Pharmacology articles within Nature Reviews Clinical Oncology

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  • Review Article |

    Despite advances in treating multiple myeloma with the proteasome inhibitor bortezomib and the immunomodulatory drugs thalidomide and lenalidomide, most patients eventually relapse. In this Review, the authors discuss how next-generation inhibitors and immunotherapy agents have been developed based on an improved understanding of the biology of the disease, and highlight the challenges associated with these therapeutic approaches.

    • Anuj Mahindra
    • , Jacob Laubach
    •  & Kenneth Anderson

  • Review Article |

    This Review article approaches the area of targeted therapies from two angles: efficacy and side effects. The authors outline the successes that have been achieved in treating cancer with targeted therapies and also discuss the pitfalls and quality of life issues that still need to be addressed.

    • Dorothy M. K. Keefe
    •  & Emma H. Bateman

  • Review Article |

    Despite the advent of HER2-directed therapies, many patients with HER2-positive early stage breast cancer relapse and die of this disease. Trials to define, refine and optimize the use of the approved HER2-targeted agents are ongoing. New approaches are being developed and a series of large trials in the adjuvant and neoadjuvant settings are planned or in progress. In this Review, Arteaga et al. describe the current treatment for HER2-positive breast cancer and provide an update on ongoing clinical trials and translational research.

    • Carlos L. Arteaga
    • , Mark X. Sliwkowski
    •  & Luca Gianni

  • Opinion |

    The use of therapy that is truly targeted to the needs and biological requirements of an individual patient is an aim for many in the oncology field. Jackson and Sood discuss the implications of targeted therapies on patients and the health-care system and discuss methods that might be used to maximize efficiency, cost effectiveness and patient survival.

    • David B. Jackson
    •  & Anil K. Sood

  • News & Views |

    Cancer medicine frequently balances probability of cure against morbidity of treatment. A recent trial in patients with Hodgkin lymphoma compared two regimens of different intensity and toxicity and examined not only the immediate results, but also the broader algorithm of care, factoring in the effects of salvage treatment and high-dose therapy.

    • Sean H. Lim
    •  & Peter W. M. Johnson

  • News & Views |

    Despite the improved progression-free survival and overall survival demonstrated by cisplatin–gemcitabine chemoradiation in a phase III randomized trial in patients with stage IIB to IVA cervical cancer, the acute and chronic toxic effects urge caution before embracing this as a new treatment paradigm.

    • Peter G. Rose

  • Case Study |

    Oral poly(ADP)-ribose polymerase (PARP) inhibitors have been shown to have great promise in the treatment of cancer inBRCA mutation carriers. This case provides evidence that these agents are efficacious in patients with PTEN deficiency but no BRCAmutations, opening up a new patient cohort for this treatment.

    • Martin D. Forster
    • , Konstantin J. Dedes
    •  & L. Rhoda Molife

  • News & Views |

    The treatment of multiple myeloma has evolved rapidly with the use of the immunomodulatory agents thalidomide and lenalidomide as well as the proteasome inhibitor bortezomib. Cavo and colleagues recently reported results of a landmark phase III study comparing thalidomide–dexamethasone with bortezomib–thalidomide–dexamethasone in newly diagnosed multiple myeloma.

    • Jacob Laubach
    • , Paul G. Richardson
    •  & Kenneth Anderson

  • News & Views |

    The recent failure of bevacizumab in the adjuvant setting has forced us to consider what has gone wrong. It is possible that with careful analysis and novel biomarkers, we may not yet have to lay bevacizumab to rest.

    • David J. Kerr
    •  & Annie M. Young

  • Review Article |

    New techniques, such as crystallography and three-dimensional modeling, can be used to assist the development of selective targeted agents for cancer treatment. In this Review, Pierotti and colleagues discuss the molecular features of KIT and PDGFRA receptor tyrosine kinases, which are druggable targets in gastrointestinal stromal tumors. The authors focus on the major challenge in kinase drug discovery—the emergence of resistance—and discuss techniques for predicting and preventing this adverse event.

    • Marco A. Pierotti
    • , Elena Tamborini
    •  & Silvana Pilotti

  • Review Article |

    Many clinical trials of targeted therapies have produced disappointing results, indicating that many challenges must be addressed to advance this field. The authors discuss the importance of novel statistical designs, the need for biopsy sampling in clinical trials and appropriate biomarker identification for improving treatment outcomes.

    • Ignacio I. Wistuba
    • , Juri G. Gelovani
    •  & Roy S. Herbst

  • Review Article |

    The translation of mRNA is a tightly regulated process that is necessary for protein synthesis, and dysregulation of this process is associated with the development and progression of cancers. This Review highlights the components of translation machinery and how alterations in these proteins and their principle upstream signaling pathways can impact on cancer. Drugs that are currently being developed to target the translational machinery are also discussed.

    • Sarah P. Blagden
    •  & Anne E. Willis

  • Review Article |

    The progression-free survival benefits from approved antiangiogenic drugs are modest and are frequently not accompanied by overall survival improvements. Recent disappointing clinical trial results (for example AVANT) have highlighted questions about the basis of drug resistance, the limitations of predictive preclinical models, and whether antiangiogenic therapy may lead to more invasive or metastatic tumor behavior.

    • John M. L. Ebos
    •  & Robert S. Kerbel

  • Review Article |

    For the treatment of early-stage breast cancer, a provocative question is whether some patients can safely be spared chemotherapy? This Review addresses this question by discussing a range of clinicopathological, biomarker and genomic techniques that may help to guide current clinical practice.

    • Philippe L. Bedard
    •  & Fatima Cardoso

  • Opinion |

    A number of biomarkers that predict clinical outcome in response to gemcitabine treatment have been identified. These markers could be used in the clinic to personalize treatment, thereby improving efficacy and reducing adverse effects. The authors of this article describe how treatment can be tailored according to the pharmacogenetics and pharmacokinetics of each patient. In particular, evaluating the status of the liver enzyme cytidine deaminase holds promise as a strategy to optimize therapy.

    • Joseph Ciccolini
    • , Cédric Mercier
    •  & Nicolas André

  • News & Views |

    An important phase III trial involving transplant-eligible patients with multiple myeloma compared bortezomib and dexamethasone (BzD) induction with the previous standard of care. BzD was associated with a higher overall response and a deeper response to therapy that translated to superior responses following high-dose therapy and autologous stem cell transplantation.

    • Jacob Laubach
    •  & Paul Richardson

  • Review Article |

    Selectively targeting cancer stem cells with novel therapeutics is gaining importance because disease recurrence after treatment-induced remissions is a major cause of morbidity and mortality. This Review discusses the pathways that are active during development, specifically the Wnt, Notch, and Hedgehog pathways, and the clinical development of therapeutic agents that target these pathways.

    • Naoko Takebe
    • , Pamela J. Harris
    •  & S. Percy Ivy

  • News & Views |

    A randomized phase III trial of patients with stage II and III colon cancer showed no benefit of adding bevacizumab to standard adjuvant oxaliplatin plus fluorouracil and leucovorin. Despite suggestive evidence of a short-term benefit, these data and other similar findings dictate that adjuvant bevacizumab should not be used in colon cancer.

    • Daniel J. Sargent

  • News & Views |

    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.

    • Sergio Giralt

  • News & Views |

    Ongoing investigation into the use of thalidomide in the treatment of multiple myeloma has demonstrated efficacy as a combination treatment during induction and as maintenance therapy. Thalidomide–doxorubicin–dexamethasone combination therapy improved response rate; however, the development of drug resistance remains a concern.

    • Antonio Palumbo

  • News & Views |

    A phase III trial investigated the efficacy of carboplatin and a taxane with and without cetuximab, a monoclonal antibody against EGFR, in patients with advanced non-small-cell lung cancer. This trial did not reveal an improvement in the primary end point of progression-free survival (according to an independent radiological review committee) with the addition of cetuximab to the carboplatin and taxane regimen. A retrospective investigation of potential biomarkers did not reveal any significant association between these biomarkers and cetuximab efficacy.

    • Thomas E. Stinchcombe
    •  & Mark A. Socinski

  • News & Views |

    Encouraging data have been reported from a randomized, double-blind, phase III trial comparing pazopanib therapy to placebo in treatment-naive and cytokine-refractory patients with advanced renal-cell carcinoma. The challenge that lies ahead is determining where pazopanib fits into the crowded therapeutic algorithms for this disease.

    • Sumanta Kumar Pal
    •  & Robert A. Figlin

  • Review Article |

    The use of azanucleosides has altered the treatment paradigm of myelodysplastic syndromes. Recently, treatment with 5-azacitidine was demonstrated to prolong survival in patients with myelodysplastic syndromes for the first time. This Review discusses the potential of these forms of treatment as monotherapy and in combination, and assesses the most recent clinical data.

    • Alfonso Quintás-Cardama
    • , Fabio P. S. Santos
    •  & Guillermo Garcia-Manero

  • Review Article |

    Metronomic chemotherapy is the chronic administration of chemotherapeutic agents at relatively low, minimally toxic doses, and with no prolonged drug-free breaks. This type of chemotherapy inhibits tumor growth primarily through anti-angiogenic mechanisms. The latest clinical trials of metronomic chemotherapy in adult and pediatric cancer patients are discussed and the authors highlight the research efforts that need to be made to facilitate the optimal development of metronomic chemotherapy in the clinic.

    • Eddy Pasquier
    • , Maria Kavallaris
    •  & Nicolas André

  • News & Views |

    Imatinib 400 mg has been the first-line therapy for chronic myeloid leukemia (CML) since 2001 but may have been licensed at too low a dose. A recent study compared the standard dose with higher doses in patients with newly diagnosed CML and found no difference in response rates at 12 months. But, is the devil in the detail?

    • Jane F. Apperley

  • News & Views |

    Although high-dose methotrexate is widely accepted as the most effective chemotherapeutic agent for primary CNS lymphoma, no optimal dose or dosing strategy has been established. Researchers from the International Extranodal Lymphoma Study Group used clinical trial data to explore whether or not an area under the curve model might be useful to optimize methotrexate dosing. The results strongly suggest that effective methotrexate dose is an important variable in patient outcome.

    • Lauren E. Abrey

  • Case Study |

    A 63-year-old male patient under chronic treatment with sorafenib for an unresectable multifocal hepatocellular carcinoma (HCC) presented with suspected variant angina. Spontaneous spasm occurred during cardiac catheterization and was revealed during coronary angiogram with the unusual feature of a retrograde transient filling of a contralateral branch. Italo Porto and colleagues contend that the effects of sorafenib treatment were primarily responsible for the major cardiovascular event observed in this case, and suggest that clinicians should be aware of this possible severe complication of sorafenib therapy.

    • Italo Porto
    • , Andrea Leo
    •  & Filippo Crea

  • News & Views |

    The addition of zoledronic acid to aromatase inhibitors is associated with improved bone mineral density, but not with an effect on clinically-meaningful end points such as fractures. The oncology community should prioritize the design of trials evaluating more relevant end points, such as fragility fracture risk, for treatment-induced bone loss and critically assess the effects of such treatment on breast cancer survival.

    • Eitan Amir
    • , Alberto Ocaña
    •  & Mark Clemons

  • News & Views |

    Dose-dense administration of paclitaxel as well as intraperitoneal administration of platinum and paclitaxel as first-line treatments provide similar advantages compared with standard treatment in advanced ovarian cancer. Both approaches, however, need to be confirmed by additional studies. A low dose of pegylated liposomal doxorubicin combined with carboplatin is superior to standard paclitaxel and carboplatin in relapsed platinum-sensitive ovarian cancer.

    • Thomas Hogberg

  • Review Article |

    The first generation of anti-cancer agents using novel nanomaterials has successfully entered widespread use and newer nanomaterials are gaining increasing interest as potential multifunctional therapeutic agents. The authors of this Review discuss how the new features of these agents could potentially allow increased cancer selectivity, changes in pharmacokinetics, amplification of cytotoxic effects, and simultaneous imaging capabilities.

    • David A. Scheinberg
    • , Carlos H. Villa
    •  & Michael R. McDevitt

  • News & Views |

    A minority of patients with primary central nervous system lymphoma (PCNSL) achieve a complete response to therapy and most patients have a poor prognosis. A recent randomized phase II trial demonstrated that the addition of high-dose cytarabine to high-dose methotrexate increases the complete response rate and improves patient outcome.

    • Stephen M. Ansell
    •  & S. Vincent Rajkumar

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