Marc Bischof

Trimodal Cancer Treatment: Beneficial Effects of Combined Antiangiogenesis, Radiation, and Chemotherapy

It has been suggested that chemotherapy and radiotherapy could favorably be combined with antiangiogenesis in dual anticancer strategy combinations. Here we investigate the effects of a trimodal strategy consisting of all three therapy approaches administered concurrently. We found that in vitro and in vivo, the antiendothelial and antitumor effects of the triple therapy combination consisting of SU11657 (a multitargeted small molecule inhibitor of vascular endothelial growth factor and platelet-derived growth factor receptor tyrosine kinases), Pemetrexed (a multitargeted folate antimetabolite), and ionizing radiation were superior to all single and dual combinations. The superior effects in human umbilical vein endothelial cells and tumor cells (A431) were evident in cell proliferation, migration, tube formation, clonogenic survival, and apoptosis assays (sub-G1 and caspase-3 assessment). Exploring potential effects on cell survival signaling, we found that radiation and chemotherapy induced endothelial cell Akt phosphorylation, but SU11657 could attenuate this process in vitro and in vivo in A431 human tumor xenografts growing s.c. on BALB/c nu/nu mice. Triple therapy further decreased tumor cell proliferation (Ki-67 index) and vessel count (CD31 staining), and induced greater tumor growth delay versus all other therapy regimens without increasing apparent toxicity. When testing different treatment schedules for the A431 tumor, we found that the regimen with radiotherapy (7.5 Gy single dose), given after the institution of SU11657 treatment, was more effective than radiotherapy preceding SU11657 treatment. Accordingly, we found that SU11657 markedly reduced intratumoral interstitial fluid pressure from 8.8 +/- 2.6 to 4.2 +/- 1.5 mm Hg after 1 day. Likewise, quantitative T2-weighed magnetic resonance imaging measurements showed that SU11657-treated mice had reduced intratumoral edema. Our data indicates that inhibition of Akt signaling by antiangiogenic treatment with SU11657 may result in: (a) normalization of tumor blood vessels that cause prerequisite physiologic conditions for subsequent radio/chemotherapy, and (b) direct resensitization of endothelial cells to radio/chemotherapy. We conclude that trimodal cancer therapy combining antiangiogenesis, chemotherapy, and radiotherapy has beneficial molecular and physiologic effects to emerge as a clinically relevant antitumor strategy.

Radiotherapy for advanced adenoid cystic carcinoma: neutrons, photons or mixed beam?

PURPOSE To compare retrospectively radiotherapy with neutrons, photons, and a photon/neutron mixed beam in patients with advanced adenoid cystic carcinoma of the head and neck. Local control, survival, distant failure, and complications were analyzed. MATERIALS AND METHODS Between 1983 and 1995, 75 patients with inoperable, recurrent, or incompletely resected adenoid cystic carcinoma of the head and neck received radiotherapy that consisted of either fast 14.1 MV DT neutrons (median dose 16 neutron Gy), linac-based photon irradiation (median dose 64 photon Gy), or both (median dose 8 neutron Gy and 32 photon Gy). Follow-up ranged from 1 to 160 months (median 51 months), and the surviving patients had a minimum follow-up of 3 years at the time of analysis. RESULTS The actuarial 5-year local control was 75% for neutrons, and 32% for both mixed beam and photons (P = 0.015, log-rank). This advantage for neutrons in local control was not transferred to significant differences in survival (P > 0.1). The survival is dictated by the tumor diseases due to distant metastases occurring in 29 (39%) of the 75 patients. Positive lymph nodes were the only significant factor (P = 0.001) associated with the development of distant metastases although negative lymph nodes did not predict absence of distant metastases, but predicted a delay of occurrence. In multivariate analysis postoperative radiotherapy (P = 0.003) and small tumor size (P = 0.01) were associated with high local control, while primary therapy (P = 0.006) and negative lymph nodes (P = 0.01) were associated with longer survival. While acute toxicity was similar in all three radiotherapy groups, severe late grade 3 and 4 toxicity tended to be more prevalent (P > 0.1) with neutrons (19%) than with mixed beam (10%) and photons (4%). CONCLUSION Fast neutron radiotherapy provides higher local control rates than a mixed beam and photons in advanced, recurrent or not completely resected adenoid cystic carcinoma of the major and minor salivary glands. Neutron radiotherapy can be recommended in patients with bad prognosis with gross residual disease (R2), with unresectable tumors, or inoperable tumors. The type of radiation does not impact survival, which is dominated by the high number of distant metastases.

Long-term survival of cancer patients compared to heart failure and stroke: A systematic review

BackgroundCancer, heart failure and stroke are among the most common causes of death worldwide. Investigation of the prognostic impact of each disease is important, especially for a better understanding of competing risks. Aim of this study is to provide an overview of long term survival of cancer, heart failure and stroke patients based on the results of large population- and hospital-based studies.MethodsRecords for our study were identified by searches of Medline via Pubmed. We focused on observed and relative age- and sex-adjusted 5-year survival rates for cancer in general and for the four most common malignancies in developed countries, i.e. lung, breast, prostate and colorectal cancer, as well as for heart failure and stroke.ResultsTwenty studies were identified and included for analysis. Five-year observed survival was about 43% for all cancer entities, 40-68% for stroke and 26-52% for heart failure. Five-year age and sex adjusted relative survival was 50-57% for all cancer entities, about 50% for stroke and about 62% for heart failure. In regard to the four most common malignancies in developed countries 5-year relative survival was 12-18% for lung cancer, 73-89% for breast cancer, 50-99% for prostate cancer and about 43-63% for colorectal cancer. Trend analysis revealed a survival improvement over the last decades.ConclusionsThe results indicate that long term survival and prognosis of cancer is not necessarily worse than that of heart failure and stroke. However, a comparison of the prognostic impact of the different diseases is limited, corroborating the necessity for further systematic investigation of competing risks.

Enhancement of Radiation Response in Osteosarcoma and Rhabomyosarcoma Cell Lines by Histone Deacetylase Inhibition

PURPOSE Histone deacetylase inhibitors (HDACIs) can enhance the sensitivity of cells to photon radiation treatment (XRT) by altering numerous molecular pathways. We investigated the effect of pan-HDACIs such as suberoylanilide hydroxamic acid (SAHA) on radiation response in two osteosarcoma (OS) and two rhabdomyosarcoma (RMS) cell lines. METHODS AND MATERIALS Clonogenic survival, cell cycle analysis, and apoptosis were examined in OS (KHOS-24OS, SAOS2) and RMS (A-204, RD) cell lines treated with HDACI and HDACI plus XRT, respectively. Protein expression was investigated via immunoblot analysis, and cell cycle analysis and measurement of apoptosis were performed using flow cytometry. RESULTS SAHA induced an inhibition of cell proliferation and clonogenic survival in OS and RMS cell lines and led to a significant radiosensitization of all tumor cell lines. Other HDACI such as M344 and valproate showed similar effects as investigated in one OS cell line. Furthermore, SAHA significantly increased radiation-induced apoptosis in the OS cell lines, whereas in the RMS cell lines radiation-induced apoptosis was insignificant with and without SAHA. In all investigated sarcoma cell lines, SAHA attenuated radiation-induced DNA repair protein expression (Rad51, Ku80). CONCLUSION Our results show that HDACIs enhance radiation action in OS and RMS cell lines. Inhibition of DNA repair, as well as increased apoptosis induction after exposure to HDACIs, can be mechanisms of radiosensitization by HDACIs.

Merkel cell carcinoma: the role of radiation therapy in general management.

Background: Merkel cell carcinoma (MCC) is a rare malignant, locally aggressive tumor of the skin. Because few data exist about the clinical course of irradiated patients, we reviewed the 17 patients treated at our institution since 1982. Patients and Methods: The median age at diagnosis was 71 years (range 47 to 88 years). Twelve patients presented with lymph node involvement (Stage II), 5 patients with negative lymph nodes (Stage I). Five patients were irradiated immediately after initial surgical excision of the primary tumor. Eleven patients underwent a surgical treatment of recurrence prior to the first irradiation. Only 1 patient received primary radiotherapy. A median dose of 52.8 Gy (range 40 to 60 Gy) in the region of the primary tumor and a median dose of 49.5 Gy (range 30 to 54 Gy) in the regional lymph nodes were delivered. Results: The median overall survival after first diagnosis was 45 months. Three-year overall survival was 57%, 5-year cause-specific survival was 73% (Kaplan Meier). Local control could be achieved in the 5 patients irradiated immediately after surgical treatment of the primary tumor. In contrast, an in-field recurrence occurred in 5 of 12 patients irradiated after surgical excision of relapsed disease. Five patients developed distant metastases. None of these patients was irradiated immediately after surgical excision of the primary tumor. Conclusions: With respect to our experience, a local control can be achieved with an immediate postoperative radiotherapy of the primary tumor site and the adjacent lymph nodes.Hintergrund: Merkel-Zell-Karzinome sind seltene maligne, aggressiv wachsende Tumoren der Haut. Da wenige Daten bestrahlter Patienten verfügbar sind, soll der Stellenwert der Strahlentherapie bei der Behandlung des Merkel-Zell-Karzinoms anhand von 17 seit 1982 in unserer Klinik behandelten Patienten diskutiert werden. Patienten und Methoden: Das mediane Alter der Patienten war 71 Jahre (47 bis 88 Jahre) bei Diagnosestellung (Tabelle 1). Zwölf Patienten präsentierten sich mit Lymphknotenbefall (Stadium II), fünf Patienten mit negativen Lymphknoten (Stadium I). Fünf Patienten wurden sofort nach Operation des Primärtumors bestrahlt. Elf Patienten wurden vor Beginn der ersten Bestrahlung an einem Rezidiv operiert. Nur ein Patient wurde primär bestrahlt. Eine mediane Dosis von 52,8 Gy (40 bis 60 Gy) wurde im Bereich der Primärtumorregion appliziert. Die regionalen Lymphabflußwege wurden mit einer medianen Dosis von 49,5 Gy (30 bis 54 Gy) bestrahlt. Ergebnisse: Das mediane Überleben nach Erstdiagnose lag bei 45 Monaten. Die Drei-Jahres-Überlebenswahrscheinlichkeit war 57% (Abbildung 1). Die krankheitsspezifische Fünf-Jahres-Überlebenswahrscheinlichkeit lag bei 73% (Kaplan-Meier). Eine lokale Kontrolle wurde bei den fünf Patienten erreicht, die sofort nach Operation des Primärtumors bestrahlt wurden. Bei fünf der elf Patienten, die erst nach Operation eines Rezidivs bestrahlt wurden, trat ein Rezidiv im Bestrahlungsfeld auf. Fünf Patienten erlitten nach Therapieabschluß eine Fernmetastasierung. Keiner dieser Patienten wurde sofort nach Operation des Primärtumors bestrahlt. Schlußfolgerung: Durch eine sofortige Bestrahlung der Tumorregion und der regionalen Lymphabflußwege nach Operation des Primärtumors kann nach unserer Erfahrung eine lokale Kontrolle der Merkel-Zell-Karzinome erreicht werden.

Radiochemotherapy in Patients With Primary Glioblastoma Comparing Two Temozolomide Dose Regimens

PURPOSE To evaluate toxicity and outcomes in patients with primary glioblastoma (GB) treated with postoperative radiochemotherapy (RCHT) with temozolomide (TMZ) comparing two dose regimens. METHODS AND MATERIALS A total of 160 patients with histologically confirmed GB were treated with postoperative RCHT with TMZ. Of the patients, 66 were female and 94 were male, with a median age of 60 years. After the primary diagnosis, a biopsy had been performed in 42 patients; a subtotal and total resection was conducted in 66 and 52 patients. Postoperative radiotherapy was applied with a median dose of 60 Gy with a median fractionation of 5 x 2Gy/week. Concomitant TMZ was prescribed at 50 mg/m(2) in 123 patients (Group A) and at 75 mg/m(2) in 37 patients (Group B). Patients were followed in 3-months intervals, with a median follow-up of 13 months. RESULTS Overall survival (OS) rates in Group A vs. Group B were 67% and 79% at 1 year and 43% vs. 49% at 2 years, respectively (p = 0.69). Progression-free survival was 49% vs. 54% at 1 year and 22% vs. 29% at 2 years (p = 0.31). Hematologic toxicity was not statistically significant over the 6-week RCHT period except for a significant decrease in platelets during Week 6 (p = 0.01) in Group B. CONCLUSIONS Overall survival seems to be comparable in both groups, although longer follow-up and a larger group of patients are needed to corroborate these results. Lower dosing of TMZ also is associated with a more beneficial toxicity profile.

Clinical Phase I/II trial to Investigate Preoperative Dose-Escalated Intensity-Modulated Radiation Therapy (IMRT) and Intraoperative Radiation Therapy (IORT) in patients with retroperitoneal soft tissue sarcoma: interim analysis

BackgroundLocal control rates in patients with retroperitoneal soft tissue sarcoma (RSTS) remain disappointing even after gross total resection, mainly because wide margins are not achievable in the majority of patients. In contrast to extremity sarcoma, postoperative radiation therapy (RT) has shown limited efficacy due to its limitations in achievable dose and coverage. Although Intraoperative Radiation Therapy (IORT) has been introduced in some centers to overcome the dose limitations and resulted in increased outcome, local failure rates are still high even if considerable treatment related toxicity is accepted. As postoperative administration of RT has some general disadvantages, neoadjuvant approaches could offer benefits in terms of dose escalation, target coverage and reduction of toxicity, especially if highly conformal techniques like intensity-modulated radiation therapy (IMRT) are considered.Methods/designThe trial is a prospective, one armed, single center phase I/II study investigating a combination of neoadjuvant dose-escalated IMRT (50–56 Gy) followed by surgery and IORT (10–12 Gy) in patients with at least marginally resectable RSTS. The primary objective is the local control rate after five years. Secondary endpoints are progression-free and overall survival, acute and late toxicity, surgical resectability and patterns of failure. The aim of accrual is 37 patients in the per-protocol population.DiscussionThe present study evaluates combined neoadjuvant dose-escalated IMRT followed by surgery and IORT concerning its value for improved local control without markedly increased toxicity.Trial registrationNCT01566123

Correlation of Patient-Related Factors and Dose- Volume Histogram Parameters with the Onset of Radiation Pneumonitis in Patients with Small Cell Lung Cancer

Purpose:To analyze the association of patient- and treatment-related factors with the onset of radiation pneumonitis in a homogeneously treated cohort of patients suffering from small cell lung cancer (SCLC).Patients and Methods:242 patients with SCLC staged as limited disease, who had been treated with chemotherapy and three-dimensional conformal radiotherapy, were retrospectively analyzed. Pneumonitis was defined by typical symptoms and radiographic findings and judged clinically relevant, if drug administration and hospitalization were necessary. Patient- (age, gender, smoking history, performance status, tumor localization, benign lung disease) and treatment-related parameters (V10–V40, mean lung dose [MLD]) were analyzed using χ2-tests for categorical parameters and logistic regression for continuous variables.Results:33 patients (13.6%) developed a clinically relevant pneumonitis, of whom three patients died. All cases of pneumonitis developed within 120 days. None of the patient-related parameters correlated significantly with the onset of pneumonitis. Considering treatment-related parameters, a significant correlation of V30 in regard to total lung and V40 in regard to ipsilateral, contralateral and total lung to the risk of pneumonitis was found. So, the estimated risk of a clinically relevant pneumonitis increased from 10% given a V30 of 13% to 30% given a V30 of 35%. In contrast, no significant correlation was found for V10 and V20 and only a trend for MLD.Conclusion:In this series, high-dose radiation volume parameters, i.e., V30 and especially V40, were identified as the most important factors for the development of radiation pneumonitis. Low-dose radiation volume parameters and clinical parameters played an inferior role in predicting the pneumonitis risk.ZusammenfassungZiel:Überprüfung der Assoziation von patienten- und therapiebezogenen Faktoren mit dem Auftreten einer radiogenen Pneumonitis in einem homogen behandelten Patientenkollektiv mit kleinzelligem Bronchialkarzinom (SCLC).Patienten und Methodik:242 Patienten mit SCLC im Stadium „limited disease“, welche mittels Chemotherapie und dreidimensionaler konformaler Radiotherapie behandelt waren, wurden retrospektiv analysiert. Pneumonitis wurde durch das Auftreten typischer Symptome und radiologischer Befunde definiert und als klinisch relevant eingestuft, wenn medikamentöse Behandlung und Klinikeinweisung nötig waren. Patienten- (Alter, Geschlecht, Rauchanamnese, Allgemeinzustand, Tumorlokalisation, gutartige Lungenerkrankung) und behandlungsbezogene Parameter (V10–V40, mittlere Lungendosis [MLD]) wurden mittels χ2-Tests für kategoriale Parameter und logistischer Regression für kontinuierliche Parameter analysiert.Ergebnisse:33 Patienten (13,6%) entwickelten eine klinisch relevante Pneumonitis, drei Patienten starben. Alle Pneumonitisfälle traten innerhalb von 120 Tagen auf. Für keinen der patientenbezogenen Parameter fand sich eine signifikante Korrelation mit dem Auftreten einer Pneumonitis. Hinsichtlich der behandlungsbezogenen Parameter zeigte sich eine signifikante Korrelation der V30 (gesamte Lunge) sowie der V40 (ipsilaterale, kontralaterale oder gesamte Lunge) mit dem Pneumonitisrisiko. So erhöhte sich das geschätzte Risiko einer klinisch relevanten Pneumonitis von 10% bei einer V30 von 13% auf 30% bei einer V30 von 35%. Im Gegensatz hierzu fanden sich keine signifikanten Korrelationen für V10 und V20 und nur ein Trend für die MLD.Schlussfolgerung:Hochdosis-Volumen-Parameter, d.h. V30 und besonders V40, konnten in dieser Serie als wichtigste Faktoren bezüglich der Entwicklung einer radiogenen Pneumonitis identifiziert werden. Niedrigdosis-Volumen-Parameter und klinische Parameter spielten eine untergeordnete Rolle bei der Vorhersage des Pneumonitisrisikos.

Human Glioblastoma and Carcinoma Xenograft Tumors Treated by Combined Radiation and Imatinib (Gleevec

Background and Purpose:Imatinib (Gleevec®, Glivec®) is an inhibitor of α- and β-platelet-derived growth factor receptors and other tyrosine kinases, that are also associated with the function of growth factors. Imatinib has been approved for the treatment of chronic myelogenous leukemia and gastrointestinal stromal tumors and is under investigation for the therapy of several other malignant tumors. Since radiotherapy is an important treatment option in many tumors, combined effects of imatinib and radiation were analyzed here.Material and Methods:In vitro, U87 cells (human glioblastoma), A431 cells (human epidermoid carcinoma), and HUVECs (human umbilical venous endothelial cells) were treated with imatinib alone and in combination with radiation. Clonogenic survival and cell proliferation were determined with and without additional radiation (0–10 Gy). In vivo, U87 and A431 cells (5 × 106) were subcutaneously injected into hind limbs of balb c nu/u mice. Drug and radiation treatments started on day 0 when tumor volumes were approximately 400–500 mm3. Tumors were treated with 5 × 5 Gy (U87) or 6 × 5 Gy (A431) on consecutive days from day 0. Imatinib was administered orally via the mouse diet starting on day 0 until the end of observation. Tumor growth and microvessel density (CD31 IHC) were analyzed.Results:In vitro, imatinib increased radiosensitivity of U87 and A431 tumor cells as well as HUVECs in both clonogenic and cell number/proliferation assays. The enhancement of radiosensitivity in HUVECs was comparable to that observed in the tumor cells. In vivo, the concurrent and continuous administration of imatinib increased tumor growth delay of fractionated radiotherapy in the carcinoma and the glioblastoma models at reduced microvessel densities. No apparent additional toxicity by the combination of radiation and imatinib versus monotherapies was observed in terms of weight, skin, or general behavior.Conclusion:Imatinib (Gleevec®), a “molecular targeted” approved drug for human malignancies, can enhance the tumor growth reduction induced by fractionated radiotherapy in glioblastoma and carcinoma models. The data provides a rationale to further investigate the combination.Hintergrund und Ziel:Die Dysregulation von Zellwachstum und Zelldifferenzierung, Hauptmerkmale der malignen Tumortransformation, entsteht durch eine chronisch-aberrante Aktivierung von Wachstumsfaktoren. Imatinib (Glivec®) inhibiert spezifische Tyrosinkinasen, wie PDGF-(„platelet-derived growth factor“) und c-KIT-Rezeptoren, welche Wachstumsrezeptoren darstellen oder mit deren Funktion assoziiert sind. Imatinib wird bei der Behandlung der chronischen myeloischen Leukämie und gastrointestinaler Stromatumoren bereits eingesetzt und bei einer Reihe weiterer Tumorentitäten in klinischen Studien untersucht. Strahlentherapie ist eine Option bei einigen dieser Tumoren, so dass die Untersuchung von Kombinationseffekten relevant ist.Material und Methodik:In vitro wurden U87-Zellen (humanes Glioblastom), A431-Zellen (humanes epidermoides Karzinom) und HUVECs (humane umbilikalvenöse Endothelzellen) bestrahlt und mit Imatinib behandelt. Klonogenes Überleben und Zellproliferation wurden bestimmt. In vivo wurden U87- und A431-Tumoren auf Balb-c-nu/u-Mäusen untersucht. Die Behandlung begann bei Tumorvolumina von 400–500 mm3 mit 5 × 5 Gy (U87) bzw. 6 × 5 Gy (A431). Imatinib wurde kontinuierlich ab Therapiebeginn gleichzeitig zur Strahlentherapie bis zum Beobachtungsende verabreicht. Die Tumorgröße und die Mikrogefäßdichte (CD31 IHC) wurden analysiert.Ergebnisse:Imatinib erhöhte die Strahlensensibilität von U87-Zellen und HUVECs, weniger ausgeprägt auch von A431-Zellen, im klonogenen und Proliferations-Assay. Der Effekt unterschied sich bei Endothelzellen nicht signifikant von jenem bei den Tumorzellen. In vivo vergrößerte die zusätzliche Gabe von Imatinib die Tumorwachstumsverzögerung durch Strahlentherapie beim Glioblastom und beim Karzinom bei deutlicher Reduktion der Mikrogefäßdichte ohne erkennbare Zunahme der Toxizität.Schlussfolgerung:Imatinib (Gleevec®) als klinisch zugelassener Vertreter der „Targeted therapy“-Medikamente kann den tumorwachstumshemmenden Effekt einer fraktionierten Strahlentherapie beim Glioblastom und bei Karzinomen verstärken, was weiter untersucht werden sollte.

Non-randomized therapy trial to determine the safety and efficacy of heavy ion radiotherapy in patients with non-resectable osteosarcoma

BackgroundOsteosarcoma is the most common primary malignant bone tumor in children and adolescents. For effective treatment, local control of the tumor is absolutely critical, because the chances of long term survival are <10% and might effectively approach zero if a complete surgical resection of the tumor is not possible. Up to date there is no curative treatment protocol for patients with non-resectable osteosarcomas, who are excluded from current osteosarcoma trials, e.g. EURAMOS1. Local photon radiotherapy has previously been used in small series and in an uncontrolled, highly individualized fashion, which, however, documented that high dose radiotherapy can, in principle, be used to achieve local control. Generally the radiation dose that is necessary for a curative approach can hardly be achieved with conventional photon radiotherapy in patients with non-resectable tumors that are usually located near radiosensitive critical organs such as the brain, the spine or the pelvis. In these cases particle Radiotherapy (proton therapy (PT)/heavy ion therapy (HIT) may offer a promising new alternative. Moreover, compared with photons, heavy ion beams provide a higher physical selectivity because of their finite depth coverage in tissue. They achieve a higher relative biological effectiveness. Phase I/II dose escalation studies of HIT in adults with non-resectable bone and soft tissue sarcomas have already shown favorable results.Methods/DesignThis is a monocenter, single-arm study for patients ≥ 6 years of age with non-resectable osteosarcoma. Desired target dose is 60-66 Cobalt Gray Equivalent (Gy E) with 45 Gy PT (proton therapy) and a carbon ion boost of 15-21 GyE. Weekly fractionation of 5-6 × 3 Gy E is used. PT/HIT will be administered exclusively at the Ion Radiotherapy Center in Heidelberg. Furthermore, FDG-PET imaging characteristics of non-resectable osteosarcoma before and after PT/HIT will be investigated prospectively. Systemic disease before and after PT/HIT is targeted by standard chemotherapy protocols and is not part of this trial.DiscussionThe primary objectives of this trial are the determination of feasibility and toxicity of HIT. Secondary objectives are tumor response, disease free survival and overall survival. The aim is to improve outcome for patients with non-resectable osteosarcoma.Trail RegistrationRegistration number (ClinicalTrials.gov): NCT01005043