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Testis cancer: on gilding the lily

2012; Elsevier BV; Volume: 24; Issue: 2 Linguagem: Inglês

10.1093/annonc/mds611

1569-8041

Derek Raghavan,

Sarcoma Diagnosis and Treatment

One of the wonderful aspects of being an oncologist in the latter part of his career is to be able to reflect upon some successes in this field over the past 30 years. When I was an oncology fellow in the late 1970s, training with Martin Tattersall, Sir Michael Peckham, the late Tim McElwain and the late B.J. Kennedy, I saw first-hand the evolution of management of germ cell malignancy. In my first year as an oncology fellow, I participated, with great sadness and frustration, in the management of many young men with metastatic testicular cancer, treated them with variants of vinblastine–bleomycin or vinblastine–actinomycin–methotrexate, and watched most of them die, much too early. With one amazing development, the introduction of cisplatin (Bristol Myers Squibb) into standard chemotherapy for testis cancer, developed initially by Einhorn [1.Einhorn L.H. Testicular cancer as a model for a curable neoplasm. The Richard and Hinda Rosenthal Foundation Award Lecture.Cancer Res. 1981; 41: 3275-3280PubMed Google Scholar], there was a complete transformation from the expectation of early death to the potential of long-term survival in most young men with this dreadful disease [1.Einhorn L.H. Testicular cancer as a model for a curable neoplasm. The Richard and Hinda Rosenthal Foundation Award Lecture.Cancer Res. 1981; 41: 3275-3280PubMed Google Scholar, 2.Peckham M.J. Barrett A. McElwain T.J. Hendry W. Raghavan D. Non-seminoma germ cell tumours (malignant teratoma) of the testis: results of treatment and an analysis of prognostic factors.Br J Urol. 1981; 53: 162-172Crossref PubMed Scopus (73) Google Scholar]. In parallel, we came to understand the significance of the tumor markers elaborated by germ cell tumors. Teams at the University of Minnesota [3.Lange P.H. McIntyre K.R. Waldmann T.A. et al.Alpha-fetoprotein and human chorionic gonadotrophin in the management of testicular tumors.J Urol. 1977; 118: 593-596Crossref PubMed Scopus (23) Google Scholar], Royal Marsden Hospital [2.Peckham M.J. Barrett A. McElwain T.J. Hendry W. Raghavan D. Non-seminoma germ cell tumours (malignant teratoma) of the testis: results of treatment and an analysis of prognostic factors.Br J Urol. 1981; 53: 162-172Crossref PubMed Scopus (73) Google Scholar, 4.Raghavan D. Gibbs J. Nogueira-Costa R. et al.The interpretation of marker protein assays: a critical appraisal in clinical studies and a xenograft model.Br J Cancer. 1980; 41: 191-194Google Scholar] and the Danish Testicular Cancer Study Group [5.Norgaard-Pedersen B. Schultz H.P. Arends J. et al.Tumour markers in testicular germ cell tumours. Five-year experience from the DATECA Study 1976–1980.Acta Radiol Oncol. 1984; 23: 287-294Crossref PubMed Scopus (53) Google Scholar] identified the importance of alpha fetoproteins, the beta subunit of human chorionic gonadotrophin, lactate dehydrogenase isoenzymes and even carcinoembryonic antigen (occasionally) as guides to the presence of germ cell malignancy and its likely histological type. Our early prognostic studies in patients following orchiectomy identified prolonged tumor marker clearance times as seminal in prognostication of worse outcomes [4.Raghavan D. Gibbs J. Nogueira-Costa R. et al.The interpretation of marker protein assays: a critical appraisal in clinical studies and a xenograft model.Br J Cancer. 1980; 41: 191-194Google Scholar, 6.Raghavan D. Peckham M.J. Heyderman E. Tobias J.S. Austin D.E. Prognostic factors in clinical stage I non-seminomatous germ-cell tumours of the testis.Br J Cancer. 1982; 45: 167-173Crossref PubMed Scopus (34) Google Scholar], and we also demonstrated the importance of T stage and other variables [6.Raghavan D. Peckham M.J. Heyderman E. Tobias J.S. Austin D.E. Prognostic factors in clinical stage I non-seminomatous germ-cell tumours of the testis.Br J Cancer. 1982; 45: 167-173Crossref PubMed Scopus (34) Google Scholar, 7.Raghavan D. Vogelzang N.J. Bosl G.J. et al.Tumor classification and size in germ-cell testicular cancer: influence on the occurrence of metastases.Cancer. 1982; 50: 1591-1595Crossref PubMed Scopus (23) Google Scholar]. Prolonged marker clearance was also shown to connote adverse prognosis in patients with metastatic disease [8.Vogelzang N.J. Lange P.H. Goldman A. Vessela R.H. Fraley E.E. Kennedy B.J. Acute changes of alphafetoprotein and human chorionic gonadotrophin during induction chemotherapy of germ cell tumors.Cancer Res. 1982; 42: 4855-4861PubMed Google Scholar]. The work building to the identification of prognostic presenting criteria for metastatic disease in the 1980s [9.Birch R. Williams S. Cone A. et al.Prognostic factors for favorable outcome in disseminated germ cell tumors.J. Clin. Oncol. 1986; 4: 400-407Crossref PubMed Scopus (250) Google Scholar, 10.Bosl G.J. Geller N. Cirrincione C. et al.Multivariate analysis of prognostic variables in patients with metastatic testicular cancer.Cancer Res. 1983; 43: 3403-3407PubMed Google Scholar] was also important, culminating in the Consensus Panel Recommendations that divided metastatic germ cell tumors into classifications of good, intermediate and poor prognosis [11.International Germ Cell Cancer Collaborative Group International germ cell consensus classification: a prognostic factor-based staging system for metastatic germ cell cancers.J Clin Oncol. 1997; 15: 594-603Crossref PubMed Scopus (1802) Google Scholar]. This allowed the practicing oncologist to give evidence-based information to prospective patients, outlining the chances of success and failure, and identifying the reasons for a detailed and structured plan of action. In general terms, this has worked pretty well, particularly for patients with good-risk disease, who can expect a very high chance of cure. Over the years, we have learned not to tinker too much with the model, discovering that attempts to replace cisplatin with carboplatin (Bristol Myers Squibb) or to delete bleomycin from standard schedules have not yielded the hypothesized benefits [12.Loehrer Sr, P.J. Johnson D. Elson P. Einhorn L.H. Trump D. Importance of bleomycin in favorable-prognosis disseminated germ cell tumors: an Eastern Cooperative Oncology Group trial.J Clin Oncol. 1995; 13: 470-476Crossref PubMed Google Scholar, 13.Levi J.A. Raghavan D. Harvey V. et al.The importance of bleomycin in combination chemotherapy for good prognosis germ cell carcinoma.J Clin Oncol. 1993; 11: 1300-1305Crossref PubMed Scopus (145) Google Scholar]. Similarly, dropping the dose has been shown to be harmful, despite the best of intentions [14.Levi J.A. Thomson D. Bishop J. et al.Dose intensity and outcome with combination chemotherapy for germ cell carcinoma.Eur J Cancer Clin Oncol. 1989; 25: 1073-1077Abstract Full Text PDF PubMed Scopus (6) Google Scholar]. Intermediate-risk cases have been a bit more problematical, and my own sense is that a study that showed three and four cycles of (cis)platinum, etoposide and bleomycin to be equivalent was insufficiently powered with intermediate-risk cases to be completely accurate [15.Saxman S.B. Finch D. Gonin R. Einhorn L.H. Long term follow up of a phase III study of three versus four cycles of bleomycin, etoposide and cisplatin in favorable-prognosis germ cell tumors. The Indiana University experience.J Clin Oncol. 1998; 16: 702-706Crossref PubMed Scopus (162) Google Scholar]. The real problem has remained in poor-risk disease, and we still have not worked out a great strategy [16.Raghavan D. Salvage or savage chemotherapy for poor-risk or relapsed testis cancer—20 years later, not much has changed.Ann Oncol. 2012; 23: 813-814Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar], despite earnest attempts using multiagent chemotherapy [17.Bower M. Newlands E.S. Holden L. et al.Treatment of men with metastatic non-seminomatous germ cell tumours with cyclical POMB/ACE chemotherapy.Ann Oncol. 1997; 8: 477-483Abstract Full Text PDF PubMed Scopus (95) Google Scholar] and transplant-intense strategies [18.Simonelli M. Rosti G. Banna G.L. et al.Intensified chemotherapy with stem-cell rescue in germ-cell tumors.Ann Oncol. 2012; 23: 812-822Abstract Full Text Full Text PDF Scopus (21) Google Scholar]. The key is to encourage patients to present earlier, with clear evidence showing that the delay in presentation is harmful [19.Bosl G.J. Vogelzang N.J. Goldman A. et al.Impact of delay in diagnosis on clinical stage of testicular cancer.Lancet. 1981; 2: 970-973Abstract PubMed Scopus (122) Google Scholar]. What a missed opportunity when the hapless US Preventive Services Task Force missed a great opportunity to educate doctors and patients about the benefits of early diagnosis, when issuing their recent ‘yes, we have no bananas’ encyclical [20.U.S. Preventive Services Task Force Screening for testicular cancer. U.S. Preventive Services Task Force reaffirmation recommendation statement.Ann Intern Med. 2011; 154: 483-486Crossref PubMed Google Scholar] which took three pages to remind us that they had no basis for changing their (non)-recommendation on testis cancer screening. For those without the benefits of early presentation, in my tertiary referral practice, I remain concerned that the most common cause of death in good/intermediate-risk testicular cancer may remain bad clinical decision process, with suboptimal selection of treatment regimens by inexperienced clinicians. For patients with bad-risk disease, referral to centers of excellence which are investigating the novel treatment approaches, in a structured fashion, makes the most sense to me. So what is the impact of the article from Dr. Massard et al. [21.Massard C. Kramar A. Beyer J. et al.Tumor marker kinetics predict outcome in patients with relapsed disseminated non-seminomatous germ cell tumors.Ann Oncol. 2013; 24: 322-328Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar]? It adds to our armamentarium, providing another algorithm for helping us to define prognosis of our patients, and perhaps allowing us to identify patients who will not get a satisfactory outcome at an earlier stage. For many years, we have been aware that acute tumor marker release, particularly for beta-human chorionic gonadotropin, can confuse the interpretation of marker decline profiles—release of this marker can make marker decline curves appear artificially prolonged, suggesting the possibility of innate drug resistance, when in reality the decline reflects a beneficial pattern of response. This problem can be overcome by regular tumor marker sampling, multiple times per week, during the induction phase. If there is a weakness in the present study, it is the potential to misidentify tumor marker release as indicative of failure of therapy. This paper is interesting and provocative, but will require external validation before this approach becomes state of the art. However, poor-risk testicular cancer is a complex and demanding disease, and it does not seem likely that linear algorithms that attempt to over-simplify the assessment of disease and the selection of treatment regimens will improve our results. The author has declared no conflicts of interest.