Radiation Therapy

This month Prostatepedia is talking about radiation therapy.

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Here’s the introduction:

Our radiation therapy discussion begins with Drs. Mack Roach and Michael Zelefsky.

Both discuss the future of radiation therapy and offer insight into escalating radiation to the prostate while minimizing dosing to surrounding normal tissue.

Two developments drive this effort. First, improved imaging provides a more detailed view of the cancer’s extent and its localization within the prostate as well as spread to adjacent structures. Dr. Zelefsky outlines MRI imaging’s impact. Dramatic advances in computer power have also allowed radiation oncologists to develop sophisticated treatment planning software. We can calculate with more precision radiation doses to be delivered to the cancer versus to surrounding normal tissue.

Radiation therapists can also focus external beam radiation with greater precision, leading to IMRT and Cyberknife. These techniques use high-energy photons.

We also developed approaches like brachytherapy and proton beam that augment or compete with photon-based treatments. Further progress in intensifying radiation dose may be limited. Drs. Roach and Zelefsky’s comments on these trends are well balanced.

Another trend is to shorten treatment duration. Current treatment plans require eight to nine weeks. Dr. W. Robert Lee outlines two randomized trials that show four to five and a half weeks of treatment is not inferior to eight to nine weeks of treatment. (Increasing daily radiation doses, a strategy called hypofractionation shortens treatment duration.) Shorter treatments are more convenient for patients. Larger doses per session may also reduce costs as radiation oncologists are paid per treatment session.

Stereotactic body radiotherapy (SBRT) is another way to shorten treatment duration. SBRT delivers five treatments over a week and a half. SBRT is at an earlier development stage; we have no randomized trials proving it is better than or equal to standard fractionation or hypofractionation. SBRT has theoretical advantages, as Dr. Zelefsky comments. Early results are promising, but SBRT’s full potential is still being explored.

Dr. Sean McBride’s clinical trial combines SBRT with cutting-edge hormonal therapy in patients with locally advanced disease at very high risk of recurrence after surgery: Gleason 8-10, a PSA >20, extracapsular spread, or cancer invasion into the seminal vesicles or lower part of the bladder.

Disappointingly, current adjuvant hormonal therapy for radiation typically uses LHRH agonists. Xtandi (enzalutimide) and Zytiga (abiraterone) have revolutionized metastatic prostate cancer treatment. Adding both to adjuvant hormonal treatment is persuasive. McBride’s trial uses an LHRH agonist with Zytiga (abitraterone) and a new drug called apalutamide (ARN 509). Apalutamide’s (ARN-509) mechanism of action is similar to Xtandi’s. This combination is frontline treatment for advanced metastatic prostate cancer, but in this trial, it is applied as adjuvant hormonal therapy for locally advanced prostate cancer. This trial promises to revolutionize treatment for locally advanced disease.

I’m very interested in metformin use for prostate cancer. In my clinic, we use metformin when we start hormonal therapy: a randomized trial shows that it reduces metabolic syndrome risk for men on hormonal therapy. Dr. Zelefsky observes that during radiation, patients on metformin have a reduction in distant metastases, risk of dying of prostate cancer, and risk of castrate resistance. This is retrospective data, though; these advantages need to be tested in a randomized controlled trial.

– Charles E. Myers, Jr., M

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Advances in Hormonal Therapy

This month Prostatepedia is talking about advances in hormonal therapy.

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Here’s the introduction:

In July, Prostatepedia discusses recent advances in hormonal therapy. For years, cancer control was confined to a small set of drugs with limited utility and too short-term effect. Everything changed with Zytiga (abiraterone) and Xtandi (enzalutimide), both of which opened the door to further advances.

In our first conversation, Dr. Thomas E. Keane reviews current agents that shut off testosterone production. Luteinizing hormone (LH) is released from the pituitary gland as a part of an elaborate system that controls serum testosterone in men. If testosterone levels fall, the amount of LH increases to stimulate the testes to produce more testosterone. If testosterone levels are too high, LH levels drop until testosterone concentration returns to normal ranges. LH release is controlled by luteinizing hormone–releasing hormone (LHRH).

Older LHRH agonists commonly used, such as Lupron (leuprolide) and Eligard (leuprolide), over-stimulate the pituitary gland and exhaust its ability to release LH. An LH surge leads to a dramatic jump in testosterone. After a few days, though, the pituitary response begins failing and LH release falls. By the end of the first week, testosterone levels generally start to gradually decline, and, after 3 to 4 weeks, reach concentrations similar to those seen after surgery.

Newer drugs bind directly to LHRH receptors in the pituitary gland to immediately stop LH release. There is a rapid drop in serum testosterone to castrate levels within days, not weeks. Because these drugs block LHRH action, we call them antagonists.

Keane also reviews the evidence that antagonist Firmagon (degarelix) may offer superior cancer control when compared to agonist Lupron (leuprolide), especially in terms of cardiovascular events in patients with preexisting heart disease.

Next, Dr. Emmanuel Antonarakis discusses AR-V7, an altered form of the androgen receptor. Antiandrogens compete with testosterone for binding to the androgen receptors. AR-V7 is missing the part of the protein that binds testosterone or the antiandrogens, yet is still able to trigger cancer cell growth. The cancer cell becomes truly independent of testosterone and resistant to drugs such as Xtandi (enzalutamide) and Zytiga (abiraterone). In contrast, the cancer remains sensitive to taxane chemotherapy drugs.

A circulating tumor cell (CTC) test developed at Johns Hopkins University can detect and quantify the AR-V7 splice variant and holds promise for physicians wishing to use it to make treatment decisions. The test is not yet FDA approved, which Antonarakis acknowledges limits the clinical utility of the test. I’m excited to share with you first-class translational research by one of today’s best young investigators.

In our third conversation, Dr. Mary-Ellen Taplin of the Dana-Farber Institute discusses galeterone, a new oral hormonal therapy agent. Galeterone combines Xtandi’s (enzalutamide) ability to block the testosterone receptor with Zytiga’s (abiraterone) ability to block testosterone production. It also degrades both testosterone and AR-V7 mutant receptors.

The ARMOR3-SV clinical trial tests the therapeutic benefit of galeterone in men with the AR-V7 mutant androgen receptor. ARMOR3-SV is an important trial: determining if a drug has clinically significant benefit for patients with aggressive prostate cancer, whose current treatment options are few. As Dr. Taplin points out, ARMOR3-SV may tell us something important about AR-V7’s clinical significance.

Finally, Dr. Brian Gonzalez discusses a genetic variation associated with an increased risk of cognitive impairment during ADT. His genetic studies use terms many might find confusing, so please read the side bar alongside his comments. His findings have profound implications for those of you on hormonal therapy.

 – Dr. Charles E. Myers