Michael Kopp

Local Recurrence Rates in Breast Cancer Patients Treated with Intraoperative Electron-Boost Radiotherapy Versus Postoperative External-Beam Electron-Boost Irradiation A Sequential Intervention Study

Background and Purpose:The purpose of this sequential intervention study was to determine the rate of local recurrences and the rate of distant metastases in patients with invasive breast cancer who had been treated with breast-conserving surgery and postoperative radiation therapy to the whole breast either with postoperative electron boost in group 1 or with intraoperative electron boost (IORT) in group 2.Patients and Methods:After breast-conserving surgery, 378 women with invasive breast cancer of tumor sizes T1 and T2 received 51–56.1 Gy of postoperative radiation therapy to the whole breast in 1.7-Gy fractions. 188 of those patients additionally received a postoperative electron boost of 12 Gy in group 1 from January 1996 to October 1998. Consecutively, from October 1998 to March 2001, 190 patients received intraoperative electron-boost radiotherapy of 9 Gy to the tumor bed in group 2. The groups were comparable with regard to age, menopausal status, tumor size, grading, and nodal status. All statistical tests were twosided.Results:During a median follow-up period of 55.3 months in group 1 and 25.8 months in group 2, local recurrences were observed in eight of 188 patients (4.3%) in group 1, and no local recurrence was seen in group 2 (p = 0.082). Distant metastases occurred in 15 of the 188 patients (7.9%) in group 1 and in two of the 190 patients (1.1%) in group 2 (p = 0.09). The 4-year actuarial rates of local recurrence were 4.3% (95% confidence interval, 1.8–8.2%) and 0.0% (95% confidence interval, 0.0–1.9%) and the 4-year actuarial rates of distant metastases were 7.9% (95% confidence interval, 4.5–12.8%) and 1.1% (95% confidence interval, 0.1–3.8%).Conclusion:Immediate IORT boost yielded excellent local control figures in this prospective investigation and appears to be superior to conventional postoperative boost in a short-term follow-up.Hintergrund und Ziel:Ziel dieser sequentiellen Interventionsstudie war die Bestimmung der Lokalrezidiv- und Fernmetastasenrate von Patientinnen mit invasivem Mammakarzinom, die mit brusterhaltender Operation und anschließender Bestrahlung der gesamten Brust, aber verschiedenen Boostbestrahlungen therapiert worden waren. Gruppe 1 erhielt eine postoperative Boostbestrahlung und Gruppe 2 eine intraoperative Radiotherapie (IORT) in Boostmodalität.Patienten und Methodik:Nach brusterhaltender Operation erhielten 378 Patientinnen mit invasivem Mammakarzinom mit T1- und T2-Tumoren eine postoperative Bestrahlung der gesamten Brust von 51–56.1 Gy in 1.7-Gy-Fraktionen. Von Januar 1996 bis Oktober 1998 bekamen 188 Patientinnen in Gruppe 1 postoperativ zusätzlich eine Elektronenboostbestrahlung von 12 Gy. Von Oktober 1998 bis März 2001 erhielten 190 Patientinnen in Gruppe 2 eine intraoperative Elektronenboostbestrahlung von 9 Gy direkt auf das Tumorbett. Beide Gruppen waren bezüglich Alter, Menopausenstatus, Tumorgröße, Grading und Nodalstatus vergleichbar. Die statistische Analyse erfolgte zweiseitig.Ergebnisse:Nach einer mittleren Nachbeobachtungszeit von 55,3 Monaten in Gruppe 1 und 25,8 Monaten in Gruppe 2 traten bei acht der 188 Patientinnen in Gruppe 1 (4,3%) Lokalrezidive auf, während es in Gruppe 2 zu keinem Lokalrezidiv kam (p = 0.082). Fernmetastasen ereigneten sich bei 15 der 188 Patientinnen (7,9%) in Gruppe 1 und zwei der 190 Patientinnen (1,1%) in Gruppe 2 (p = 0.09). Die 4-Jahres-Raten für Lokalrezidive betrugen 4,3% (95%-Konfidenzintervall 1,8–8,2%) und 0% (95%- Konfidenzintervall 0–1,9%) und die 4-Jahres-Raten für Fernmetastasen 7,9% (95%-Konfidenzintervall 4.5–12,8%) und 1,1% (95%-Konfidenzintervall 0,1–3,8%).Schlussfolgerung:Die intraoperative Boostbestrahlung zeigt exzellente Ergebnisse bezüglich der Lokalrezidivrate und scheint der postoperativen Boostbestrahlung in der Kurzzeitnachbeobachtung überlegen zu sein.

Local recurrence rates in breast cancer patients treated with intraoperative electron-boost radiotherapy versus postoperative external-beam electron-boost irradiation

Background and Purpose:The purpose of this sequential intervention study was to determine the rate of local recurrences and the rate of distant metastases in patients with invasive breast cancer who had been treated with breast-conserving surgery and postoperative radiation therapy to the whole breast either with postoperative electron boost in group 1 or with intraoperative electron boost (IORT) in group 2.Patients and Methods:After breast-conserving surgery, 378 women with invasive breast cancer of tumor sizes T1 and T2 received 51–56.1 Gy of postoperative radiation therapy to the whole breast in 1.7-Gy fractions. 188 of those patients additionally received a postoperative electron boost of 12 Gy in group 1 from January 1996 to October 1998. Consecutively, from October 1998 to March 2001, 190 patients received intraoperative electron-boost radiotherapy of 9 Gy to the tumor bed in group 2. The groups were comparable with regard to age, menopausal status, tumor size, grading, and nodal status. All statistical tests were twosided.Results:During a median follow-up period of 55.3 months in group 1 and 25.8 months in group 2, local recurrences were observed in eight of 188 patients (4.3%) in group 1, and no local recurrence was seen in group 2 (p = 0.082). Distant metastases occurred in 15 of the 188 patients (7.9%) in group 1 and in two of the 190 patients (1.1%) in group 2 (p = 0.09). The 4-year actuarial rates of local recurrence were 4.3% (95% confidence interval, 1.8–8.2%) and 0.0% (95% confidence interval, 0.0–1.9%) and the 4-year actuarial rates of distant metastases were 7.9% (95% confidence interval, 4.5–12.8%) and 1.1% (95% confidence interval, 0.1–3.8%).Conclusion:Immediate IORT boost yielded excellent local control figures in this prospective investigation and appears to be superior to conventional postoperative boost in a short-term follow-up.Hintergrund und Ziel:Ziel dieser sequentiellen Interventionsstudie war die Bestimmung der Lokalrezidiv- und Fernmetastasenrate von Patientinnen mit invasivem Mammakarzinom, die mit brusterhaltender Operation und anschließender Bestrahlung der gesamten Brust, aber verschiedenen Boostbestrahlungen therapiert worden waren. Gruppe 1 erhielt eine postoperative Boostbestrahlung und Gruppe 2 eine intraoperative Radiotherapie (IORT) in Boostmodalität.Patienten und Methodik:Nach brusterhaltender Operation erhielten 378 Patientinnen mit invasivem Mammakarzinom mit T1- und T2-Tumoren eine postoperative Bestrahlung der gesamten Brust von 51–56.1 Gy in 1.7-Gy-Fraktionen. Von Januar 1996 bis Oktober 1998 bekamen 188 Patientinnen in Gruppe 1 postoperativ zusätzlich eine Elektronenboostbestrahlung von 12 Gy. Von Oktober 1998 bis März 2001 erhielten 190 Patientinnen in Gruppe 2 eine intraoperative Elektronenboostbestrahlung von 9 Gy direkt auf das Tumorbett. Beide Gruppen waren bezüglich Alter, Menopausenstatus, Tumorgröße, Grading und Nodalstatus vergleichbar. Die statistische Analyse erfolgte zweiseitig.Ergebnisse:Nach einer mittleren Nachbeobachtungszeit von 55,3 Monaten in Gruppe 1 und 25,8 Monaten in Gruppe 2 traten bei acht der 188 Patientinnen in Gruppe 1 (4,3%) Lokalrezidive auf, während es in Gruppe 2 zu keinem Lokalrezidiv kam (p = 0.082). Fernmetastasen ereigneten sich bei 15 der 188 Patientinnen (7,9%) in Gruppe 1 und zwei der 190 Patientinnen (1,1%) in Gruppe 2 (p = 0.09). Die 4-Jahres-Raten für Lokalrezidive betrugen 4,3% (95%-Konfidenzintervall 1,8–8,2%) und 0% (95%- Konfidenzintervall 0–1,9%) und die 4-Jahres-Raten für Fernmetastasen 7,9% (95%-Konfidenzintervall 4.5–12,8%) und 1,1% (95%-Konfidenzintervall 0,1–3,8%).Schlussfolgerung:Die intraoperative Boostbestrahlung zeigt exzellente Ergebnisse bezüglich der Lokalrezidivrate und scheint der postoperativen Boostbestrahlung in der Kurzzeitnachbeobachtung überlegen zu sein.

A Dosimetric Comparison of IORT Techniques in Limited-Stage Breast Cancer

Background and Purpose:For intraoperative radiotherapy (IORT) during breast-conserving treatment four different techniques have been addressed: interstitial brachytherapy, an inflatable balloon with a central high-dose-rate source (MammoSite), a miniature orthovolt system (Intrabeam), and linac-based electron radiotherapy (IOERT). The dosimetric properties of these methods are compared.Material and Methods:Planning target volumes (PTVs) of the same size but of different shapes are assumed, corresponding to the technique’s specific situs. Dose distributions for the PTVs and for surrounding tissues are demonstrated by dose-volume histograms and a list of physical parameters. A dose inhomogeneity index (DII) is introduced to describe the deviation of a delivered from the prescribed dose, reaching its minimal value 0 in case of perfect homogeneity.Results:In terms of DII, IOERT reaches the lowest value followed by the MammoSite, the Intrabeam and interstitial implants. The surrounding tissues receive the smallest average dose with IOERT, closely followed by the orthovolt system.Conclusion:When comparing simplified geometric figures, IOERT delivers the most homogeneous dose distributions. However, in clinical reality PTVs often present asymmetric shapes instead of ideal geometries. Due to a strictly centric dose fall-off, any system with a round central applicator will have technical limits. During IOERT margin-directed applicator guidance is possible and interstitial brachytherapy allows for polygonal dose shaping. These techniques seem to be superior for asymmetric PTV irradiation.Hintergrund und Ziel:Für die intraoperative Radiotherapie (IORT) des konservativ operierten Mammakarzinoms sind vier Techniken in Gebrauch: die interstitielle Brachytherapie, ein aufblasbarer Ballon mit einer zentralen High-Dose-Rate-Quelle (Mammo-Site), ein Miniatur-Orthovoltsystem (Intrabeam) sowie Elektronen am Linac (IOERT). Die dosimetrischen Eigenschaften dieser Methoden werden verglichen.Material und Methodik:Für jede dieser Techniken werden Planungszielvolumina (PTVs) des gleichen Volumens, aber unterschiedlicher Form angenommen, die dem jeweiligen typischen Situs zum Zeitpunkt der Applikation entsprechen (Abbildung 1, Tabellen 1 und 2). Die Dosisverteilungen (Abbildung 2) inner- und außerhalb der PTVs werden mittels Dosis-Volumen-Histogrammen und einer Reihe von Parametern miteinander verglichen (Abbildung 3, Tabelle 3). Ein Dosisinhomogenitätsindex (DII) wird vorgestellt, der die Abweichung einer verabreichten von einer vorgeschriebenen Dosis beschreibt und im Fall einer perfekten Homogenität den Minimalwert 0 erreicht.Ergebnisse:In Bezug auf den DII erreicht die IOERT den niedrigsten Wert, gefolgt von MammoSite, dem Orthovoltsystem und den interstitiellen Implantaten. Das umgebende Gewebe erhält die geringste mittlere Dosis mittels IOERT, knapp gefolgt vom Intrabeam (Abbildung 3, Tabelle 3).Schlussfolgerung:Die IOERT zeigt die homogenste Dosisverteilung. In der klinischen Realität weisen PTVs aber häufig asymmetrische anstelle idealgeometrischer Formen auf. Durch den strikten zentralen Dosisabfall bestehen bei Systemen mit runden zentralen Applikatoren technische Limitationen. Während einer IOERT ist eine asymmetrische Applikatorführung möglich, die interstitielle Brachytherapie erlaubt eine polygonale Dosisformung, weshalb diese beiden Verfahren zur Erfassung asymmetrischer PTVs überlegen scheinen (Abbildung 4).

The Salzburg concept of intraoperative radiotherapy for breast cancer: results and considerations.

Aim of this study is to show that ipsilateral breast tumor recurrence (IBTR) after breast conserving surgery can be reduced by proper surgery and modern radiotherapy techniques. Three hundred and seventy eight women with stage I or II breast cancer had breast conserving surgery and received 51–56.1 Gy of postoperative radiation to the whole breast in 1.7 Gy fractions, but patients received different boost strategies. Group 1 (n = 188) received electron boost radiation of 12 Gy subsequent to the irradiation to the whole breast, group 2 (n = 190) received intraoperative electron boost radiation of 9 Gy directly to the tumor bed, followed by whole breast irradiation. After a median follow up period of 81.0 months in group 1 and a median follow up period of 51.1 months in group 2, 12 IBTRs (6.4%) could be observed in group 1 and no IBTR could be observed in group 2 (0.0%). The 5‐year actuarial rates of IBTR were 4.3% (95% CI, 1.9–8.3%) and 0.0% (95% CI, 0.0–1.9%), respectively (p = 0.0018). The 5‐year actuarial rates of distant recurrence were 8.6% (95% CI, 4.9–13.5%) and 4.2% (95% CI, 1.8–8.2%), respectively (p = 0.08). The 5 year disease‐free survival rates were 90.9% (95% CI, 85.8–94.7%) in group 1 and 95.8% (95% CI, 91.8–98.2%) in group 2 (p = 0.064). Immediate IORT‐boost and whole breast irradiation yields excellent local control at 5 years, and was associated with a statistically significant decreased rate of IBTR compared with a similar cohort of patients treated with whole breast irradiation and conventional electron boost.

“Augmented Reality” in Conventional Simulation by Projection of 3-D Structures into 2-D Images

Background and Purpose:In this study, a new method is introduced, which allows the overlay of three-dimensional structures, that have been delineated on transverse slices, onto the fluoroscopy from conventional simulators in real time.Patients and Methods:Setup deviations between volumetric imaging and simulation were visualized, measured and corrected for 701 patient isocenters.Results:Comparing the accuracy to mere virtual simulation lacking additional X-ray imaging, a clear benefit of the new method could be shown. On average, virtual prostate simulations had to be corrected by 0.48 cm (standard deviation [SD] 0.38), and those of the breast by 0.67 cm (SD 0.66).Conclusion:The presented method provides an easy way to determine entity-specific safety margins related to patient setup errors upon registration of bony anatomy (prostate 0.9 cm for 90% of cases, breast 1.3 cm). The important role of planar X-ray imaging was clearly demonstrated. The innovation can also be applied to adaptive image-guided radiotherapy (IGRT) protocols.Hintergrund und Ziel:Es wird ein Verfahren vorgestellt, das die Einblendung von dreidimensionalen Strukturen, die zuvor z.B. auf axialen Schnittbildern segmentiert wurden, in Durchleuchtungsaufnahmen am konventionellen Simulator in Echtzeit erlaubt.Patienten und Methodik:Mit dieser Technologie wurden an 701 Patientenisozentren Lagerungsunterschiede zwischen der Schnittbildgebung und der Simulation visualisiert, vermessen und korrigiert.Ergebnisse:Im Vergleich der Genauigkeit mit der rein virtuellen Simulation, bei der auf Röntgenbildgebung verzichtet wird, zeigte sich eine deutliche Überlegenheit der neuen Methode. Im Mittel wurden virtuell simulierte Prostatabestrahlungen um 0,48 cm (Standardabweichung [SD] 0,38) und jene der Mamma um 0,67 cm (SD 0,66) korrigiert.Schlussfolgerung:Das vorgestellte Verfahren erlaubt die einfache Bestimmung entitätsspezifischer Sicherheitsränder für Lagerungsungenauigkeiten von knöchernen Strukturen (Prostatabestrahlung 0,9 cm für 90% der Fälle, Mamma 1,3 cm; Tabelle 2). Die Bedeutung von planarer kV-Bildgebung konnte gezeigt werden. Das innovative Verfahren ist auch im Rahmen von Protokollen zur adaptiven, bildgeführten Radiotherapie (IGRT) einsetzbar.

Augmented reality in conventional simulation by projection of 3-D structures into 2-D images: a comparison with virtual methods.

Background and Purpose:In this study, a new method is introduced, which allows the overlay of three-dimensional structures, that have been delineated on transverse slices, onto the fluoroscopy from conventional simulators in real time.Patients and Methods:Setup deviations between volumetric imaging and simulation were visualized, measured and corrected for 701 patient isocenters.Results:Comparing the accuracy to mere virtual simulation lacking additional X-ray imaging, a clear benefit of the new method could be shown. On average, virtual prostate simulations had to be corrected by 0.48 cm (standard deviation [SD] 0.38), and those of the breast by 0.67 cm (SD 0.66).Conclusion:The presented method provides an easy way to determine entity-specific safety margins related to patient setup errors upon registration of bony anatomy (prostate 0.9 cm for 90% of cases, breast 1.3 cm). The important role of planar X-ray imaging was clearly demonstrated. The innovation can also be applied to adaptive image-guided radiotherapy (IGRT) protocols.Hintergrund und Ziel:Es wird ein Verfahren vorgestellt, das die Einblendung von dreidimensionalen Strukturen, die zuvor z.B. auf axialen Schnittbildern segmentiert wurden, in Durchleuchtungsaufnahmen am konventionellen Simulator in Echtzeit erlaubt.Patienten und Methodik:Mit dieser Technologie wurden an 701 Patientenisozentren Lagerungsunterschiede zwischen der Schnittbildgebung und der Simulation visualisiert, vermessen und korrigiert.Ergebnisse:Im Vergleich der Genauigkeit mit der rein virtuellen Simulation, bei der auf Röntgenbildgebung verzichtet wird, zeigte sich eine deutliche Überlegenheit der neuen Methode. Im Mittel wurden virtuell simulierte Prostatabestrahlungen um 0,48 cm (Standardabweichung [SD] 0,38) und jene der Mamma um 0,67 cm (SD 0,66) korrigiert.Schlussfolgerung:Das vorgestellte Verfahren erlaubt die einfache Bestimmung entitätsspezifischer Sicherheitsränder für Lagerungsungenauigkeiten von knöchernen Strukturen (Prostatabestrahlung 0,9 cm für 90% der Fälle, Mamma 1,3 cm; Tabelle 2). Die Bedeutung von planarer kV-Bildgebung konnte gezeigt werden. Das innovative Verfahren ist auch im Rahmen von Protokollen zur adaptiven, bildgeführten Radiotherapie (IGRT) einsetzbar.

Intraoperative radiotherapy for early breast cancer

Jayant Vaidya and colleagues (July 10, p 91) suggest that a single dose of targeted intraoperative radiotherapy (TARGIT) should be considered as an alternative to external-beam radiotherapy delivered over several weeks for selected patients with breast cancer. We consider the results of this trial preliminary and immature since the follow-up is much too short to draw any conclusions about local recurrence rates. The fi nding in this trial that most local recurrences occur in years 2 and 3 do not imply that local recurrences after this time will not occur. When using an orthovoltage technique with a very low-dose penetration to a depth of 1 cm, the rate of in-breast recurrences has to be observed extremely carefully in the long term. The median time to true local recurrences is somewhere between 40 months and 65 months, and out-quadrant relapses occur later than that. Furthermore, the Kaplan-Meier plots in fi gure 4 show that, of 2232 patients at risk, only 420 (19%) completed 4-year follow-up (212 in the TARGIT group). Of these 212 patients, only 86% received intra operative radio therapy alone, meaning that about 14% received external-beam radiotherapy as well. 65% of patients also received endocrine treatment, which is known to be associated with a signifi cant decrease or at least delay in the rate of local recurrences, which become apparent after more than 5 years’ follow-up. Another area of concern is the postpathology stratum: 672 patients had a postpathology entry to the trial, meaning that about 336 patients allocated to TARGIT (most of the Danish and the Australian patients) were referred for a second surgical procedure. In those cases, targeted intraoperative radiotherapy was not an intraoperative treatment in the classic sense—a second surgical procedure had to be done for no reason other than the application of the radiation therapy. Overall, we advise against the use of targeted intraoperative radiotherapy as a single shot outside a clinical trial until the long-term follow-up data for non-inferiority are available.

External beam radiation for prevention of intimal hyperplasia in peripheral arterial bypasses

PURPOSE Neointimal hyperplasia is one of the limiting factors in infrainguinal prosthetic vascular grafting. We conducted a pilot study to assess the possible role of radiotherapy for the prevention of this proliferating cellular process. METHODS AND MATERIALS Ten patients (7 men, 3 women; median age: 73 years) suffering from critical leg ischemia were treated by infrainguinal revascularization using 6-mm polytetrafluoroethylene. Postoperative radiation therapy of the anastomotic sites started within 24 h. A dose of 20.4 Gy was delivered in 12 fractions in 2.5 weeks by external beam radiation with electrons. The target volume was defined as the clip-marked anastomotic region plus a 1.5-cm safety margin in each direction. RESULTS Radiation therapy was technically feasible in all cases without radiation-related side effects. In one patient, radiotherapy had to be terminated prematurely, because of a hematoma at the distal anastomotic site with consequent skin necrosis. One patient developed an occlusion of a suprainguinal graft without anastomotic stenosis after 9 months; 2 other grafts occluded at 12-month intervals. At a median follow-up of 16 months, the remaining 6 patients had no signs of restenosis. CONCLUSIONS The restenosis rate of peripheral vascular grafts after external beam radiation was lower than expected without additional treatment. The value of this approach will now be determined in a randomized prospective trial.

Preliminary Observations on the Need for Control Angiography after Peripheral Endovascular Brachytherapy Using a Centering Balloon

Purpose: To examine the need for completion angiography after endovascular femoropopliteal brachytherapy using a centering catheter. Methods: Nine consecutive patients (7 men; mean age 68 years, range 53–79) were enrolled in a double-blinded multicenter randomized trial of endovascular brachytherapy after femoropopliteal balloon angioplasty. All patients underwent postdilation angiography, after which the centering catheter was placed in the dilated segment. The patients were randomized and transferred to the radiotherapy unit; the centering catheter was inflated only in patients randomized to receive brachytherapy (18 Gy of γ radiation delivered to the target site 2 mm from an iridium-192 source axis). Because the local ethics committee required angiography after any interventional procedure (not stipulated in the study protocol), our patients were taken back to the angiosuite for angiography. Results: There were no complications of angioplasty or centering catheter introduction. In the 5 patients randomized to brachytherapy, the median inflation time of the centering catheter was 12.1 minutes (range 9.1–13.3). The completion angiogram following brachytherapy showed peripheral embolization in 2 patients and lesion recoil that required redilation in another; all the complications were confined to the treatment group. Conclusions: Three of 5 patients who received brachytherapy via a centering catheter demonstrated sequelae on postradiation angiography. Therefore, as in any other peripheral vascular intervention, completion angiography after brachytherapy seems to be essential in preventing delayed diagnosis of procedural complications.

Intraoperative Electron Radiotherapy (IOERT) in the Treatment of Primary Breast Cancer

IOERT (intraoperative electron radiotherapy) in breast cancer is used either as a boost (10-12 Gy) followed by whole breast irradiation (WBI) or as full-dose partial breast irradiation (PBI, 20-24 Gy) during breast-conserving surgery. IOERT has the longest evidence of all IORT techniques. When administered as a boost, excellent low local recurrence rates were observed in long-term follow-up >5 years. Even in high-risk groups like triple-negative or locally advanced breast cancers, IOERT contributes to long-term local control rates of more than 90%. For selected low-risk groups, IOERT as PBI with 21 Gy seems to be a viable treatment alternative to standard WBI. IOERT has been shown to be advantageous for several reasons: Geographic misses are avoided due to direct visualization of the tumor bed; thus, a high single dose is delivered with utmost precision to small volumes, completely sparing the skin and ensuring good long-term cosmetic outcome. Furthermore, high single doses seem to induce biological mechanisms with verifiable antitumor capability in in-vitro cell-line studies. In addition, IOERT markedly shortens the overall treatment time both in combination with (now mostly hypofractionated) WBI or as a PBI in selected low-risk constellations.