Stefan Dinges

IMPACT OF THE FILLING STATUS OF THE BLADDER AND RECTUM ON THEIR INTEGRAL DOSE DISTRIBUTION AND THE MOVEMENT OF THE UTERUS IN THE TREATMENT PLANNING OF GYNAECOLOGICAL CANCER

PURPOSEnDetermination of the impact of the filling status of the organs at risk (bladder and rectum) on the uterus mobility and on their integral dose distribution in radiotherapy of gynaecological cancer.nnnMETHODSnIn 29 women suffering from cervical or endometrial cancer two CT scans were carried out for treatment planning, one with an empty bladder and rectum, the second one with bladder and rectum filled. The volumes of the organs at risk were calculated and in 14 patients, receiving a definitive radiotherapy, the position of the uterus within the pelvis was shown using multiplanar reconstructions. After generation of a 3D treatment plan the dose volume histograms were compared for empty and filled organs at risk.nnnRESULTSnThe mobility for the corpus uteri with/without bladder and rectum filling was in median 7 mm (95%-confidence interval: 3-15 mm) in cranial/caudal direction and 4 mm (0-9 mm) in posterior/anterior direction. Likewise, cervical mobility was observed to be 4 mm (-1-6 mm) mm in cranial/caudal direction. A full bladder led to a mean reduction in organ dose in median from 94-87% calculated for 50% of the bladder volume (P < 0.05, Wilcoxons matched-pairs signed-ranks test). For 66% of the bladder volume the dose could be reduced in median from 78 to 61% (P < 0.005) and for the whole bladder from 42 to 39% (P < 0.005), respectively. No significant contribution of the filling status of the rectum to its integral dose burden was noticed.nnnCONCLUSIONSnDue to the mobility of the uterus increased margins between CTV and PTV superiorly, inferiorly, anteriorly and posteriorly of 15, 6 and 9 mm each, respectively, should be used. A full bladder is the prerequisite for an integral dose reduction.

RATIONALE FOR USING INVASIVE THERMOMETRY FOR REGIONAL HYPERTHERMIA OF PELVIC TUMORS

PURPOSEnInvasive thermometry for regional hyperthermia is time-consuming, uncomfortable, and risky for the patient. We tried to estimate the benefit/cost ratio of invasive thermometry in regional hyperthermia using the radiofrequency system BSD-2000.nnnMETHODS AND MATERIALSnWe evaluated 182 patients with locally advanced pelvic tumors that underwent regional hyperthermia. In every patient a tumor-related temperature measurement point was obtained either by invasive or minimally invasive catheter measurement tracks. In the earlier period for every patient an intratumoral measurement point was decided as obligatory and intratumoral catheters were implanted intraoperatively, CT guided, or under fluoroscopy. In the later period, invasive thermometry often was avoided, if a measurement point in or near the tumor was reached by an endoluminally inserted catheter (rectal, vaginal, cervical, urethral, or vesical). For every patient side effects and complications referred to thermometry were evaluated and compared with the potential benefit of the invasively achieved temperature data. The suitability of endolumimally registered temperatures is analyzed to estimate local feasibility (specific absorption rate achieved) and local effectiveness (thermal parameters correlated with response).nnnRESULTSnIn 74 of 182 patients invasive thermometry was performed, at most CT-guided for soft tissue sarcomas and rectal recurrences. In 14 of 74 (19%) side effects such as local inflammation, pain, or abscess formation occurred that enforced removal of the catheter. However, local problems were strongly correlated with the dwell time of the catheter and nearly never occurred for dwell times less than 5 days. Fortunately, no fatal complications (e.g., bleeding or perforation) occurred during or after implantation which could be attributed to the invasive thermometry procedure. Endoluminal tumor-related temperature rises per time unit (to estimate power density) were correlated with intratumoral rises at the same patients (where both measurements were available). For a subgroup of patients pooled in two Phase II studies with rectal (n = 37) and cervical (n = 18) carcinomas thermal parameters derived from endoluminal measurements were correlated with response or local control, resp.nnnCONCLUSIONSnIf a tumor-related endoluminal temperature measurement point is available, additional invasive thermometry gives no further information to improve the power deposition pattern. For primary rectal and cervical cancer, and probably as well for prostate, bladder and anal cancer, endoluminal measurements are suitable to estimate local feasibility and effectiveness. Therefore, invasive thermometry is dispensable in the majority of patients. In some selected cases, temperature measurement in the tumor center is required to estimate the maximum temperature. In those cases, dwell time of catheters should be minimized--and it should be considered to perform invasive thermometry at the beginning (one or two heat treatments).

High Dose Rate Brachytherapy of Localized Prostate Cancer

Abstract Objective: We evaluated the safety and efficacy of high dose rate (HDR) brachytherapy using Iridium-192 (Ir 192) and 3D conformal external beam radiotherapy in patients with localized prostate cancer. Methods: A total of 444 patients with localized prostate cancer underwent combined radiotherapy with interstitial Ir 192 and 3D conformal external beam radiotherapy between December 1992 and March 2001. The 230 patients, treated between December 1992 and December 1997 were analyzed. All patients underwent laparoscopic pelvic lymph node dissection to exclude patients with lymphatic involvement. Ir 192 was delivered twice with a 1-week interval in HDR remote control technique. The interstitial dose from December 1992 to December 1993 was 10Gy, after December 1993 the dose was reduced to 9Gy per treatment session. The interstitial application was followed by external beam radiation of 45Gy for cT1–cT2 and 50.4Gy for cT3 tumor (40Gy from December 1992 to December 1993). Progression was defined as biochemical failure according to ASTRO criteria, e.g. three consecutive PSA rises following the PSA nadir. Results: The median PSA value decreased from 12.8 to 0.93ng/ml 12 months after treatment. Median PSA value was 0.47 after 24 months, 0.30ng/ml after 36 months and 0.18ng/ml after 60 months. 68% of the biopsies were negative 24 months after therapy. Progression-free rate was 100% for cT1 tumors, 75% for cT2 and 60% for stage-cT3 on 5-year follow-up. Five-year overall survival was 93%, 5-year disease-specific survival was 98%. Initial PSA value Conclusions: Combined HDR brachytherapy with Ir 192 is an alternative treatment option especially for patients with cT3 prostate cancer. Initial PSA value, stage and grade, are important prognostic factors.

The TCD50 and regrowth delay assay in human tumor xenografts: Differences and implications

The response to irradiation of five human xenograft cell lines--a malignant paraganglioma, a neurogenic sarcoma, a malignant histiocytoma, a primary lymphoma of the brain, and a squamous cell carcinoma--were tested in nude mice. All mice underwent 5 Gy whole body irradiation prior to xenotransplantation to minimize the residual immune response. The subcutaneous tumors were irradiated at a tumor volume of 120mm3 under acutely hypoxic conditions with single doses between 8 Gy and 80 Gy depending on the expected radiation sensitivity of the tumor line. Endpoints of the study were the tumor control dose 50% (TCD50) and the regrowth delay endpoints growth delay, specific growth delay, and the tumor bed effect corrected specific growth delay. Specific growth delay and corrected specific growth delay at 76% of the TCD50 was used in order to compare the data to previously published data from spheroids. The lowest TCD50 was found in the lymphoma with 24.9 Gy, whereas the TCD50 of the soft tissue sarcomas and the squamous cell carcinoma ranged from 57.8 Gy to 65.6 Gy. The isoeffective dose levels for the induction of 30 days growth delay, a specific growth delay of 3, and a corrected specific growth delay of 3 ranged from 15.5 Gy (ECL1) to 37.1 Gy (FADU), from 7.2 Gy (ENE2) to 45.6 Gy (EPG1) and from 9.2 Gy (ENE2) to 37.6 Gy (EPG1), respectively. The corrected specific growth delay at 76% of the TCD50 was correlated with the number of tumor rescue units per 100 cells in spheroids, which was available for three tumor lines, and with the tumor doubling time in xenografts (n = 5). The TCD50 values corresponded better to the clinical experience than the regrowth delay data. There was no correlation between TCD50 and any of the regrowth delay endpoints. This missing correlation was most likely a result of large differences in the number of tumor rescue units in human xenografts of the same size.

Vergleich unterschiedlicher dreidimensionaler Bestrahlungstechniken bei der lokalen Strahlentherapie des Prostatakarzinoms

ZielVier verschiedene SD-Bestrahlungstechniken wurden hinsichtlich der Dosishomogenität im Targetvolumen und der Dosis-Volumen-Belastung der Risikoorgane in AbhÄngigkeit vom Tumorstadium untersucht.Patienten und MethodeBei 17 Patienten wurden eine 3D-Rotations-, Vier-Felder-, Fünf-Felder- und Sechs-Felder-Technik erstellt. Sechs Patienten wiesen ein Stadium T1N0M0, sieben Patienten ein Stadium T2N0M0 und vier Patienten ein Stadium T3N0M0 auf. Dosiert wurde auf den Referenzpunkt im Isozentrum (100%). Die 95%-Isodose mute das Planungszielvolumen umschlieen. Es wurden bei allen Techniken Multileaf-Kollimatoren verwendet und Dosis-Volumen-Histogramme für das Planungszielvolumen und die Risikoorgane (Blase, Rektum, Hüftköpfe) erstellt und miteinander verglichen. Der Vergleich erfolgte jeweils bei 33%, 50% und 66% Volumen des jeweiligen Risikoorgans.ErgebnisseHinsichtlich der Dosishomogenität im Targetvolumen zeigte sich kein Unterschied. Eine signifikante Differenz wurde bei der Blasenbelastung zwischen der Sechs-Felder- und der Vier-Felder-Technik nur bei 50% Volumenanteil (p = 0,034), zwischen Sechs-Felder- und Rotationstechnik sowie zwischen Fünf-Felder- und Rotationstechnik bei allen Volumenanteilen gesehen. Bei der Belastung des Rektums ergab sich eine signifikante Differenz zwischen der Sechs- und der Vier-Felder-Technik bei T1- und T2-Tumoren sowohl bei 50% (p = 0,033) als auch bei 66% (p = 0,011). Bei den T3-Tumoren ergaben sich hinsichtlich der Rektumbelastung keine signifikanten Unterschiede. Die beste Schonung der Hüftköpfe wurde durch die Rotationstechnik erzielt.SchlufolgerungBei der kleinvolumigen Bestrahlung der Prostata ist bei T1/2-Tumoren durch die Sechs-Felder-Technik die beste Schonung von Rektum und Blase zu erzielen, bei gröerem Planungszielvolumen und bei Einschlu der SamenblÄschen sollten andere Techniken, wie zum Beispiel eine dreidimensional geplante Vier-Felder-Technik, zur besseren Schonung der Risikoorgane angewendet werden.AbstractPurposeFour different three-dimensional planning techniques for localized radiotherapy of prostate cancer were compared with regard to dose homogeneity within the target volume and dose to organs at risk, dependent upon tumor stage.Patients and MethodsSix patients with stage T1, 7 patients with stage T2 and 4 patients with stage T3 were included in this study. Four different 3D treatment plans (rotation, 4-field, 5-field and 6-field technique) were calculated for each patient. Dose was calculated with the reference point at the isocenter (100%). The planning target volume was encompassed within the 95% isodose surface. All the techniques used different shaped portal for each beam. Dose volume histograms were created and compared for the planning target volume and the organs at risk (33%, 50%, 66% volume level) in all techniques.ResultsThe 4 different three-dimensional planning techniques revealed no differences concerning dose homogeneity within the planning target volume. The dose volume distribution at organs at risk show differences between the calculated techniques. In our study the best protection for bladder and rectum in stage T1 and T2 was achieved by the 6-field technique. A significant difference was achieved between 6-field and 4-field technique only in the 50% volume of the bladder (p = 0.034), between the 6-field and rotation technique (all volume levels) and between 5-field and rotation technique (all volume levels). In stage T1, T2 6-field and 4-field technique in 50% (p = 0.033) and 66% (p = 0.011) of the rectum volume. In stage T3 a significant difference was not observed between the 4 techniques. The best protection of head of the femur was achieved by the rotation technique.ConclusionIn the localized radiotherapy of prostate cancer in stage T1 or T2 the best protection for bladder and rectum was achieved by a 3D-planned conformai 6-field technique. If the seminal vesicles have been included in the target volume and in the case of large planning target volume other techniques should be taken for a better protection for organs at risk e. g. a 3D-planned 4-field technique box technique.PURPOSEnFour different three-dimensional planning techniques for localized radiotherapy of prostate cancer were compared with regard to dose homogeneity within the target volume and dose to organs at risk, dependent upon tumor stage.nnnPATIENTS AND METHODSnSix patients with stage T1, 7 patients with stage T2 and 4 patients with stage T3 were included in this study. Four different 3D treatment plans (rotation, 4-field, 5-field and 6-field technique) were calculated for each patient. Dose was calculated with the reference point at the isocenter (100%). The planning target volume was encompassed within the 95% isodose surface. All the techniques used different shaped portal for each beam. Dose volume histograms were created and compared for the planning target volume and the organs at risk (33%, 50%, 66% volume level) in all techniques.nnnRESULTSnThe 4 different three-dimensional planning techniques revealed no differences concerning dose homogeneity within the planning target volume. The dose volume distribution at organs at risk show differences between the calculated techniques. In our study the best protection for bladder and rectum in stage T1 and T2 was achieved by the 6-field technique. A significant difference was achieved between 6-field and 4-field technique only in the 50% volume of the bladder (p = 0.034), between the 6-field and rotation technique (all volume levels) and between 5-field and rotation technique (all volume levels). In stage T1, T2 6-field and 4-field technique in 50% (p = 0.033) and 66% (p = 0.011) of the rectum volume. In stage T3 a significant difference was not observed between the 4 techniques. The best protection of head of the femur was achieved by the rotation technique.nnnCONCLUSIONnIn the localized radiotherapy of prostate cancer in stage T1 or T2 the best protection for bladder and rectum was achieved by a 3D-planned conformal 6-field technique. If the seminal vesicles have been included in the target volume and in the case of large planning target volume other techniques should be taken for a better protection for organs at risk e. g. a 3D-planned 4-field technique box technique.

Correlation between primary chemo- and radiation sensitivity in a panel of highly malignant human soft tissue sarcoma xenografts

BACKGROUND AND PURPOSEnSensitivity to radiation and sensitivity to cytotoxic drugs have been proposed to be independent properties of tumour cells. However, very few clinical or experimental studies have tested this hypothesis. Therefore, we evaluated the response to ionizing radiation and to four cytotoxic drugs in a panel of 12 human soft tissue sarcoma cell lines using the xenograft system.nnnMATERIAL AND METHODSnNMRI-nu/nu nude mice with subcutaneous tumours received at a tumour volume of 120-200 mm3 either single dose, single agent chemotherapy with 350 mg/kg ifosfamide, 200 mg/kg dacarbazine, 10 mg/kg doxorubicin, 6.6 mg/kg cisplatin, or 24 Gy local tumour irradiation under acutely hypoxic conditions from a cobalt-60 source. Tumour response to radiotherapy and chemotherapy was measured as specific growth delay (SGD).nnnRESULTSnA significant correlation was found between SGD after radiotherapy and SGD after decarbazine (P < 0.001) and doxorubicin (P = 0.05), whereas no correlation could be demonstrated for cisplatin. For ifosfamide, the correlation reached borderline significance. The maximal response to any of the four tested chemotherapeutic drugs correlated very well with the response to radiotherapy (P < 0.001).nnnCONCLUSIONnThe results suggest that radiation sensitivity and chemosensitivity are not independent properties of soft tissue sarcoma cell lines.

Hypofractionation with simultaneous integrated boost for early breast cancer@@@Hypofraktionierte Bestrahlung mit simultan-integriertem Boost beim frühen Mammakarzinom: Results of the German multicenter phase II trial (ARO-2010-01)@@@Ergebnisse einer deutschen Phase-II-Multizenterstudie (ARO-2010-01)

PurposeTo evaluate the feasibility of hypofractionation with SIB in all settings in Germany to prepare a multicenter treatment comparison.MethodsEligible patients had histopathologically confirmed breast cancer operated by BCS. Patients received WBI 40.0 Gy in 16 fractions of 2.5 Gy. A SIB with 0.5 Gy per fraction was administered to the tumor bed, thereby giving 48.0 Gy in 16 fractions to the boost-PTV sparing heart, LAD, lung, contralateral breast. The primary study objective was feasibility, administration of specified dose in 16 fractions within 22–29 days with adherence to certain dose constraints (heart; LAD; contralateral breast); secondary endpoints were toxicity, QoL.Results151 patients were recruited from 7 institutions between 07/11-10/12. 10 patients met exclusion criteria prior to irradiation. All but two patients (99xa0%) received the prescribed dose in the PTVs. Adherence to dose constraints and time limits was achieved in 89xa0% (95xa0% CI 82xa0% to 93xa0%). 11 AE were reported in 10 patients; five related to concurrent endocrine therapy. Two of the AEs were related to radiotherapy: grade 3 hot flushes in two cases. QoL remained unchanged.ConclusionHypofractionation with a SIB is feasible and was well tolerated in this study.ZusammenfassungHintergrundDie ARO-2010-01-Studie prüfte die Durchführbarkeit einer hypofraktionierten Bestrahlung mit simultan-integriertem Boost (SIB) in unterschiedlichen Versorgungseinrichtungen zur Vorbereitung einer multizentrischen Vergleichsstudie.MethodenIn die Studie rekrutiert wurden Patientinnen mit histopathologisch gesichertem Mammakarzinom nach brusterhaltender Operation. Bestrahlt wurde die Brust mit 40,0 Gy in 16 Fraktionen à 2,5 Gy Einzeldosis; zusätzlich wurde bei jeder Fraktion ein simultan- integrierter Boost mit 0,5 Gy appliziert, so dass im Boost-PTV (Planungszielvolumen) eine Dosis von 48 Gy in 16 Fraktionen erreicht wurde. Das primäre Zielkriterium war die Durchführbarkeit, definiert als Verabreichung von 48 Gy GD in 16 Fraktionen in mindestens 22 d bis maximal 29 d Therapiezeit unter Einhaltung von Grenzdosen (Lunge, Herz, LAD, kontralaterale Brust); sekundäre Endpunkte waren Toxizität und Lebensqualität.ErgebnisseZwischen 07/2011 und 10/2012 wurden 151 Patientinnen in 7 Prüfzentren rekrutiert. Bei 10 Patientinnen wurden vor der Strahlentherapie Ausschlusskriterien festgestellt. Fast alle Patientinnen (99u2009%) erhielten die verschriebene Dosis im PTV. Grenzdosen und Zeitlimits wurden in 89u2009% (95u2009% CI 82u2009% bis 93u2009%) eingehalten. 11 unerwünschte Ereignisse wurden bei 10 Patientinnen gemeldet; fünf in Verbindung mit gleichzeitiger endokriner Therapie. In 2 Fällen wurde eine kausale Beziehung zur Strahlentherapie angegeben: Grad-3-Hitzewallungen. Die Lebensqualität blieb unverändert.SchlussfolgerungenDie hypofraktionierte Bestrahlung mit simultan-integriertem Boost konnte in dieser multizentrischen Studie in Praxen und Strahlenkliniken problemlos durchgeführt werden. Die Verträglichkeit war in dieser Studie gut.

Hypofractionation with simultaneous integrated boost for early breast cancerHypofraktionierte Bestrahlung mit simultan-integriertem Boost beim frühen Mammakarzinom

PurposeTo evaluate the feasibility of hypofractionation with SIB in all settings in Germany to prepare a multicenter treatment comparison.MethodsEligible patients had histopathologically confirmed breast cancer operated by BCS. Patients received WBI 40.0 Gy in 16 fractions of 2.5 Gy. A SIB with 0.5 Gy per fraction was administered to the tumor bed, thereby giving 48.0 Gy in 16 fractions to the boost-PTV sparing heart, LAD, lung, contralateral breast. The primary study objective was feasibility, administration of specified dose in 16 fractions within 22–29 days with adherence to certain dose constraints (heart; LAD; contralateral breast); secondary endpoints were toxicity, QoL.Results151 patients were recruited from 7 institutions between 07/11-10/12. 10 patients met exclusion criteria prior to irradiation. All but two patients (99xa0%) received the prescribed dose in the PTVs. Adherence to dose constraints and time limits was achieved in 89xa0% (95xa0% CI 82xa0% to 93xa0%). 11 AE were reported in 10 patients; five related to concurrent endocrine therapy. Two of the AEs were related to radiotherapy: grade 3 hot flushes in two cases. QoL remained unchanged.ConclusionHypofractionation with a SIB is feasible and was well tolerated in this study.ZusammenfassungHintergrundDie ARO-2010-01-Studie prüfte die Durchführbarkeit einer hypofraktionierten Bestrahlung mit simultan-integriertem Boost (SIB) in unterschiedlichen Versorgungseinrichtungen zur Vorbereitung einer multizentrischen Vergleichsstudie.MethodenIn die Studie rekrutiert wurden Patientinnen mit histopathologisch gesichertem Mammakarzinom nach brusterhaltender Operation. Bestrahlt wurde die Brust mit 40,0 Gy in 16 Fraktionen à 2,5 Gy Einzeldosis; zusätzlich wurde bei jeder Fraktion ein simultan- integrierter Boost mit 0,5 Gy appliziert, so dass im Boost-PTV (Planungszielvolumen) eine Dosis von 48 Gy in 16 Fraktionen erreicht wurde. Das primäre Zielkriterium war die Durchführbarkeit, definiert als Verabreichung von 48 Gy GD in 16 Fraktionen in mindestens 22 d bis maximal 29 d Therapiezeit unter Einhaltung von Grenzdosen (Lunge, Herz, LAD, kontralaterale Brust); sekundäre Endpunkte waren Toxizität und Lebensqualität.ErgebnisseZwischen 07/2011 und 10/2012 wurden 151 Patientinnen in 7 Prüfzentren rekrutiert. Bei 10 Patientinnen wurden vor der Strahlentherapie Ausschlusskriterien festgestellt. Fast alle Patientinnen (99u2009%) erhielten die verschriebene Dosis im PTV. Grenzdosen und Zeitlimits wurden in 89u2009% (95u2009% CI 82u2009% bis 93u2009%) eingehalten. 11 unerwünschte Ereignisse wurden bei 10 Patientinnen gemeldet; fünf in Verbindung mit gleichzeitiger endokriner Therapie. In 2 Fällen wurde eine kausale Beziehung zur Strahlentherapie angegeben: Grad-3-Hitzewallungen. Die Lebensqualität blieb unverändert.SchlussfolgerungenDie hypofraktionierte Bestrahlung mit simultan-integriertem Boost konnte in dieser multizentrischen Studie in Praxen und Strahlenkliniken problemlos durchgeführt werden. Die Verträglichkeit war in dieser Studie gut.

Laparoskopisch-pelvine Lymphadenektomie nach definitiver Strahlentherapie des Prostatakarzinoms

Es handelt sich um eine hochaktuelle Untersuchung zur Frage der adjuvanten Hormontherapie zur Bestrahlung des fortgeschrittenen Prostatakarzinoms, die bislang kontrovers diskutiert wurde. Die Arbeit sttitzt die These for eine adjuvante Therapie mit LHRH-Agonisten. Dies gilt um so mehr, als die EORTC-Studie 22 863 inzwischen sogar einen allgemeinen Oberlebensvorteil fiir die adjuvante Goserelin-Therapie bei Patienten mit Prostatakarzinom in lokal fortgeschrittenen Stadien gezeigt hat [1]. Allerdings sind einige kritische Anmerkungen zu machen.