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

The Hopes and Hypes from ASCO 2016

Last month in oncology was dominated by the news coming from the ASCO annual meeting - some excellent research, some practice-changing data, some humbling reality-check information - but also many “hype-driven” studies accompanied with exaggerated news coverage. I have uploaded a separate blog post on the major studies that made headlines during the ASCO meeting, as well as some important studies that were ignored by the media. Please check out my ASCO 2016 special blog here.

The Impatient TIGER has been shot dead

The authors of TIGER-X trial have published an update to the rociletinib data stating that the response rates in the original publication were inflated because - wait for it - they didn’t wait for it! Yes, they didn’t wait for the response to be confirmed after at least 4 weeks, as per the RECIST protocol. But if you look back at the original study, below the table for response, they have mentioned that they measured response based on RECIST criteria! So, basically what happened was that some patients they thought had responded in fact didn’t show response when confirmed with a later scan. Thus, the response rate has dropped.

Oncology drug development is moving at such a high speed that you’re sure to miss a thing or two if you close your eyes even for a moment. Maybe I closed my eyes for too long— that’s why I didn’t notice that phase I trials no longer were meant for dosing and safety data alone. This phase I trial was also supposed to measure response rates, PFS and even quality of life as secondary endpoints. Yes, for a phase I trial! Why the need for such a haste? Is “primum non nocere” no longer the guiding principle for clinical trials? Thankfully, the rociletinib issue has come to the light - but it’s not hard to imagine that rociletinb represents only the tip of the iceberg. How many other drugs must have escaped our scrutiny?

The concluding remark of this correspondence is “This case offers a clear lesson regarding the importance of continued follow-up and supports a strong recommendation to publish rates of confirmed response according to RECIST”.  Hmm... but a lesson to whom? We have always been under the impression that the response rates reported in studies are confirmed response rates.

We have recently seen a big change in drug development process in oncology with the so-called “seamless development” without the classical demarcation of trials to sequential phase I-IV. It is, however, essential to keep in mind the important pitfalls and cautions that accompany this approach. As this NEJM perspective concludes:

“Even as we strive to provide earlier access to highly effective anticancer agents, we cannot abandon our commitment to well-designed, well-conducted clinical trials. Such studies are the only way to obtain the high-quality efficacy and safety data that will enable clinicians to counsel patients about a drug’s risks and benefits, permit patients to make informed choices about their treatment, and ultimately facilitate widespread global access to highly effective new anticancer agents through regulatory approval and reimbursement.”

By the way, this perspective was co-authored by Dr. Richard Pazdur, who has recently been appointed the head of FDA’s Oncology Center of Excellence. His major responsibility would be to caution us to keep our feet on the ground while aiming for the moonshot. 

You can also read a beautiful biographical summary of what went wrong with rociletinib in this commentary in Annals of Oncology.

A TOAD that cannot croak

Toads are known for their croaking sounds - their masculine mating calls used to attract females. Although male toads don’t have prostate glands, humans do and these can be a site of cancer with increasing age. Sadly, prostate cancer is fuelled by androgen hormones - the same hormones that enable males to enjoy a good sexual life.

Androgen deprivation therapy (ADT) in various forms is the standard treatment for patients with prostate cancer who are ineligible for curative treatment or who present with PSA relapse after curative treatment - but timing of ADT is controversial. A trial, termed TOAD (!), tested whether immediate ADT provided any benefit over delayed (> 2 years) ADT in terms of survival. This trial was beset with slow accrual – 293 men recruited versus the target of 750, and showed that immediate ADT improved OS versus delayed ADT ( 5-year OS 91.2% v 86.4%, log-rank p = 0.047, unadjusted HR after cox-regression 0.55, p = 0.050, adjusted HR 0.54, p = 0.074). For PSA relapse patients only (only 32 patients had non-curable disease- so this is basically a trial for PSA relapse patients anyway), the 5 year OS rates were 84.3% v 78.2% ( log-rank p = 0.10). Adverse effects related to ADT was seen in 78% men in immediate group versus 47% men in delayed group and quality of life decreased by 6% in immediate group versus 3% in delayed group. The study authors have done a good job here by refraining from recommending immediate ADT as a standard treatment. They conclude honestly that this data provides important information for discussing the treatment options for prostate cancer patients.

Indeed, the survival rates are pretty impressive in this trial and these data are helpful in discussing the treatment options with patients. Although immediate treatment with ADT seemed to provide some favourable survival results, this has been achieved at a cost of increased adverse events and fall in quality of life. Further, most of the deaths have been unrelated to prostate cancer. ADT is notorious for sexual side effects. It is no surprise that the researchers found that patients preferred to delay ADT during enrolment in this study. The study doesn’t provide comparative incidences of sexual side effects and sexual quality of life in the two cohorts, and the comparative benefits for low risk versus high risk patients. The gains in survival should be carefully balanced against these issues of no difference in prostate cancer-related deaths and increased sexual side effects.

Needlessly to say, most men value their sexual health a lot; but are not always open to discuss it with their doctors. So, there should be no hesitancy on our part to clearly communicate the effects of treatments on sexual health - and this discussion should take place before starting the therapy. I have met some patients who would rather continue to smoke and drink, rather than improve their survival by some months. This would be true for sexual function as well: if I were a toad, I would rather save my ability to croak than to improve the possibility of living a bit longer in recluse. What toad would I be if I couldn’t croak!

But, every patient is unique with unique preferences - that’s why shared decision making is important. There are also evidences now that ADT could be related to depression and other psychiatric problems - what percentage of this is related to sexual side effects remains to be known.  Also, for PSA relapse, ADT is not the only option. For patients whose primary treatment was radical surgery, radiotherapy (RT) is another reasonable treatment choice upon biochemical relapse. Another study has now shown that compared to RT alone, RT 3-month of ADT significantly improved 5 year PFS by 10 months without any improvement in OS. Needless to say, observation alone does remain an important choice for selected patients.

Evidences from studies like these help, but evidence alone can’t care. Caring is our responsibility. Borrowing the words from the expert Dr. Victor Montori: “Each option is a hypothesis, tested in thought experiments in conversation. In these experiments, clinician and patient work together to imagine the impact, favourable and unfavourable, each pertinent option could have over the patient situation. Medicine practiced in this way is not easy. It takes deliberate practice and expertise. It requires clinical curiosity and generosity, and a great deal of compassion, empathy, and humanity. And in doing all these, we must not punish patient with the heavy burden of our arrogant knowledge. Rather, we must care.” If you haven’t read this blog by Dr. Montori, you have truly missed an opportunity to become a better physician.

STRIVEing to understand the prostate
If you found the prostate cancer discussion above confusing, keep striving to understand, because there’s more. In castration- resistant prostate cancer, the STRIVE study has shown a more than one year of PFS benefit with enzalutamide versus bicalutamide. However, OS data are not known, and there is no evidence to suggest that upfront enzalutamide would be better than sequential therapy with bicalutamide followed by enzalutamide. Enzalutamide is also very expensive compared to bicalutamide. Further, in the setting of chemohormonal therapy for high volume disease, it is not known whether enzalutamide performs better than bicalutamide.

Yes, the landscape of prostate cancer treatment is getting increasingly complex. But again, data don’t provide care, physcians do - and we do that by discussing every option with our patients. Patient-physician communication is the best biomarker available to personalise the therapy - whatever informed choice the patient makes is the best treatment. This, truly, is the individualised treatment.

Can HERACLES lift precision oncology?

Tremendous success has been achieved in the treatment of metastatic colorectal cancer (CRC) in the last decade. Besides the classic chemotherapy backbone of fluorouracil compounds, oxaliplatin and irinotecan, we now have 3 angiogenesis inhibitors (bevacizumab, aflibercept, ramucirumab) ,  2 anti-EGFR antibodies (cetuximab, panitumumab), 1 multikinase inhibitor (regorafenib) and 1 cytotoxic agent (TAS-102) approved in metastatic colorectal cancer. However, despite having these new targeted drugs in our armamentarium, the overall survival has improved only modestly while the treatment costs have risen insanely.

A study termed HERACLES showed that refractory HER2 positive disease could have some response to trastuzumab plus lapatinib. Before someone tries to present this study as a landmark finding in support of precision oncology, I should explain that by “some response” in the preceding sentence, I meant 30% objective response. By that I meant only 8 patients as the sample size is only 27. Indeed, only 5% of KRAS wild patients were HER2 positive, and hence the small N in this study, but without randomisation you can’t really be sure if blocking HER2 with these drugs really improves survival for the patient compared to taking other drugs (such as TAS-102) or even placebo.

MAGE in a MAZE

Here, we have the biggest adjuvant trial in non-small cell lung cancer testing an immunotherapeutic MAGE-A3 in patients with resected MAGE-A3 positive NSCLC. After screening 13,849 patients, this trial randomized 2312 patients in 2:1 ratio to receive the immunotherapeutic or placebo.

The result: adjuvant treatment with the MAGE-A3 immunotherapeutic did not increase disease-free survival compared with placebo. Of course, many hopeful trials end up negative but I think this trial should not have been conducted in the first place. Conducting phase 3 trials require huge resources including not only financial and logistic arrangements but also physicians’ and patients’ time and commitment. So, all phase 3 trials should be conducted only on the basis of solid phase 2 evidence. The evidence for this trial comes from this phase 2 trial.

You can see that in this phase 2 trial, there was NO improvement in disease free interval, disease free survival or overall survival. No improvement. How can this be a basis for conducting such a large phase 3 trial? The conclusion of the abstract for the phase 2 trial was startling. It reads: “In this early development study with a limited number of patients, postoperative MAGE-A3 immunisation proved to be feasible with minimal toxicity. These results are being investigated further in a large phase III study.”

It seems the conclusion of this study was written before the results. The results are negative: how can this justify a phase 3?

There have been concerns that it has become too difficult to enrol patients in clinical trials. These huge numbers of patients could have been enrolled in other trials with a stronger rationale. MAGE is a synonym for magician, sorcerer. Cancer treatment is no sorcery. It needs evidence. Evidences are built on steps. The steps of clinical trials and their importance should not be ignored.

The Road Less Travelled
An important paper on AML genomics shows that AML could be classified into 11 distinct subtypes based on the molecular subgroups that reflect the discrete paths in the evolution of AML. This article is a bit difficult to understand for a normal clinician. The gist of it is that we can reclassify AML now based on various distinct genomic characteristics involved in evolution of AML, and this classification can have prognostic and possibly, therapeutic implications. A well-written editorial helps put this article into context in an understandable language.

PET negative: statistically negative but clinically positive
Bleomycin is a toxic drug. Hodgkin’s lymphoma patients are usually young. So, unless there is a pressing reason, you don’t want to prescribe this toxic agent to a young patient. ABVD has remained the standard treatment for HL since decades and PET scan after 2 course of ABVD is known to be predictive—PET negative patients have excellent PFS rates compared to PET positives. So, can we avoid this toxic bleomycin after 2 cycles among the PET negative patients that usually fare well? Researchers conducted a non-inferiority trial to address this important question (non-inferior trials do have their roles in such settings, don’t they?). Patients who are PET negative after 2 cycles were randomised to receive ABVD versus AVD and found no difference in PFS or OS at 3 years.  5% difference was considered the non-inferiority limit and the 95% CI in PFS difference just crosses this margin (-3.2 to 5.3). In any case, we know that 95% is not a magic interval, and the upper limit of CI at 4.9 or 5.3 won’t make much of a difference. Plus the OS is similar. There is now no reason for the PET negative patients to keep receiving bleomycin.

Further research should focus on helping those patients who remained PET positive after 2 cycles - they receive the toxic BEACOPP and still fare poorly!

New standard of care for Burkitt’s lymphoma?
The addition of rituximab to LMB chemotherapy regimen improved the 3 year event free survival and 3 year OS rate significantly in patients with Burkitt’s lymphoma without added toxicity. This could represent a new standard of care and opens up avenues for future studies of chemoimmunotherapy in this disease.

Merck becomes first in Merkel-Cell Carcinoma
The race between nivolumab and pembrolizumab is really interesting to watch. For a rare tumour like Merkel-cell carcinoma, pembrolizumab has shown excellent results with 56% objective response rate, irrespective of viral-positivity status. Again, this is a non-randomised study. So should these results be taken as strong evidence given the rarity of the cancer? Or should we demand a randomised trial even for rare cancers? I really can’t make up my mind regarding this issue - it is a very complex problem. Lowering the bar for drug approval is a disservice to patients with rare cancer, while withholding possibly good treatments because sufficient patients haven’t yet been recruited, also seems illogical. So, I will let the experts talk instead: this from the Rare Cancers Initiative, and this from Dr. Prasad. I would like to hear your opinion in this issue after you have read these papers.

Let me take a selfie
Self-citation is considered to be the "selfie" of academicians. Please allow me to take one selfie here and inform you about a review on cheaper options in CINV prevention that my team and I published last month in JGO. Although financial toxicity has now been acknowledged as an important factor to consider in making treatment decisions in oncology, the cost of supportive care is usually ignored in this equation.

In LICs, sometimes the cost of supportive care can exceed the cost of cancer treatment-especially conditions like chemotherapy-induced nausea and vomiting that require prophylaxis in each cycle of chemotherapy. This review could be useful to oncologists working in LICs.

Last month, we also published the first report of bone marrow transplantation in Nepal. Not a trial or a research on transplant - just a report that bone marrow transplant (BMT) has been performed in Nepal. While the developed nations have been performing many trials on transplant, in a LIC like Nepal, BMT service is only starting. This provides a reality check to many transplant patients and physicians all over the world who take so many privileges for granted. There are many countries where transplant services have not yet dawned.

Malignancies are slowly overtaking infectious diseases as the leading cause of morbidity and mortality in LICs but unfortunately, LICs aren’t yet ready to fight this battle. The difference in cancer care standards between LICs and HICs has become so big that it is not even possible for an oncologist in one setting to properly communicate with an oncologist in the other. With the personal experience of cancer care in both Nepal and Japan, it pains my heart to see the rampant waste of resources in HICs on marginal therapies while people in LICs are deprived of life-saving treatments. I am sorry to complain about this, but many in HICs are indeed blind to the plight of LICs, and thereby ungrateful to the privileges we take for granted in HICs. As a representative of oncologists and patients from LICs, I am just trying to say “Me, too”.

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 last month's blog here.