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).

High control rate in patients with chondrosarcoma of the skull base after carbon ion therapy: first report of long-term results.

BACKGROUND: The current study was performed to evaluate the safety and effectiveness of irradiation with carbon ions using raster scanning as well as prognostic factors in patients with skull base chondrosarcomas. METHODS: Between 1998 and 2008, 79 patients with chondrosarcoma of the skull base were treated using carbon ions in raster scanning. The applied median total dose was 60 gray equivalent (GyE) at 3 GyE per fraction. Local control and overall survival (OS) were evaluated using the Kaplan-Meier method. Long-term toxicity was quantitatively assessed using questionnaires. RESULTS: The median follow-up after irradiation was 91 months (range, 3 months-175 months). Within the follow-up, 10 patients developed local disease recurrence. The 3-year, 5-year, and 10-year local control rates were 95.9%, 88%, and 88%, respectively; the corresponding OS rates were 96.1%, 96.1%, and 78.9%, respectively. With a median follow-up of 110 months after first diagnosis, the corresponding 3-year, 5-year, and 10-year OS rates were 97.5%, 97.5%, and 91.5%, respectively. Age ≤ 45 years and boost volume ≤ 55 mL were associated with significantly better local control rates. We observed a clinically relevant improvement in cranial nerve deficits 7 to 10 years after treatment (range, 45.5%-53.3%) compared with the baseline (73.4%). During follow-up, none of the patients in the current study developed a secondary malignancy. CONCLUSIONS: Carbon ion therapy is a safe and effective treatment in patients with chondrosarcoma of the skull base. For further evaluation, a prospective randomized phase 3 trial comparing protons versus carbon ions has been recruiting patients with low-grade and intermediate-grade chondrosarcoma of the skull base since 2009.

Highly effective treatment of skull base chordoma with carbon ion irradiation using a raster scan technique in 155 patients: first long-term results.

BACKGROUND: The current study was conducted to evaluate the long-term results of irradiation with carbon ions in a raster scanning technique in patients with skull base chordomas. METHODS: Between 1998 and 2008, a total of 155 patients (76 men and 79 women) with a median age of 48 years (range, 15 years-85 years) were irradiated with carbon ions using a raster scan technique. The irradiation was performed at the Society for Heavy Ion Research in Darmstadt, Germany. The median total dose was 60 gray (relative biological effectiveness) at 3 gray (relative biological effectiveness) per fraction. The median boost planning target volume was 70 mL (range, 2 mL-294 mL). Local control (LC) and overall survival (OS) were evaluated using the Kaplan-Meier method, whereas long-term toxicity was evaluated via questionnaires. RESULTS: The median follow-up was 72 months (range, 12 months-165 months). All patients had residual macroscopic tumors at the initiation of radiotherapy. The authors observed 55 local recurrences during follow-up, as well as systemic disease progression in 4 patients. The resulting 3-year, 5-year, and 10-year LC rates were 82%, 72%, and 54%, respectively, whereas the 3-year, 5-year, and 10-year OS rates were 95%, 85%, and 75%, respectively. Age <48 years and a boost volume >75 mL were associated with a significantly improved LC and OS. Primary treatment resulted in a significantly better OS probability. No higher late toxicity could be detected after carbon ion treatment. CONCLUSIONS: Carbon ion therapy appears to be a safe and effective treatment for patients with skull base chordoma, resulting in high LC and OS rates.

Active raster scanning with carbon ions: reirradiation in patients with recurrent skull base chordomas and chondrosarcomas.

PURPOSE: To evaluate the safety and efficacy of reirradiation with carbon ions in patients with relapse of skull base chordoma and chondrosarcoma. PATIENTS AND METHODS: Reirradiation with carbon ions was performed on 25 patients with locally recurrent skull base chordoma (n = 20) or chondrosarcoma (n = 5). The median time between the last radiation exposure and the reirradiation with carbon ions was 7 years. In the past, 23 patients had been irradiated once, two patients twice. Reirradiation was delivered using the active raster scanning method. The total median dose was 51.0 GyE carbon ions in a weekly regimen of five to six fractions of 3 GyE. Local progression-free survival (LPFS) was evaluated using the Kaplan-Meier method; toxicity was evaluated using the NCI Common Terminology Criteria for Adverse Events (CTCAE v.4.03). RESULTS: The treatment could be finished in all patients without interruption. In 80% of patients, symptom control was achieved after therapy. The 2-year-LPFS probability was 79.3%. A PTV volume of < 100 ml or a total dose of > 51 GyE was associated with a superior local control rate. The therapy was associated with low acute toxicity. One patient developed grade 2 mucositis during therapy. Furthermore, 12% of patients had tympanic effusion with mild hypacusis (grade 2), while 20% developed an asymptomatic temporal lobe reaction after treatment (grade 1). Only one patient showed a grade 3 osteoradionecrosis. CONCLUSION: Reirradiation with carbon ions is a safe and effective method in patients with relapsed chordoma and chondrosarcoma of the skull base.

Hematologic Toxicity and Bone Marrow-Sparing Strategies in Chemoradiation for Locally Advanced Cervical Cancer: A Systematic Review.

The standard treatment for locally advanced cervical cancer typically includes concomitant chemoradiation, a regimen known to induce severe hematologic toxicity (HT). Particularly, pelvic bone marrow dose exposure has been identified as a contributing factor to this hematologic toxicity. Chemotherapy further increases bone marrow suppression, often necessitating treatment interruptions or dose reductions. A systematic search for original articles published between 1 January 2006 and 7 January 2024 that reported on chemoradiotherapy for locally advanced cervical cancer and hematologic toxicities was conducted. Twenty-four articles comprising 1539 patients were included in the final analysis. HT of grade 2 and higher was observed across all studies and frequently exceeded 50%. When correlating active pelvic bone marrow and HT, significant correlations were found for volumes between 10 and 45 Gy and HT of grade 3 and higher. Several dose recommendations for pelvic bone and pelvic bone marrow sparing to reduce HT were established, including V10 < 90-95%, V20 < 65-86.6% and V40 < 22.8-40%. Applying dose constraints to the pelvic bone/bone marrow is a promising approach for reducing HT, and thus reliable implementation of therapy. However, prospective randomized controlled trials are needed to define precise dose constraints and optimize clinical strategies.

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.

Randomized phase II trial of hypofractionated proton versus carbon ion radiation therapy in patients with sacrococcygeal chordoma-the ISAC trial protocol.

BACKGROUND: Chordomas are relatively rare lesions of the bones. About 30% occur in the sacrococcygeal region. Surgical resection is still the standard treatment. Due to the size, proximity to neurovascular structures and the complex anatomy of the pelvis, a complete resection with adequate safety margin is difficult to perform. A radical resection with safety margins often leads to the loss of bladder and rectal function as well as motoric/sensoric dysfunction. The recurrence rate after surgery alone is comparatively high, such that adjuvant radiation therapy is very important for improving local control rates. Proton therapy is still the international standard in the treatment of chordomas. High-LET beams such as carbon ions theoretically offer biologic advantages in slow-growing tumors. Data of a Japanese study of patients with unresectable sacral chordoma showed comparable high control rates after hypofractionated carbon ion therapy only. METHODS AND DESIGN: This clinical study is a prospective randomized, monocentric phase II trial. Patients with histologically confirmed sacrococcygeal chordoma will be randomized to either proton or carbon ion radiation therapy stratified regarding the clinical target volume. Target volume delineation will be carried out based on CT and MRI data. In each arm the PTV will receive 64 GyE in 16 fractions. The primary objective of this trial is safety and feasibility of hypofractionated irradiation in patients with sacrococygeal chordoma using protons or carbon ions in raster scan technique for primary or additive treatment after R2 resection. The evaluation is therefore based on the proportion of treatments without Grade 3-5 toxicity (CTCAE, version 4.0) up to 12 months after treatment and/or discontinuation of the treatment for any reason as primary endpoint. Local-progression free survival, overall survival and quality of life will be analyzed as secondary end points. DISCUSSION: The aim of this study is to confirm the toxicity results of the Japanese data in raster scan technique and to compare it with the toxicity analysis of proton therapy given in the same fractionation. Using this data, a further randomized phase III trial is planned, comparing hypofractionated proton and carbon ion irradiation. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01811394.