Orbital retinoblastoma: where do we go from here?

Diagnosis of orbital retinoblastoma traditionally carries a dismal prognosis. Although its incidence is less in the developed countries, it continues to contribute to an epidemic of extraocular disease at diagnosis in the developing world. Orbital retinoblastoma encompasses a wide range of distinct clinical entities with varying tumor load. There are no standard treatment protocols as of now but the current preferred management is multimodal with a combination of initial high-dose chemotherapy, surgery, external beam radiotherapy and prolonged chemotherapy for 12 cycles. Though orbital retinoblastoma is a catastrophic event, rapid advances on many fronts, especially the genetic, makes the future appear brighter than what it is now. This review looks at all the new frontiers that are in store in the near as well as the distant future. Looking at the ever expanding horizons makes one believe of a definite hope that one day we will conquer this disease as we have conquered many others in the past.     

Selecting targets for cancer prevention: where do we go from here?

Given the lack of progress in curing metastatic epithelial cancers, there is intense interest in, and a sound scientific rationale for, pursuing strategies to prevent cancer. However, although several clinical trials have shown efficacy in cancer prevention, few have resulted in changes to medical practice, and some trials have even shown harm. Recent experiences with serious side effects identified in cancer prevention trials underscore the need to re-evaluate our approach to clinical chemopreventive drug development, and to establish a framework for agent selection for future trials.     

Acute myeloid leukemia in adults: where do we go from here?

Although 30-40% of newly diagnosed younger patients with acute myeloid leukemia (AML) can be cured with current approaches, the overall outcome has not improved in recent years. In addition, the outcome in adults > 60 years of age remains dismal with < 10% of patients achieving remission remaining alive and disease free. Results of randomized clinical trials in AML evaluating high-dose cytosine arabinoside, changes in anthracyclines, the use of hematopoietic growth factors, stem cell transplantation in first remission, and modulation of the multidrug resistance phenotype are reviewed. New directions for clinical trials include the use of nonmyeloablative allogeneic stem cell transplantation as a form of "immunotherapy", refinements in autologous stem cell transplantation, and possibly manipulations of neoangiogenesis in the bone marrow and incorporation of newer agents, such as gemtuzumab zogamicin into treatment regimens. It is likely, however, that future advances will be a consequence of a better understanding of the biology of leukemic stem cells, and issues related to such studies are discussed.     

Systemic therapy for advanced carcinoid tumors: where do we go from here?

Carcinoid tumors are relatively indolent, but the treatment of advanced disease remains a challenge. Liver-directed therapies are a consideration in patients with liver-dominant disease. Somatostatin analogs (SSTa) are routinely used to control hormone-mediated symptoms (carcinoid syndrome), but the identification of systemic agents with antitumor efficacy has proven difficult. Aside from octreotide for small bowel carcinoid (which is associated with delayed progression), no treatment has proven antitumor activity. Chemotherapy seems to be of limited value. The role of interferon is also controversial; it is typically used after failure of octreotide. Peptide receptor radionuclide therapy may have activity in patients with SST receptor-expressing tumors, but randomized controlled trials are lacking. Advances in the understanding of the mechanisms underlying tumor progression have led to the identification of several potential therapeutic targets (including the vascular endothelial growth factor [VEGF] and mammalian target of rapamycin [mTOR] signaling pathways), but none has been definitively validated in carcinoid. Everolimus is associated with a trend toward improved progression-free survival in patients with progressive carcinoid, but is not approved for this indication. Therefore, a serious unmet need remains for additional therapeutic strategies for patients with advanced disease. Several avenues are under study, including the use of novel SSTa; VEGF and mTOR inhibitors; and agents that interfere with insulin growth factor 1 receptor and AKT signaling. Moving forward, optimizing patient selection based on clinical features or biomarkers holds promise for identifying individuals most likely to benefit from therapy.     

Molecularly targeted therapy in renal cell carcinoma: where do we go from here?

The angiogenic phenotype of renal cell carcinoma results from vascular endothelial growth factor pathway activation. Several different strategies targeting various aspects of the pathway have emerged as clinically relevant therapeutics in metastatic renal cell carcinoma. Key clinical data regarding these approaches are presented in this article. Furthermore, there are several considerations as to the further development of these agents and their appropriate application in metastatic renal cell carcinoma, such as timing of therapy, choice of initial therapy, continued role of debulking nephrectomy and toxicity concerns. These issues are discussed in light of current data and strategies for further drug development are presented.     

Molecular therapies of colorectal cancer: where will we go from here?

Until the late 1990’s colorectal cancer had a poor prognosis with a median survival of 12 months for metastatic disease. The discovery of molecular mechanisms for malignant transformation, tumor growth, angiogenesis, and metastasis formation have opened an abundance of biologic insights and subsequent therapeutic approaches, which have led to improved prognosis in many cancers, among them colorectal cancer. While inhibition of vascular endothelial growth factor (VEGF) either by blocking antibodies or synthetic soluble receptor fragments—the so-called VEGF-traps—have been shown to be beneficial when combined with chemotherapy, blocking antibodies against the epidermal growth factor receptor (EGFR) have revealed cytotoxic activity as monotherapy or in combination with chemical agents. Recently, the tyrosine kinase inhibitor regorafenib has been shown to be beneficial as a monotherapy in the salvage treatment setting for metastatic colorectal cancer (mCRC) patients. However, as major driver mechanisms for malignant transformation in colorectal cancer have so far not been accounted, we may expect an abundance of novel therapeutic options in CRC. In this review, novel promising therapeutic approaches will be outlined.