晚期肝细胞癌的靶向治疗进展

目前,原发性肝细胞癌（HCC）是居全球第5位的常见肿瘤,并且在肿瘤相关性死亡中排第3位。大部分肝细胞癌患者诊断时已无法手术切除并且中位生存期很短,由于传统的细胞毒药物对晚期肝细胞癌疗效有限,本文总结目前靶向治疗领域的一些进展,希望将来在肝细胞癌系统治疗方面能够获得实质性突破。     

Systemic therapy of advanced hepatocellular carcinoma: how hopeful should we be?

Worldwide, hepatocellular carcinoma (HCC) is the fifth most common cancer and the third most common cause of cancer-related death. In the U.S., 18,510 new cancers of the liver and intrahepatic bile duct are expected in 2006, with an estimated 16,200 deaths. The incidence rates for HCC in the U.S. continued to rise steadily through 1998 and doubled during the period 1975-1995. Unresectable or metastatic HCC carries a poor prognosis, and systemic therapy with cytotoxic agents provides marginal benefit. A majority of HCC patients (>80%) presents with advanced or unresectable disease. Even for those with resected disease, the recurrence rate can be as high as 50% at 2 years. Because of the poor track record of systemic therapy in HCC, there has been a sense of nihilism for this disease in the oncology community for decades. However, with the arrival of newly developed molecularly targeted agents and the success of some of these agents in other traditionally challenging cancers, like renal cell carcinoma, there has recently been renewed interest in developing systemic therapy for HCC. This review attempts to concisely summarize the historical perspective and the current status of systemic therapy development in HCC.     

Hepatocellular carcinoma: systemic therapies and future perspectives

Hepatocellular carcinoma is (HCC) the most common primary malignancy of the liver in adults. It is also the fifth most common solid cancer worldwide and the third leading cause of cancer-related deaths. Treatment options for HCC include liver transplantation, surgical resection, locoregional therapies and chemotherapy. The median survival time of patients following the diagnosis of unresectable disease is approximately 6–20 months, whereas the 5-year survival is less than 5%. Given the projected increase in incidence of HCC due to hepatitis C virus infection and obesity related cirrhosis, there is an urgent need for more intensive research in this cancer. In this article, we review the systemic options available for patients with HCC, its molecular pathogenesis and future therapeutic directions with special emphasis on immune-based and molecularly-targeted therapy.     

Targeted therapies in colorectal cancer: surgical considerations

Colorectal cancer (CRC) is a leading worldwide health concern that is responsible for thousands of deaths each year. The primary source of mortality for patients with CRC is the development and subsequent progression of metastatic disease. The most common site for distant metastatic disease is the liver. Although patients with metastatic disease to the liver have several effective treatment options, the only one for cure remains surgical resection of the liver metastases. Historically, most patients with liver metastases have had unresectable disease, and only a small percentage of patients have undergone complete curative resection. However, improved systemic therapies have led to an evolution in strategies to treat metastatic CRC to the liver. Under most conditions the management of these patients remains complex; and as chemotherapy options and new targeted therapies continue to improve outcomes, it is clear that a multidisciplinary approach must be the foundation on which advanced surgical and medical techniques are employed. Here, in this review, we highlight the role of targeted therapies in the surgical management of patients with metastatic CRC to the liver.Key Words: Colorectal cancer (CRC), metastatic colorectal cancer (mCRC), liver, targeted therapies, chemotherapy, surgical management     

Curable Metastatic Colorectal Cancer

In the United States and Europe, colorectal cancer (CRC) is the third most common malignancy and the second leading cause of cancer-related death for men and women. In the course of their disease, many patients will present with metastasis, with the liver and lung being the most common locations. Untreated metastatic disease carries a poor prognosis. However, cure is still possible for selected patients with stage IV CRC. Surgical resection provides the best chance for cure, and chemotherapy can be a valuable adjunct when given in a (neo-)adjuvant fashion or as conversion therapy to downsize initially unresectable tumors. For unresectable metastases, alternative treatment options include radiofrequency ablation and hepatic artery infusion. Additional local therapies are being explored, including chemoembolization, radioembolization, and stereotactic body radiation therapy. Prospective randomized trials are needed to further clarify the roles of these novel treatment options in the clinician’s repertoire for metastatic CRC.     

The treatment of advanced gastric cancer: new findings on the activity of the taxanes

Globally, gastric cancer is one of the most common types of cancer and one of the most frequent causes of cancer-related death. Despite many advances in the diagnosis and treatment of this disease, the prognosis for gastric cancer remains poor, especially in more advanced stages. In metastatic disease, benefits in survival and quality of life have been demonstrated in patients with unresectable or metastatic gastric cancer receiving chemotherapy plus best supportive care versus best supportive care alone. The taxanes, which are among the most promising cytotoxic agents in clinical use, have shown encouraging activity in early-phase studies as single agents and in combination regimens in the treatment of advanced gastric cancer. Recently, interim results of a randomized phase III trial comparing the triplet of docetaxel, cisplatin, and 5-fluorouracil with a standard reference regimen of cisplatin and 5-fluorouracil were reported. Patients treated with the docetaxel-containing regimen had a statistically superior response rate and time to disease progression as well as a clinically significant prolongation of survival. This study underscores the importance of developing new therapeutic options for patients with advanced gastric cancer.     

Cellular based treatment modalities for unresectable hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver and is unfortunately associated with an overall poor prognosis and high mortality. Early and intermediate stages of HCC allow for treatment with surgical resection, ablation and even liver transplantation, however disease progression warrants conventional systemic therapy. For years treatment options were limited to molecular-targeting medications, of which sorafenib remains the standard of care. The recent development and success of immune checkpoint inhibitors has proven to be a breakthrough in the treatment of HCC, but there is an urgent need for the development of further novel therapeutic treatments that prolong overall survival and minimize recurrence. Current investigation is focused on adoptive cell therapy including chimeric antigen receptor-T cells (CAR-T cells), T cell receptor (TCR) engineered T cells, dendritic cells, natural killer cells, and tumor infiltrating lymphocyte cells, which have shown remarkable success in the treatment of hematological and solid tumor malignancies. In this review we briefly introduce readers to the currently approved systemic treatment options and present clinical and experimental evidence of HCC immunotherapeutic treatments that will hopefully one day allow for revolutionary change in the treatment modalities used for unresectable HCC. We also provide an up-to-date compilation of ongoing clinical trials investigating CAR-T cells, TCR engineered T cells, cancer vaccines and oncolytic viruses, while discussing strategies that can help overcome commonly faced challenges when utilizing cellular based treatments.     

Palliation of malignant dysphagia in esophageal cancer: a literature-based review

Esophageal cancer is a lethal malignancy and adenocarcinoma of the esophagus is increasing in incidence. Most patients present with locally advanced, unresectable or metastatic disease.The 5-year survival rate of patients with esophageal cancer is < 20%. Dysphagia is the most common presenting symptom of this disease and leads to nutritional compromise, pain, and deterioration of quality of life. Palliation is an important goal of esophageal cancer therapy. Severity is commonly measured using a dysphagia grade, and dysphagia is an integral component of quality-of-life instruments, such as FACT-E and EORTC-OES 24. Investigation of dysphagia includes radiographic studies such as barium or Gastrografin swallow, esophagogastroduodenoscopy, endoscopic ultrasonography, and other staging studies for esophageal cancer. Current management options for the palliation of dysphagia include esophageal dilatation, intraluminal stents, Nd:YAG laser therapy, photodynamic therapy, argon laser, systemic chemotherapy, external beam radiation therapy, brachytherapy, and combined chemoradiation therapy. The clinical situation, local expertise, and cost effectiveness play an important role in choosing the appropriate treatment modality.The benefits and disadvantages of these approaches along with a concise review of the literature are presented.     

Traitement systémique du carcinome hépatocellulaire

Systemic cytotoxic treatments provide marginal benefit in unresectable or metastatic HCC. With the arrival of molecularly targeted agents, there has been renewed interest in developing novel systemic treatments for HCC. For the first time, results of a phase III randomized, placebo-controlled trial were recently presented in which sorafenib demonstrated improved survival in patients with advanced HCC. Therefore, sorafenib is now the new standard for the first-line treatment of advanced HCC. The identification of predictive factors and the search for new molecules remain major challenges for this poor prognostic disease.     

New options for the management of castration-resistant prostate cancer: a case perspective

Prostate cancer is the leading cause of cancer and second leading cause of death among men. Management of localized disease is fairly straight-forward, but treatment for locally advanced or metastatic disease is much less so. Androgen-deprivation therapy serves as the foundation of treatment for patients with locally advanced or metastatic disease. Although most patients with prostate cancer show a response to medical or surgical castration, many eventually experience a hormone-refractory, incurable state. Until recently, therapeutic options for CRPC have been limited and focused on systemic chemotherapeutic options. Unfortunately, however, this provides a minimal increase in overall survival, at the cost of significant additional toxicities. Therefore, much research has gone into developing other suitable therapies with potentially less toxicity. This article uses a case study approach to discuss new options for the treatment of castration-resistant prostate cancer.     

Systemic therapy for hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a common cancer worldwide. Most patients present at a stage when surgical resection is no longer possible, and face a dismal prognosis. Locoregional and intra-arterial treatments are feasible and effective only in selected patients with disease confined to the liver. For patients with extrahepatic disease or a blocked portal venous system, systemic chemotherapy is the only treatment option available. Systemic therapy has not been successful in the past, with very low response rates to single-agent chemotherapy. Recently, however, there have been reports that combination chemotherapy with currently available agents may make some initially unresectable tumors resectable and, in some cases, induce complete pathologic responses. This has led to a reconsideration of systemic therapy for HCC, the current status of which is described in this review.     

Development of sorafenib and other molecularly targeted agents in hepatocellular carcinoma

It is well appreciated that hepatocellular carcinoma (HCC) represents one of the most challenging malignancies of worldwide importance. In fact, HCC is the fifth most common cancer and the third most common cause of cancer-related death globally. The incidence rates for HCC in the U.S. and Western Europe have been rising. Unresectable or metastatic HCC carries a poor prognosis, and systemic therapy with cytotoxic agents provides marginal benefit. Because of the poor track record of systemic therapy in HCC, there has been a sense of nihilism for this disease in the oncology community for decades. However, with the arrival of newly developed, molecularly targeted agents and the success of some of these agents in other traditionally challenging cancers, such as renal cell carcinoma, there has been renewed interest in developing novel systemic therapy in HCC. At the recent Annual Meeting of the American Society of Clinical Oncology, results of a phase 3, randomized, placebo-controlled trial were presented in which sorafenib demonstrated improved survival in patients with advanced HCC. This landmark study represents the first agent that has demonstrated an improved overall survival benefit in this disease and sets the new standard for first-line treatment of advanced HCC. For this review, the author concisely summarized the current status of molecularly targeted agents that are under clinical development in advanced HCC.     

Current role of hepatic artery infusion and isolated liver perfusion for the treatment of colorectal cancer liver metastases

There are many treatment options for patients with metastatic colorectal carcinoma confined to the liver. Surgical resection alone can result in significant prolongation of survival in patients with favorable prognostic factors. Randomized studies of hepatic artery infusion therapy after complete resection of liver metastases have demonstrated improvements in hepatic recurrence-free survival but no impact on overall survival. Randomized trials evaluating the treatment of unresectable disease with hepatic artery infusion therapy have demonstrated higher response rates (31%-50%) than those seen with systemic chemotherapy (8%-20%) but no survival benefit. Vascular isolation and perfusion of the liver with chemotherapy with or without biologic agents under hyperthermic conditions is another regional modality that has been explored for the treatment of unresectable colorectal cancer liver metastases. Large series report high partial response rates (68%-77%), with responses being achieved in patients with advanced tumor burden and in those who have disease progression through prior treatment of hepatic metastases.     

Systemic treatment of vulvar cancer

Squamous cell carcinoma of the vulva is a rare disease, accounting for approximately 5% of cancers of the female genital tract. Standard therapy for early-stage vulvar cancer mainly comprises of surgery of the vulva and groins. In locally advanced or metastatic vulvar cancer, neoadjuvant or definitive chemoradiation is often considered as an alternative treatment option. Given its rarity, the level of evidence for different treatment modalities is poor and few clinical trials have been performed on this disease. Therefore indication criteria for systemic treatment in advanced stage vulvar cancer vary widely among countries and institutions. This review focuses on the different systemic treatment options for patients with locally advanced, recurrent or metastatic vulvar cancer, and highlights the need for an international multicenter approach to identify the most effective therapeutic options.     

Management of gastrointestinal stromal tumors in the era of tyrosine kinase inhibitors

Opinion statement Gastrointestinal stromal tumors (GIST) represent the most common type of mesenchymal malignancy in the gastrointestinal tract. With the discovery of uncontrolled KIT tyrosine kinase signaling as a critical component in the pathogenesis of this disease, the diagnostic and treatment options for patients with GIST have evolved rapidly. Pathology review by an experienced pathologist is critical to the classification of this disease. Expert and definitive surgery remains the mainstay of treatment in patients with localized, resectable disease. Imatinib mesylate has been shown to be the first successful systemic therapy for patients with metastatic or unresectable disease and has revolutionized the treatment of this often rapidly progressive and fatal disease. Ongoing studies are evaluating the role of imatinib in the preoperative and postsurgical adjuvant settings. Although resistance to imatinib will appear over time, there is reason for optimism that the mechanisms of resistance will be identified and eventually overcome. The application of molecular understanding of GIST to the development of a selective, scientifically rational therapy is a classic example of multidisciplinary translational oncology research.     

Molecular and immune targets in cutaneous squamous cell carcinoma

Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer and often confers a good prognosis. Though surgery is the gold standard of treatment, unresectable or metastatic disease can necessitate systemic therapy. Of systemic agents, there is increasing interest in the use of immunotherapies and targeted therapy. Further study into the driver mutations in cSCC has identified opportunities for targeted therapy. In this review, we discuss both current and investigational immune and molecular targets of therapy for cSCC.     

Contrasting Some Differences in Managing Advanced Unresectable Hepatocellular Carcinoma Between the East and the West

Hepatocellular carcinoma (HCC) is a common malignancy worldwide, although its aetiologies vary significantly between the East and the West. About a half of HCC cases present with advanced unresectable HCC at the time of diagnosis, leading to a worse prognosis. Over the past 20 years, the treatment paradigm for advanced unresectable HCC has shifted from an entirely palliative approach to a multidisciplinary treatment, with continuous reassessment and possible repeat treatment attributed to the advent of novel and improved local, regional and systemic therapeutic options, contributed by both the East and the West. An individualised treatment plan should be determined for each patient, as there can be substantial differences in the decision-making and treatment response to the same treatment for different patients and different patient populations. This review provides a summary of the recent advances in management and compares Eastern and Western strategies for HCC.     

Current Management of Hepatocellular Cancer

Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver, being the fifth most frequent cancer worldwide. It usually occurs in the setting of chronic liver disease and has a poor prognosis if untreated. Following the diagnosis, this disease requires multidisciplinary management. Orthotopic liver transplantation is theoretically the best treatment for early, unresectable HCC. However, the major practical obstacle is the extreme shortage of organs, which makes this a practical option only in selected patients. In this report we describe new advancements in diagnosis, classification, and treatment that have emerged in the field of HCC in recent years.     

Immune checkpoint inhibitors in hepatocellular carcinoma: A review of current clinical trials

Hepatocellular carcinoma (HCC) is the most common primary liver cancer with a poor prognosis due to advanced disease presentation or recurrence despite curative-intent resection. Since the approval of sorafenib in 2007, few systemic therapies offered a significant improvement in treatment outcomes. Over the last 3 years, however, rapid advancements in the field of immunotherapy have led to approval of checkpoint inhibitors in 2020 for use in advanced HCC. Since then, a few other clinical trials have shown promising results in the adjuvant and neoadjuvant setting. The objective of this review is to summarize data from existing clinical trials evaluating the use of systemic immune checkpoint inhibitors in HCC and to follow the natural evolution of this development across the metastatic, adjuvant, and neoadjuvant landscapes.     

Indonesian consensus on systemic therapies for hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is a deadly cancer with a rising incidence in the last 20 years. Most patients are diagnosed late when curative treatment is no longer feasible. With the background of chronic liver disease in most patients, the management of HCC becomes more complicated, in which well-preserved liver function is a prerequisite for locoregional or systemic therapies. In 2008, sorafenib became the first systemic agent proven to provide survival benefit for patients with advanced-stage HCC. For nearly a decade, no treatment has succeeded in providing better results than sorafenib. However, numerous advances in systemic therapies have emerged in the last 5 years to fulfill the unmet needs of effective therapeutic options. Several agents have been approved for clinical use after positive results in phase III clinical trials, including lenvatinib, regorafenib, cabozantinib, ramucirumab, and lastly immune checkpoint inhibitor atezolizumab in combination with bevacizumab, a monoclonal antibody targeting the vascular endothelial growth factor. With various options available, knowledge on the clinical evidence of each drug, their safety profile, as well as the patient characteristics and preferences become mandatory in clinical decision making. The objective of this consensus is to help clinicians, health-care workers, and policy makers in providing best clinical care for HCC patients.