Hope it’s not too late to wish a wonderful 2017 to all my readers. I would like to express my deepest gratitude for your support in 2016 and hope you will be kind enough to continue the same in 2017.
2016 was an important year in oncology providing us with some hopes and many hypes. I have summarized the major advances in oncology from last year in this blog.
The treatment is safe, OK, but what’s the point?
In one study, a photodynamic therapy showed improved PFS versus active surveillance in low-risk prostate cancer. This was another super hyped study (if high altmetrics is your target, try writing about PSA). One news outlet reported that the industry was seeking approval of this treatment “as early as possible, because for now, all they can tell their many callers is that the trial is over and the treatment is no longer available.” The authors of the study argue that it doesn’t have much toxicity. But the fact of the matter is low risk prostate cancer doesn’t require immediate treatment. One of the biggest trials in this context, the PROTECT, has shown no difference in overall survival (OS) with active surveillance (AS) versus radical treatments. In fact, experts are now debating whether we should reconsider the label of 'cancer' for low-risk prostate cancer because most of the people with this diagnosis don’t die of prostate cancer. In this context, why is it exciting to have this treatment that will merely prolong PFS? Improving PFS versus no active treatment (AS) is not a good enough bar to estimate efficacy. Patients should live longer by taking this agent. If they don’t, we would be just over-treating our patients albeit with a sexy drug! Did I mention that this drug is derived from bacteria found at the bottom of the sea, injected into blood and is activated in prostate by laser beams?
The authors argue that this treatment is safe but if it is unhelpful, safety alone doesn’t make much sense. Surely the authors don’t consider financial toxicity under safety issues, because I am sure it’s not cheap to find bacteria under the bottom of the sea and use laser beams to activate the drug.
In my previous blog highlighting the important advances in oncology from last year, I asked why S-1 hasn’t be accepted by global community for advanced pancreatic cancer despite improving OS by 21 months. It didn’t even receive good media attention. It had a poor altmetric score of 29 (versus 1344 for this prostate trial). I think I now have the answer: because it was not immunotherapy, not developed from under the ocean, doesn’t need laser and is not expensive.
CAR-T cell therapy in glioblastoma: a lesson on medical journalism
CAR-T cell therapy has had an undulating story in oncology with some hopes in haematological malignancies alternating with technical difficulties, safety concerns and temporary FDA halting. Recently, a study was published in NEJM that showed CAR T-cell therapy produced regression of glioblastoma. Glioblastoma is a highly lethal cancer, and CAR-T cell therapy hasn’t shown as much promise in solid tumours as it has done in blood cancers. Thus, it’s natural that this study made a lot of news and sparked hopes among many cancer patients. Everyone is now excited that CAR-T cell therapy could be the 'game changer' for glioblastoma that we’d all been waiting for. Well, the catch is….. this report was not a study; it was just a case-report. Yes, this study was observation in ONE patient! In this patient, the response with CAR-T therapy was sustained for 7.5 months after which the tumour recurred. I have no complaints about this paper; it’s a nice report providing some reasons for cautious optimism. But the astronomical hype it has received, fuelled by the comments from the authors in media has baffled me. Can’t we please remain truthful? We have no idea whether this therapy works in other patients, no idea whether it improves survival, no idea if it’s safe. Although the media was full of how exciting and safe this treatment was, we can’t conclude safety from 1 patient, especially given the history of some lethal toxicity with this approach. I also take this opportunity to request the medical journalists to take the opinions of some uninvolved experts while publishing such news. Most news I read on this 'study' included the opinion of one of the authors involved in it. Of course, if you ask me about my own study, I will say nothing but good things about it. It doesn’t make sense. Please get opinions from uninvolved experts to really know how meaningful the study is.
Similarly, another instance of remarkable response by T cell transfer was observed in a patient with KRAS mutated colorectal cancer. I will discuss about it in detail when there’s actually some demonstrable benefit to patients at large.
FALCON still flying high?
The FIRST trial showed that fulvestrant had better outcomes (time to tumour progression and OS) versus anastrozole as first line hormone therapy in advanced breast cancer in a phase II setting. FALCON was a nice double-dummy phase III trial that confirmed this benefit by showing a 2.8 months improvement in PFS with fulvestrant versus anastrozole. With the introduction of CDK inhibitors such as palbociclib and ribociclib into the treatment landscape, one could argue the significance of these results but it should be remembered that the CDK inhibitors (hormone therapy) are yet to show any OS advantage in RCTs, have higher toxicity and their cost per month is over 10,000 USD; more than 10 times that of fulvestrant. The authors correctly argue that fulvestrant monotherapy can provide a reasonable alternative to the expensive 'ciclibs, especially when aggressive therapy is not needed or in low income countries. Given the history of bevacizumab and everolimus in breast cancer (these drugs showed very impressive PFS advantage in breast cancer that failed to translate to survival benefit), I think it is premature to get tremendously excited about the CDK inhibitors without seeing any survival data yet. However, the sad thing is that even fulvestrant costs more than 10 times that of anastrozole. Another factor to consider in making shared decision between fulvestrant versus anastrozole is that fulvestrant is an intramuscular injection while anastrozole is an oral drug. I wonder how more useful such trials would be if they just added a couple of questionnaires to evaluate patients’ preference as well.
Cancer drugs, survival and ethics
A European phase II trial has shown that regorafenib could have some efficacy in non-adipocytic sarcoma. However, pazopanib is already approved for this indication and I wonder how ethical it is to have an arm that receives placebo. The BMJ Analysis paper highlighting the perverse incentives and ethical crisis of oncology trials comes to mind. The modern oncology trials answer the questions that are needed for approval and marketing; they don’t answer the questions that clinicians and patients need answering. To the investigators credit, however, they’ve planned a new cohort of patients who had already received prior pazopanib-only in this cohort it is ethical to ask patients to get randomized to placebo.
It is also appropriate here to mention this nice study where the authors assessed 53 new cancer drugs approved between 2003 and 2013 and found that only 43% increased OS by more than 3 months and that 45% reduced patient safety. Yes, we are making some progress in our fight against cancer but it is clearly not enough. If there are enough incentives to keep testing marginal me-too drugs, the situation won’t improve.
Unfortunate for patients, but good reporting practice
A phase II study was conducted to compare selumetinib plus MK-2206 versus mFOLFOX in patients with metastatic pancreatic cancer who had progressed on gemcitabine-based therapy. Unfortunately, both the OS and PFS were shorter in the experimental arm. The OS was shorter by 2.8 months (although this was NOT significant) and PFS was shorter by 0.1 months (this WAS significant- funny statistics!). The author could have downplayed shorter OS by stating the lack of significance but credit to them that they have unambiguously reported OS as shorter. I have seen some other trial reports where even after finding no benefit in any efficacy, the authors beat about the bush by saying biomarkers are needed to identify the subgroup that benefits. Thankfully, the authors stay true here.
Not yet ASSURED of S-TRAC
The S-TRAC trial published in NEJM last month tested the efficacy of adjuvant sunitinib in high-risk renal cancer after surgery. This trial showed some benefit in disease-free survival with the use of 1 year of adjuvant sunitinib versus placebo without any survival benefit (yet). Should this change practice? The answer should be a clear “no” because improving survival is of utmost importance when prescribing a drug as toxic as sunitinib for 1 year in the adjuvant setting. Furthermore, another similar trial named ASSURE has shown that this strategy doesn’t even improve DFS, much less OS. When a toxic drug has shown conflicting DFS benefit and no OS, we are at more risk of harming the patient than benefiting him/her by using this agent. What’s the solution? Only open data can provide reliable answer by allowing individual patient data analysis. For such scenarios where trials are completed and provide opposite results, it should be compulsory to open and pool the data for the sake of greater good. This brings me to my selfie.
Let me take a selfie
Because there is no open data for individual patient analysis, the next best thing is to conduct a meta-analysis with trial level data. I conducted a meta-analysis of the above two trials and it is now published in Annals of Oncology. Unsurprisingly, there was no benefit in DFS or OS with clear increase in adverse events with the use of sunitinib as adjuvant therapy for high-risk renal cancer.
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 his previous blogs here.
(17 Feb 2017)