Growth speed of large brain metastases between diagnostic and radiosurgical planning MRI and predictors of rapid tumor growth.

PURPOSE: We aimed to assess volumetric changes of large brain metastases (≥ 2 cm) between their diagnosis and planning for treatment with fractionated stereotactic radiation surgery (fSRS). Predictors of rapid tumor growth were also analyzed. MATERIALS AND METHODS: One hundred nine patients harboring 126 large brain metastases were retrospectively evaluated. Tumor characteristics were evaluated on diagnostic magnetic resonance imaging (dMRI) and MRI performed when planning fSRS (pMRI). Average tumor growth rate and percentage growth rate were calculated. Predictors of rapid growth (percentage growth rate > 5%) were determined using multivariate logistic regression. RESULTS: Both tumor diameter and volume were significantly larger on pMRI than on dMRI (P < 0.001). Median tumor percentage growth rate was 2.6% (range, - 10.8-43.3%). Eighty-eight tumors (70%) were slow-growing (percentage growth rate < 5%) and 38 (30%) grew rapidly (percentage growth rate ≥ 5%). Major peritumoral edema and no steroids were predictors of rapid tumor growth. CONCLUSION: Large brain metastases can grow considerably between the time of diagnosis and the time of fSRS treatment planning. We recommend the time between dMRI and fSRS treatment initiation be as short as possible.

The combination of stereotactic radiosurgery with immune checkpoint inhibition or targeted therapy in melanoma patients with brain metastases: a retrospective study.

BACKGROUND: Evidence pointing to a synergistic effect of stereotactic radiosurgery (SRS) with concurrent immunotherapy or targeted therapy in patients with melanoma brain metastases (BM) is increasing. We aimed to analyze the effect on overall survival (OS) of immune checkpoint inhibitors (ICI) or BRAF/MEK inhibitors initiated during the 9 weeks before or after SRS. We also evaluated the prognostic value of patients' and disease characteristics as predictors of OS in patients treated with SRS. METHODS: We identified patients with BM from cutaneous or unknown primary origin melanoma treated with SRS between 2011 and 2018. RESULTS: We included 84 patients. The median OS was 12 months (95% CI 9-20 months). The median follow-up was 30 months (95% CI 28-49). Twenty-eight patients with newly diagnosed BM initiated anti-PD-1 +/-CTLA-4 therapy (n = 18), ipilimumab monotherapy (n = 10) or BRAF+/- MEK inhibitors (n = 11), during the 9 weeks before or after SRS. Patients who received anti-PD-1 +/-CTLA-4 mAb showed an improved survival in comparison to ipilimumab monotherapy (OS 24 vs. 7.5 months; HR 0.32, 95% 0.12-0.83, p = 0.02) and BRAF +/-MEK inhibitors (OS 24 vs. 7 months, respectively; HR 0.11, 95% 0.04-0.34, p = 0.0001). This benefit remained significant when compared to the subgroup of patients treated with dual BRAF/MEK inhibition (BMi) (n = 5). In a multivariate Cox regression analysis an age > 65, synchronous BM, > 2 metastatic sites, > 4 BM, and an ECOG > 1 were correlated with poorer prognosis. A treatment with anti-PD-1+/-CTLA-4 mAbs within 9 weeks of SRS was associated with better outcomes. The presence of serum lactate dehydrogenase (LDH) levels ≥ 2xULN at BM diagnosis was associated with lower OS (HR 1.60, 95% CI 1.03-2.50; p = 0.04). CONCLUSIONS: The concurrent administration of anti-PD-1+/-CTLA-4 mAbs with SRS was associated with improved survival in melanoma patients with newly diagnosed BM. In addition to CNS tumor burden, the extension of systemic disease retains its prognostic value in patients treated with SRS. Elevated serum LDH levels are predictors of poor outcome in these patients.

A cortical thickness and radiation dose mapping approach identifies early thinning of ribs after stereotactic body radiation therapy.

BACKGROUND AND PURPOSE: High rates of spontaneous rib fractures are associated with thoracic stereotactic body radiation therapy (SBRT). These fractures likely originate within the cortical bone and relate to the cortical thickness (Ct.Th). We report the development and application of a novel Ct.Th and radiation dose mapping technique to assess early site-specific changes of cortical bone in ribs. MATERIALS AND METHODS: Rib Ct.Th maps were constructed from pre-SBRT and 3month post-SBRT CT scans for 28 patients treated for peripheral lung lesions. The Ct.Th at approximately 50,000 homologous points within the entire rib cage was determined pre- and post-SBRT. Each rib was then divided into 30 homologous regions. The mean dose and thinning were determined per section. RESULTS: Regions of ribs that received ⩾10Gy exhibited significant thinning of cortical bone (p=0.001). The mean Ct.Th percent difference (95% CI) in regions receiving 10-20Gy, 20-30Gy, 30-40Gy, and ⩾40Gy were -7% (-4%,-11%), -14% (-18%,-11%), -15% (-19%,-11%), and -18% (-22%,-15%) respectively. Regions receiving >20Gy experienced significantly more thinning than regions receiving lower doses. CONCLUSIONS: Substantial early cortical bone thinning was observed post-SBRT in regions of ribs that received ⩾10Gy. The rapid thinning of ribs may predispose ribs to fracture after SBRT.

Radiobiological mechanisms of stereotactic body radiation therapy and stereotactic radiation surgery.

Despite the increasing use of stereotactic body radiation therapy (SBRT) and stereotactic radiation surgery (SRS) in recent years, the biological base of these high-dose hypo-fractionated radiotherapy modalities has been elusive. Given that most human tumors contain radioresistant hypoxic tumor cells, the radiobiological principles for the conventional multiple-fractionated radiotherapy cannot account for the high efficacy of SBRT and SRS. Recent emerging evidence strongly indicates that SBRT and SRS not only directly kill tumor cells, but also destroy the tumor vascular beds, thereby deteriorating intratumor microenvironment leading to indirect tumor cell death. Furthermore, indications are that the massive release of tumor antigens from the tumor cells directly and indirectly killed by SBRT and SRS stimulate anti-tumor immunity, thereby suppressing recurrence and metastatic tumor growth. The reoxygenation, repair, repopulation, and redistribution, which are important components in the response of tumors to conventional fractionated radiotherapy, play relatively little role in SBRT and SRS. The linear-quadratic model, which accounts for only direct cell death has been suggested to overestimate the cell death by high dose per fraction irradiation. However, the model may in some clinical cases incidentally do not overestimate total cell death because high-dose irradiation causes additional cell death through indirect mechanisms. For the improvement of the efficacy of SBRT and SRS, further investigation is warranted to gain detailed insights into the mechanisms underlying the SBRT and SRS.

Radiobiological mechanisms of stereotactic body radiation therapy and stereotactic radiation surgery

Despite the increasing use of stereotactic body radiation therapy (SBRT) and stereotactic radiation surgery (SRS) in recent years, the biological base of these high-dose hypo-fractionated radiotherapy modalities has been elusive. Given that most human tumors contain radioresistant hypoxic tumor cells, the radiobiological principles for the conventional multiple-fractionated radiotherapy cannot account for the high efficacy of SBRT and SRS. Recent emerging evidence strongly indicates that SBRT and SRS not only directly kill tumor cells, but also destroy the tumor vascular beds, thereby deteriorating intratumor microenvironment leading to indirect tumor cell death. Furthermore, indications are that the massive release of tumor antigens from the tumor cells directly and indirectly killed by SBRT and SRS stimulate anti-tumor immunity, thereby suppressing recurrence and metastatic tumor growth. The reoxygenation, repair, repopulation, and redistribution, which are important components in the response of tumors to conventional fractionated radiotherapy, play relatively little role in SBRT and SRS. The linear-quadratic model, which accounts for only direct cell death has been suggested to overestimate the cell death by high dose per fraction irradiation. However, the model may in some clinical cases incidentally do not overestimate total cell death because high-dose irradiation causes additional cell death through indirect mechanisms. For the improvement of the efficacy of SBRT and SRS, further investigation is warranted to gain detailed insights into the mechanisms underlying the SBRT and SRS.

Clinical effects of stereotactic radiation surgery in patients with metastatic melanoma.

We examined the effectiveness of stereotactic radiation surgery (SRS) in 14 patients with brain metastasis in our hospital. The age of the patients ranged 45-85 years old (mean, 65). Brain metastasis was detected by neurological symptoms in seven patients and by regular imaging examination in the remaining patients. The number of metastatic lesions in the brain before SRS ranged 1-11 (median, 2). The treatment number of SRS was 1-4 times (median, 2). Six of 14 patients had neurological symptoms before SRS. Overall survival (OS) after SRS was 1.7-21.2 months (median, 8.2). The progression-free survival (PFS) after SRS was 0.9-10.5 months (median, 2.2). The result of univariate analysis showed that the application of two or more courses of SRS was significantly related to OS (P = 0.005). Single metastatic lesion (P = 0.051) and no extracranial lesion (P = 0.055) showed a slight tendency to be related to disease-free survival (DFS). Neither lactate dehydrogenase nor neurological symptoms were significantly related to OS or DFS. Although OS and DFS after SRS were not very long, the treatment of brain metastases has the potential to prevent neurological events. Repeating SRS may be accepted as a local therapy in the multimodal approach including new molecular targeting drugs for metastatic melanoma.

On-line Setup for Lung Cancer Patient in Stereotactic Radiation Surgery using CBCT

PURPOSE: On-line setup procedure was performed before treatment for lung cancer patient for stereotactic radiation surgery (SRS) using recently introduced Cone Beam CT. MATERIALS AND METHODS: Cone Beam CT was performed for 10 patients who did SRS during 18 July and 1 September, 2006 using On Board Imager (OPB) system made by Varian, USA. The treatment position of patient was corrected comparing Images obtaining from CBCT and used in treatment planning. RESULTS: Comparing the CBCT images and CT images used in treatment planning, the movement of the couch is 2.3+/-2.3 mm, 1.8+/-2.8 mm, 0.3+/-3.5 mm for vertical, lateral, and longitudinal direction. It took about 1 hr for conventional treatment procedure in image acquisition of CT before treatment and image registration. But it took about 4~7 minute in on-line setup using CBCT (1~2 min for image acquisition using CBCT, 2~3 min for CT reconstruction of 2.5 mm slice thickness, 1~2 min for on-line setup using image registration). CONCLUTION: The accurate treatment could be performed after tumor localization for SRS using CBCT images. And the consumed time for tumor localization was reduced significantly.