[Multimodal treatment of sarcomas: standards and new aspects in pharmacological and radio-oncological treatment]. / Multimodale Therapien bei Sarkomen: Standards und Neues in der medikamentösen und radioonkologischen Behandlung.

BACKGROUND: Patients with localized high-risk soft tissue sarcoma are at high risk for both local recurrence and distant metastases despite optimal surgical treatment. OBJECTIVE: Importance of preoperative or postoperative chemotherapy and hyperthermia. METHODS: Evaluation and overview of published study results. RESULTS: Preoperative or postoperative radiotherapy is considered as standard for patients with localized high-risk soft tissue sarcoma. The results of two randomized studies on neoadjuvant chemotherapy showed a survival benefit. As both studies did not have a control arm without chemotherapy but in one case the superiority of anthracycline/ifosfamide-based chemotherapy in combination with hyperthermia over chemotherapy alone and in the other case the superiority of anthracycline/ifosfamide-based chemotherapy over histology-specific chemotherapy were shown, the formal proof of the superiority of this treatment is still missing. Stratifying the patients treated in the so far largest randomized adjuvant chemotherapy trial according to current risk criteria ( http://www.sarculator.com ) revealed a significant survival benefit for patients at high risk of recurrence. CONCLUSION: For high-risk soft tissue sarcomas, multimodal treatment strategies involving perioperative chemotherapy, radiotherapy and, if possible, hyperthermia should be considered in addition to tumor resection. Preoperative chemotherapy should be given preference over postoperative chemotherapy based on available data.

Regional deep hyperthermia: quantitative evaluation of predicted and direct measured temperature distributions in patients with high-risk extremity soft-tissue sarcoma.

BACKGROUND: Temperature distributions resulting from hyperthermia treatment of patients with high-risk soft-tissue sarcoma (STS) were quantitatively evaluated and globally compared with thermal simulations performed by a treatment planning system. The aim was to test whether the treatment planning system was able to predict correct temperature distributions. METHODS: Five patients underwent computed tomography (CT) fluoroscopy-guided placement of tumor catheters used for the interstitial temperature measurements. For the simulations, five 3 D patient models were reconstructed by segmenting the patient CT datasets into different tissues. The measured and simulated data were evaluated by calculating the temperature change ( ΔT ), T90, T50, T20, Tmean, Tmin and Tmax, as well as the 90th percentile thermal dose (CEM43T90). In order to measure the agreement between both methods quantitatively, the Bland-Altman analysis was applied. RESULTS: The absolute difference between measured and simulated temperatures were found to be 2°, 6°, 1°, 4°, 5° and 4 °C on average for Tmin, Tmax, T90, T50, T20 and Tmean, respectively. Furthermore, the thermal simulations exhibited relatively higher thermal dose compared to those that were measured. Finally, the results of the Bland-Altman analysis showed that the mean difference between both methods was above 2 °C which is considered to be clinically unacceptable. CONCLUSION: Given the current practical limitations on resolution of calculation grid, tissue properties, and perfusion information, the software SigmaHyperPlan™ is incapable to produce thermal simulations with sufficient correlation to typically heterogeneous tissue temperatures to be useful for clinical treatment planning.

Activity and safety of crizotinib in patients with alveolar soft part sarcoma with rearrangement of TFE3: European Organization for Research and Treatment of Cancer (EORTC) phase II trial 90101 'CREATE'.

Background: Alveolar soft part sarcoma (ASPS) is an orphan malignancy associated with a rearrangement of transcription factor E3 (TFE3), leading to abnormal MET gene expression. We prospectively assessed the efficacy and safety of the MET tyrosine kinase inhibitor crizotinib in patients with advanced or metastatic ASPS. Patients and methods: Eligible patients with reference pathology-confirmed ASPS received oral crizotinib 250 mg bd. By assessing the presence or absence of a TFE3 rearrangement, patients were attributed to MET+ and MET- sub-cohorts. The primary end point was the objective response rate (ORR) according to local investigator. Secondary end points included duration of response, disease control rate (DCR), progression-free survival (PFS), progression-free rate, overall survival (OS) and safety. Results: Among 53 consenting patients, all had a centrally confirmed ASPS and 48 were treated. A total of 45 were eligible, treated and assessable. Among 40 MET+ patients, 1 achieved a confirmed partial response (PR) that lasted 215 days and 35 had stable disease (SD) as best response (ORR: 2.5%, 95% CI 0.6% to 80.6%). Further efficacy end points in MET+ cases were DCR: 90.0% (95% CI 76.3% to 97.2%), 1-year PFS rate: 37.5% (95% CI 22.9% to 52.1%) and 1-year OS rate: 97.4% (95% CI 82.8% to 99.6%). Among 4 MET- patients, 1 achieved a PR that lasted 801 days and 3 had SD (ORR: 25.0%, 95% CI 0.6% to 80.6%) for a DCR of 100% (95% CI 39.8% to 100.0%). The 1-year PFS rate in MET- cases was 50% (95% CI 5.8% to 84.5%) and the 1-year OS rate was 75% (95% CI 12.8% to 96.1%). One patient with unknown MET status due to technical failure achieved SD but stopped treatment due to progression after 17 cycles. The most common crizotinib-related adverse events were nausea [34/48 (70.8%)], vomiting [22/48 (45.8%)], blurred vision [22/48 (45.8%)], diarrhoea (20/48 (41.7%)] and fatigue [19/48 (39.6%)]. Conclusion: According to European Organization for Research and Treatment of Cancer (EORTC) efficacy criteria for soft tissue sarcoma, our study demonstrated that crizotinib has activity in TFE3 rearranged ASPS MET+ patients. Clinical trial number: EORTC 90101, NCT01524926.

Activity and safety of crizotinib in patients with advanced clear-cell sarcoma with MET alterations: European Organization for Research and Treatment of Cancer phase II trial 90101 'CREATE'.

BACKGROUND: Clear-cell sarcoma (CCSA) is an orphan malignancy, characterized by a specific t(12;22) translocation, leading to rearrangement of the EWSR1 gene and overexpression of MET. We prospectively investigated the efficacy and safety of the tyrosine kinase inhibitor crizotinib in patients with advanced or metastatic CCSA. PATIENTS AND METHODS: Patients with CCSA received oral crizotinib 250 mg twice daily. Primary end point was objective response rate (ORR), secondary end points included duration of response, disease control rate (DCR), progression-free survival (PFS), progression-free rate (PFR), overall survival (OS), OS rate and safety. The study design focused on MET+ disease with documented rearrangement of the EWSR1 gene by fluorescence in situ hybridization. RESULTS: Among 43 consenting patients with the local diagnosis of CCSA, 36 had centrally confirmed CCSA, 28 of whom were eligible, treated and assessable. Twenty-six out of the 28 patients had MET+ disease, of whom one achieved a confirmed partial response and 17 had stable disease (SD) (ORR 3.8%, 95% confidence interval: 0.1-19.6). Further efficacy end points in MET+ CCSA were DCR: 69.2% (48.2% to 85.7%), median PFS: 131 days (49-235), median OS: 277 days (232-442). The 3-, 6-, 12- and 24-month PFR was 53.8% (34.6-73.0), 26.9% (9.8-43.9), 7.7% (1.3-21.7) and 7.7% (1.3-21.7), respectively. Among two assessable MET- patients, one had stable disease and one had progression. The most common treatment-related adverse events were nausea [18/34 (52.9%)], fatigue [17/34 (50.0%)], vomiting [12/34 (35.3%)], diarrhoea [11/34 (32.4%)], constipation [9/34 (26.5%)] and blurred vision [7/34 (20.6%)]. CONCLUSIONS: The PFS with crizotinib in MET+ CCSA is similar to results achieved first-line in non-selected metastatic soft tissue sarcomas with single-agent doxorubicin. The PFS is similar to results achieved with pazopanib in previously treated sarcoma patients. CLINICAL TRIAL NUMBER: EORTC 90101, EudraCT number 2011-001988-52, NCT01524926.

Impact of chemotherapy in uterine sarcoma (UtS): review of 13 clinical trials from the EORTC Soft Tissue and Bone Sarcoma Group (STBSG) involving advanced/metastatic UtS compared to other soft tissue sarcoma (STS) patients treated with first line chemotherapy.

OBJECTIVE: UtS are a group of uncommon tumors representing 1% of malignant neoplasms of the female genital tract, and 7% of sarcomas. The objective of this study was to evaluate the factors associated with the clinical behavior UtS. METHODS: Information on 269 patients with advanced or metastatic first line UtS treated by chemotherapy was available in a database containing information on 3270 patients with advanced soft tissue sarcomas (STS) entered in EORTC-STBSG clinical trials between 1977 and 2010. The chemotherapy was aggregated in 4 categories: anthracyclines alone, ifosfamide alone, the combination of doxorubicin and ifosfamide, and CYVADIC. RESULTS: Among the 269 UtS pts, there were 231 deaths (median OS 10.4months, 95% CI: 9.1-11.9) and 257 progressions and/or deaths (median PFS 4.1months, 95% CI: 3.5-4.9). Multivariate analyses reported PS (p<0.001) only to be a statistically significant prognostic factor for OS in UtS; for PFS, LMS histology (p=0.025) is associated with a better outcome. There was no relationship between the 4 groups of chemotherapy regimens and impact on clinical outcomes. Histological subtype was significantly correlated with response to chemotherapy (RR: LMS 19% vs other 33%, p=0.026). Ifosfamide single agent yielded only 5% of RR. CONCLUSIONS: Clearly, UtS are very aggressive neoplasms with poor outcome when treated with chemotherapy consisting of anthracyclines with or without ifosfamide or cyclophosphamide. New strategies are urgently needed.

[Operative therapy of abdominal and retroperitoneal sarcoma]. / Operative Therapie der abdominellen und retroperitonealen Sarkome.

Retroperitoneal soft tissue sarcomas are characterized by a high rate of local recurrence. Complete tumor resection is the only potentially curative therapeutic option. The concept of a systematic compartmental resection is to remove the tumor en bloc with a margin of uninvolved tissue and organs. This is frequently only achieved by multivisceral resection which often includes kidney, colon, pancreas and parts of the diaphragm or the psoas muscle. The adoption of such a policy of multivisceral organ resection improves the proportion of curative resections and, ultimately, results in lower local recurrence rates. The present article comprehensively describes the operative procedures, perioperative treatment and the oncological results of surgery for retroperitoneal sarcomas. The role of surgery in oncological treatment plans and the importance of specialized centres are outlined in detail.

[Systemic therapy and hyperthermia for locally advanced soft tissue sarcoma]. / Systemische Therapie und Hyperthermie beim lokal fortgeschrittenen Weichteilsarkom.

Patients with high-risk soft tissue sarcomas (FNCLCC grades 2-3, > 5 cm and deep lying) are at a high risk of local recurrence or distant metastases despite optimal surgical tumor resection. Therefore, multimodal treatment should be considered for this difficult to treat patient group. Besides surgery, radiation therapy and chemotherapy, hyperthermia has become a valid, complementary treatment option within multimodal treatment concepts. Hyperthermia in this context means the selective heating of the tumor region to temperatures of 40-43 °C for 60 min by microwave radiation in addition to simultaneous chemotherapy or radiation therapy. A randomized phase III study demonstrated that the addition of hyperthermia to neoadjuvant chemotherapy improved tumor response and was associated with a minimal risk of early disease progression as compared to chemotherapy alone. The addition of hyperthermia to a multimodal treatment regimen for high-risk soft tissue sarcoma consisting of surgery, radiation therapy and chemotherapy, either in the neoadjuvant or adjuvant setting after incomplete or marginal tumor resection, significantly improved local progression-free and disease-free survival. Based on these results and due to the generally good tolerability of hyperthermia, this treatment method in combination with chemotherapy should be considered as a standard treatment option within multimodal treatment approaches for locally advanced high-risk soft tissue sarcoma.

[Hemato-oncological diseases]. / Hämatoonkologische Krankheitsbilder.

Acquired inhibitors of coagulation cause a life-threatening disease. Clinically newly occurring hemorrhagic diathesis combined with prolonged activated partial thromboplastin time (aPTT) time is diagnostically indicative and can be confirmed by a positive plasma exchange test. For thrombotic thrombocytopenic purpura and hemolytic uremic syndrome (TTP-HUS) the diagnosis of Coombs negative hemolytic anemia together with thrombocytopenia should lead to the detection of fragmentocytes in peripheral blood smears. Hairy cell leukemia is a rare subgroup of chronic B-cell neoplasia with the clinical signs of pancytopenia and splenomegaly which characteristically stain positive for CD103. The gastrointestinal stromal tumor (GIST) has nothing in common with classical soft tissue sarcoma based on the activating mutation of the KIT or PDGFRA gene (positivity for CD117). In all of these disorders the correct diagnosis has a major influence on patient outcome. For the case of acquired inhibitors of coagulation immunosuppressive therapy and substitution of coagulation factors (e.g. recombinant factor VIIa) or for TTP-HUS the immediate start of plasma exchange are mandatory. For hairy cell leukemia a very effective treatment exists with purine analogs (e.g. cladribine) and for metastatic inoperable GIST with tyrosine kinase inhibitors (e.g. imatinib).

Erucylphosphohomocholine, the first intravenously applicable alkylphosphocholine, is cytotoxic to acute myelogenous leukemia cells through JNK- and PP2A-dependent mechanisms.

Alkylphospholipids and alkylphosphocholines (APCs) are promising antitumor agents, which target the plasma membrane and affect multiple signal transduction networks. We investigated the therapeutic potential of erucylphosphohomocholine (ErPC3), the first intravenously applicable APC, in human acute myelogenous leukemia (AML) cells. ErPC3 was tested on AML cell lines, as well as AML primary cells. At short (6-12 h) incubation times, the drug blocked cells in G2/M phase of the cell cycle, whereas, at longer incubation times, it decreased survival and induced cell death by apoptosis. ErPC3 caused JNK 1/2 activation as well as ERK 1/2 dephosphorylation. Pharmacological inhibition of caspase-3 or a JNK 1/2 inhibitor peptide markedly reduced ErPC3 cytotoxicity. Protein phosphatase 2A downregulation by siRNA opposed ERK 1/2 dephosphorylation and blunted the cytotoxic effect of ErPC3. ErPC3 was cytotoxic to AML primary cells and reduced the clonogenic activity of CD34(+) leukemic cells. ErPC3 induced a significant apoptosis in the compartment (CD34(+) CD38(Low/Neg) CD123(+)) enriched in putative leukemia-initiating cells. This conclusion was supported by ErPC3 cytotoxicity on AML blasts showing high aldehyde dehydrogenase activity and on the side population of AML cell lines and blasts. These findings indicate that ErPC3 might be a promising therapeutic agent for the treatment of AML patients.

AraU accumulation in patients with renal insufficiency as a potential mechanism for cytarabine neurotoxicity.

Neurotoxicity of cytarabine (AraC) is believed to be related to renal insufficiency. We examined the plasma pharmacokinetics of AraC and its deamination product uracil arabinoside (AraU) in four patients with AML and concomitant severe renal insufficiency after treatment with AraC. Additionally, in one of these patients the concentration of intracellular AraCTP, the active metabolite of AraC, was analysed. Patients 2 and 3 were treated with AraC 1.0 g/m(2) infused for 3 h at 12-h intervals on days 1-4. Patient 1 received the same schedule of AraC with 0.5 g/m(2) and patient 4 with 0.25 g/m(2) AraC. Plasma concentrations of AraC, AraU and the intracellular concentration of AraCTP were analysed at different time points using HPLC. AraC pharmacokinetics in patients with severe renal insufficiency was comparable to patients with normal renal function. Peak plasma levels as well as intracellular AraCTP kinetics were also not significantly influenced by renal dysfunction. As expected from the high dose AraC pharmacokinetic parameters, the AraU serum levels accumulated during treatment. Under the conditions of renal impairment, AraU half-life was about 75 h and the AUC was about 12-fold higher than for patients with normal renal function. AraU could be the pathophysiologic cause for the known correlation between the incidence of neurotoxicity and renal insufficiency in high-dose AraC. To avoid AraU accumulation, intermittent hemodialysis during high-dose AraC treatment could be a suitable method considering the low protein-binding and low distribution volume of AraU.

[Clinical impact of locoregional hyperthermia in gynecological oncology]. / Einsatzmöglichkeiten der lokoregionären Hyperthermie in der gynäkologischen Onkologie.

In the last decade progress in gynecological oncology has been achieved mainly by new cytotoxic drugs and advances in radiation technology. For example, the use of taxanes in the primary therapy of ovarian cancers and of combined radio-chemotherapy in cervical cancer has led to significant prolongations of survival. However, in case of relapse most gynaecological malignancies are associated with very poor prognosis. Efficacy of local and systemic therapy can be increased by combining radiotherapy and/or chemotherapy with locoregional hyperthermia (LRH). Increasing the temperature of the target tissue up to 41-43 degrees C leads to local hyperaemia and the tumor tissue becomes more responsive to cytotoxic interventions. In several prospective randomized studies the combination between LRH and radiotherapy was superior to radiotherapy alone in terms of local control (e. g. chest wall recurrence in breast cancer) and has led to longer overall survival in advanced cervical cancer. Platinum derivatives and other cytotoxic drugs have shown synergistic effects with LRH and the combination of both has elicited high response rates in recurrent cervical cancer. In phase-II-clinical trials the newly developed liposomal anthracyclines demonstrated synergistic effects with LRH in patients with refractory ovarian cancer. Our own experience has shown that adding LRH to radio- and/or chemotherapy is well tolerated by the patients. Despite of the fact, that the available data are still preliminary, the inclusion of LRH into multimodal cancer therapy concepts appears to be very promising. Well-designed comparative studies are still needed to evaluate the role of hyperthermia as an adjunct to conventional cancer therapy.

Paramagnetic thermosensitive liposomes for MR-thermometry.

MR-thermometry methods have been developed for the guidance and control of thermal therapies such as thermal ablation or regional hyperthermia. However, they are limited to the measurement of temperature changes and, thus, cannot be used to assess absolute temperature values. Paramagnetic thermosensitive liposomes are innovative contrast agents offering the potential to overcome these limitations. They are composed of a gadolinium- or manganese-based compound enclosed by a phospholipid membrane with a distinct gel-to-liquid crystalline phase transition temperature (Tm). At this temperature, the phospholipid membrane changes from a gel-phase to a liquid-crystalline phase which is associated with an increased transmembrane permeability towards solutes and water. Under these conditions, both types of paramagnetic thermosensitive liposomes demonstrate a significant increase in longitudinal (T1) relaxivity, attributed to the release of paramagnetic material from the liposome and/or to the increased water exchange rate between the liposome interior and exterior. Paramagnetic thermosensitive liposomes have already been successfully studied in animal models and have demonstrated a clear correlation between tissue temperature changes and signal intensity changes in MRI. Nevertheless, before entering clinical trials they have to be studied in more detail with regard to dose, pharmacokinetics and toxicity.

[Principles, technology and indication of hyperthermia and part body hyperthermia]. / Prinzip, Technik und Indikation der Hyperthermie und Teilkörperhyperthermie.

Clinical hyperthermia with controlled alteration of temperature (40 to 44 degrees C) in the target area is used in interdisciplinary treatment concepts for tumor treatment in combination with radiation and/or radiotherapy. Besides the direct cytotoxic power of hyperthermia there is an immunomodulatory effect and a radiation and chemotherapy sensitizing effect in the heated tissue. Clinical hyperthermia is an invasive or non-invasive supply of energy to the body of the patient, which leads to an artificial heating of the tumor and the surrounded tissue. The clinical hyperthermic procedures should take into account the oncologic disease and its pattern of organ involvement. There are three different types of hyperthermia: local hyperthermia (LHT), regional hyperthermia (RHT) and part body hyperthermia (PBH). PBH is used to heat regions of the body in case of metastatic disease, e. g. to the abdomen. I and phase II trials could show that the effects of radiation and chemotherapy can be altered by the simultaneous addition of hyperthermia. Data of trials involving skin metastasis in malignant melanoma, local relapse in breast cancer, tumors of the head and neck with regional lymph node metastasis, as well as trials in colorectal tumors, bladder cancer, pancreatic cancer, cervical cancer and sarcoma are presented. The results shows, that response to treatment can be improved by hyperthermia.