Commentary By: Theresa Ryan, M.D. Assistant Professor, Division of Oncology
During the first five days in June, the American Society of Clinical Oncology met in Chicago for their 43rd annual meeting. The theme of this meeting was “Translating Research into Practice,” emphasizing the society’s goal of enhancing patient care by creating a forum wherein the latest advances in translational and clinical cancer research are presented in the context of our current understanding of cancer biology. Many abstracts presented will lay the groundwork for further research. A number will likely have immediate impact. While I can not do justice to the scope of the meeting, I have highlighted a few of the presentations that I believe will have the greatest immediate impact on the practice of oncology as well as outline challenges for the future.
Abstract #1: “Randomized phase III trial of Sorafenib vs. placebo in patients with advanced hepatocellular carcinoma.” Results of the SHARP trial.
Importance: HCC is the 3rd cause of cancer death globally. HCC is expected to rise in incidence in the West. No standard therapy exists for advanced HCC.
Background: Sorafenib is a orally bioavailable multikinase inhibitor with anti-angiogenic, pro-apoptotic and Raf kinase inhibitory activity,
The Trial: A large, multicenter, randomized, placebo-controlled phase III trial evaluated the efficacy and safety of Sorafenib vs. placebo. This trial was stopped early as it met it pre-defined early stopping criteria. The HR for overall survival was 0.69 (95% CI: 0.55, 0.87; p=0.0006), representing a 44% improvement in overall survival vs. placebo. Median overall survival was 10.7 vs. 7.9 mos. Most frequent toxicities were diarrhea, hand-foot skin reaction, fatigue, and bleeding. The conclusions of the authors were that Sorafenib was well tolerated and is the first agent to demonstrate a statistically significant improvement in overall survival for patients with advanced HCC. This effect is clinically meaningful and establishes sorafenib as first-line treatment for these pts.
The editorial: While the improvement in overall survival is probably one only an oncologist could become excited about; this truly does represent a significant advance in our understanding and treatment of HCC. Traditional chemotherapy agents are essentially ineffective. This trial combined with the encouraging positive results of other (smaller) trials employing an “anti-angiogenic” strategy (bevacuzimab, sunitinib) provides a rationale upon which to develop future trials in HCC.
Abstract #2: “A randomized, controlled, double-blind phase III study of bevacuzumab/a-IFN vs. placebo/a-IFN as first line therapy in metastatic renal cell carcinoma.
Importance: Approximately 60% of clear cell RCCs are associated with mutation of the von Hippel-Lindau gene, with subsequent up regulation of hypoxia inducible factor (HIF) which regulates a variety of genes involved in tumor proliferation, angiogenesis and progression.
Background: Bevacizumab is a monoclonal antibody that inhibits tumor angiogenesis by targeting VEGF.
The Trial: A phase III trial was conducted to evaluate the efficacy and safety of bevacuzimab in combination with a-IFN revealed a significantly increased PFS (10.2 vs. 5.4 mo) (HR=0.63; p<0.0001) and objective tumor response rate (30.6% vs. 12.4%; p<0.0001). No unexpected safety events were observed.
The editorial: Since December 2005, three targeted agents have been approved by the FDA for the treatment of advanced RCC: sorafenib, sunitinib and temsirolimus. Like, HCC until recently there was NO standard therapy for advanced RCC. This trial again confirms an anti-angiogenic strategy based on extensive pre-clinical rationale as fruitful in the treatment of RCC. Important questions remain including studying the combination and sequencing of agents, defining mechanisms of resistance, exploring the utility of repeat treatment and investigating biomarkers that will help identify those patients which will most benefit from a specific agent.
Abstract #3 A randomized trial of prophylactic cranial irradiation (PCI) vs. no PCI in extensive small cell lung cancer after response to chemotherapy.
Importance: Development of brain metastases is often accompanied by deterioration of physical and psychological functioning, response to therapy is poor; major impact on quality of life.
Background: PCI significantly reduces the risk of brain metastases and improves survival in patients with limited stage small cell lung cancer.
The trial: Patients with confirmed extensive SCLC and any response to 4-6 cycles of chemotherapy were randomized to receive PCI or no PCI. PCI significantly reduced the risk of symptomatic brain metastases (P<0.0001, HR=0.27, CI: 0.16-0.44). The 1-yr cumulative incidence of symptomatic BM was 14.6% on PCI vs. 40.4%. PCI had no impact on extra-cranial progression rates but it significantly prolonged progression-free survival time (P=0.0218, HR=0.76, CI: 0.59-0.96) and overall survival (P=0.0033, HR=0.68, CI: 0.52-0.88). The 1-year survival rate was 27.1% for the PCI and 13.3% for the control arm. The authors concluded that as PCI significantly reduces the risk of symptomatic brain metastases, and significantly improves both disease-free and overall survival in patients with ED SCLC. PCI should be offered to all ED patients showing a response to initial chemotherapy.
The editorial: Even without the (surprising) improvement in overall survival, the magnitude of reduction in the risk of symptomatic brain metastases for patients with extensive stage small cell lung cancer makes PCI a new “standard” of care.
There are two other topics that will have a much broader and sustained impact on the practice of oncology and society in general for the near future.
First were the results of the landmark Oncology Workforce Study published in the March 2007 issue of the Journal of Oncology Practice. This study projected that during the next decade, when an increasing proportion of the U.S. population will need access to oncology services, the availability of such services is expected to dwindle. In fact the study projected a shortage of 2550-4080 oncologists by the year 2020. Options to help close that gap include increasing the number of oncology fellowship positions, increasing use of nonphysician clinicians, increasing the role of primary care physicians in the care of patients in remission and redesigning service delivery.
The second is that if current trends continue, by the year 2020, 10.3 million people could die from cancer each year. Nearly three-quarters of those individuals will reside in developing countries. During the plenary session, the keynote speaker Nancy Brinker a cancer activist and founder of the Susan G Komen for the Cure Foundation, described this as an “oncoming tsunami” that will overwhelm the medical system of developing countries. With the ever increasing expense of the treatment of cancer, prevention will need to play an even greater role.