Dual energy CT allows for improved characterization of response to antiangiogenic treatment in patients with metastatic renal cell cancer.

OBJECTIVES: To evaluate the potential role of dual energy CT (DECT) to visualize antiangiogenic treatment effects in patients with metastatic renal cell cancer (mRCC) while treated with tyrosine-kinase inhibitors (TKI). METHODS: 26 patients with mRCC underwent baseline and follow-up single-phase abdominal contrast enhanced DECT scans. Scans were performed immediately before and 10 weeks after start of treatment with TKI. Virtual non-enhanced (VNE) and colour coded iodine images were generated. 44 metastases were measured at the two time points. Hounsfield unit (HU) values for VNE and iodine density (ID) as well as iodine content (IC) in mg/ml of tissue were derived. These values were compared to the venous phase DECT density (CTD) of the lesions. Values before and after treatment were compared using a paired Student's t test. RESULTS: Between baseline and follow up, mean CTD and DECT-derived ID both showed a significant reduction (p < 0.005). The relative reduction measured in percent was significantly greater for ID than for CTD (49.8 ± 36,3 % vs. 29.5 ± 20.8 %, p < 0.005). IC was also significantly reduced under antiangiogenic treatment (p < 0.0001). CONCLUSIONS: Dual energy CT-based quantification of iodine content of mRCC metastases allows for significantly more sensitive and reproducible detection of antiangiogenic treatment effects. KEY POINTS: • A sign of tumour response to antiangiogenic treatment is reduced tumour perfusion. • DECT allows visualizing iodine uptake, which serves as a marker for vascularization. • More sensitive detection of antiangiogenic treatment effects in mRCC is possible.

[Rational imaging of metastasized tumor diseases]. / Rationale Bildgebung bei metastasierten Tumorerkrankungen.

Most anticancer medications are effective only in subgroups of patients. Despite considerable improvements in histopathological and molecular pathological diagnostics, tumor response in the individual patient still remains unpredictable. Measuring tumor shrinkage by cross-sectional imaging procedures in patients with metastatic cancer represents the current standard for documenting the effectiveness of anticancer therapy. In addition to the large number of different imaging procedures computed tomography (CT) is certainly the best established and most widely available technique for assessing tumor response. This manuscript reviews the necessity and rationality of imaging procedures for monitoring tumor response in patients with metastatic cancer.

Tumor response and clinical outcome in metastatic gastrointestinal stromal tumors under sunitinib therapy: comparison of RECIST, Choi and volumetric criteria.

PURPOSE: Purpose of the study was to compare radiological treatment response according to RECIST, Choi and volumetry in GIST-patients under 2nd-line-sunitinib-therapy and to correlate the results of treatment response assessment with disease-specific survival (DSS). PATIENTS AND METHODS: 20 patients (mean: 60.7 years; 12 male/8 female) with histologically proven GIST underwent baseline-CT of the abdomen under imatinib and follow-up-CTs 3 months and 1 year after change to sunitinib. 68 target lesions (50 hepatic, 18 extrahepatic) were investigated. Therapy response (partial response (PR), stable disease (SD), progressive disease (PD)) was evaluated according to RECIST, Choi and volumetric criteria. Response according to the different assessment systems was compared and correlated to the DSS of the patients utilizing Kaplan-Meier statistics. RESULTS: The mean DSS (in months) of the response groups 3 months after therapy change was: RECIST: PR (0/20); SD (17/20): 30.4 (months); PD (3/20) 11.6. Choi: PR (10/20) 28.6; SD (8/20) 28.1; PD (2/20) 13.5. Volumetry: PR (4/20) 29.6; SD (11/20) 29.7; PD (5/20) 17.2. Response groups after 1 year of sunitinib showed the following mean DSS: RECIST: PR (3/20) 33.6; SD (9/20) 29.7; PD (8/20) 20.3. Choi: PR (10/20) 21.5; SD (4/20) 42.9; PD (6/20) 23.9. Volumetry: PR (6/20) 27.3; SD (5/20) 38.5; PD (9/20) 19.3. CONCLUSION: One year after modification of therapy, only partial response according to RECIST indicated favorable survival in patients with GIST. The value of alternate response assessment strategies like Choi criteria for prediction of survival in molecular therapy still has to be demonstrated.

Adjuvant therapy in primary GIST: state-of-the-art.

BACKGROUND: The management of primary gastrointestinal stromal tumours (GISTs) has evolved with the introduction of adjuvant therapy. Recently reported results of the SSG XVIII/AIO trial by the Scandinavian Sarcoma Group (SSG) and the German Working Group on Medical Oncology (AIO) represent a significant change in the evidence for adjuvant therapy duration. The objectives of this European Expert Panel meeting were to describe the optimal management and best practice for the systemic adjuvant treatment of patients with primary GISTs. MATERIALS AND METHODS: A panel of medical oncology experts from European sarcoma research groups were invited to a 1-day workshop. Several questions and discussion points were selected by the organising committee prior to the conference. The experts reviewed the current literature of all clinical trials available on adjuvant therapy for primary GISTs, considered the quality evidence and formulated recommendations for each discussion point. RESULTS: Clinical issues were identified and provisional clinical opinions were formulated for adjuvant treatment patient selection, imatinib dose, duration and patient recall, mutational analysis and follow-up of primary GIST patients. Adjuvant imatinib 400 mg/day for 3 years duration is a standard treatment in all patients with significant risk of recurrence following resection of primary GISTs. Patient selection for adjuvant therapy should be based on any of the three commonly used patient risk stratification schemes. R1 surgery (versus R0) alone is not an indication for adjuvant imatinib in low-risk GIST. Recall and imatinib restart could be proposed in patients who discontinued 1-year adjuvant imatinib within the previous 3 months and may be considered on a case-by-case basis in patients who discontinued within the previous year. Mutational analysis is recommended in all cases of GISTs using centralised laboratories with good quality control. Treatment is not recommended in an imatinib-insensitive D842V-mutated GIST. During adjuvant treatment, patients are recommended to be clinically assessed at 1- to 3-month intervals. Upon discontinuation, computed tomography scan (CT) scans are recommended every 3 to 4 months for 2 years when the risk of relapse is highest, followed by every 6 months until year 5 and annually until year 10 after treatment discontinuation. CONCLUSIONS: Key points in systemic adjuvant treatment and clinical management of primary GISTs as well as open questions were identified during this European Expert Panel meeting on GIST management.

Phase III study of nilotinib versus best supportive care with or without a TKI in patients with gastrointestinal stromal tumors resistant to or intolerant of imatinib and sunitinib.

BACKGROUND: This phase III open-label trial investigated the efficacy of nilotinib in patients with advanced gastrointestinal stromal tumors following prior imatinib and sunitinib failure. PATIENTS AND METHODS: Patients were randomized 2:1 to nilotinib 400 mg b.i.d. or best supportive care (BSC; BSC without tyrosine kinase inhibitor, BSC+imatinib, or BSC+sunitinib). Primary efficacy end point was progression-free survival (PFS) based on blinded central radiology review (CRR). Patients progressing on BSC could cross over to nilotinib. RESULTS: Two hundred and forty-eight patients enrolled. Median PFS was similar between arms (nilotinib 109 days, BSC 111 days; P=0.56). Local investigator-based intent-to-treat (ITT) analysis showed a significantly longer median PFS with nilotinib (119 versus 70 days; P=0.0007). A trend in longer median overall survival (OS) was noted with nilotinib (332 versus 280 days; P=0.29). Post hoc subset analyses in patients with progression and only one prior regimen each of imatinib and sunitinib revealed a significant difference in median OS of >4 months in favor of nilotinib (405 versus 280 days; P=0.02). Nilotinib was well tolerated. CONCLUSION: In the ITT analysis, no significant difference in PFS was observed between treatment arms based on CRR. In the post hoc subset analyses, nilotinib provided significantly longer median OS.

Dual energy CT for monitoring targeted therapies in patients with advanced gastrointestinal stromal tumor: initial results.

PURPOSE: Advanced gastrointestinal stromal tumours (GISTs) are treated with tyrosine kinase inhibitors, which also have antiangiogenic properties. Dual-energy CT (DECT) allows to acquire semi-quantitative iodine images which might correlate with blood pool and tumor vascularity. In this feasibility-study, we correlated lesional iodine uptake estimations in correlation to tumor size changes under targeted therapy as first step in the evaluation of dedicated DECT based strategies for monitoring molecular therapies in GIST. PATIENTS AND METHODS: 48 tumor lesions in 18 patients with metastasized histologically proven GIST under tyrosine kinase inhibitor (TKI) therapy were analyzed. Patients were examined with a dual-source CT in dual-energy mode (Voltage tube A: 80 kV, tube B: 140 kV). Using the dual-energy software virtual unenhanced, selective iodine (overlay) and mixed CT numbers (similar to CT numbers at 120 kV) of lesions were calculated. The largest diameter of each lesion on cross-sectional axial images was measured. The mean difference of overlay CT numbers in the baseline and follow-up examinations was calculated and this marker of lesional iodine uptake was compared to lesional size changes under molecular therapy. RESULTS: Utilizing the cut-off value 15 HU of change in overlay, DECT allowed to identify lesions with a stable, increased or decreased lesional iodine uptake with corresponding typical lesion size change patterns after 3 months of targeted therapy: 30 lesions had no significant change of overlay CT numbers (OL) (mean: -2.4 HU) or lesion size (mean: +1.5%). A strong decline of the OL (mean: - 24 HU) in 13 lesions was combined with a pronounced growth (mean: + 26%). 5 lesions showed a strong increase of the absolute OL (mean: + 23 HU) associated with a moderate increase in size (+ 8%). CONCLUSION: Determination of the overlay CT number with DECT enables to stratify metastases with stable, increasing or decreasing iodine uptake over time with -in our collective- typical lesion size change patterns. Investigation of a larger patient cohort, comparison to histology, alternate imaging biomarkers and correlatrion to long-term response will further clarify the significance of these findings for monitoring targeted therapies in GIST.

[Combined functional and morphological imaging of sarcomas: significance for diagnostics and therapy monitoring]. / Kombinierte funktionelle und morphologische Bildgebung bei Sarkomen : Stellenwert für Diagnostik und Therapiemonitoring.

(18)F-fluorodeoxyglucose positron-emission tomography (FDG-PET) and especially hybrid FDG-PET/CT is becoming more and more accepted for the clinical management of adult and pediatric patients with sarcomas. By integrating the CT component the specificity in particular but also the sensitivity of the modality are improved further. With PET/CT a complete staging including the detection of lung metastases is feasible in a single examination. For patients with primary bone and soft tissue sarcomas FDG-PET/CT is utilized for diagnosis, staging and restaging, metabolic tumor grading, guidance of biopsies, detection of tumor recurrence and therapy monitoring. Furthermore, it has been demonstrated that FDG uptake of the tumor prior to treatment and changes of FDG uptake after therapy significantly correlate with histopathologic response and survival of patients. Therefore, PET and PET/CT have a prognostic value. In the future new perspectives of hybrid PET/CT imaging will arise by introducing novel radiotracers and combined functional imaging of tumor metabolism and perfusion. High resolution MRI is essential for local evaluation of the primary tumor and preoperative planning with assessment of possible infiltration of vascular or neural structures. Contrast-enhanced MRI remains a key tool in the diagnosis of recurrent disease, especially in tumors which are not hypermetabolic. Dynamic contrast-enhanced MR sequences can significantly contribute to therapy monitoring. More research is necessary to prospectively compare dynamic contrast-enhanced MRI and FDG-PET/CT for evaluation of local and recurrent diseases.

Thermochemotherapy in patients with extremity high-risk soft tissue sarcomas (HR-STS).

PURPOSE: We report data from phase II trials examining the efficacy of multimodality treatment with neoadjuvant chemotherapy, hyperthermia, surgery, radiation and postoperative thermochemotherapy in adult patients with high-risk sarcomas of the extremities. PATIENTS AND METHODS: From 1991 to 2001 47 patients with high risk soft tissue sarcoma of the extremities were prospectively treated in two clinical trials with a treatment plan of four cycles of etoposide, ifosfamide and doxorubicin combined with regional hyperthermia followed by surgery, radiation and adjuvant chemotherapy. RESULTS: Objective response rate assessable in 39 patients was 21% (one complete and seven partial responses). A favourable histological response (>75% tumour necrosis) was observed in 34% of the 35 evaluable patients who had surgical resection. Median overall survival (OS) was 105 months. The five-year probability of local failure-free survival (LFFS), distant disease-free survival (DDFS), event-free survival (EFS) and OS were 48%, 55%, 35% and 57%, respectively. There were no significant differences between responders and non-responders of minimum temperatures (Tmin) and time-averaged temperatures achieved in 50% (T(50)) and 90% (T(90)) at all measured tumour sites. Response to this neoadjuvant regimen predicted for prolonged LFFS (p = 0.0123), but not for OS (p = 0.2). Limb preservation was achieved in 37 patients (79%) and did not result in inferior DDFS (52% versus 50%) or OS (61% versus 50%) at five years (p = 0.8) in comparison to patients who underwent amputation. CONCLUSION: Response to combined modality treatment with RHT and neoadjuvant chemotherapy was predictive for an improved LFFS and led to limb preservation in 79% of patients with extremity sarcomas.

Paclitaxel in patients with advanced angiosarcomas of soft tissue: a retrospective study of the EORTC soft tissue and bone sarcoma group.

RATIONALE: Angiosarcomas of soft tissue represent a heterogenous group of rare sarcomas with specific clinical behaviour and risk factors. Paclitaxel appears to induce tumour control in a higher proportion of patients with angiosarcoma, as compared to other sarcomas. The objective of this retrospective study was to assess the anti-tumour activity of this compound in a multicentre setting. METHOD: Clinical data from patients with angiosarcomas of soft tissue treated with single agent paclitaxel were collected from the centres of the soft tissue and bone sarcoma group of EORTC, using a standardised data collection form. Paclitaxel could be given every three weeks, or weekly. Statistical analysis was performed using SAS software. RESULTS: Data from 32 patients were collected from 10 centres. There were 17 males, 15 females, with a median age of 60.4 years (range, 25-91). Primary angiosarcomas were located in scalp and face in 8 patients (25%) and at other primary sites in 24 patients (75%). All patients had intermediate (n=13) or high grade (n=19) primary tumours. Thirteen (40%) patients had been pretreated with doxorubicin-based first-line-chemotherapy and three of them (9%) had also received second-line chemotherapy with ifosfamide. Eleven (34%) patients had been irradiated before as treatment for angiosarcoma. In 8 (25%) patients, the angiosarcoma occurred at sites of prior radiation therapy for other malignancies. The response rate was 62% (21/32) in the whole series, 75% (6/8) in scalp angiosarcomas and 58% (14/24) in other primary sites. The median time to progression was 7.6 months (range, 1-42) for the whole group. For the face/scalp group it was 9.5 months, and for patients with angiosarcomas at other sites it was 7.0 months, respectively. CONCLUSION: Paclitaxel was found to be an active agent in angiosarcoma of soft tissue in this retrospective analysis. These results need to be confirmed in a prospective randomised phase II study.

Cardiac markers (BNP, NT-pro-BNP, Troponin I, Troponin T, in female amateur runners before and up until three days after a marathon.

PURPOSE: Transient cardiac ventricular dysfunction or sudden cardiac deaths have been reported for male athletes participating in marathon racing. Less is known about the myocardial response in females. We examined natriuretic peptides and cardiac troponins in female athletes after a marathon. METHODS: At the 31st real,- Berlin Marathon plasma levels of NT-pro-BNP, BNP, cTnI and cTnT were measured in 15 women (age 35+/-6 years; finishing times between 3:22 h and 5:21 h) at four different time points (before, immediately after, day one and day three). RESULTS: An increase in [NT-pro-BNP] was observed immediately after the marathon (median [NT-pro-BNP] before: 39.6 pg ml(-1), after: 138.6 pg ml(-1), p=0.003) with a further increase on day one. [BNP] did not increase immediately after the marathon but increased on day one (median [BNP] before: 15 pg ml(-1), day one: 27.35 pg ml(-1), p=0.006). On day three, [NT-pro-BNP] and [BNP] returned to initial values. [cTnI] was under the detection limit prior to the marathon in all runners. [cTnT] was under the detection limit before the marathon except in one runner who presented a concentration of 0.03 ng ml(-1). Cardiac troponins (median [cTnl] after: 0.098 ng ml(-1), p=0.028; median [cTnT] after: 0.032 ng ml(-1), p=0.012) increased immediately after the marathon and returned to initial values on day one [cTnT] and three [cTnI]. DISCUSSION: Parameters representing cardiac stress increased in females after a marathon. Different kinetics of natriuretic peptides BNP and NT-pro-BNP post-marathon could be due to their different half-lives and dependence on renal function. The increase of cTnI and cTnT may result from minor myocardial lesions.

[18F]-FDG-PET in clinical stage I/II non-seminomatous germ cell tumours: results of the German multicentre trial.

PURPOSE: The aim of this study was to determine the predictive values of 2-[fluorine-18]fluoro-2-deoxy-D-glucose-positron emission tomography (FDG-PET) in primary staging in patients with newly diagnosed non-seminomatous germ cell tumour (NSGCT) clinical stage I/II. PATIENTS AND METHODS: The hypothesis was that FDG-PET would improve the negative predictive value (NPV) from 70% to 90%, thus requiring a total of 169 patients. All scans underwent visual analysis by a reference team of nuclear medicine physicians. Results were validated by histology following retroperitoneal lymph node dissection. RESULTS: Only 72 of the planned 169 patients were included, due to poor accrual. The prevalence of nodal involvement was 26%. Correct nodal staging by FDG-PET was achieved in 83% compared with correct computed tomography (CT) staging in 71%. CT had a sensitivity and specificity of 41% and 95%, respectively. Positive predictive value (PPV) and NPV were 87% and 67%, respectively. FDG-PET had a sensitivity and specificity of 66% and 98%, respectively. PPV was 95%. The primary end point was not reached, with an NPV of 78%. CONCLUSION: FDG-PET as a primary staging tool for NSGCT yielded only slightly better results than CT. Both methods had a high specificity while false-negative findings were more frequent with CT. FDG-PET is mostly useful as a diagnostic tool in case of questionable CT scan.

Water immersion is associated with an increase in aquaporin-2 excretion in healthy volunteers.

Here, we report the alterations in renal water handling in healthy volunteers during a 6 h thermoneutral water immersion at 34 to 36 degrees C. We found that water immersion is associated with a reversible increase in total urinary AQP2 excretion.

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.

Ifosfamide, carboplatin and etoposide (ICE) as second-line regimen alone and in combination with regional hyperthermia is active in chemo-pre-treated advanced soft tissue sarcoma of adults.

PURPOSE: To evaluate the efficacy and safety of the combination of ICE (ifosfamide 1.5 g m(-2), carboplatin 100 mg m(-2) and etoposide 150 mg m(-2), days 1-4, q 28 days, G-CSF 5 microg kg(-1) starting from day 6) alone and in combination with regional hyperthermia (RHT) in soft tissue sarcoma (STS) refractory to previous standard doxorubicin-ifosfamide-based chemotherapy. PATIENTS AND METHODS: Twenty patients with advanced STS of different histological sub-types were treated with the ICE regimen with 13 patients receiving additional RHT. A median of four courses of ICE were administered with RHT on days 1 and 3 (60 min, T(max) 42 degrees C). RESULTS: The objective response rate was 20%, with four partial responses (all treated with hyperthermia). In addition, two patients showed mixed responses and five patients stable disease. After a median follow-up time of 15 months, median time to progression was 6 months. Progression free rate estimates were 60% and 45% at 3 and 6 months, respectively. Median overall survival for all patients was 14.6 months. CONCLUSION: These results suggest that ICE alone or combined with RHT shows activity as second-line therapy in doxorubicin-ifosfamide-refractory STS.

[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.

Ifosfamide with regional hyperthermia in soft-tissue sarcomas.

For high-risk soft tissue sarcomas (HR-STS) of adults, new treatment strategies are needed to improve outcome with regard to local control and overall survival. Therefore, systemic chemotherapy has been integrated either after (adjuvant) or before (neoadjuvant) optimal local treatment by surgery and radiotherapy in HR-STS. The combination with regional hyperthermia as a new treatment strategy seems to open a new therapeutic window.