The majority of men with prostate cancer never know that they have the disease and die from other causes. So, what are the benefits of screening more? When a cancer is unlikely to impact a man’s life, is the risk of over-detection and overtreatment worth it? Or will it make more people unnecessarily sick due to side effects of treatment? Recent insights now suggest we should indeed rather focus efforts on developing personalized treatments tailored to an individual’s cancer for optimal outcomes.
Slow growing prostate cancer is common and low risk
While prostate cancer is relatively common, it is often slow growing, so poses a low risk compared to more aggressive cancers. As such, one of the major conundrums in prostate cancer is whether systematic screening should be introduced.
While seemingly a good idea, screening might actually do more harm than good. With a peak diagnosis at around the age of 70, most men with prostate cancer are unaware that they have the disease, and, crucially, don’t die from it. “In Belgium, 10% of men will have a prostate cancer diagnosis and 2% of these will die from it. However, in postmortem studies on 80-year-olds who died from other causes, this diagnosis rate rises to 60%. This means that most men never knew that they had a cancer,” says Wouter Everaerts, urologist and surgical training director at University of Leuven specializing in pelvic cancers like prostate and bladder cancer. “If you start systematic prostate cancer screening, you will start diagnosing more slow growing cancers and making more people sick as a result of treatment side effects,” continues Everaerts.
Currently, prostate cancer diagnosis is largely made through opportunistic screening after a patient discusses their condition with a clinician. Decisions to screen are largely based on patient age, family history, presence of certain genetic mutations, such as in BRCA1 or BRCA2, or presence of symptoms like problems with urination. Unlike for cervical, colon, or breast cancer, there are no organized, systematic screening programs for prostate cancer in Europe. This is largely because the harms of overtreatment, including erectile dysfunction, loss of sexual potency, incontinence, anxiety and depression, might outweigh the benefits of the treatment itself.
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The problem with PSA
Historically, screening methods used levels of prostate serum antigen (PSA) to aid diagnosis. However, recent findings from the CAP (Cluster Randomized Trial of PSA Testing for Prostate Cancer) study revealed that PSA screening had little effect on reducing absolute deaths. It also highlighted that PSA screening may miss aggressive cancers in some men. This is because not all aggressive cancers cause highly elevated PSA levels. Instead, they may produce levels similar to non-aggressive tumors, leading to underdiagnosis and undertreatment, suggesting we need a more personalized approach to screening and therapies.
“Do we have to focus on finding more cancers? Is this really the best way forward? Or should we focus on finding only the aggressive cancers through smarter screening and developing better treatments?” asks Everaerts. “Prostate cancer has many faces. We have very slow growing cancers or very aggressive cancers, so I think the biggest challenge is for us to find patient tailored management. In which patients can you stay conservative and in which patients do you have to remove the prostate and pull out all the stops in terms of treatment?”
Does less treatment equal better care for most men?
Recently, the ProtecT (Prostate testing for cancer and Treatment) study evaluated the effectiveness of three treatment interventions for men who had prostate cancer that had not metastasized. Men were randomly assigned to one of three groups – 1) active monitoring of the cancer by regular testing of PSA levels; 2) radiotherapy, where hormone blockers and radiation were used to shrink tumors; or 3) surgery to remove the prostate.
The trial followed over 1,600 men diagnosed with prostate cancer in the UK between 1999 and 2009. It found that there were no significant differences in prostate cancer deaths between the three groups, suggesting that most men with localized prostate cancer can avoid or delay harsh treatments and the associated side effects. Men in the surgery group and radiotherapy group suffered from increased incontinence and a more rapid drop in sexual function compared to active monitoring, suggesting less treatment does equal better care.
Despite this, while active surveillance had fewer side effects compared to either radiation or surgery, men in this group were more likely to have their cancer progress or spread compared with the other groups, possibly due to the relatively insensitive nature of the PSA test. Metastasis occurred in around 9% of men in the active monitoring group, compared with 5% in the two other groups highlighting the need for personalized treatments.
A personalized approach to prostate cancer treatment
Some approaches in the personalized prostate cancer screening and treatment toolbox are helping to identify aggressive cancers and reduce the harms of side effects. For instance, magnetic resonance imaging (MRI) is now preferred as a non-invasive and accurate method to detect and tailor management from the start. “Previously, if PSA was elevated, we would take prostate biopsies even without imaging the tumor. Now, with MRI, if there’s nothing detected on the images you can be between 90 to 95% sure that there’s no cancer, meaning you don’t need to do biopsies. You also have a lower risk of diagnosing non-aggressive cancers,” explains Everaerts. This MRI approach also allows for more targeted biopsies to the lesion itself instead of the prostate as a whole and is more popular than blood-based biomarkers which would still require confirmation by MRI.
In instances where metastasis does occur, experts in Belgium have pioneered an approach called metastasis-directed therapy. Metastasis-directed therapy targets each metastatic tumor either surgically or with radiotherapy. It’s a promising targeted treatment strategy with excellent progression-free survival and low toxicity compared to much harsher systemic therapies like androgen receptor blockers. “Some cancers will evolve quickly and you’ll have to give the patient a lot of drugs from the start. With other patients, treating an individual metastasis is sufficient.”
Recent research is aiming to further personalize treatments for metastatic prostate cancer patients by identifying the mutations in a patient’s tumor that could make it more susceptible to certain therapies, helping uro-oncology specialists to decide which drugs are most likely to benefit individual patients. The ProBio trial found that patients should be treated primarily with types of drugs called androgen receptor pathway inhibitors (ARPi), as they gave better treatment responses and longer life expectancy than chemotherapy, but that this effect depends on the mutations that the patient’s tumor carries. It also helped to identify patients that would be less likely to benefit from this therapy, avoiding any unnecessary side effects.
Another personalized treatment is possible if a patient has mutations in the BRCA genes. Novel drugs called PARP inhibitors (for poly ADP ribose polymerase) can be given to these patients to improve quality of life and survival.
Finally, localized treatments for prostate cancer are also rapidly evolving. With the implementation of surgical robots for minimally invasive surgery, urologists try to reduce the side effects of prostate cancer surgery. On the other hand, a radiotherapy-based treatment, called hypofractionation, optimizes the delivery of radiation while minimizing exposure to surrounding healthy tissues. It reduces the number of times patients need radiation five-fold while reducing side effects and maximizing efficiency.
For most patients, the outlook is good
Despite all these advances, determining which patients to treat with which approach to maximize treatment efficiency while limiting side effects can still be tricky. A carefully considered mix of approaches is often the best course of action early in treatment. “We try to give a combination of therapies from the start because we see that bringing some of the therapies earlier in the treatment actually improve survival in the long run,” says Everaerts.
Overall, the outlook for prostate cancer patients is good. Most men with a non-aggressive prostate cancer diagnosis can delay or avoid harsh treatments without harming their chances of survival. The presence of numerous studies indicating that systematic screening has limited benefits, enables a shift in focus to developing tailored treatments with better outcomes for those patients with aggressive prostate cancer that might have spread. All these developments still merit thoughtful evaluation by doctors and their patients as they carefully weigh treatment decisions.
