Oncologists Can Now Better Detect and Treat Oligometastatic Prostate Cancer, Leading to Improved Survival

CURE, CURE® Genitourinary Cancer 2022 Special Issue,

“I believe the key for many is to turn prostate cancer from a lethal disease to a chronic disease. That’s what we’re trying to do,” says an expert at the University of California, San Francisco.

As a retired urologist, Mark Samberg, 72, of Sacramento, California, was familiar with what would happen after receiving a prostate cancer diagnosis in 2020.

The advantage he had was better understanding his diagnosis, treatment and what came with it.

The disadvantage was knowing what might happen to him.

“Being a physician, you know the right questions to ask,” he says. “The bad part, of course, is that you’ve already seen the end of the book a few times, how the story could possibly end. That’s the scary part.”

One portion of his diagnosis he was familiar with was that his disease was in an oligometastatic setting — a sort of intermediate state that is more advanced than locally-confined disease but is not yet full-blown metastatic disease — a state that many patients may not know even exists.

There is renewed interest in and growing clinical evidence of an “oligometastatic” state. Patients with oligometastases have a low volume of metastatic disease and limited sites of involvement and can experience prolonged disease-free intervals and possibly even improved overall survival through a combination of systemic and local therapies such as chemotherapy and radiation. An important aspect of this definition is that local therapies could feasibly be used to remove or eradicate areas of disease that are visible by scanning techniques and that medical therapy could address microscopic cancer that is not easily discernable.

Defining Oligometastatic Prostate Cancer

The concept of an oligometastatic state was proposed in 1995 by oncologists Samuel Hellman and Ralph Weichselbaum, and prostate cancer, because of its long natural history and high prevalence, has become an important focus of research investigating the potential value of more precise treatment for oligometastatic disease.

“The oligometastatic hypothesis suggests that there may be patients who have disease spread to other parts of the body, but if we are very focused about treating them, we may be able to get all of the cancer or at least help the patient do better for longer and keep some of the medical approaches available for later,” explains Dr. Ryan Phillips, a radiation oncologist at Mayo Clinic in Rochester, Minnesota.

“The reason to appreciate that it exists is we can better tailor the treatment to the individual.”

According to Dr. Neha Vapiwala, professor and vice chair of education, radiation oncology, at the University of Pennsylvania in Philadelphia, oligometastatic prostate cancer has traditionally been defined by the detection of one to five metastatic sites on conventional imaging, such as CAT scans, PET scans, MRI and technetium bone scans.

“In years past, using the conventional imaging technologies that were available, if we saw up to five lesions, the thinking was that this patient’s disease might have a different natural history than someone who presents with many more lesions,” Vapiwala notes. “We might be able to intervene with treatment that’s more aggressive, targeting the handful of lesions that are seen, usually in addition to the normal systemic therapy we would give, with the idea of reducing tumor burden and, ideally, prolonging progression-free survival. But the ‘quality’ — meaning location and type — of metastatic disease also matters, not just the quantity. And this upper limit of five may not remain relevant as we learn more through molecular imaging.”

Vapiwala says there are essentially two medical camps regarding the aggressive treatment of the prostate gland, if not yet treated, and/or sites of metastatic disease, and its role in enhancing survival. One side believes that while new imaging technologies detect small lesions earlier and more accurately, allowing for safer treatment, ultimately nothing changes regarding overall survival.

“Then you have individuals who say no, it’s not just simply iatrogenic (relating to illness caused by medical examination or treatment) stage migration; we’re not just diagnosing them earlier, but because we’re intervening, we’re making an impact,” Vapiwala says. “And some of these aggressively treated patients do have a robust treatment response or at least remain on a protracted course, and do not inevitably develop explosive disease later. This supports the idea that this is a different phenotype, a different biology altogether.”

The most common metastatic sites for prostate cancer are lymph nodes and bones, and this was true for Samberg, who was found to have lesions on his lumbar spine and scapula, as well as some lymph nodes, following a diagnosis of prostate cancer.

Samberg’s cancer journey started in 2019 when he began experiencing more frequent urination and other symptoms indicative of benign prostatic hypertrophy despite an active, healthy lifestyle. In early January 2020, he visited a colleague who told him his rectal exam was abnormal and referred him to a specialist at the University of California, San Francisco. By then, his prostate-specific antigen (PSA) level had progressed from 1.7 to 3.8 (the normal range is between 1.0 and 2.5).

Samberg underwent an MRI in February 2020, which he found concerning. A biopsy was scheduled, then everything shut down because of COVID-19. Months later, Samberg finally received his diagnosis and a Gleason score of 4+4, which is considered high-risk disease. Imaging during his pretreatment work-up revealed the metastases. Samberg’s treatment included androgen deprivation therapy with leuprolide, stereotactic body radiation, radiation to the metastatic sites and several cycles of Keytruda (pembrolizumab) as part of a clinical trial.

Because of his work as a urologist himself, Samberg was familiar with the concept of an oligometastatic state.

However, this was not the case for Chuck Pappas, 72, of Plymouth, Minnesota, whose prostate cancer journey involved three separate incidences over a course of several years. A rise in his PSA heralded each new bout, suggesting metastases that were later confirmed via imaging. Pappas underwent prostate surgery, stereotactic body radiation and combined treatment with radiation and leuprolide. He was declared cancer free in May.

His care team at Mayo Clinic in Rochester, Minnesota, never used the phrase “oligometastatic disease,” Pappas says, likely because he was a layman.

“But I believe that’s what I had because when they first started my radiation treatment, they found a few lesions, which later progressed to my lymph nodes,” he observes. “Looking back, it certainly fits.”

Phillips confirmed that is what it was.

Advances in Imaging

Oligometastatic disease is most effectively diagnosed through imaging, which is more sensitive today than ever before. One of the most effective new technologies is prostate-specific membrane antigen (PSMA) PET imaging, which has been available in Europe and Australia for several years and received U.S. Food and Drug Administration approval in 2021. This is the imaging technology that revealed Samberg’s metastases.

“PSMA PET imaging has been a big game changer for us because it allows us to diagnose metastatic disease much earlier,” says Dr. Peter Carroll, professor of urology at the University of California, San Francisco in the department of urology. “It has shown that when we do that, we change treatment recommendations substantially. In the past, we might have given radiation or hormonal therapy alone. Now, with earlier detection, we’re offering treatments like stereotactic body radiation with or without hormonal therapy or surgery for metastatic disease. What we don’t know yet is how that translates to long-term disease-free survival.”

Samberg said he was grateful to receive PSMA PET imaging.

“My metastases likely would not have been detected under our standard work-up regimen,” he said. “In fact, they did the standard imaging and didn’t see the lesions that the PSMA PET scan showed.”

Equally exciting is the choline C-11 PET scan, which uses a radioactive form of the vitamin choline as a tracer to help detect sites of recurrent prostate cancer. This is the technology that revealed Pappas’ nodal metastases. A low-dose CT scan is commonly done at the same time to help further show internal anatomy, the Mayo Clinic reports.

Older imaging technologies, while not as sensitive, still have value, Vapiwala observes.

“MRI can still be very useful, in particular, MRI of the pelvis,” she notes. “There are also centers around the world that are very focused on whole body, or multiparametric MRI. In many places technetium scans remain standard for evaluation of the bony skeleton. But increasingly we’re seeing PET imaging supplementing if not replacing these scans for staging and clinical decision-making.”

The American Society of Clinical Oncology, in a report titled “Approach to Oligometastatic Prostate Cancer,” advises a multimodal treatment approach to patients with oligometastatic disease “with evidence for surgery, radiotherapy, and systemic therapy, alone or in combination, improving patient outcomes.”

Androgen deprivation therapy (ADT), in which the patient’s testosterone level is lowered in an attempt to hold the cancer in check for as long as possible, has proved especially effective, notes Phillips.

“There are other complementary medications, including more advanced androgen-directed therapies, that can make this approach last longer and be more effective,” he adds. “What we’re learning more and more is that for patients who have a limited number of detectable areas of spread, being more aggressive in treating those areas can add a lot of value and help patients live longer. The way we do that, most commonly, is with targeted radiation. There are also times where we use surgery or other ablation techniques such as radio frequency ablation or cryotherapy.”

Answering the Big Questions

Prostate cancer in the oligometastatic setting has been a topic of study for several years as researchers seek to better understand the disease and develop more effective diagnostic imaging technologies and treatment.

“There are some big questions around oligometastatic prostate cancer, and I believe we have the answers to many,” says Carroll. “The first is, can we diagnose this disease state better than we had in the past? And the answer is yes. We’re clearly seeing that when we diagnose it earlier, we’re changing treatment recommendations based on historical paradigms in imaging. So we’re diagnosing it more commonly and treating it differently. The big question is. Are the outcomes any better? How many quality-adjusted life years will it add? That remains to be determined. My feeling, based on the evidence to date, is that it will be beneficial. What I don’t know is the magnitude of that benefit or the financial cost.”

Vapiwala hopes to add to that discussion through the ongoing national phase 3 randomized INDICATE trial. Patients with rising PSA after prostatectomy and no evidence of metastases on conventional imaging all receive standard of care pelvic RT and short-term androgen deprivation but are randomly assigned based on their baseline PET scan finding to local therapy intensification with metastasis-directed RT if they have PET-positive disease outside the pelvis or system therapy intensification with apalutamide if they are PET-negative outside the pelvis.

“We’re asking, if we find disease on PET only and make treatment decisions based on that, are we making a meaningful difference in clinical outcomes?” Vapiwala asks. “If we see a few lesions and chase after them, it might make us feel better, but are we actually helping the patient?”

Other areas of research opening doors include the following:

  • Outcomes of Observation vs Stereotactic Ablative Radiation for Oligometastatic Prostate Cancer,” published in 2020 in the Journal of the American Medical Association, found stereotactic ablative radiotherapy promising for men with recurrent hormone-sensitive oligometastatic prostate cancer who wish to delay the start of ADT.
  • Researchers at the University of Florida are evaluating the outcomes of patients treated with an investigational radiation regimen using stereotactic radiotherapy for oligometastatic prostate cancer, and to establish efficacy and safety.
  • Mayo Clinic is collaborating with Johns Hopkins University on research looking at oligometastatic prostate cancer treated with targeted radiation with or without the addition of a bone-specific radiopharmaceutical. “It’s an infusion of radium, which goes to areas of bone disease and may treat microscopic spread in the bones that we can’t yet detect,” reports Phillips.

Thanks to recent advances in diagnosis and treatment, the risk that oligometastatic prostate cancer will eventually become terminal is far less than in years past, oncologists say.

“All men who have metastatic disease are at risk of dying from it,” notes Carroll. “I believe the key for many is to turn prostate cancer from a lethal disease to a chronic disease. That’s what we’re trying to do.”

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