Noninferiority of Local Control and Comparable Toxicity of Intensity Modulated Radiation Therapy With Simultaneous Integrated Boost in Breast Cancer: 5-Year Results of the IMRT-MC2 Phase III Trial.

PURPOSE: The IMRT-MC2 trial was conducted to demonstrate the noninferiority of conventionally fractionated intensity modulated radiation therapy with a simultaneous integrated boost to 3-dimensional conformal radiation therapy with a sequential boost for adjuvant breast radiation therapy. METHODS AND MATERIALS: A total of 502 patients were randomized between 2011 and 2015 for the prospective, multicenter, phase III trial (NCT01322854). Five-year results of late toxicity (late effects normal tissue task force-subjective, objective, management, and analytical), overall survival, disease-free survival, distant disease-free survival, cosmesis (Harvard scale), and local control (noninferiority margin at hazard ratio [HR] of 3.5) were analyzed after a median follow-up of 62 months. RESULTS: The 5-year local control rate for the intensity modulated radiation therapy with simultaneous integrated boost arm was non-inferior to the control arm (98.7% vs 98.3%, respectively; HR, 0.582; 95% CI, 0.119-2.375; P = .4595). Furthermore, there was no significant difference in overall survival (97.1% vs 98.3%, respectively; HR, 1.235; 95% CI, 0.472-3.413; P = .6697), disease-free survival (95.8% vs 96.1%, respectively; HR, 1.130; 95% CI, 0.487-2.679; P = .7758), and distant disease-free survival (97.0% vs 97.8%, respectively; HR, 1.667; 95% CI, 0.575-5.434; P = .3601). After 5 years, late toxicity evaluation and cosmetic assessment further showed no significant differences between treatment arms. CONCLUSIONS: The 5-year results of the IMRT-MC2 trial provide strong evidence that the application of conventionally fractionated simultaneous integrated boost irradiation for patients with breast cancer is both safe and effective, with noninferior local control compared with 3-dimensional conformal radiation therapy with sequential boost.

Methods of Esthetic Assessment after Adjuvant Whole-Breast Radiotherapy in Breast Cancer Patients: Evaluation of the BCCT.core Software and Patients' and Physicians' Assessment from the Randomized IMRT-MC2 Trial.

The present analysis compares the esthetics assessment by the BCCT.core software in relation to patients' and physicians' ratings, based on the IMRT-MC2 trial. Within this trial, breast cancer patients received breast-conserving surgery (BCS) and adjuvant radiotherapy. At the baseline, 6 weeks, and 2 years after radiotherapy, photos of the breasts were assessed by the software and patients' and physicians' assessments were performed. Agreement rates of the assessments and their correlation with breast asymmetry indices were evaluated. The assessments of the software and the physicians were significantly correlated with asymmetry indices. Before and 6 weeks after radiotherapy, the patients' self-assessment was only correlated with the lower breast contour (LBC) and upward nipple retraction (UNR), while after 2 years, there was also a correlation with other indices. Only a slight agreement between the BCCT.core software and the physicians' or patients' assessment was seen, while a moderate and substantial agreement was detected between the physicians' and the patients' assessment after 6 weeks and 2 years, respectively. The BCCT.core software is a reliable tool to measure asymmetries, but may not sufficiently evaluate the esthetic outcome as perceived by patients. It may be more appropriate for a long-term follow-up, when symmetry appears to increase in importance.

Quality of life after simultaneously integrated boost with intensity-modulated versus conventional radiotherapy with sequential boost for adjuvant treatment of breast cancer: 2-year results of the multicenter randomized IMRT-MC2 trial.

BACKGROUND: We recently published 2-year results of the prospective, randomized IMRT-MC2 trial, showing non-inferior local control and cosmesis in breast cancer patients after conventionally fractionated intensity-modulated radiotherapy with simultaneously integrated boost (IMRT-SIB), compared to 3D-conformal radiotherapy with sequential boost (3D-CRT-seqB). Here, we report on 2-year quality of life results. PATIENTS AND METHODS: 502 patients were enrolled and randomized to IMRT-SIB (50.4 Gy in 1.8 Gy fractions with a 64.4 Gy SIB to the tumor bed) or to 3D-CRT-seqB (50.4 Gy in 1.8 Gy fractions, followed by a sequential boost of 16 Gy in 2 Gy fractions). For quality of life (QoL) assessment, patients completed the QLQ-C30 and QLQ-BR23 questionnaires at baseline, 6 weeks and 2 years after radiotherapy. RESULTS: Significant differences between treatment arms were seen 6 weeks after radiotherapy for pain (22.3 points for IMRT vs. 27.0 points for 3D-CRT-seqB; p = 0.033) and arm symptoms (18.1 points for IMRT vs. 23.6 points for 3D-CRT-seqB; p = 0.013), both favoring IMRT-SIB. Compared to baseline values, both arms showed significant improvement in global score (IMRT: p = 0.009; 3D-CRT: p = 0.001) after 2 years, with slight deterioration on the role (IMRT: p = 0.008; 3-D-CRT: p = 0.001) and social functioning (IMRT: p = 0.013, 3D-CRT: p = 0.001) as well as the future perspectives scale (IMRT: p = 0.003; 3D-CRT: p = 0.0034). CONCLUSION: This is the first randomized phase III trial demonstrating that IMRT-SIB was associated with slightly superior QoL compared to 3-D-CRT-seqB. These findings further support the clinical implementation of SIB in adjuvant breast cancer treatment.

Intensity Modulated Radiation Therapy (IMRT) With Simultaneously Integrated Boost Shortens Treatment Time and Is Noninferior to Conventional Radiation Therapy Followed by Sequential Boost in Adjuvant Breast Cancer Treatment: Results of a Large Randomized Phase III Trial (IMRT-MC2 Trial).

PURPOSE: In the modern era, improvements in radiation therapy techniques have paved the way for simultaneous integrated boost irradiation in adjuvant breast radiation therapy after breast conservation surgery. Nevertheless, randomized trials supporting the noninferiority of this treatment to historical standards of care approach are lacking. METHODS: A prospective, multicenter, randomized phase 3 trial (NCT01322854) was performed to analyze noninferiority of conventional fractionated intensity modulated radiation therapy with simultaneous integrated boost (IMRT-SIB) to 3-D conformal radiation therapy with sequential boost (3-D-CRT-seqB) for breast cancer patients. Primary outcomes were local control (LC) rates at 2 and 5 years (noninferiority margin at hazard ratio [HR] of 3.5) as well as cosmetic results 6 weeks and 2 years after radiation therapy (evaluated via photo documentation calculating the relative breast retraction assessment [pBRA] score [noninferiority margin of 1.25]). RESULTS: A total of 502 patients were randomly assigned from 2011 to 2015. After a median follow-up of 5.1 years, the 2-year LC for the IMRT-SIB arm was noninferior to the 3-D-CRT-seqB arm (99.6% vs 99.6%, respectively; HR, 0.602; 95% CI, 0.123-2.452; P = .487). In addition, noninferiority was also shown for cosmesis after IMRT-SIB and 3-D-CRT-seqB at both 6 weeks (median pBRA, 9.1% vs 9.1%) and 2 years (median pBRA, 10.4% vs 9.8%) after radiation therapy (95% CI, -0.317 to 0.107 %; P = .332). Cosmetic assessment according to the Harvard scale by both the patient and the treating physician as well as late-toxicity evaluation with the late effects normal tissues- subjective, objective, management, analytic criteria, a score for the evaluation of long-term adverse effects in normal tissue, revealed no significant differences between treatment arms. In addition, there was no difference in overall survival rates (99.6% vs 99.6%; HR, 3.281; 95% CI: -0.748 to 22.585; P = .148) for IMRT-SIB and 3-D-CRT-seqB, respectively. CONCLUSIONS: To our knowledge, this is the first prospective trial reporting the noninferiority of IMRT-SIB versus 3-D-CRT-seqB with respect to cosmesis and LC at 2 years of follow-up. This treatment regimen considerably shortens adjuvant radiation therapy times without compromising clinical outcomes.

Acute toxicity of normofractionated intensity modulated radiotherapy with simultaneous integrated boost compared to three-dimensional conformal radiotherapy with sequential boost in the adjuvant treatment of breast cancer.

BACKGROUND: Intensity-modulated radiotherapy (IMRT) improves dose homogeneity and late toxicity compared to simple tangential techniques in adjuvant whole-breast radiotherapy for patients with breast cancer. Simultaneous-integrated boost (SIB) radiotherapy shortens the overall treatment time and improves dose homogeneity. However, prospective randomized trials regarding IMRT with SIB for adjuvant radiotherapy in breast cancer are lacking. METHODS: The IMRT-MC2 (MINT) trial is a phase III prospective randomized controlled trial comparing IMRT with SIB (Arm A: whole breast 28 × 1.8 Gy, Boost 28 × 2.3 Gy) to 3D-conformal radiotherapy with a sequential boost (Arm B: whole breast 28 × 1.8 Gy, boost 8 × 2 Gy) in patients with breast cancer after BCS. Indication for boost radiotherapy was defined as age < 70 years or age > 70 years with presence of additional risk factors. This is a retrospective analysis of acute toxicity at one of two trial sites. RESULTS: Five hundred two patients were randomized, of which 446 patients were eligible for this analysis. There was no statistically significant difference in terms of any grade radiation dermatitis between the two treatment arms at the end of treatment (p = 0.26). However, radiation dermatitis grade 2/3 (29.1% vs. 20.1 and 3.5% vs. 2.3%) occurred significantly more often in Arm A (p = 0.02). Breast/chest wall pain at the first follow-up visit was significantly more common in patients treated on Arm B (p = 0.02). CONCLUSIONS: Treatment on both arms was well tolerated, however there were some differences regarding radiodermatitis and breast pain. Further analyses are ongoing. TRIAL REGISTRATION: clinicaltrials.gov , NCT01322854 , registered 24th March 2011.

Resistance Exercise and Inflammation in Breast Cancer Patients Undergoing Adjuvant Radiation Therapy: Mediation Analysis From a Randomized, Controlled Intervention Trial.

PURPOSE: To explore the mediating role of inflammatory parameters in the development of fatigue, pain, and potentially related depressive symptoms during radiation therapy for breast cancer and its mitigation by resistance exercise. METHODS AND MATERIALS: Breast cancer patients scheduled for adjuvant radiation therapy were randomized to 12-week progressive resistance exercise training (EX) or a relaxation control group. Interleukin-6 (IL-6) and interleukin-1 receptor antagonist (IL-1ra) were measured in serum samples collected before, at the end, and 6 weeks after radiation therapy from 103 chemotherapy-naïve participants. Fatigue was assessed with the multidimensional Fatigue Assessment Questionnaire, pain with the European Organization for Research and Treatment of Cancer QLQ-C30, and depressive symptoms with the Center for Epidemiologic Studies Depression Scale. Analysis of covariance models, partial correlations, Freedman-Schatzkin tests, and R(2) effect-size measures for mediation were calculated. RESULTS: The analysis of covariance models revealed a significant intervention effect on IL-6 (P=.010) and the IL-6/IL-1ra ratio (P=.018), characterized by a marked increase during radiation therapy among controls, but no significant change in EX. Interleukin-1 receptor antagonist did not change significantly in either group (P=.88). Increased IL-6 and IL-6/IL-1ra levels at the end of radiation therapy were significantly associated with increased physical fatigue and pain 6 weeks after radiation. We observed significant partial mediation by IL-6 and IL-6/IL-1ra of the effect of resistance exercise on physical fatigue (Freedman-Schatzkin P=.023 and P<.001) and pain (both P<.001). Hereby IL-6 and IL-6/IL-1ra mediated between 15% and 24% of the variance of physical fatigue and pain explained by the intervention. CONCLUSIONS: This randomized, controlled trial showed a significantly increased proinflammatory cytokine level after adjuvant radiation therapy in breast cancer patients. This effect was counteracted by progressive resistance exercise training. Interleukin-6 and the IL-6/IL-1ra ratio seemed to mediate the beneficial effect of exercise on physical fatigue and pain but only to a small extent.

Factors influencing participation in a randomized controlled resistance exercise intervention study in breast cancer patients during radiotherapy.

BACKGROUND: Over the past years knowledge about benefits of physical activity after cancer is evolving from randomized exercise intervention trials. However, it has been argued that results may be biased by selective participation. Therefore, we investigated factors influencing participation in a randomized exercise intervention trial for breast cancer patients. METHODS: Non-metastatic breast cancer patients were systematically screened for a randomized exercise intervention trial on cancer-related fatigue. Participants and nonparticipants were compared concerning sociodemographic characteristics (age, marital status, living status, travel time to the training facility), clinical data (body-mass-index, tumor stage, tumor size and lymph node status, comorbidities, chemotherapy), fatigue, and physical activity. Reasons for participation or declination were recorded. RESULTS: 117 patients (52 participants, 65 nonparticipants) were evaluable for analysis. Multiple regression analyses revealed significantly higher odds to decline participation among patients with longer travel time (p=0.0012), living alone (p=0.039), with more comorbidities (0.031), previous chemotherapy (p=0.0066), of age≥70 years (p=0.025), or being free of fatigue (p=0.0007). No associations were found with BMI or physical activity. By far the most frequently reported reason for declination of participation was too long commuting time to the training facility. CONCLUSIONS: Willingness of breast cancer patients to participate in a randomized exercise intervention study differed by sociodemographic factors and health status. Neither current physical activity level nor BMI appeared to be selective for participation. Reduction of personal inconveniences and time effort, e.g. by decentralized training facilities or flexible training schedules, seem most promising for enhancing participation in exercise intervention trials. TRIAL REGISTRATION: Registered at ClinicalTrials.gov: NCT01468766 (October 2011).

Single-dose radiosurgical treatment for hepatic metastases--therapeutic outcome of 138 treated lesions from a single institution.

BACKGROUND: Local ablative therapies such as stereotactically guided single-dose radiotherapy or helical intensity-modulated radiotherapy (tomotherapy) with high single-doses are successfully applied in many centers in patients with liver metastasis not suitable for surgical resection. This study presents results from more than 10 years of clinical experience and evaluates long-term outcome and efficacy of this therapeutic approach. PATIENTS AND METHODS: From 1997 to 2009 a total of 138 intrahepatic tumors of 90 patients were irradiated with single doses of 17 to 30 Gy (median dose 24 Gy). Median age of the patients was 64 years (range 31-89 years). Most frequent underlying tumor histologies were colorectal adenocarcinoma (70 lesions) and breast cancer (27 lesions). In 35 treatment sessions multiple targets were simultaneously irradiated (up to four lesions at once). Local progression-free (PFS) and overall survival (OS) after treatment were investigated using uni- and multiple survival regression models. RESULTS: Median overall survival of all patients was 24.3 months. Local PFS was 87%, 70% and 59% after 6, 12 and 18 months, respectively. Median time to local progression was 25.5 months. Patients with a single lesion and no further metastases at time of RT had a favorable median PFS of 43.1 months according to the Kaplan-Meier estimator. The type of tumor showed a statistical significant influence on local PFS, with a better prognosis for breast cancer histology than for colorectal carcinoma in uni- and multiple regression analysis (p = 0.05). Multiple regression analysis revealed no influence of planning target volume (PTV), patient age and radiation dose on local PFS. Treatment was well tolerated with no severe adverse events. CONCLUSION: This study confirms safety of SBRT in liver lesions, with 6- and 12 months local control of 87% and 70%. The dataset represents the clinical situation in a large oncology setting, with many competing treatment options and heterogeneous patient characteristics.

Randomized controlled trial to evaluate the effects of progressive resistance training compared to progressive muscle relaxation in breast cancer patients undergoing adjuvant radiotherapy: the BEST study.

BACKGROUND: Cancer-related fatigue (CRF) is one of the most common and distressing side effects of cancer and its treatment. During and after radiotherapy breast cancer patients often suffer from CRF which frequently impairs quality of life (QoL). Despite the high prevalence of CRF in breast cancer patients and the severe impact on the physical and emotional well-being, effective treatment methods are scarce.Physical activity for breast cancer patients has been reported to decrease fatigue, to improve emotional well-being and to increase physical strength. The pathophysiological and molecular mechanisms of CRF and the molecular-biologic changes induced by exercise, however, are poorly understood.In the BEST trial we aim to assess the effects of resistance training on fatigue, QoL and physical fitness as well as on molecular, immunological and inflammatory changes in breast cancer patients during adjuvant radiotherapy. METHODS/DESIGN: The BEST study is a prospective randomized, controlled intervention trial investigating the effects of a 12-week supervised progressive resistance training compared to a 12-week supervised muscle relaxation training in 160 patients with breast cancer undergoing adjuvant radiotherapy. To determine the effect of exercise itself beyond potential psychosocial group effects, patients in the control group perform a group-based progressive muscle relaxation training. Main inclusion criterion is histologically confirmed breast cancer stage I-III after lumpectomy or mastectomy with indication for adjuvant radiotherapy. Main exclusion criteria are acute infectious diseases, severe neurological, musculosceletal or cardiorespiratory disorders. The primary endpoint is cancer-related fatigue; secondary endpoints include immunological and inflammatory parameters analyzed in peripheral blood, saliva and urine. In addition, QoL, depression, physical performance and cognitive capacity will be assessed. DISCUSSION: The BEST study is the first randomized controlled trial comparing progressive resistance training with muscle relaxation training in breast cancer patients during adjuvant radiotherapy. Based on the analysis of physiological, immunological and inflammatory parameters it will contribute to a better understanding of the physiological and psychosocial effects and the biological mechanisms of resistance training. The ultimate goal is the implementation of optimized intervention programs to reduce fatigue, improve quality of life and potentially the prognosis after breast cancer. TRIAL REGISTRATION: ClinicalTrials.gov NCT01468766.

Omission of axillary dissection according to ACOSOG Z0011: impact on adjuvant treatment recommendations.

OBJECTIVE: A recent, randomized trial (ACOSOG Z0011) has demonstrated that omission of completion axillary lymph node dissection (ALND) in patients with one or two sentinel lymph node (SLN) metastases treated with breast conserving therapy (BCT) does not have a negative impact on survival. This study evaluates the impact of omitting ALND on adjuvant treatment recommendations. METHODS: Performing a search of our clinical database, we identified patients meeting the main inclusion and exclusion criteria of ACOSOG Z0011 treated at the University of Heidelberg Breast Center. We performed blinded mock interdisciplinary tumor boards based on patient and tumor characteristics as well as (1) SLN information or (2) final nodal status after ALND. Differences between treatment recommendations were noted and analyzed. RESULTS: A total of 132 patients were included; 80.3 % of these had one and 19.7 % had two metastatic sentinel nodes with a rate of micrometastases only of 19.7 %, and 39.7 % of patients had additional nonsentinel node metastases upon ALND. Overall, there was a change in adjuvant chemotherapy in 18.2 % of cases. Treatment recommendations based on ALND lead to a more aggressive therapy in 16.6 % of cases, all of them with additional metastatic nonsentinel nodes. Chemotherapy was not recommended in only two cases (1.5 %) based on ALND. Based on ALND, irradiation of the supraclavicular and infraclavicular nodes was added in 5.3 % of patients. CONCLUSIONS: Completion ALND for patients with one or two metastatic sentinel nodes in pT1-2 cN0 PBC treated with BCT does have a relevant impact on adjuvant treatment. This should be considered in shared decision making.

Neoadjuvant chemoradiation with Gemcitabine for locally advanced pancreatic cancer.

INTRODUCTION: To evaluate efficacy and secondary resectability in patients with locally advanced pancreatic cancer (LAPC) treated with neoadjuvant chemoradiotherapy (CRT). PATIENTS AND METHODS: A total of 215 patients with locally advanced pancreatic cancer were treated with chemoradiation at a single institution. Radiotherapy was delivered with a median dose of 52.2 Gy in single fractions of 1.8 Gy. Chemotherapy was applied concomitantly as gemcitabine (GEM) at a dose of 300 mg/m2 weekly, followed by adjuvant cycles of full-dose GEM (1000 mg/m2). After neoadjuvant CRT restaging was done to evaluate secondary resectability. Overall and disease-free survival were calculated and prognostic factors were estimated. RESULTS: After CRT a total of 26% of all patients with primary unresectable LAPC were chosen to undergo secondary resection. Tumour free resection margins could be achieved in 39.2% (R0-resection), R1-resections were seen in 41.2%, residual macroscopic tumour in 11.8% (R2) and in 7.8% resection were classified as Rx. Patients with complete resection after CRT showed a significantly increased median overall survival (OS) with 22.1 compared to 11.9 months in non-resected patients. Median OS and disease-free survival (DFS) of all patients were 12.3 and 8.1 months respectively. In most cases the first site of disease progression was systemic with hepatic (52%) and peritoneal (36%) metastases. DISCUSSION: A high percentage of patients with locally advanced pancreatic cancer can undergo secondary resection after gemcitabine-based chemoradiation and has a relative long-term prognosis after complete resection.

Simultaneous integrated boost for adjuvant treatment of breast cancer--intensity modulated vs. conventional radiotherapy: the IMRT-MC2 trial.

BACKGROUND: Radiation therapy is an essential modality in the treatment of breast cancer. Addition of radiotherapy to surgery has significantly increased local control and survival rates of the disease. However, radiotherapy is also associated with side effects, such as tissue fibrosis or enhanced vascular morbidity. Modern radiotherapy strategies, such as intensity modulated radiotherapy (IMRT), can shorten the overall treatment time by integration of the additional tumor bed boost significantly. To what extent this might be possible without impairing treatment outcome and cosmetic results remains to be clarified. METHODS/DESIGN: The IMRT-MC2 study is a prospective, two armed, multicenter, randomized phase-III-trial comparing intensity modulated radiotherapy with integrated boost to conventional radiotherapy with consecutive boost in patients with breast cancer after breast conserving surgery. 502 patients will be recruited and randomized into two arms: patients in arm A will receive IMRT in 28 fractions delivering 50.4 Gy to the breast and 64.4 Gy to the tumor bed by integrated boost, while patients in arm B will receive conventional radiotherapy of the breast in 28 fractions to a dose of 50.4 Gy and consecutive boost in 8 fractions to a total dose of 66.4 Gy. DISCUSSION: Primary objectives of the study are the evaluation of the cosmetic results 6 weeks and 2 years post treatment and the 2- and 5-year local recurrence rates for the two different radiotherapy strategies. Secondary objectives are long term overall survival, disease free survival and quality of life. TRIAL REGISTRATION: ClinicalTrials.gov Protocol ID: NCT01322854.

Treatment of locally advanced carcinomas of head and neck with intensity-modulated radiation therapy (IMRT) in combination with cetuximab and chemotherapy: the REACH protocol.

BACKGROUND: Primary treatment of carcinoma of the oro-/hypopharynx or larynx may consist of combined platinum-containing chemoradiotherapy. In order to improve clinical outcome (i.e. local control/overall survival), combined therapy is intensified by the addition of the EGFR inhibitor cetuximab (Erbitux®). Radiation therapy (RT) is carried out as intensity-modulated RT (IMRT) to avoid higher grade acute and late toxicity by sparing of surrounding normal tissues. METHODS/DESIGN: The REACH study is a prospective phase II study combining chemoradiotherapy with carboplatin/5-Fluorouracil (5-FU) and the monoclonal epidermal growth factor-receptor (EGFR) antibody cetuximab (Erbitux®) as intensity-modulated radiation therapy in patients with locally advanced squamous-cell carcinomas of oropharynx, hypopharynx or larynx.Patients receive weekly chemotherapy infusions in the 1st and 5th week of RT. Additionally, cetuximab is administered weekly throughout the treatment course. IMRT is delivered as in a classical concomitant boost concept (bid from fraction 16) to a total dose of 69,9 Gy. DISCUSSION: Primary endpoint of the trial is local-regional control (LRC). Disease-free survival, progression-free survival, overall survival, toxicity, proteomic and genomic analyses are secondary endpoints. The aim is to explore the efficacy as well as the safety and feasibility of this combined radioimmunchemotherapy in order to improve the outcome of patients with advanced head and neck cancer. TRIAL REGISTRATION: ISRCTN87356938.

Time- and dose-dependency of radiographic normal tissue changes of the lung after stereotactic radiotherapy.

PURPOSE: Normal tissue changes (NTC) of the normal lung parenchyma are commonly seen after stereotactic single-dose radiotherapy (radiosurgery) of lung tumors. The aim of this study was to investigate the extent and dynamics of NTCs after radiosurgery. METHODS AND MATERIALS: Fifty lung tumors in 49 patients were treated with radiosurgery. Follow-up CTs were anatomically matched to the treatment planning CTs, incorporating the treatment plan and enabling spatial correlation of initial radiation dose distribution and subsequent NTCs of the lung. Lung parenchyma was divided into nine areas of different radiation dose exposures (range, 6-35 Gy). Areas were investigated and compared at different time points according to the development of NTCs. RESULTS: Twenty-six patients developed NTCs during follow-up. The evaluation of the dependency of the extent of NTCs on the amount of radiation dose lead to a linear model for the fixed effects: Fraction of reacting volume =Intercept(T) +0.0208 * Dose ("Dose" should be given in Gy). Dose had a slope of 0.0208 (fraction of normal tissue reaction/Gy) (SE 0.000804, p < 0.0001), implying a significant correlation between dose level and the extent of NTC. CONCLUSION: For radiosurgery of lung tumors, a significant correlation of radiation dose and the extent of NTCs could be demonstrated. Using the introduced formula, a preview on the extent of NTCs to develop in normal lung parenchyma according to the dose level can be performed.

4D-CT-based target volume definition in stereotactic radiotherapy of lung tumours: comparison with a conventional technique using individual margins.

PURPOSE: To investigate the dosimetric benefit of integration of 4D-CT in the planning target volume (PTV) definition process compared to conventional PTV definition using individual margins in stereotactic body radiotherapy (SBRT) of lung tumours. MATERIAL AND METHODS: Two different PTVs were defined: PTV(conv) consisting of the helical-CT-based clinical target volume (CTV) enlarged isotropically for each spatial direction by the individually measured amount of motion in the 4D-CT, and PTV(4D) encompassing the CTVs defined in the 4D-CT phases displaying the extremes of the tumour position. Tumour motion as well as volumetric and dosimetric differences and relations of both PTVs were evaluated. RESULTS: Volumetric examinations revealed a significant reduction of the mean PTV by 4D-CT from 57.7 to 40.7 cm(3) (31%) (p<0.001). A significant inverse correlation was found for the motion vector and the amount of inclusion of PTV(4D) in PTV(conv) (r=-0.69, 90% confidence limits: -0.87 and -0.34, p=0.007). Mean lung dose (MLD) was decreased significantly by 17% (p<0.001). CONCLUSIONS: In SBRT of lung tumours the mere use of individual margins for target volume definition cannot compensate for the additional effects that the implementation of 4D-CT phases can offer.

Long-term outcome of postoperative irradiation in patients with newly diagnosed WHO grade III anaplastic gliomas.

PURPOSE: Patients with anaplastic gliomas have a more favorable overall survival than patients with glioblastomas. In most analyses, WHO grade III and 1V tumors are not analyzed separately. The present analysis reports outcome after postoperative radiotherapy in patients with WHO grade III gliomas. PATIENTS AND METHODS: Between January 1988 and January 2007, 127 patients with WHO grade III tumors were treated with radiotherapy; the histological classification was pure astrocytoma in 104 patients, oligoastrocytoma in 12 and pure oligodendroglioma in 11 patients. Median age was 48 years. After the primary diagnosis, a biopsy had been performed in 72 patients; subtotal and total resections were performed in 37 and 18 patients, respectively. In all patients radiotherapy was applied with a median dose of 60 Gy in conventional fractionation. The median follow-up time was 18 months. RESULTS: Median overall survival was 17 months. Overall survival was significantly influenced by the extent of surgery. Median overall survival was 32 months after complete resection, 36 months after subtotal resection, and 12 months after biopsy. Median overall survival was 7 months for patients with anaplastic astrocytomas, 44 months for patients with mixed tumors, and 47 months for those with pure oligodendrogliomas. Age significantly influenced overall survival. Median progression-free survival was 9 months; the extent of neurosurgical resection significantly influenced progression-free survival. CONCLUSION: Patients with WHO grade III anaplastic astrocytomas, oligodendrogliomas and oligoastrocytomas show favorable overall survival after postoperative radiotherapy compared with glioblastoma patients and should therefore be analyzed separately. Radiochemotherapy might further improve outcome.

Palliative radiotherapy of retrobulbar orbit metastases due to breast cancer.

BACKGROUND: In breast cancer, the occurrence of retrobulbar metastases of the orbit is rare compared to intraocular metastases. The clinical symptoms are quite different. Impairment of vision, exophthalmus, double vision, vertigo, and pain reduce patients' quality of life. PATIENTS AND METHODS: The benefit of palliative irradiation of the orbit was researched retrospectively in 7 patients. This report also presents the first case in the literature of a breast cancer patient with bi-orbital enophthalmus caused by bilateral retrobulbar metastases that were successfully treated with radiotherapy. Irradiation was performed by photon or electron beams (20-50 Gy). Clinical restaging was done at the end of radiotherapy and 6 weeks thereafter. RESULTS: After irradiation, 6 out of 7 patients showed a distinct clinical response with good palliation and no major side effects. Exophthalmus, pain, and vertigo were significantly reduced in all cases. Double vision disappeared in 3 out of 4 patients, eye muscle paralysis in 5 out of 6 patients. The median overall survival after irradiation of the orbit was 7.3 months. CONCLUSION: Palliative radiotherapy of retrobulbar metastases of breast cancer is very effective in reducing acute clinical symptoms and increasing quality of life. Nonetheless, patients have a poor prognosis.

Radiochemotherapy with temozolomide as re-irradiation using high precision fractionated stereotactic radiotherapy (FSRT) in patients with recurrent gliomas.

PURPOSE: To evaluate outcome after fractionated stereotactic radiotherapy (FSRT) and concomitant daily temozolomide (TMZ) in patients with recurrent gliomas. MATERIALS AND METHODS: Twenty-five patients with recurrent or progressive gliomas were treated with FSRT in combination with TMZ at the Department of Radiation Oncology, University of Heidelberg. Histologic classification at primary diagnosis included low-grade astrocytoma in 7 patients (28%), grade III gliomas in 10 patients (40%) and glioblastoma in 8 patients (32%). All patients had undergone at least one neurosurgical resection, which was complete in 5 patients (20%), subtotal in 13 patients (52%) and a biopsy only in 7 patients (28%). Nineteen patients (76%) had undergone neurosurgical resection for tumor recurrence. All patients had received radiation therapy with a median dose of 60 Gy. The median time interval between primary RT and re-irradiation was 36 months. Using FSRT, we applied a median total dose of 36 Gy in a median fractionation of 5 x 2 Gy/week. Chemotherapy with TMZ was applied in a median dose of 50 mg/m(2). RESULTS: Median overall survival was 59 months. Median survival from re-irradiation was 8 months. Actuarial survival rates at 6 and 12 months were 81% and 25%. Median PFS was 5 months; actuarial PFS rates at 6 and 12 months were 48% and 16%. Treatment could be completed in all patients as scheduled without interruptions >3 days. No severe treatment-related side effects could be observed. CONCLUSION: Re-irradiation and TMZ is safe and effective in a subgroup of patients with recurrent gliomas. Further evaluation of radiochemotherapy regimens for recurrent or progressive gliomas is warranted.

Influence of radiotherapy treatment concept on the outcome of patients with localized ependymomas.

PURPOSE: To assess the outcome of 57 patients with localized ependymomas treated with radiotherapy (RT). METHODS AND MATERIALS: Fifty-seven patients with localized ependymomas were treated with RT. Histology was myxopapillary ependymoma (n = 4), ependymoma (n = 23), and anaplastic ependymoma (n = 30). In 16 patients, irradiation of the craniospinal axis (CSI) was performed with a median dose of 20 Gy. Forty-one patients were treated with local RT, with a local dose of 45 Gy to the posterior fossa, including a boost to the tumor bed of 9 Gy. In 19 patients, the tumor bed was irradiated with a median dose of 54 Gy. RESULTS: Overall survival after primary diagnosis was 83% and 71% at 3 and 5 years. Five-year overall survival was 80% in low-grade and 79% in high-grade tumors. Survival from RT was 79% at 3 and 64% at 5 years. We could not show a significant difference in overall survival between CSI and local RT only. Freedom of local failure was 67% at 5 years in patients treated with CSI and 60% at 5 years after local RT. A rate of 83% for distant failure-free survival could be observed in the CSI group as opposed to 93% in the group receiving local RT only. CONCLUSION: Local RT in patients with localized tumors is equieffective to CSI. The radiation oncologist must keep in mind that patients with localized ependymomas benefit from local doses > or =45 Gy.

Stereotactic single-dose radiotherapy of lung metastases.

BACKGROUND: Stereotactic treatment approaches lead to a significant reduction of irradiated volumes, which should make pulmonary targets more accessible to radiotherapy. PATIENTS AND METHODS: Between May 1997 and December 2005, 61 patients received stereotactic single-dose dose treatment for 71 pulmonary metastases. Doses to the isocenter ranged from 12 to 30 Gy. Survival and local tumor control rates were evaluated prospectively. RESULTS: After a median follow-up period of 14 months the actuarial overall survival was 78.4%, 65.1%, and 47.8% 12, 24, and 36 months after therapy, respectively. There was a significantly better survival (p = 0.023) for patients not developing further metastases during follow-up. The actuarial local progression-free rate was 88.6%, 73.7%, and 63.1% 12, 24, and 36 months after therapy. Although the majority of patients (70.4%) developed perifocal normal-tissue changes, these were not related to clinically relevant toxicities. CONCLUSION: Stereotactic single-dose radiotherapy is a feasible, safe and effective local treatment option for solitary pulmonary metastases in patients with contraindications to surgery or for palliation of symptomatic pulmonary metastases.