Arndt-Christian Müller

Distribution of Prostate Sentinel Nodes: A SPECT-Derived Anatomic Atlas

PURPOSE The randomized Radiation Therapy Oncology Group 94-13 trial revealed that coverage of the pelvic lymph nodes in high-risk prostate cancer confers an advantage (progression-free survival and biochemical failure) in patients with ≥15% risk of lymph node involvement. To facilitate an improved definition of the adjuvant target volume, precise knowledge regarding the location of the relevant lymph nodes is necessary. Therefore, we generated a three-dimensional sentinel lymph node atlas. METHODS AND MATERIALS In 61 patients with high-risk prostate cancer, a three-dimensional visualization of sentinel lymph nodes was performed using a single photon emission computed tomography system after transrectal intraprostatic injection of 150 to 362 (median 295) mega becquerel (MBq) (99m)Technetium-nanocolloid (1.5-3 h after injection) followed by an anatomic functional image fusion. RESULTS In all, 324 sentinel nodes in 59 of 61 patients (96.7%) were detected, with 0 to 13 nodes per patient (median 5, mean 5.3). The anatomic distribution of the sentinel nodes was as follows: external iliac 34.3%, internal iliac 17.9%, common iliac 12.7%, sacral 8.6%, perirectal 6.2%, left paraaortic 5.3%, right paraaortic 5.3%, seminal vesicle lymphatic plexus 3.1%, deep inguinal 1.5%, superior rectal 1.2%, internal pudendal 1.2%, perivesical 0.9%, inferior rectal 0.9%, retroaortic 0.3%, superficial inguinal 0.3%, and periprostatic 0.3%. CONCLUSIONS The distribution of sentinel nodes as detected by single photon emission computed tomography imaging correlates well with the distribution determined by intraoperative gamma probe detection. A lower detection rate of sentinels in close proximity to the bladder and seminal vesicles is probably caused by the radionuclide accumulation in the bladder. In regard to intensity-modulated radiotherapy techniques, the presented anatomic atlas may allow optimized target volume definitions.

Simultaneous 68Ga-DOTATOC-PET/MRI for IMRT treatment planning for meningioma: first experience.

PURPOSE To evaluate intensity-modulated radiotherapy (IMRT) treatment planning based on simultaneous positron-emission tomography and magnetic resonance imaging (PET/MRI) of meningioma. METHODS AND MATERIALS A meningioma patient was examined prior to radiotherapy with dedicated planning computed tomography (CT), MRI, PET/CT with gallium-68-labeled DOTATOC (68Ga-DOTATOC), and simultaneous 68Ga-DOTATOC-PET/MRI. The first gross target volume (GTV) was defined based on a combination of separate MR and 68Ga-DOTATOC-PET/CT imaging (GTVPET/CT+MR). Then, the simultaneous PET/MR images were used to delineate a second GTV (GTVPET/MR) by following exactly the same delineation strategy. After an isotropic expansion of those volumes by a 4-mm safety margin, the resulting planning target volumes (PTVs) were compared by calculating the intersection volume and the relative complements. A cross-evaluation of IMRT plans was performed, where the treatment plan created for the PTVPET/CT+MR was applied to the PET/MR-based PTVPET/MR. RESULTS Generally, target volumes for IMRT treatment planning did not differ between MRI plus 68Ga-DOTATOC-PET/CT and simultaneous PET/MR imaging. Only in certain regions of the GTV were differences observed. The overall volume of the PET/MR-based PTV was approximately the same as that obtained from PET/CT data. A small region of infiltrative tumor growth next to the main tumor mass was better visualized with combined PET/MR due to smaller PET voxel sizes and improved recovery. An IMRT treatment plan was optimized for the PTVPET/CT+MR. The evaluation of this plan with respect to the PTVPET/MR showed parts of the target volume that would not have received the full radiation dose after delineation of the tumor, based on simultaneous PET/MR. CONCLUSION This case showed that differences in target volumes delineated on the basis of separate MR and PET/CT and simultaneous PET/MR may be observed that can have significant consequences for an effectively applied radiotherapy treatment plan.

Acute Toxicity and Quality of Life After Dose-Intensified Salvage Radiation Therapy for Biochemically Recurrent Prostate Cancer After Prostatectomy: First Results of the Randomized Trial SAKK 09/10

PURPOSE Patients with biochemical failure (BF) after radical prostatectomy may benefit from dose-intensified salvage radiation therapy (SRT) of the prostate bed. We performed a randomized phase III trial assessing dose intensification. PATIENTS AND METHODS Patients with BF but without evidence of macroscopic disease were randomly assigned to either 64 or 70 Gy. Three-dimensional conformal radiation therapy or intensity-modulated radiation therapy/rotational techniques were used. The primary end point was freedom from BF. Secondary end points were acute toxicity according to the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.0) and quality of life (QoL) according to the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaires C30 and PR25. RESULTS Three hundred fifty patients were enrolled between February 2011 and April 2014. Three patients withdrew informed consent, and three patients were not eligible, resulting in 344 patients age 48 to 75 years in the safety population. Thirty patients (8.7%) had grade 2 and two patients (0.6%) had grade 3 genitourinary (GU) baseline symptoms. Acute grade 2 and 3 GU toxicity was observed in 22 patients (13.0%) and one patient (0.6%), respectively, with 64 Gy and in 29 patients (16.6%) and three patients (1.7%), respectively, with 70 Gy (P = .2). Baseline grade 2 GI toxicity was observed in one patient (0.6%). Acute grade 2 and 3 GI toxicity was observed in 27 patients (16.0%) and one patient (0.6%), respectively, with 64 Gy, and in 27 patients (15.4%) and four patients (2.3%), respectively, with 70 Gy (P = .8). Changes in early QoL were minor. Patients receiving 70 Gy reported a more pronounced and clinically relevant worsening in urinary symptoms (mean difference in change score between arms, 3.6; P = .02). CONCLUSION Dose-intensified SRT was associated with low rates of acute grade 2 and 3 GU and GI toxicity. The impact of dose-intensified SRT on QoL was minor, except for a significantly greater worsening in urinary symptoms.

Differential effects of anti-apoptotic Bcl-2 family members Mcl-1, Bcl-2, and Bcl-xL on celecoxib-induced apoptosis.

The cyclooxygenase-2 inhibitor Celecoxib is a potent inducer of apoptosis in tumor cells. In most cellular systems Celecoxib induces apoptosis via an intrinsic, mitochondrial apoptosis pathway. We recently showed that in Bax-negative Jurkat cells expression of pro-apoptotic Bak is essential for Celecoxib-induced mitochondrial damage and apoptosis induction. Aim of the present study was to identify specific pro- and anti-apoptotic members of the Bcl-2 family involved in the regulation of Bak activation, and subsequent apoptosis upon treatment with Celecoxib in the Jurkat cell model. Our results show that apoptosis in response to Celecoxib required the presence of Noxa and downregulation of the anti-apoptotic protein Mcl-1. Celecoxib-induced Bak activation and subsequent apoptosis could be inhibited by overexpression of Bcl-xL but not by the very similar Bcl-2. In Bcl-xL-overexpressing cells neutralization of both, Mcl-1 and Bcl-xL, was prerequisite for an efficient induction of apoptosis. Our data reveal an important role of the Mcl-1/Noxa axis for Celecoxib-induced apoptosis and suggest that Celecoxib may be of value for treatment of tumors addicted to Mcl-1 and for combined treatment approaches targeting anti-apoptotic Bcl-2 family members.

Prospective evaluation of a hydrogel spacer for rectal separation in dose-escalated intensity-modulated radiotherapy for clinically localized prostate cancer

BackgroundAs dose-escalation in prostate cancer radiotherapy improves cure rates, a major concern is rectal toxicity. We prospectively assessed an innovative approach of hydrogel injection between prostate and rectum to reduce the radiation dose to the rectum and thus side effects in dose-escalated prostate radiotherapy.MethodsAcute toxicity and planning parameters were prospectively evaluated in patients with T1-2 N0 M0 prostate cancer receiving dose-escalated radiotherapy after injection of a hydrogel spacer. Before and after hydrogel injection, we performed MRI scans for anatomical assessment of rectal separation. Radiotherapy was planned and administered to 78 Gy in 39 fractions.ResultsFrom eleven patients scheduled for spacer injection the procedure could be performed in ten. In one patient hydrodissection of the Denonvillier space was not possible. Radiation treatment planning showed low rectal doses despite dose-escalation to the target. In accordance with this, acute rectal toxicity was mild without grade 2 events and there was complete resolution within four to twelve weeks.ConclusionsThis prospective study suggests that hydrogel injection is feasible and may prevent rectal toxicity in dose-escalated radiotherapy of prostate cancer. Further evaluation is necessary including the definition of patients who might benefit from this approach. Trial registration: German Clinical Trials Register DRKS00003273.

Combined PET/MR Imaging Using 68 Ga-DOTATOC for Radiotherapy Treatment Planning in Meningioma Patients

Hybrid imaging is beneficial for improved medical diagnosis and therapy planning today. Hybrid imaging describes the prospective correlation of two or more complementary sets of imaging information, such as functional and anatomical image volumes. Correlation can be performed through physically combined imaging modalities, such as PET/CT, SPECT/CT, or PET/MR. Here we present first results from employing fully integrated PET/MR tomography for intensity-modulated radiotherapy (IMRT) treatment planning in patients with meningioma using [(68)Ga]-DOTATOC as the biomarker of choice. Combined PET/MR offers higher soft tissue contrast and the ability to add functional information to the plain combination of MR-based anatomy and PET-based metabolic and molecular information. Furthermore, fully integrated PET/MR employs novel PET technology that is neither available in PET-only nor PET/CT systems. Despite the current lack of broad clinical evidence, integrated PET/MR may become particularly important and clinically useful for improved, individualized RT therapy planning for brain lesions. In particular, logistical and diagnostic benefits of integrated PET/MR-based treatment planning over treatment planning based on PET/CT data may be expected in meningioma patients.

Use of EORTC Target Definition Guidelines for Dose-Intensified Salvage Radiation Therapy for Recurrent Prostate Cancer: Results of the Quality Assurance Program of the Randomized Trial SAKK 09/10

PURPOSE Different international target volume delineation guidelines exist and different treatment techniques are available for salvage radiation therapy (RT) for recurrent prostate cancer, but less is known regarding their respective applicability in clinical practice. METHODS AND MATERIALS A randomized phase III trial testing 64 Gy vs 70 Gy salvage RT was accompanied by an intense quality assurance program including a site-specific and study-specific questionnaire and a dummy run (DR). Target volume delineation was performed according to the European Organisation for the Research and Treatment of Cancer guidelines, and a DR-based treatment plan was established for 70 Gy. Major and minor protocol deviations were noted, interobserver agreement of delineated target contours was assessed, and dose-volume histogram (DVH) parameters of different treatment techniques were compared. RESULTS Thirty European centers participated, 43% of which were using 3-dimensional conformal RT (3D-CRT), with the remaining centers using intensity modulated RT (IMRT) or volumetric modulated arc technique (VMAT). The first submitted version of the DR contained major deviations in 21 of 30 (70%) centers, mostly caused by inappropriately defined or lack of prostate bed (PB). All but 5 centers completed the DR successfully with their second submitted version. The interobserver agreement of the PB was moderate and was improved by the DR review, as indicated by an increased κ value (0.59 vs 0.55), mean sensitivity (0.64 vs 0.58), volume of total agreement (3.9 vs 3.3 cm(3)), and decrease in the union volume (79.3 vs 84.2 cm(3)). Rectal and bladder wall DVH parameters of IMRT and VMAT vs 3D-CRT plans were not significantly different. CONCLUSIONS The interobserver agreement of PB delineation was moderate but was improved by the DR. Major deviations could be identified for the majority of centers. The DR has improved the acquaintance of the participating centers with the trial protocol.

Small Cell Carcinoma of Vulva

Background and Purpose:Extrapulmonary small cell carcinoma (EPSCC) is a rare disease, which has a slightly better prognosis than small cell lung cancer, but still dismal. Gynecologic small cell malignancies tend to show a better survival than similar histologies of other regions. However, of five reported cases of vulvar manifestation only one patient was disease-free at the time of publication with limited follow-up.Case Report:The authors describe a case of locally advanced small cell vulva carcinoma infiltrating the anal sphincter and urethra with spread to inguinal lymph nodes treated by radiochemotherapy and regional hyperthermia. After three cycles of carboplatin/ etoposide, computed tomography and magnetic resonance imaging indicated only little regressive transformations but overall stable disease. Surgical options were excluded. Therefore, curative radiotherapy to a total dose of > 65 Gy to macroscopic tumor, chemotherapy with cisplatin weekly, and regional hyperthermia were performed. Acute severe toxicity was limited to skin reactions. Despite the disadvantageous situation with inguinal lymph node metastases and chemoresistance, the multimodal therapy yielded a 5-year disease-free survival.Conclusion:Thus, the trimodal regimen of radiochemotherapy plus regional hyperthermia offered a curative chance in spite of resistance to the standard chemotherapy for irresectable, locally advanced small cell carcinoma of the vulva. Therefore, this approach merits further evaluation for limited disease of EPSCC.ZusammenfassungHintergrund und Ziel:Extrapulmonale kleinzellige Karzinome (EPSCC) sind eine seltene Tumorentität, die eine etwas bessere Prognose als kleinzellige Bronchialkarzinome besitzt. Innerhalb dieser Entität zeigen gynäkologische Tumoren ein etwas besseres Überleben. Allerdings war von den fünf beschriebenen Fällen kleinzelliger Vulvakarzinome zum Zeitpunkt der Auswertung nur eine Patientin mit kurzer Nachsorge tumorfrei.Fallbericht:Die Autoren beschreiben den Fall einer Patientin mit lokal fortgeschrittenem kleinzelligen Vulvakarzinom, welches den Sphincter ani, die Urethra und die inguinalen Lymphknoten involvierte. Nach der initialen Chemotherapie mit Carboplatin/ Etoposid zeigten sich leichte regressive Veränderungen, aber messtechnisch keine relevante Größenabnahme im Sinne einer „stabilen Erkrankung“. Operative Behandlungsmöglichkeiten bestanden nicht. Daher wurde als kurative Modalität eine definitive Radiochemotherapie mit > 65 Gy auf den makroskopischen Tumor mit simultaner wöchentlicher Cisplatingabe plus lokoregionaler Tiefenhyperthermie durchgeführt (Abbildung 1). Höhergradige Akuttoxizitäten beschränkten sich auf die Haut. Trotz der ungünstigen Ausgangssituation mit lymphogener Metastasierung und fehlendem Ansprechen auf die initiale Chemotherapie konnte mit der multimodalen Therapie ein krankheitsfreies Überleben von 5 Jahren erreicht werden (Abbildung 2).Schlussfolgerung:Die trimodale Therapie mit Radiotherapie, Chemotherapie und Hyperthermie eröffnete trotz der initialen Resistenz gegenüber der Standardchemotherapie einen kurativen Ansatz bei einem inoperablen, lokal fortgeschrittenen kleinzelligen Vulvakarzinom. Dieses Ergebnis kann einen Ausgangspunkt für die Diskussion der Therapieoptionen von lokal begrenzten EPSCC bilden.

Importance of Bak for celecoxib-induced apoptosis

The selective cyclooxygenase-2 (COX-2) inhibitor celecoxib constitutes the prototype of pro-apoptotic agents acting through the intrinsic death pathway in a Bcl-2 independent manner. To gain further insight into celecoxib-mediated apoptosis regulation at the level of the mitochondria we tested in how far the crucial pro-apoptotic Bcl-2 proteins Bak and Bax were involved using clones of the Bax-deficient Jurkat T-lymphoma cell model either expressing Bak (Jurkat Bak positive) or being negative for Bak (Jurkat Bak negative), or overexpressing Bcl-2 (Jurkat Bcl-2). Celecoxib induced substantial apoptosis in Jurkat Bak-positive cells. Overexpression of Bcl-2 had only limited protective effects. However, loss of Bak-expression conferred almost complete resistance of Jurkat cells to celecoxib-induced apoptosis. Neither enhanced celecoxib-concentrations nor prolonged incubation times were sufficient to normalize apoptotic rates upon celecoxib-treatment in these Bak/Bax-negative cells. In line with that observation, siRNA-mediated silencing of Bak in the Bak-positive Jurkat cells largely reduced the extent of celecoxib-induced cell death. Interestingly, in celecoxib-sensitive Bak-positive cells, celecoxib-treatment resulted in down-regulation of the anti-apoptotic Bcl-2 protein Mcl-1 which may contribute to celecoxib-mediated activation of Bak-dependent apoptosis. Taken together our data clearly show for the first time the functional relevance of Bak for celecoxib-induced apoptosis in Bax-deficient Jurkat T-lymphoma cells.

SCLC extensive disease – treatment guidance by extent or/and biology of response?

In extensive disease of small cell lung cancer a doubling of the one-year-survival rate was reported in August 2007 by prophylactic cranial irradiation applied to patients who experienced any response to initial chemotherapy. We discuss the treatment concept of extensive disease in the face of the latest results and older studies with additional thoracic irradiation in this subgroup. A randomized trial with prophylactic cranial irradiation published in 1999 demonstrated an improvement of 5-year-overall-survival for complete responders (at least at distant levels) receiving additional thoracic radiochemotherapy compared to chemotherapy alone (9.1% vs. 3.7%). But, these results were almost neglected and thoracic radiotherapy was not further investigated for good responders of extensive disease. However, in the light of current advances by prophylactic cranial irradiation these findings are noteworthy on all accounts. Considering both, a possible interpretation of these data could be a survival benefit of local control by simultaneous thoracic radiochemotherapy in the case of improved distant control due to chemotherapy and prophylactic cranial irradiation. Furthermore the question arises whether the tumor biology indicated by the response to chemotherapy should be integrated in the present classification.