Reviews & Analysis

The ZODIAC trial reported that the addition of vandetanib to docetaxel in second-line treatment of unselected patients with metastatic non-small-cell lung cancer resulted in a statistically significant improvement in progression-free survival compared with docetaxel alone. Identification of biomarkers to assist in molecular selection of patients for targeted therapy is a tool for 'smart' clinical trial design.

A clinical trial of patients with pharmacogenomically selected non-small-cell lung cancer clearly demonstrated an improvement in progression-free survival after gefitinib treatment compared with standard chemotherapy. This report is the first to suggest that personalized therapy based on pharmacogenomics could be standardized in the treatment of lung cancer.

Image-guided core biopsy (IGCB) of the peritoneum and omentum is a minimally invasive, safe and accurate diagnostic tool for patients with suspected malignancy. With the use of either ultrasound or CT guidance, this technique provides sufficient material to enable assessment of specific cancer subtypes, distinguish recurrence from a new disease process, and inform prognosis. In this Review, the authors discuss IGCB and its clinical applications, and critically examine available alternatives.

TheTP53gene is mutated in 50% of reported cancer cases and the p53 pathway is often partially inactivated in the remaining 50%. Clinical trials assessing agents that exploit the p53 system are ongoing. This Review discusses the mechanism of action of these treatments and the future of p53-based therapy.

Adjuvant assessment tools for prognosis and prediction of treatment benefit in breast cancer aid clinical decision making; however, all these tools have limitations. For an individual diagnosed with early-stage breast cancer, recommendation of systemic therapy and selecting the most appropriate agent remains a challenge. The authors highlight the issues in choosing the most appropriate adjuvant therapy and provide some suggestions for how current assessment tools can be used to tailor treatment.

Genetic testing for breast cancer susceptibility is widely available in North America and in Europe. The optimum treatment of women with breast (or ovarian) cancer and aBRCA1 or BRCA2 mutation may be different from that of non-carriers. Thus, identifying the BRCAmutation status in patients could assist appropriate decision making for individualized cancer prevention, screening and treatment.

Chronic lymphocytic leukemia (CLL) can present as an acute leukemia that is aggressive and life threatening or in an indolent form that will not require treatment over decades. A number of methods are available to clinicians for the prediction of disease progression and survival on an individual basis, including clinical staging systems and a plethora of novel molecular and biological factors that correlate with the outcome of CLL. This Review provides a concise discussion of the most important discoveries and gives guidance on how to implement novel prognostic tools in the clinical management of CLL by applying the criteria of evidence, relevance, and simplicity to the selection of prognostic markers.

Circulating tumor cells (CTCs) have a crucial role in the metastatic cascade, tumor dissemination and progression. Furthermore, CTCs are involved in treatment failure, therapy resistance and disease progression. New therapeutic possibilities are offered by the established clinical prognostic and predictive value of CTCs with the additional possibility of using them for the real-time monitoring of systemic-therapy efficacy. This Review discusses the future clinical applications of CTCs in breast cancer including the incorporation of CTCs as end points in clinical trials and the blockade of tumor dissemination and self seeding via the therapeutic targeting of CTCs.

Synthetic lethality has emerged as a novel approach to treat cancer. Inhibitors of poly (ADP-ribose) polymerase, a target that has synthetic lethality withBRCAmutations, have already shown promise in clinical trials. The authors of this Review describe the clinical application of synthetic lethality for patients with breast cancer, and discuss biomarkers that can be used to select patients who will respond to this therapy. Other potential genes that could be involved in synthetic lethality, and are thus new targets, are also explored.

Radio-embolization using radioactive microspheres allows the delivery of high-dose internal radiotherapy to malignant tumors of the liver. The surrogate for measuring flow dynamics for radio-embolization planning does not best represent treatment efficacy. Therefore, Morgan et al. propose that imaging protocols sensitive to changes in vasculature are likely to represent useful predictive markers of malignant lesions that could benefit from radio-embolization.

The efficacy of nilotinib and dasatinib as frontline treatment of chronic myeloid leukemia has been documented in small phase II studies. Now, two clinical trials have assessed the effectiveness of second-generation tyrosine kinase inhibitors in comparison with standard dose imatinib at 1 year. Will these results change our current practice?

A randomized phase III trial that assessed treatment with cisplatin plus gemcitabine or gemcitabine alone for patients with advanced biliary tract cancer has provided evidence for a new standard treatment option for these patients. The therapeutic outcome (that is, overall survival, disease-free survival, and disease control rate), was significantly better in the combination arm with no increase in toxic effects.

Doublet fluoropyrimidine-based chemotherapy is the standard of care for the first-line treatment of metastatic colorectal cancer (mCRC). However, single fluoropyrimidine-based therapy remains an important alternative. In this article, we highlight the potential impact of a recent trial assessing the addition of bevacizumab to capecitabine in the first-line treatment of mCRC.

Adjuvant vaginal brachytherapy was compared with adjuvant pelvic radiation therapy in patients with high-intermediate-risk uterine cancers in the PORTEC-2 trial. The results suggest that vaginal brachytherapy is the treatment of choice; however, the inclusion of very few patients with grade 2 or 3 disease limits generalizability of the results to these subgroups.

Ovarian cancer that recurs more than 6 months following primary chemotherapy can respond to many different drugs, but retreatment with a combination of carboplatin and paclitaxel has become a standard of care. A combination of pegylated liposomal doxorubicin and carboplatin may provide a slightly, but significantly, greater therapeutic index than carboplatin and paclitaxel.

Triple-negative breast cancer tumors relapse more frequently in spite of good initial response to chemotherapy, and have a worse prognosis than hormone receptor-positive, luminal subtypes. New systemic therapies are urgently needed because hormonal therapies and HER2-targeted agents are ineffective in this group of tumors. Poly (ADP-ribose) polymerase inhibitors, angiogenesis inhibitors, EGFR-targeted agents, and src kinase and mTOR inhibitors are among the therapeutic agents being actively investigated in clinical trials in these patients.

This article reviews resistance to chemotherapy in metastatic castration-resistant prostate cancer (CRPC), which is a result of mechanisms of resistance specific to prostate cancer and to general mechanisms common to different cancer types. New therapies targeting these mechanisms are outlined and their potential impact in future and ongoing clinical trials is discussed. Knowledge of the mechanisms of drug resistance offers great hope for future effective therapy; however, drug resistance in metastatic CRPC is multifactorial and complex and the development of new medical therapies remains challenging.

Nanotechnology offers great promise for the detection, prevention and treatment of cancer. Current limitations of this technology include the heterogeneous distribution of nanoparticles to tumors, caused in part by the physiological barriers presented by the abnormal tumor vasculature and interstitial matrix. This Review discusses these barriers and summarizes strategies that have been developed to overcome them. It additionally examines design considerations for the optimization of delivery of nanoparticles to tumors.

A study by Atkin and coauthors has demonstrated reduced mortality by screening average-risk patients with a single use of flexible sigmoidoscopy for colorectal cancer. This large UK trial of 170,432 subjects aged 55–64 years (median 60.2 years) randomized patients 2:1 to control or single flexible sigmoidoscopy. Reduction in colorectal cancer incidence was 23% and cancer mortality was reduced by 31% in the intention-to-treat population. In this News & Views article we discuss the role of flexible sigmoidoscopy in population-based screening for colorectal cancer.

Palumbo and coauthors report on the results of a randomized trial comparing two doses of melphalan in patients with symptomatic multiple myeloma. Overall complete response rates, median progression-free survival and projected 5-year overall survival were significantly higher among patients receiving the higher melphalan dose. These results confirm that for this patient population melphalan 200 mg/m² should remain the gold standard conditioning regimen.