Independent blogger Dr Bishal Gyawali rounds up 2016's publications in oncology

2016 was an important year for me, as I started to write blogs for ecancer starting in May. I would like to thank you all immensely for your continued love and support, both for me and my blogs. The blogs exist for a reason and that is to satisfy you and your quest for a quick unbiased update of what’s happening in oncology lately. Truly, it’s impossible to follow every study closely, much less read between the lines and that’s the reason I decided to undertake that responsibility. I stay deeply grateful to all of you who have helped shape this blog into what it is today.

As we enter the end of this year, I summarise some of the most important studies in medical oncology from 2016. I have grouped them into 2 headings: the High Value studies and the others. The High Value studies are the most important studies that either led to practice-change or have the potential to greatly influence patient outcomes. The “Other Studies” are other important take-home studies from 2016. Then numbers within the headings mean nothing. This blog doesn’t touch upon haematological malignancies.

1. The long term follow up results have shown that adding PCV to radiotherapy improves survival by 5.5 years with a hazard ratio of 0.59. Yes, you read it right-it’s 5.5 years, not months. Such a high bar is what the patients ideally expect of us in oncology. Although this was already standard practice in most institutions, this should be now in every institution.
2. I don’t know if it’s ever possible to discuss the management of PSA-detected prostate cancers without being dichotomised into a “PSA-lover” or a “PSA-hater” but the PROTECT trial was one of the most important trials of 2016. All I will say here is for PSA-detected low risk prostate cancers, it’s most appropriate to protect patients’ prostates and their sexual health by active surveillance as the survival doesn’t differ but quality of life declines if you choose to chop the prostates off or burn them down with radiotherapy. Sometimes not intervening could be the best thing we can do. But of course, medicine is never that simple and individual decision making is complex with many caveats coming into play which I discuss here.
3. Eribulin should be the standard of care for advanced sarcoma post chemotherapy after prolonging OS. However, sarcoma is an interesting disease and this OS benefit was achieved without benefit in PFS. On the other hand, trabectidin prolonged PFS meaningfully but had no effect on OS. In any case, given the higher toxicities and lack of OS benefit with trabectidin, eribulin should be the standard agent after progression on standard chemotherapy. Unfortunately, many patients with sarcoma have too poor PS as disease progresses and both these agents can usually not be used. On first line, however, a phase 2 study has shown an OS benefit of nearly 1 year by adding olaratumab to doxorubicin! Such OS gains are unprecedented in sarcoma and although this was a small phase 2, this agent should be a standard until we have a definitive phase 3 study.
4. For patients with squamous cell cancer of head and neck nodal stage N2/N3, PET-scan-based surveillance post-chemoradiotherapy can save them from undergoing unnecessary neck operations with no difference in survival. This approach also seems to be cost-effective. Where PET scans are not a logistic/financial issue, this should be a practice changing result.
5. Nivolumab failed to improve outcomes in 1^st line non-small cell lung cancer (NSCLC) but pembrolizumab won the competition by showing PFS and OS benefit in the same setting; albeit only among those patients whose tumour was positive for PD-L1 by more than 50%. Pembrolizumab should now be the standard 1^st line agent for patients with PD-L1 positivity and no EGFR mutations. For patients with EGFR mutations who develop resistance to 1^st line EGFR TKIs due to development of T790M mutations, osimertinib should be the standard.
6. For recurrent squamous cell carcinoma of head and neck, nivolumab is now the standard based on improved OS results in this trial presented at ESMO 2016. The median OS benefit, however, is less than 3 months and begs the question of whether it’s worth the toxicity (including financial).
7. A study from France showed that the use of a web application not only significantly improved survival, but also led to better PS upon relapse, receiving early supportive care and lesser exposure to scans compared to standard follow-up. And this improvement in survival was more than what we saw with immunotherapies: 7 months. Did anyone rush to incorporate this strategy into their practice? How much more noise would have been heard had any drug delivered a similar 7 months of benefit?
8. A Japanese trial, JASPAC 01, showed that as adjuvant treatment of pancreatic cancer, S-1 improves the OS by a sizeable 21 months compared with gemcitabine! Again, I wonder why such a big margin of benefit doesn’t bring big news of excitement in Europe and US. While it’s true that S-1 showed higher toxicities in the Western population compared to the Asian population in past studies for other cancers, isn’t it worth testing (at lower doses?) for pancreatic cancer again? Aren’t the toxicities with immunotherapies more troublesome than those with S-1? Instead, ESPAC4 trial was celebrated at ASCO where adding capecitabine to gemcitabine for the same indication found a survival benefit of 2.5 months. That’s two and a half months benefit while the benefit with S-1 was twenty one months.  I am in no way criticising the ESPAC4 trial which I think is an important step forward; but I am disillusioned at the discrepancies in interpreting clinical trial results by the global oncology community. A couple of months of PFS benefit with new expensive therapies bring the biggest of headlines while this trial showing 21 months of OS benefit in pancreatic cancer is dying silently.
9. Cabozantinib and Nivolumab have shown survival benefits over everolimus in 2^nd line treatment of renal cell cancer. Their toxicities differ however, and this should help in making treatment choice. Cabozantinib also showed survival gains in a phase 2 trial over sunitinib alone as a first line agent. However, adjuvant sunitinib should not yet be considered standard despite one of the two phase 3 RCTs showing a positive effect because a meta-analysis of these two trials didn’t confirm any benefit.
10. Bevacizumab became the first agent to show a survival benefit over platinum-pemetrexed chemotherapy in malignant pleural mesothelioma and should be a standard of care. However, the benefit in median OS is less than 3 months, with real adverse events, which demand a clear discussion of risk-benefits with the patient. One more caveat to consider is that the control arm in this trial received only 6 cycles of pemetrexed while many oncologists use pemetrexed as maintenance until progression.
11. Olanzapine should now be considered a standard antiemetic for the prevention of chemotherapy induced nausea and vomiting based on results from this trial. However, I support starting with olanzapine plus palonosetron plus dexamethasone regimen rather than the four drug regimen used in this trial for reasons explained here and here. You can also listen to my interview on this agenda here.
12. Start running, limiting your food intake and skipping junk food or drinks to control your waist size because according to this report from the IARC, obesity is now linked to virtually any cancer you can think of! Don’t get angry at me - you need this advice before your holidays!
13. But don’t go and have your thyroid scanned (unless symptomatic) because apparently there’s an epidemic of thyroid cancer diagnoses. If you don’t heed this advice, this is what will happen: A small nodule will be detected in your thyroid, you will be labelled a thyroid cancer patient, you will visit many doctors because most of us don’t know what to do with such a small nodule, and finally you’ll meet someone who will operate to take that cancer out of your body during which your laryngeal nerves may get damaged and your voice may change or get lost. But don’t worry, your thyroid nodule will now not be seen on scans. Will you live longer? Probably not.

The Other Studies

1. The MINDACT study assessed the utility of Mammaprint in deciding whether or not to use chemotherapy in patients with early breast cancer and found that when clinical risks (C-R) and genomic risks (G-R) are discordant, women could avoid taking chemotherapy if their G-R is low despite high C-R (provided the non-inferiority margin is acceptable to the patient). This trial also showed that if the C-R is low, there is no added advantage of chemotherapy just because the G-R is high. This is a very important study with some caveats to ponder upon which I discuss here.   
2. A post-hoc analysis of CALGB/SWOG 80405 trial presented at ASCO 2016 showed that right sided colon cancers have poor prognoses and respond poorly to anti-EGFR antibodies compared to left sided cancers. This finding has been supported by other analyses published before and after that presentation, but they are all post hoc analysis nevertheless. My take away is that it is not necessary yet to scare patients with right sided tumours of poor prognoses, because of the limitations associated with retrospective studies. However, regarding selection of treatment plan, because bevacizumab is a standard first line option to add to chemotherapy and is cheaper to anti EGFR antibodies, I don’t see any reason to use anti EGFR in first line for right sided tumours despite having evidences for poor efficacy (although not prospective). The current NCCN guidelines also mention anti-EGFR antibodies only for left sided tumors, which makes sense to me.
3. The most-talked about study from ASCO 2016 was the MA.17R study that showed 10 years of letrozole versus 5 years of the same drug improved 5-year DFS by 4%. This is not practice changing for me, for reasons I describe in detail here.
4. Trastuzumab biosimilar has been found to have comparable safety and efficacy to Herceptin in a phase III trial. This should allow more patients worldwide to have access to this life saving drug in breast cancer.
5. Niraparib maintenance seems to be effective as maintenance therapy in platinum sensitive recurrent ovarian cancer regardless of BRCA mutation status with impressive hazard ratios. Although this should now be practice changing, how much of this PFS will translate to OS benefit is something I eagerly look forward to.
6. Alectinib is the standard first line agent in Japan for ALK-positive advanced NSCLC based on results from the J-ALEX study although the world might be waiting for the global ALEX study. I have absolutely no idea whether upfront alectinib is better than crizotinib-alectinib sequence. Or crizotinib-ceritinib sequence for that matter as longer PFS with ceritinib versus chemotherapy was also confirmed at ESMO 2016.
7. Atezolizumab for second line treatment of urothelial cancer is exciting but this expensive agent produced response only in 15% patients, and we have no marker to identify those 15%. Survival data from a randomized trial are desired.
8. 3 years of 10mg/kg ipilimumab was shown to prolong OS when used as adjuvant treatment for stage III melanoma. This was presented at ESMO 2016 and made headlines, but I baulk at the dose, duration and price! I discuss this in detail here.
9. The GOG 262 study showed no benefit with dose dense paclitaxel for ovarian cancer unlike a previous Japanese study; however, the addition of bevacizumab likely confounded the results. For those patients without bevacizumab, weekly paclitaxel did seem to do better. Considering the cost-effectiveness of dose dense paclitaxel over standard paclitaxel plus bevacizumab, dose dense paclitaxel should be considered a high priority choice; although I look forward to seeing the mature survival data.
10. The RADIANT-4 showed that everolimus improved PFS substantially for patients with neuroendocrine tumours of the lung or GIT and definitely provides an option where other options are scarce. However, it didn’t improve OS. Asking a drug to improve OS over placebo is a very low bar in my opinion, and it failed to meet that low bar. Whether or not to use this agent for this indication is an agenda for shared decision making.
11. Although already confirmed in 2015, results from STAMPEDE were published in 2016 and confirmed that upfront chemohormonal therapy should be the standard of care in hormone naïve prostate cancer patients.
12. Enzalutamide was found to prolong PFS significantly and meaningfully compared with bicalutamide in two randomized phase II trials: the TERRAIN and the STRIVE trial. Whether this translates to OS benefit is not known. If receiving enzalutamide upon progression could provide similar OS, there would be no meaning to start with this expensive agent.
13. Nab paclitaxel was found to achieve higher rates of pathological complete response rates versus paclitaxel when used as neoadjuvant strategy in early breast cancer. Whether this higher pCR rates translate to survival benefit is not known but “nab” in nab paclitaxel stands for “not affordable brand”.
14. Palbociclib has shown impressive PFS benefits with fulvestrant or letrozole in hormone receptor positive breast cancer, but given similar experiences with everolimus and bevacizumab in breast cancer, I am reluctant to acknowledge that these PFS benefits would translate to OS no matter how impressive. I discuss these issues in detail here. The same caveat applies to another ciclib- ribociclib.
15. For patients with 1-3 brain metastases, stereotactic radiosurgery alone provides better quality of life, less deterioration of cognitive function and similar survival compared to addition of whole brain radiation therapy according to this study.
16. A nice lesson in drug development and trial reporting has been provided by the story of rociletinib in lung cancer and its TIGER trials. Please read about this story in detail here.
17. Adaptive trial designs were a topic of discussion in 2016 as two drugs “graduated” in the I-SPY2 trial in breast cancer. However, many questions and challenges remain to be addressed with such trial designs. I discuss them in detail here.
18. Immunotherapies are not magic bullets. We saw some failures of immunotherapies in 2016, such as this, this, this and this.

I wish all my dear readers a Merry Christmas and a very happy new year 2017. May this new year bring us health, happiness and “the serenity to accept the things we cannot change, courage to change the things we can, and wisdom to know the difference”.

Happy Holidays!

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.