Günther Gademann

Geldanamycin: the prototype of a class of antitumor drugs targeting the heat shock protein 90 family of molecular chaperones.

Despite tremendous advances in basic and clinical oncology, the prognosis for most patients with neoplastic diseases is still dismal. Therefore, new therapeutic strategies must be sought. A novel drug for the treatment of malignant diseases should have a mechanism of action different from those known for established oncological therapeutics. In addition, it is desirable to attempt to relate the antitumor activity of a candidate compound with molecular effects on proteins relevant for the pathogenesis of malignant diseases. Geldanamycin (GA; NSC 122750) has the potential to fulfill the aforementioned criteria. It was first purified in 1970 from the broth of Streptomyces hygroscopicus var geldanus var nova (DeBoer et al 1970). As a benzoquinone ansamycin (BA), it consists of a quinone ring and a hydrophobic ansa bridge (Fig 1; Rinehart and Shield 1976). The DNA sequences responsible for GA biosynthesis have been previously characterized (Allen and Ritchie 1994). The antineoplastic effect of GA was already noted in its first description (DeBoer et al 1970). Fig. 1.  Structural formula of geldanamycin Molecular studies revealed the binding of GA to members of the heat shock protein 90 (Hsp90) family of molecular chaperones (Whitesell et al 1994). Interference with the function of these Hsps seems to be the major mechanism of action of GA. This review focuses on oncological aspects and will not deal with other biological activities of GA, such as its virucidal (Li et al 1977) or ischemia protective (Conde et al 1997) effects.

Computed Tomography–Guided High-Dose-Rate Brachytherapy in Hepatocellular Carcinoma: Safety, Efficacy, and Effect on Survival

PURPOSE To determine the safety and efficacy of computed tomography (CT)-guided brachytherapy in hepatocellular carcinoma (HCC). METHODS AND MATERIALS A total of 83 patients were recruited, presenting with 140 HCC- lesions. Treatment was performed by CT-guided high-dose-rate (HDR) brachytherapy with an iridium-192 source. The primary endpoint was time to progression; secondary endpoints included local tumor control and overall survival (OS). A matched-pair analysis with patients not receiving brachytherapy was performed. Match criteria included the Cancer of the Liver Italian Program (CLIP) score, alpha-fetoprotein, presence, and extent of multifocal disease. For statistical analysis, Kaplan-Meier and Cox regression were performed. RESULTS Mean and median cumulative TTP for all patients (n = 75) were 17.7 and 10.4 months. Five local recurrences were observed. The OS after inclusion reached median times of 19.4 months (all patients), 46.3 months (CLIP score, 0), 20.6 months (CLIP score, 1) 12.7 months, (CLIP score, 2), and 8.3 months (CLIP score, >or=3). The 1- and 3-year OS were 94% and 65% (CLIP score, 0), 69% and 12% (CLIP score, 1), and 48% and 19% (CLIP score, 2), respectively. Nine complications requiring intervention were encountered in 124 interventions. Matched-pair analysis revealed a significantly longer OS for patients undergoing CT-guided brachytherapy. CONCLUSION Based on our results the study treatment could be safely performed. The study treatment had a beneficial effect on OS in patients with advanced HCC, with respect to (and depending on) the CLIP score and compared with OS in a historical control group. A high rate of local control was also observed, regardless of applied dose in a range of 15 to 25 Gy.

Treatment of hepatic metastases of breast cancer with CT-guided interstitial brachytherapy - a phase II-study.

PURPOSE The aim of the study was the evaluation of feasibility, safety and effectiveness of interstitial brachytherapy for the treatment of hepatic metastases of breast cancer. MATERIALS AND METHODS Forty-one consecutive patients with 115 unresectable hepatic metastases of breast cancer were included in this phase-II-trial. They were treated in 69 interventions of CT-guided-interstitial-brachytherapy of the liver. Brachytherapy was applied as a single fraction high-dose-irradiation (15-25Gy (Gray)) using a (192)Ir-source of 10Ci. Nineteen patients presented systemically pretreated extrahepatic tumors. Primary endpoints were complications, local tumor control and progression-free survival. RESULTS The median tumor diameter was 4.6 cm (1.5-11 cm). The median irradiation time per intervention was 26.5 min (range: 7-47 min). The applied median minimal dose at the CTV (clinical target volume) margin was 18.5 Gy (12-25 Gy). In 69 interventions and during the postinterventional period, one major complication (symptomatic post-interventional bleeding) (1.5%) and six minor complications occurred (8.7%). The median follow-up time was 18 months (range: 1-56). After 6, 12 and 18 months, local tumor control was 97%, 93.5% and 93.5%, intra- and extrahepatic progression free survival was 53%, 40% and 27%, and overall survival was 97%, 79% and 60%, respectively. CONCLUSION CT-guided-brachytherapy is safe and effective for the treatment of liver metastases of breast cancer.

Radiotherapy of Liver Metastases Comparison of Target Volumes and Dose-Volume Histograms Employing CT- or MRI-Based Treatment Planning

Purpose:To assess differences in delineated target volumes of liver metastases using contrast-enhanced CT and different MRI sequences for radiation treatment planning.Patients and Methods:25 patients with 43 colorectal liver metastases were recruited. Tumor margins were defined by two experienced radiologists. The resulting D90 was assessed and the CT-based 3-D dose distribution merged with the according MRI dataset by employing image fusion. A theoretical D90 as a result of MRI-based treatment planning was assessed for various MRI sequences individually.Results:In venous phase contrast-enhanced CT, the mean tumor volume was 20 ml; T1-weighted (T1w) MRI, 27 ml; contrast-enhanced T1w 42 ml; T2w 65 ml. The difference between the target volumes as assessed by either CT or MRI was 181% for T1w images, 178% for contrast-enhanced T1w, and 246% for T2w sequences. All differences were statistically significant (p < 0.05).The analysis of the dose-volume histograms revealed statistically significant differences (i.e., for the D90) for the different target volumes specified by CT and MRI: mean D90 on CT, 18 Gy; plain T1w, 16 Gy; contrast-enhanced T1w, 15.5 Gy; T2w, 12 Gy. Hence, delineation of a larger target volume in T2w MRI compared to contrast-enhanced CT resulted in a smaller D90.The mean differences of tumor volumes assessed by CT and plain T1w were significantly higher in the group of patients showing local tumor recurrences as compared to patients with long-term local tumor control (p = 0.002).Conclusion:For treatment planning of liver metastases, the use of either plain T1w or T2w sequences is recommended to delineate the clinical target volume as completely as possible and not to miss potential tumor cell congregations in the surroundings as in CT.Ziel:Beurteilung von Unterschieden in der Abgrenzung von Zielvolumina bei kontrastmittelverstärkter CT- und MRT-gestützter Bestrahlungsplanung.Patienten und Methodik:25 Patienten mit 43 Lebermetastasen kolorektalen Ursprungs wurden in dieser Studie untersucht. Zur Definition der Zielvolumina wurden CT- und MRT-Untersuchungen verwendet, die Konturierung der Tumorränder wurde von zwei erfahrenen Radiologen vorgenommen. Die D90 wurde nach Bildfusionierung der CT-basierten dreidimensionalen Dosisverteilungen mit den MRT-Datensätzen beurteilt. Eine theoretische D90 als Resultat der MRT-basierten Bestrahlungsplanung wurde bestimmt.Ergebnisse:In der venösen Phase der kontrastmittelverstärkten CT-Untersuchung betrug das mittlere Tumorvolumen 20 ml; MRT T1-gewichtet (T1w) 27 ml; kontrastmittelverstärkte T1w 42 ml; T2w 65 ml. Die Unterschiede der Zielvolumina im Verhältnis zur CT-gestützten Planung betrugen 181% für T1w-, 178% für kontrastmittelverstärkte T1w- und 246% für T2w-Sequenzen. Alle Unterschiede stellten sich als signifikant heraus (p < 0,05). Im Vergleich zur kontrastmittelverstärkten CT resultierte somit das Bemessen des Tumorvolumens im T2w MRT in einer niedrigeren D90.Die Analyse der Dosis-Volumen-Histogramme zeigte signifikante Unterschiede der verschiedenen Volumina. Die mittlere D90 betrug bei CT 18 Gy, bei nativer T1w 16 Gy, bei kontrastmittelverstärkter T1w 15,5 Gy und bei T2w 12 Gy.Die mittleren Unterschiede des Zielvolumens durch CT- und native T1w-gestützte MRT-Bestrahlungsplanung waren in der Gruppe der Patienten mit lokalen Tumorrezidiven signifikant höher als in der Gruppe mit langfristiger lokaler Kontrolle (p = 0,002).Schlussfolgerung:Für die Bestrahlungsplanung der Therapie von Lebermetastasen wird die Verwendung von nativen T1w- oder T2w-Sequenzen zur Abgrenzung des Zielvolumens empfohlen, um eine möglichst vollständige Erfassung der Metastase einschließlich evtl. vorhandener peripherer Tumorausläufer zu erreichen.

CT-guided brachytherapy (CTGB) versus interstitial laser ablation (ILT) of colorectal liver metastases: an intraindividual matched-pair analysis.

Purpose:To compare local tumor control after percutaneous tumor ablation by interstitial laser therapy (ILT) or CT-guided brachytherapy (CTGB).Patients and Methods:In a matched pair analysis including 18 patients with 36 liver metastases of colorectal primary, both ILT and CTGB were performed in different lesions. The following matching factors were considered: (i) tumor size ≤ 5 cm, and (ii) execution of chemotherapy after tumor ablation. Primary endpoint was local tumor control.Results:Treated lesions were identical in terms of tumor size and all matching criteria were fulfilled in all patients except for the performance of adjuvant chemotherapy. Median follow-up was 14 months (3–24 months) for both groups. Only five of 18 patients (28%) demonstrated local tumor progression after CTGB, whereas in ten of 18 patients (56%) tumor progression was found after ILT. Differences encountered were significant for all patients (p = 0.04), whereas in those who fulfilled all matching criteria (n = 14) the level of statistical significance was not reached (p = 0.23).Conclusion:CTGB demonstrated superior local tumor control compared to ILT in long-term follow-up.Ziel:Intraindividueller Vergleich lokaler Kontrollraten nach perkutaner Tumorablation mit interstitieller Lasertherapie (ILT) oder CT-gestützter Brachytherapie (CTGB) von intrahepatischen Metastasen bei kolorektalem Karzinom.Patienten und Methodik:Eine Matched-Pair-Analyse wurde bei 18 Patienten mit insgesamt 36 Lebermetastasen eines kolorektalen Karzinoms durchgeführt. Je eine Metastase wurde mit perkutaner Tumorablation mit ILT und je eine mit CTGB behandelt. Bei den Patienten mit identischer Tumorhistologie wurden folgende Faktoren betrachtet: 1. Tumorgröße ≤ 5 cm und 2. Durchführung oder Verzicht auf eine adjuvante Chemotherapie. Als primärer Endpunkt wurde die lokale Tumorkontrolle definiert.Ergebnisse:Die Verteilung der Tumorgrößen war gleich, und alle Patienten erreichten volle Übereinstimmung bis auf den Vergleichsfaktor der adjuvanten Chemotherapie. Die mediane Beobachtungszeit betrug 14 Monate (3–24 Monate) für beide Gruppen. Fünf von 18 Patienten (28%) hatten eine lokale Tumorprogression nach CTGB und zehn von 18 Patienten (56%) nach ILT. Die Differenz zwischen den Gruppen war für alle Patienten signifikant (p = 0,04). Bei der Betrachtung der Patienten mit völliger Übereinstimmung wurde die Signifikanzgrenze nicht erreicht (p = 0,23).Schlussfolgerung:Die CTGB zeigt in der Langzeitbeobachtung überlegene lokale Tumorkontrollraten im Vergleich zur ILT.

Management of Cerebral Metastases from Malignant Melanoma: Results of a Combined, Simultaneous Treatment with Fotemustine and Irradiation

We report results of a conservative treatment for brain metastases from malignant melanoma with a combination of irradiation and chemotherapy (fotemustine and/or DTIC). To date, 12 patients have been treated. There was a complete remission of the brain metastases in four patients. In two patients a partial remission was observed. The mean survival of the responder was 8.2 months (95% confidence interval 3.8–12.6 months). The most common side effects were thrombocytopenia, leukopenia, and alopecia. Altogether, the treatment was well tolerated. As the outcome of patients with brain metastases from malignant melanoma is generally poor, this combined chemo- and radiation therapy may provide improved care for such patients.

Value of diffusion weighted MR imaging as an early surrogate parameter for evaluation of tumor response to high-dose-rate brachytherapy of colorectal liver metastases

BackgroundTo assess the value of diffusion weighted imaging (DWI) as an early surrogate parameter for treatment response of colorectal liver metastases to image-guided single-fraction 192Ir-high-dose-rate brachytherapy (HDR-BT).MethodsThirty patients with a total of 43 metastases underwent CT- or MRI-guided HDR-BT. In 13 of these patients a total of 15 additional lesions were identified, which were not treated at the initial session and served for comparison. Magnetic resonance imaging (MRI) including breathhold echoplanar DWI sequences was performed prior to therapy (baseline MRI), 2 days after HDR-BT (early MRI) as well as after 3 months (follow-up MRI). Tumor volume (TV) and intratumoral apparent diffusion coefficient (ADC) were measured independently by two radiologists. Statistical analysis was performed using univariate comparison, ANOVA and paired t test as well as Pearsons correlation.ResultsAt early MRI no changes of TV and ADC were found for non-treated colorectal liver metastases. In contrast, mean TV of liver lesions treated with HDR-BT increased by 8.8% (p = 0.054) while mean tumor ADC decreased significantly by 11.4% (p < 0.001). At follow-up MRI mean TV of non-treated metastases increased by 50.8% (p = 0.027) without significant change of mean ADC values. In contrast, mean TV of treated lesions decreased by 47.0% (p = 0.026) while the mean ADC increased inversely by 28.6% compared to baseline values (p < 0.001; Pearsons correlation coefficient of r = -0.257; p < 0.001).ConclusionsDWI is a promising imaging biomarker for early prediction of tumor response in patients with colorectal liver metastases treated with HDR-BT, yet the optimal interval between therapy and early follow-up needs to be elucidated.

Radiotherapy of Liver Metastases

Purpose:To assess differences in delineated target volumes of liver metastases using contrast-enhanced CT and different MRI sequences for radiation treatment planning.Patients and Methods:25 patients with 43 colorectal liver metastases were recruited. Tumor margins were defined by two experienced radiologists. The resulting D90 was assessed and the CT-based 3-D dose distribution merged with the according MRI dataset by employing image fusion. A theoretical D90 as a result of MRI-based treatment planning was assessed for various MRI sequences individually.Results:In venous phase contrast-enhanced CT, the mean tumor volume was 20 ml; T1-weighted (T1w) MRI, 27 ml; contrast-enhanced T1w 42 ml; T2w 65 ml. The difference between the target volumes as assessed by either CT or MRI was 181% for T1w images, 178% for contrast-enhanced T1w, and 246% for T2w sequences. All differences were statistically significant (p < 0.05).The analysis of the dose-volume histograms revealed statistically significant differences (i.e., for the D90) for the different target volumes specified by CT and MRI: mean D90 on CT, 18 Gy; plain T1w, 16 Gy; contrast-enhanced T1w, 15.5 Gy; T2w, 12 Gy. Hence, delineation of a larger target volume in T2w MRI compared to contrast-enhanced CT resulted in a smaller D90.The mean differences of tumor volumes assessed by CT and plain T1w were significantly higher in the group of patients showing local tumor recurrences as compared to patients with long-term local tumor control (p = 0.002).Conclusion:For treatment planning of liver metastases, the use of either plain T1w or T2w sequences is recommended to delineate the clinical target volume as completely as possible and not to miss potential tumor cell congregations in the surroundings as in CT.Ziel:Beurteilung von Unterschieden in der Abgrenzung von Zielvolumina bei kontrastmittelverstärkter CT- und MRT-gestützter Bestrahlungsplanung.Patienten und Methodik:25 Patienten mit 43 Lebermetastasen kolorektalen Ursprungs wurden in dieser Studie untersucht. Zur Definition der Zielvolumina wurden CT- und MRT-Untersuchungen verwendet, die Konturierung der Tumorränder wurde von zwei erfahrenen Radiologen vorgenommen. Die D90 wurde nach Bildfusionierung der CT-basierten dreidimensionalen Dosisverteilungen mit den MRT-Datensätzen beurteilt. Eine theoretische D90 als Resultat der MRT-basierten Bestrahlungsplanung wurde bestimmt.Ergebnisse:In der venösen Phase der kontrastmittelverstärkten CT-Untersuchung betrug das mittlere Tumorvolumen 20 ml; MRT T1-gewichtet (T1w) 27 ml; kontrastmittelverstärkte T1w 42 ml; T2w 65 ml. Die Unterschiede der Zielvolumina im Verhältnis zur CT-gestützten Planung betrugen 181% für T1w-, 178% für kontrastmittelverstärkte T1w- und 246% für T2w-Sequenzen. Alle Unterschiede stellten sich als signifikant heraus (p < 0,05). Im Vergleich zur kontrastmittelverstärkten CT resultierte somit das Bemessen des Tumorvolumens im T2w MRT in einer niedrigeren D90.Die Analyse der Dosis-Volumen-Histogramme zeigte signifikante Unterschiede der verschiedenen Volumina. Die mittlere D90 betrug bei CT 18 Gy, bei nativer T1w 16 Gy, bei kontrastmittelverstärkter T1w 15,5 Gy und bei T2w 12 Gy.Die mittleren Unterschiede des Zielvolumens durch CT- und native T1w-gestützte MRT-Bestrahlungsplanung waren in der Gruppe der Patienten mit lokalen Tumorrezidiven signifikant höher als in der Gruppe mit langfristiger lokaler Kontrolle (p = 0,002).Schlussfolgerung:Für die Bestrahlungsplanung der Therapie von Lebermetastasen wird die Verwendung von nativen T1w- oder T2w-Sequenzen zur Abgrenzung des Zielvolumens empfohlen, um eine möglichst vollständige Erfassung der Metastase einschließlich evtl. vorhandener peripherer Tumorausläufer zu erreichen.

Prospective randomized trial of enoxaparin, pentoxifylline and ursodeoxycholic acid for prevention of radiation-induced liver toxicity.

Background/Aim Targeted radiotherapy of liver malignancies has found to be effective in selected patients. A key limiting factor of these therapies is the relatively low tolerance of the liver parenchyma to radiation. We sought to assess the preventive effects of a combined regimen of pentoxifylline (PTX), ursodeoxycholic acid (UDCA) and low-dose low molecular weight heparin (LMWH) on focal radiation-induced liver injury (fRILI). Methods and Materials Patients with liver metastases from colorectal carcinoma who were scheduled for local ablation by radiotherapy (image-guided high-dose-rate interstitial brachytherapy) were prospectively randomized to receive PTX, UDCA and LMWH for 8 weeks (treatment) or no medication (control). Focal RILI at follow-up was assessed using functional hepatobiliary magnetic resonance imaging (MRI). A minimal threshold dose, i.e. the dose to which the outer rim of the fRILI was formerly exposed to, was quantified by merging MRI and dosimetry data. Results Results from an intended interim-analysis made a premature termination necessary. Twenty-two patients were included in the per-protocol analysis. Minimal mean hepatic threshold dose 6 weeks after radiotherapy (primary endpoint) was significantly higher in the study treatment-group compared with the control (19.1 Gy versus 14.6 Gy, p = 0.011). Qualitative evidence of fRILI by MRI at 6 weeks was observed in 45.5% of patients in the treatment versus 90.9% of the control group. No significant differences between the groups were observed at the 12-week follow-up. Conclusions The post-therapeutic application of PTX, UDCA and low-dose LMWH significantly reduced the extent and incidence fRILI at 6 weeks after radiotherapy. The development of subsequent fRILI at 12 weeks (4 weeks after cessation of PTX, UDCA and LMWH during weeks 1–8) in the treatment group was comparable to the control group thus supporting the observation that the agents mitigated fRILI. Trial Registration EU clinical trials register 2008-002985-70 ClinicalTrials.gov NCT01149304

CT-Guided Brachytherapy (CTGB) versus Interstitial Laser Ablation (ILT) of Colorectal Liver Metastases

Purpose:To compare local tumor control after percutaneous tumor ablation by interstitial laser therapy (ILT) or CT-guided brachytherapy (CTGB).Patients and Methods:In a matched pair analysis including 18 patients with 36 liver metastases of colorectal primary, both ILT and CTGB were performed in different lesions. The following matching factors were considered: (i) tumor size ≤ 5 cm, and (ii) execution of chemotherapy after tumor ablation. Primary endpoint was local tumor control.Results:Treated lesions were identical in terms of tumor size and all matching criteria were fulfilled in all patients except for the performance of adjuvant chemotherapy. Median follow-up was 14 months (3–24 months) for both groups. Only five of 18 patients (28%) demonstrated local tumor progression after CTGB, whereas in ten of 18 patients (56%) tumor progression was found after ILT. Differences encountered were significant for all patients (p = 0.04), whereas in those who fulfilled all matching criteria (n = 14) the level of statistical significance was not reached (p = 0.23).Conclusion:CTGB demonstrated superior local tumor control compared to ILT in long-term follow-up.Ziel:Intraindividueller Vergleich lokaler Kontrollraten nach perkutaner Tumorablation mit interstitieller Lasertherapie (ILT) oder CT-gestützter Brachytherapie (CTGB) von intrahepatischen Metastasen bei kolorektalem Karzinom.Patienten und Methodik:Eine Matched-Pair-Analyse wurde bei 18 Patienten mit insgesamt 36 Lebermetastasen eines kolorektalen Karzinoms durchgeführt. Je eine Metastase wurde mit perkutaner Tumorablation mit ILT und je eine mit CTGB behandelt. Bei den Patienten mit identischer Tumorhistologie wurden folgende Faktoren betrachtet: 1. Tumorgröße ≤ 5 cm und 2. Durchführung oder Verzicht auf eine adjuvante Chemotherapie. Als primärer Endpunkt wurde die lokale Tumorkontrolle definiert.Ergebnisse:Die Verteilung der Tumorgrößen war gleich, und alle Patienten erreichten volle Übereinstimmung bis auf den Vergleichsfaktor der adjuvanten Chemotherapie. Die mediane Beobachtungszeit betrug 14 Monate (3–24 Monate) für beide Gruppen. Fünf von 18 Patienten (28%) hatten eine lokale Tumorprogression nach CTGB und zehn von 18 Patienten (56%) nach ILT. Die Differenz zwischen den Gruppen war für alle Patienten signifikant (p = 0,04). Bei der Betrachtung der Patienten mit völliger Übereinstimmung wurde die Signifikanzgrenze nicht erreicht (p = 0,23).Schlussfolgerung:Die CTGB zeigt in der Langzeitbeobachtung überlegene lokale Tumorkontrollraten im Vergleich zur ILT.