Reviews on Recent Clinical Trials - Volume 4, Issue 2, 2009

The Gynecologic Oncology Group (GOG) has conducted multiple trials related to neoplasms of the uterine corpus. Recently, several of these trials have been presented and/or published. Areas of focus included the feasibility of laparoscopic staging for endometrial cancer, the adjuvant management of locally advanced endometrial cancer, whole abdominal irradiation in maximally resected advanced endometrial carcinoma, and combination chemotherapy regimens for stage I and II carcinosarcoma after primary surgery and for advanced or recurrent carcinosarcoma. This article will discuss the background and details of each of these important advances.

The potential for angiotensin II (AII) to promote tumor growth has been suspected based on its known hormonal actions and its vasoconstrictor effect. It has been suggested that angiotensin-converting enzyme (ACE) inhibitors may offer protection against cancer and may prevent carcinogenesis. Several studies report that AII can induce neovascularization in experimental systems by way of the AII type 1 receptor (AT1R). AT1R is also frequently expressed in such human tumors as skin cancer, renal cell carcinoma, and breast cancer. A growing number of recent studies focusing on treatment with an AT1R antagonist have demonstrated that angiotensin receptor blockade (ARB) appears to inhibit not only the growth of cancer cells but also tumor angiogenesis. We describe here the effects of AT1R blockade that implicate tumor angiogenesis in urogenital cancer since ARB may be an alternative modality for anti-cancer treatment.

Flawed evaluation of clinical trial quality allows flawed trials to thrive (get funded, obtain IRB approval, get published, serve as the basis of regulatory approval, and set policy). A reasonable evaluation of clinical trial quality must recognize that any one of a large number of potential biases could by itself completely invalidate the trial results. In addition, clever new ways to distort trial results toward a favored outcome may be devised at any time. Finally, the vested financial and other interests of those conducting the experiments and publishing the reports must cast suspicion on any inadequately reported aspect of clinical trial quality. Putting these ideas together, we see that an adequate evaluation of clinical quality would need to enumerate all known biases, update this list periodically, score the trial with regard to each potential bias on a scale of 0% to 100%, offer partial credit for only that which can be substantiated, and then multiply (not add) the component scores to obtain an overall score between 0% and 100%. We will demonstrate that current evaluations fall well short of these ideals.

Chronic obstructive pulmonary disease (COPD) is an inflammatory disease of the lungs in which airways inflammation related mainly to smoking causes progressive airflow obstruction and chronic respiratory symptoms such as dyspnea or cough. COPD therapy in stable state is mainly inhalatory with bronchodilators and inhaled corticosteroids and the regimen depends on disease severity. Inhaled bronchodilators are the mainstay of maintenance therapy in COPD whether given alone or added to other inhaled medications. Current therapeutic guidelines are based on data from studies assessing long-term impact of such therapies on outcome measures such as lung function, survival, exacerbations or health-related quality of life (HRQoL). This is a review discussing the data regarding to inhaled bronchodilators with a focus on a long-acting anticholinergic, tiotropium bromide.

Bisphosphonate osteonecrosis (BON) is a relatively recent adverse drug event that affects the oral cavity almost exclusively. It has been reported in individuals with metastatic breast, prostate, and lung cancer as well as in multiple myeloma. It has also been reported in a small subset of individuals who have been treated with bisphosphonate therapy for osteoporosis and Paget's disease of bone. Published studies to date have been characterized by relatively small sample sizes. Based on these studies, incidence appears to range between 0.1% and 11% depending on the population being studied and a number of other co-factors that have not been completely understood. The pathobiology of BON has not been fully elucidated and risk factors involved in the process need confirmation. Patients with this complication have altered quality of life and can suffer from discomfort and pain. Management is difficult and, while many treatment protocols have been proposed, at best they have only had partial success. This review of literature discusses a number of issues involving BON, with focus on the definition, possible association of BON and bisphosphonate therapy, pathobiology of BON and several additional research questions that need further investigation.

Chemoradiation is the major treatment option in unresectable, locally advanced non-small cell lung cancer. Many clinical trials have evaluated the efficacy of different combinations of chemotherapy and radiotherapy in this heterogeneous patient population. Early clinical trials showed a survival advantage of sequential chemo-RT compared to radiation alone. Subsequent trials demonstrated that concurrent chemo-RT improved survival over sequential chemo-RT. More recent studies have suggested that there is no advantage to adding induction chemotherapy prior to concurrent chemo-RT, or to adding consolidation chemotherapy after concurrent chemo-RT. Various clinical trials have used different chemotherapy regimens, though there is still no consensus about those which are most effective. Additionally, different radiotherapeutic strategies have included hyperfractionation vs. standard fractionation, use of 3-dimensional techniques, and altering total radiation dose. As these methods are being perfected, much attention has turned toward the use of molecularly targeted therapies. This review summarizes recent clinical trials examining the role of chemo-RT in locally advanced non-small cell lung cancer and the movement toward personalized medicine.

Oral bisphosphonate dosing schedules have evolved from the original daily regimens to weekly (alendronate and risedronate) and monthly (risedronate and ibandronate) regimens. Intravenous (i.v.) bisphosphonates are administered less frequently—quarterly ibandronate injection and yearly zoledronic acid i.v. infusion. Comparative fracture efficacy among BP options is increasingly a focus of debate. The approved daily oral BPs and annual zoledronic acid infusion demonstrated vertebral fracture prevention in clinical trials; however, nonvertebral fracture prevention results varied. Nondaily regimens of licensed agents (except for zoledronic acid) were approved via “bridging trials”, which compared changes in bone mineral density and bone turnover markers with the approved daily regimen and generally collected fractures as adverse events. Head-to-head antifracture efficacy trials directly comparing available BPs are unlikely because the required sample sizes, durations and costs would be prohibitively large. Observational studies and the concept of annual cumulative exposure, used recently to evaluate the efficacy of nondaily ibandronate regimens, provide alternative methods to compare BP efficacy. At this time, the available trial and meta-analysis evidence supports effective reduction of vertebral fractures and NVFs with all approved BP regimens. This article presents a comprehensive review of the key efficacy data for currently available BPs, including their nondaily regimens, to assist clinicians in assessing treatment options for NVF prevention.

Management of hematological malignancies (HM) during pregnancy remains unsolved. Presence of adverse events in mother and child: spontaneous abortion, stillborn, premature, low-weight and congenital abnormalities have been attributed to the use of chemotherapy, especially during first trimester. We reviewed the English and Spanish literature of reports which documented the use of chemotherapy for HM during pregnancy, in order to evaluate the association of adverse events in mother and the fetus. We reviewed 1395 cases of this association, although adverse events was more frequent that did not complicate pregnancy, other causes such as concomitant illness or maternal complications and use of other potentially toxic drugs during pregnancy had not been considered. No clear differences was observed if chemotherapy were administered during 1° or 2° and 3° trimester of pregnancy. Longer follow-up was not available in most reports. We cannot confirm the presence of late toxicity secondary to chemotherapy and radiotherapy, because data are not available. We conclude that the use of chemotherapy can be safely administered during 2° and 3° trimester. Taking into consideration the dates of these brief reports no appear that the use of chemotherapy during first trimester could be dangerous to mother and fetus. It is necessary to consolidate all dates of this association to come to definitive conclusions.