Early adverse effects from prostate cancer therapy predict long-term complications
Key takeaways:
- Short-term adverse effects after radiation therapy for prostate cancer correlated with risk for long-term complications.
- Overall, rates of long-term toxicity remained low.
Men who experience acute adverse effects after radiation therapy for prostate cancer may be at higher risk for more serious long-term urinary and bowel complications, according to results of a meta-analysis published in Lancet Oncology.
Researchers at UCLA Health Jonsson Comprehensive Cancer Center evaluated data from more than 6,500 men who received prostate radiotherapy in one of six randomized phase 3 trials.
Median follow-up was 72 months (interquartile range, 61-94).
Results showed a correlation between acute grade 2 or higher genitourinary toxicity and late grade 2 or higher genitourinary toxicity (OR = 2.2; 95% CI, 1.88-2.57). Acute grade 2 or higher gastrointestinal toxicity correlated with late grade 2 or higher gastrointestinal toxicity (OR = 2.53; 95% CI, 2.07-3.08).
Also, acute grade 2 or higher genitourinary toxicity correlated with reduced urinary quality of life (OR = 1.41; 95% CI, 1.17-1,68), and acute grade 2 or higher gastrointestinal toxicity correlated with reduced bowel quality of life (OR = 1.52; 95% CI, 1.26-1.83).
“This does support our idea that lowering short-term side effects may lead to reduced long-term side effects,” senior author Amar U. Kishan, MD, executive vice chair of radiation oncology at David Geffen School of Medicine at UCLA, told Healio. “This has obvious implications for clinical trial design and may allow for more practical trials to demonstrate whether interventions are helpful for reducing late toxicity.”
Healio spoke with Kishan about the implications of the findings and the next steps in research.
Healio: How prevalent are short-term adverse events after prostate cancer treatment?
Kishan: In radiation oncology, we distinguish between short-term or acute side effects — which occur within the first 90 days of radiation and are generally short-lived — and long-term or chronic side effects, which occur later, can last longer and have a more profound impact on quality of life.
The pathophysiology behind these side effects can be very different. Short-term toxicity likely relates to the dose received at the time of radiation by the nearby organs that could be sensitive to this. That is driven by acute inflammatory signals or pathways related to DNA damage. Late toxicity likely is driven by a fibrotic, late immune response that might involve multiple physiologic pathways and effects mediated by the local microenvironment.
In the radiation oncology literature, there have been smaller, often retrospective studies that have supported the existence of what we call a consequential late effect. That’s the idea that the damage delivered and received at the time of radiation manifests as an acute toxicity, but may pop up again later as a late toxicity. However, that has not been definitively shown or shown in a large study.
Healio: What motivated you to conduct this study?
Kishan: The goal of my research effort is to improve the efficacy of treatments for prostate cancer and improve quality of life for patients after treatment. We’ve conducted several studies with this goal in mind, including an evaluation of whether high-precision radiation — in this case with very precise MRI-guided radiation — reduces short-term side effects. We found this was the case, and then later found that it reduced late side effects, as well.
We believe late toxicity would be harder to modify given the complicated biological pathways, but it may be easier to modify acute toxicity by having more precise radiation delivery and reducing the dose to some of these nearby organs at risk. We wanted to see whether we could find true evidence of a consequential late-effect phenomenon.
Healio: How did you conduct this study?
Kishan: We analyzed individual patient data from more than 6,500 men treated in six randomized phase 3 trials that had detailed, individual-level data on both short-term and long-term toxicity affecting the urinary and bowel systems. This work was made possible by the Meta-Analysis of Randomized trials in Cancer of the Prostate (MARCAP) Consortium, a repository of individual patient data for patients enrolled in clinical trials — specifically radiation trials — for localized prostate cancer.
Healio: What did you find?
Kishan: Experiencing acute toxicity increased the rate of late toxicity from 7.5% to 12.5%. For bowel toxicity, experiencing acute toxicity increased the rate of late toxicity from 12.7% to 22.5%. We also looked at patient-reported quality of life. We found the odds of having a clinically significant decline in urinary quality of life was 1.4 times higher for men who had moderate acute urinary toxicity, and the odds of having a clinically significant decline in bowel quality of life was 1.5 times higher for men who had moderate acute bowel toxicity.
Healio: What are the potential implications of these findings?
Kishan: The rates of long-term toxicity overall were quite low. That is reassuring to both patients and physicians, because these were trials conducted many years ago and our radiation technologies have improved.
This also has implications for clinical trial design. If we can show a meaningful difference in acute toxicity of a certain magnitude, we may be able to predict that we could show a difference down the line in late toxicity. That’s very helpful because, given how rare late toxicity is, it may be impractical to have a large trial to show that an intervention can effectively reduce it. However, if we can show that there is a correlation between acute toxicity and later toxicity, it can help us address it.
Additionally, efforts to improve early toxicity may bear fruit for patients as far as reducing late toxicity. In our day-to-day conversations with patients, if we know they went through their treatment without much acute toxicity, we can be more comfortable counseling them that they’re in a good space with regard to risk for late toxicity.
Healio: What is the next step in your research?
Kishan: We have multiple ongoing and planned projects looking at ways to reduce acute toxicity. We plan to study novel technologies like adaptive radiotherapy, using an early toxicity endpoint to see if they might help use potentially reduce late toxicity. We also have a lot of work going on trying to identify predictors of higher risk for late toxicity. We’re looking at identifying genetic markers that may be able to identify patients who might be at high risk for long-term radiation side effects.
References:
For more information:
Amar U. Kishan, MD, can be reached at aukishan@mednet.ucla.edu.
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