Michael Pinkawa

Assessment of Treatment Response in Patients with Glioblastoma Using O-(2-18F-Fluoroethyl)-l-Tyrosine PET in Comparison to MRI

The assessment of treatment response in glioblastoma is difficult with MRI because reactive blood–brain barrier alterations with contrast enhancement can mimic tumor progression. In this study, we investigated the predictive value of PET using O-(2-18F-fluoroethyl)-l-tyrosine (18F-FET PET) during treatment. Methods: In a prospective study, 25 patients with glioblastoma were investigated by MRI and 18F-FET PET after surgery (MRI-/FET-1), early (7–10 d) after completion of radiochemotherapy with temozolomide (RCX) (MRI-/FET-2), and 6–8 wk later (MRI-/FET-3). Maximum and mean tumor-to-brain ratios (TBRmax and TBRmean, respectively) were determined by region-of-interest analyses. Furthermore, gadolinium contrast-enhancement volumes on MRI (Gd-volume) and tumor volumes in 18F-FET PET images with a tumor-to-brain ratio greater than 1.6 (Tvol 1.6) were calculated using threshold-based volume-of-interest analyses. The patients were grouped into responders and nonresponders according to the changes of these parameters at different cutoffs, and the influence on progression-free survival and overall survival was tested using univariate and multivariate survival analyses and by receiver-operating-characteristic analyses. Results: Early after completion of RCX, a decrease of both TBRmax and TBRmean was a highly significant and independent statistical predictor for progression-free survival and overall survival. Receiver-operating-characteristic analysis showed that a decrease of the TBRmax between FET-1 and FET-2 of more than 20% predicted poor survival, with a sensitivity of 83% and a specificity of 67% (area under the curve, 0.75). Six to eight weeks later, the predictive value of TBRmax and TBRmean was less significant, but an association between a decrease of Tvol 1.6 and PFS was noted. In contrast, Gd-volume changes had no significant predictive value for survival. Conclusion: In contrast to Gd-volumes on MRI, changes in 18F-FET PET may be a valuable parameter to assess treatment response in glioblastoma and to predict survival time.

pO(2) Polarography versus positron emission tomography ([(18)F] fluoromisonidazole, [(18)F]-2-fluoro-2'-deoxyglucose). An appraisal of radiotherapeutically relevant hypoxia.

Background and Purpose:The aim of the present study was to validate ([18F] fluoromisonidazole (FMISO) and [18F]-2-fluoro-2’-deoxyglucose (FDG) positron emission tomography (PET) for determination of radiotherapeutically relevant hypoxia by the gold standard for measuring tissue oxygenation in human tumors, the computerized polarographic needle electrode system (pO2 histography).Patients and Methods:Up to now, a total of 16 patients with a metastatic neck lymph node from a primary squamous carcinoma of the head and neck underwent pO2 and PET measurements. Tumor tissue pO2 was measured with polarographic needle electrodes using a pO2 histograph (Eppendorf®). Under CT control, the needle electrode was placed in the tumor without general or local anesthesia. To assess the biological and clinical relevance of oxygenation measurement, the relative frequency of pO2 readings, with values ≤ 2.5, ≤ 5.0, and ≤ 10.0 mmHg, as well as mean and median pO2 were recorded.All PET studies were carried out using an ECAT EXACT 922/47® scanner with an axial field of view of 16.2 cm. FMISO PET consisted of one static scan of the relevant region, performed 120 min after intravenous administration. The acquisition and reconstruction parameters were as follows: 15-min emission scanning and 4-min transmission scanning with 68Ge rod sources. FDG PET of the lymph node metastasis was performed 68 ± 11 min after intravenous administration, applying the whole-body tool with 8-min emission scanning and 4-min transmission scanning per bed position.Results:In order to detect possible relations between the different relevant polarographically measured parameters of tumor hypoxia and FMISO PET data-based oxygenation values, the Pearson correlation coefficient was calculated. Average (r > 0.5) to high correlation (r > 0.7) was found between tumor-to-muscle ratio of FMISO after 2 h and parameters of hypoxic fraction (pO2 readings with values ≤ 2.5, ≤ 5.0, and ≤ 10.0 mmHg as well as mean and median). No correlations could be shown between FDG PET parameters and polarographically determined tumor oxygenation status.Conclusion:Summarizing the FMISO uptake represents a global value for macroscopic tumor parts. As a noninvasive measurement this method seems highly feasible to evaluate the state of oxygenation in subjacent tumors.Hintergrund und Ziel:Ziel dieser Untersuchung war die Validierung von [18F]-Fluormisonidazol-(FMISO-) und [18F]-Fluordeoxyglucose-( FDG-)Positronenemissionstomographie (PET) zur Erfassung der strahlentherapeutisch relevanten Hypoxie durch das computergestützte polarographische Nadelelektrodensystem (pO2-Histographie), das den Goldstandard zur Festlegung der Gewebeoxygenierung in menschlichen Tumoren darstellt.Patienten und Methodik:Bis jetzt wurden bei insgesamt 16 Patienten mit metastatisch befallenen Halslymphknoten eines Plattenepithelkarzinoms der Kopf-Hals-Region pO2- und PET-Messungen durchgeführt. Der pO2 des Tumorgewebes wurde mit Hilfe polarographischer Feinnadelelektroden eines pO2-Histographen (Eppendorf®) gemessen. Die Nadelelektrode wurde CT-gesteuert ohne Lokalanästhesie positioniert. Als Grad für die biologische und klinische Relevanz wurden die relative Häufigkeit der pO2-Messwerte ≤ 2,5, ≤ 5,0 und ≤ 10,0 mmHg sowie der Mittelwert und der Median dokumentiert.Die PET-Untersuchungen wurden an einem Vollring-Tomographen (ECAT EXACT 922/47®; Siemens/CTI) durchgeführt. Die FMISO-PET erfolgte als statische Aufnahme der relevanten Region 120 min p.i. Folgende Akquisitions- und Rekonstruktionsparameter wurden verwendet: 15-minütige Emissionsmessung und 4-minütige Transmissionsmessung mit Hilfe von 68Ge-Stabquellen. Die FDG-PET der metastatisch befallenen Halslymphknoten wurde 68 ± 11 min p.i. unter Verwendung eines Ganzkörperprotokolls mit einer Emissionsmessung von 8 min und einer Transmissionsmessung von 4 min pro Bettposition durchgeführt.Ergebnisse:Um mögliche Korrelationen zwischen den verschiedenen relevanten, polarographisch gemessenen Parametern der Tumorhypoxie und den mittels FMISO-PET gewonnenen Messdaten zu detektieren, wurde der Pearson-Korrelationskoeffizient berechnet. Es zeigte sich eine mittlere (r > 0,5) bis hohe Korrelation (r > 0,7) zwischen dem Tumor/Muskel-Quotienten der FMISO-Aufnahme 2 h p. i. und den verschiedenen Hypoxieparametern (pO2-Messwerte ≤ 2,5, ≤ 5,0, ≤ 10,0 mmHg sowie Mittelwert und Median der pO2-Messwerte). Keine Korrelation konnte zwischen den FDG-PET-Parametern und dem polarographisch bestimmten Tumoroxygenierungsstatus aufgezeigt werden.Schlussfolgerung:Die mit PET gemessene FMISO-Aufnahme gibt einen globalisierten Messwert für makroskopische Anteile des Tumors wieder. Aufgrund des nichtinvasiven Charakters scheint diese Methode besonders geeignet, den Oxygenierungsstatus bei tiefer liegenden Tumoren zu erfassen.

A Multi-institutional Clinical Trial of Rectal Dose Reduction via Injected Polyethylene-Glycol Hydrogel During Intensity Modulated Radiation Therapy for Prostate Cancer: Analysis of Dosimetric Outcomes

PURPOSE To characterize the effect of a prostate-rectum spacer on dose to rectum during external beam radiation therapy for prostate cancer and to assess for factors correlated with rectal dose reduction. METHODS AND MATERIALS Fifty-two patients at 4 institutions were enrolled into a prospective pilot clinical trial. Patients underwent baseline scans and then were injected with perirectal spacing hydrogel and rescanned. Intensity modulated radiation therapy plans were created on both scans for comparison. The objectives were to establish rates of creation of ≥ 7.5 mm of prostate-rectal separation, and decrease in rectal V70 of ≥ 25%. Multiple regression analysis was performed to evaluate the associations between preinjection and postinjection changes in rectal V70 and changes in plan conformity, rectal volume, bladder volume, bladder V70, planning target volume (PTV), and postinjection midgland separation, gel volume, gel thickness, length of PTV/gel contact, and gel left-to-right symmetry. RESULTS Hydrogel resulted in ≥7.5-mm prostate-rectal separation in 95.8% of patients; 95.7% had decreased rectal V70 of ≥ 25%, with a mean reduction of 8.0 Gy. There were no significant differences in preinjection and postinjection prostate, PTV, rectal, and bladder volumes. Plan conformities were significantly different before versus after injection (P=.02); plans with worse conformity indexes after injection compared with before injection (n=13) still had improvements in rectal V70. In multiple regression analysis, greater postinjection reduction in V70 was associated with decreased relative postinjection plan conformity (P=.01). Reductions in V70 did not significantly vary by institution, despite significant interinstitutional variations in plan conformity. There were no significant relationships between reduction in V70 and the other characteristics analyzed. CONCLUSIONS Injection of hydrogel into the prostate-rectal interface resulted in dose reductions to rectum for >90% of patients treated. Rectal sparing was statistically significant across a range of 10 to 75 Gy and was demonstrated within the presence of significant interinstitutional variability in plan conformity, target definitions, and injection results.

Application of a spacer gel to optimize three-dimensional conformal and intensity modulated radiotherapy for prostate cancer

BACKGROUND AND PURPOSE The aim was to evaluate the impact of a spacer gel on the dose distribution, applying three-dimensional conformal (3D CRT) and intensity modulated radiotherapy (IMRT) planning techniques. MATERIAL AND METHODS The injection of a spacer gel (10 ml SpaceOAR™) was performed between the prostate and rectum under transrectal ultrasound guidance in 18 patients with prostate cancer. 3D CRT and IMRT treatment plans were compared based on CT before and after injection (78 Gy prescription dose). RESULTS In contrast to the PTV and bladder, significant advantages (p<0.01) resulted in respect of all analysed rectal dose values comparing pre spacer with post spacer plans for both techniques. Rectal NTCP (normal tissue complication probability) reached the lowest percentage after spacer injection irrespective of the technique, with a mean reduction of >50% for both IMRT and 3D CRT. Significantly (p<0.01) higher D(mean), and V(78) for the PTV were reached with IMRT vs. 3D CRT plans, with a smaller rectum V(76) but larger rectum V(50). CONCLUSIONS The injection of a spacer gel between the prostate and anterior rectal wall is associated with considerably lower doses to the rectum and consequentially lower NTCP values irrespective of the radiotherapy technique.

Dose-escalation using intensity-modulated radiotherapy for prostate cancer – Evaluation of the dose distribution with and without 18F-choline PET-CT detected simultaneous integrated boost

BACKGROUND AND PURPOSE The aim of the study was to evaluate the impact of a dose escalation to an (18)F-choline PET-CT defined simultaneous integrated boost (IB) on the dose distribution and changes of the equivalent uniform dose (EUD). MATERIALS AND METHODS PET-CT was performed in 12 consecutive patients for treatment planning. An intraprostatic lesion was defined by a tumour-to-background uptake value ratio >2 (GTV(PET)). Dose escalation was focused only on the intraprostatic lesion. Two comparisons were evaluated: whole prostate irradiation to 76 Gy+/-boost to 80 Gy (C1) and whole prostate irradiation to 66.6 Gy+/-boost to 83.25 Gy (C2). RESULTS PTV/GTV(PET)+margins were covered by a mean EUD of 75.9/76.1 Gy vs. 77.1/80.1 Gy (C1) and 66.5/66.2 Gy vs. 71.1/82.9 Gy (C2) (p<0.01, respectively). Concerning the organs at risk, EUD increased slightly with an additional boost (mean EUD for bladder: C1 53.2 Gy vs. 53.8 Gy; C2 43.0 Gy vs. 45.1 Gy; for rectum: C1 52.0 Gy vs. 52.6 Gy; C2 43.0 Gy vs. 45.4 Gy; p<0.01, respectively). The distance to the organs at risk had a significant impact on the respective maximum doses in the treatment plans with IB. CONCLUSIONS Treatment planning with IB allows an individually adapted dose escalation. The therapeutic ratio can be improved by a considerable dose escalation to the macroscopic tumour, but only minor EUD changes to the bladder and rectum.

Erectile Dysfunction After External Beam Radiotherapy for Prostate Cancer

BACKGROUND There is a lack of prospective studies focusing on the sexual quality of life of prostate cancer patients after conformal radiotherapy (RT). OBJECTIVE To evaluate the incidence, progression, and predictive factors for erectile dysfunction (ED). DESIGN, SETTING AND PARTICIPANTS Patients who responded to the sexual domain of the Expanded Prostate Cancer Index Composite (EPIC) questionnaire before and more than 1 yr after RT and never received an antiandrogen treatment were included (n=123). INTERVENTION RT dose was 70.2-72 Gy. Eleven patients used a phosphodiesterase-5 (PDE-5) inhibitor. MEASUREMENTS Patients responded to the EPIC questionnaire before (time A), at the last day (B), a median time of 2 mo after (C), and 16 mo after (D) RT. In a multivariate analysis, risk factors (patient age, prostate volume, planning target volume, use of PDE-5 inhibitor, comorbidities) were tested for their independent effects on ED before and after RT. RESULTS AND LIMITATIONS Sexual function and bother scores had already decreased by the end of RT (median function and bother scores at times A/B/C/D: 41/30/32/24 and 75/50/50/50). Initial function scores correlated well with late function scores (r=0.7; p<0.001). The ability to have an erection was reported by 81%/72%/74%/60% (preserved erectile ability in 70% at time D), erections firm enough for sexual intercourse by 44%/33%/35%/27% (preserved erections sufficient for intercourse in 53% at time D) of patients. A higher patient age and diabetes were predictive of both a pre-existing ED and a post-RT acquired ED. Nightly erections before treatment proved prognostically favourable (at least weekly vs. < weekly-hazard ratio of 5.9 for preserved erections sufficient for intercourse; p=0.01). Higher rates of ED can be expected with longer follow-up. CONCLUSIONS The incidence of ED progressively increases after RT. Patient age and diabetes are risk factors for both pre-treatment and RT-associated ED. Nightly erections before RT proved prognostically favourable.

Stereotactic Body Radiation Therapy (SBRT) for treatment of adrenal gland metastases from non-small cell lung cancer

Background:Metastatic disease from a non-small cell lung cancer to the adrenal gland is common, and systemic treatment is the most frequent therapeutic option. Nevertheless, in patients suffering from an isolated adrenal metastasis, a survival benefit could be achieved after surgical resection. Stereotactic body radiation treatment (SBRT) increase local tumor control and could be an alternative option. We present our initial institutional experiences with SBRT for adrenal gland metastases.Patients and Methods:Between July 2002 and September 2009, 18 patients with a non-small cell lung cancer and adrenal metastasis received SBRT. An isolated adrenal metastasis was diagnosed in 13 patients, while 5 patients with multiple metastatic lesions had SBRT due to back pain. Depending on treatment intent and target size, the dose/fraction concept varied from 5 x 4 Gy to 5 x 8 Gy. Dose was given with an isotropic convergent beam technique to a median maximum dose of 132% to the target’s central part.Results:The mean clinical (CTV) and planning target volume (PTV) was 89 cm³ (5–260 cm³) and 176 cm³ (20–422 cm³). A median progression-free survival time (PFS) of 4.2 months was obtained for the entire patient group, with a markedly increased PFS of 12 months in 13 patients suffering from an isolated metastasis of the adrenal gland. After a median follow-up of 21 months, 10 of 13 patients (77%) with isolated adrenal metastasis achieved local control. In these patients, median overall survival (OS) was 23 months.Conclusion:SBRT is a feasible and safe technique for lung cancer patients with adrenal gland metastasis. In patients with an isolated adrenal metastasis median OS of 23 months was excellent and comparable to data after surgical removal, but noninvasive. Acute side effects were mild.Hintergrund:Nebennierenmetastasen nichtkleinzelliger Bronchialkarzinome sind häufig, und die systemische Therapie ist die meistgenutzte Behandlungsoption. Im Fall von Patienten mit isolierter Nebennierenmetastase verzeichnen chirurgische Daten einen Überlebensgewinn nach einer Resektion. Die extrakranielle stereotaktische Radiotherapie (ESRT) bietet aufgrund der sehr guten lokalen Kontrolle eine nichtinvasive Alternative. Wir präsentieren unsere institutionellen Erfahrungen mit der ESRT von Nebennierenmetastasen.Patienten und Methodik:Zwischen Juli 2002 und September 2009 wurden 18 Patienten mit Nebennierenmetastasen bei nichtkleinzelligen Bronchialkarzinomen mit ESRT behandelt (Tabelle 1). Eine isolierte Nebennierenmetastase wurde in 13 Fällen diagnostiziert, 5 Patienten wurden aufgrund von Flankenschmerzen bei multipel metastasiertem Tumorleiden behandelt. Abhängig von der Behandlungsintention und dem Bestrahlungsvolumen variierte das Dosierungs-/Fraktionierungskonzept zwischen 5 x 4 Gy bis 5 x 8 Gy. Die Dosis wurde appliziert über eine isozentrische conformale Mehrfeldertechnik mit einem medianen Dosismaximum von 132% im Tumorzentrum.Ergebnisse:Das mittlere klinischen Zielvolumen (CTV) und das mittlere Planungszielvolumen (PTV) lag bei 89 cm³ (5–260 cm³) bzw. 176 cm³ (20–422 cm³) (Tabelle 2). Die mediane progressionsfreie Zeit (PFS) von allem Patienten lag bei 4,2 Monaten bei deutlich längerer PFS von 12 Monaten für die 13 Patienten mit isolierter Nebennierenmetastase (Abb. 2). Nach einer medianen Nachbeobachtung von 21 Monaten waren 10 (77%) dieser 13 Patienten lokal kontrolliert mit einem medianen Überleben von 23 Monaten (Abb. 3).Schlussfolgerung:ESRT ist eine praktikable und sichere Technik zur Behandlung von Patienten mit Nebennierenmetastasen nichtkleinzelliger Bronchialkarzinome. Das mediane Überleben von 23 Monaten der Patienten mit isolierter Nebennierenmetas-tase ist exzellent und vergleichbar mit chirurgischen Daten, dabei mit dem Vorteil der nicht invasiven Behandlungsmethode und geringer Nebenwirkungsrate.

Application technique: placement of a prostate-rectum spacer in men undergoing prostate radiation therapy.

Study Type – Therapy (case series)

Image-guided radiotherapy for prostate cancer

PurposeTo evaluate inter- and intrafraction organ motion with an ultrasound-based prostate localization system (BAT®) for patients treated with intensity-modulated radiotherapy for prostate cancer.Patients and MethodsAfter set-up to external skin marks, 260/219 ultrasound-based alignments were performed before/after irradiation in 32 consecutive patients. Image quality was classified as good, satisfactory or poor. Patient- and imaging-related parameters were analyzed to identify predictors for poor image quality. Shifts in relation to the treatment planning computed tomography (CT) were recorded before/after irradiation in the superior-inferior (SI), anterior-posterior (AP) and right-left (RL) directions to determine inter-/intrafraction prostate motion.ResultsThe thickness of tissue anterior to the bladder and bladder volume during the ultrasound localization as well as an inferior prostate position relative to public symphysis (determined in treatment planning CT) were found to be independent predictors of a poor image quality. Interfraction shifts (mean ± standard deviation: −0.2 ± 4.8 [SI], 2.4 ± 6.6 [AP] and 1.9 ± 4.6 [RL]) varied much stronger than intrafraction shifts (0.0 ± 2.0 [SI], 0.6 ± 2.2 [AP] and 0.2 ± 1.9 [RL]). A larger pressure of the ultrasound probe (determined as a larger reduction of the distance abdominal skin to prostate between the planning CT and the ultrasound) was applied in case of poor image quality, associated with larger systematic posterior prostate displacements.ConclusionIntrafraction prostate shifts are considerably smaller in comparison to interfraction shifts. Bladder filling and a small pressure on the ultrasound probe are crucial to achieve an adequate image quality without systematic prostate displacements.ZusammenfassungZielBestimmung der inter- und intrafraktionellen Organbewegung mit einem ultraschallbasierten Lokalisationssystem der Prostata (BAT®) bei mit intensitätsmodulierter Radiotherapie behandelten Patienten mit Prostatakarzinom.Patienten und MethodikNach Lagerung entsprechend der externen Hautmarkierung wurden 260/219 ultraschallbasierte Positionierungen vor/nach Bestrahlung bei 32 konsekutiven Patienten durchgeführt. Die Bildqualität wurde als gut, zufriedenstellend oder schlecht bewertet. Patienten- und bildgebungsabhängige Parameter wurden zur Identifikation von Prädiktoren für schlechte Bildqualität analysiert. Verschiebungen im Verhältnis zur Bestrahlungsplanungs-Computertomographie(-CT) wurden in der superior-inferioren (SI), anterior-posterioren (AP) und Rechts-links-(RL-)Achse vor/nach Bestrahlung dokumentiert, um inter-/intrafraktionelle Prostatabewegungen zu bestimmen.ErgebnisseSowohl die Dicke des Gewebes ventral der Blase und das Blasenvolumen während der Ultraschalllokalisation als auch eine inferiore Prostatalage relativ zur Symphyse (bestimmt im Bestrahlungsplanungs-CT) fanden sich als unabhängige Prädiktoren einer schlechten Bildqualität. Interfraktionelle Verschiebungen (Mittelwert ± Standardabweichung: −0,2 ± 4,8 [SI], 2,4 ± 6,6 [AP] und 1,9 ± 4,6 [RL]) variierten viel stärker als intrafraktionelle Verschiebungen (0,0 ± 2,0 [SI], 0,6 ± 2,2 [AP] und 0,2 ± 1,9 [RL]). Ein stärkerer Druck auf die Ultraschallsonde (als eine größere Reduktion des Abstandes Bauchhaut zu Prostata zwischen dem Planungs-CT und dem Ultraschall bestimmt) wurde vor allem bei schlechter Bildqualität ausgeübt, verbunden mit größeren systematischen dorsalen Prostataverschiebungen.SchlussfolgerungIntrafraktionelle Prostataverschiebungen sind deutlich geringer als interfraktionelle Verschiebungen. Blasenfüllung und ein geringer Druck auf die Ultraschallsonde sind zum Erzielen einer adäquaten Bildqualität ohne systematische Prostataverschiebungen entscheidend.

Dose-escalation using intensity-modulated radiotherapy for prostate cancer - evaluation of quality of life with and without 18 F-choline PET-CT detected simultaneous integrated boost

BackgroundIn comparison to the conventional whole-prostate dose escalation, an integrated boost to the macroscopic malignant lesion might potentially improve tumor control rates without increasing toxicity. Quality of life after radiotherapy (RT) with vs. without 18F-choline PET-CT detected simultaneous integrated boost (SIB) was prospectively evaluated in this study.MethodsWhole body image acquisition in supine patient position followed 1 h after injection of 178-355MBq 18F-choline. SIB was defined by a tumor-to-background uptake value ratio > 2 (GTVPET). A dose of 76Gy was prescribed to the prostate (PTVprostate) in 2Gy fractions, with or without SIB up to 80Gy. Patients treated with (n = 46) vs. without (n = 21) SIB were surveyed prospectively before (A), at the last day of RT (B) and a median time of two (C) and 19 month (D) after RT to compare QoL changes applying a validated questionnaire (EPIC - expanded prostate cancer index composite).ResultsWith a median cut-off standard uptake value (SUV) of 3, a median GTVPET of 4.0 cm3 and PTVboost (GTVPET with margins) of 17.3 cm3 was defined. No significant differences were found for patients treated with vs. without SIB regarding urinary and bowel QoL changes at times B, C and D (mean differences ≤3 points for all comparisons). Significantly decreasing acute urinary and bowel score changes (mean changes > 5 points in comparison to baseline level at time A) were found for patients with and without SIB. However, long-term urinary and bowel QoL (time D) did not differ relative to baseline levels - with mean urinary and bowel function score changes < 3 points in both groups (median changes = 0 points). Only sexual function scores decreased significantly (> 5 points) at time D.ConclusionsTreatment planning with 18F-choline PET-CT allows a dose escalation to a macroscopic intraprostatic lesion without significantly increasing toxicity.