MOTIVATION AND ROLE OF CLINICAL TRIALS FOR AN ONCOLOGIST’S SUCCESSFUL CLINICAL PRACTICE

By Timur Mitin, MD, PhD, Associate Professor of Radiation Medicine at Oregon Health and Science University, Medical Director of the Tuality/OHSU Cancer Center (Portland, USA).

Motivation is a personal factor and it is difficult to come up with one formula for motivation, just like it is impossible to deduce a formula of happiness.  Nevertheless, there are some common themes that may be shared by members of the same medical specialty.  Those who appreciate a full night of uninterrupted sleep may not be the happiest trauma surgeons.  Those who fall asleep in a dark room and instead love meeting new people – should think twice before becoming diagnostic radiologists.

What about oncologists?  This is one of the most rapidly growing clinical fields, with new clinical evidence changing the treatment standards several times per year.  One needs to enjoy this pace, enjoy the ever-changing scenery, feel comfortable with incorporating new evidence into clinical practice, not be frightened to come to work on Thursday and treat a new patient differently from the way a previous patient was treated on Wednesday.  Oncologist’s professional life depends on the results of clinical trials.  Clinical trials define what we tell our patients, what treatments we offer, how we manage complications and recurrences.

There are two types of oncologists – those who are in the driver seat, and those who are in the passenger seat.  Drivers like to participate in the clinical trials and establish the new standard of care, passengers like to be told how best to treat their patients. So, let me share with you what I like about being in the driver’s seat.

There is no one single factor that drives my motivation and motivation of my colleagues.  To a certain extent, it is the interplay of all of these components that makes the ride fun.  But I will focus today on three factors.

The first factor is innovation.  Researchers have established that it takes on average 17 years to translate a clinical finding into clinical practice [1].  And that’s not just a time lapse between discovering a molecule in the lab and making it into a new drug buster. There is a significant gap even between the publication of a randomized clinical trial and incorporation of these findings into the standard practice. As a faculty member of the Oregon State medical school, I frequently work with medical students and residents.  One of my strategy to introduce them to the field of oncology is to dissect a clinical question, looking at the clinical evidence supporting a particular treatment recommendation, and then study the patterns of care in the United States – both using a large national cancer database to look at how US patients were actually treated over the past years, and also emailing online surveys to oncologists to get a sense of real-time attitudes and believes of practicing physicians.

Let’s look at some examples. A large randomized clinical trial of preoperative vs postoperative chemoradiation in rectal cancer was published in the New England Journal of Medicine in 2004 [2].  This randomized trial revealed improvement in local control, higher chance of sphincter preservation and decreased toxicity with preoperative administration of chemoradiation.  We analyzed the patterns of care in the United States and indeed noticed a slow trend of uptake of this practice – over the course of a decade [3]. Unfortunately, it was not overnight! On the other hand, two randomized trials have recently established short-course preoperative radiation therapy in rectal cancer as either equivalent or perhaps even superior to long course chemoradiation therapy.  One was published in 2012 [4], the other in 2016 [5]. And yet 94% of US radiation oncologists in 2018 prefer long-course chemoradiotherapy, with some citing better survival and better local control as the reasons for their practice [6].  So, despite existing evidence from randomized clinical trials, the actual clinical practice may be very different, and often it is because the information has not reached the physicians, or physicians just like to stick to the old treatment paradigm and don’t want to change their practice.  What about less common malignancies, where there is no randomized evidence?  Several retrospective analyses, published in prestigious journals, revealed association between adjuvant radiation and chemoradiation therapies in resected gallbladder cancer [7-9]. Yet, we saw almost no uptake of these treatment modalities over the past decade in the United States, even for patients with advanced disease at presentation, in which surgery is unlikely to offer any meaningful chance of cure [10].

Clearly, oncologists who enroll their patients on clinical trials offer their patients either the current standard of care – i.e. treatment in the control arm, or perhaps even the future standard of care.  They do not treat patients based on outdated treatment algorithms that have been replaced by new clinical evidence 17 years ago. 

The second factor for me is confidence – confidence that I deliver the best therapy to my patients when I enroll them in the clinical trials.  The randomized clinical trial of adjuvant radiation therapy in resectable pancreatic cancer – Radiation Therapy Oncology Group (RTOG) 9704 – showed that patients whose radiation therapy treatment plans met the protocol guidelines – had a better overall survival [11]. Remember that on cooperative group studies all treatment plans are reviewed centrally by expert radiation oncologists, and treatment plans that don’t meet the requirements are returned back for revision.  The magnitude of the impact of a treatment protocol violation was greater than the presence of a positive surgical margin and similar to the impact of the primary tumor size.  A large meta-analysis published in 2013 showed that RTOG 9704 was not an exception – and indeed in other large cooperative group studies, radiation therapy protocol deviation was associated with worse local control and survival [12].

As a member of a radiation protocol quality assurance team on the currently enrolling clinical trial InPACT in locally advanced non-metastatic penile cancer, I frequently have to return many treatment plans back to investigators for corrections – even to investigators from very well-known large academic institutions.  And in return, I am hopeful that when I treat my patients with other malignant conditions, expert physicians will review my plans and will send them back to me for corrections, if these plans don’t meet the protocol conditions.  In essence, I receive a free consultation from an expert in the field and feel more confident that my patients receive the best care they can obtain – without having to travel far from their homes.

The last, but probably the most important, factor that drives me to participate in clinical trials – is hope. Hope, that my patients will be randomized to a winning arm and will receive a treatment that will give them a better chance of survival. Southwest Oncology Group (SWOG) is a large cooperative group in North America that has been treating patients since 1970s.  The group recently analyzed all positive treatment trials between 1970 and 2015 and calculated the number of life-years gained by patients enrolled on the winning arms of these trials [13]. This number was over 3 million! So, I am always hopeful that my patient will be randomized to a winning arm and will live longer and happier.  And whereas in the past the survival difference with various treatments was usually incremental, with new targeted and immune therapies, we see truly unprecedented results where patients with metastatic cancer have a real chance to achieve disease remission that lasts for many years – a phenomenon we call “cure”.

Among other factors that may motivate some oncologists to participate in clinical trials may be:

  • Feeling protected against malpractice litigations. Since the protocols are being developed by national experts, and undergo review and approval by the entire institution, if there is an undesirable outcome from the treatment on the protocol, usually patients are not as likely to bring a lawsuit against the treating physician.
  • Some cancer centers actually incentivize financially enrollment of patients on clinical trials.
  • These clinical trials allow for direct access to some of the thought leaders and experts in the field. Just asking an expert to review your case may not be met with great enthusiasm.  But a question pertaining to the management of a clinical protocol patient gets the attention of the protocol principal investigator immediately.

So, for each clinician, the motivations may be different.  For the majority of oncologists who prefer to be in the driver seat the main reason, in my opinion, is the rush of adrenaline – the fun of being at the forefront of clinical oncology, defining new standards of care and offering their patients the most cutting-edge therapies.

References

  1. Morris ZS, Wooding S, Grant J. The answer is 17 years, what is the question: understanding time lags in translational research. J R Soc Med 2011; 104: 510-520.
  2. Sauer R, Becker H, Hohenberger W, et al. Preoperative versus Postoperative Chemoradiotherapy for Rectal Cancer. N Engl J Med 2004; 351:1731-1740.
  3. Sineshaw HM, Jemal A, Thomas CR Jr, Mitin T. Changes in treatment patterns for patients with locally advanced rectal cancer in the United States over the past decade: An analysis from the National Cancer Data Base. Cancer 2016; 122(13):1996-2003.
  4. Ngan SY, Burmeister B, Fisher RJ, et al. Randomized trial of short-course radiotherapy versus long-course chemoradiation comparing rates of local recurrence in patients with T3 rectal cancer: Trans-Tasman Radiation Oncology Group trial 01.04. J Clin Oncol 2012; 30(31):3827-33.
  5. Bujko K, Wyrwicz L, Rutkowski A. et al. Long-course oxaliplatin-based preoperative chemoradiation versus 5 × 5 Gy and consolidation chemotherapy for cT4 or fixed cT3 rectal cancer: results of a randomized phase III study. Ann Oncol 2016; 27(5):834-42.
  6. Yahya et al. ASTRO 2018; poster.
  7. Wang SJ, Fuller CD, Kim JS, et al. Prediction model for estimating the survival benefit of adjuvant radiotherapy for gallbladder cancer. J Clin Oncol 2008; 26(13):2112-7.
  8. Mayo SC, Shore AD, Nathan H, et al. National trends in the management and survival of surgically managed gallbladder adenocarcinoma over 15 years: a population-based analysis. J Gastrointest Surg. 2010; 14(10):1578-91.
  9. Wang SJ, Lemieux A, Kalpathy-Cramer J, et al. Nomogram for predicting the benefit of adjuvant chemoradiotherapy for resected gallbladder cancer. J Clin Oncol 2011; 29(35):4627-32.
  10. Mitin T, Enestvedt CK, Jemal A, Sineshaw HM. Limited Use of Adjuvant Therapy in Patients With Resected Gallbladder Cancer Despite a Strong Association With Survival. J Natl Cancer Inst. 2017; 109(7).
  11. Abrams RA1, Winter KA, Regine WF, et al. Failure to adhere to protocol specified radiation therapy guidelines was associated with decreased survival in RTOG 9704–a phase III trial of adjuvant chemotherapy and chemoradiotherapy for patients with resected adenocarcinoma of the pancreas. Int J Radiat Oncol Biol Phys. 2012; 82(2):809-16.
  12. Ohri N1, Shen X, Dicker AP, et al. Radiotherapy protocol deviations and clinical outcomes: a meta-analysis of cooperative group clinical trials. J Natl Cancer Inst. 2013; 105(6):387-93.
  13. Unger JM, LeBlanc M, Blanke CD. The Effect of Positive SWOG Treatment Trials on Survival of Patients With Cancer in the US Population. JAMA Oncol. 2017; 3(10):1345-1351.