Marion Hindemith

5-year results of accelerated partial breast irradiation using sole interstitial multicatheter brachytherapy versus whole-breast irradiation with boost after breast-conserving surgery for low-risk invasive and in-situ carcinoma of the female breast: a randomised, phase 3, non-inferiority trial

BACKGROUND In a phase 3, randomised, non-inferiority trial, accelerated partial breast irradiation (APBI) for patients with stage 0, I, and IIA breast cancer who underwent breast-conserving treatment was compared with whole-breast irradiation. Here, we present 5-year follow-up results. METHODS We did a phase 3, randomised, non-inferiority trial at 16 hospitals and medical centres in seven European countries. 1184 patients with low-risk invasive and ductal carcinoma in situ treated with breast-conserving surgery were centrally randomised to either whole-breast irradiation or APBI using multicatheter brachytherapy. The primary endpoint was local recurrence. Analysis was done according to treatment received. This trial is registered with ClinicalTrials.gov, number NCT00402519. FINDINGS Between April 20, 2004, and July 30, 2009, 551 patients had whole-breast irradiation with tumour-bed boost and 633 patients received APBI using interstitial multicatheter brachytherapy. At 5-year follow-up, nine patients treated with APBI and five patients receiving whole-breast irradiation had a local recurrence; the cumulative incidence of local recurrence was 1.44% (95% CI 0.51-2.38) with APBI and 0.92% (0.12-1.73) with whole-breast irradiation (difference 0.52%, 95% CI -0.72 to 1.75; p=0.42). No grade 4 late side-effects were reported. The 5-year risk of grade 2-3 late side-effects to the skin was 3.2% with APBI versus 5.7% with whole-breast irradiation (p=0.08), and 5-year risk of grade 2-3 subcutaneous tissue late side-effects was 7.6% versus 6.3% (p=0.53). The risk of severe (grade 3) fibrosis at 5 years was 0.2% with whole-breast irradiation and 0% with APBI (p=0.46). INTERPRETATION The difference between treatments was below the relevance margin of 3 percentage points. Therefore, adjuvant APBI using multicatheter brachytherapy after breast-conserving surgery in patients with early breast cancer is not inferior to adjuvant whole-breast irradiation with respect to 5-year local control, disease-free survival, and overall survival. FUNDING German Cancer Aid.

Accelerated Partial Breast Irradiation: 5-Year Results of the German-Austrian Multicenter Phase II Trial Using Interstitial Multicatheter Brachytherapy Alone After Breast-Conserving Surgery

PURPOSE To evaluate the impact of accelerated partial breast irradiation on local control, side effects, and cosmesis using multicatheter interstitial brachytherapy as the sole method for the adjuvant local treatment of patients with low-risk breast cancer. METHODS AND MATERIALS 274 patients with low-risk breast cancer were treated on protocol. Patients were eligible for the study if the tumor size was < 3 cm, resection margins were clear by at least 2 mm, no lymph node metastases existed, age was >35 years, hormone receptors were positive, and histologic grades were 1 or 2. Of the 274 patients, 175 (64%) received pulse-dose-rate brachytherapy (D(ref) = 50 Gy). and 99 (36%) received high-dose-rate brachytherapy (D(ref) = 32.0 Gy). RESULTS Median follow-up was 63 months (range, 9-103). Only 8 of 274 (2.9%) patients developed an ipsilateral in-breast tumor recurrence at the time of analysis. The 5-year actuarial local recurrence-free survival probability was 98%. The 5- year overall and disease-free survival probabilities of all patients were 97% and 96%, respectively. Contralateral in-breast malignancies were detected in 2 of 274 (0.7%) patients, and distant metastases occurred in 6 of 274 (2.2%). Late side effects ≥ Grade 3 (i.e., breast tissue fibrosis and telangiectasia) occurred in 1 patient (0.4%, 95%CI:0.0-2.0%) and 6 patients (2.2%, 95%CI:0.8-4.7%), respectively. Cosmetic results were good to excellent in 245 of 274 patients (90%). CONCLUSIONS The long-term results of this prospective Phase II trial confirm that the efficacy of accelerated partial breast irradiation using multicatheter brachytherapy is comparable with that of whole breast irradiation and that late side effects are negligible.

Effects of low dose radiation therapy on adjuvant induced arthritis in rats.

Purpose : Substantial clinical evidence shows the efficacy of low dose radiotherapy (RT) in the treatment of painful osteoarthritis. Experimental investigations into these empirically clinical observations remain scarce. This study investigated in vivo the effects of daily 5 1.0Gy versus 5 0.5Gy on adjuvant induced arthritis in rats in order to explore whether there is a dose dependence of anti-inflammatory efficacy. Materials and methods : Adjuvant arthritis in female Lewis rats was induced by intradermal injection of heat inactivated Mycobacterium tuberculosis on day 0. Both hind paws were X-irradiated daily from days 15 to 19 after induction according to four protocols (15 animals/group): group 1, 5 1.0Gy (non-arthritic animals); group 2, sham-irradiated control; group 3, 5 1.0Gy; group 4, 5 0.5Gy. The clinical parameters arthritis score (AS), hind paw volume (HPV), body weight, and erythrocyte sedimentation rate (ESR) were determined. On days 21 and 30 histological sections of at least 12 ankle joints per group were analysed semi-quantitatively. Results : Local irradiation of non-arthritic rats (group 1) with 5 1 Gy did not induce any arthritic signs. Sham-irradiated arthritic rats (group 2) showed a full-blown arthritic syndrome. Treatment of arthritic rats with 5 1 Gy (group 3) or 5 0.5Gy (group 4) led to a reduction of mean AS from day 21 to 29 compared with group 2 (days 27-29-group 3: p =0.037; group 4: p =0.034), with no differences in efficacy between groups 3 and 4. Concurrently, following radiation treatment there was no further increase in HPV. At the end of the observation period, this effect demonstrated a dose-dependent level of significance (days 27-29-group 3: p =0.0036; group 4: p =0.039). A significant decrease in the ESR was noted in both irradiated arthritic groups on day 21 (group 3: p =0.015; group 4: p =0.006). The histopathological analysis revealed a highly significant reduction of cartilage and bone destruction on day 30 in both irradiated groups. Conclusions : This study confirms by objective criteria the anti-iinflammatory efficacy of low dose RT and gives some indication for a dose dependence of its efficacy.PURPOSE Substantial clinical evidence shows the efficacy of low dose radiotherapy (RT) in the treatment of painful osteoarthritis. Experimental investigations into these empirically clinical observations remain scarce. This study investigated in vivo the effects of daily 5 x 1.0 Gy versus 5 x 0.5 Gy on adjuvant induced arthritis in rats in order to explore whether there is a dose dependence of anti-inflammatory efficacy. MATERIALS AND METHODS Adjuvant arthritis in female Lewis rats was induced by intradermal injection of heat inactivated Mycobacterium tuberculosis on day 0. Both hind paws were X-irradiated daily from days 15 to 19 after induction according to four protocols (15 animals/group): group 1, 5 x 1.0 Gy (non-arthritic animals); group 2, sham-irradiated control; group 3, 5 x 1.0 Gy; group 4, 5 x 0.5 Gy. The clinical parameters arthritis score (AS), hind paw volume (HPV), body weight, and erythrocyte sedimentation rate (ESR) were determined. On days 21 and 30 histological sections of at least 12 ankle joints per group were analysed semi-quantitatively. RESULTS Local irradiation of non-arthritic rats (group 1) with 5 x 1 Gy did not induce any arthritic signs. Sham-irradiated arthritic rats (group 2) showed a full-blown arthritic syndrome. Treatment of arthritic rats with 5 x 1 Gy (group 3) or 5 x 0.5 Gy (group 4) led to a reduction of mean AS from day 21 to 29 compared with group 2 (days 27-29--group 3: p=0.037; group 4: p=0.034), with no differences in efficacy between groups 3 and 4. Concurrently, following radiation treatment there was no further increase in HPV. At the end of the observation period, this effect demonstrated a dose-dependent level of significance (days 27-29--group 3: p=0.0036; group 4: p=0.039). A significant decrease in the ESR was noted in both irradiated arthritic groups on day 21 (group 3: p=0.015; group 4: p=0.006). The histopathological analysis revealed a highly significant reduction of cartilage and bone destruction on day 30 in both irradiated groups. CONCLUSIONS This study confirms by objective criteria the anti-inflammatory efficacy of low dose RT and gives some indication for a dose dependence of its efficacy.

Inhibition of the iNOS pathway in inflammatory macrophages by low-dose X-irradiation in vitro. Is there a time dependence?

Background: Low radiation doses (≤ 1.25 Gy), if applied 6 h before or after stimulation, are known to inhibit the inducible nitric oxide synthase (iNOS) pathway in inflammatory macrophages in vitro. We therefore investigated the time dependence and the underlying molecular mechanism of this effect, since it may be involved in the clinically observed anti-inflammatory and analgesic efficacy of low-dose radiotherapy. Material and Methods: Metabolic activity, nitric oxide (NO) production, iNOS- and hemoxygenase 1-(HO-1-)protein and -mRNA expression by macrophages in vitro after stimulation with LPS/IFN-γ (0.1 μg ml−1/100 U ml−1) were investigated. Irradiation was performed at 6, 4, 2 h before and 0, 2, 4, 6 h after stimulation with doses ranging from 0.3 to 10 Gy. For each group, three independent experiments were performed over a period of 30 h with sampling intervals of 3 h. Results: In stimulated macrophages, metabolic activity was not affected by radiation doses up to 10 Gy. A dose-dependent modulation of the cumulative NO production was observed with significant inhibition by low radiation doses ≤ 1.25 Gy) and return to control level and even higher concentrations by higher doses (≤ 5 Gy). The degree of inhibition did not show any significant time dependence within the experimental time window used. The iNOS-mRNA expression 3–18 h following stimulation and subsequent irradiation was not affected by doses ≤ 1.25 Gy. The iNOS-protein expression 6–24 h following stimulation and subsequent irradiation was reduced by doses ≤ 1.25 Gy. By contrast, neither HO-1-protein nor HO-1-mRNA expression at the same time points was influenced by these low doses. Conclusion: The inhibitory interference of low radiation doses with the iNOS pathway in inflammatory macrophages appears to be based on radiation effects on the translational and posttranslational control mechanisms of iNOS activity. However, contrary to our working hypothesis this is not related to radiation-induced induction of HO-1 expression and thereby increased degradation of heme which is essential for iNOS activity. Thus, other posttranslational modifications such as the proteasome degradation pathway might be involved.Hintergrund: Niedrige Strahlendosen (≤ 1,25 Gy), wenn 6 h vor oder nach Zellstimulation appliziert, können die Aktivität der induzierbaren Stickoxidsynthase (iNOS) inflammatorischer Makrophagen in vitro inhibieren. Wir untersuchten die Zeitabhängigkeit und mögliche molekulare Wirkmechanismen dieses Effekts, da er in die klinisch beobachtete antiinflammatorische und analgetische Wirksamkeit der niedrig dosierten Strahlentherapie involviert sein könnte. Material und Methodik: Metabolische Aktivität, kumulative Stickoxid-(NO-)Produktion, iNOS- und Hämoxygenase-1-(HO-1-)Protein- und -mRNA-Expression durch Makrophagen wurden nach Stimulation mit LPS/IFN-γ (0,1 μg ml−1/100 U ml−1) in vitro untersucht. Die Bestrahlung erfolgte entweder 6, 4, 2 h vor oder 0, 2, 4, 6 h nach Stimulation mit Dosen von 0,3–10,0 Gy. Für jede Gruppe wurden drei unabhängige Experimente über eine Zeitraum von 30 h mit Zeitintervallen von 3 h durchgeführt. Ergebnisse: Die metabolische Aktivität stimulierter Makrophagen blieb nach Stahlendosen ≤ 10 Gy unbeeinflusst. Es wurde eine dosisabhängige, diskontinuierliche Modulation der kumulativen NO-Produktion mit signifikanter Inhibition durch niedrige Strahlendosen (≤ 1,25 Gy) und Rückkehr zu Kontrollwerten oder höheren Konzentrationen nach Dosen ≤ 5 Gy beobachtet. Das Ausmaß der Inhibition zeigte innerhalb des untersuchten experimentellen Zeitfensters keine signifikante Zeitabhängigkeit. Die iNOSmRNA-Expression blieb 3–18 h nach Stimulation und unmittelbar anschließender Bestrahlung mit Dosen ≤ 1,25 Gy unbeeinflusst. Die iNOS-Protein-Expression war 6–24 h nach Stimulation und unmittelbar anschließender Bestrahlung mit Dosen ≤ 1,25 Gy vermindert. Im Gegensatz dazu war weder die HO-1-Protein- noch die HO-1-mRNA-Expression zu den gleichen Zeitpunkten nach diesen niedrigen Dosen beeinflusst. Schlussfolgerung: Die inhibitorische Interferenz niedriger Strahlendosen mit dem iNOS-Pathway inflammatorischer Makrophagen scheint auf Strahleneffekten auf die translationellen und posttranslationellen Kontrollmechanismen der iNOS-Aktivität zu beruhen. Im Gegensatz zu unserer Arbeitshypothese ist dies nicht durch eine Induktion des Stressproteins HO-1 durch niedrige Dosen und die dadurch bedingte gesteigerte Degradation von Häm als essentiellem oxidativem Kofaktor der iNOS-Aktivität zu erklären. Andere posttranslationelle Modifikationen wie der Proteasom-Degradations-Pathway könnten involviert sein.

Inhibition of the iNOS Pathway in Inflammatory Macrophages by Low-Dose X-Irradiation In Vitro

Background: Low radiation doses (≤ 1.25 Gy), if applied 6 h before or after stimulation, are known to inhibit the inducible nitric oxide synthase (iNOS) pathway in inflammatory macrophages in vitro. We therefore investigated the time dependence and the underlying molecular mechanism of this effect, since it may be involved in the clinically observed anti-inflammatory and analgesic efficacy of low-dose radiotherapy. Material and Methods: Metabolic activity, nitric oxide (NO) production, iNOS- and hemoxygenase 1-(HO-1-)protein and -mRNA expression by macrophages in vitro after stimulation with LPS/IFN-γ (0.1 μg ml−1/100 U ml−1) were investigated. Irradiation was performed at 6, 4, 2 h before and 0, 2, 4, 6 h after stimulation with doses ranging from 0.3 to 10 Gy. For each group, three independent experiments were performed over a period of 30 h with sampling intervals of 3 h. Results: In stimulated macrophages, metabolic activity was not affected by radiation doses up to 10 Gy. A dose-dependent modulation of the cumulative NO production was observed with significant inhibition by low radiation doses ≤ 1.25 Gy) and return to control level and even higher concentrations by higher doses (≤ 5 Gy). The degree of inhibition did not show any significant time dependence within the experimental time window used. The iNOS-mRNA expression 3–18 h following stimulation and subsequent irradiation was not affected by doses ≤ 1.25 Gy. The iNOS-protein expression 6–24 h following stimulation and subsequent irradiation was reduced by doses ≤ 1.25 Gy. By contrast, neither HO-1-protein nor HO-1-mRNA expression at the same time points was influenced by these low doses. Conclusion: The inhibitory interference of low radiation doses with the iNOS pathway in inflammatory macrophages appears to be based on radiation effects on the translational and posttranslational control mechanisms of iNOS activity. However, contrary to our working hypothesis this is not related to radiation-induced induction of HO-1 expression and thereby increased degradation of heme which is essential for iNOS activity. Thus, other posttranslational modifications such as the proteasome degradation pathway might be involved.Hintergrund: Niedrige Strahlendosen (≤ 1,25 Gy), wenn 6 h vor oder nach Zellstimulation appliziert, können die Aktivität der induzierbaren Stickoxidsynthase (iNOS) inflammatorischer Makrophagen in vitro inhibieren. Wir untersuchten die Zeitabhängigkeit und mögliche molekulare Wirkmechanismen dieses Effekts, da er in die klinisch beobachtete antiinflammatorische und analgetische Wirksamkeit der niedrig dosierten Strahlentherapie involviert sein könnte. Material und Methodik: Metabolische Aktivität, kumulative Stickoxid-(NO-)Produktion, iNOS- und Hämoxygenase-1-(HO-1-)Protein- und -mRNA-Expression durch Makrophagen wurden nach Stimulation mit LPS/IFN-γ (0,1 μg ml−1/100 U ml−1) in vitro untersucht. Die Bestrahlung erfolgte entweder 6, 4, 2 h vor oder 0, 2, 4, 6 h nach Stimulation mit Dosen von 0,3–10,0 Gy. Für jede Gruppe wurden drei unabhängige Experimente über eine Zeitraum von 30 h mit Zeitintervallen von 3 h durchgeführt. Ergebnisse: Die metabolische Aktivität stimulierter Makrophagen blieb nach Stahlendosen ≤ 10 Gy unbeeinflusst. Es wurde eine dosisabhängige, diskontinuierliche Modulation der kumulativen NO-Produktion mit signifikanter Inhibition durch niedrige Strahlendosen (≤ 1,25 Gy) und Rückkehr zu Kontrollwerten oder höheren Konzentrationen nach Dosen ≤ 5 Gy beobachtet. Das Ausmaß der Inhibition zeigte innerhalb des untersuchten experimentellen Zeitfensters keine signifikante Zeitabhängigkeit. Die iNOSmRNA-Expression blieb 3–18 h nach Stimulation und unmittelbar anschließender Bestrahlung mit Dosen ≤ 1,25 Gy unbeeinflusst. Die iNOS-Protein-Expression war 6–24 h nach Stimulation und unmittelbar anschließender Bestrahlung mit Dosen ≤ 1,25 Gy vermindert. Im Gegensatz dazu war weder die HO-1-Protein- noch die HO-1-mRNA-Expression zu den gleichen Zeitpunkten nach diesen niedrigen Dosen beeinflusst. Schlussfolgerung: Die inhibitorische Interferenz niedriger Strahlendosen mit dem iNOS-Pathway inflammatorischer Makrophagen scheint auf Strahleneffekten auf die translationellen und posttranslationellen Kontrollmechanismen der iNOS-Aktivität zu beruhen. Im Gegensatz zu unserer Arbeitshypothese ist dies nicht durch eine Induktion des Stressproteins HO-1 durch niedrige Dosen und die dadurch bedingte gesteigerte Degradation von Häm als essentiellem oxidativem Kofaktor der iNOS-Aktivität zu erklären. Andere posttranslationelle Modifikationen wie der Proteasom-Degradations-Pathway könnten involviert sein.

Low-dose X-irradiation of adjuvant-induced arthritis in rats: Efficacy of different fractionation schedules

Background and Purpose:Low-dose radiotherapy is widely accepted as a very effective treatment option for inflammatory symptoms associated with painful degenerative joint disorders. Radiation doses and fractionation schedules in practical use are empirical and mainly based on clinical observations. Experimental data are rare. The efficacy of low-dose X-irradiation on adjuvant induced arthritis in rats using different fractionation schemes was investigated in vivo, in order to explore whether there is a dose and fractionation dependence.Material and Methods:Adjuvant arthritis in female Lewis rats (n = 128) was induced by intradermal injection of heat-inactivated Mycobacterium tuberculosis on day 0. Both arthritic hind paws were sham-irradiated (group 1: days 10–14; group 2: days 15–19; group 3: days 22–26) or X-irradiated with either 5 × 1.0 Gy (group 4: days 10–14; group 6: days 15–19; group 8: days 22–26; group 10: days 10, 12, 14, 16, and 18) or 5 × 0.5 Gy (group 5: days 10–14; group 7: days 15–19; group 9: days 22–26; group 11: days 10, 12, 14, 16, and 18; group 12: days 10–14 and 22–26). The clinical parameters arthritis score (AS), hind paw volume (HPV), and body weight were determined.Results:A significant decrease of the clinical arthritis parameters was observed following 5 × 0.5 Gy or 5 × 1.0 Gy during the acute maximum of the inflammatory response (days 15–19). The most pronounced treatment effect was reached after two daily fractionated series of 5 × 0.5 Gy with an early treatment onset (days 10–14) and repetition in interval (days 22–26). After the application of 5 × 1.0 Gy on days 10–14 or in a protracted scheme (days 10, 12, 14, 16, and 18), only a nonsignificant positive trend could be detected. Daily fractionated X-irradiation in the chronic phase of adjuvant arthritis (days 22–26) did not show any positive clinical effect.Conclusion:Low-dose radiotherapy is able to prevent a full-blown arthritic reaction if given during the florid phase of adjuvant arthritis. Two series of 5 × 0.5 Gy with an early treatment onset (days 10–14) and repetition in interval (days 22–26) were the most effective treatment schedule in this experimental study.Hintergrund und Ziel:Die niedrig dosierte Strahlentherapie wird als effektive Behandlungsoption bei schmerzhaften, entzündlich reaktivierten degenerativen Gelenkerkrankungen angesehen. Die verwendeten Einzeldosen und Fraktionierungen basieren im Wesentlichen auf klinisch-empirischen Beobachtungen. Experimentelle Untersuchungen sind sehr selten. Das Ziel dieser Studie war die Beurteilung der klinischen Wirksamkeit verschiedener Fraktionierungsschemata und Einzeldosen in einem experimentellen Arthritismodell der Ratte, um zu überprüfen, ob eine Dosis- oder Fraktionierungsabhängigkeit vorliegt.Material und Methodik:Bei weiblichen Lewis-Ratten (n = 128) wurde durch intradermale Injektion von hitzeinaktiviertem Mycobacterium tuberculosis am Tag 0 eine Adjuvansarthritis induziert. Beide Hinterpfoten arthritischer Versuchstiere wurden scheinbestrahlt (Gruppe 1: Tage 10–14; Gruppe 2: Tage 15–19; Gruppe 3: Tage 22–26) oder lokal bestrahlt mit entweder 5 × 1,0 Gy (Gruppe 4: Tage 10–14; Gruppe 6: Tage 15–19; Gruppe 8: Tage 22–26; Gruppe 10: Tage 10, 12, 14, 16 und 18) oder 5 × 0,5 Gy (Gruppe 5: Tage 10–14; Gruppe 7: Tage 15–19; Gruppe 9: Tage 22–26; Gruppe 11: Tage 10, 12, 14, 16 und 18; Gruppe 12: Tage 10–14 und 22–26). Die klinischen Parameter Arthritisscore (AS), Hinterpfotenvolumen (HPV) und Körpergewicht wurden im Verlauf bestimmt.Ergebnisse:Nach 5 × 0,5 Gy oder 5 × 1,0 Gy während des akuten Entzündungsmaximums (Tage 15–19) konnte eine signifikante Reduktion der klinischen Arthritisparameter beobachtet werden. Der günstigste Behandlungseffekt wurde mit zwei täglich fraktionierten Serien von 5 × 0,5 Gy bei frühzeitigem Behandlungsbeginn (Tage 10–14) und Wiederholung im Intervall (Tage 22–26) erreicht. Nach 5 × 1,0 Gy an den Tagen 10–14 oder in einem protrahierten Schema (Tage 10, 12, 14, 16 und 18) war lediglich ein nichtsignifikanter positiver Trend nachweisbar. Die tägliche fraktionierte Bestrahlung in der chronischen Phase der Adjuvansarthritis (Tage 22-26) zeigte keinen positiven klinischen Effekt.Schlussfolgerung:Eine niedrig dosierte Strahlentherapie ist in der Lage, die volle Ausprägung einer arthritischen Reaktion zu verhindern, wenn sie während der floriden Phase der Adjuvansarthritis appliziert wird. In dieser Studie waren zwei Bestrahlungsserien von 5 × 0,5 Gy mit frühzeitigem Behandlungsbeginn (Tage 10–14) und Wiederholung im Intervall (Tage 22–26) das effektivste Behandlungsschema.

ACCELERATED PARTIAL BREAST IRRADIATION WITH INTERSTITIAL IMPLANTS: RISK FACTORS ASSOCIATED WITH INCREASED LOCAL RECURRENCE

PURPOSE To analyze patient, disease, and treatment-related factors regarding their impact on local control after interstitial multicatheter accelerated partial breast irradiation (APBI). METHODS AND MATERIALS Between November 2000 and April 2005, 274 patients with early breast cancer were recruited for the German-Austrian APBI Phase II trial (ClinicalTrials.gov identifier: NCT00392184). In all, 64% (175/274) of the patients received pulsed-dose-rate (PDR) brachytherapy and 36% (99/274) received high-dose-rate (HDR) brachytherapy. Prescribed reference dose for HDR brachytherapy was 32 Gy in eight fractions of 4 Gy, twice daily. Prescribed reference dose in PDR brachytherapy was 49.8 Gy in 83 consecutive fractions of 0.6 Gy each hour. Total treatment time was 3 to 4 days. RESULTS The median follow-up time was 64 months (range, 9-110). The actuarial 5-year local recurrence free survival rate (5-year LRFS) was 97.7%. Comparing patients with an age <50 years (49/274) vs. ≥50 years (225/274), the 5-year LRFS resulted in 92.5% and 98.9% (exact p = 0.030; 99% confidence interval, 0.029-0.032), respectively. Antihormonal treatment (AHT) was not applied in 9% (24/274) of the study population. The 5-year LRFS was 99% and 84.9% (exact p = 0.0087; 99% confidence interval, 0.0079-0.0094) in favor of the patients who received AHT. Lobular histology (45/274) was not associated with worse local control compared with all other histologies (229/274). The 5-year LRFS rates were 97.6% and 97.8%, respectively. CONCLUSIONS Local control at 5 years is excellent and comparable to therapeutic successes reported from corresponding whole-breast irradiation trials. Our data indicate that patients <50 years of age ought to be excluded from APBI protocols, and that patients with hormone-sensitive breast cancer should definitely receive adjuvant AHT when interstitial multicatheter APBI is performed. Lobular histology need not be an exclusion criterion for future APBI trials.

Low-Dose X-Irradiation of Adjuvant-Induced Arthritis in Rats

Background and Purpose:Low-dose radiotherapy is widely accepted as a very effective treatment option for inflammatory symptoms associated with painful degenerative joint disorders. Radiation doses and fractionation schedules in practical use are empirical and mainly based on clinical observations. Experimental data are rare. The efficacy of low-dose X-irradiation on adjuvant induced arthritis in rats using different fractionation schemes was investigated in vivo, in order to explore whether there is a dose and fractionation dependence.Material and Methods:Adjuvant arthritis in female Lewis rats (n = 128) was induced by intradermal injection of heat-inactivated Mycobacterium tuberculosis on day 0. Both arthritic hind paws were sham-irradiated (group 1: days 10–14; group 2: days 15–19; group 3: days 22–26) or X-irradiated with either 5 × 1.0 Gy (group 4: days 10–14; group 6: days 15–19; group 8: days 22–26; group 10: days 10, 12, 14, 16, and 18) or 5 × 0.5 Gy (group 5: days 10–14; group 7: days 15–19; group 9: days 22–26; group 11: days 10, 12, 14, 16, and 18; group 12: days 10–14 and 22–26). The clinical parameters arthritis score (AS), hind paw volume (HPV), and body weight were determined.Results:A significant decrease of the clinical arthritis parameters was observed following 5 × 0.5 Gy or 5 × 1.0 Gy during the acute maximum of the inflammatory response (days 15–19). The most pronounced treatment effect was reached after two daily fractionated series of 5 × 0.5 Gy with an early treatment onset (days 10–14) and repetition in interval (days 22–26). After the application of 5 × 1.0 Gy on days 10–14 or in a protracted scheme (days 10, 12, 14, 16, and 18), only a nonsignificant positive trend could be detected. Daily fractionated X-irradiation in the chronic phase of adjuvant arthritis (days 22–26) did not show any positive clinical effect.Conclusion:Low-dose radiotherapy is able to prevent a full-blown arthritic reaction if given during the florid phase of adjuvant arthritis. Two series of 5 × 0.5 Gy with an early treatment onset (days 10–14) and repetition in interval (days 22–26) were the most effective treatment schedule in this experimental study.Hintergrund und Ziel:Die niedrig dosierte Strahlentherapie wird als effektive Behandlungsoption bei schmerzhaften, entzündlich reaktivierten degenerativen Gelenkerkrankungen angesehen. Die verwendeten Einzeldosen und Fraktionierungen basieren im Wesentlichen auf klinisch-empirischen Beobachtungen. Experimentelle Untersuchungen sind sehr selten. Das Ziel dieser Studie war die Beurteilung der klinischen Wirksamkeit verschiedener Fraktionierungsschemata und Einzeldosen in einem experimentellen Arthritismodell der Ratte, um zu überprüfen, ob eine Dosis- oder Fraktionierungsabhängigkeit vorliegt.Material und Methodik:Bei weiblichen Lewis-Ratten (n = 128) wurde durch intradermale Injektion von hitzeinaktiviertem Mycobacterium tuberculosis am Tag 0 eine Adjuvansarthritis induziert. Beide Hinterpfoten arthritischer Versuchstiere wurden scheinbestrahlt (Gruppe 1: Tage 10–14; Gruppe 2: Tage 15–19; Gruppe 3: Tage 22–26) oder lokal bestrahlt mit entweder 5 × 1,0 Gy (Gruppe 4: Tage 10–14; Gruppe 6: Tage 15–19; Gruppe 8: Tage 22–26; Gruppe 10: Tage 10, 12, 14, 16 und 18) oder 5 × 0,5 Gy (Gruppe 5: Tage 10–14; Gruppe 7: Tage 15–19; Gruppe 9: Tage 22–26; Gruppe 11: Tage 10, 12, 14, 16 und 18; Gruppe 12: Tage 10–14 und 22–26). Die klinischen Parameter Arthritisscore (AS), Hinterpfotenvolumen (HPV) und Körpergewicht wurden im Verlauf bestimmt.Ergebnisse:Nach 5 × 0,5 Gy oder 5 × 1,0 Gy während des akuten Entzündungsmaximums (Tage 15–19) konnte eine signifikante Reduktion der klinischen Arthritisparameter beobachtet werden. Der günstigste Behandlungseffekt wurde mit zwei täglich fraktionierten Serien von 5 × 0,5 Gy bei frühzeitigem Behandlungsbeginn (Tage 10–14) und Wiederholung im Intervall (Tage 22–26) erreicht. Nach 5 × 1,0 Gy an den Tagen 10–14 oder in einem protrahierten Schema (Tage 10, 12, 14, 16 und 18) war lediglich ein nichtsignifikanter positiver Trend nachweisbar. Die tägliche fraktionierte Bestrahlung in der chronischen Phase der Adjuvansarthritis (Tage 22-26) zeigte keinen positiven klinischen Effekt.Schlussfolgerung:Eine niedrig dosierte Strahlentherapie ist in der Lage, die volle Ausprägung einer arthritischen Reaktion zu verhindern, wenn sie während der floriden Phase der Adjuvansarthritis appliziert wird. In dieser Studie waren zwei Bestrahlungsserien von 5 × 0,5 Gy mit frühzeitigem Behandlungsbeginn (Tage 10–14) und Wiederholung im Intervall (Tage 22–26) das effektivste Behandlungsschema.

Quality-of-life results for accelerated partial breast irradiation with interstitial brachytherapy versus whole-breast irradiation in early breast cancer after breast-conserving surgery (GEC-ESTRO): 5-year results of a randomised, phase 3 trial

BACKGROUND Previous results from the GEC-ESTRO trial showed that accelerated partial breast irradiation (APBI) using multicatheter brachytherapy in the treatment of early breast cancer after breast-conserving surgery was non-inferior to whole-breast irradiation in terms of local control and overall survival. Here, we present 5-year results of patient-reported quality of life. METHODS We did this randomised controlled phase 3 trial at 16 hospitals and medical centres in seven European countries. Patients aged 40 years or older with 0-IIA breast cancer were randomly assigned (1:1) after breast-conserving surgery (resection margins ≥2 mm) to receive either whole-breast irradiation of 50 Gy with a boost of 10 Gy or APBI using multicatheter brachytherapy. Randomisation was stratified by study centre, tumour type, and menopausal status, with a block size of ten and an automated dynamic algorithm. There was no masking of patients or investigators. The primary endpoint of the trial was ipsilateral local recurrence. Here, we present 5-year results of quality of life (a prespecified secondary endpoint). Quality-of-life questionnaires (European Organisation for Research and Treatment of Cancer QLQ-C30, breast cancer module QLQ-BR23) were completed before radiotherapy (baseline 1), immediately after radiotherapy (baseline 2), and during follow-up. We analysed the data according to treatment received (as-treated population). Recruitment was completed in 2009, and long-term follow-up is continuing. The trial is registered at ClinicalTrials.gov, number NCT00402519. FINDINGS Between April 20, 2004, and July 30, 2009, 633 patients had accelerated partial breast irradiation and 551 patients had whole-breast irradiation. Quality-of-life questionnaires at baseline 1 were available for 334 (53%) of 663 patients in the APBI group and 314 (57%) of 551 patients in the whole-breast irradiation group; the response rate was similar during follow-up. Global health status (range 0-100) was stable in both groups: at baseline 1, APBI group mean score 65·5 (SD 20·6) versus whole-breast irradiation group 64·6 (19·6), p=0·37; at 5 years, APBI group 66·2 (22·2) versus whole-breast irradiation group 66·0 (21·8), p=0·94. The only moderate, significant difference (difference of 10-20 points) between the groups was found in the breast symptoms scale. Breast symptom scores were significantly higher (ie, worse) after whole-breast irradiation than after APBI at baseline 2 (difference of means 13·6, 95% CI 9·7-17·5; p<0·0001) and at 3-month follow-up (difference of means 12·7, 95% CI 9·8-15·6; p<0·0001). INTERPRETATION APBI with multicatheter brachytherapy was not associated with worse quality of life compared with whole-breast irradiation. This finding supports APBI as an alternative treatment option after breast-conserving surgery for patients with early breast cancer. FUNDING German Cancer Aid.