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A prognostic risk estimator that incorporates genomic data and clinical factors could allow for the elimination of androgen deprivation therapy (ADT) in some men with intermediate- or high-risk prostate cancer following radiation therapy (RT), a researcher reported.

In a retrospective validation study involving nearly 750 men who received dose-escalated RT, those with a combined clinical cell-cycle risk (CCR) score below a cutoff of 2.112 had a 10-year risk of distant metastasis of just 4.1%, regardless of National Comprehensive Cancer Network (NCCN) risk group, while those above the threshold had a 10-year risk of 25.3%, reported Jonathan Tward, MD, PhD, of the University of Utah in Salt Lake City.

In those with the lower score, differences were negligible based on receipt of RT alone (4.2%), or RT plus ADT (3.9%), according to the findings presented at the virtual Genitourinary Cancers Symposium (GUCS).

Numerous studies have shown that adding ADT decreases risk of metastasis in men with prostate cancer, said Tward. "Nevertheless, this clear relative benefit may become clinically questionable when the baseline risk of metastasis in any population or individual is low."

Tward noted that about 70% of prostate cancer patients would fall below the threshold used in the study, meaning that half of men with unfavorable intermediate-risk prostate cancer, one in five of those with high-risk disease, and one in 20 with very-high-risk disease could potentially omit ADT.

CCR score combines the cell cycle progression (CCP) score, using the Prolaris test, with the UCSF Cancer of the Prostate Risk Assessment (CAPRA) score -- which factors in age, prostate-specific antigen levels, Gleason score, T stage, and percentage of positive cores on biopsy.

Prior research had established a CCR score of 2.112 as a cutoff where men with intermediate- or high-risk prostate cancer derived minimal benefit from multimodality therapies, but the study carried certain limitations, included that RT dose and duration of ADT were not accounted for. Also, different types of RT techniques were used and there was a relatively small number of radiation subsets.

The current validation study addressed these issues and showed CCR score to be a better prognosticator of metastasis at 10 years compared with CAPRA or CCP scores alone:

• CCR: HR 2.21 (95% CI 1.70-2.87, C-index 0.78)

• CAPRA: HR 1.39 (95% CI 1.22-1.58, C-index 0.71)

• CCP: HR 2.04 (95% CI 1.48-2.79, C-index 0.69)

And CCR score was more accurate compared to the NCCN risk subgroups (C-index 0.72). In all NCCN subgroups (favorable, unfavorable intermediate, high/very high), the risk of metastasis at 10 years was below 5% when patients had a CCR score below the cutoff.

"Adding ADT to RT adds unnecessary morbidity for an extremely small absolute risk reduction in metastasis-free survival for many in the unfavorable intermediate-risk and a significant minority of high-risk men," Tward said.

In EORTC 22991 for example, which was composed primarily of men with non-bulky and intermediate-risk disease, the absolute risk of distant metastasis at 10 years dropped from about 8% to 5% with the addition of ADT -- resulting in a number needed to treat of about 30 people to prevent one case of metastasis. A suggested that most men would like to see an absolute risk reduction in metastatic disease of 5% to consider ADT over RT alone, said Tward.

GUCS discussant Richard Valicenti, MD, of UC Davis School of Medicine, cautioned that no biomarker has been prospectively tested and shown to improve long-term outcomes in men with higher-risk prostate cancer.

"Clearly, the CCR score may provide highly precise personalized estimates and justifies testing in tiered and appropriately powered non-inferiority studies, according to NCCN risk groups," he said. "Such studies could establish a highly individualized de-intensified approach to treating prostate cancer conditioned on a below-the-multimodality-threshold strategy."

He pointed to the , which is currently underway and will test such a personalized de-intensification approach for men with high-risk prostate cancer using the Decipher genomic risk classifier.

The current study examined CCR score in 741 evaluable patients with biopsy-proven intermediate- (70%) or high-risk (30%) prostate cancer based on NCCN criteria. Tward and colleagues obtained biopsy tissue and performed genetic testing retrospectively, years after patients were treated, eliminating risk of bias in treatment decisions. Median follow-up was 5.9 years.

Patients were included if they had received external beam radiation therapy using modern techniques and modern dose-escalated radiation (≥75.6 Gy at 1.8 Gy per fraction) with CT-based treatment planning. Those receiving pelvic nodal radiotherapy were allowed. Use and duration of ADT had to have been captured.

About half of patients had been treated with ADT combined with RT. In men with unfavorable intermediate-risk cancer, ADT duration was considered "sufficient" if they received at least 4 months of ADT, and at least 18 months for men with high-risk cancer -- matching current NCCN guideline recommendations. Less than half (44%) received some but not sufficient ADT, per this criteria.

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