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Immunomodulatory properties and molecular effects in inflammatory diseases of low-dose X-irradiation
(2012)
Inflammatory diseases are the result of complex and pathologically unbalanced multicellular interactions. For decades, low-dose X-irradiation therapy (LD-RT) has been clinically documented to exert an anti-inflammatory effect on benign diseases and chronic degenerative disorders. By contrast, experimental studies to confirm the effectiveness and to reveal underlying cellular and molecular mechanisms are still at their early stages. During the last decade, however, the modulation of a multitude of immunological processes by LD-RT has been explored in vitro and in vivo. These include leukocyte/endothelial cell adhesion, adhesion molecule and cytokine/chemokine expression, apoptosis induction, and mononuclear/polymorphonuclear cell metabolism and activity. Interestingly, these mechanisms display comparable dose dependences and dose-effect relationships with a maximum effect in the range between 0.3 and 0.7 Gy, already empirically identified to be most effective in the clinical routine. This review summarizes data and models exploring the mechanisms underlying the immunomodulatory properties of LD-RT that may serve as a prerequisite for further systematic analyses to optimize low-dose irradiation procedures in future clinical practice.
BACKGROUND: We retrospectively evaluated the efficacy and toxicity of gross tumor volume (GTV) mean-dose-optimized and real-time motion-compensated robotic stereotactic body radiation therapy (SBRT) in the treatment of liver metastases.
METHODS: Between March 2011 and July 2015, 52 patients were treated with SBRT for a total of 91 liver metastases (one to four metastases per patient) with a median GTV volume of 12 cc (min 1 cc, max 372 cc). The optimization of mean GTV dose was prioritized during treatment planning at the potential cost of planning target volume (PTV) coverage reduction while adhering to safe normal tissue constraints. The delivered median GTV biological effective dose (BED10) was 142.1 Gy10 (range, 60.2 Gy10 -165.3 Gy10) and the prescribed PTV BED10 ranged from 40.6 Gy10 to 112.5 Gy10 (median, 86.1 Gy10). We analyzed local control (LC), progression-free interval (PFI), overall survival (OS), and toxicity.
RESULTS: Median follow-up was 17 months (range, 2-49 months). The 2-year actuarial LC, PFI, and OS rates were 82.1, 17.7, and 45.0 %, and the median PFI and OS were 9 and 23 months, respectively. In univariate analysis histology (p < 0.001), PTV prescription BED10 (HR 0.95, CI 0.91-0.98, p = 0.002) and GTV mean BED10 (HR 0.975, CI 0.954-0.996, p = 0.011) were predictive for LC. Multivariate analysis showed that only extrahepatic disease status at time of treatment was a significant factor (p = 0.033 and p = 0.009, respectively) for PFI and OS. Acute nausea or fatigue grade 1 was observed in 24.1 % of the patients and only 1 patient (1.9 %) had a side effect of grade ≥ 2.
CONCLUSIONS: Robotic real-time motion-compensated SBRT is a safe and effective treatment for one to four liver metastases. Reducing the PTV prescription dose and keeping a high mean GTV dose allowed the reduction of toxicity while maintaining a high local control probability for the treated lesions.
Background: For prostate cancer treatment, treatment options with minimal side effects are desired. External beam radiation therapy (EBRT) is non-invasive, standard of care and delivered in either conventional fractionation over 8 weeks or with moderate hypo-fractionation over about 5 weeks. Recent advances in radiotherapy technology have made extreme hypo-fractionated stereotactic body radiation therapy (SBRT) of prostate cancer feasible, which has not yet been introduced as a standard treatment method in Germany. Initial results from other countries are promising, but long-term results are not yet available. The aim of this study is to investigate feasibility and effectiveness of SBRT for prostate cancer in Germany.
Methods/design: This German bi-center single group trial (HYPOSTAT) is designed to evaluate feasibility and effectiveness, as measured by toxicity and PSA-response, respectively, of an extreme hypo-fractionated SBRT regimen with five fractions of 7 Gy in treatment of localized low and intermediate risk prostate cancer. The target volume includes the prostate with or without the base of seminal vesicles depending on risk stratification and uncertainty margins that are kept at 3–5 mm. SBRT treatment is delivered with the robotic CyberKnife system, which was recently introduced in Germany. Acute and late toxicity after one year will be evaluated according to Common Terminology Criteria for Adverse Events (CTCAE v. 4.0), Radiation Therapy Oncology Group (RTOG) and International Prostate Symptom Score (IPSS) Scores. The quality of life will be assessed before and after treatment with the EORTC QLQ C30 questionnaire. Hypothesizing that the proportion of patients with grade 2 side effects or higher is less or equal than 2.8%, thus markedly lower than the standard EBRT percentage (17.5%), the recruitment target is 85 patients.
Discussion: The HYPOSTAT trial aims at demonstrating short term feasibility of extreme hypo-fractioned SBRT for the treatment of prostate cancer and might be used as the pilot study for a multi-center multi-platform or for randomized-controlled trials comparing conventional radiotherapy with SBRT for localized prostate cancer in the future. The study concept of patient enrollment, follow up and evaluation by multiple public university clinics and actual patient treatment in dedicated private radiosurgery practices with high-tech radiation equipment is unique for clinical trials.
Study status: The study is ongoing and currently recruiting patients.
Trial registration: Registration number: NCT02635256 (clinicaltrials.gov). Registered 8 December 2015