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Last Month in Oncology with Dr. Bishal Gyawali: July 2017

Independent ecancer blogger Dr Bishal Gyawali rounds up the latest publications in oncology

How much more evidence do we need?

Last year we had the results from the PROTECT trial comparing active surveillance (AS), radiotherapy (RT) and radical prostatectomy (RP) among patients with PSA detected localized prostate cancer with a median follow up of 10 years. We saw that these patients rarely die of prostate cancer, and both overall mortality and prostate cancer mortality didn’t differ across the three groups. However, patients randomised to RT and RP suffered more toxicities than AS. The obvious conclusion was that AS is enough for most patients and PSA based screening mightn’t be necessary. Obviously, nuances apply and I have discussed them in detail here.

Last month, 20 year follow up results from the PIVOT trial- another big trial testing RP versus observation- was published. It has similar conclusions: “Surgery was not associated with significantly lower all-cause or prostate-cancer mortality than observation. Surgery was associated with a higher frequency of adverse events than observation but a lower frequency of treatment for disease progression, mostly for asymptomatic, local, or biochemical progression.”

Both the PROTECT and PIVOT conclude similarly that immediate treatment isn’t necessary and AS would be sufficient. The interventions like surgery and RT come with toxicities, and if we can avoid them without compromising survival, that’s obviously the most prudent strategy. In this context, an important study published in JCO also shows that among long-term survivors of localized prostate cancer “Overall, 14.6% expressed treatment decision regret: 8.2% of those whose disease was managed conservatively, 15.0% of those who received surgery, and 16.6% of those who underwent radiotherapy”.

However, I am surprised to see that some experts still advocate immediate treatment. How much evidence do we need before we give up on our pet theory/practice/belief?

Appropriately, the NEJM also has a nice perspective article on AS as a viable solution to overtreatment.

A Basket of new trial designs

There is a nice review in NEJM if you want to learn in detail about the newer designs of clinical trials that have become the buzzwords in modern oncology: basket, umbrella and platform. In oncology, these trial designs are getting increasingly common as we try to accelerate the drug development. I totally understand that we need better drugs faster. Hence, the need for novel trial designs. But it is also important to remember the many pitfalls associated with these newer drug designs. I have discussed them previously in my commentary of the I-SPY 2 trial. It is important to understand these pitfalls because speed is not the only thing the oncology community needs.

Speed supersedes safety and efficacy?

Speaking of speed, we have recently seen some accelerated approvals-such as that for pembrolizumab and nivolumab for MSI-high or deficient MMR tumours- by the FDA based on response rates in single arm trials alone. I understand the need for early access to better therapies. I also know that response rates fall in phase III trials compared with early phase trials and that many drugs that looked promising in early phases actually fail in later lines. What I don’t understand is how is it OK for drugs that are provided 'accelerated approval' to not be tested in a subsequent RCT, or fail a subsequent RCT and still retain the approval. It is imperative for all indications receiving 'accelerated approval' to have a robust confirmatory RCT; it’s a surprise that this even needs be said! Without those studies, an honest conversation between an oncologist and the patient would be something like:  “Look, here is a new, super expensive, super toxic FDA approved drug for your cancer. We don’t know if it prolongs your life compared to the cheaper control or if you might be better off not doing anything. We don’t know whether this will make you feel better. But, some patients’ tumour size has decreased with this drug! We find that with scans. But we don't know if that tumour size would have decreased with other treatment as well because we have never compared them! We also don’t know that decreasing tumour size would make you live longer! So, do you want to take this drug?”

This drug is good; it doesn’t make you feel worse

Olaparib - a month of which costs more than 12,000 USD - improved only PFS in patients with BRCA mutated relapsed platinum-sensitive ovarian cancer when used as maintenance in a phase 3 trial. OS data are immature but at the time of this analysis, OS wasn’t longer with olaparib versus placebo. Maintenance therapy by default has to improve OS; improving only PFS using maintenance therapy doesn’t make sense. But my biggest surprise was the conclusion that olaparib improved PFS “with no detrimental effect on quality of life”! Isn’t it imperative to improve quality of life for a drug that prolongs only PFS but not OS? This seems to be a nice strategy: Instead of making better drugs, let’s lower the benchmark so much that every drug is a game-changer!

Show me one positive trial…please!

For all the noise of precision oncology, the fact is that there is currently not a single randomized trial to show that the precision approach to cancer care improves outcomes compared with the conventional approach. However, for all its flaws, there exists an RCT, which shows that precision approach doesn’t provide any additional benefit. So, I think it’s premature to ask for “making precision oncology the standard of care”. Don’t get me wrong, I’m all for precision oncology but don’t we need data first? Precision oncology is great, but how? When? What did it accomplish that conventional didn't? How many lives did it save? At what cost?

Anyways, one reason why precision oncology hasn’t been able to deliver is, in my opinion, imprecision in the measurement and validity of biomarkers - the very foundation of precision medicine. I write in my commentary (plus debate) in JNCCN about how the biomarkers that we have are unreliable, how precision oncology cannot be considered successful yet, and how achieving precision in measuring biomarkers is important for the success of precision medicine. Thankfully, JNCCN has made this commentary open-access, so you can read it for free.

Immunomumabs aren’t the answer to all cancers

It is easy to get swept away in hype and believe that immunotherapies are the answer to every cancer; but immunotherapies don’t seem to have the Midas touch we hoped they’d have. Another sobering story comes unfortunately in a cancer that lacks options and is a real “unmet need”. Tremelimumab has failed to improve survival versus placebo among patients with relapsed malignant mesothelioma in the DETERMINE trial.

Conventional chemotherapy stands tall

Another unmet need in oncology is sarcoma and here there is further bad news. Although treatment options for sarcoma have expanded slightly in recent years with the introduction of pazopanib, eribulin, trabectedin and olaratumab in the metastatic setting, the standard (neo)adjuvant treatment regimens have remained the same for past many years. In an important phase 3 RCT, the European colleagues tested whether a histology driven treatment of sarcoma conferred better outcomes compared with blanket treatment with epirubicin plus ifosfamide in the neoadjuvant setting. Unfortunately, it didn’t and the current standard remains the same; epirubicin plus ifosfamide with its toxicities and limited benefits. In this trial, the control arm performed significantly superiorly to the experimental arm.

Let me take a selfie

In fact, regorafenib seems to be a selfie of sorafenib; but with some edits to make it look more beautiful. You could say regorafenib is an expensive version of sorafenib. In a new policy paper in Nature Reviews Clinical Oncology, we show that although regorafenib received approval in 2nd line treatment of hepatocellular carcinoma, the real benefit it provides is minimal and only to a select few patients with HCC. Further, regorafenib wasn’t tested against sorafenib and costs more than sorafenib; so down the drain goes the argument that me-too drugs drive competition and lead to lower prices!

 

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. He is also a medical consultant at Anticancer Fund, a not-for-profit organization based in Belgium as well as holds an affiliation at Institute of Cancer Policy, UK. 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.

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