Agenda science: turning nothing into something: a response to the editorial by Oldenburg et al. and its featured article by Vidal et al.
Authors: C. Kollmannsberger, C. Nichols
Journal: Annals of Oncology (2015)

There is an old joke about why academic battles are so fierce. It is because the differences are so small. The ‘battle’ that appears to be brewing over the management of high-risk clinical stage I (CSI) testicular nonseminoma (HR-CSI-NS) has become overblown and unconstructive. The crux is that we are ‘burdened’ by having two management pathways, active surveillance (AS) and adjuvant chemotherapy (AC), that lead to cure and high-quality life after orchiectomy for HR-CSI-NS. To date and withstanding the paper by Vidal et al. and the accompanying editorial by Oldenburg et al., no easily discernible differences in long-term outcomes and quality of life are apparent [1.Oldenburg J. Cullen M. Tandstad T. Primum non nocere: do we harm stage I testicular cancer patients less by applying adjuvant chemotherapy than by failing to present this option?.Ann Oncol. 2015; 26: 255-256Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar, 2.Vidal A.D. Thalmann G.N. Karamitopoulou-Diamantis E. Fey M.F. Studer U.E. Long-term outcome of patients with clinical stage I high-risk nonseminomatous germ-cell tumors 15 years after one adjuvant cycle of bleomycin, etoposide, and cisplatin chemotherapy.Ann Oncol. 2015; 26: 374-377Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar]. In the context of the disease as a whole, the management of HR-CSI-NS hardly is an unmet need. In brief, the conveniently timed and unplanned analysis of a very small adjuvant study by Vidal et al. of high-risk patients receiving a single cycle of modified bleomycin, etoposide, cisplatin (BEP) contributes little to our understanding of late effects of AC. In our view, this was not a study in any modern sense of the word. Was this analysis for late effects stipulated at the initiation of the study? Were patients re-consented for late contact? Why was this effort done now? If the investigators were truly interested in elucidating clinical differences, why was there not a comparator group? There is no evidence that validated instruments were used and the inexactitude of the effort is astounding with no attempts to comprehensively assess important issues such as impact on social domains, physiology, hormonal balances, fertility and formal testing for lung and auditory functions. In fact and based on long experience, the results obtained in the Vidal study are exactly what you get when you see and examine patients long periods out from BEP×2 or BEP×3. Very few have clinically significant complaints and you can only unearth persistent toxicity by careful questioning or specific testing for subclinical concerns. Most experienced investigators believe if you were to look carefully for subclinical signs and symptoms or surrogate markers of late toxicity, you will find it. Such toxicities and subclinical issues likely are related to the number of chemotherapy cycles and there likely will be, with careful comprehensive measurements, a small difference between one and three cycles of BEP just as there will be a difference between zero and one cycle. The magnitude of these toxicity differences is almost certainly small and remains unknown. The effort of Vidal does not inform this area further. What is of concern is that this article prompted an editorial that adds only heat, but no light to the supposed controversy regarding management of HR-CSI-NS. Several of the authors of the editorial have considerable expertise in the area of careful assessment of long-term toxicity related to both the disease and treatment [3.Haugnes H.S. Bosl G.J. Boer H. et al.Long-term and late effects of germ cell testicular cancer treatment and implications for follow-up.J Clin Oncol. 2012; 30: 3752-3763Crossref PubMed Scopus (198) Google Scholar, 4.Oldenburg J. Hypogonadism and fertility issues following primary treatment for testicular cancer.Urol Oncol. 2015; pii: S1078-S1439(15)00047-2Google Scholar, 5.Hjelle L.V. Gundersen P.O. Oldenburg J. et al.Long-term platinum retention after platinum-based chemotherapy in testicular cancer survivors: a 20-year follow-up study.Anticancer Res. 2015; 35: 1619-1625PubMed Google Scholar]. Yet, these experienced investigators used these casually obtained data to support their position strongly favoring AC in HR-CSI-NS. This strikes us as inexplicable. In addition to promoting their agenda, the authors of the editorial only focus on late toxicity of AC. We are astonished how easily the authors recommend chemotherapy and completely ignore the significant acute and occasionally life-threatening toxicities of even one cycle of BEP which includes the occasional treatment-related death [6.Albers P. Siener R. Krege S. et al.Randomized phase III trial comparing retroperitoneal lymph node dissection with one course of bleomycin and etoposide plus cisplatin chemotherapy in the adjuvant treatment of clinical stage I nonseminomatous testicular germ cell tumors: AUO trial AH 01/94 by the German Testicular Cancer Study Group.J Clin Oncol. 2008; 26: 2966-2972Crossref PubMed Scopus (257) Google Scholar, 7.Tandstad T. Dahl O. Cohn-Cedermark G. et al.Risk-adapted treatment in clinical stage I nonseminomatous germ cell testicular cancer: the SWENOTECA management program.J Clin Oncol. 2009; 27: 2122-2128Crossref PubMed Scopus (203) Google Scholar, 8.Panella M. Ross J.E. Garvin K. Martin A. Cardiac sudden death as a result of acute coronary artery thrombosis during chemotherapy for testicular carcinoma.J Forensic Sci. 2010; 55: 1384-1388Crossref PubMed Scopus (9) Google Scholar]. In addition, they catalyze the discussion with implications that ‘surveillance-ISTS’ ignore patients autonomy, lack clinical equipoise, and offer patients only forceful and unbalanced recommendations [1.Oldenburg J. Cullen M. Tandstad T. Primum non nocere: do we harm stage I testicular cancer patients less by applying adjuvant chemotherapy than by failing to present this option?.Ann Oncol. 2015; 26: 255-256Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar, 9.Oldenburg J. Aparicio J. Beyer J. et al.Personalizing, not patronizing: the case for patient autonomy by unbiased presentation of management options in stage I testicular cancer.Ann Oncol. 2014; 26: 833-838Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar]. These allegations of ‘patronizing’ or even ‘harming’ patients have come across in several publications recently and, as far as we can tell, are based on a misunderstanding that ‘equipoise’ which applies primarily to ethics of clinical investigations applies in the same manner to clinical care [1.Oldenburg J. Cullen M. Tandstad T. Primum non nocere: do we harm stage I testicular cancer patients less by applying adjuvant chemotherapy than by failing to present this option?.Ann Oncol. 2015; 26: 255-256Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar, 9.Oldenburg J. Aparicio J. Beyer J. et al.Personalizing, not patronizing: the case for patient autonomy by unbiased presentation of management options in stage I testicular cancer.Ann Oncol. 2014; 26: 833-838Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar]. As far as we are aware, the accusers have no first-hand knowledge of the nature of the practice of testicular cancer in the ‘offending’ institutions. It is also curiously unexplained how groups who purportedly are advocates of clinical equipoise and patient autonomy report an overwhelming choice of AC of a magnitude that Americans seem to choose AS. It is also unexplained why within some of these same European jurisdictions there are large pockets of patients who ‘choose’ carboplatin as AC for CSI seminoma adjacent to large pockets who ‘choose’ AS. It may be explainable by the authors previous statement of their ‘believes’ which includes ‘Helping the patient in deciding which management suits him’. The exact extend and nature of the ‘help’ remained unfortunately unexplained [9.Oldenburg J. Aparicio J. Beyer J. et al.Personalizing, not patronizing: the case for patient autonomy by unbiased presentation of management options in stage I testicular cancer.Ann Oncol. 2014; 26: 833-838Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar]. We should remember that patients are coming to us for a reason and that reason is to have you as a physician apply your experience and expertise, your understanding and sometimes even your hunches to help them in their medical situation. Even the most educated and sophisticated patient is looking to you as a physician to apply your science and your art to their individual situation. This is embodied in one of the most frequently questions posited by patients. ‘Doctor, what would you do?’ There is no shame in making a recommendation among very nuanced options after laying out those options. Not only is it not shameful, it is what good and ethical physicians do and it is what patients want and require from us. In conclusion, an important point of the Oldenburg editorial is that, if a patient chooses and their treating physician has experience with delivering such therapy, AC for HR-CSI-NS should be a single cycle of standard BEP [6.Albers P. Siener R. Krege S. et al.Randomized phase III trial comparing retroperitoneal lymph node dissection with one course of bleomycin and etoposide plus cisplatin chemotherapy in the adjuvant treatment of clinical stage I nonseminomatous testicular germ cell tumors: AUO trial AH 01/94 by the German Testicular Cancer Study Group.J Clin Oncol. 2008; 26: 2966-2972Crossref PubMed Scopus (257) Google Scholar, 7.Tandstad T. Dahl O. Cohn-Cedermark G. et al.Risk-adapted treatment in clinical stage I nonseminomatous germ cell testicular cancer: the SWENOTECA management program.J Clin Oncol. 2009; 27: 2122-2128Crossref PubMed Scopus (203) Google Scholar]. It is not a sin to choose it, recommend it or to deliver it just as it is not a sin to choose, recommend or delivery AS in the same setting. Both are equally effective management options which need to be considered in the context of the patient's individual needs and preferences. Let's not expend any further stomach acid on this issue, agree that we all are ethical and capable physicians trying to bring the best solutions to our patients and continue to collaborate on meeting the real unmet needs of our patients. The authors have declared no conflicts of interest.