Profiles in Cancer Research
Dr. Robert Motzer
Attending Physician, Genitourinary Oncology Service, Memorial Sloan-Kettering Cancer Center, and Professor of Medicine, Weill Medical College, Cornell University
In the 20 years since he became the first oncologist at Memorial Sloan-Kettering Cancer Center (MSKCC) to focus on advanced kidney cancer, Dr. Robert Motzer has led more than 50 clinical trials in patients with the disease and in men who have testicular cancer. He has published more than 300 papers in the medical literature, and his research has contributed to the development of three of the four targeted drugs (sorafenib, sunitinib, temsirolimus, and everolimus) that within the past 5 years have begun to transform metastatic kidney cancer from a lethal malignancy to a chronic disease.
The decision to pursue a career as an oncologist and clinical researcher came to Dr. Motzer on his first day of oncology rounds as a medical student at the University of Michigan in the late 1970s.
“I was struck by the extent of the unmet need cancer patients had for effective treatment,” he recalled. Nowhere was the inadequacy of treatment more evident to him than in kidney cancer. “Kidney cancer was considered to be about the worst from the standpoint of treatment futility,” he said. Kidney tumors were notoriously resistant to both chemotherapy and radiation therapy. Although early stage renal cancer could sometimes be cured by surgery, a diagnosis of advanced kidney cancer generally meant a life expectancy of a year or 2 at most.
From the mid-1980s until 2005, standard therapy for metastatic kidney cancer consisted of the biologic agents interferon alpha and interleukin-2 (IL-2). Results from trials of these agents were inconsistent, however, and the absence of reliable criteria for evaluating patients’ prognosis made it difficult to compare trial findings. “I thought a standard prognostic system would help us to compare outcomes across different centers, so that when an effective drug came along, we would have a baseline for assessing its effect,” Dr. Motzer explained.
He established a database of 670 patients with newly diagnosed metastatic kidney cancer who had been treated with interferon in MSKCC clinical trials. Working with MSKCC biostatisticians, he then identified five risk factors that correlated with overall survival in this patient population. Patients with none of these risk factors survived the longest and were thus considered a favorable-risk group. Patients with one or two risk factors survived a shorter time and constituted an intermediate-risk group, whereas those with three or more risk factors had the poorest survival and represented a poor-risk group.
Subsequent analyses have shown that these risk classifications accurately predict survival in other subgroups of patients with advanced kidney cancer. Known as the MSKCC risk system, or informally as the “Motzer criteria,” these factors have been independently validated and are now widely used as standard criteria both in selecting patients for participation in clinical trials and in recommending treatment options to patients not enrolled in trials.
“The Motzer criteria have provided clinical investigators with an extremely useful quantitative measure both for identifying patients who are most appropriate for clinical trials in metastatic kidney cancer and for evaluating the effectiveness of the targeted agents being studied in those trials,” said Dr. W. Marston Linehan, chief of the Urologic Oncology Branch in NCI’s Center for Cancer Research.
In his latest project, Dr. Motzer is trying to determine the optimal way of sequencing therapy for advanced kidney cancer with the multiple drugs that are available. “The limitations of these agents have been that complete remissions are uncommon and most patients’ disease does progress at some point,” he said. “However, we are in a situation similar to that of colon and breast cancer, where patients can be treated sequentially with different agents.”
He is a principal investigator for two international phase III trials of promising second-generation targeted agents, axitinib and pazopanib, as well as for a study to identify the molecular characteristics of tumors that respond to treatment with sunitinib. “If we understand the underlying biology of the pattern of response, we can begin to individualize treatment,” he said. “The goal is to identify which agent is the right one for each patient.”
In addition to his work on advanced kidney cancer, Dr. Motzer participates in trials aimed at improving therapy for difficult-to-treat germ cell tumors. These trials have helped to establish the value of adding paclitaxel to multi-drug chemotherapy for this disease and have also shown that high-dose chemotherapy followed by stem-cell rescue did not improve treatment outcomes compared with conventional-dose chemotherapy in patients with poor-risk metastatic germ-cell tumors.
After toiling for 2 decades in a relative backwater of cancer research, Dr. Motzer said that he is gratified to see kidney cancer finally getting some attention as a result of recent treatment breakthroughs.
“When I entered this field, kidney cancer was not considered a rewarding area in which to work. But the success of these new agents has brought a lot of attention to kidney cancer,” he said. “That’s bringing more researchers into the field and has resulted in more patients being referred to medical oncologists for clinical trials. I am hopeful that these developments will help to bring further advances in kidney cancer treatment to the clinic in the near future.”