László Mangel

Electron and high-dose-rate brachytherapy boost in the conservative treatment of stage I-II breast cancer: First results of the randomized Budapest boost trial

Background and Aims: To evaluate the effect of electron and high-dose-rate brachytherapy (HDR BT) boost on local tumor control (LTC), side effects and cosmesis after breast-conserving surgery (BCS) in a prospective randomized study. Patients and Methods: 207 women with stage I–II breast cancer who underwent BCS were treated by 50 Gy irradiation to the whole breast and then randomly assigned to receive either a boost to the tumor bed (n = 104) or no further radiotherapy (n = 103). Boost treatments consisted of either 16 Gy electron irradiation (n = 52) or 12–14,25 Gy HDR BT (n = 52). Breast cancer-related events, side effects, and cosmetic results were assessed. Results: At a median follow-up of 5.3 years, the crude rate of local recurrences was 6.7% (7/104) with and 15.5% (16/103) without boost. The 5-year probability of LTC, relapse-free survival (RFS), and cancer-specific survival (CSS) was 92.7% vs. 84.9% (p = 0.049), 76.6% vs. 66.2% (p = 0.044), and 90.4% vs. 82.1% (p = 0.053), respectively. There was no significant difference in LTC between patients treated with electron or HDR BT boost (94.2% vs. 91.4%; p = 0.74). On multivariate analysis, patient age < 40 years (RR: 4.53), positive margin status (RR: 4.17), and high mitotic activity index (RR: 3.60) were found to be significant risk factors for local recurrence. The incidence of grade 2–3 side effects was higher in the boost arm (17.3% vs. 7.8%; p = 0.03). However, the rate of excellent/good cosmetic results was similar for the two arms (85.6% vs 91.3%; p = 0.14). Cosmesis was rated as excellent/good in 88.5% of patients treated with HDR BT and 82.7% of patients with electron boost (p = 0.29). Conclusions: Boost dose significantly improves LTC and RFS in patients treated with BCS and radiotherapy. In spite of the higher incidence of late side effects in the boost arm, boost dose is strongly recommended for patients at high risk for local recurrence. Positive or close margin status, high mitotic activity index, and young patient age should be viewed as absolute indications for tumor bed boost. LTC and cosmesis are excellent and similar to patients boosted with either HDR BT or electrons.Hintergrund und Ziel: In einer prospektiv randomisierten Studie werden die Effekte eines Elektronenboosts und eines High-Dose-Rate-Brachytherapie-(HDR-BT-)Boosts bezüglich lokaler Tumorkontrolle (LTC), Nebenwirkungen und kosmetischer Ergebnisse nach brusterhaltender Operation (BCS) evaluiert. Patienten und Methodik: 207 Patientinnen mit Brustkarzinomen im Stadium I–II wurden einer BCS zugeführt. Postoperativ erfolgte eine perkutane Radiatio der gesamten Brust bis 50 Gy. Daran schloss sich willkürlich entweder eine Boostbestrahlung des Tumorbetts (n = 104) oder keine weitere Radiatio (n = 103) an. Die Boostbestrahlung erfolgte perkutan mit 16 Gy Elektronen (n = 52) oder in Form einer HDR-BT mit 12–14,25 By (n = 52). Untersucht wurden LTC, Nebenwirkungen und kosmetische Ergebnisse. Ergebnisse: Die mediane Nachbeobachtungszeit betrug 5,3 Jahre. Die Lokalrezidivrate lag mit Boostbestrahlung bei 6,7% (7/104), ohne Boost bei 15,5% (16/103). Die 5-Jahres-Überlebensrate für LTC, für die rezidivfreie Überlebenszeit (RFS) und für die krebsspezifische Überlebenszeit (CSS) betrugen 92,7% vs. 84,9% (p = 0,049), 76,6% vs. 66,2% (p = 0,044) und 90,4% vs. 82,1% (p = 0,053). Bezüglich der LTC bestand kein signifikanter Unterschied zwischen Patienten, die mit einem Elektronen- oder HDR-BT-Boost behandelt wurden (94,2% vs. 91,4

CT-Image Based Conformal Brachytherapy of Breast Cancer The Significance of Semi-3-D and 3-D Treatment Planning

; p = 0,74). Die multivariate Analyse zeigte, dass Faktoren wie Patientenalter > 40 Jahre (RR: 4,53), positive Resektionsränder (RR: 4,17) und ein hoher Mitoseaktivitätsindex (RR: 3.60) das Risiko eines lokalen Rezidivs signifikant erhöhen. Die Inzidenz von Nebenwirkungen Grad 2–3 war im Boost-Arm höher (17,3% vs. 7,8%; p = 0,03). Allerdings waren die sehr guten kosmetischen Ergebnisse in beiden Armen gleich (85,6% bs. 91,3%, p = 0,14). Sehr gute kosmetische Ergebnisse wurden bei 88,5% der Patientinnen mit HDR-BT-Boost und 82,7% der Patientinnen mit Elektronenboost erreicht (p = 0,29). Schlussfolgerungen: Die Boost-Dosis verbessert signifikant LTC und RFS bei Patientinnen, die einer BCS und anschließender Radiatio zugeführt wurden. Obwohl eine höhere Inzidenz an Spätnebenwirkungen im Boost-Arm gefunden wurde, wird eine Boost-Dosis für Patientinnen mit hohem Risiko für die Entwicklung eines Lokalrezidivs empfohlen. Unserer Meinung nach ist bei Faktoren wie positive Schnittränder, schmaler Sicherheitssaum, hoher Mitoseaktivitätsindex und niedriges Patientenalter, die absolute Indikation zur Boost-Bestrahlung des Tumorbetts gegeben. LTC und die kosmetischen Ergebnisse sind sehr gut und unterscheiden sich nicht in Bezug auf Elektronenboost oder HDR-BT-Boost.

Role of early radiotherapy in the treatment of supratentorial WHO Grade II astrocytomas: long-term results of 97 patients.

Purpose: To compare the conventional 2-D, the simulator-guided semi-3-D and the recently developed CT-guided 3-D brachytherapy treatment planning in the interstitial radiotherapy of breast cancer. Patients and Methods: In 103 patients with T1-2, N0-1 breast cancer the tumor bed was clipped during breast conserving surgery. Fifty-two of them received boost brachytherapy after 46 to 50 Gy teletherapy and 51 patients were treated with brachytherapy alone via flexible implant tubes. Single, double and triple plane implant was used in 6, 89 and 8 cases, respectively. The dose of boost brachytherapy and sole brachytherapy prescribed to dose reference points was 3 times, 4.75 Gy and 7 times 5.2 Gy, respectively. The positions of dose reference points varied according to the level (2-D, semi-3-D and 3-D) of treatment planning performed. The treatment planning was based on the 3-D reconstruction of the surgical clips, implant tubes and skin points. In all cases the implantations were planned with a semi-3-D technique aided by simulator. In 10 cases a recently developed CT-guided 3-D planning system was used. The semi-3-D and 3-D treatment plans were compared to hypothetical 2-D plans using dose-volume histograms and dose non-uniformity ratios. The values of mean central dose, mean skin dose, minimal clip dose, proportion of underdosaged clips and mean target surface dose were evaluated. The accuracy of tumor bed localization and the conformity of planning target volume and treated volume were also analyzed in each technique. Results: With the help of conformal semi-3-D and 3-D brachytherapy planing we could define reference dose points, active source positions and dwell times individually. This technique decreased the mean skin dose with 22.2% and reduced the possibility of geographical miss. We could achieve the best conformity between the planning target volume and the treated volume with the CT-image based 3-D treatment planning, at the cost of worse dose homogeneity. The mean treated volume was reduced by 25.1% with semi-3-D planning, however, it was increased by 16.2% with 3-D planning, compared to the 2-D planning. Conclusion: The application of clips into the tumor bed and the conformal (semi-3-D and 3-d) planning help to avoid geographical miss. CT is suitable for 3-D brachytherapy planning. Better local control with less side effects might be achieved with these new techniques. Conformal 3-D brachytherapy calls for new treatment planning concepts, taking the irregular 3-D shape of the target volume into account. The routine clinical application of image-based 3-D brachytherapy is a real aim in the very close future.Ziel: Zu vergleichen sind die konventionelle 2D-, die simulatorgestützte Semi-3D- und das heutzutage entwickelte CT-geplante 3D-Brachytherapie-Planungssystem bei der interstitiellen Radiotherapie des Mammakarzinoms. Patienten und Methode: Bei 103 Patientinnen mit Mammakarzinom der Stadien T1-2, N0-1 wurde das Tumorbett mit Klips während der brusterhaltenden Operation markiert. 52/103 Patientinnen haben einen Brachytherapie-Boost nach 46 bis 50 Gy Teletherapie bekommen, und 51 von ihnen wurden mit alleiniger Brachytherapie mit plastischen Kathetern behandelt. Die Dosen des Brachytherapie-Boosts und der alleinigen Brachytherapie (bezogen auf die Dosisreferenzpunkte) waren 3mal 4,75 Gy und 7mal 5,2 Gy. Die Positionen der Dosisreferenzpunkte änderten sich in Abhängigkeit von der verwendeten Bestrahlungsplanung (2D, Semi-3D und 3D). Die Implantation wurde in einer, zwei und drei Ebenen in sechs, 89 und acht Fällen appliziert. Die Behandlungsplanung gründete sich auf die 3D-Rekonstruktion der chirurgischen Klips, der Katheter und der Hautpunkte. In allen Fällen wurde die Implantation mit simulatorgestützter Semi-3D-Technik geplant. Bei zehn Patientinnen wurde ein CT-gestütztes 3D-Planungssystem angewendet. Die Semi-3D- und 3D-Bestrahlungspläne wurden mit den hypothetischen 2D-Plänen unter Verwendung des Dosis-Volumen-Histogramms und Dosis-Non-Uniformitäts-Verhältnisses verglichen. Die Werte der durchschnittlichen Zentraldosis, Hautdosis, minimaler Klipdosis, des Verhältnisses der unterdosierten Klips und der durchschnittlichen Dosis an der Oberfläche des Zielvolumens wurden berechnet. Die Genauigkeit der Lokalisation des Tumorbetts und die Konformität des Planungszielvolumens und des Bestrahlungsvolumen wurden bei allen Techniken analysiert. Ergebnisse: Mit Hilfe der konformellen Semi-3D- und 3D-Brachytherapie-Planung konnten wir die Referenzdosispunkte, die aktiven Quellenpositionen und Quellenstandzeiten definieren. Diese Technik verringerte die durchschnittliche Hautdosis um 22,2% und reduzierte die Möglichkeit des geographischen Fehlers. Die beste Konformität zwischen Zielvolumen und Bestrahlungsvolumen konnten wir mit der CT-gestützten 3D-Bestrahlungsplanung erreichen, allerdings auf Kosten einer schlechteren Dosishomogenität. Mit der Semi-3D-Planung reduzierte sich das durchschnittliche Bestrahlungsvolumen um 25,1%, mit der 3D-Planung wurde es, verglichen mit der 2D-Planung, um 16,2% erhöht. Schlußfolgerung: Klipmarkierung des Tumorbetts und die konformelle (Semi-3D- und 3D-) Planung Helfen, den geographischen Fehler zu verhindern. Das CT ist für die 3D-Brachytherapie-Planung geeignet. Mit dieser neuen Technik ist eine bessere lokale Kontrolle mit weniger Nebenwirkungen erreichbar. Die konformelle 3D-Brachytherapie braucht eine neue Bestrahlungskonzeption, die die irreguläre dreidimensionale Form des Zielvolumens berücksichtigt. Die Etablierung der CT-gestützten 3D-Brachytherapie in die klinische Routine ist ein erstrebenswertes Ziel.

Iodine-125 Brachytherapy of Brain Stem Tumors

AbstractObject: To determine principal prognostic factors and the effect of timing of radiotherapy (RT) on disease-specific survival (DSS) and progression-free survival (PFS) in WHO Grade II astrocytomas. Methods: Histologic slides of 166 consecutive patients with the original tissue diagnosis of low-grade, non-pilocytic astrocytoma were reviewed. One-hundred and six were selected where two additional certified neuropathologist agreed on the grading of WHO Grade II astrocytoma. In 97 out of 106 cases follow-up informations were available. Early postoperative RT was given to 36 out of 97 patients (37%). The two groups of patients (early vs. delayed RT) were well balanced in respect to extent of surgery and other main clinical prognostic factors. Median follow-up of surviving patients was 79 months. The 5- and 10-year PFS was 52.2% and 30.7% with early RT and 39.5% and 12.4% with delayed RT (p = 0.0388). In respect to DSS, there was no significant difference in the 5- and 10-year actuarial survival rate according to the timing of RT (60.5% and 26.5% vs. 66.6% and 23.7%; p = 0.7545). Age (p = 0.0145) and extent of surgery (p = 0.0473) were significant prognostic variables in respect to DSS. Subdividing the irradiated group based on the extent of surgery, early RT in the subtotal group significantly improved 5-year PFS (60.0% vs. 12.4%; p = 0.0036) and DSS (66.7% vs. 49.8%; p = 0.0389). However, postoperative RT had no influence on PFS (p = 0.6812) and DSS (p = 0.3987) in the group with extensive resection. Conclusion: Early postoperative RT in subtotally resected, Grade II astrocytomas significantly improves both progression-free and disease-specific survival. Early RT does not benefit patients with extensive resection, RT should be withheld in these patients untill progression.

Evaluation of Geometrically Optimized Single- and Double-plane Interstitial High Dose Rate Implants with Respect to Conformality and Homogeneity

Purpose:To report on iodine-125 (125I) interstitial irradiation in the treatment of brain stem tumors.Patients and Methods:Two patients with brain stem tumors were treated with CT- and image fusion-guided 125I stereotactic brachytherapy.Results:By March 2003, the patients had been followed up for 47 and 13 months, respectively. In case 1, the tumor volume was 1.98 cm3 on the control CT, indicating a 65.5% shrinkage as compared to a target volume of 5.73 cm3 at the time of brachytherapy. In case 2, shrinkage was more distinct. After irradiation, the cyst volume was 0.16 cm3 on the control MRI, indicating a 97.4% shrinkage as compared to a target volume of 6.05 cm3 at the time of brachytherapy, i. e., the metastasis had virtually disappeared.Conclusion:CT- and image fusion-guided 125I stereotactic brachytherapy can be performed during the biopsy session. The procedure can be well planned dosimetrically and is surgically precise.Ziel:Beschreibung der interstitiellen Jod-125-(125I-)Brachytherapie bei der Behandlung von Hirnstammtumoren.Patienten und Methodik:Bei zwei Patienten mit Hirnstammtumoren wurde eine durch CT und Fusionsbild gesteuerte interstitielle 125I-Brachytherapie durchgeführt.Ergebnisse:Bis März 2003 betrugen die Nachuntersuchungszeiten der beiden Patienten 47 bzw. 13 Monate. Im ersten Fall lag das Tumorvolumen auf dem Kontroll-CT bei 1,98 cm3, was eine Schrumpfung um 65,5% anzeigte. Im zweiten Fall fiel diese Änderung deutlicher aus. Das Kontroll-MRT ergab eine Schrumpfung von 97,4%, d. h., die Metastase war praktisch verschwunden.Schlussfolgerung:Die durch CT und Fusionsbild gesteuerte interstitielle 125I-Brachytherapie lässt sich dosimetrisch gut planen, und die Methode ist chirurgisch präzise.

Cost-effectiveness analysis of intensity-modulated radiation therapy with normal and hypofractionated schemes for the treatment of localised prostate cancer

The use of a stepping source in high dose rate brachytherapy supported with dwell-time optimization makes it possible to deviate from the classical dosimetry systems. Dose distributions of single- and double-plane implants were analysed for conformality and homogeneity at idealized target volumes. The Paris system was used for catheter positioning and target volume determination. Geometric optimization and individual dose prescription were applied. Volumetric indices and dose parameters were calculated at optimal active length, which was found to be equal to target volume length. The mean conformality, homogeneity, external volume and overdose volume indices were 0.78, 0.67, 0.22 and 0.13, respectively. The average minimum target and reference doses were 69% and 86%, respectively. Comparisons between the volumetric indices of geometrical optimized and non-optimized implants were also performed, and a significant difference was found regarding any index. The geometrical optimization resulted in superior conformality and slightly inferior homogeneity. At geometrically optimized implants, the active length can be reduced compared to non-optimized implants. Volumetric parameters and dose-volume histogram-based individual dose prescription are recommended for quantitative assessment of interstitial implants.

RESILIENCE: Phase III Randomized, Double-Blind Trial Comparing Sorafenib With Capecitabine Versus Placebo With Capecitabine in Locally Advanced or Metastatic HER2-Negative Breast Cancer

The aim of our analysis was to compare the cost-effectiveness of high-dose intensity-modulated radiation therapy (IMRT) and hypofractionated intensity-modulated radiation therapy (HF-IMRT) versus conventional dose three-dimensional radiation therapy (3DCRT) for the treatment of localised prostate cancer. A Markov model was constructed to calculate the incremental quality-adjusted life years and costs. Transition probabilities, adverse events and utilities were derived from relevant systematic reviews. Microcosting in a large university hospital was applied to calculate cost vectors. The expected mean lifetime cost of patients undergoing 3DCRT, IMRT and HF-IMRT were 7,160 euros, 6,831 euros and 6,019 euros respectively. The expected quality-adjusted life years (QALYs) were 5.753 for 3DCRT, 5.956 for IMRT and 5.957 for HF-IMRT. Compared to 3DCRT, both IMRT and HF-IMRT resulted in more health gains at a lower cost. It can be concluded that high-dose IMRT is not only cost-effective compared to the conventional dose 3DCRT but, when used with a hypofractionation scheme, it has great cost-saving potential for the public payer and may improve access to radiation therapy for patients.

Image fusion analysis of volumetric changes after interstitial low-dose-rate iodine-125 irradiation of supratentorial low-grade gliomas.

Micro‐Abstract A previous randomized phase II trial suggested that sorafenib might enhance the efficacy of capecitabine in patients with metastatic breast cancer. However, in this randomized, placebo‐controlled phase trial of 537 patients with advanced HER2‐negative breast cancer, we found that the combination of sorafenib with capecitabine did not improve progression‐free survival, overall survival, or overall response rate, but increased treatment‐related toxicities and discontinuations. Introduction: Sorafenib is a multikinase inhibitor with antiangiogenic/antiproliferative activity. In this randomized, double‐blind, placebo‐controlled phase III trial, we assessed first‐ or second‐line capecitabine with sorafenib or placebo in patients with locally advanced/metastatic HER2‐negative breast cancer resistant to a taxane and anthracycline and with known estrogen/progesterone receptor status. Patients and Methods: A total of 537 patients were randomized to capecitabine 1000 mg/m2 orally twice per day for days 1 to 14 every 21 days with oral sorafenib 600 mg/d or placebo. The primary end point was progression‐free survival (PFS). Patients were stratified according to hormone receptor status, previous chemotherapies for metastatic breast cancer, and geographic region. Results: Treatment with sorafenib with capecitabine, compared with capecitabine with placebo, did not prolong median PFS (5.5 vs. 5.4 months; hazard ratio [HR], 0.973; 95% confidence interval [CI], 0.779‐1.217; P = .811) or overall survival (OS; 18.9 vs. 20.3 months; HR, 1.195; 95% CI, 0.943‐1.513; P = .140); or enhance overall response rate (ORR; 13.5% vs. 15.5%; P = .515). Any grade toxicities (sorafenib vs. placebo) included palmar‐plantar erythrodysesthesia syndrome (PPES; 79.2% vs. 59.6%), diarrhea (47.3% vs. 37.8%), mucosal inflammation (15.4% vs. 6.7%), and hypertension (26.2% vs. 5.6%). Grade 3/4 toxicities included PPES (15.4% vs. 7.1%), diarrhea (4.2% vs. 6.4%), and vomiting (3.5% vs. 0.7%). Conclusion: The combination of sorafenib with capecitabine did not improve PFS, OS, or ORR in patients with HER2‐negative advanced breast cancer. Rates of Grade 3 toxicities were higher in the sorafenib arm. Graphical abstract: Compared with capecitabine with placebo, capecitabine with sorafenib did not significantly prolong progression‐free survival in patients with HER2‐negative advanced/metastatic breast cancer. Figure. No Caption available.

Conkiss: conformal kidneys sparing 3D noncoplanar radiotherapy treatment for pancreatic cancer as an alternative to IMRT.

Abstract Julow, J., Major, T., Mangel, L., Bajzik, L. and Viola, A. Image Fusion Analysis of Volumetric Changes after Interstitial Low-Dose-Rate Iodine-125 Irradiation of Supratentorial Low-Grade Gliomas. Radiat. Res. 167, 438–444 (2007). The aim of this study was to compare the volumes of tumor necrosis, reactive zone and edema with the three-dimensional dose distributions after brachytherapy treatments of gliomas. The investigation was performed an average of 14.2 months after low-dose-rate 125I interstitial irradiation of 25 inoperable low-grade gliomas. The prescribed dose was 50–60 Gy to the tumor surface. Dose planning and image fusion were performed with the BrainLab-Target 1.19 software. In the CT/ MRI images, the “triple ring” (tumor necrosis, reactive ring and edema) developing after the interstitial irradiation of the brain tumors was examined. The images with the triple ring were fused with the planning images, and the isodose curves were superimposed on them. The volumes of the three regions were measured. The average dose at the necrosis border was determined from the isodose distribution. For quantitative assessment of the dose distributions, the dose nonuniformity ratio (DNR), homogeneity index (HI), coverage index (CI) and conformal index (COIN) were calculated. The relative volumes of the different parts of the triple ring after the interstitial irradiation compared to the reference dose volume were the following: necrosis, 40.9%, reactive zone, 47.1%, and edema, 367%. The tumor necrosis developed at 79.1 Gy on average. The average DNR, HI, CI and COIN were 0.45, 0.24, 0.94 and 0.57, respectively. The image fusion analysis of the volume of tumor necrosis, reactive ring and edema caused by interstitial irradiation and their correlation with the dose distribution provide valuable information for patient follow-up, treatment options, and effects and side effects of radio therapy.

Az első onkológiai ellátás időfaktorának szerepe a daganatos betegségek túlélési mutatóiban. Irodalmi áttekintés

When treating pancreatic cancer using standard (ST) 3D conformal radiotherapy (3D-CRT) beam arrangements, the kidneys often receive a higher dose than their probable tolerance limit. Our aim was to elaborate a new planning method that--similarly to IMRT--effectively spares the kidneys without compromising the target coverage. Conformal kidneys sparing (CONKISS) 5-field, noncoplanar plans were compared with ST plans for 23 consecutive patients retrospectively. Optimal beam arrangements were used consisting of a left- and right-wedged beam-pair and an anteroposterior beam inclined in the caudal direction. The wedge direction determination (WEDDE) algorithm was developed to adjust the adequate direction of wedges. The aimed organs at risk (OARs) mean dose limits were: kidney <12 Gy, liver <25 Gy, small bowels <30 Gy, and spinal cord maximum <45 Gy. Conformity and homogeneity indexes with z-test were used to evaluate and compare the different planning approaches. The mean dose to the kidneys decreased significantly (p < 0.05): left kidney 7.7 vs. 10.7 Gy, right kidney 9.1 vs. 11.7 Gy. Meanwhile the mean dose to the liver increased significantly (18.1 vs. 15.0 Gy). The changes in the conformity, homogeneity, and in the doses to other OARs were not significant. The CONKISS method balances the load among the OARs and significantly reduces the dose to the kidneys, without any significant change in the conformity and homogeneity. Using 3D-CRT the CONKISS method can be a smart alternative to IMRT to enhance the possibility of dose escalation.