What can we learn from Herceptin trials in metastatic breast cancer?

Herceptin (trastuzumab), an anti-HER2 monoclonal antibody, is the first oncogene-targeted therapy to be developed for the treatment of metastatic breast cancer. The Herceptin clinical trial program has demonstrated that treatment with Herceptin provides substantial clinical benefits when used either as monotherapy or in combination with a number of chemotherapeutic agents. Of note, accurate assessment of HER2 status is essential to ensure that the patients most likely to benefit from Herceptin are identified: patients with immunohistochemistry (IHC) 3+ or fluorescence in-situ hybridization (FISH)-positive disease gain the greatest clinical benefits. In addition, clinical benefits appear to be greater the earlier Herceptin is used, although there is currently no direct clinical evidence to indicate whether an initial strategy of combination therapy is better than monotherapy or vice versa. Herceptin has been shown to be generally well tolerated. The most severe adverse events are rare serious infusion-related reactions and cardiotoxicity. These adverse events can be managed by standard care and patients at risk can often be identified prior to the initiation of Herceptin treatment. Currently, Herceptin should be given until disease progression, but there could be benefit in continuing treatment beyond disease progression.     

What can oncologists learn from HIV?

Developments in HIV-related medicine have significant implications for the practice of oncology. Although HIV is a relatively new discipline within medicine, the identification and therapeutic targeting of HIV has been rapid. Furthermore, political lobbying has sculpted scientific research and patient care. Rational drug design has reduced morbidity and mortality to such an extent that the development of predictive surrogate endpoints has been necessary to enable randomised assessments of new protocols to continue. These studies now include the routine detection of resistance to tailor specific therapies to the patient. The involvement of affected communities in dynamically modelled studies have shown the efficacy of new, preventive strategies and debates about such approaches have improved the standard of care. In this review, we discuss what oncologists can learn from the HIV epidemic.     

What have we learnt from previous phase II trials to help in the management of childhood brain tumours?

Contrary to major advances in cure rates observed for almost all childhood cancers, progress in reducing brain tumour survival rates remains very limited. Although new drug development in oncology is founded on principles outlined in the organised methodology of phase I, II, and III trials, based on rigorous study design using standardised criteria, this approach has been applied very slowly in the field of neuro-oncology. There are multiple explanations for the paucity of well-conducted prospective clinical trials, such as the rarity and the heterogeneity of these tumours, and the reluctance of some investigators to enroll their patients in constraining trials. Data from the past two decades shows that several methodological problems preclude the drawing of any definite conclusions for the majority of drugs assessed. Among them, the necessity of a central neuropathological and neuroradiological review has been highlighted in, at least, two multicentric studies. Changes in histological diagnosis and grade have been reported in a proportion as high as 20%, and changes in response rate in 14% of the cases. This review of phase II trials for brain tumours reveals a wide array of sometimes arbitrary response definitions, that is if response is defined at all, and most series have enrolled small numbers of patients. We report on the different problems encountered in childhood brain tumours in these phase II trials, and their impact on phase III trials.     

What can we learn from geographical comparisons of childhood cancer survival?

With improvements in treatment for childhood cancer, comparisons of survival rates between countries have become important to inform future health policies and treatment strategies. Population-based cancer registry data are viewed as the gold standard for such comparisons, but even these have potential confounding factors. Here, we review the interpretation of recent geographical comparisons of childhood cancer survival from the viewpoint of the British Isles, a region with a 45-year record of national population-based cancer registration and a national childhood cancer clinical trials organisation in place for nearly 30 years. Using national data on referral patterns to tertiary paediatric oncology centres, we explore some of the reasons for lower survival rates in the past for some tumour groups and anticipate continued improvement in the next decade. Participation in international clinical trials coincided with rapid gains in survival for hepatoblastoma. This exemplifies the potential benefits of international collaborative clinical research, particularly for rare subgroups.     

What can we learn from the phenomenon of preferential lymph node metastasis in carcinoma?

Lymph nodes are the most common and earliest site of malignancies arising in epithelia. However, the reason for this pattern of preferential metastasis is not clear. This article reviews features of the metastatic process and lymph node microenvironment which might potentiate lymph node metastases. There is intriguing evidence that preferential lymph node metastasis is due to (1) the efficiency of lymph nodes as filters of the tumor cells which arrive there, and (2) the probability that adhesive interactions, normally governing the generation of different T-cell immune responses, are responsible for this efficiency and may also promote invasion and proliferation of tumor cells in the lymph node. Manipulation of the cytokine environment in a lymph node draining a primary epithelial tumor may alter both the expression of cell adhesion molecules within the node and the subsequent metastatic ability of the tumor cells arriving at it.     

What can we learn from the population incidence of cancer? Armitage and Doll revisited

Most cancers occur with the same characteristic pattern of incidence. The simplicity of this pattern is in contrast to the perceived complexity of carcinogenesis. Therefore, age-onset statistics represent a tempting set of data and have provoked many bold but often misguided conclusions concerning the physiopathological mechanisms of cancer. Half a century has passed since the original multistage theory of Armitage and Doll. Although their basic notion of a healthy cell becoming malignant in several rate-limiting steps is still accepted, prevailing wisdom about the nature and number of these steps has never settled into a consensus. Why have we been unable to elucidate the quantitative dependence of cancer incidence on the molecular processes that feature in its aetiology? In this review we aim to provide answers for this question.     

Why phase II trials in cervical chemoprevention are negative: what have we learned?

Cervical cancer is an important cause of mortality in women worldwide, and the cervix is a well-established clinical, cytologic, and histopathologic model of carcinogenesis. The cervix is easily accessible for examination and biopsy, and colposcopy improves visualization. Identifying chemopreventives in cervical cancer requires rigorous study design: dose de-escalating phase I, IIa trials; placebo-controlled phase IIb trials; and multicenter phase III trials. Reduction in disease incidence and surrogate endpoint biomarkers (SEB) may be trial endpoints. The goal of chemoprevention studies is to prevent or delay the development of cancer. Each agent requires a phase I or IIa trial for each organ site. Phase I, IIa studies of micronutrients, retinoids, -difluoromethylornithine, and indole-3-carbinol have demonstrated response rates of up to 70%, but results of placebo-controlled phase IIb studies have been disappointing and their findings confounded by the high regression rates in placebo-treated patients. Enhancement of research methods, including sufficient enrollment guided by power calculations, uniform biopsy at study entry and exit, and strict progression through trial design phases would ensure valid and reliable results. Because human papillomavirus (HPV) is the major etiologic agent, pretrial laboratory and animal studies should have demonstrated the efficacy of the chemopreventive agent to decrease HPV viral protein expression or HPV tumor induction. SEB modulation must be characterized in any trial's earliest phases before use in phases IIb and III. Lessons learned in chemoprevention will serve as a basis for immunoprevention and vaccine trials.     

What do, can and should we learn from models to evaluate potential anticancer agents?

Transfer of new anticancer agents from bench to clinical trial takes in excess of 10 years and costs up to US $500 million. Despite this massive commitment, many more new agents fail in the clinical trials than are successful. The poor performance of many investigational anticancer agents in the clinic implies that the preclinical models used to evaluate them are flawed, inappropriately used or the information they generate is misinterpreted. This article reviews current practice and the range of preclinical models available. The author provides a personal perspective on what information is needed and how in the future this might best be obtained from preclinical models to more effectively inform the transfer of novel, active agents into clinical practice.     

Treating (low-risk) DCIS patients: What can we learn from real-world cancer registry evidence?

Breast Cancer Research and Treatment - Results from active surveillance trials for ductal carcinoma in situ (DCIS) will not be available for > 10 years. A model based on real-world data...