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Journal of Clinical Oncology, Vol 26, No 11 (April 10), 2008: pp. 1783-1785 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.15.2991
Bleomycin in Testicular Cancer: Will Pharmacogenomics Improve Treatment Regimens?University Medical Center Eppendorf, University of Hamburg, Hamburg, Germany Bleomycin is an antibiotic with anticancer properties produced by Streptomyces verticillus. It was identified in 1966, and one of its mechanisms of action is breaking the DNA double helix by the production of free radicals, a process that is oxygen and iron dependent. Bleomycin is metabolized in the kidney, with 50% of the dose eliminated within 4 hours after administration.1 Furthermore, it is inactivated by an enzyme, bleomycin hydrolase, which is present in both in normal and tumor cells.2 Bleomycin has a long history in cancer treatment, and it has been used as cytotoxic agent against many malignant tumors such as germ cell cancers, lymphomas, Hodgkin's disease, head and neck cancer, and Kaposi's sarcoma.3 Among its side effects are allergic reactions, mucositis, mild myelosuppression, hyperkeratosis and pigmentation changes of the skin, and, in particular, pulmonary fibrosis. It is the latter toxicity that has led to a limitation of the total cumulative dose of bleomycin applied in cancer patients to a maximum of approximately 360 mg. Bleomycin has been most intensively studied in patients with germ cell cancer. The treatment of metastatic germ cell cancer with modern cisplatin-based combination regimens such as cisplatin, etoposide, and bleomycin (PEB) today results in cure in approximately 80% of patients.4 The factors known to be associated with treatment outcome are the extent of metastatic disease and serum levels of tumor markers such as human chorionic gonadotropin, alpha fetoprotein, and lactate dehydrogenase. On the basis of these prognostic factors patients are classified into those with good, intermediate, or poor prognosis and either three (good prognosis) or four cycles (intermediate and poor prognosis) of PEB represent current standard treatment for patients with metastatic disease. The standard PEB regimen uses cisplatin at 20 mg/m2 days 1 through 5 (total 100 mg/m2 per cycle), etoposide 100 mg/m2 days 1 through 5 (500 mg/m2 per cycle), and bleomycin 30 mg/wk. This results in a cumulative dose with three administrations of bleomycin per cycle of 270 mg in three cycles and 360 mg in four cycles of PEB. It has been shown that bleomycin is associated with an approximate 1% risk for death due to bleomycin-induced pulmonary fibrosis.5 Investigators from the Royal Marsden Hospital in the United Kingdom have used their prospectively collected testicular cancer research database of 835 patients to identify those with the highest risk for bleomycin-associated pulmonary disease.5 While overall 6.8% of patients were affected, there were eight deaths (1%); on multivariate analysis, patients with a glomerular filtration rate less than 80 mL/min, age older than 40 years, stage IV disease at presentation, and a cumulative dose of bleomycin older than 300 mg were those at highest risk. However, the metabolism of bleomycin also includes inactivation of the drug via bleomycin hydrolase. In a recent investigation published in this issue of the Journal of Clinical Oncology, investigators from the University Medical Center of Groningen, the Netherlands, have demonstrated that variations in the bleomycin hydrolase gene are associated with reduced survival in patients with testicular germ cell cancer receiving cisplatin- and bleomycin-based combination chemotherapy.5a It seems quite understandable that both toxicity as well as tumor response can be influenced by polymorphisms of genes involved in the metabolism of cytotoxic agents as has been postulated for the polymorphism in the dihydropyrimidine dehydrogenase (DPD) gene for the treatment of colorectal cancer with fluorouracil.6 It has also been reported that in mice lacking the activity of bleomycin hydrolase, an increased risk of bleomycin-induced pulmonary toxicity exists.7 In contrast, an increased enzymatic activity may be associated with tumor resistance to bleomycin. In the bleomycin hydrolase gene, a polymorphic site A1450G has been identified. This single nucleotide polymorphism (SNP) leads to the presence of either isoleucine or valine as amino acid residue at 443.8 This change is thought to be actively involved in controlling enzymatic activity. Based on this hypothesis, the investigators at Groningen have screened their patients for the presence of SNP A1450G and correlated these changes with the outcome of treatment for metastatic testicular cancer. The analysis was performed in peripheral blood samples where available, but also in paraffin-embedded histological material and in tumor tissue. The cohort used for this analysis comprises 362 patients among which 304 patients were evaluable and successfully analyzed for DNA samples. With a median survival time of more than 10 years for the group of patients treated from 1977 to 2003, an interesting result was observed: 140 (46%) patients had wild-type AA allele, 133 (44%) patients had heterozygous AG, and 31 (10%) patients had the homozygous variant GG. Overall, 41 patients died from testicular cancer, and three patients died from pulmonary toxicity. Ten of 31 patients of the GG group died, while 31 of 273 patients died in the total group of AA and AG patients. There was a highly significant association between the presence of GG allele and reduced survival. However, none of the pulmonary deaths occurred in patients with GG. In multivariate analysis, there was a hazard ratio of 5 for a higher risk of death from testicular cancer and development of refractory disease for patients harboring the GG genotype compared with those of a normal or heterozygous variant. In fact, presence of the GG polymorphism was the most significant prognostic marker in relation to the International Germ Cell Collaborative Group tumor stage. It is particularly notable that survival curves for testicular cancer–related survival were more than 20% inferior in GG patients compared with those with other allelic variants. This striking finding would clearly alter treatment regimens in testicular cancer and would mean that for patients with the presence of the SNP resulting in GG allelic changes, a treatment with cisplatin, etoposide, and ifosfamide may be preferred over cisplatin, etoposide and bleomycin. However, let us consider some of the strengths and the weaknesses of the current analysis. It is a reasonable study with a large number of patients from a single center with almost uniform treatment throughout the last 20 years. It also uses a well-defined patient cohort, thus making it possible to eliminate several interfering clinical characteristics. It also allows for detection of the effect of genotypic changes on long-term survival because of the high overall survival rate of these patients. Thus, it may not be surprising that this finding is made in the setting of testicular cancer, a disease with long-term survival rates of 80% to 90%. The impact of this finding on the change of established treatment regimens would be truly significant. However, we also have to consider some weaknesses and unresolved points. The measurement of the genetic polymorphism does not tell us the real enzymatic activity of the bleomycin hydrolase; there are no data on bleomycin plasma levels or altered half-life showing that the genetic changes really impact bleomycin levels. It should also be considered that the SNP analysis was partially analyzed in tumor cells as well. It may be that this polymorphism by itself can affect the prognosis of patients with testicular cancer independent of treatment with bleomycin. Furthermore, the investigators state that there were no differences in renal function in the different subgroups. However, it has been shown before that even minor modifications in renal function have a significant impact on bleomycin toxicity and the induction of pulmonary changes. Therefore, clear data on renal function are necessary to strengthen these findings. Finally, the authors state that the chemotherapy regimens given to these patients as well as the clinical stages were not different among the subgroups with different genotypes. However—although not significant due to the small number of patients—the cumulative bleomycin dose was somewhat higher in patients with GG genotype (360 mg) compared with patients with AA and AG (270 mg; Table 15a). This is in contrast to the finding that the cisplatin dose was the same in all groups. Interestingly, the median cumulative dose of cisplatin in all groups was 400 mg/m2, indicating that most of the patients received four cycles of cisplatin- and bleomycin-containing chemotherapy. This is in contrast to the fact that most patients in all groups were patients with good prognosis, where three cycles are considered standard treatment today. There are two aspects that require further general discussion: One is the investigation of the same group looking at bleomycin long-term toxicity in almost a similar group of testicular cancer patients.9 In that study published in 2005, 340 patients were evaluated and 38 (11%) patients developed bleomycin pulmonary toxicity, 1% with fatal outcome. The risk for bleomycin pulmonary toxicity did not differ according to genotype distribution. As previously reported by the Royal Marsden investigators, pulmonary toxicity was mostly correlated with the age of the patient and reduced pretreatment creatinine clearance. In the setting of pulmonary toxicity, bleomycin pharmacokinetics seems to depend much more on renal function than on bleomycin hydrolase activity as determined by SNP polymorphism. The second aspect is the role of bleomycin in testicular cancer, which has been investigated in several well-controlled randomized clinical trials. In 1997, de Wit et al10 reported an important randomized European Organization for Research and Treatment of Cancer trial comparing etoposide and cisplatin alone with etoposide, bleomycin, and cisplatin for patients with good-prognosis, metastatic, nonseminomatous testicular cancer. Of 395 patients in this trial, 87% with etoposide and platinum (EP) and 95% with bleomycin, etoposide, and platinum (BEP) achieved a complete response with chemotherapy followed by postchemotherapy surgery. While this difference was significant, eight (4%) patients on each treatment arm had relapsed after a median follow-up of 7.5 years, with no significant difference in time to progression and survival in long-term follow-up.10 A second randomized trial compared the equivalence of three or four cycles of bleomycin, etoposide, and cisplatin in good-prognosis germ cell cancer.11 In the good-prognosis group of the International Germ Cell Collaborative Group classification this 2001 study found that three cycles of BEP with a total dose of 270 mg of bleomycin are equivalent to four cycles of BEP using a total dose of 360 mg of bleomycin (in addition to cisplatin and etoposide given in the fourth cycle). Thus, even a reduction of 25% in bleomycin dose from four to three cycles did not alter treatment outcome. As cited for the first study, the treatment outcome of regimens without bleomycin, when up to four cycles of cisplatin are given—which has most likely been done in the current study cohort—did not show a large difference in long-term outcome, particularly not a difference of 20% as observed in the current investigation. The final study shedding light onto this question has recently been published by French investigators.12 In this trial, 262 patients were randomly assigned to either three cycles PEB or four cycles EP. There was a slightly lower progression-free survival of 86% for four EP compared with 93% for three PEB, and there was no significant difference in long-term follow-up. Taking together all these results, and accounting for the fact that most patients in the Groningen investigation were probably treated with four cycles of cisplatin- and bleomycin-containing chemotherapy, it is surprising that a long-term survival difference of almost 20% was observed for patients with the GG genotype effecting bleomycin hydrolase. This is a large effect attributed to bleomycin metabolism in the treatment of testicular cancer when compared with the three randomized studies cited above. These studies have clearly defined that bleomycin is necessary for the treatment of testicular cancer, but have found differences with or without bleomycin that are in a much smaller range. This points out that there may be more behind these genotypic changes than just the alteration of the pharmacokinetics of bleomycin. In summary, de Haas et al5a gives good evidence for the importance of pharmacogenomic studies in the treatment of patients with testicular cancer. It appears surprising that the overall large difference in treatment outcome can be attributed to a single SNP, effecting the hydrolyze gene altering bleomycin metabolism, and these findings cannot yet be introduced into clinical practice. However, it shows that the development of new molecular and genetic prognostic factors for the treatment of testicular cancer will be likely to help us identify those patients with excellent responses that may be treated with current treatment regimens and with potentially less toxicity. On the other hand, we may identify early those patients with refractory disease who need new treatment. Thus, we should use the homogenous treatment regimens and patient cohorts in testicular cancer to learn more about pharmacokinetics, pharmacogenomics, and additional molecular prognostic factors to redefine and further optimize treatment. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. REFERENCES 1. Azambuja E, Fleck JF, Batista RG, et al: Bleomycin lung toxicity: Who are the patients with increased risk? Pulm Pharmacol Ther 18:363-366, 2005[CrossRef][Medline] 2. Lazo JS, Boland CJ, Schwartz PE: Belomycin hydrolase activity and cytotoxicity in human tumors. Cancer Res 42:4026-4031, 1982 3. Chen XL, Li WB, Zhou AM, et al: Role of endogenous peroxynitrite in pulmonary injury and fibrosis induced by bleomycin A5 in rats. Acta Pharmacol Sin 24:697-702, 2003[Medline] 4. de Wit R: Refining the optimal chemotherapy regimen in good prognosis germ cell cancer: Interpretation of the current body of knowledge. J Clin Oncol 25:4346-4349, 2007 5. O'Sullivan JM, Huddart RA, Norman AR, et al: Predicting the risk of bleomycin lung toxicity in patients with germ-cell tumours. Ann Oncol 14:91-96, 2003 5. de Haas EC, Zwart N, Meijer C, et al: GVariation in Bleomycin Hydrolase Gene is Associated with Reduced Survival after Chemotherapy for Testicular Germ Cell Cancer. J Clin Oncol 26:1817-1823, 2008 6. Van Kuilenburg AB, Meinsma R, Zoetekouw L, et al: High prevalence of the IVS14+ 1G>A mutation in the dihydropyrimidine dehydrogenase gene of patietns with severe 5-fluorouracil-associated toxicity. Phamacogenetics 12:555-558, 2002[CrossRef] 7. Lazo JS, Humphreys CJ: Lack of metabolism as the biochemical basis of bleomycin-induced pulmonary toxicity. Proc Natl Acad Sci U S A 80:3064-3068, 1983 8. Brömme D, Rossi AB, Smeekens SP, et al: Human bleomycin hydrolase: Molecular cloning, sequencing, functional expression, and enzymatic characterization. Biochem 35:6706-6714, 1996[CrossRef][Medline] 9. Nuver J, Lutke Holzik MF, van Zweeden M, et al: Genetic variation in the bleomycin hydrolase gene and bleomycin-induced pulmonary toxicity in germ cell cancer patients. Pharmacogenet Genom 15:399-405, 2005 10. de Wit R, Stoter G, Kaye SB, et al: Importance of bleomycin in combination chemotherapy for good-prognosis testicular nonseminoma: A randomized study of the European Organization for Research and Treatment of Cancer Genitourinary Tract Cancer Cooperative Group. J Clin Oncol 15:1837-1843, 1997 11. de Wit R, Roberts JT, Wilkinson PM, et al: Equivalence of three or four cycles of bleomycin, etoposide, and cisplatin chemotherapy and of a 3- or 5-day schedule in good-prognosis germ cell cancer: A randomized study of the European Organization for Research and Treatment of Cancer Genitourinary Tract Cancer Cooperative Group and the Medical Research Council. J Clin Oncol 19:1629-1640, 2001 12. Culine S, Kerbrat P, Kramar A, et al: Refining the optimal chemotherapy regimen for good-risk metastatic nonsemimatous germ-cell tumors: A randomized trial of the Genito-Urinary Group of the French Federation of Cancer Centers (GETUC T93BP). Ann Oncol 18:917-924, 2007 Related Article
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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