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Multimodality Treatment Best in High-Risk Node-Positive Prostate Cancer

Goodwin, Peter M.

doi: 10.1097/01.COT.0000513319.75997.08

MILAN, Italy—Patients with node-positive prostate cancer being treated with prostatectomy could derive benefit from early multimodality therapy combining androgen deprivation therapy (ADT) with radiotherapy (RT)—on top of surgery—if they have pathological features indicating high risk, according to findings reported at the European Multidisciplinary Meeting on Urological Cancers.

Combining ADT with RT soon after prostatectomy improved overall survival as much as 40 percent in the highest-risk patients, according to analysis of data from studies conducted at three institutions—Memorial Sloan Kettering Cancer Center in New York, the Mayo Clinic in Rochester, Minn., and San Raffaele Hospital in Milan.

“It is the patients who are supposed to [technically] have the worst mortality from the disease that have the best survival when they receive the treatment,” said co-investigator Karim Touijer, MD, MPh, Attending Physician at the Department of Urology in the Sidney Kimmel Center for Prostate and Urologic Cancers at Memorial Sloan Kettering Cancer Center.

He said that while the most common approach to node-positive disease after prostatectomy was observation—followed by treatment only if there was progression—his analysis suggested a potential net benefit from combining RT and ADT in patients who had additional risk factors on top of nodal spread.

He said studies were urgently needed to confirm any benefit since the natural history of patients with nodal disease after radical prostatectomy indicated that even—without further treatment—30 percent of all patients were free from recurrence by 10 years. And this figure rose to 45 percent among patients with only one or two nodes.

Pathological features can discriminate the 80 percent of patients with nodal disease who had favorable characteristics and would be candidates for observation, he noted. But it was important to identify those at the high risk because they could benefit from a multimodality approach.

In his research from the three institutions, patients with node-positive prostate cancer were divided into three groups after prostatectomy—those who had additional treatment with external beam RT, those who received the same RT combined with ADT, and patients assigned to no further treatment until relapse.

“We looked at a combined data set of nearly 1,400 patients [who] received one of three strategies: observed until they failed biochemically then treatment started; automatically received hormonal therapy for life; or received the combination of hormonal and radiation therapy,” Touijer said, adding that patients who received the combination of ADT and external beam RT started with the worst disease yet had the best overall survival.

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Local Treatment Benefit

Researchers concluded there was great value in local control of the disease, despite the belief that if a patient had lymph-node metastases after radical prostatectomy the disease was already distant and systemic.

“What this data shows us is that maybe some patients are like that but not all of them, and not the majority, [and] that if we still focus—with all the treatments that we have available—to control the disease locally and regionally we can improve survival,” Touijer said.

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Not All Nodal Disease the Same

And analysis of the National Cancer Database (including 70% of all patients treated at U.S. cancer centers) had given “external validation of these findings.”

“Close to 5,000 patients were treated by observation followed by treatment after failure, radiation alone, hormonal therapy alone, or a combination of hormonal and radiation therapy,” Touijer said, noting that subcategories of patients with nodal disease clearly needed different treatment because there was a wide spectrum of risk and patients with the worst pathological features benefited the most from combining surgery, ADT, and RT.

“We did statistical risk groups based on Gleason grade, clinical stage, invasion of the seminal vesicles, T4 disease, positive surgical margins—all the elements shown to be predictive in most prostate cancers in many series. And the worse these features are the better the separation and the advantage in overall survival if we added radiation and hormone therapy.”

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ADT Monotherapy

The three-institutional data set revealed no difference in overall survival between patients who were observed and those treated with lifetime ADT.

“When we tried to look in detail at cancer-specific survival, we saw there was an advantage to androgen deprivation therapy. But when we looked at death from other causes—not cancer causes—we saw there was [also] a detriment,” Touijer explained.

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Radiation Therapy

Node-positive patients assigned after prostatectomy to RT alone lived longer than patients allocated to ADT alone.

“The assumption is that thorough surgery followed by radiation therapy is controlling the source of the disease and seems to make a difference in terms of survival. [But] the combination of both [ADT and RT] seems to give the best result.”

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But Touijer repeated that prospective clinical trials were needed to remove potentially confounding variables in these retrospective data, warning that these therapies could also have deleterious effects.

“One always has to balance the risk and benefit. But in terms of survival, it looks like multimodality therapy has a clear advantage,” he said.

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Multidisciplinary Team

“A prudent way forward is for surgeons to reach out to radiation therapists and medical oncologists when they are dealing with patients [who] have lymph node metastases after radical prostatectomy and happen to have a Gleason 8, 9, or 10, pathological stage T3b or T4, positive surgical margins, and a higher nodal count and really carefully look at the value of a multimodality approach for these patients—because it may alter their survival,” Touijer concluded.

Peter M. Goodwin is a contributing writer.

Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.
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