Medical treatment of advanced testicular cancer

Genitourinary Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
JAMA The Journal of the American Medical Association (Impact Factor: 30.39). 03/2008; 299(6):672-84. DOI: 10.1001/jama.299.6.672
Source: PubMed

ABSTRACT The medical treatment of advanced testicular germ cell tumors has changed over the past 30 years, with long-term survival now achieved in the majority of patients. Clinicians need to be familiar with the available treatment regimens for testicular cancer and their associated toxic effects.
To review the treatments used for advanced testicular germ cell tumors and their associated short-term and long-term complications.
A search was performed of all English-language literature (1966 to October 2007) within the MEDLINE database using the terms neoplasms, germ cell, or embryonal or testicular neoplasms restricted to humans, drug therapy, complications, and mortality. The Cochrane Register of Controlled Trials Databases (through October 2007) was also searched using the terms testicular cancer or germ cell tumors. Bibliographies were reviewed to extract other relevant articles. One hundred eighty-six articles were selected based on pertinence to advanced testicular cancer treatment, associated complications, and late relapses with an emphasis on randomized controlled trials.
The treatment of advanced testicular germ cell tumors with cisplatin combination chemotherapy is based on risk stratification (good, intermediate, or poor prognosis) according to pretreatment clinical features of prognostic value. Clinical trials have demonstrated that approximately 90% of patients classified as having a good prognosis achieve a durable complete remission to either 4 cycles of etoposide and cisplatin or 3 cycles of cisplatin, etoposide, and bleomycin. Complete responses are achieved less frequently for patients with intermediate- and poor-risk germ cell tumors, in whom 4 cycles of bleomycin, etoposide, and cisplatin remains the standard of care. Second- and third-line programs, including high-dose chemotherapy, also have curative potential. Chronic toxicities associated with therapy include cardiovascular disease, infertility, and secondary malignancies. Late relapses may also occur.
Clinical trials have led to evidence-based treatment recommendations for advanced testicular cancer based on risk stratification. Clinicians should be familiar with the potential complications of these therapies.

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    • "There were three treatment-related deaths in the first study but none in the second. A systematic review (including searches of Medline, American Society of Clinical Oncology annual meeting abstracts [2007] [2008] [2009] [2010] [2011] [2012] [2013], and reference lists from related reviews [20] [21] [22]) identified 12 randomised trials of novel treatments versus BEP in intermediate-or poor-prognosis patients (Table 4). Even the largest of these was only powered to detect an absolute PFS benefit of 15% [3]; several failed to recruit the targeted sample size. "
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    ABSTRACT: Background Standard chemotherapy for poor-prognosis metastatic nonseminoma has remained bleomycin, etoposide, and cisplatin (BEP) for many years; more effective regimens are required. Objective To explore whether response rates with a new intensive chemotherapy regimen, CBOP/BEP (carboplatin, bleomycin, vincristine, cisplatin/BEP), versus those in concurrent patients treated with standard BEP justify a phase 3 trial. Design, setting, and participants We conducted a phase 2 open-label randomised trial in patients with germ cell tumours of any extracranial primary site and one or more International Germ Cell Cancer Collaborative Group poor-prognosis features. Patients were randomised between 2005 and 2009 at 16 UK centres. Intervention BEP (bleomycin 30 000 IU) was composed of four cycles over 12 wk. CBOP/BEP was composed of 2 × CBOP, 2 × BO, and 3 × BEP (bleomycin 15 000 IU). Outcome measurements and statistical analysis Primary end point was favourable response rate (FRR) comprising complete response or partial response and normal markers. Success required the lower two-sided 90% confidence limit to exclude FRRs <60%; 44 patients on CBOP/BEP gives 90% power to achieve this if the true FRR is ≥80%. Equal numbers were randomised to BEP to benchmark contemporary response rates. Results and limitations A total of 89 patients were randomised (43 CBOP/BEP, 46 BEP); 40 and 41, respectively, completed treatment. CBOP/BEP toxicity, largely haematologic, was high (96% vs 63% on BEP had Common Terminology Criteria for Adverse Events v.3 grade ≥3). FRRs were 74% (90% confidence interval [CI], 61–85) with CBOP/BEP, 61% with BEP (90% CI, 48–73). After a median of 58-mo follow-up, 1-yr progression-free survival (PFS) was 65% and 43%, respectively (hazard ratio: 0.59; 95% CI, 0.33–1.06); 2-yr overall survival (OS) was 67% and 61%. Overall, 3 of 14 CBOP/BEP and 2 of 18 BEP deaths were attributed to toxicity, one after an overdose of bleomycin during CBOP/BEP. The trial was not powered to compare PFS. Conclusions The primary outcome was met, the CI for CBOP/BEP excluding FRRs <61%, but CBOP/BEP was more toxic. PFS and OS data are promising but require confirmation in an international phase 3 trial. Patient summary In this study we tested a new, more intensive way to deliver a combination of drugs often used to treat men with testicular cancer. We found that response rates were higher but that the CBOP/BEP regimen caused more short-term toxicity. Because most patients are diagnosed when their cancer is less advanced, it took twice as long to complete the trial as expected. Although we plan to carry out a larger trial, we will need international collaboration. Trial registration ISRCTN53643604;
    European Urology 07/2014; 67(3). DOI:10.1016/j.eururo.2014.06.034 · 12.48 Impact Factor
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    • "Mechanisms of resistance are multiple (Siddik, 2003; Galluzzi et al., 2012): some of them are activated before cisPt binds to cytoplasmic targets and DNA (Aida et al., 2005; McWhinney et al., 2009; Ishida et al., 2010; Chen and Kuo, 2010; Yamasaki et al., 2011), or during adduct cisPt/DNA formation (Gifford et al., 2004; Sakai et al., 2008; Tajeddine et al., 2008; Olaussen, 2009; Shachar et al., 2009; Roos et al., 2009; Kamal et al., 2010). Other mechanisms function after the binding to DNA (Brozovic et al., 2004; Feldman et al., 2008; Pinho et al., 2009; Michaud et al., 2009; Wang et al., 2010; Yuan et al., 2010; Janson et al., 2011) or could be sustained by alterations in signaling pathways that are not directly engaged by cisPt (Fijolek et al., 2006; Ren et al., 2008; Shen et al., 2010; Hu and Friedman, 2010). "
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    ABSTRACT: Cisplatin induces apoptosis through different pathways. The intrinsic apoptotic pathway is mediated by mitochondria, which, as a result of cisplatin treatment, undergo morphological alterations. The aim of this study was to investigate cisplatin-induced mitochondrial functional and morphological long-term effects in neuroblastoma B50 rat cells. To this purpose, we followed evaluated different several apoptotic markers by means of flow cytometry, confocal and electron microscopy and western blotting techniques. We applied different treatment protocols based on the incubation of the neuroblastoma B50 rat cells with 40μM cisplatin: i) for 48h and harvesting of the cells at the end of the treatment; ii further recovery in drug-free medium for 7 days post-treatment; iii) conditions as in ii) followed by re-seeding in normal medium and growth for a further 4 days. We observed apoptosis induction after the first treatment and after the recovery from cell death after long-term culture in drug-free medium. Interestingly, the latter phenomenon was characterized by mitochondrial elongation and mitochondrial protein rearrangement. In recovered and re-seeded cells, mitochondrial equilibrium moved toward fusion, possibly protecting cells from apoptosis.
    NeuroToxicology 10/2012; 34. DOI:10.1016/j.neuro.2012.10.011 · 3.05 Impact Factor
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    • "The complications associated with late diagnosis diminish the prospects of cure and are usually fatal. Fatal outcomes because of late diagnosis are unfortunate and unnecessary because TC is treatable and curable when diagnosed early [9] [18]. "
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    ABSTRACT: Background Testicular cancer (TC) is the most common malignancy among men aged 15–35 years and although Africa has one of the lowest prevalence rates, TC is often diagnosed late. The aim of this study was to describe TC knowledge, perceived risk and barriers to testicular self-examination (TSE) among young males in Uganda.Method Self-administered questionnaires and a systematic random sampling technique were used to collect data from 323 male students in a Ugandan University.ResultsThe participants were mostly in the 18–22 years age range (59%) (mean age = 22 ± 2.5 years). The majority of participants (87%) did not know what age group was most at risk for TC, when to perform TSE (71%) or whether testicular lumps are a sign of TC (77%). Participants mostly perceived their risk for TC as being either low (32%) or moderate (58%). The mean perceived risk for TC was 1.8 ± 0.61 and few participants (14%) were performing TSE regularly. Most participants (80%) reported a lack of skill for performing TSE as well as perceiving TSE as embarrassing (87%) and time consuming (79%). Self-reported practice of TSE was found to be associated with different aspects of TC knowledge (P = 0.01).Conclusion Young male Ugandans have little knowledge about TC and perceive their risk for this disease to be low. Findings show that having good knowledge about TC is associated with performing TSE. Implications for practice are that health care providers should scale-up health education about TC to empower young males with the knowledge and skills required for cancer preventive practices and behaviors.
    Journal of Men s Health 03/2012; 9(1):36-44. DOI:10.1016/j.jomh.2011.11.004 · 0.68 Impact Factor
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