Protecting our prostates from the PSA tests

It’s the month of prostates again!

Widespread adoption of PSA screening tests before having good evidence of efficacy has led to difficulty in conducting trials and de-implementing screening practice upon evidence of poor risk-benefit profile. A new perspective in NEJM nicely argues the pitfalls of the two major PSA trials and implications of the US Preventive Services Task Force guidelines. How best to treat low risk prostate cancers detected by PSA tests is unfortunately still debated: active surveillance alone or immediate intervention with surgery or radiotherapy. The PROTECT trial tested these three approaches in an RCT and concluded that prostate cancer specific survival as well as overall survival don’t differ (and are very low overall) no matter which approach is undertaken, but side effects do vary.  The irony here is that we are trying to figure out the best approach to treating something that might never kill the patient. If such widespread PSA testing were not in place, there would have been no need to mull over the best treatment option for PSA detected prostate cancer. In any case, no matter how many commentaries or editorials I read on PSA testing and managing PSA-detected prostate cancer, my approach remains the same - as I explained here - unless some new evidence to the contrary arrives.

However, prostate cancer continues to make headlines. Two important prospective cohort studies assessing the association between patient related quality of life outcomes with three options of treatment were published in JAMA. After reading these studies, my conclusions remain the same. The side effects differ by each strategy and some side effects may get better with time and some not (the two reports provide conflicting results for some outcomes). However, here is the sad news: only 16.8% patients in one study and only 27.5% patients in the other chose active surveillance! Why? Or should I rather ask, why did so many males become patients by undertaking the PSA tests?

The arrogance of preventive oncology

Somehow, exciting ideas on preventing cancer supported by huge meta-analysis of observational studies crumble down under the tests of randomised trials. David Sackett, 15 years ago, argued that preventive medicine displays all three elements of arrogance. I think that’s simply because preventive medicine has seldom been put to trial. In an important RCT, vitamin D and calcium didn’t decrease the incidence of all cause cancer among postmenopausal healthy women. In the discussion, the authors try to come up with various hypotheses for why there was no statistical difference in incidence of cancer as a result of Vitamin D and calcium supplementation in their trial. However, they failed to think of a much simpler explanation: Vitamin D and calcium do not prevent cancer.

Drug Repurposing: where did we fail?

I am a big fan of any approach that tries to improve the accessibility and affordability of cancer drugs globally. Metronomics and drug repurposing are two such approaches and I get excited by studies exploring them. Two studies of drug repurposing published in JCO got me excited this month; however, the excitement turned to sadness as both were negative. First, celecoxib failed to improve outcomes in patients with hormone naïve prostate cancer. Second, statin didn’t improve outcomes in patients with small cell lung cancer (SCLC).

Statins, in particular, came as a blow because many non-randomized studies suggested they could be useful. A lot of money and resources have been spent on doing those observational studies on statins. The third paragraph of the introduction of the statin paper tells the story very well. All we needed was a well-conducted RCT! The RCT was done and the results are negative. I am not happy, but at least I can move on.

However, I do think the choice of drug and cancer was not ideal. This trial used pravastatin, which is not an ideal statin as the accompanying editorial pointed out. Most importantly, SCLC is not a good tumour type to test the efficacy of statins. SCLC is an incredibly difficult-to-treat tumour and many targeted therapies and some immunotherapies have failed to improve outcomes in this disease. It’s difficult to assume that a drug repurposed for cancer would improve outcomes in so stubborn a malignancy. Table 3 of the article lists all the RCTs of statins conducted in oncology. We can see that most of those trials were not large and robust. Thus, although the editorial argues that no further RCTs of statins in cancer are justified, I think we should give statin at least one more shot using a better selected statin and dose in another tumour type. If it’s okay to conduct 3 huge RCTs of an expensive and toxic drug like bevacizumab in adjuvant colorectal cancer in the hope of chasing any small positive signal, and if continued testing of expensive angiogenesis inhibitors in ovarian cancer is okay despite consistent negative results, why shouldn’t we give this cheap and relatively safe statin another chance in an RCT? But no more observational studies, please. Not of statins, aspirin, metformin or vitamins.

Prudence in moving to phase 3

Have you ever heard of clusterin protein or the drug custirsen? Well, you don’t have to because this drug that inhibits the protein didn’t improve outcomes in prostate cancer in a phase 3 trial. I am not interested in this drug either but the only reason I am mentioning it here is because this trial is accompanied by a good editorial. This editorial appropriately questions the rationale in hastily moving to phase 3 trials without having good phase 2 data.  The editorial concludes: “Although powering a phase 2 trial to measure objective responses might prolong the accrual period modestly, this delay could be a smaller price to pay than the price of a large, negative, phase 3 trial”. Amen!

Choosing wisely or avoiding wisely?

Antiemetics overuse in patients receiving chemotherapy is a common problem in oncology as this recent study from Japan has shown. Particularly in countries like Japan where most of the costs of treatment are covered by the government, such overuse is very common. ASCO had previously launched a campaign called Choosing Wisely and identified overuse of antiemetics as one area of intervention. Another paper examined the effect of this Choosing Wisely recommendation on antiemetic prescription behaviour and revealed that the effects were only short-term. I think the main problem is in approach: Choosing Wisely implicitly suggests that we have to choose, we have to do something. I would suggest a better term: Avoiding Wisely. Avoiding Wisely implicitly encourages avoiding futile, harmful and expensive treatments. Speaking of Avoiding Wisely,…

Let me take a selfie

It’s been a while since I last took a selfie!

I have always been baffled at some of the practices in oncology that clearly made no sense - both medically and financially. I thought it was a double standard of oncologists to raise their voices against high cost of anticancer drugs and yet prescribe some very expensive therapies, despite the availability of equally effective cheaper options. I was already aware of Choosing Wisely initiatives, but the recommendations were limited and general. So, I wanted to make my own list of specific practices that we should avoid to reduce financial toxicity to patients and health care systems. I call it my list of Avoiding Wisely: practices to avoid rather than choose. This is published in ecancermedicalscience journal and also covered by Medscape Oncology. Of course, this list is not exhaustive and I plan to keep updating it.

Speaking of updating the Avoiding Wisely list.....

Avoid originators when biosimilars are available

This is one more item to add to the list when I update it because this study has verified again that biosimilar erythropoietin stimulating agents (ESAs) provide similar outcomes compared with originator ESAs in patients with cancer and chronic kidney disease. Unfortunately though, the uptake of biosimilars in clinical practice seems dismal despite lower costs and similar outcomes. I discuss these issues in detail in this commentary.

No JASPAC, only ESPAC?

ESPAC 4 trial that showed that addition of capecitabine to adjuvant gemcitabine improves survival in pancreatic cancer has now been published in The Lancet. The median overall survival has significantly increased by 2.5 months with the addition of capecitabine. The accompanying editorial celebrates this but completely fails to mention the JASPAC 1 trial or the drug S-1 that showed an improvement of more than 21 months compared with (not in addition to) gemcitabine. I have written previously about how baffling I find it that the Western world can afford to ignore these results. I was further surprised that the editorial on ESPAC4 didn’t even discuss S-1 to put things into perspective. I am not arguing that the Western world should immediately accept S-1, but doesn’t a benefit of 21 months in pancreatic cancer deserve at least a trial for cancer patients living in the West? Should S-1 be renamed as Nippolimumab and be priced the same as checkpoint inhibitors for the Western world to take any notice?

Bearing a new life will not shorten your own

It is very reassuring to know that pregnancy doesn’t affect survival among women with breast cancer. I can’t stress enough the value of such studies. Having a diagnosis of breast cancer shatters any woman’s world. Only a young woman with breast cancer can understand how much extra stress and anxiety the diagnosis of breast cancer will add if she’s planning to start a family. This study reassures women that pregnancy around the time of, or after, diagnosis of breast cancer, does not worsen survival. Having said that, I would advise patients who wish to conceive and are not in a hurry to wait for at least 6 months after breast cancer diagnosis because the survival seems to be the best for this cohort.

Other mentions

1. In Nature Reviews Clinical Oncology, there is a nice series of three commentaries on anticancer drugs approved in 2016. One discusses the surge of checkpoint inhibitors, another discusses the clinical benefit of the new drugs and the third discusses the value of those drugs in terms of cost-benefit.
2. Addition of temozolomide to radiation therapy seemed to benefit elderly patients with glioblastoma. This is another example that tells us that chronological age alone shouldn’t be a factor in making treatment decisions.
3. If you are the type of oncologist who still doesn’t consider early referral to palliative care as important, here is another study that shows the benefit of early palliative care by improving patients’ quality of lives.

Bishal Gyawali, MD is a postgraduate trainee in medical oncology at the Graduate School of Medicine, Nagoya University, Japan, where he is also a PhD candidate under the Japanese government scholarship. His areas of clinical and research interests include evidence-based oncology practice, global oncology, cancer policy, cancer management in resource-limited settings, financial toxicities of cancer treatment, clinical trial methods and supportive treatment of cancer. He has no conflicts of interest to declare. Dr Gyawali tweets at @oncology_bg. Read his previous blog posts here.