This article is more than 5 years old. Information may no longer be current.
I’d like to agree with you … but then we’d both be wrong!
Click Here to Manage Email Alerts
I sometimes fear that I am a natural curmudgeon, or at the very least a true cynic.
If you have read my recent editorials and op-eds, it may seem I constantly try to swim upstream, against the flow of current medical and political thought. However, on this particular item, I hope you will agree that I’m on the right track.
I have been an oncologist for decades, and have watched a mixture of great success and some dramatic failures in our battles against the range of cancers. Sadly, I also think we have begun to lower the bar for success, in our quest to be perceived to be providing value to the community, and because of the impact of public relations and media presence in all that we do. It seems we need to keep a careful sense of context when we set our oncology battle targets and then claim success.
Derek Raghavan
In this issue of HemOnc Today, we have decided to focus on outcomes in oncology. This is a theme that has recently been addressed by an ASCO task force on parameters for clinical trials (Ellis LM. J Clin Oncol. 2014;32:1277-1280), and some of the statistical pitfalls of modern oncology have been covered in recent HemOnc Today editorials by myself and my fellow chief medical editor, John Sweetenham, MD.
Historical context
It is important to emphasize a few points of history to understand the trajectory of the past 30 to 40 years.
In 1977, my first year as an oncology fellow, median survival figures for metastatic cancers of the pancreas, stomach, esophagus and colon, lung, skin (especially melanoma), kidney and bladder, as well as glioblastoma, were considerably less than 12 months. Actually, median survival for most of them was less than 6 months.
Admittedly, we have made some real progress in some of the cancers listed above, which should be a source of pride and a sense of achievement. Generally that progress has represented a quantum leap — such as PVB or PEB in testicular cancer, or MVAC or CMV in bladder cancer — rather than being characterized by incremental baby steps.
However, we also need to understand that stage migration has favored our outcomes today, rather than those of the teams that worked diligently to make progress more than 30 years ago. The attitudes of the gatekeepers of the spectrum of oncological disorders, the primary care physicians and surgeons, have changed dramatically during this time, and there is generally a much greater tendency for earlier referral for consideration of the role of systemic therapy.
As you will realize, the introduction of CT and MRI scans, PET imaging, and the use of novel biochemical markers (eg, PSA, CA-125, CA-19.9, etc) introduced since the 1970s has allowed us to identify recurrence and metastasis much earlier after definitive local therapy. This often leads to earlier identification of the presence of occult metastases, which we usually can track down by our newer scanning techniques.
For example, my first phase 2 trial of neoadjuvant cisplatin chemotherapy for invasive bladder cancer was launched just as routine CT scanning was introduced into staging of that disease. As a result, we were able to image much more precisely than our medical forebears, who were only able to use physical examination, plain radiographs, or radionuclide liver and bone scans to identify distant metastases, and who assessed the retroperitoneum predominantly by physical examination (to detect large masses) or by identifying deviation of the ureters on IV pyelograms.
It is not surprising that our phase 2 study seemed to show a dramatic improvement in outcome, but this was not confirmed by the following phase 3 trial, in which both arms had the benefit of CT staging. History tells us that the hypothesis was correct but simply required refinement of treatment with the introduction of more effective regimens — such as MVAC or CMV — to improve cure rates. Imagine the delay if we had contented ourselves with a false-positive phase 2 trial and delayed further progress by another decade!
Quest for ‘real progress’
Returning to the present, we need to recognize that stage migration, by itself, should have contributed greatly to survival increments for many of the malignancies under consideration, whether receiving treatment de novo or at first relapse.
Thus, I have become concerned when some of our present-day investigators cry “Victory!” (with caveats) in their reporting of phase 2 and phase 3 trials in which median survival still sits at 12 months or less, without more than a hint of an increment in long-term survival. I just can’t get excited about a median survival hike from 6 months to 12 months as representing anything more than progress by a very small increment, particularly without a substantial change in the tail of the survival curve.
We have made significant progress in the treatment of metastatic renal carcinoma and melanoma. This clearly would not have happened if pioneers such as Ronald M. Bukowski, MD, and Robert J. Motzer, MD, fatigued after years of negative trials, had succumbed to the need for false reporting and had accepted low response rates and tiny increments in OS as an excuse to report positive trials. Rather, they chose to hold the line, report negative trials in an accurate context, and awaited real progress before issuing their declarations of success. That robust investigation pattern led to the successes of today.
The recent ASCO subcommittee appears to have set a very low bar indeed for several domains of investigation, and I’m disappointed to see so many investigators of great talent and expertise accepting mediocre outcomes and tabulating them as if they are acceptable.
I agree with them that we are at the beginning of a new era, and the panoply of molecularly predicted targeted therapies offers huge promise. If, however, we accept such low standards, we will remain satisfied with these harbingers of success, and that will slow true progress.
We should be trying to identify new agents that really work — and which will lead to more than a doubling of survival at 1 or 2 years — and we should discontinue our focus on incremental PFS gains and meaningless hazard ratios.
For example, a litany of phase 2 reports in metastatic bladder cancer, augmented by stage migration, led to the illusion that progress was being made after the creation of the MVAC and CMV regimens. Today, we know that gemcitabine–cisplatin has produced similar results with less toxicity, but that no true progress has been made in more than a decade.
With the provocative data relating to PD-L1 and immunotherapeutics and MET targeting in advanced bladder cancer, I hope we are about to make real progress. Let’s make sure we measure it stringently, with the hope that median survival will increase beyond 24 to 30 months for metastatic disease.
In turn, this may be a model for therapy development in the other cancers listed above, and we can enter a new era of raising the bar and celebrating true progress.
For more information:
Derek Raghavan, MD, PhD, FACP, FRACP, FASCO, is HemOnc Today’s Chief Medical Editor, Oncology. He can be reached at derek.raghavan@carolinashealthcare.org.
Disclosure: Raghavan reports no relevant financial disclosures.