ONCOLOGY Vol 24 No 14

The article by Rove et al represents a comprehensive review of the recent clinical advances in the treatment of metastatic, castrate-refractory prostate cancer. The therapeutic armamentarium for the treatment of prostate cancer remains limited compared to other malignancies, such as breast cancer. It took approximately 14 years after mitoxantrone data emerged for us to see the approval of another chemotherapy agent, docetaxel. The successful outcome of recent clinical trials confirms that true advancement in prostate cancer treatment can be achieved by rational and rigorous clinical testing, but participation in prostate cancer clinical trials remains low, especially participation by African-American patients. Research study enrollment should be a high priority for those health care professionals who treat this disease.

Resistance to androgen deprivation is an ominous milestone in the natural history of metastatic prostate cancer:this disease state, now referred to as castration-refractory prostate cancer (CRPC), is historically associated with a median survival of less than two years. Until recently, only docetaxel (in combination with prednisone or estramustine) demonstrated a benefit in overall survival vs comparator therapy with mitoxantrone plus prednisone.[1,2] However, in the past year, compelling data in support of several promising new treatments for CRPC have been reported. The new data offer evidence-based treatment options, but also raise many questions for patient management and future clinical research.

Prostate cancer will be diagnosed in one of six men during their lifetimes, and a small portion of these will progress after primary and salvage therapies. For many years, there were few treatment options for these patients after routine hormonal maneuvers, and standard of care since the early 2000s has consisted primarily of docetaxel, which improved survival over the previous first-line therapy mitoxantrone. In recent years, however, new therapies have begun to emerge to treat this devastating form of prostate cancer. This review examines the mechanisms behind these therapeutics and the key trials seeking to validate their clinical use.

Each year, nearly 60,000 new cases of melanoma are reported in the United States. The vast majority of these are cured by surgery. However, 8,000 of these patients are found to have metastatic melanoma beyond the scope of surgical cure-and this number closely approximates the annual number of deaths from this disease. This statistic illustrates the lack of progress that had been made in the treatment of advanced melanoma over the last several decades.

Currently there are only three FDA-approved drugs available for the treatment of metastatic melanoma: dacarbazine, interleukin-2, and the lesser-used hydroxyurea. None of these drugs has been shown to improve overall survival (OS). The review by Thumar and Kluger provides a well-balanced overview of ipilimumab, the first agent to demonstrate a survival benefit in patients with metastatic melanoma.[1] The response to ipilimumab is most notable for its durability, a feature rarely observed in patients with high tumor burden or in response to other systemic therapies. However, a minority of patients (10% to 15%) treated with ipilimumab meet standard criteria for radiographic response. In this commentary, we focus on the question of how we can build on the success of ipilimumab. We briefly review one area of active investigation: the combination of ipilimumab with targeted inhibitors of BRAF.

Antibody-based targeting of the immune suppressor molecule cytotoxic T-lymphocyte antigen 4 (CTLA-4) with ipilimumab has been studied in metastatic melanoma in a number of clinical trials, including a recent phase III trial. This marks the first randomized clinical trial reporting an overall survival benefit using immune modulation in metastatic melanoma. Along with its therapeutic benefits, ipilimumab presents unique challenges to clinicians; these are related to the monitoring of treatment response and the management of drug-related toxicities. This drug is currently being investigated in various cancers, and its indications are likely to be expanded.

In the era of evidence-based medicine, clinical guidelines, and personalized medicine, one would think that convincing clinical trial data would influence clinical practice if disseminated in an appropriate manner. However, it has been estimated that only 50% of current medical practice is evidence-based, clearly demonstrating a compelling need to collect and analyze additional data to better inform practice. Current data are usually gathered from a variety of sources, including clinical trials, observational studies, and meta-analyses. Yet according to Jeff Forringer, CEO of IntrinsiQ, data from oncology practices provide real-world outcomes that give better insight into the efficacy of cancer therapeutics.

The berries of Lycium barbarum, a perennial plant native to Asia and southeastern Europe, have been used for centuries in traditional Chinese medicine to treat poor vision, anemia, inflammation, and cough. They are also consumed as food and used in soup recipes.

The case of recurrent pancreatic cancer presented in this issue of ONCOLOGY by Dr. Dasari and colleagues illustrates the significant challenges faced by both medical and surgical oncologists in the management of pancreatic adenocarcinoma. This case describes an all-too-common clinical scenario: A thorough preoperative assessment indicating resectable disease, but with the initial medical oncology assessment revealing overt metastatic disease. The development of distant metastases in the short interval between pre-operative and post-operative staging reflects the aggressive underlying biology associated with a subset of patients with this malignancy. New insight into the genetic evolution of pancreas adenocarcinoma from Yachida and colleagues suggests that the latent period between initial development of pancreas adenocarcinoma and development of metastases is measured in years, however detection of the diagnosis at an early stage remains an ongoing challenge for clinicians.[1]

In this issue of ONCOLOGY, the case and discussion provided by Dasari and colleagues highlight a significant problem for many patients with potentially resectable pancreatic cancer (PC)-the rapid emergence of preexisting metastatic disease. The authors describe the case of a 57-year-old woman with a resectable tumor after staging evaluation and management which included an endoscopic ultrasound (EUS), CT imaging, and endoscopic retrograde cholangiopancreatography (ERCP) with insertion of an endobiliary stent. Although the results from EUS are not detailed in the report, there were apparently no preoperative features to suggest more advanced disease, and she underwent surgery. Four weeks later, she presented with advanced disease manifested by an elevated CA 19-9, bilobar liver metastases, and possible local recurrence. This case illustrates some important considerations in the management of PC as we discuss here.

The University of Colorado Denver School of Medicine faculty hold weekly second opinion conferences focusing on cancer cases that represent most major cancer sites. Patients seen for second opinions are evaluated by an oncologic specialist. Their history, pathology, and radiographs are reviewed during the multidisciplinary conference, and then specific recommendations are made. These cases are usually challenging, and these conferences provide an outstanding educational opportunity for staff, fellows, and residents in training.The second opinion conferences include actual cases from genitourinary, lung, melanoma, breast, neurosurgery, gastrointestinal, and medical oncology. On an occasional basis, ONCOLOGY will publish the more interesting case discussions and the resultant recommendations. We would appreciate your feedback; please contact us at second.opinion@uchsc.edu.

This timely manuscript by Bunnell and Shulman highlights critical issues that challenge our ability to provide care to cancer patients in the next 20 years. Each of the concerns the authors identify has a momentum of its own. In combination, they have the makings of a perfect health care storm. The time to further address these matters is now.

There is concern and growing evidence that the supply of medical oncologists in the United States will be insufficient to meet the needs of future patients. With an aging population and increasing complexity of cancer therapies, it is clear there will be more patients and that they will live longer and require expert care. It is equally clear that the number of specialists trained in cancer medicine is not growing fast enough to meet projected needs, so new models of care will need to be designed and implemented. Innovation in practice models will require the integration of non-physician practitioners (nurse practitioners and physician assistants) into multidisciplinary teams, broader use of technology to allow virtual consultations and the secure exchange of vital health information, increased utilization of community services, and public acceptance.

The number of cancer patients and cancer survivors continues to increase rapidly amid predictions of a shortfall in physicians to care for them. In addition, newer cancer therapies have become increasingly complex and resource-intensive, compounding the impending workforce shortage. Simultaneously, the growing understanding of the biologic heterogeneity of cancer and the development of pharmacogenomics have opened up the possibility of personalized approaches to cancer diagnosis and treatment. Such personalization has been promulgated as a means of decreasing the cost of drug development, improving the efficacy of treatments, and reducing treatment toxicity. Although there have been notable successes, the fulfillment of these promises has been inconsistent. Providing care for future cancer patients will require the development of innovative delivery models. Moreover, new approaches to clinical research design, to the assessment of therapeutic value, and to the approval of and reimbursement for diagnostics and treatments are needed.

The authors provide a timely and relevant review of the role that the immune system plays in regulating tumor growth and how immune modulation can alter tumor response. This review follows from the recently published phase III trial of ipilimumab,[1] a monoclonal antibody to cytotoxic T-lymphocyte antigen 4 (CTLA-4) and the first therapy in several decades to produce prolonged overall survival (OS) in patients with metastatic melanoma. While this outcome underscores the importance of this therapy in treating metastatic melanoma, its clinical applicability, at least on a widespread level, necessitates further exploration.