, although it increases the risk of grade 3 (or greater) adverse events.