Neoadjuvant Treatments for Advanced Resectable Melanoma

Neoadjuvant therapy has demonstrated promise as a treatment modality in resectable advanced-stage melanoma. Treatment has evolved beyond chemotherapy, with the utilization of biochemotherapy, immunotherapy, and targeted therapy in the neoadjuvant setting. These therapies have shown better progression-free survival and melanoma-specific survival when compared with patients that proceed directly to surgery. Ongoing clinical trials will continue to propel research forward to improve the available options for patients with resectable advanced regional disease.     

Adjuvant therapy for malignant melanoma

Malignant melanoma is increasing in incidence worldwide, and many patients remain at a significant risk of recurrence following surgical resection. Over the past 30 years, interferon-α has been the only agent approved for adjuvant therapy of melanoma. This review summarizes the rationale for adjuvant therapy, and discusses the roles of interferon, immunotherapy, chemotherapy and radiation therapy in the adjuvant setting. New approaches and novel combinations that appear promising for the adjuvant therapy of malignant melanoma are also outlined.     

直肠癌的新辅助治疗

为了保留肛门、减少复发、延长生存,新辅助化放疗已成为直肠癌治疗的重要组成部分.本文详细论述了直肠癌新辅助治疗的发展和现状.探讨了新辅助放疗、新辅助放化疗与单纯手术及辅助化放疗相比的优劣.     

Two new trifunctional antibodies for the therapy of human malignant melanoma

Trifunctional antibodies are able to redirect T cells and Fcgamma receptor(+) accessory immune cells to tumor targets. The simultaneous activation of these different classes of effector cells results in efficient killing of the tumor cells by different mechanisms such as phagocytosis and perforin-mediated cytotoxicity. Here, we introduce 2 new trifunctional antibodies specific for human melanoma. These trifunctional antibodies recognize with one binding arm CD3 on human T cells. The other binding arm is directed against melanoma-associated proteoglycans or melanoma-associated gangliosides (GD2 as well as GD3). They mediate specific lysis of various melanoma cell lines in correlation with the level of antigen expression in short-term cytotoxicity experiments. A combination of the 2 trifunctional antibodies was equally or even more efficient. Moreover, they induced a strong Th1 cytokine pattern with high amounts of IFN-gamma and low or no IL-4. Accordingly, CD4(+) and especially CD8(+) T cells expanded, whereas B cells, NK cells and monocytes decreased. The cytokine response was up to 16-fold higher when tumor cells were present. IFN-gamma reached cytotoxic concentrations for SK-MEL-23 melanoma cells. The induction of a T-cell-activatory and melanoma cell-inhibitory cytokine milieu together with the redirection of T-cell- and accessory cell-mediated cytotoxicity are interesting features of these trifunctional antibodies. They may be a new option for the therapy of human malignant melanoma.     

Adjuvant immunotherapy for melanoma

Adjuvant immunotherapy was administered to 84 lymph-node-negative and 25 lymph-node-positive melanoma patients. This active specific homologous cell protein preparation was given after aggressive surgery and given over 2 years. Projected and observed survival rates are presented as well as other clinical and pathologic characteristics such as female-to-male ratio, site of primary, level and depth of invasion. The projected 5-year survival rates are 90% for all stage I with 89% for females and 94% for males. Lower extremity stage I projected 5-year survival rate was 88% for all, 87% for females, and 100% for males. The projected 5-year survival rate for stage II was 68% overall and 100% for lower extremity. Only two of five patients with an unknown primary have expired. All of these results are improved over expected survival. Hopefully a randomized prospective study will be stimulated to ascertain the basis for this improvement.     

Systemic therapy of malignant melanoma

The present status of medical treatment of malignant melanoma is briefly reviewed, both with regard to adjuvant therapy for individuals with high-risk melanoma and a high probability of harbouring subclinical rnicrometastases, as well as to therapy for establised disseminated (macrometastatic) disease. At present, disseminated, macrometastatic melanoma is incurable in the majority of cases. Single agent chemotherapy has modest effects and results in disease remission in a minority of patients, usually of short duration, Combination chemotherapy, or the combination of chemotherapeutic drugs and cytokines, results in increased response rates and occasionally remissions of prolonged duration. So far, no regimen has demonstrated improved survival compared to single agent therapy in disseminated melanoma. New insights into the mechanisms of resistance to chemotherapeutic drugs may lead to development of predictive tests that can identify individuals with tumors sensitive to a specific agent, as well as to the development of strategies to circumvent drug resistance. It has recently been shown that adjuvant therapy of high-risk melanoma with large doses of interferon-α2b significantly prolongs relapse-free and overall survival, at the price of considerable toxicity. Ongoing studies aim to define the optimum dose and duration of adjuvant interferon therapy. Recent advances in molecular biology and immunology may lead to the development of new treatment modalities, such as improved vaccines and other biologic therapies, which may benefit patients with malignant melanoma.     

食管癌的新辅助治疗进展

新辅助治疗是在成功的术后辅助治疗经验基础上提出的术前辅助治疗。其目的是增加手术切除肿瘤的可能性并提高患者的生存率,包括新辅助化疗、新辅助放疗和新辅助放化疗。本文拟就食管癌的新辅助治疗作一综述。     

Neoadjuvant therapy for localized pancreatic cancer: guiding principles

The management of localized pancreatic cancer (PC) remains controversial. Historically, patients with localized disease have been treated with surgery followed by adjuvant therapy (surgery-first approach) under the assumption that surgical resection is necessary, even if not sufficient for cure. However, a surgery-first approach is associated with a median overall survival of only 22-24 months, suggesting that a large proportion of patients with localized PC have clinically occult metastatic disease. As a result, adjuvant therapy has been recommended for all patients with localized PC, but in actuality, it is often not received due to the high rates of perioperative complications associated with pancreatic resections. Recognizing that surgery may be necessary but usually not sufficient for cure, there has been growing interest in neoadjuvant treatment sequencing, which benefits patients with both localized and metastatic PC by ensuring the delivery of oncologic therapies which are commensurate with the stage of disease. For patients who have clinically occult metastatic disease, neoadjuvant therapy allows for the early delivery of systemic therapy and avoids the morbidity and mortality of a surgical resection which would provide no oncologic benefit. For patients with truly localized disease, neoadjuvant therapy ensures the delivery of all components of the multimodality treatment. This review details the rationale for a neoadjuvant approach to localized PC and provides specific recommendations for both pretreatment staging and treatment sequencing for patients with resectable and borderline resectable (BLR) disease.     

Treatment of melanoma of unknown primary in the era of immunotherapy and targeted therapy: A Dutch population-based study

Melanoma of unknown primary (MUP) may have a different biology to melanoma of known primary, but clinical trials of novel therapies (e.g., immune checkpoint or BRAF/MEK inhibitors) have not reported the outcomes in this population. We therefore evaluated the overall survival (OS) among patients with MUP in the era of novel therapy. Data for stage III or IV MUP were extracted from a nationwide database for the period 2003–2016, with classification based on the eighth edition of the American Joint Committee on Cancer criteria. The population was divided into pre- (2003–2010) and post- (2011–2016) novel therapy eras. Also, OS in the post-novel era was compared between patients with stage IV MUP by whether they received novel therapy. In total, 2028 of 65,110 patients (3.1%) were diagnosed with MUP. Metastatic sites were known in 1919 of 2028 patients, and most had stage IV disease (53.8%). For patients with stage III MUP, the 5-year OS rates were 48.5% and 50.2% in the pre- and post-novel eras, respectively (p = 0.948). For those with stage IV MUP, the median OS durations were unchanged in the pre-novel era and post-novel era when novel therapy was not used (both 4 months); however, OS improved to 11 months when novel therapy was used in the post-novel era (p < 0.001). In conclusion, more than half of the patients with MUP are diagnosed with stage IV and the introduction of novel therapy appears to have significantly improved the OS of these patients.     

A role for topical 5-fluorouracil therapy in melanoma

Topical 5-fluorouracil (Efudex) has been shown to be of great value in the treatment of skin cancers, Marjolin ulcers, and advanced squamous cell carcinoma of the mouth and esophagus. It has been advocated for use on patients with melanocytic dysplasia and lentigo maligna melanoma. This report confirms the use of topical 5-FU for lentigo maligna melanoma and melanocytic dysplasia. In melanomas with poor prognosis, preoperative treatment with topical 5-FU converts the cellular infiltrate from acute inflammatory cells to round cells which have been shown to be T-cells. We believe this preoperative stimulation of the patients' own immune reaction to the tumor may be of great significance in improving the surgical results for melanomas with a poor prognosis.     

胃癌的新辅助治疗

胃癌的预后极差,其死亡率居于所有癌症的第二位。尽管手术切除肿瘤是首选治疗方案,但术后死亡率仍高达60％以上。为了提高治愈性（RO）切除率,降低术后死亡率,延长生存期,提高生活质量,各国医学工作者进行了大量的研究。本文将对近年来胃癌新辅助治疗进展作一综述。     

胰腺癌:新辅助治疗

In spite of the high mortality in pancreatic cancer, significant progress is being made. This review discusses multimodality therapy for patients with pancreatic cancer. Surgical therapy currently offers the only potential monomodal cure for pancreatic adenocarcinoma. However only 10%-20% of patients present with tumors that are amenable to resection, and even after resection of localized cancers, long term survival is rare. The addition of chemoradiation therapy significantly increases median survival. To achieve long-term success in treating this disease it is therefore increasingly important to identify effective neoadjuvant/adjuvant multimodality therapies. Preoperative chemoradiation for potentially resectable pancreatic cancer has the following advantages： （1） neoadjuvant treatment would eliminate the delay of adjuvant treatment due to postoperative complications; （2） neoadjuvant treatment could avoid unnecessary surgery for patients with metastatic disease evident on restaging after neoadjuvant therapy; （3） downstaging after neoadjuvant therapy may increase the likelihood for negative surgical margins; and （4） neoadjuvant treatment could prevent peritoneal tumor cell implantation and dissemination caused during surgery. This review systematically summarizes the current status, controversies, and prospects of neoadjuvant treatment of pancreatic cancer.     

Managing leptomeningeal melanoma metastases in the era of immune and targeted therapy

Melanoma frequently metastasizes to the brain, with CNS involvement being clinically evident in ～30% of patients (as high as 75% at autopsy). In ～5% cases melanoma cells also metastasize to the leptomeninges, the sub‐arachnoid space and cerebrospinal fluid (CSF). Patients with leptomeningeal melanoma metastases (LMM) have the worst prognosis and are characterized by rapid disease progression (mean survival 8‐10 weeks) and a death from neurological causes. The recent years have seen tremendous progress in the development of targeted and immune therapies for melanoma that has translated into an increased survival benefit. Despite these gains, the majority of patients fail therapy and there is a suspicion that the brain and the leptomeninges are a “sanctuary” sites for melanoma cells that escape both targeted therapy and immunologic therapies. Emerging evidence suggests that (1) Cancer cells migrating to the CNS may have unique molecular properties and (2) the CNS/leptomeningeal microenvironment represents a pro‐survival niche that influences therapeutic response. In this Mini‐Review, we will outline the clinical course of LMM development and will describe how the intracranial immune and cellular microenvironments offer both opportunities and challenges for the successful management of this disease. We will further discuss the latest data demonstrating the potential use of BRAF inhibitors and immune therapy in the management of LMM, and will review future potential therapeutic strategies for the management of this most devastating complication of advanced melanoma.     

肿瘤生物治疗开启黑素瘤临床治疗新时代

恶性黑素瘤是一类进展快预后差的恶性肿瘤,对传统放化疗均不敏感,晚期患者5年生存率不足5%。随着单克隆抗体、小分子化合物、过继性免疫细胞和溶瘤病毒等生物治疗技术的研发,肿瘤生物治疗为恶性黑素瘤的临床治疗开启了一个新的时代。2011年到2014年,CTLA-4单抗Ipilimumab,PD-1单抗Pembrolizumab、Nivolumab,BRAF抑制剂Vemurafinib、Dabrafinib和MEK抑制剂Trametinib等相继获得FDA批准用于治疗晚期黑素瘤患者,同时多种自体免疫细胞疗法如TIL、CAR-T,以及溶瘤病毒T-VEC等也都在其各自的临床试验中获得了可靠的疗效证据。肿瘤生物治疗以其独特的治疗优势,打破了恶性黑素瘤临床研究近50年的沉寂。然而,我国恶性黑素瘤的生物治疗临床研究尚处于起步阶段,多种生物治疗技术在中国的推广仍需进一步的临床佐证。但随着研究的不断深入,尤其是细胞免疫学、分子生物学和肿瘤遗传学等学科的发展和融合,越来越多的生物治疗方法将逐渐应用于临床,造福于更多的恶性黑素瘤患者。     

恶性黑色素瘤的免疫治疗现状与进展

恶性黑色素瘤是一种高度恶性,易转移,预后差,对化疗放疗均不敏感的恶性肿瘤。随着肿瘤免疫学、分子生物学技术的迅速发展,过继免疫治疗、生物化学治疗、肿瘤疫苗、靶向治疗以及佐剂等治疗恶性黑色素瘤的方法显示了良好的应用前景。免疫治疗已逐渐成为肿瘤综合治疗的一个重要组成部分,文章就该方面的研究进展进行综述。