Natural Interferon-Alpha Alone and in Combination with Conventional Therapies in Non-Small Cell Lung Cancer

Fourteen previously untreated patients with non-small cell lung cancer (NSCLC) were treated with natural interferon-alpha (IFN) in combination with conventional therapies. The planned dose of IFN was 6 × 10⁶ IU/d.i.m. 5 days a week for 12 weeks. After 12 weeks of IFN monotherapy patients with M0 disease underwent twice-daily fractionated radiotherapy (RT), 55 Gy/4F/30d, while IFN continued. Patients with M1 disease received 3 cycles of chemotherapy (CT) concomittantly with IFN. CT consisted of cisplatinum (P) 90 mg/m² i.v. on days 1, 28, and 56 and of vindesine (VDS) 3 mg/m² i.v. once a week 5 times and every other week thereafter for up to 8 courses. Thirteen patients were evaluable for response and toxicity. There were 9 patients with epidermoid, 3 with adeno- and one with large cell carcinoma. In 12 of 13 patients, the disease remained stable for 1 month during IFN monotherapy and one acheived a minimal response, which lasted 4 weeks. Of seven patients who completed the 12-week course of IFN monotherapy, 4 achieved stable disease (SD) and 3 had progressive disease. Three patients received RT and one received CT in combination with IFN as their subsequent treatment. There were 3 partial responses (2/3 after RT + IFN, 1/1 after CT + IFN), and 1 SD. Fatigue and weight loss were the most severe side-effects during IFN monotherapy. The combination of IFNs with conventional therapies might be clinically useful. We recommend further testing in larger studies.     

Low-Dose Aminoglutethimide Plus Steroid Replacement in Advanced Breast Cancer Patients Resistant to Conventional Therapies

In an attempt to define the activity and toxicity of low-dose aminoglutethimide plus steroid replacement in advanced breast cancer, we treated 40 patients with aminoglutethimide 500 mg/day + hydrocortisone 50 mg/day. Previous treatment consisted of additive hormones in 29 patients, oophorectomy in 8, and chemotherapy in 32. Among the 37 patients evaluablefor response and toxicity, 5 objective responses (16.2%) and 20 stable diseases (54%) were noted. Toxicity, absent in 23 patients (62.I %) and mild in 14, consisted mainly of Grade I (WHO) nausea, drowsiness, cutaneous rash, and dizziness. Responders and patients with stable disease experienced a similar survival (median not reached at 22 months). Aminoglutethimide at low doses appears to be beneficial in patients refractory to conventional therapies even if the objective response rate is low.     

Molecular Targeted Therapies for Patients with Refractory Thyroid Cancer

The recent availability of molecular targeted therapies leads to reconsideration of the treatment strategy in patients with distant metastases from differentiated thyroid carcinoma who are resistant to radioiodine therapy, and in patients with metastatic medullary thyroid carcinoma. In patients with progressive disease, treatment with kinase inhibitors should be offered, preferably in the context of a prospective trial.     

Targeted Therapies for Metastatic Esophagogastric Cancer

The prognosis and long-term survival for patients with metastatic esophagogastric cancer (EGC) is poor. Historically, the mainstay of treatment has been combination chemotherapy. More recently, a number of targeted therapies have been developed and are being studied with the goal of improving response rate and survival in patients with metastatic EGC. To date, the only targeted therapy which has been clinically approved is trastuzumab which targets the HER2/Neu oncogene. However, only a small group of patients with EGCs are HER2 amplified, and there are other important targets/pathways which play a role in the development of these cancers that are currently being studied. With the identification of these other clinically relevant pathways, it is anticipated that several other therapies will be approved in the future.     

Dendritic Cell Cancer Vaccines for Treatment of Colon Cancer

Despite advances in treatment modalities, colorectal cancer (CRC) still accounts for about half a million deaths yearly worldwide. The majority of metastatic CRC are unresectable, and of those who undergo resection, few are cured. Advances in chemotherapy and targeted therapy have improved survival, but options remain limited, making the case for incorporating novel modalities in CRC treatment paradigm. Our improved understanding of the tumor immune microenvironment had led to the development of novel immunotherapeutic agents that have been tested in clinical trials such as cancer vaccines. Cancer vaccines are designed to activate the effector immune cells in order to generate an immune response against tumors. Dendritic cell vaccines offer potential benefits for CRC patients but requires further evaluation. We reviewed the role of dendritic cells in the colorectal tumor microenvironment and dendritic cancer vaccine studies in colorectal cancer.     

Targeted Therapies for Breast Cancer Brain Metastases

The management of breast cancer, the most common cancer in the female population, has changed dramatically over years with the introduction of newer therapies. An increased incidence of brain metastases in recent years has created a challenge for oncologists because this population continues to have a poorer prognosis compared to metastatic breast cancer without central nervous system involvement. Historically, the exclusion of breast cancer patients with brain metastases from clinical trials has made treatment options even more limited. Nonetheless, more recently, this unmet need has been recognized by basic and clinical researchers and has led to the development of targeted therapies with better blood–brain barrier penetration and intracranial efficacy. Here we review targeted therapies directed at human epidermal growth factor receptor type 2 (HER2), vascular endothelial growth factor (VEGF), mammalian target of rapamycin (mTOR), epidermal growth factor receptor (EGFR), cyclin-dependent kinase 4 and 6 (CDK4/6) and poly(ADP-ribose) polymerase (PARP) for breast cancer patients with brain metastases. These therapies aim to be more efficacious and less toxic to represent a paradigm shift in the management of breast cancer brain metastases.     

Systemic Therapies for Advanced Squamous Cell Anal Cancer

Purpose of Review

We aim to summarise the available evidence on systemic therapies for advanced anal cancer.

Recent Findings

There is no universal consensus on the management of this condition and the prognosis remains poor. Nevertheless, significant progress has been recently made including completion of the first, ever-conducted, randomised trial in the first-line setting, investigation of immunotherapy in the refractory setting and use of comprehensive genomic profiling for a better molecular characterisation of this disease and the identification of novel potential targets.

Summary

The combination of a platinum agent and a fluoropyrimidine is generally considered the standard first-line treatment. Other cytotoxic agents, especially docetaxel and paclitaxel, have shown activity in both the chemotherapy-naive and chemo-refractory setting and are currently being investigated in clinical trials. Finally, further to the promising results of early clinical trials, immunotherapy with checkpoint inhibitors (i.e. nivolumab and pembrolizumab) is likely to become a standard second-line treatment option.

     

Dendritic Cell-Based Vaccines in Cancer

Therapeutic vaccines that can activate the immune system to destroy malignancies hold the promise of a low-toxicity, precisely targeted anticancer treatment modality. Because dendritic cells (DCs) are central to the activation of antigen-specific immune responses, DCs loaded with tumor antigens are of considerable interest as therapeutic vaccines. Preclinical studies have demonstrated the potency of DC-based immunizations in promoting tumor rejection. Continued preclinical and clinical studies are assessing a number of important parameters regarding the formulation and administration regimen of DC-based vaccines and have provided support for phase I and II studies. Thus far, DC-mediated immunizations have been well tolerated, with few toxicities reported. Tumor regression has been reported in up to 30% of patients, particularly with immunologically sensitive tumors such as melanoma. Biologic activity, measured as activation of antigen-specific T cells, is reported in up to 100% of patients immunized against potent recall antigens, such as tetanus toxoid, and up to 30% of those immunized against tumor antigens. Current clinical trials are increasingly testing DC-based vaccines in patients with minimal residual disease, such as following attempted curative surgery or following high-dose chemotherapy and stem-cell support where clinical benefit is likely to be the greatest. Newer strategies are focusing on further modifications to DCs to increase their immuno stimulatory potency. These include newer methods of antigen loading, better techniques for DC maturation, strategies to enhance polarization of DCs to ensure the induction of T helper cell type 1 immune responses, and the administration of adjunctive cytokines to augment the immune response following immunization.     

Standard and Emerging Therapies for Metastatic Differentiated Thyroid Cancer

Differentiated thyroid cancer accounts for >90% of cases of thyroid cancer, with most patients having an excellent prognosis. Distant metastases occur in 10%–15% of patients, decreasing the overall 10-year survival rate in this group to 40%. Radioactive iodine has been the mainstay of treatment for distant metastases, with good results when lesions retain the ability to take up iodine. For patients with metastatic disease resistant to radioactive iodine, treatment options are few and survival is poor. Chemotherapy and external beam radiotherapy have been used in these patients, but with disappointing results. In recent years, our understanding of the molecular pathways involved in thyroid cancer has increased and a number of molecular targets have been identified. These targets include the proto-oncogenes BRAF and RET, known to be common mutations in thyroid cancer; vascular endothelial growth factor receptor and platelet-derived growth factor receptor, associated with angiogenesis; and the sodium-iodide symporter, with the aim of restoring its expression and hence radioactive iodine uptake. There are now multiple trials of tyrosine kinase inhibitors, angiogenesis inhibitors, and other novel agents available to patients with metastatic thyroid cancer. This review discusses both traditional and novel treatments for metastatic differentiated thyroid cancer with a particular focus on emerging treatments for patients with radioactive iodine–refractory disease.     

非小细胞肺癌靶向治疗研究进展

目前肺癌的生物靶向药物抗表皮生长因子受体(Epidermal Growth Factor Receptor,EGFR)已成功地应用于肺癌临床治疗.但肺癌分子生物学机制十分复杂,新的生物靶点药物在临床中的重要作用日益受到关注.本文对上述分子生物学标志物在肺癌治疗中的作用及其相关临床研究进展进行综述.     

非小细胞肺癌靶向治疗研究进展

靶向针对表皮生长因子受体(EGFR)和血管内皮生长因子受体(VEGFR)的药物已取得临床获益,部分针对其他通路的新药也已在临床试验阶段.通过对患者生物标志物的测定,对其进行合理的靶向药物治疗将取得更大的临床获益.文章对非小细胞肺癌生物靶向治疗药物的研究进展及靶向药物的联合治疗进行综述.     

The Future of Systemic Therapies for Localised Prostate Cancer

In the last decade, many systemic therapies have become available to improve survival in the setting of castration-resistant prostate cancer. Once effective treatments for advanced and incurable disease have been established, these agents are generally explored in the adjuvant and neoadjuvant settings to evaluate their role in increasing the chance of cure for localised disease. Clinical trials evaluating new therapies in high-risk prostate cancer can broadly be divided into two categories. Phase III (and some phase II) trials generally evaluate treatments that have already been shown to provide clinical benefit in the advanced disease setting; whereas smaller phase I (and some phase II) trials often serve as proof-of-principle assessments in the development of novel agents. The goal of this review is to provide an overview of present and ongoing clinical trials of both of these categories, evaluating the promise of systemic therapies in the setting of high-risk localised prostate cancer. We undertook a search of Ovid Medline, Embase and clinicaltrials.gov for prospective clinical studies assessing systemic therapy for early stage prostate cancer, either before or after definitive local treatment (surgery or radiation) from 2000 onwards. This resulted in 53 studies, of which 29 were deemed worthy of this overview and are presented herein, broadly divided by mechanism of action. Clearly, the arena evaluating the future of systemic therapies for localised prostate cancer will be a very active one.