Molekular zielgerichtete Therapie

Zusammenfassung: Bis vor knapp 10Jahren stützte sich die Tumortherapie auf 3Säulen: die Chirurgie, die Strahlentherapie und die zytostatische Chemotherapie. Eine definitive Heilung im Bereich der soliden Tumoren versprach meist nur eine vollständige Entfernung des Tumors durch den Chirurgen. Radiotherapeuten und Onkologen konnten nur einem kleinen Teil ihrer Patienten langfristig helfen. Antikörpertherapien, Antitumorvakzinierungen oder gar genspezifische, individualisierte Therapieformen existierten zwar als Visionen, diese schienen Mitte der 90er-Jahre von einer klinischer Anwendung noch weit entfernt. Mit der Einführung des Antikörpers Rituximab (1997) und des Tyrosinkinaseinhibitors Imatinib (2001) in die klinische Praxis kamen 2 neuartige Substanzen auf den Markt, die Denken und Vorstellungen in der Onkologie grundsätzlich veränderten. Diese Therapeutika ließen aus Visionen Realitäten werden, die der Pharmaindustrie, den Klinikern und Patienten neue Perspektiven bezüglich Machbarkeit und kommender Möglichkeiten im Bereich der Tumortherapie eröffnet haben. Im Folgenden soll ein Überblick über die Entwicklung der 4.Säule der Tumortherapie, der sog. "targeted therapy", gegeben werde

Selective Intra-arterial Chemotherapy with Floxuridine as Second- or Third-Line Approach in Patients with Unresectable Colorectal Liver Metastases

Background: An outcome assessment was performed of patients with unresectable colorectal liver metastases (CRLM) treated in second or third line with floxuridine (FUDR)-based hepatic artery infusion (HAI). Methods: Twenty-three patients who were pretreated with systemic (immuno)chemotherapy received FUDR-HAI alone or combined with systemic chemotherapy. We reviewed patient charts and our prospective patient database for survival and associated risk factors. Results: Patients received FUDR-HAI for unresectable CRLM from January 2000 to September 2010. Twelve patients (52%) received concurrent systemic chemotherapy. Median overall survival (OS), progression-free survival (PFS), and hepatic PFS were 15.6months (range, 2.5-55.7months), 3.9months (range, 0.7-55.7months), and 5.5months (range, 1.6-55.7months), respectively. The liver resection rate after HAI was 35%. PFS was better in patients undergoing secondary resection than in patients without resection (hazard ratio [HR] 0.21; 95% confidence interval [95% CI] 0.07-0.66; P=0.0034), while OS showed a trend toward improvement (HR 0.4; 95% CI 0.13-1.2; P=0.09). No differences were observed in OS (P=0.69) or PFS (P=0.086) in patients who received FUDR-HAI alone compared with patients treated with combined regional and systemic chemotherapy. No statistically significant differences were seen in patients previously treated with one chemotherapy line compared with patients treated with two lines. Presence of extrahepatic disease was a negative risk factor for PFS (liver-only disease: HR 0.03; 95% CI 0.0032-0.28; P<0.0001). Toxicities were manageable with dose modifications and supportive measures. Conclusions: FUDR-HAI improves PFS and results in a trend toward improved OS in selected patients able to undergo liver resection after tumor is downsize

Lack of Effective Anti-Apoptotic Activities Restricts Growth of Parachlamydiaceae in Insect Cells

The fundamental role of programmed cell death in host defense is highlighted by the multitude of anti-apoptotic strategies evolved by various microbes, including the well-known obligate intracellular bacterial pathogens Chlamydia trachomatis and Chlamydia (Chlamydophila) pneumoniae. As inhibition of apoptosis is assumed to be essential for a successful infection of humans by these chlamydiae, we analyzed the anti-apoptotic capacity of close relatives that occur as symbionts of amoebae and might represent emerging pathogens. While Simkania negevensis was able to efficiently replicate within insect cells, which served as model for metazoan-derived host cells, the Parachlamydiaceae (Parachlamydia acanthamoebae and Protochlamydia amoebophila) displayed limited intracellular growth, yet these bacteria induced typical features of apoptotic cell death, including formation of apoptotic bodies, nuclear condensation, internucleosomal DNA fragmentation, and effector caspase activity. Induction of apoptosis was dependent on bacterial activity, but not bacterial de novo protein synthesis, and was detectable already at very early stages of infection. Experimental inhibition of host cell death greatly enhanced parachlamydial replication, suggesting that lack of potent anti-apoptotic activities in Parachlamydiaceae may represent an important factor compromising their ability to successfully infect non-protozoan hosts. These findings highlight the importance of the evolution of anti-apoptotic traits for the success of chlamydiae as pathogens of humans and animals

Molekular zielgerichtete Therapie

Until recently, cancer therapy was based on three modalities: surgery, radiotherapy, and cytostatic chemotherapy. In most instances treatment of solid tumors was a surgical domain. For patients with incomplete resection or relapse after surgery, radiotherapy and chemotherapy usually offered only partial response and mostly of limited duration. By the mid-1990s visions of antibody-based therapies, vaccination strategies, and even gene-specific therapies existed but seemed far from clinical practice. United States Federal Drug Administration approval of the humanized antibody rituximab (1997) and the tyrosine kinase inhibitor imatinib (2001) has changed perceptions of oncologic treatment. These drugs turned visions into reality and led the pharmaceutical industry, clinicians, and patients to new perspectives. This article gives an overview of the development of this fourth modality in cancer therapy, so-called targeted therapy

Severe neutropenia during cabazitaxel treatment is associated with survival benefit in men with metastatic castration-resistant prostate cancer (mCRPC): A post-hoc analysis of the TROPIC phase III trial

Background: Cabazitaxel significantly improves overall survival (OS) in men with metastatic castration-resistant prostate cancer (mCRPC) progressing during or after docetaxel, but is associated with a higher rate of grade >= 3 neutropenia compared with docetaxel. We thus examined the relationship between cabazitaxel-induced grade >= 3 neutropenia, baseline neutrophil-lymphocyte ratio (NLR) and treatment outcomes. Methods: Data from the experimental arm of the TROPIC phase 3 trial which randomly assigned men with mCRPC to cabazitaxel or mitoxantrone every 3 weeks, both combined with daily prednisone, were analysed. The influence on OS (primary end-point) and progression-free survival (PFS) of at least one episode of grade >= 3 neutropenia during cabazitaxel therapy was investigated using Cox regression models, adjusted for pain at baseline. The relationships with prostate-specific antigen (PSA) responses during cabazitaxel therapy and baseline NLR were also analysed. Findings: The occurrence of grade >= 3 neutropenia during cabazitaxel therapy was associated with a prolonged OS (median 16.3 versus 14.0 months, hazard ratio (HR) [95% confidence interval] = 0.65 [0.43-0.97], p = 0.035), a twice longer PFS (median 5.3 versus 2.6 months, HR = 0.56 [0.40-0.79], p = 0.001) and a higher confirmed PSA response >= 50% (49.8% versus 24.4%, p = 0.005), as compared with patients who did not develop grade >= 3 neutropenia. Grade >= 3 neutropenia was more common in case of NLR <3 as compared with NLR >= 3 at baseline (88.8% versus 75.3%, p = 0.002). Combining low NLR at baseline and grade >= 3 neutropenia during therapy was associated with the longest OS (median 19.2 months) while high NLR at baseline and no grade >= 3 neutropenia was associated with a poor OS (median 12.9 months, HR 0.46 [0.28-0.76], p = 0.002). In the subgroup of neutropenic patients the median OS was 19.7 months in those treated with granulocyte colony-stimulating factor (G-CSF) and 16 months on those without G-CSF support. Interpretation: This post-hoc analysis of TROPIC suggests that the occurrence of grade >= 3 neutropenia with cabazitaxel is associated with improved OS and PFS. Patients with a low NLR at baseline were more likely to develop grade >= 3 neutropenia during cabazitaxel therapy and showed the longest OS. High NLR at baseline and no grade >= 3 neutropenia during therapy was associated with poor outcomes which may suggest insufficient drug exposure or a limited impact on the tumour-associated immune response. Primary or secondary prophylactic use of G-CSF had no adverse impact for outcome. If prospectively confirmed, these results would justify maintaining the intended cabazitaxel dose of 25 mg/m(2) whenever possible. (C) 2015 Elsevier Ltd. All rights reserved

Effects of an outpatient physical exercise program on hematopoietic stem-cell transplantation recipients: a randomized clinical trial

Patients who undergo hematopoietic stem cell transplantation (HSCT) often experience physical and psychological problems, even long after treatment has been completed. This study was performed to evaluate the effects of a 12-week outpatient physical exercise program, incorporating aerobic and strength exercises, as compared to a usual care control condition on patients’ physical performance and psychosocial well-being. Methods: Patients who had completed HSCT up to 6 months earlier were randomly assigned to a supervised physical exercise program (n = 64) or a usual care control group (n = 67). Primary outcomes were quantified physical performance and self-reported physical functioning. Secondary outcomes were body composition measurement, quantified walking activity and patient-reported outcomes (physical activity, fatigue and health-related quality of life). Assessments were at baseline, immediately after program completion and at 3-month follow-up. Results: Significant intervention effects were observed at both post-treatment and follow-up on physical performance measures. No other outcomes yielded statistically significant group differences. Conclusion: Physical exercise should be considered in the management of HSCT recipients to improve physical performance after discharge from hospital. Further research is needed to determine how the program can be enhanced so that improved physical performance also translates into improved physical and psychosocial functioning in daily life