Richard Holy

Safety and Efficacy of Stereotactic Body Radiotherapy for Stage I Non-Small-Cell Lung Cancer in Routine Clinical Practice A Patterns-of-Care and Outcome Analysis

Introduction: To evaluate safety and efficacy of stereotactic body radiotherapy (SBRT) for stage I non–small-cell lung cancer (NSCLC) in a patterns-of-care and patterns-of-outcome analysis. Methods: The working group “Extracranial Stereotactic Radiotherapy” of the German Society for Radiation Oncology performed a retrospective multicenter analysis of practice and outcome after SBRT for stage I NSCLC. Sixteen German and Austrian centers with experience in pulmonary SBRT were asked to participate. Results: Data of 582 patients treated at 13 institutions between 1998 and 2011 were collected; all institutions, except one, were academic hospitals. A time trend to more advanced radiotherapy technologies and escalated irradiation doses was observed, but patient characteristics (age, performance status, pulmonary function) remained stable over time. Interinstitutional variability was substantial in all treatment characteristics but not in patient characteristics. After an average follow-up of 21 months, 3-year freedom from local progression (FFLP) and overall survival (OS) were 79.6% and 47.1%, respectively. The biological effective dose was the most significant factor influencing FFLP and OS: after more than 106 Gy biological effective dose as planning target volume encompassing dose (N = 164), 3-year FFLP and OS were 92.5% and 62.2%, respectively. No evidence of a learning curve or improvement of results with larger SBRT experience and implementation of new radiotherapy technologies was observed. Conclusion: SBRT for stage I NSCLC was safe and effective in this multi-institutional, academic environment, despite considerable interinstitutional variability and time trends in SBRT practice. Radiotherapy dose was identified as a major treatment factor influencing local tumor control and OS.

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.

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.

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.

Definition of stereotactic body radiotherapy

This report from the Stereotactic Radiotherapy Working Group of the German Society of Radiation Oncology (Deutschen Gesellschaft für Radioonkologie, DEGRO) provides a definition of stereotactic body radiotherapy (SBRT) that agrees with that of other international societies. SBRT is defined as a method of external beam radiotherapy (EBRT) that accurately delivers a high irradiation dose to an extracranial target in one or few treatment fractions. Detailed recommendations concerning the principles and practice of SBRT for early stage non-small cell lung cancer (NSCLC) are given. These cover the entire treatment process; from patient selection, staging, treatment planning and delivery to follow-up. SBRT was identified as the method of choice when compared to best supportive care (BSC), conventionally fractionated radiotherapy and radiofrequency ablation. Based on current evidence, SBRT appears to be on a par with sublobar resection and is an effective treatment option in operable patients who refuse lobectomy.ZusammenfassungDie Arbeitsgruppe „Stereotaktische Radiotherapie“ der Deutschen Gesellschaft für Radioonkologie (DEGRO) erarbeitete eine Definition der Körperstereotaxie (SBRT), die sich an vorhandene internationale Definitionen anlehnt: Die SBRT ist eine Form der perkutanen Strahlentherapie, die mit hoher Präzision eine hohe Bestrahlungsdosis in einer oder wenigen Bestrahlungsfraktionen in einem extrakraniellen Zielvolumen appliziert. Zur Praxis der SBRT beim nichtkleinzelligen Bronchialkarzinom (NSCLC) im frühen Stadium werden detaillierte Empfehlungen gegeben, die den gesamten Ablauf der Behandlung von der Indikationsstellung, Staging, Behandlungsplanung und Applikation sowie Nachsorge umfassen. Die Körperstereotaxie wurde als Methode der Wahl im Vergleich zu Best Supportive Care, zur konventionell fraktionierten Strahlentherapie sowie zur Radiofrequenzablation identifiziert. Die Ergebnisse nach SBRT und sublobärer Resektion erscheinen auf aktueller Datenbasis ebenbürtig. Die SBRT ist die Methode der Wahl, wenn Patienten einen operativen Eingriff in Form der Lappenresektion ablehnen.

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.

Combination of Dose Escalation with Technological Advances (Intensity-Modulated and Image-Guided Radiotherapy) Is Not Associated with Increased Morbidity for Patients with Prostate Cancer

Purpose:The aim was to evaluate treatment-related morbidity after intensity-modulated (IMRT) and image-guided (IGRT) radiotherapy with a total dose of 76 Gy in comparison to conventional conformal radiotherapy (3DCRT) up to 70.2–72 Gy for patients with prostate cancer.Patients and Methods:All patients were prospectively surveyed prior to, on the last day, as well as after a median time of 2 and 16 months after RT using a validated questionnaire (Expanded Prostate Cancer Index Composite). Criteria for the 78 matched pairs after IMRT vs. 3DCRT were patient age, use of antiandrogens, treatment volume (± whole pelvis), prognostic risk group, and urinary/bowel/sexual quality of life (QoL) before treatment.Results:QoL changes after dose-escalated IMRT were found to be similar to QoL changes after 3DCRT in all domains. Only sexual function scores more than 1 year after RT decreased slightly more after 3DCRT in comparison to IMRT (mean 9 vs. 6 points; p = 0.04), with erections firm enough for intercourse in 14% vs. 30% (p = 0.03). Painful bowel movements were reported more frequently after 3DCRT vs. IMRT 2 months after treatment (≥ once a day in 10% vs. 1%; p = 0.03), but a tendency for higher rectal bleeding rates was found after IMRT vs. 3DCRT more than 1 year after RT (≥ rarely in 20% vs. 9%; p = 0.06).Conclusion:Combination of dose escalation with technological advances (IMRT and IGRT) is not associated with increased morbidity for patients with prostate cancer.ZusammenfassungZiel:Ziel war die Analyse therapiebedingter Morbidität nach intensitätsmodulierter (IMRT) und bildgeführter (IGRT) Radiotherapie mit einer Gesamtdosis von 76 Gy im Vergleich zur konventionellen konformalen Radiotherapie (3DCRT) bis 70,2–72 Gy bei Patienten mit einem Prostatakarzinom.Patienten und Methoden:Alle Patienten wurden prospektiv vor Beginn, am letzten Tag, median 2 Monate und 16 Monate nach RT mittels eines validierten Fragebogens befragt (Expanded Prostate Cancer Index Composite). Kriterien für 78 gematchte Paare nach IMRT vs. 3DCRT waren das Patientenalter, der Einsatz eines Antiandrogens, Zielvolumen (± Becken), prognostische Risikogruppe und Lebensqualität (LQ) beim Wasserlassen/Stuhlgang/Sexualität vor der Behandlung.Ergebnisse:LQ-Veränderungen nach dosiseskalierter IMRT waren den LQ-Veränderungen nach 3DCRT in allen Domänen sehr ähnlich. Nur der Punktwert für die sexuelle Funktion fiel über ein Jahr nach der Behandlung nach 3DCRT etwas mehr als nach IMRT (durchschnittlich 9 vs. 6 Punkte; p = 0,04), mit ausreichender Erektion für Geschlechtsverkehr in 14% vs. 30% (p = 0,03). Schmerzhafter Stuhlgang wurde zwei Monate nach Therapie häufiger nach 3DCRT als nach IMRT berichtet (≥ 1-mal täglich in 10% vs. 1%; p = 0,03); jedoch fand sich über ein Jahr nach RT die Tendenz zu einer häufigeren Rate rektaler Blutungen nach IMRT als nach 3DCRT (≥ selten in 20% vs. 9%; p = 0,06).Schlussfolgerung:Die Verknüpfung einer Dosiseskalation mit technologischen Fortschritten (IMRT und IGRT) ist bei Patienten mit einem Prostatakarzinom nicht mit erhöhter Morbidität assoziiert.

Applicability of the linear-quadratic formalism for modeling local tumor control probability in high dose per fraction stereotactic body radiotherapy for early stage non-small cell lung cancer.

BACKGROUND AND PURPOSE To compare the linear-quadratic (LQ) and the LQ-L formalism (linear cell survival curve beyond a threshold dose dT) for modeling local tumor control probability (TCP) in stereotactic body radiotherapy (SBRT) for stage I non-small cell lung cancer (NSCLC). MATERIALS AND METHODS This study is based on 395 patients from 13 German and Austrian centers treated with SBRT for stage I NSCLC. The median number of SBRT fractions was 3 (range 1-8) and median single fraction dose was 12.5 Gy (2.9-33 Gy); dose was prescribed to the median 65% PTV encompassing isodose (60-100%). Assuming an α/β-value of 10 Gy, we modeled TCP as a sigmoid-shaped function of the biologically effective dose (BED). Models were compared using maximum likelihood ratio tests as well as Bayes factors (BFs). RESULTS There was strong evidence for a dose-response relationship in the total patient cohort (BFs>20), which was lacking in single-fraction SBRT (BFs<3). Using the PTV encompassing dose or maximum (isocentric) dose, our data indicated a LQ-L transition dose (dT) at 11 Gy (68% CI 8-14 Gy) or 22 Gy (14-42 Gy), respectively. However, the fit of the LQ-L models was not significantly better than a fit without the dT parameter (p=0.07, BF=2.1 and p=0.86, BF=0.8, respectively). Generally, isocentric doses resulted in much better dose-response relationships than PTV encompassing doses (BFs>20). CONCLUSION Our data suggest accurate modeling of local tumor control in fractionated SBRT for stage I NSCLC with the traditional LQ formalism.

Definition of stereotactic body radiotherapy: principles and practice for the treatment of stage I non-small cell lung cancer.

This report from the Stereotactic Radiotherapy Working Group of the German Society of Radiation Oncology (Deutschen Gesellschaft für Radioonkologie, DEGRO) provides a definition of stereotactic body radiotherapy (SBRT) that agrees with that of other international societies. SBRT is defined as a method of external beam radiotherapy (EBRT) that accurately delivers a high irradiation dose to an extracranial target in one or few treatment fractions. Detailed recommendations concerning the principles and practice of SBRT for early stage non-small cell lung cancer (NSCLC) are given. These cover the entire treatment process; from patient selection, staging, treatment planning and delivery to follow-up. SBRT was identified as the method of choice when compared to best supportive care (BSC), conventionally fractionated radiotherapy and radiofrequency ablation. Based on current evidence, SBRT appears to be on a par with sublobar resection and is an effective treatment option in operable patients who refuse lobectomy.ZusammenfassungDie Arbeitsgruppe „Stereotaktische Radiotherapie“ der Deutschen Gesellschaft für Radioonkologie (DEGRO) erarbeitete eine Definition der Körperstereotaxie (SBRT), die sich an vorhandene internationale Definitionen anlehnt: Die SBRT ist eine Form der perkutanen Strahlentherapie, die mit hoher Präzision eine hohe Bestrahlungsdosis in einer oder wenigen Bestrahlungsfraktionen in einem extrakraniellen Zielvolumen appliziert. Zur Praxis der SBRT beim nichtkleinzelligen Bronchialkarzinom (NSCLC) im frühen Stadium werden detaillierte Empfehlungen gegeben, die den gesamten Ablauf der Behandlung von der Indikationsstellung, Staging, Behandlungsplanung und Applikation sowie Nachsorge umfassen. Die Körperstereotaxie wurde als Methode der Wahl im Vergleich zu Best Supportive Care, zur konventionell fraktionierten Strahlentherapie sowie zur Radiofrequenzablation identifiziert. Die Ergebnisse nach SBRT und sublobärer Resektion erscheinen auf aktueller Datenbasis ebenbürtig. Die SBRT ist die Methode der Wahl, wenn Patienten einen operativen Eingriff in Form der Lappenresektion ablehnen.