Last Month in Oncology with Dr. Bishal Gyawali: September 2016

18 Oct 2016

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

First, my apologies for being late in updating the blog for September. I was busy with the ESMO Congress and have made video blogs instead, summarising the major results presented at the meeting. It was a nice experience to actually talk in person and summarizer the highlights of ESMO 2016 for you. If you haven’t yet, please check out the video blogs here and here.

The PROTECT trial was probably the most talked about study in oncology in September. I have already commented on that study in a separate blog here.

Here, I discuss other important studies in oncology from the month of September.

Is there such a thing as too much “Avastin” optimism?

We recently wrote an editorial in ecancermedicalscience titled “Negative trials in ovarian cancer: Is there such a thing as too much optimism?" In that editorial, we argue against conducting lots of phase 3 trials without having sound phase 2 data of efficacy and concluding positively based on statistical significance despite clinically futile results in ovarian cancers. Lately, I have started to realise a similar pattern with bevacizumab (Avastin) for breast cancers. There were reasons why FDA took the bold step of revoking the approval of bevacizumab for breast cancers.

Since then, despite consistently negative OS among trials, there has been no decline in phase 3 studies of bevacizumab in breast cancer-just in the hope of getting something to stick to in order to hail the drug as positive for breast cancer. Astonishingly tenacious, the Avastin trials in breast cancer don’t seem to be giving up until an overpowered trial in some special setting finally attains that elusive P of less than5%. In May, I criticised bevacizumab in the context of the BEVERLY-1 trial in breast cancer. In September, we have the TURANDOT trial (seriously, who named this trial?) that set out to show non-inferiority of bevacizumab-capecitabine compared with bevacizumab-paclitaxel with regards to overall survival. 

Both these regimens have not yet demonstrated better overall survival versus chemo alone. But they want to prove that one bevacizumab-chemotherapy combination is non-inferior to another bevacizumab-chemotherapy combination. Well, you know what else would be non-inferior? Sneezing through your right nostril would be non-inferior to sneezing through your left nostril. But we don’t conduct such studies. Why not? Because it would be pointless! First, you need to show sneezing is helpful - only then does comparing left versus right make any sense. We don’t know bevacizumab is helpful, but we are conducting this trial with an odd name comparing two different bevacizumab regimens. Why?

Maybe I have an answer. I just attended the ESMO congress in Copenhagen and there were a couple of industry stalls where they provided you with a virtual reality experience. They take you to a virtual scuba dive and among the sharks, you get the chance to see the response rate tables for their drug. From the bottom of ocean floor, comes the Kaplan Meier graphs. In the rocks, there are waterfall plots. It’s really an amazing experience. But what’s the point? Why spend so much in telling me things that I would research myself if I were really interested? But again, what’s the point in this TURANDOT trial too? I have come to realise that there’s no point in looking for any points in these trials. Luckily, I get to rant here and vent my frustration. How do you take out your anger/surprise/bewilderment when you see such trials published in “good” journals?

Imprecise Precision Oncology

I can’t wrap my head around the fact that “precision” oncology relies on very “imprecise” method of testing for multiple genetic alterations and targeting them irrespective of sites of origin. Endeavours such as basket trials lump all tumour types together based on a common genetic alteration but we now know that the same genetic alteration behaves differently according to tumour types. So, our way should be to investigate the genetic alterations in each cancer separately like EGFR for lung cancers.

Another nice study showing promise was targeting BRAF in papillary thyroid cancer with vemurafenib. Good response rates but concerning side effects as >60% patients had serious adverse events with vemurafenib in this non-randomised, open label phase 2 study.

All fine and good, until I read the conclusion: “As such, this agent represents a potential new treatment option for these patients.”  Really?  What would be wrong here if the authors instead said: “this could represent a new treatment option but needs to be confirmed in a double blind phase 3 RCT” - ! Maybe the funder would be angry?

The Precision Oncology Illusion
Vinay Prasad has (again) thrown cold waters over the hypes of precision medicine by showing the reality of where we exactly stand with regards to precision oncology in his Nature perspective. By contrast, there was a JCO article celebrating the recommendations by NCCN to do molecular profiling of all advanced bladder cancers. That was a big surprise coming from NCCN, because bladder cancer doesn’t have a single approved targeted agent proven to act in any mutation that might be discovered.

Also, another obvious question, is "why bladder cancer?" Further, despite not having any actionable target, what’s the cause for celebration just because you can do molecular profiling! We do things because they ultimately improve outcomes, not because we enjoy doing them.

By the way, here’s a fun game to play. It took me 15 minutes to read (not scroll) through the COI list of all authors in the JCO paper.  How fast can you read through the same COI list? Why not try to beat me!

That’s why they are called surrogates
Overall survival benefit in Phase III RCTs provide the best evidence for the efficacy of any agent. Any benefit in phase II trials or any benefit in other markers in phase III trials are just surrogates and they should be treated as such. That’s the lesson from this negative trial of cabozantinib in prostate cancer, despite getting positive results in phase 2 trials and despite positive results with regards to surrogate markers such as bone scan responses, radiographic PFS, skeletal events, circulating tumour cells and bone biomarkers. Surrogates are called surrogates because they are a proxy for the truth.

Conflicting Editorials
One subgroup analysis of the AURELIA trial has shown that the benefit of adding bevacizumab to chemotherapy might be of greater benefit for those with secondary platinum resistance versus primary platinum resistance in metastatic platinum resistant ovarian cancer. An accompanying editorial commenting on this work concludes: “we cannot simply conclude that saving the first validated targeted therapy, and maybe the ‘best’ (bevacizumab), should be preferentially used later in the treatment paradigm. It remains fundamental to solid tumor oncology that utilizing the most active agents early provides maximal opportunities for clinical benefit”.

I find these concluding lines concerning because bevacizumab is not the best targeted therapy (being first targeted therapy versus last has no clinical significance) and most importantly, it has consistently failed to improve survival especially when used early (in 1st line) but has shown some benefit in later lines.

I would instead conclude: “It remains fundamental to oncology that the editorials are written by experts who don’t have relevant conflicts of interest. In this big world, there is no shortage of experts without conflicts that can provide an unbiased commentary. Having a long COI list is not the testimony of expertise.”

Let me take a selfie
Mammography screening of breast cancer is a matter of controversy because it has not shown to improve overall mortality. It does seem to reduce breast cancer specific mortality in a certain age group, but is ineffective for women at younger ages. For low-income countries, mammographic screening does not represent a good value for investment because of younger age of breast cancer patients and competing causes of death. Mammography further leads to many false positives. Nevertheless, low- and middle-income countries have recently begun to incorporate mammography screening into their health agenda.

As low-income countries try to fight off the future tsunami of cancer patients, the low-income countries need to be very careful in deciding the priorities for national cancer policy programmes, and must not spend their limited financial reserves in conducting futile campaigns such as mammography screening. This is what we highlight in our September paper “Should low income countries invest in breast cancer screening?”.

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.