Prevention of ER-negative breast cancer: where do we stand?

Oestrogen receptor-negative and triple-negative breast cancers are types of aggressive tumours that account for approximately 30 and 15% of total breast cancers, respectively. Selective oestrogen receptor modulators and aromatase inhibitors are unable to treat and prevent these subtypes of mammary tumours. Thus, it is worth identifying new pathways, biomarkers, and agents that are effective in the treatment and prevention of these subtypes. Several classes of drugs have been studied, and many are still currently under investigation. We have attempted to conduct a state-of-the-art study on this important issue.     

Vascular-targeting agents and radiation therapy in lung cancer: where do we stand in 2005?

With recent Food and Drug Administration approval of the anti-vascular endothelial growth factor (VEGF) antibody for the treatment of colon cancer, it may be possible to achieve similar progress in the treatment of locally advanced lung cancer. Antiangiogenic therapies in the clinic are a reality, and it is important to demonstrate that they can be used safely with conventional modalities, including radiation therapy (RT). Strategies under scrutiny in preclinical and clinical studies include the use of endogenous inhibitors of angiogenesis, use of agents that target VEGF and VEGF receptor signaling, targeting endothelial-related integrins during angiogenesis, and targeting the preexisting immature vessels growing within tumors (ie, vascular targeting). Regardless of the approach, it is necessary to address whether angiogenesis is a consistent phenomenon within the lung parenchyma around a cancer and a relevant target and whether inhibiting angiogenesis will improve current lung cancer therapies without increasing toxicity. Vascular-targeting agents (VTAs) are an interesting class of agents that have the potential to enhance RT, but their clinical promise has yet to be realized. In preclinical models, these agents selectively destroy the tumor vasculature, initiating a rapid centralized necrosis within established tumors. Characteristically, after treatment with VTAs, a rim of viable tumor cells remains at the periphery of the tumor, which remains well perfused and should therefore be relatively sensitive to radiation-induced cytotoxicity. This review will focus on VTAs in the treatment of lung cancer and includes a discussion of combination studies with RT in the laboratory and some of the hurdles in the clinical application of these agents.     

Postoperative radiation therapy for lung cancer: where do we stand?

Lung cancer is the leading cause of cancer mortality in the United States. Local recurrence after surgery for operable disease has long been recognized as a hindrance to long-term survival. Postoperative radiation therapy was logically explored as a means to improve local control and survival. Multiple randomized trials were conducted, many showing improved local control, but none demonstrated a statistically significant survival benefit. In fact, a meta-analysis showed a rather large survival detriment, presumably from treatment-related complications. Radiation therapy has evolved over the years, and more modern treatment planning and delivery has the potential to treat sites deemed at high risk of recurrence while limiting the dose to critical intrathoracic structures, which should decrease the risk of treatment-related complications. Recent studies have supported this supposition. Similarly, since cancer is often a systemic disease, local control will become a more pressing issue as systemic micrometastatic disease is eradicated with effective chemotherapy. Unfortunately, randomized trials testing the effectiveness of modern postoperative radiation therapy in the chemotherapy era have not been performed. Clinicians must therefore counsel patients regarding the risk of disease recurrence after surgery, the potential but unproven benefit of postoperative radiation therapy, and the possibility of treatment-related complications.     

External hypofractionated whole-breast radiotherapy: now where does accelerated partial breast irradiation stand?

Breast-conserving therapy (BCT) has emerged as a viable option for suitable breast cancer patients who are desirous of preserving the breast. The major advantage of BCT is the good cosmetic outcome with disease-free and overall survival similar to mastectomy. In this article, I have compared two emerging modalities for treating a preserved breast with radiotherapy. These two techniques in breast cancer - accelerated partial breast irradiation (APBI) and hypofractionated whole breast external beam radiotherapy - have their respective merits and drawbacks, and this article attempts to dissect the issue.     

Research in castration-resistant prostate cancer: what does the future hold?

Prostate cancer (PCa) is the most common non-skin cancer diagnosed in North America, and it affects 1 in 6 men. Patients with recurrent or metastatic pca will inevitably develop castration-resistant disease after an initial period of hormone responsiveness. The standard first-line treatment for men with castration-resistant pca (CRPC) is docetaxel, but further treatment options are limited. This review summarizes the research being conducted in CRPC, with specific regard to immunotherapy and to novel targeted therapies directed against the androgen axis, vascular endothelial growth factor, chaperone proteins, the phosphoinositide 3 kinase/Akt/phosphatase and tensin homolog/mammalian target of rapamycin pathway, and endothelin-1.     

Antiangiogenic agents in the management of non-small cell lung cancer: Where do we stand now and where are we headed?

Several therapies targeting angiogenesis are currently in development for non-small cell lung cancer (NSCLC). This review discusses results of recent clinical trials evaluating chemotherapy plus antiangiogenic therapy for NSCLC. Bevacizumab, an anti-VEGF antibody, is currently approved for the treatment of advanced NSCLC in combination with carboplatin and paclitaxel. Completed phase III trials evaluating bevacizumab plus chemotherapy have shown prolonged progression-free survival; however, not all trials showed significant improvement in overall survival (OS). Phase III trials of the tyrosine kinase inhibitors (TKIs) vandetanib and sorafenib and the vascular disrupting agent ASA404 also failed to improve OS compared with chemotherapy alone. Clinical trials are ongoing involving several new antiangiogenic therapies, including ramucirumab, aflibercept, cediranib, BIBF 1120, sunitinib, pazopanib, brivanib, ABT-869, axitinib, ABT-751, and NPI-2358; several of these agents have shown promising phase I/II results. Results from recently completed and ongoing phase III trials will determine if these newer antiangiogenic agents will be incorporated into clinical practice.     

Particle therapy in lung cancer: Where do we stand?

BACKGROUND: From a theoretical point of view, charged particles should lead to superior results compared to photons. In this review, we searched for clinical evidence that protons or C-ions are really beneficial to patients with lung cancer. METHODS: A systematic literature review based on an earlier published comprehensive review was performed and updated until November 1st 2007. RESULTS: Ten fully published series, all dealing with non-small cell lung cancer (NSCLC), mainly stage I, were identified. No phase III trials were found. On proton therapy, 2-5 year local tumor control rates varied between 87% and 57%. The 2 year/5 year overall survival and 2 year/5 year cause specific survival varied between 31-74%/23% and 58-86%/46%, respectively. Late side effects were observed in about 10% of the patients. For C-ion therapy, the local tumor control rate was 77%, while 95% when using a hypofractionated radiation schedule. The 5 year overall survival and cause specific survival rates were 42% and 60%, respectively. Slightly better results were reported when using hypofractionation, 50% and 76%, respectively. The reported late side effects for C-ions were 4%. CONCLUSION: The results with charged particles, at least for stage I disease, seem to be promising. A gain can be expected in reduction of late side effects, especially after treatment with C-ions. Available data demonstrate that particle therapy in general is a safe and feasible treatment modality. Although current results are promising, more evidence is required before particle therapy can become internationally the standard treatment for (subsets of) lung cancer patients.     

Recent translational research: antiangiogenic therapy for breast cancer – where do we stand?

The central importance of angiogenesis and our understanding of how new blood vessels are formed have led to the development of novel antiangiogenic therapies. Although the number of agents in development has grown exponentially, only one phase III trial in breast cancer has been completed. In that study the addition of bevacizumab to capecitabine did not extend the progression-free survival of patients with refractory disease as compared with capecitabine monotherapy. Early enthusiasm for antiangiogenic therapy must give way to clinical reality. Our challenge now is to exploit better the activity of antiangiogenic agents seen in the early clinical studies.     

FDG-PET in staging lung cancer: how does it change the algorithm?

BACKGROUND: In patients with lung cancer, positron emission tomography (PET) using fluor-18-fluorodesoxyglucose (FDG) may be used both to detect extrathoracic metastases (ETM) and for mediastinal lymph node staging (MLS), potentially reducing the need for mediastinoscopy. We assessed the added value of FDG-PET in detecting ETM and focused on the reliability of FDG-PET and mediastinoscopy for MLS. PATIENTS AND METHODS: In 72 consecutive patients with non-small cell lung cancer, the impact of adding FDG-PET to full conventional clinical staging was prospectively analyzed. The predictive value of FDG-PET findings and tumor location for pathologic mediastinal lymph node status were assessed in a logistic regression analysis. RESULTS: Unexpected extrathoracic metastases were detected by FDG-PET in 15% of patients. In MLS overall negative and positive predictive values were 71 and 83% for FDG-PET, and 92 and 100% for mediastinoscopy. However, the negative predictive value of FDG-PET was only 17% in case of FDG-PET positive N1 nodes and/or a centrally located primary tumor, whereas it was 96% in case of FDG-PET negative N1 nodes and a non-centrally located primary tumor. CONCLUSION: By incorporating FDG-PET in clinical staging, 15% of patients with lung cancer are upstaged due to unexpected extrathoracic metastases. In case of a negative mediastinal FDG-PET, mediastinoscopy can only be omitted in the presence of a non-centrally located primary tumor and without FDG-PET positive N1 nodes.     

Pancreatic NETs: where do we stand now?

The systemic management of patients with pancreatic neuroendocrine tumors includes chemotherapy and targeted agents such as everolimus and sunitinib. Which treatment to favor in a particular patient is not known. The most commonly used chemotherapy agents are streptozocin and temozolamide, often prescribed in combination with fluoropyrimidines. A potential biomarker for selection of temozolomide-based chemotherapy is O-6-methylguanine-DNA-methyltrasferase expression. Chemotherapy yields higher response rates and may be preferable in patients with higher-grade tumors and those who are symptomatic. The mammalian target of rapamycin inhibitor everolimus has shown improvement in progression-free survival (PFS) in a robust, well-conducted phase III study. Everolimus, however, can induce limiting toxicities that may result in treatment discontinuation and does not improve survival. However, the objective response rate is very low. Sunitinib, likewise, increases PFS but the data comes from a smaller trial which was terminated early. Sunitinib displays a different toxicity profile and is associated with a trend towards improved overall survival. It is clear that biomarkers to properly select the most effective agents in an individual patient are needed.