Study changes how physicians treat metastatic prostate cancer

Intermittent hormone therapy not as effective as continuous hormone therapy, authors say


  • Carrie Printz

The authors of a study published April 4 in the New England Journal of Medicine concluded that intermittent hormone therapy is not as effective as continuous hormone therapy in treating many patients with metastatic prostate cancer, and are now counseling their patients to undergo the latter.[1]

“Clinically, we found that intermittent was not as good as continuous, but we did not prove that the difference was statistically significant,” says Maha Hussain, MD, the study's principal investigator and associate director of clinical research at the University of Michigan Comprehensive Cancer Center in Ann Arbor. “There was a difference of about 7 months in median survival.”

Although the trial did not statistically prove absolutely that intermittent therapy was inferior, the authors believe from observing the study data that it is, she adds. Hormone therapy in hormone-sensitive prostate cancer has been shown to extend the lives of patients, but it can cause a variety of problematic side effects, including moodiness, hot flashes, sexual dysfunction, and bone loss. Historically, physicians prescribed intermittent or “pulsed” therapy in which treatment is stopped until signs of prostate cancer reappear in order to give patients relief from symptoms.

Dr. Hussain and colleagues undertook the study to prove that intermittent treatment was at least as good as or not significantly worse than continuous hormone therapy. The study, led by the Southwest Oncology Group (SWOG), followed 1535 men with metastatic prostate cancer for a median of almost 10 years. The study results indicated that men with less advanced prostate cancer who received intermittent therapy died an average of 2 years sooner than those on continuous therapy. The findings first received attention when they were announced last year at the annual meeting of the American Society of Clinical Oncology.

Survival for men with more metastatic disease was more modest, leading to the average of 7 months difference between the 2 therapies that Dr. Hussain discussed. Still, that survival difference is longer than other interventions, which only extend life for advanced metastatic patients by an average of 2 or 3 months, says Ian Thompson Jr., MD, director of the Cancer Therapy and Research Center at the University of Texas Health Science Center at San Antonio and senior author of the study.

Dr. Hussain adds that although the study showed that intermittent therapy produced some gains in quality of life, the gains only occurred early on and that as they continued to follow patients, “those elements proved not significant.” As a result, she and colleagues recommended that continuous hormone treatment should be the standard of care. Still, she adds, “What we come up with in clinical trials is important for standards of care for the population at large, but it doesn't mean that an individual patient might not be served better with intermittent treatment. A doctor needs to explain to patients who are having significant side effects that they could explore intermittent, but that continuous therapy is the optimal choice from a survival perspective.”

The vast majority of patients with metastatic cancer in her practice have chosen continuous therapy, yet if they have significant side effects, Dr. Hussain said she and colleagues would consider palliating them with other measures or stopping the treatment for a period of time. “There has never been a trial testing intermittent therapy in patients with metastatic disease as big as this trial and looking at survival as the outcome,” she says. “We feel this is the definitive trial in the setting of metastatic disease. It may not have all the answers to all the questions, but I think the issue of intermittent therapy has been investigated quite a bit, and these are the best results we're going to get thus far.”

Quality of Life Versus Quantity of Life

Judd Moul, MD, director of the Duke University Prostate Center in Durham, North Carolina, believes that the SWOG study “is a big trial that seemed to say continuous hormone therapy might provide a little bit better chance for longer survival.” Still, he adds that most of his clinic's patients who do not have obvious metastatic disease (for example, a patient who has biochemical recurrence but negative bone or computed tomography scans) are initially offered intermittent therapy. The study, however, has led him and his colleagues to counsel patients with metastatic disease slightly differently than before.

The study primarily shows a survival advantage with continuous therapy for patients who have “good performance status, minimal metastatic disease,” but for patients with very advanced disease or no visible metastases it did not make a significant difference, he says. “This [article] is a very important, large study with long-term follow-up, but still it takes time for some of these ideas to percolate down to docs in the trenches,” he says. “And I still think that intermittent versus continuous therapy will be a hotly debated topic because there are some patients who do prefer quality of life over quantity of life.”

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A doctor needs to explain to patients who are having significant side effects that they could explore intermittent, but that continuous therapy is the optimal choice from a survival perspective.

—Maha Hussain, MD

Gautam Jha, MBBS, MS, a medical oncologist and hematologist who treats patients with prostate cancer at the University of Minnesota in Minneapolis, agrees. “This is very helpful information that has come out,” he says. “I wouldn't use it as a complete and absolute set of recommendations because those of us who treat patients with prostate cancer know that everyone is different. Some people do OK with side effects while others refuse therapy even in light of progressive disease because they have so much difficulty tolerating them.”

Dr. Jha notes that he has had one patient who has been on intermittent therapy for the last 10 years. The patient skips treatment in the summers and feels much better when he is off the therapy. Age also can play a role in the decision, he says. Younger patients who are tolerating side effects better and want to be more aggressive in their treatment may be more likely to opt for continuous therapy than people in their 80s who may be more likely to die from other causes, he says.

Questions Remain

Dr. Moul adds there are several unanswered questions regarding hormonal treatment of prostate cancer, including:

  • The appropriate prostate-specific antigen level at which to restart treatment after it has been stopped;
  • How long a treatment cycle should be;
  • Whether lutinizing hormone-releasing hormone (LHRH) pure antagonists would be more potent in intermittent therapy than LHRH agonists, which are the primary drugs that have been used in clinical trials; and
  • Whether oral hormone therapy could be used in intermittent therapy. It is not quite as potent as injections, but it can better preserve sexual libido and erectile function.

Meanwhile, Dr. Hussain believes that clinical trials in new hormone-sensitive metastatic prostate cancer need to focus on how to significantly improve outcomes for patients so that it eventually becomes a more chronic disease that potentially could be cured down the road. One example of such a trial is SWOG 1216, which is studying whether the addition of TAK- 700 (a drug similar to abiraterone) to hormonal therapy can extend survival for patients with metastatic prostate cancer.