Immunotherapy of biliary tract cancer

Biliary tract cancers (BTCs), which encompass intra- and extrahepatic cholangiocarcinomas as well as gallbladder carcinomas, are one of the most aggressive malignancies. Although the development of systemic chemotherapy approaches has made progress, the prognosis of BTC remains poor. Chronic inflammation plays an important role in the carcinogenesis of BTC, highlighting the immune etiology of this disease. Immunotherapy has emerged as a promising new modality of treatment for BTC. Here, we summarize the relevant tumor immunology of BTC and recently completed and ongoing clinical trials of immunotherapy for BTC.     

胆道肿瘤的免疫治疗

胆道肿瘤（BTC）侵袭性强,早期诊断率仅为10％。研究显示,吉西他滨联合顺铂方案现已成为晚期 BTC 的标准一线化疗方案,但疗效仍不满意。免疫细胞的浸润以及免疫相关的微环境可以抑制多种不同类型的肿瘤。研究发现,肿瘤浸润性 CD8＋细胞毒 T 细胞和 CD4＋T 细胞数量与 BTC 的预后密切相关,提示 BTC 的免疫治疗可能是一种新的手段。     

Carcinoma of the upper urinary tract

BACKGROUND:

Carcinomas of the upper urinary tract are uncommon tumors that usually occurred in elderly patients. Competing causes of mortality should be considered when treating these patients.

METHODS:

All patients with upper urinary tract tumors who were treated surgically at Centre Hospitalier Universitaire de Québec and affiliated hospitals from 1978 to 2001 were retrospectively reviewed. Clinical and pathologic variables were assessed from both the preoperative and postoperative periods of management, and clinical outcomes were tracked. Competing risks regression, Cox proportional hazards modeling, and multiple imputation were used to assess predictors of cancer‐related and competing risks?related mortality in both preoperative and postoperative settings.

RESULTS:

Competing risks were responsible for 46% of deaths in this cohort of 168 patients. Preoperatively, the most important predictor of cancer‐related mortality was a clinically invasive tumor (hazards ratio [HR], 3.97; P < .001), whereas increasing age (HR, 1.07; P < .001) was found to be the most important predictor of competing mortality. Postoperatively, tumor grade was the most important predictor of cancer‐related mortality (HR, 3.92; P < .001) whereas constitutional symptoms (HR, 1.91; P = .015) and increasing age (HR, 1.06; P < .001) were found to be predictive of competing mortality.

CONCLUSIONS:

In the current study, stage and grade were found to be the 2 most important independent predictors of survival in patients with tumors of the upper urinary tract and were highly correlated. Pain or weight loss was found to be a novel predictor of survival in this cancer. Although a survival disadvantage was not noted for women, nephron‐sparing surgery, ureteral tumors, or older patients with respect to cancer, competing causes of mortality were found to be responsible for greater than one‐third of observed deaths and age was the best predictor of this occurrence. Cancer 2009. © 2009 American Cancer Society.     

Image diagnostics for carcinoma of the biliary tract

Although it is clear that US is the procedure which should be selected as a method of the first choice to detect carcinoma of the biliary tract, a rational selection and combination of diagnostic procedures are essential for further evaluation on the nature or extension of tumor and its resectability. The next procedure which should be selected after US, in our opinion, is ERCP which can be followed by ERBD, if necessary, because it is useful to know the site and extension of tumor. However, the cases who have the lesion at the upper portion of the biliary tract or which is considered to be unresectable should be converted to percutaneous transhepatic approaches (PTC, PTBD, PTCS) at this stage as a method of next choice with diagnostic and subsequent therapeutic purposes. On the other hand, EUS is also an important first line diagnostic procedure to delineate the lesion at the lower portion of the biliary tract which can be used in parallel with ERCP. In this paper, usefulness of EUS was strongly advocated, because the information concerning the extension and resectability of tumor are also provided with it as it is obtained with CT, MRT and angiography. Cytology of bile, cholecystography, percutaneous transhepatic cholangioscopy and biopsy under endoscopic control carried out after percutaneous transhepatic drainage of the gallbladder are the procedures used for the diagnosis of gallbladder carcinoma, but they should be only indicated in the cases, in which early carcinoma is strongly suspected, because it cannot provide us any information necessary to make therapeutic plan in the cases with advanced carcinoma.     

Preoperative imaging of biliary tract cancers

Many imaging techniques are available for the evaluation of patients with malignant obstructive jaundice. Ultrasonography, in experienced hands, is valuable for evaluating the local extent of the disease, but its usefulness for staging distant metastases is limited. When used properly, CT and MR imaging can provide valuable information about the extent of local tumor involvement and distant metastases. These noninvasive techniques provide images of the bile ducts and vascular images that are comparable in quality to those obtained with more invasive procedures, such as PTC, ERCP, and angiography, and do not have the risk for complications of these invasive techniques.     

Multidisciplinary treatment of biliary tract cancers

Ninety-six patients referred for radiation therapy to Washington University affiliated institutions with tumors of the extrahepatic biliary tree form the basis of this report. Patients were examined with regard to demographic factors, tumor primary site, presenting symptoms, methods of diagnosis, and methods of management. The median survival of all 96 patients in this series was 11 months. There was no significant difference between patients with gallbladder cancer and patients with cancer of the biliary ductal system. There was a statistically significant improvement in survival in those patients undergoing resection as management or as a component of the management of their tumors (P = 0.02). Patients receiving >4,000 cGy of radiation therapy had an improved survival compared to those patients receiving ≤4,000 cGy of radiation therapy (P = 0.003). While surgical resection improved survival for those patients undergoing removal of all gross tumor, this effect was noted especially in patients with gallbladder cancer. © Wiley-Liss, Inc.     

Molecular pathology of biliary tract cancers

The molecular mechanisms underlying the development, growth and metastatic diffusion of biliary tract cancers are still undefined. The increase in worldwide incidence and mortality of cholangiocarcinoma justifies the impellent need to clarify the intracellular mechanisms triggering the malignant transformation of the biliary epithelium and growth of biliary malignancies. A more complete characterization of the molecular pathology of bile duct cancers could lead to the identification of valid targets for the diagnosis and therapy of these devastating malignancies. This review describes the scientific progress made over the past decades with regard to the understanding of the molecular processes of cholangiocarcinogenesis.     

Trends of management of carcinoma of the biliary tract

Trends of management of carcinoma of the biliary tract are described. Ultrasonography has made it possible to perform non-invasive and routine examination for biliary disorders and to find early cancer of the gallbladder. Moreover, endoscopic ultrasonography has enabled to make a differential diagnosis and a staging diagnosis. Percutaneous transhepatic cholangioscopy has been used as the most precise diagnostic procedure and peroral cholangioscopy has been introduced as a more convenient endoscopy. Although percutaneous transhepatic biliary drainage is considered to be hazardous and disadvantageous procedure in Western countries, it is essential in Japan where radical and extended operation are frequently performed. In Japan, major hepatectomies, pancreatoduodenectomy and/or combined resections of major vessels are aggressively adopted for advanced gallbladder cancers. However, such operations are still much dangerous and long-term survivors are few. Therefore, application of these extended operation for this advanced disease should be carefully re-examined. Various hepatectomies with caudate loberesection have been performed for patients with carcinoma of the hepatic hilus. Liver transplantation is also attempted for this disease, however, not accepted generally. Pylolus preserving pancreatoduodenectomy is now being accepted for biliary malignancies, which brings excellent quality of life.     

Pancreatic and biliary tract cancers]

There are several tumor markers for pancreatic and biliary tract cancers, such as carcinoembryonal antigen, pancreatic enzyme, carbohydrate antigen and tumor associated gene. CA19-9 and SPan-1, which are type I carbohydrate antigens, are especially useful among these tumor markers. Combination assays of these tumor markers improve the positive rate for these cancers. These tumor markers are useful not only in diagnosis but also in assessing the therapeutic efficacy and early detection of recurrence after operation.     

胆系肿瘤化学治疗进展

胆系肿瘤包括胆囊癌和胆管癌发病率呈上升趋势。本病病因复杂,症状不典型,诊断时通常已处于晚期,预后极差。临床研究显示,对于不能手术的进展期患者,化疗和(或)姑息性胆道减压可以提高患者的生活质量。一系列Ⅱ期临床研究结果提示,单药化疗的客观有效率为8%~30%,而联合化疗的有效率为10%~60%。由于胆系肿瘤发生率低,目前尚无大型Ⅲ期临床研究探讨不同化疗方案在生存期和生活质量上的影响,但Ⅱ期临床研究的共识是,对于一般情况好或有肿瘤相关症状的进展期患者应该给予姑息化疗,而出现严重非肿瘤相关疾病的患者应该避免化疗;内镜操作,如PTCD或ERCP支架和光动力治疗,是重要的支持治疗,对于恶性胆道梗阻患者可以应用胆汁引流延长生存和改善生活质量。在目前试验的化疗药物中,健择的毒性比似乎最好,但疗效仍不满意,需要联合其他药物。在联合方案中,健择联合奥沙利铂(GEMOX)方案似乎是最好的方案之一总生存期长达15·4个月;而从近期疗效来看,健择联合顺铂(GP)方案目前的结果最好,总有效率达64%。随着分子生物学的研究进展,相信针对胆系肿瘤的靶向治疗将成为可能。     

Small cell carcinoma of the pancreas and biliary tract

Four cases of anaplastic carcinoma of the pancreas or biliary tract were studied clinicopathologically and immunohistochemically. All four cases were intermediate cell type and contained a minimum amount of microscopic foci of differentiated glandular adenocarcinoma. Argyrophilic tumor cells were not seen in any of the four tumors. Immunohistochemically, no tumor was positive for hormonal products, but all tumors were positive for epithelial markers. These findings suggest that the anaplastic carcinoma are not derived from argyrophilic cells, but rather from adenocarcinomas which have the potential for anaplastic metaplasia. The long-term survival of one patient emphasized the importance of chemotherapy in the treatment of small cell carcinoma of the pancreas and biliary tract.     

Endogenous N-nitrosation and cancer of the biliary tract.

Evidence is presented that N-nitroso compounds occur in bile from patients who have undergone surgery for gallstones or had gastrectomy and from unoperated persons. It is unlikely, therefore, that local formation of nitrosamines can account for the excess risk for gallbladder cancer in the first two groups. Gastric formation remains the likeliest hypothesis.     

Systemic therapy for biliary tract cancers

Biliary tract cancers (BTCs) are invasive carcinomas that arise from the epithelial lining of the gallbladder and bile ducts. These include intrahepatic, perihilar, and distal biliary tree cancers as well as carcinoma arising from the gallbladder. Complete surgical resection offers the only chance for cure; however, only 10% of patients present with early-stage disease and are considered surgical candidates. Among those patients who do undergo "curative" resection, recurrence rates are high; thus, for the majority of BTC patients, systemic chemotherapy is the mainstay of their treatment plan. Patients with unresectable or metastatic BTC have a poor prognosis, with a median overall survival time of <1 year. Despite a paucity of randomized phase III data, a consensus on first-line systemic therapy is emerging. In this review, we discuss the clinical experience with systemic treatment of BTC, focusing on the rationale for a first-line regimen as well as future directions in the field.     

干扰素在胆系肿瘤治疗中的作用及其研究进展

干扰素是一种具有广泛生物活性的细胞因子,具有多方面的抗肿瘤作用。干扰素家族包括Ⅰ、Ⅱ、Ⅲ 3种类型。研究表明,Ⅰ型干扰素尤其是INF-α2b联合单药氟尿嘧啶（5-FU）或以其为基础的化疗方案对胆系肿瘤有效, 联合HELF方案（羟基喜树碱+足叶乙甙+亚叶酸钙+5-FU）对晚期胆囊癌疗效较好;Ⅱ型干扰素除有较好的免疫调节作用外,可有效抑制胆系肿瘤细胞生长和促进细胞凋亡,在与钙调素（CaM）拮抗剂、米非司酮及中药等联合运用时可增效;Ⅲ型干扰素目前仅用于病毒性疾病的治疗,但基础研究证实其抗肿瘤作用明确,值得进一步研究。本文就干扰素在胆系肿瘤治疗中的作用及其研究进展作一综述。     

晚期胆道系统肿瘤的内科治疗

内科治疗是治疗晚期胆道系统肿瘤的重要手段.吉西他滨是最有效的药物之一,吉西他滨联合顺铂已成为标准方案.二线方案的相关研究甚少.靶向治疗有望成为新的标准,但需大型临床试验证实.     

Role of laparoscopy in the evaluation of biliary tract cancer

Patients with malignancies of the biliary tract have a dismal prognosis. As in most abdominal cancers, resection is the only effective treatment with potential for cure. Preoperative staging is not completely accurate, however, and a significant number of patients with biliary carcinoma undergo unnecessary laparotomy. As imaging technology improves, more patients with unresectable disease will be identified, avoiding the need for a laparotomy. Laparoscopy is a major addition, but its usefulness in staging of abdominal malignancies continues to evolve. The importance of laparoscopy to better predict the resectability in liver malignancies increasingly has been recognized. Conversely, the use of staging laparoscopy for other cancers has shown little benefit. For hilar cholangiocarcinoma and gallbladder cancer, the authors' analysis of 100 patients supports the use of staging laparoscopy for assessing these tumors. In this series, staging laparoscopy correctly identified unresectable disease and prevented unnecessary laparotomy in one third of patients. Patients with unresectable disease that was not detected at laparoscopy most often had locally advanced tumors. LUS did not contribute to the assessment of resectability in these patients. The yield of laparoscopy was lower for hilar cholangiocarcinoma, but could be improved by targeting patients who are at higher risk for occult unresectable disease, such as patients with T2 or T3 lesions. These patients and patients with primary gallbladder carcinoma have a high incidence of metastatic disease and should undergo laparoscopic staging before attempting at resection.     

Reproductive history and cancer of the biliary tract in women

Although reproductive factors have been shown to be related to the composition of bile and functioning of the biliary system, their relationship with biliary tract cancer has not been studied in detail. Between 1984 and 1987 we conducted a case-control study of 75 women with cancer of the biliary tract and 252 controls from the general population. An interviewer-administered questionnaire was used to collect information on reproductive history. The information was obtained from the responders themselves (direct response) or from relatives (indirect response). Our results indicate that younger age at menarche, early age at first pregnancy, higher number of pregnancies and prolonged fertility may enhance the risk of cancer of the biliary tract. Overall, increased exposure to endogenous oestrogens and progesterone constitutes a higher risk. © 1994 Wiley-Liss, Inc.     

Extra-hepatic biliary tract metastases from breast cancer

A retrospective review was conducted of 49 breast cancer patients who were seen at the Massachusetts General Hospital from 1962 to 1978 and who developed biliary tract metastases. Although these findings were incidental at autopsy in 21 patients, clinical evidence of extra-hepatic biliary involvement developed in 28. This was documented radiographically, surgically, and/or confirmed at autopsy. Although most patients had previous or concurrent nonbiliary tract metastases, in 6 patients the initial site of failure was in the extra-hepatic biliary system. Analysis of the 28 patients in the clinical group revealed that initial management with radiation therapy alone produced a response in 3 of 6 patients. However, when radiation was coupled with bypass surgery and/or adjuvant chemotherapy, a response occurred in 3 of 3; the total radiation therapy response rate was 6/9. Chemotherapy given either alone or in combination with surgery produced a response in only one of 7 patients. All 4 irradiated patients who were treated with a time-dose-fractionation (TDF) > 40 had a complete response compared to a complete response in only 2 of 8 with a TDF ≤ 40. The median survival of the irradiated group was 6 months compared to 3.3 months in the treated-unirradiated patients and 0.7 months in the untreated patients. The onset of jaundice in a breast cancer patient does not necessarily indicate progressive hepatic involvement. Patients with extrahepatic metastatic obstruction are being recognized increasingly and should be treated vigorously, especially since such patients with no liver parenchymal involvement have a greater survival (median 6 months) than those with liver involvement (median 1.8 months).