scholarly journals PS1 - 140 The Effect of Timing of Stereotactic Radiosurgery Treatment of Melanoma Brain Metastases Treated with Ipilimumab

Author(s):  
O. Cohen-Inbar

Melanoma represents the third most common cause of CNS metastases. Immunotherapy has evolved as a treatment option for patients with stage-IV melanoma. Stereotactic radiosurgery (SRS) also elicits an immune response within the brain and may interact with immunotherapy. We report a cohort of patients treated for brain metastasis with immunotherapy and evaluate the effect of SRS timing on the intracranial response. Methods: All consecutively treated melanoma patients receiving Ipilimumab and SRS for their brain metastasis were included in the retrospective analysis. 46 patients harboring 232 brain metastases were reviewed. The median clinical follow-up was 7.9 months (3-42.6). Median age was 63 years (24.3-83.6). 32 patients received SRS before or during ipilimumab cycles (Group-A) whereas 14 patients received SRS after the ipilimumab treatment (Group-B). Radiographic and clinical responses were assessed at approximately 3 months intervals after SRS. Results: The two cohorts were comparable in pertinent pre-treatment aspects with the exception of SRS timing relative to ipilimumab. Local recurrence free duration (LRFD) was significantly longer in Group-A patients (19.6 months, range 1.1-34.7 months) as compared to group-B patients (3 months, range 0.4-20.4 months), respectively (p=0.002). Post-SRS perilesional edema was more significant in Group-A. Conclusions: The effect of SRS and ipilimumab in attaining LRFD seems greater when SRS is performed before or during ipilimumab treatments. The timing of immunotherapy and SRS may effect LRFD and post-radiosurgical edema. The interactions between immunotherapy and SRS warrant further investigation so as to optimize the therapeutic benefits and mitigate the risks associated with multimodality, targeted therapy.

2017 ◽  
Vol 127 (5) ◽  
pp. 1007-1014 ◽  
Author(s):  
Or Cohen-Inbar ◽  
Han-Hsun Shih ◽  
Zhiyuan Xu ◽  
David Schlesinger ◽  
Jason P. Sheehan

OBJECTIVEMelanoma represents the third most common cause of CNS metastases. Immunotherapy has evolved as a treatment option for patients with Stage IV melanoma. Stereotactic radiosurgery (SRS) also elicits an immune response within the brain and may interact with immunotherapy. The authors report on a cohort of patients treated for brain metastases with immunotherapy and evaluate the effect of SRS timing on the intracranial response.METHODSAll consecutively treated melanoma patients receiving ipilimumab and SRS for treatment of brain metastases at the University of Virginia between 2009 and 2014 were included in this retrospective analysis; data from 46 patients harboring 232 brain metastases were reviewed. The median duration of clinical follow-up was 7.9 months (range 3–42.6 months). The median age of the patients was 63 years (range 24.3–83.6 years). Thirty-two patients received SRS before or during ipilimumab cycles (Group A), whereas 14 patients received SRS after ipilimumab treatment (Group B). Radiographic and clinical responses were assessed at approximately 3-month intervals after SRS.RESULTSThe 2 cohorts were comparable in pertinent baseline characteristics with the exception of SRS timing relative to ipilimumab. Local recurrence–free duration (LRFD) was significantly longer in Group A (median 19.6 months, range 1.1–34.7 months) than in Group B patients (median 3 months, range 0.4–20.4 months) (p = 0.002). Post-SRS perilesional edema was more significant in Group A.CONCLUSIONSThe effect of SRS and ipilimumab on LRFD seems greater when SRS is performed before or during ipilimumab treatments. The timing of immunotherapy and SRS may affect LRFD and postradiosurgical edema. The interactions between immunotherapy and SRS warrant further investigation so as to optimize the therapeutic benefits and mitigate the risks associated with multimodality, targeted therapy.


Neurosurgery ◽  
1991 ◽  
Vol 28 (2) ◽  
pp. 201-205 ◽  
Author(s):  
Yukitaka Ushio ◽  
Norio Arita ◽  
Toru Hayakawa ◽  
Heitaro Mogami ◽  
Hiroshi Hasegawa ◽  
...  

Abstract A controlled randomized study was carried out to evaluate the effects of chemotherapy in patients with brain metastases from lung carcinoma. One hundred patients were randomly divided into three groups at the time of diagnosis or after surgery for metastases. Group A received radiotherapy alone; Group B received radiotherapy and chloroethylnitrosoureas (methyl-CCNU, 100-120 mg/m2, or ACNU 80-100 mg/m2, every 6-8 weeks), and Group C received radiotherapy and a combination of chloroethylnitrosoureas and tegafur (300 mg/m2. daily). Of the 100 patients, 88 could be evaluated. The reduction rates of the tumors of the patients in whom tumor was not surgically removed or not totally removed were compared. Complete resolution of the tumor was noted in 29, 69, and 63% of the patients in Groups A, B, and C, respectively, Tumor regression of ⩾50% was seen in 36, 69. and 74% of the patients in Groups A, B, and C, respectively. The difference in the response rates of Groups A and C was statistically signficiant (P<0.05). Median survival after the start of treatment for brain metastasis was 27, 30.5, and 29 weeks in Groups A, B, and C, respectively. There was 1 long-term survivor (more than 5 years) in Group A, 3 in Group B, and 1 in Group C. The main cause of death was deterioration attributable to the primary lesion or systemic metastasis, and no statistical difference was noted in survival time among the groups. Our results indicate that combination chemotherapy with chloroethylnitrosoureas and tegafur has an additive effect on radiotherapy in reducing or eliminating brain metastases from lung carcinoma, and that brain metastasis is well controlled by multidisciplinary treatment including chemotherapy.


2014 ◽  
Vol 121 (5) ◽  
pp. 1148-1157 ◽  
Author(s):  
Shinya Watanabe ◽  
Masaaki Yamamoto ◽  
Yasunori Sato ◽  
Takuya Kawabe ◽  
Yoshinori Higuchi ◽  
...  

Object Recently, an increasing number of patients with brain metastases, even patients over 80 years of age, have been treated with stereotactic radiosurgery (SRS). However, there is little information on SRS treatment results for patients with brain metastases 80 years of age and older. The authors undertook this study to reappraise whether SRS treatment results for patients 80 years of age or older differ from those of patients who are 65–79 years old. Methods This was an institutional review board–approved, retrospective cohort study. Among 2552 consecutive brain metastasis patients who underwent SRS during the 1998–2011 period, we studied 165 who were 80 years of age or older (Group A) and 1181 who were age 65–79 years old (Group B). Because of the remarkable disproportion in patient numbers between the 2 groups and considerable differences in pre-SRS clinical factors, the authors conducted a case-matched study using the propensity score matching method. Ultimately, 330 patients (165 from each group, A and B) were selected. For time-to-event outcomes, the Kaplan-Meier method was used to estimate overall survival and competing risk analysis was used to estimate other study end points, as appropriate. Results Although the case-matched study showed that post-SRS median survival time (MST, months) was shorter in Group A patients (5.3 months, 95% CI 3.9–7.0 months) than in Group B patients (6.9 months, 95% CI 5.0–8.1 months), this difference was not statistically significant (HR 1.147, 95% CI 0.921–1.429, p = 0.22). Incidences of neurological death and deterioration were slightly lower in Group A than in Group B patients (6.3% vs 11.8% and 8.5% vs 13.9%), but these differences did not reach statistical significance (p = 0.11 and p = 0.16). Furthermore, competing risk analyses showed that the 2 groups did not differ significantly in cumulative incidence of local recurrence (HR 0.830, 95% CI 0.268–2.573, p = 0.75), rates of repeat SRS (HR 0.738, 95% CI 0.438–1.242, p = 0.25), or incidence of SRS-related complications (HR 0.616, 95% CI 0.152–2.495, p = 0.49). Among the Group A patients, post-SRS MSTs were 11.6 months (95% CI 7.8–19.6 months), 7.9 months (95% CI 5.2–10.9 months), and 2.8 months (95% CI; 2.4–4.6 months) in patients whose disease status was modified–recursive partitioning analysis (RPA) Class(es) I+IIa, IIb, and IIc+III, respectively (p < 0.001). Conclusions Our results suggest that patients 80 years of age or older are not unfavorable candidates for SRS as compared with those 65–79 years old. Particularly, even among patients 80 years and older, those with modified-RPA Class I+IIa or IIb disease are considered to be favorable candidates for more aggressive treatment of brain metastases.


2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e20019-e20019
Author(s):  
Karim Tazi ◽  
Cody Chiuzan ◽  
Keisuke Shirai

e20019 Background: Historically, melanoma with brain metastases has a poor prognosis and is a major contributor to patient morbidity and mortality. Recently, the use of ipilimumab has improved overall survival in stage IV melanoma; however, the outcome of patients with brain metastases remains unclear. In this retrospective medical record review, we report the outcome of patients with stage IV melanoma with brain metastases treated with ipilimumab and brain stereotactic radiosurgery (SRS). Methods: All patients with metastatic melanoma treated with ipilimumab from April 2010 to March 2012 were identified and stratified by presence (A) or absence (B) of brain metastases. All patients with brain metastases received SRS. Performance status, dates of stage IV diagnosis, brain SRS and cycle 1 of ipilimumab administration were recorded. We used the Disease Specific Graded Prognostic Assessment (DS-GPA) to estimate the predicted survival. Overall survival was defined as time (months) from the date of the stage IV diagnosis and the time of ipilimumab administration to death or last follow-up. Survival curves were estimated using the Kaplan-Meier method, and compared using a two-tailed log-rank test. Results: Twelve of 30 patients treated with ipilimumab had brain metastases. Median age was 66 years. Median DS-GPA score was 3 (estimated mean survival of 8.7 months). Four patients (33%) in group A and 6 patients (33%) in group B died as of last follow-up. Median number of SRS treatment was 1 (1 to 4), and median total treated lesions were 3 (1-14). Median survivals from date of Stage IV for A and B were 29.1 and 32.9 months, respectively (p=0.67). The estimated 2 year survival rates from date of cycle 1 ipilimumab administration for A and B were 58% (95% CI: 32-100%) and 55% (95% CI: 32-93%), respectively. Ten out of 12 patients in group A maintained an ECOG PS of 0-1 as of last follow-up. Conclusions: Survival of patients with melanoma brain metastases treated with ipilimumab combined with SRS may be comparable to patients without brain metastases. Ipilimumab and SRS do not seem to adversely impact quality of life.


Neurosurgery ◽  
1989 ◽  
Vol 24 (6) ◽  
pp. 798-805 ◽  
Author(s):  
Lisa M. DeAngelis ◽  
Lynda R. Mandell ◽  
H. Tzvi Thaler ◽  
David W. Kimmel ◽  
Joseph H. Galicich ◽  
...  

ABSTRACT To assess the value of whole brain radiotherapy (WBRT) after complete resection of a single brain metastasis we reviewed the records of 98 patients who had elective craniotomy between 1978 and 1985. Seventy-nine patients received postoperative WBRT (Group A) and 19 patients no radiotherapy (RT) (Group B). Neurological relapse was designated as local (i.e., at the site of the original metastasis) or distant (i.e., elsewhere in the brain). Postoperative WBRT significantly prolonged the time to any neurological relapse (P = 0.034) with a 1-year recurrence rate of 22% in Group A and 46% in Group B patients; however, it did not specifically control either local or distant cerebral recurrence. Recurrence of metastatic brain disease was not affected by location of the original lesion; however, meningeal relapse occurred in 38% of cerebellar lesions, but only in 4.7% of supratentorial metastases (P = 0.003). The total radiation dose or fractionation scheme of RT did not affect survival nor time to neurological relapse. The median survival was 20.6 and 14.4 months for Groups A and B, respectively (not statistically different). Forty-eight percent of Group A and 47% of Group B patients survived for 1 year or longer; however, 11% of patients who had received RT and survived 1 year developed severe radiation-induced dementia. All patients with radiation-related cerebral damage received hypo-fractionated RT with high daily fractions as commonly designed for rapid palliation of macroscopic brain metastases. Thus, postoperative WBRT may be an important adjunct to complete resection of a single brain metastasis, particularly in patients with limited or no systemic disease who have the potential for long-term survival or even cure, but it carries a substantial risk of late neurological toxicity when hypofractionated RT schedules are used. For these good-risk patients, postoperative WBRT should be administered by standard fractionation schemes of 180 to 200 cGy/day to a total of 4000 to 4500 cGy, or hyperfractionation, which provides even lower doses/fraction to minimize potential neurotoxicity while delivering a maximally efficacious total dose, should be considered.


2013 ◽  
Vol 118 (6) ◽  
pp. 1258-1268 ◽  
Author(s):  
Masaaki Yamamoto ◽  
Takuya Kawabe ◽  
Yasunori Sato ◽  
Yoshinori Higuchi ◽  
Tadashi Nariai ◽  
...  

Object Although stereotactic radiosurgery (SRS) alone for patients with 4–5 or more tumors is not a standard treatment, a trend for patients with 5 or more tumors to undergo SRS alone is already apparent. The authors' aim in the present study was to reappraise whether SRS results for ≥ 5 tumors differ from those for 1–4 tumors. Methods This institutional review board–approved retrospective cohort study used the authors' database of prospectively accumulated data that included 2553 consecutive patients who underwent SRS, not in combination with concurrent whole-brain radiotherapy, for brain metastases (METs) between 1998 and 2011. These 2553 patients were divided into 2 groups: 1553 with tumor numbers of 1–4 (Group A) and 1000 with ≥ 5 tumors (Group B). Because there was considerable bias in pre-SRS clinical factors between Groups A and B, a case-matched study was conducted. Ultimately, 1096 patients (548 each in Groups A and B) were selected. The standard Kaplan-Meier method was used to determine post-SRS survival and the post-SRS neurological death–free survival times. Competing risk analysis was applied to estimate cumulative incidences of local recurrence, repeat SRS for new lesions, neurological deterioration, and SRS-induced complications. Results The post-SRS median survival time was significantly longer in the 548 Group A patients (7.9 months, 95% CI 7.0–8.9 months) than in the 548 Group B patients (7.0 months 95% [CI 6.2–7.8 months], HR 1.176 [95% CI 1.039–1.331], p = 0.01). However, incidences of neurological death were very similar: 10.6% in Group A and 8.2% in Group B (p = 0.21). There was no significant difference between the groups in neurological death–free survival intervals (HR 0.945, 95% CI 0.636–1.394, p = 0.77). Furthermore, competing risk analyses showed that there were no significant differences between the groups in cumulative incidences of local recurrence (HR 0.577, 95% CI 0.312–1.069, p = 0.08), repeat SRS (HR 1.133, 95% CI 0.910–1.409, p = 0.26), neurological deterioration (HR 1.868, 95% CI 0.608–1.240, p = 0.44), and major SRS-related complications (HR 1.105, 95% CI 0.490–2.496, p = 0.81). In the authors' cohort, age ≤ 65 years, female sex, a Karnofsky Performance Scale score ≥ 80%, cumulative tumor volume ≤ 10 cm3, controlled primary cancer, no extracerebral METs, and neurologically asymptomatic status were significant factors favoring longer survival equally in both groups. Conclusions This retrospective study suggests that increased tumor number is an unfavorable factor for longer survival. However, the post-SRS median survival time difference, 0.9 months, between the two groups is not clinically meaningful. Furthermore, patients with 5 or more METs have noninferior results compared to patients with 1–4 tumors, in terms of neurological death, local recurrence, repeat SRS, maintenance of good neurological state, and SRS-related complications. A randomized controlled trial should be conducted to test this hypothesis.


2010 ◽  
Vol 113 (Special_Supplement) ◽  
pp. 48-52 ◽  
Author(s):  
Toru Serizawa ◽  
Masaaki Yamamoto ◽  
Yasunori Sato ◽  
Yoshinori Higuchi ◽  
Osamu Nagano ◽  
...  

Object The authors retrospectively reviewed the results of Gamma Knife surgery (GKS) used as the sole treatment for brain metastases in patients who met the eligibility criteria for the ongoing JLGK0901 multi-institutional prospective trial. They also discuss the anticipated results of the JLGK0901 study. Methods Data from 1508 consecutive cases were analyzed. All of the patients were treated at the Gamma Knife House of Chiba Cardiovascular Center or the Mito Gamma House of Katsuta Hospital between 1998 and 2007 and met the following JLGK0901 inclusion criteria: 1) newly diagnosed brain metastases, 2) 1–10 brain lesions, 3) less than 10 cm3 volume of the largest tumor, 4) no more than 15 cm3 total tumor volume, 5) no findings of CSF dissemination, and 6) no impairment of activities of daily living (Karnofsky Performance Scale score < 70) due to extracranial disease. At the initial treatment, all visible lesions were irradiated with GKS without upfront whole-brain radiation therapy. Thereafter, gadolinium-enhanced MR imaging was performed every 2–3 months, and new distant lesions were appropriately retreated with GKS. Patients were divided into groups according to numbers of tumors: Group A, single lesions (565 cases); Group B, 2–4 tumors (577 cases); and Group C, 5–10 tumors (366 cases). The differences in overall survival (OS) were compared between groups. Results The median age of the patients was 66 years (range 19–96 years). There were 963 men and 545 women. The primary tumors were in the lung in 1114 patients, gastrointestinal tract in 179, breast in 105, urinary tract in 66, and other sites in 44. The overall mean survival time was 0.78 years (0.99 years for Group A, 0.68 years for Group B, and 0.62 years for Group C). The differences between Groups A and B (p < 0.0001) and between Groups B and C (p = 0.0312) were statistically significant. Multivariate analysis revealed significant prognostic factors for OS to be sex (poor prognostic factor: male, p < 0.0001), recursive partitioning analysis class (Class I vs Class II and Class II vs III, both p < 0.0001), primary site (lung vs breast, p = 0.0047), and number of tumors (Group A vs Group B, p < 0.0001). However, no statistically difference was detected between Groups B and C (p = 0.1027, hazard ratio 1.124, 95% CI 0.999–1.265). Conclusions The results of this retrospective analysis revealed an upper CI of 1.265 for the hazard ratio, which was lower than the 1.3 initially set by the JLGK0901 study. The JLGK0901 study is anticipated to show noninferiority of GKS as sole treatment for patients with 5–10 brain metastases compared with those with 2–4 in terms of OS.


Author(s):  
Yukinori Okada ◽  
Mariko Kobayashi ◽  
Mio Shinozaki ◽  
Tatsuyuki Abe ◽  
Naoki Nakamura

Abstract Aim: To identify prognostic factors and investigate patient survival after whole-brain radiotherapy (WBRT) for initial brain metastases arising from non-small cell lung cancer (NSCLC). Methods: Patients diagnosed with NSCLC between 1 January 2010 and 30 September 2019, and who received WBRT upon first developing a brain metastasis, were investigated. Overall survival was determined as related to age, sex, duration between initial examination and brain metastasis detection, stage at the first examination, presence of metastases outside the brain, blood analysis findings, brain metastasis symptoms, radiotherapy dose and completion, imaging findings, therapeutic course of chemotherapy and/or radiation therapy, histological type, and gene mutation status. Results: Thirty-one consecutive patients (20 men and 11 women) with a mean age of 63·8 years and median survival of 129 days were included. Multivariate analysis with stepwise testing was performed to investigate differences in survival according to gene mutation status, lactate dehydrogenase (LDH) level, irradiation dose, WBRT completion and Stage status. Of these, a statistically significant difference in survival was observed in patients with gene mutation status (hazard ratio: 0·31, 95% CI: 0·11–0·86, p = 0·025), LDH levels <230 vs. ≥230 IU/L (hazard ratio: 4·08, 95% CI: 1·45–11·5, p < 0·01) received 30 Gy, 30 Gy/10 fractions to 35 Gy/14 fractions, and 37·5 Gy/15 fractions (hazard ratio: 0·26, 95% CI: 0·09–0·71, p < 0·01), and stage IV versus non-stage IV (hazard ratio: 0·13, 95 CI:0·02–0·64, p < 0·01) Findings: Gene mutation, LDH, radiation dose and Stage are prognostic factors for patients with initial brain metastases who are treated with WBRT.


Author(s):  
Bijal Majiwala ◽  
Trupti Warude ◽  
Amrutkuvar Pawar

Objective: To compare the effects of isometric (stability) and isotonic training on core muscle in patients with non-specific low back pain on pain, endurance, and functional disability.Methods: Forty participants of both genders aged between 20 and 35 years suffering from non-specific low back pain were taken and equally divided into two groups: Group A isometric exercise and Group B isotonic exercise, both the group received baseline treatment of transcutaneous electrical nerve stimulation and hot moist pack. Outcomes measure visual analog scale, endurance test, and modified Oswestry disability index were used the pre-treatment and at the end of 4 weeks.Results: Experiment of both the groups showed a non-significant improvement in pain, endurance, and functional disability. Except for extensor endurance test which shows significant different in Group A.Conclusion: Both isometric and isotonic exercises are equally effective in reducing pain, increase endurance, and improve functional disability in patients with non-specific low back pain.


2006 ◽  
Vol 21 (3) ◽  
pp. 168-176 ◽  
Author(s):  
Míriam Elias Cavallini ◽  
Nelson Adami Andreollo ◽  
Konradin Metze ◽  
Marina Raquel Araújo

PURPOSE: To evaluate and to compare macro and microscopically the intense injuries of the gastric mucosa of rats which were caused by NSAIDS celecoxib and indomethacin and the gastric cytoprotection with omeprazole and misoprostol. METHODS: The sample is formed by one hundred and fifty Wistar rats with average weight 200 g, distributed in four groups, such as: Group A, subdivided in groups A1 and A2 - pre-treatment with omeprazole (20 mg/rat) during seven days and on the 8th day - use of NSAIDS, concerning A1 (20 rats) were given celecoxib (1mg/rat) and A2 (20 rats) were given indomethacin. The Group B, subdivided in group B1 and B2 - pre-treatment with misoprostol (20mg/rat) during seven days and on the 8th day use of NSAIDS, concerning B1 (20 rats) were given celecoxib (1 mg/ rat) and B2 (20 rats) were given indomethacin (12.5 mg/rat). The Group C: were not given cytoprotection during seven days, from the 7th to the 8th day - fast of food and water ad libitum, on the 8th day of NSAIDS use, concerning C1 (20 rats) were given celecoxib, C2 (20 rats) were given indomethacin (12.5 mg/ rat), C3 (20 rats) were given celecoxib (200mg/rato), and Group D - control group, concerning 10 rats were observed during seven days ingesting food and water ad libitum. On the 9th day, the stomachs were taken out and were macro and microscopically evaluated for the identification of the gastric injuries. RESULTS: On the macroscopic studies, the groups A2, B2 and C2 presented a remarkable high number of injuries for cm² /animal, respectively 18.55 injuries for cm² /animal, 16.25 injuries for cm² /animal and 13.55 injuries for cm²/animal. On the microscopic studies, the percentage of the injured mucosa, presented expressive difference among the groups A1, B1, C1 when compared to the groups A2, B2, C2 (p<0.0001). The average of the length/injury and the average of the depth of the injuries did not present expressive statistics differences among the groups A2, B2 and C2. The average of the edema presented expressive statistics difference among the groups A2 and D; B2 and C2 and between C2 and D (p < 0.05). CONCLUSIONS: The indomethacin on the applied concentration causes a great number of macroscopic and microscopic injuries to gastric mucosa of rats when compared to celecoxib which does not cause lesions. Omeprazole and misoprostol on the applied concentrations do not present macroscopic and microscopic effectiveness on the gastric cytoprotection when applying indomethacin. Considering the microscopic analysis of the average of the edema, the group of animals, which was given misoprostol as cytoprotection, presented a lower average compared to the group which was given omeprazole.


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