AUA Summit - Chemotherapy


Racing to Win: Knocking Out Cancer with Chemotherapy

The race to cure cancer has been a marathon physicians and researchers have been running for decades. But, since the advent of chemotherapeutic treatments, more hurdles are being cleared than ever before. For without surgery and effective, though toxic, drugs to stop cancers in their tracks, many cancer victims might not be the survivors they are today.

Hard work and ingenuity from urology's top innovators ensure that patients have many more options for treatment and cure. Thanks to chemotherapy, some urologic cancers—such as testicular, bladder and Wilms tumor—have a remarkably higher rate of cure.

The most striking chemotherapeutic advances-drugs such as cisplatin, bleomycin and etoposide-have made testicular cancer, the most common malignancy in young men, also the most treatable. A few decades ago, if these "germ cell tumors" had metastasized, the patient usually died. But, today's anti-cancer drugs can produce cures even of the far advanced testicular cancer, remissions for prostate cancer and prolonged remissions and cures for bladder cancer patients. In 1910, German bacteriologist Paul Ehrlich gave momentum to selectively targeting toxic chemicals for specific diseases by using salvarsan to treat syphilis. Paving the way for antibacterial drugs, Ehrlich's work also piqued the interest in similar "magic bullets" for cancer. While University of Chicago's Charles B. Huggins (a Nobel laureate), C.V. Hodges and William W. Scott introduced hormone therapy for advanced prostate cancer in 1941, headway on testicular cancer treatment was not made until the 1960s, when actinomycin D became a standard. Some 40 percent to 50 percent of patients responded while 10 percent achieved complete remission.

By the mid-1970s, Melvin L. Samuels, of the University of Texas MD Anderson Cancer Center, capitalized on the synergistic benefits of vinblastine and bleomycin. By combining drugs that interrupted different stages of the cell cycle, Samuels increased the proportion of patients who experienced response and remission.

An important breakthrough came in 1965 when Barnett Rosenberg, a Michigan State University chemist, discovered that platinum analogues inhibited bacterial growth. Out of this research grew cisplatin, a compound that would prove to have anti-tumor effects. Today, cisplatin is an essential ingredient in many of today's chemotherapeutic regimens, including testicular and bladder cancer. It places itself between DNA strands in such a way that rapidly dividing abnormal cells cannot replicate, producing cell death and tumor shrinkage. If shrinkage is great enough, then complete tumor disappearance is possible.

Clinical trials of cisplatin began in the early 1970s, led by Roswell Park's D.J. Higby and H.J. Wallace, who observed responses in testicular cancer. Memorial Sloan-Kettering's Robert B. Golbey and Indiana University's Lawrence H. Einhornconfirmed the drug's potency against testicular cancer. The biggest breakthrough came when Einhorn and John P. Donohue reported in 1977 that the combination of cisplatin, vinblastine and bleomycin together with surgery after chemotherapy could achieve complete remissions in up to 85 percent of patients.

For patients with a durable complete remission, doctors could eventually "cure" 70 to 80 percent of testicular cancer patients. Urologists had more varied success with other cancers. Memorial Sloan Kettering Cancer Center's Alan Yagoda led the research in the 1970s and 1980s to develop a combination therapy-methotrexate vinblastine, Adriamycin and cisplastin (MVAC)—that would result in two-thirds of bladder cancer patients achieving remission. Other scientists confirmed that MVAC could shrink bladder cancer, permitting surgical or radiological interventions. This treatment plan generally produced short-term results, since only 10 percent of bladder cancer patients were disease-free after five years.

During the 1980-90s, less-toxic but equally effective drugs were studied. For testicular cancer, etoposide replaced vinblastine. Based on work at Indiana University and Memorial Sloan-Kettering, the regimen prescribed most often for testicular cancer today is etoposide and cisplatin with or without bleomycin. For bladder cancer, gemcitabine + cisplatin was shown to be as effective as MVAC. Androgen-blocking Casodex and flutamide are now keystones in alleviating the symptoms of metastatic prostate cancer, and chemotherapeutic combinations are showing early promise in hormone-resistant disease.

One of the most revolutionary advances in cancer therapy has been so called 'targeted' approaches where specific cancer genes, and the proteins they make, can be the targets of drug therapy, potentially sparing healthy tissues that don't express the genes. The use of imatinib or Gleevec for certain lymphomas that expressed the gene abl or c-kit. The drug heralded the use of other agents and soon Dr. James Yang and Steven Rosenberg of the NIH led a major study that first showed that kidney cancers could be treated with Avastin, an inhibitor of a gene product that is abnormal in tumors expressing VHL. The preliminary success of Avastin changed the paradigm of the treatment of metastatic kidney cancers creating a monumental groundshift in the way these potentially lethal tumors may be controlled. Drugs like sunitinib and evirolimus are commonly used to slow the progression of advanced kidney tumors which previously had been untreatable.

Targeted therapy now plays a role in almost all cancers, including prostate tumors, the most common solid organ tumor in non-smoking men. Agents such as Xtandi, enzalutamide, abiraterone, and Xofigo promise the newest approaches to advancing the quality of life in advanced prostate cancer since the use of hormone deprivation more than a half century ago.

With neural networking arrays and ‘big data' computational genetics, the horizon now includes ‘personalized' approaches to urologic cancer whereby a patient's tumor's specific ‘fingerprint' can be used to empower prediction and prognosis like never before and potentially create agents that specifically attack that patient's tumor. Meticulous clinical trials that combine the expertise and variety of a broad range of scientists, patients, and stakeholders are the only way to improve today's standard of care. Though it will take great endurance to finish this research race, the win will be worth the effort.

Rainer Engel, MD
John Phillips, MD