Independent ecancer blogger Dr Bishal Gyawali rounds up the latest publications in oncology.
Treatment for prostate cancer detected by PSA testing is one of the highly controversial topics in uro-oncology. In fact, routine PSA testing to detect prostate cancer is in itself a matter of debate. The treatment options for cancers thus detected include active surveillance (AS), surgery (radical prostatectomy, RP) or radiotherapy (RT). The Prostate Testing for Cancer and Treatment (PROTECT) trial compared these three options against each other in the setting of a randomised controlled trial (RCT) with the primary endpoint of prostate-cancer mortality and secondary endpoint of rates of disease progression, metastases and overall mortality at a median of 10 years of follow-up. They also measured patient reported outcomes for up to 6 years.
First, conducting this trial to its completion was a huge undertaking and the investigators should be congratulated. This is a well conducted RCT and the study reporting is excellent. Unfortunately though, the results from this study didn’t settle the debate of managing PSA-detected prostate cancer. Here’s why.
In 10 years of follow up, only 17 prostate-cancer-specific deaths occurred, much below what was expected while designing the trial. So, any discussions on prostate cancer specific mortality (the primary endpoint) is based on only these 17 deaths out of 1643 patients randomised ( 545 to AS, 553 to RP and 545 to RT). Of these 17, 8 deaths occurred among men randomised to AS, 5 to RP and 4 to RT. I don’t think we’ll need any statistics to say that there was no difference among the three groups. Regarding all-cause mortality, 59, 55 and 55 men respectively died in these three cohorts-again no difference. So, it is pretty clear that both cancer specific and overall survival don’t differ no matter what treatment you receive. On this background, clearly AS seems the preferred approach that would avoid harms of treatment and provide the same survival. Admittedly, we are concluding this only on the basis of 17 prostate cancer deaths and 169 total deaths.
But, here comes the catch: both metastases and disease progression were more than double in the AS group compared to RP/RT groups. Clearly, immediate local treatment decreased the rate of disease progressing or metastasising. If you see the absolute numbers though, this difference doesn’t look that drastic despite being statistically significant: 33 men in the AS group metastasised compared to 13 in the RT group and 16 in the RT group. Further complicating the matter, more than 50% of patients randomised to AS group had received a radical intervention (RP, RT) within this 10 years.
With regards to side effects, AS performed better than both the other groups. Urinary incontinence remained worse in the RP group than in the RT and AS groups at all time points. At 6 months, the rates of use of absorbent pads were 46% in the RP group, 5% in RT group and 4% in AS group compared with 1% at baseline. At the end of 6 years, these numbers were 17% v 4% v 8% respectively. The ability to have erections firm enough to have an intercourse fell from 67% at baseline to 52%, 22% and 12% at 6 months for the AS, RT and RP groups respectively. At 6 years, these rates were 30%, 27% and 17% respectively. Bowel function and bother scores including bloody stools were worse for RT groups compared to the other two. Health related quality of life didn’t seem to differ across the groups.
Now, with this evidence from the Protect trial, we are faced with two important questions in clinical practice:
1. How do we approach these patients who have prostate cancer detected on PSA tests?
2. Is routine PSA screening recommended?
I find ample evidence from this trial to recommend AS with confidence to most of my own patients. For up to 10 years, cancer specific survival and overall survival will be the same as with RP/RT, nearly half will avoid any radical intervention for up to 10 years and will have better urinary, sexual and bowel functions. These adverse effects are not trivial. We need to think from the patient’s perspective: is the evidence enough to undertake RP/RT and the consecutive side effects of the treatment for …the same survival? Although the chances of developing metastases would be low, if there are more chances of dying due to something else, would it be in patient’s benefit to undergo these radical treatments for saving himself of prostate metastases. If a patient comes to me and asks “what would YOU do doc?”, my answer is clear: “I would go with AS”. But of course, I would do that after laying down all the evidences in favor of and against all the three options. And telling him that we don’t know survival data for beyond 10 years.
But every patient is unique and no patient represents the “most patients” in clinical trials. Hence the need for individualised treatment to the patient in front of you.
If I have a patient who is afraid of developing metastases and wouldn’t get peace of mind without treatment, I would be equally happy to recommend treatment. Both RP/RT seem equally effective, but if he wants to maintain an erection, I would recommend RT. If he hates bloody stools more than anything else, RP is better.
And, of course, comes the question of age. The patients in this trial were of 50-69 years of age. And the data we have is from 10 years of follow-up. So, if a patient of 65 seeks opinion, I’ll tell him that his chance of dying by the age of 75 doesn’t differ depending on which treatment he chooses and that this would matter less beyond the age of 75 as other competing causes of death like stroke and CVD increase substantially. So, maybe undergoing RT/RP wouldn’t be worth it compared to the side-effects. But, maybe for a younger patient, I‘ll let him know that these results are based on only 17 prostate cancer deaths in 10 years, rate of developing metastases is lower with intervention and that beyond 10 years, we don’t know whether there will be any difference in survival. So he may choose surgery but that it carries a risk of erection loss. Alternatively, he may choose radiotherapy but it will increase the risk of bowel complications.
Although the accompanying editorial tried to exaggerate the interaction of age on prostate cancer deaths, there were only 5 versus 12 deaths in the <65 and > 65 age group cohorts making such conclusions far-fetched. The editorial also expanded on the side effects of any treatment for metastases in the AS group, but given that more than 40% of patients randomised to AS in this trial had received intervention by 6 years, such side effects should have been observed in this patient reported outcomes measurement.
And perhaps the most important, comes the question of tumour stage and grade. More than three-fourth patients in this trial had Gleason 6 and stage T1c disease. 20 and 17 more men in the AS group developed metastases compared with RP and RT respectively in this trial. Whether those men all belonged to higher grade disease is an important piece of information missing from the publication. Also, of those 50% of AS men who went on to receive radical intervention by year 10, what percentage had higher grade disease? If these answers are known, it would be very easy to make a generalised recommendation that for low risk early stage disease, AS would be sufficient. But, with the information we have, I would recommend RP/RT more strongly than AS for patients with higher grade, higher risk prostate cancer detected on PSA tests.
With the current data, I don’t think routine PSA based screening test should be recommended - there were only 17 deaths in total in 10 years among 1643 men with PSA-detected prostate cancers. And this represented only 10% of all-cause deaths in these men. That means very few men with PSA-detected prostate cancer die of this disease in 10 years irrespective of treatment modality chosen. 90% of deaths are likely to be due to conditions other than prostate cancer. So why would we want to detect prostate cancer with PSA tests so enthusiastically? And even if you do, this report says that avoiding immediate treatment won’t harm the chances of survival. Further, what is not measured in such RCTs is the mental anguish of having told that you’ve prostate cancer. Forget false positives and unnecessary interventions; even if the patient has a truly positive low grade prostate cancer detected on PSA tests, we are hurting the patient by giving him a diagnosis of cancer when in fact he would more likely die of something else. Many patients will live with the fear of harboring cancer inside his body; and even if we tell him that AS would be equally good and interventions not required, the mental damage we do on the patient and his family with the diagnosis of “cancer” is something I can’t put into words. Just ask them with open ears and you’ll know.
Many experts, and better-learned men, have debated on these two questions before. After the PROTECT trial, this debate has again escalated. Social media and even mainstream media are full of this debate, with every expert finding something in this trial to promote his own agenda. Debate is usually good for medicine as it encourages us to look at things from completely different angles.
But I discovered a very sad thing in this debate, and that is the fact that doctors were camped into “PSA-lovers” and “PSA-haters” groups! I couldn’t believe my eyes when I read statements like these: “PSA-haters are gonna show the mortality graphs but..” and “PSA-lovers must be very happy that metastases rates were lower…."
I also found phrases like “less is more camps”, “surveillance lovers” and even “surgeons” implying that all urosurgeons would recommend RP and “radiotherapists” implying all of them would recommend RT. I saw these phrases used very casually and comfortably. It broke my heart.
I am in no position to challenge these experts who have vast experience, but I didn’t take pursue a specialty in oncology to be a “PSA-lover” or a “PSA-hater”. Why should I support/oppose either camp? All I ever do, will do, or hope to do is lay down all the evidence in front of the patient and help him reach an informed decision.
I am not going to recommend PSA screening for all, neither am I going to not recommend PSA screening for all. For those who come with PSA detected prostate cancer at my clinic, I am not going to recommend AS for all; neither am I going to recommend RP/RT for all. Isn’t that what individualised treatment means?
Why should I join any camp? Why should anyone join any camp? I am neither “AS-lover” nor “AS-hater”, neither “PSA-lover” nor “PSA-hater”! I can’t make any blanket recommendation for all patients. If a longer follow-up does show a benefit for RP/RT or if PSA based screening is judged to be of value, someone might think the “PSA-lovers” or the “intervention” camp have won and rebuke at the loss of “PSA-haters” or “AS” camps.
But I will be the happiest man that day because we’ll have had a definite answer to a controversial problem. I will be the happiest man that day because medicine would have won, patients would have won. It’s only the patients’ win that truly matters.
Bishal Gyawali (MD) is an independent blogger. He is undergoing his postgraduate training in medical oncology at the Graduate School of Medicine, Nagoya University, Japan, where he is also a PhD candidate under the Japanese government scholarship. He also serves as visiting faculty at the department of Hemato-Oncology in Nobel Hospital, Kathamandu, Nepal. He graduated in medicine from Institute of Medicine, Tribhuwan University, Nepal in 2011 with seven gold medals for his academic excellence. He has been honoured with “Student of the Decade award” and “Best Student Award” for his academic excellence in Nepal. His areas of interest include evidence-based oncology practice, cost-effectiveness of cancer therapies and economic feasibility of cancer management in low-income countries. Dr Gyawali tweets at @oncology_bg. Dr Gyawali is an independent blogger and his views are not representative of ecancer. Read more from Bishal here.
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