State-of-the-Art Update on Prostate Cancer

The 2014 Genitourinary Cancers Symposium, held in San Francisco from January 29 to February 1, brought together more than 3,100 participants from around the world involved in the care of patients with genitourinary malignancies. The abstract presentations and plenary discussions offered the latest clinical and basic science data that will affect patient management immediately and well into the future.

During the course of the meeting, The ASCO Post had the opportunity to speak with several of the world’s leading authorities about the state of the art in screening, diagnosis, and treatment for prostate and kidney cancers. In this first installment of our two-part report on genitourinary malignancies, we talked to Peter T. Scardino, MD, FACS, Chair of Surgery and former Chair of Urology at Memorial Sloan Kettering Cancer Center in New York, and Howard M. Sandler, MD, MS, FASTRO, Chair of Radiation Oncology at Cedars-Sinai Medical Center, and a member in the Cedars-Sinai Samuel Oschin Comprehensive Caner Institute, Los Angeles, about the latest approaches to managing prostate cancer.

A CONVERSATION WITH
PETER T. SCARDINO, MD, FACS

PSA Screening

What is your current perspective on screening for prostate cancer?

Screening for prostate cancer with prostate-specific antigen (PSA) will continue to be practiced and will be endorsed by national screening agencies once the problems of current screening methods are resolved. A man’s PSA level at midlife (age 45–50) is a more powerful predictor of his lifetime risk of dying of prostate cancer than his family history or ethnicity. As the power of PSA to predict risk for death from prostate cancer becomes clearer, PSA levels at midlife will be used to risk-adjust screening intensity and duration.

Men with a PSA level below the median at age 45 to 50 can be screened every 5 years until age 60. If their PSA level remains below the median at 60, no further screening will be necessary. Men with intermediate PSA levels (1–3 ng/mL) will be screened less frequently than they are today, every 2 to 4 years, to reduce the risk of false-positives. And men with PSA levels greater than 3 ng/mL will be considered for biopsy after an evaluation that includes the use of new marker panels such as phi (Prostate Health Index, Beckman Coulter) and the 4K (four-kallikrein) panel (in development at OPKO Diagnostics), both of which have been shown to markedly increase the specificity of PSA testing and reduce the need for biopsies.

These new testing guidelines will allow many men with elevated PSA levels to avoid a biopsy and yet be followed safely, without the risk of missing high-grade cancers. New urinary molecular markers, in addition to prostate cancer antigen 3 (PCA3), will be developed to better predict which men with an elevated PSA level should have a biopsy.

Imaging Studies

What are your thoughts about imaging studies for prostate cancer?

Imaging will continue to improve, particularly magnetic resonance imaging (MRI), which when performed as a multiparametric test, is reasonably accurate for the detection of clinically significant cancers. Not only could multiparametric MRI be used in men with an elevated PSA to identify appropriate patients for biopsy, it will also be used with ultrasound fusion or MRI guidance to change the strategy for biopsy from systematic random biopsies back to targeted biopsies, as performed in previous decades when finger guidance was the prime technique for biopsy targeting.

Used together with MRI, molecular positron-emission tomography (PET) imaging will provide more accurate detection of clinically significant cancers within the prostate that will allow better local staging and treatment planning with surgery or radiation, as well as accurate tumor localization and characterization for effective focal ablation. Even more exciting, optical imaging of prostate cancer during a surgical procedure will allow more complete excision of the cancer and of the normal gland (to avoid “benign” PSA relapse requiring salvage radiotherapy), as well as targeted dissection of involved regional lymph nodes, which will become essential once prospective studies document the therapeutic value of lymphadenectomy.

Focal Therapy

Could you discuss current concepts in focal therapy for prostate cancer?

Technology now exists to ablate regions within the prostate using a variety of modalities, including lasers, photodynamics, high-intensity focused ultrasound, cryotherapy, and electroporation, among others. These approaches have already proven capable of thoroughly ablating regions within the prostate with much less impact on sexual, urinary, and bowel function than radical surgery or radiotherapy.

The limiting factor for focal therapy has been our inability to identify the exact location, size, and extent of cancer within the prostate, as well as its biologic potential. But better anatomic imaging (MRI) and molecular imaging will overcome this problem, and partial ablation of the prostate will become as readily accepted as partial nephrectomy for renal tumors, if well designed trials establish the clinical benefit of focal ablation.

Molecular Profiling

How is molecular profiling being used in prostate cancer management?

Once a cancer is identified within the prostate, the most difficult decision is whether to monitor the patient in an active surveillance program or to proceed immediately with radical surgery or radiotherapy. The decision hinges on the assessment of the biologic potential or level of aggressiveness of the cancer, which can be difficult to determine with standard clinicopathologic measures.

Molecular profiling of prostate cancer is now commercially available, with RNA profiles developed by Genomic Health (Oncotype DX) and Myriad (Prolaris), and numerous other techniques currently in development. These profiling strategies provide prognostic information independent of Gleason grade and PSA levels.

With improved profiling, patients can be triaged to active surveillance or to radical therapy more appropriately and with greater confidence. I see a rapid expansion of molecular profiling for prostate cancer using such techniques as copy number alteration and mutation analysis, expression arrays, methylation abnormalities, and metabolomics, as well as microscopic image analysis.

Active Surveillance

Please describe the current role of active surveillance in prostate cancer.

As a consequence of these technologic innovations, active surveillance will expand rapidly and be offered to more than half of patients diagnosed with prostate cancer. These patients will be safely monitored over long periods of time, with treatment delayed until evidence of a cancer with aggressive characteristics.

Clinical trials will define more clearly the eligibility criteria for active surveillance, both for the patient (age and comorbidity) and the tumor (grade, biologic aggressiveness, and imaging characteristics). Of course, a substantial minority of patients on active surveillance will develop more aggressive prostate cancers that will require definitive therapy, and the risk will likely increase among survivors followed for more than a decade, given the logarithmic growth rate of cancer.

Radical Prostatectomy

How is the use of radical prostatectomy evolving in prostate cancer treatment?

Radical prostatectomy procedures will become more complex, as patients with more advanced disease are selected for treatment. More extensive lymphadenectomy will become routine as detection methods improve, including intraoperative imaging of the cancer, and the therapeutic value of lymphadenectomy becomes apparent.

Function-preserving radical prostatectomy will become more challenging with complete ablation of large extracapsular tumors; techniques such as nerve grafting to replace resected cavernous nerves and methods to strengthen the distal urinary sphincter will become even more important. Surgery for resection of the primary tumor will become accepted as effective multimodality therapy proves capable of curing many men with locally extensive or limited metastatic prostate cancer.

The remarkable advances in systemic therapy for prostate cancer, including potent new antiandrogens (enzalutamide [Xtandi]), inhibitors of testosterone synthesis (abiraterone [Zytiga]), classic chemotherapy (taxanes, including docetaxel and cabazitaxel [Jevtana Kit]), and immunotherapy (vaccines such as sipuleucel-T [Provenge] and checkpoint blockade with ipilimumab [Yervoy] and anti–PD-1 antibody), will be used in combination with radical surgery for locoregional disease in patients with locally extensive and limited metastatic disease who cannot be cured by local therapy alone.

A CONVERSATION WITH
HOWARD M. SANDLER, MD, MS, FASTRO

Evolution of Radiotherapy

Dr. Sandler, how has the use of radiation therapy in prostate cancer changed in the new millennium?

Radiation oncology for genitourinary tumors, mostly prostate cancer, has evolved over the past 2 decades from relatively crude radiation portals that affected large portions of pelvic-localized bowel uninvolved by prostate cancer (which led to acute and chronic gastrointestinal distress) to current highly targeted radiation treatments that focus with great precision on the prostate itself and a slim margin of surrounding extraprostatic tissue. This has resulted in a marked reduction in acute and chronic complications.

Interestingly, despite the older, two-dimensional approach using large radiation fields to treat pelvic lymphatic tissue, research showed that those large fields failed to encompass the prostate itself adequately due to uncertainties in prostate localization during the planning and treatment process. Those uncertainties were caused, in part, by the failure to account for prostatic motion due to variations in rectal and bladder filling. With current techniques, we can irradiate a smaller volume with more conformality, more precision, and fewer side effects and simultaneously treat to higher, more effective doses.

Stereotactic Body Radiotherapy

What is the role of stereotactic body radiotherapy in prostate cancer treatment?

Improvements in radiotherapy techniques led to important changes in the external-beam concept. While traditional radiation biology teaching suggests that fractionated treatment, such as 8 weeks of daily radiation sessions, provides a good risk-benefit ratio, the ability to treat small volumes with precision has led to the development of short, five-fraction approaches using a technique called stereotactic body radiotherapy (SBRT). The “body” is included in the name because this technique evolved from central nervous system or “head” tumor techniques.

The intensity of the five-fraction approach can lead to more genitourinary toxicity if the volume treated is too large or if the treatment is delivered imprecisely. However, there have been enough single-institution studies assessing the benefit of stereotactic body radiotherapy for prostate cancer that in 2013, the American Society for Radiation Oncology (ASTRO) said, “data supporting the use of SBRT for prostate cancer have matured to a point where SBRT could be considered an appropriate alternative for select patients with low- to intermediate-risk disease.”

Thus, over the next 2 years, one might expect a substantial increase in the use of stereotactic body radiotherapy for prostate cancer, given the convenience of the five-fraction approach compared with longer treatment strategies.

Looking Ahead

What other changes in radiotherapy for prostate cancer might be coming in the near future?

In addition to the increased use of stereotactic body radiotherapy, other new aspects of radiation oncology for prostate cancer include ongoing and future trials that will build on our current template of either short- or long-term androgen deprivation in combination with radiotherapy for intermediate-risk and high-risk cancer, respectively.

For example, the Radiation Therapy Oncology Group (RTOG) is examining the potential benefit of inhibiting androgen synthesis with TAK-700 for high-risk patients above and beyond the conventional androgen deprivation that is provided with luteinizing hormone–releasing hormone (LHRH) agonists or antagonists alone. This trial and others will be exploring how the current enriched environment of medications for the castration-resistant patient population might be beneficial—especially combined with radiotherapy—for the hormone-naive patient. ■

Disclosure: Dr. Scardino is a scientific advisor to OPKO, the company that licensed the 4K score from Memorial Sloan Kettering Cancer Center and is developing it for clinical use. Dr. Sandler reported no potential conflicts of interest.

Richard J. Boxer, MD, FACS, is Visiting Professor at the David Geffen School of Medicine at UCLA and Clinical Professor at the University of Wisconsin, Madison. He is also an Associate Editor of The ASCO Post.