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Last Month in Oncology with Dr Bishal Gyawali: August 2016

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

Don’t take my weight lightly

Until a few years ago, I used to chuckle with self-satisfaction whenever I read any research linking obesity with cardiovascular disease or cancer.

I think I had pride at being thin and maybe a subconscious contempt towards being obese.

A feeling similar to what you, as a nonsmoker, experience while reading an essay on the harms of smoking. But that was the story of a few years ago.

Add a couple of years filled with hours of sedentary work and litres of alcohol, I now feel afraid and embarrassed to read papers such as this by the International Agency for Research on Cancer.

My BMI now belongs to the overweight category and according to this latest review there is now sufficient evidence to say that I am at increased risk for nearly all cancers: oesophageal, gastric, colorectal, liver, gallbladder, pancreas, renal, thyroid, breast and uterus.

Oh, not the last two-my gender protects me against them, thankfully.

Even meningioma and multiple myeloma - diseases I thought had nothing to do with my pants size - are now shown to have enough evidence of association with obesity!

To rub salt into the fat, another study has shown that the risk for all-cause mortality is also significantly higher for we fat mortals compared with our lean counterparts.

Thus, we can no longer take our weights lightly, folks. Let’s do whatever it has to be done: long have we sat, let’s get up and run!

Let’s give up that desire to grab food even after the stomach is nearly full. No junks. No alcohol. No, that’s too radical - control alcohol! Go to the gym. Let’s burn those calories!

Multiple options in multiple myeloma

The treatment paradigm for multiple myeloma has evolved so greatly in last few years that only an expert can dare to comment.

I, therefore, don’t want to comment in detail on this study that showed excellent PFS benefit (HR 0.39, 95% CI 0.28 to 0.53) with addition of daratumumab to bortezomib plus dexamethasone combination among patients with relapsed or refractory multiple myeloma.

However, I am not happy with the control arm: bortezomib plus dexamethasone. In this trial, 65.5% had received previous treatment with bortezomib - usually, a new proteasome inhibitor or an IMiD would be prescribed for such patients.

Maybe some clue lies in this paragraph:

'Janssen Research and Development sponsored the trial. The sponsor and investigators were jointly responsible for the trial design and the statistical analysis plan (available with the protocol). The investigators and associated research teams collected the data, which were compiled and maintained by the sponsor. One of the authors who was an employee of the sponsor was the physician responsible for the trial. Professional medical writers were funded by the sponsor to prepare the manuscript for submission.'

Now compare that with this in the MINDACT trial report:

'The drugs that were administered during the study were provided by Novartis, Sanofi-Aventis, and F. Hoffmann–La Roche, which had no other role in the study, were not involved in the collection or analysis of the data, and did not contribute to the writing of the manuscript.'

Which study would you rather believe?

Financial conflicts of interest

Speaking of financial conflicts of interest (FCOI), two studies in JAMA Oncology have shed further lights on the problems of FCOI in oncology practice and research.

NCCN guidelines are one of the most referred to and trusted sources of information for oncology practitioners worldwide but 81% of the guideline authors had at least one FCOI.

Another study showed that most of the FCOI disclosure slides at ASCO meetings were flashed so fast that ordinary mortals couldn’t read. An accompanying editorial discusses the complexities of FCOI in medical research: there are definite benefits to industry-academia collaboration, but there are also palpable risks of bias as a result of this FCOI.

So, how best to address this issue? Is a mere disclosure enough? Although these are complex issues and need in-depth discussions among the concerned authorities, there are at least two important steps that can be taken immediately in my opinion:

  1. Most of the COI statements in academic publications are visible only with the full text or pdf of the article, but not the abstract. In reality, the majority of the readers read only the abstracts of the articles. Hence, FCOI disclosure should be attached with the abstract itself and not hidden behind a paywall. The FCOI statements should be visible while viewing abstracts in databases such as PUBMED itself.
  2. Only those experts that have no FCOI should be asked by the guidelines committee or the journals to provide expert opinions. There is surely no lack of experts in the medical community to provide an expert objective commentary-having COIs is not equivalent to expertise.
     

Would you scan Heisenberg’s thyroid?

In my last blog about the MINDACT trial in breast cancer, I discussed how precision medicine is a great example of Heisenberg’s uncertainty principle.

With increasing precision in diagnosis, we are faced with increasing uncertainties in making treatment decisions. For instance, we are now detecting alarmingly high number of thyroid cancer cases with precision, but are uncertain about how best to manage them.

There is no evidence that detecting these thyroid cancers early with ultrasound scan would change the outcomes. Notwithstanding, we have been performing huge number of scans, detecting large number of early thyroid cancers and wondering what to do with them.

But the problem is that we don’t just wait and wonder! We want to do something with that tiny thyroid mass now that we have detected it! Doing satisfies the vanity of us being doctors.

As a result, many of us end up harming the patients by offering surgeries and invasive treatments; although our intentions were noble.

Thus, improved precision is not always a good thing. Why would you want to find something if you don’t know what to do with it?

The STORM of overdiagnoses

Our addiction with finding a tumour and doing something about it is incomprehensibly strong.

Mammography is not known to prevent overall mortality. It does prevent breast cancer related mortality without preventing all-cause mortality in the age group of 50-69 but the magnitude of benefit is small.

While the utility of mammography itself is debated, the investigators of the STORM-2 study “examined whether integrating 3D mammography with either standard 2D mammography acquisitions or with synthetic 2D images (reconstructed from 3D mammography) would detect more cases of breast cancer than 2D mammography alone”.

And guess what? In 9677 screens, 2D-3D mammography, 2D synthetic–3D mammography and 2D mammography alone detected respectively 82, 85 and 61 cases of breast cancer (the newer methods detected nearly 20-25 more cases) but the rate of false positives in these respective groups were 381, 427 and 328 respectively (nearly 60-100 MORE cases of false positives with the newer methods). What a trade-off!

Save breasts

Now that we have detected breast cancer early, should we do breast conserving surgery followed by radiation or perform mastectomy?

Of course, we go with the former unless absolute reasons exist to do mastectomy. But we can now recommend breast conserving surgery (plus radiotherapy) with more confidence because this population-based study from Netherlands shows better survival results with this strategy versus mastectomy.

Multiple lessons in one trial

Recently, we have seen that many patients enter RCTs to get treated with the new agent. This problem is severe with open label randomized trials, where patients are too disappointed being randomized to control arms.

However, trials such as this make us realise just how many people have been saved from unnecessary toxicities and harms of new therapies by being randomized to placebo or control arms.

This study found that adding zoledronate (zometa) to standard chemotherapy in osteosarcoma was not effective.

The 3Y event free survival rate was 63.4% in the control arm versus 57.1% in the zometa arm: a substantial 6% lower event free survival with the addition of zometa that nearly missed statistical significance (95% CI 0·95–1·96). More or newer may or may not be better and it is this clinical equipoise that forms the basis for conducting a RCT.

Another important lesson from this trial concerns the media and public hype surrounding animal experiments. Nearly on a daily basis, we see the lay press filled with news of some breakthrough treatments that can cure some cancers.

But if you look for the original study that formed the basis for such news, you find that it was an experiment conducted in mice or other animals. Some news stories entirely fail to mention this important fact; that it was an animal experiment.

Those who do mention it do so not in the title or the first paragraph but somewhere towards the end of the article which most of us don’t read.

The basis for conducting the above phase III trial of zometa in osteosarcoma was also animal experiments.

Many experiments in lab animals including mice showed that zometa had efficacy in osteosarcomas. But in a well conducted RCT in humans, those results couldn’t be replicated.

This brings us to another important topic of discussion: The importance of RCTs.

Recently, NEJM has published a few opinion pieces such as this where the experts have questioned the significance of RCTs in modern era. But, it’s only an RCT that can provide the definitive answer to the efficacy/harm of an intervention.

If we had no RCTs, we would be giving zometa to our osteosarcoma patients and harming them because zometa made biological sense and provided good results in animal experiments.

Indeed, RCT has its flaws but the solution to a bad RCT is a good RCT, not no RCT. Please read a great argument in favor of RCTs by Dr. Vinay Prasad here.


Let me take a selfie

Speaking of Vinay Prasad, he and I have together published an editorial in the ecancermedicalscience journal where we talk about the recent negative trials in ovarian cancer, the importance of differentiating clinical meaning from statistical significance and the need to conduct big phase 3 RCTs only when backed with good phase 2 data.

By the way, I have been writing this “let me take a selfie” section in my monthly blog since May. So you can understand my big surprise when these two big scientists (their surnames look like selfies of each other!) published a paper in PNAS on August titled - wait for it - “Science in the Age of Selfies”!  And they use selfies for precisely the same meaning - self promotion!

If not for anything else, you should read that paper just for the photo of a cute looking Einstein taking a selfie.

Preserving fertility

This study published in JCO shows that GnRH agonists mayn’t be effective in preserving ovarian function and fertility in lymphoma survivors treated with chemotherapy.

Although an earlier study among patients with breast cancer showed probable benefit of GnRH agonist, currently the safest bet is to recommend oocyte preservation before chemotherapy.

This editorial discusses the complexities of pharmacotherapy based fertility preservation techniques in good detail.

The fatal attraction to testing - again!

In July’s blog, I covered the fatal attraction to testing CA-125 in ovarian cancer patients to detect relapse.

In August, we have another study on addiction to testing; this time it’s excessive serum tumour markers and imaging assessments in women with metastatic breast cancer. The accompanying editorial is also a good read.

But, seriously, who keeps the count?

How did such news of huge importance escape my attention! I am writing about it now, just in case you were as unaware about it as myself. Ejaculation decreases your risk of prostate cancer! Yes, that’s it. A good, happy news for all guys. Of guys between 20-29 yrs old, compared with those who ejaculated 4-7 times per month (poor guys!), those who ejaculated > 21 times per month (what? Are they real?) had 19% lower risk of prostate cancer incidence. With age, this benefit increases. For those between 40-49 yrs of age, the risk decreases by 22%! There you have it. Keep calm and carry on!

But he must be a beast who did > 21 ejaculations a month at the age of 40s, you might argue. I got more good news from another study just published. Analysis of the REDUCE study has shown that the use of PDE 5 inhibitors such as sildenafil was safe and in fact, was associated with an inverse trend of prostate cancer diagnosis in North American men. Good luck.


And finally

It’s important to keep in mind that capecitabine treatment can lead to loss of fingerprints which can have important legal consequences. You might find it interesting to note the authors’ affiliations in this paper.

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