Novel treatments for recurrent prostate cancer

Most men who are diagnosed with prostate cancer and who undergo curative treatment will not have a biochemical recurrence of the disease. A considerable number of men, however, will notice a rise in prostate-specific antigen (PSA) following primary treatment, suggesting a treatment failure and a recurrence of the disease.

Lance A. Mynderse, M.D., a urologist at Mayo Clinic in Rochester, Minn., explains that regardless of the type of treatment a patient undergoes, whether radiation, cryoablation or surgical removal of the prostate, the rate of primary treatment failure is significant. Historical data mined from the Mayo Clinic prostatectomy registry of more than 20,000 men indicates 26 to 30 percent of men who have the procedure will have a rise in their PSA following surgery, ultimately indicating a biochemical recurrence of the disease. The percent is even higher for those who undergo radiation. "Because of the wide variety of protocols for patients undergoing radiation, the number of patients who experience a biochemical recurrence of the disease is higher and more variable — between 38 and 50 percent," says Dr. Mynderse.

For patients who experience a recurrence, traditional treatment options have been historically limited to either radiation or hormonal therapy. Mayo Clinic urologists, however, offer patients advanced clinical options, including novel treatments specifically for recurrent prostate cancer. A multidisciplinary team of radiologists, oncologists, cancer researchers, pathologists and surgeons is dedicated to specifically meeting the needs of this growing patient population.

At the heart of this approach is a prostate cancer clinic, headed by urologist and cancer researcher Eugene D. Kwon, M.D., of Mayo Clinic in Rochester. The clinic is designed specifically to evaluate suspected recurrences of the disease, and to ensure that those patients have the opportunity to take part in any appropriate novel treatment. "This clinic is set up for the patient whose cancer has metastasized or not. We are offering something more than what has been done for years for these patients, whether it is a clinical trial, a novel application of radiation, a novel application of ablative technology or state-of-the-art imaging," says R. Jeffrey Karnes, M.D., another Mayo Clinic urologist in Rochester.

Imaging — early detection of the recurrence

When prostate cancer does recur, Mayo Clinic urologists utilize imaging modalities to detect the disease at its earliest stage — even at very low PSA levels — as low as < 0.58 ng/mL. "Imaging capabilities are often unable to detect the disease in patients with low PSAs, even in centers that have a lot of expertise in imaging modalities. It requires building a program that really does tell you a lot more with the imaging," says Dr. Mynderse.

Because of its high level of sensitivity, endorectal coil magnetic resonance imaging (MRI) can often identify cases of local recurrence, allowing for the precise pinpointing of the suspected area to be biopsied. This imaging modality is used in the evaluation of biochemical recurrence to help guide prostatic fossa biopsies under transrectal ultrasound (TRUS), thus identifying patients suitable for localized salvage therapy. The MRI followed by the biopsy allows for the early detection of prostate cancer recurrence, a cancer that is often not detected with typical imaging modalities.

In a Mayo Clinic study, Dr. Mynderse and his colleagues Brian J. Linder, M.D., and Akira Kawashima, M.D., Ph.D., in Rochester, studied 188 patients with a biochemical prostate cancer recurrence following radical prostatectomy. These patients underwent endorectal coil MRI with dynamic gadolinium-contrast enhancement to determine the possible recurrence of prostate cancer in the surgical bed. The MRI followed by TRUS-guided biopsy of the prostatic fossa confirmed local recurrence in 138 of the 188 patients. Dr. Mynderse explains further, "Use of the MRI to start and then the biopsy technique, which proves the spot on the MRI, are critical parts of finding the cancer recurrence." He explains that the technology also enables clinicians to look at the lymph nodes in and around the rectum, a potential hiding place that is very hard to detect with other types of imaging.

For those patients whose next treatment course requires radiation, use of the endorectal coil MRI followed by TRUS-guided biopsy provides Mayo Clinic radiologists with a valuable tool. Putting markers at the site of the positive biopsy allows the radiation oncologist to pinpoint the radiation and design specific targeted treatment. Dr. Mynderse explains that when the tumor can be identified and located, large regions do not have to be radiated. "If we can tell the clinician precisely where the tumor is with this imaging, he or she has a better target on which to focus the radiation," he emphasizes.

Immunotherapy

Dr. Kwon, a Mayo Clinic urologist and cancer researcher, is a pioneer in prostate tumor cell immunotherapy studies. Along with his laboratory colleagues, he is tackling recurrent prostate cancer with immunotherapy. Development of a two-step immunotherapy for prostate cancer provides a treatment option previously unavailable to men with widespread disease or inoperable prostate cancers. Dr. Kwon is optimistic that a two-step approach — a combination of hormonal and anti-cytotoxic T lymphocyte-associated antigen (CTLA) treatment strategies — will provoke a stronger, more focused immune response against prostate tumors. Step one in this two-step immunotherapy approach begins with hormone therapy to initiate an immune response that activates T cells and guides them to the tumor site. In the second step, the T cell fighting capability is prolonged by using the anti-CTLA-2 antibody. The anti-CTLA-4 antibody works by blocking the T-cell off-switch receptor.

Two developments in Dr. Kwon's research lab led to the development of the two-step immunotherapy:

  • A new mouse model that spontaneously develops prostate cancer provided a deepened understanding of how to use the immune system to destroy tumor cells
  • One of Dr. Kwon's collaborators identified new strategies for activating T cells, a central component to his research

Dr. Kwon explains that T cells can recognize and kill tumor cells. So when the T cell is manipulated appropriately, it can find and destroy the prostate tumor without destroying other normal cells in the body. Researchers also discovered that T cells are self-regulating. Once activated, they make receptors that work as off-switches to stop the attack.

C-11 choline imaging

"C-11 choline positron emission tomography and computerized tomography (PET-CT) scans are a more advanced way in which Mayo Clinic clinicians are better able to detect the recurrence of the disease beyond the capabilities of conventional imaging," explains Dr. Karnes. Mayo Clinic is the only medical center in North America that is able to use the C-11 choline PET-CT scans to detect the recurrence of prostate cancer.

In two retrospective studies of prostate cancer patients at Mayo Clinic who underwent C-11 choline PET-CT imaging between September 2007 and November 2010, Dr. Karnes validated the use of the C-11 choline PET-CT scans as an evaluation tool. These studies found the C-11 choline PET-CT scans to be important staging and potentially therapeutic tools.

The first study evaluated 176 patients with a biochemical recurrence after primary treatment failure. The study sought to assess the capability of the C-11 choline PET-CT scans' ability to delineate prostate cancer distribution and extent after primary treatment failure. Results of the study found use of the C-11 choline PET-CT scans to be clinically useful in detecting treatable lesions not identified by conventional imaging in 32 percent of patients. The study results concluded that the optimal value for lesion detection is approximately 2.0 ng/mL.

"Use of the scans improves the staging and treatment of the cancer by finding the lesions earlier in the course of disease progression, offering patients a more timely course of treatment, rather than further systemic treatment," explains Dr. Karnes. "The big advantage of this technology is it gives you a big decision point because it is capable of seeing things that CT and bone scan are not able to do. So this scan is really critical," concurs Dr. Mynderse.

The second study evaluated the accuracy of the C-11 choline PET-CT scans in the diagnosis of consolidated prostate cancer recurrence in men with biochemical failure after primary treatment. This study also found the scans to be valuable. Dr. Karnes analyzed data for 36 patients who underwent salvage prostatectomy. At the time of the PET scans, the mean and median PSA levels were 5.3 ng/mL and 2.8 ng/mL, respectively. C-11 choline PET-CT scans delivered a sensitivity of 88 percent and a positive predictive value of 94 percent. The results show that the C-11 choline PET-CT scans are an accurate diagnostic tool for detecting localized disease recurrences, and in select cases they can be treated with salvage surgical resection.

MR-guided cryoablation

Yet another novel treatment available to Mayo Clinic patients with recurrent prostate cancer is MR-guided cryoablation. Exclusive to Mayo Clinic, a customized freezing unit adapted to an MRI-compatible device allows an ablative team to freeze and destroy prostate tumors. The procedure, performed under anesthesia and MRI guidance, targets two to five cryotherapy probes through the skin to in and around the region where the tumor has been confirmed by a positive biopsy. A urethral warming catheter is used to protect the urethra from damage.

"Essentially, you watch the ice grow in real time. You are freezing in multiple planes and destroying regions identified and proven to be cancer with biopsy," explains Dr. Mynderse.

Mayo Clinic studies have found salvage MR-guided cryoablation of localized prostate cancer recurrence to be safe, feasible and effective, offering an alternative to patients who typically would have radiation as the next course of treatment. "This is a really unique opportunity whose development was critical to advance treatment options for patients," emphasizes Dr. Mynderse.