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).

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Prediction of radiation-induced changes in the lung after stereotactic body radiation therapy of non-small-cell lung cancer.

PURPOSE: To estimate the risk of radiation-induced changes in the lung before single-dose treatment (stereotactic body radiation therapy [SBRT]) of lung cancer, the quantitative dose-response and volume-response relations must be known. METHODS AND MATERIALS: A total of 64 patients treated for non-small-cell lung cancer with single doses of 20-30 Gy were classified according to the occurrence or nonoccurrence of perifocal changes in the lung detected by CT. Patients without toxic events in the lung were required to have >or=6 months of follow-up. The mean dose (D(mean)) in the ipsilateral lung and the volume receiving >7 or 10 Gy (V7 and V10, respectively) were used to calculate the dose-response and volume-response curves. The predictive value of additional variables was also investigated. RESULTS: Of the 64 patients, 83% exhibited the selected endpoint. The tolerance values at a 50% probability of toxic events were 1.2 +/- 0.7 Gy for the D(mean) and 5.8 +/- 3.0% and 3.1 +/- 2.0% for V7 and V10, respectively. A nonsignificant shift to higher doses was seen for the dose-response curve for the upper compared with the lower part of the lung. CONCLUSION: The D(mean), V7, and V10 can be used to predict the risk of lung toxicity after SBRT treatment of non-small-cell lung cancer. Because of the lack of patients with low prescribed doses, however, the related uncertainty of this prediction is still relatively large. The D(mean), V7, and V10 are equally well suited. The additional investigated variables did not provide significant advantages. The lower part of the lung appears to be more radiosensitive than the upper.

Carbon ion radiotherapy of skull base chondrosarcomas.

PURPOSE: To evaluate the effectiveness and toxicity of carbon ion radiotherapy in chondrosarcomas of the skull base. PATIENTS AND METHODS: Between November 1998 and September 2005, 54 patients with low-grade and intermediate-grade chondrosarcomas of the skull base have been treated with carbon ion radiation therapy (RT) using the raster scan technique at the Gesellschaft für Schwerionenforschung in Darmstadt, Germany. All patients had gross residual tumors after surgery. Median total dose was 60 CGE (weekly fractionation 7 x 3.0 CGE). All patients were followed prospectively in regular intervals after treatment. Local control and overall survival rates were calculated using the Kaplan-Meier method. Toxicity was assessed according to the Common Terminology Criteria (CTCAE v.3.0) and the Radiation Therapy Oncology Group (RTOG)/European Organization for Research and Treatment of Cancer (EORTC) score. RESULTS: Median follow-up was 33 months (range, 3-84 months). Only 2 patients developed local recurrences. The actuarial local control rates were 96.2% and 89.8% at 3 and 4 years; overall survival was 98.2%at 5 years. Only 1 patient developed a mucositis CTCAE Grade 3; the remaining patients did not develop any acute toxicities >CTCAE Grade 2. Five patients developed minor late toxicities (RTOG/EORTC Grades 1-2), including bilateral cataract (n = 1), sensory hearing loss (n = 1), a reduction of growth hormone (n = 1), and asymptomatic radiation-induced white matter changes of the adjacent temporal lobe (n = 2). Grade 3 late toxicity occurred in 1 patient (1.9%) only. CONCLUSIONS: Carbon ion RT is an effective treatment for low- and intermediate-grade chondrosarcomas of the skull base offering high local control rates with low toxicity.

Changes in salivary gland function after radiotherapy of head and neck tumors measured by quantitative pertechnetate scintigraphy: comparison of intensity-modulated radiotherapy and conventional radiation therapy with and without Amifostine.

PURPOSE: The aim of this study was to compare changes in salivary gland function after intensity-modulated radiotherapy (IMRT) and conventional radiotherapy (RT), with or without Amifostine, for tumors of the head-and-neck region using quantitative salivary gland scintigraphy (QSGS). METHODS AND MATERIALS: A total of 75 patients received pre- and post-therapeutic QSGS to quantify the salivary gland function. In all, 251 salivary glands were independently evaluated. Changes in the maximum uptake (DeltaU) and relative excretion rate (DeltaF) both pre- and post-RT were determined to characterize radiation-induced changes in the salivary gland function. In addition, dose-response curves were calculated. RESULTS: In all groups, maximum uptake and relative excretion rate were reduced after RT (DeltaU

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.

Radiation-induced changes of brain tissue after radiosurgery in patients with arteriovenous malformations: correlation with dose distribution parameters.

PURPOSE: To investigate the correlation of radiation-induced changes of brain tissue after radiosurgery in patients with cerebral arteriovenous malformations (AVMs) with treatment planning and dose distribution parameters. METHODS AND MATERIALS: The data from 73 AVM patients with complete follow-up information who underwent stereotactic linear accelerator radiosurgery at our institution between 1993 and 1998 were analyzed. Patients were treated with 11-14 noncoplanar fields shaped by a micromultileaf collimator. A median dose of 19 Gy (range, 13.3-22 Gy) was prescribed to the 80% isodose, which completely encompassed the target. Patients were followed at 3-month intervals the first year and then every 6 months with MRI and neurologic examinations. No patient developed radiation necrosis. The end point of radiation-induced tissue changes on follow-up neuroimaging (i.e., edema, blood-brain barrier breakdown [BBBB], and edema and/or BBBB combined) was evaluated. Each end point was further differentiated into four levels with respect to the extent of the image change (i.e., small, intermediate, large, and very large). The correlation of each end point was investigated for several treatment planning parameters, including prescribed dose and the absolute size of the AVM target volume. In addition, a number of dose-volume variables were calculated from each patient's dose distribution in the brain, including the mean dose to a specified volume of 16 and 20 cm(3) that was given the highest dose (Dmean16 and Dmean20, respectively), and the absolute and percentage of brain volume (including the AVM target) receiving a dose of at least 8, 10, and 12 Gy (V8-V12, and V8(rel)-V12(rel), respectively). These parameters were also determined excluding the AVM target volume from the considered volume (subscript "excl"). The correlation of all treatment planning and dose-volume parameters with outcome was assessed in univariate Cox proportional hazards models. The results were assessed by p values (statistical significance for p < or =0.05), residual deviance (ResDev) of the fits, and odds ratios. RESULTS: The prescribed dose was not predictive of outcome (p >0.05 for all end points). The AVM target volume correlated significantly with large edema, as well as large edema and/or BBBB. V12 and Dmean20 were significantly associated with all end points, except very large edema and large BBBB. Patients with V12 of 27.6 cm(3) (Dmean20 of 18.9 Gy) had a 2.8-fold (fourfold) higher risk of developing edema and/or BBBB with large extent than those with V12 of 4.2 cm(3) (Dmean20 of 8.4 Gy). For all end points, V12(rel) correlated worse with outcome compared with V12 (e.g., end point of large edema and/or BBBB: ResDev = 85.8 and 86.5 for V12 and V12(rel), respectively). Excluding the AVM target volume from the considered irradiated volume led to only small changes in the resulting correlations (e.g., end point of small edema and/or BBBB: ResDev = 99.0 and 98.7 for V12 and V12(excl), respectively, and ResDev = 96.1 and 96.1 for Dmean20 and Dmean20(excl), respectively). Throughout the analysis, V8-V12, Dmean20, and Dmean16 yielded similar results and none of these parameters could be favored over the others. CONCLUSION: Radiation-induced changes of brain tissue after AVM radiosurgery can be well predicted by single dose distribution parameters that are a function of both dose and volume. These can be used to quantify dose-volume response relations. Studies of this nature will eventually help to improve our current understanding of the mechanisms leading to radiation-induced tissue changes after AVM radiosurgery and to optimize radiosurgery treatment planning.

Stereotactic single-dose radiotherapy of stage I non-small-cell lung cancer (NSCLC).

PURPOSE: The treatment of early-stage lung cancers is a primary domain of thoracic surgery, leading to persuasive results. In patients with medical contraindications, radiotherapy is an alternative, although with considerably worse outcome. Radiotherapy is associated with the risk of severe acute side effects and a permanent decrease of lung function. By the introduction of an extracranial stereotactic treatment technique, the amount of normal tissue in the high-dose region can be reduced, allowing the performance of single-dose treatment with high, biologically effective doses. METHODS AND MATERIALS: Between October 1998 and May 2001, 10 patients with histologically confirmed Stage I non-small-cell lung cancer were treated with stereotactic single-dose radiotherapy. A self-developed stereotactic frame was used for patient positioning and navigation. Total doses applied ranged from 19 to 26 Gy. After treatment, regular CT-based follow-up was performed. RESULTS: During a median follow-up period of 14.9 months, the tumors in 8 of 10 patients were locally controlled. The actuarial overall survival was 80% and 64%, respectively, 12 and 24 months after therapy. Actuarial local recurrence-free survival reached 88.9% and 71.1%, respectively. Therapy-related perifocal normal-tissue reaction occurred in 70% of all treated patients, although no major clinical symptoms were seen. In 5 patients, systemic metastases were found during follow-up; 1 patient developed suspect mediastinal lymph nodes. CONCLUSION: Stereotactic single-fraction radiotherapy is a feasible, safe, and effective procedure for the treatment of Stage I non-small-cell lung cancer. It promises high local control with a reduced overall treatment time. However, further investigation in a larger patient collective with extended follow-up is necessary.

Evaluation of salivary gland function after treatment of head-and-neck tumors with intensity-modulated radiotherapy by quantitative pertechnetate scintigraphy.

PURPOSE: To evaluate salivary gland function after inversely planned stereotactic intensity-modulated radiotherapy (IMRT) for tumors of the head-and-neck region using quantitative pertechnetate scintigraphy. METHODS AND MATERIALS: Since January 2000, 18 patients undergoing IMRT for cancer of the head and neck underwent pre- and posttherapeutic scintigraphy to examine salivary gland function. The mean dose to the primary planning target volume was 61.5 Gy (range 50.4-73.2), and the median follow-up was 23 months. In all cases, the parotid glands were directly adjacent to the planning target volume. The treatment planning goal was for at least one parotid gland to receive a mean dose of <26 Gy. Two quantitative parameters (change in maximal uptake and change in the relative excretion rate before and after IMRT) characterizing the change in salivary gland function after radiotherapy were determined. These parameters were compared with respect to the dose thresholds of 26 and 30 Gy for the mean dose. In addition, dose-response curves were calculated. RESULTS: Using IMRT, it was possible in 16 patients to reduce the dose for at least one parotid gland to < or =26 Gy. In 7 patients, protection of both parotid glands was possible. No recurrent disease adjacent to the protected parotid glands was observed. Using the Radiation Therapy Oncology Group/European Organization for the Research and Treatment of Cancer scoring system, only 3 patients had Grade 2 xerostomia. No greater toxicity was seen for the salivary glands. The change in the relative excretion rate was significantly greater, if the parotid glands received a mean dose of > or =26 Gy or > or =30 Gy. For the change in maximal uptake, a statistically significant difference was seen only for the parotid glands and a dose threshold of 30 Gy. For the end point of a reduction in the parotid excretion rate of >50% and 75%, the dose-response curves yielded a dose at 50% complication probability of 34.8 +/- 3.6 and 40.8 +/- 5.3 Gy, respectively. CONCLUSION: Using IMRT, it is possible to protect the parotid glands and reduce the incidence and severity of xerostomia in patients. Doses <26-30 Gy significantly preserve salivary gland function. The results support the hypothesis that application of IMRT does not lead to increased local failure rates.