Ipilimumab (Ipi), a monoclonal antibody against cytotoxic T-lymphocyte antigen-4, has been shown to improve survival in patients with metastatic melanoma. In this single-institution study, we ...investigated the safety and efficacy of stereotactic radiosurgery (SRS) for patients with melanoma brain metastases (BMs) who also received Ipi.
From 2005 to 2011, 46 patients with melanoma received Ipi and underwent single-fraction SRS for BMs. A total of 113 BMs (91% intact, 9% postoperative) were treated with a median dose of 21 Gy (range, 15-24 Gy). Ipi was given at 3 mg/kg (54%) or 10 mg/kg (46%) for a median of 4 doses (range, 1-21). Adverse events were recorded with the use of the Common Terminology Criteria for Adverse Events 3.0. Kaplan-Meier methods were used to estimate survival, and Cox regression was used to investigate associations.
Fifteen patients received SRS during Ipi, 19 received SRS before Ipi, and 12 received SRS after Ipi. Overall survival (OS) was significantly associated with the timing of SRS/Ipi (P=.035) and melanoma-specific graded prognostic assessment (P=.013). Patients treated with SRS during or before Ipi had better OS and less regional recurrence than did those treated with SRS after Ipi (1-year OS 65% vs 56% vs 40%, P=.008; 1-year regional recurrence 69% vs 64% vs 92%, P=.003). SRS during Ipi also yielded a trend toward less local recurrence than did SRS before or after Ipi (1-year local recurrence 0% vs 13% vs 11%, P=.21). On magnetic resonance imaging, an increase in BM diameter to >150% was seen in 50% of patients treated during or before Ipi but in only 13% of patients treated after Ipi. Grade 3 to 4 toxicities were seen in 20% of patients.
Overall, the combination of Ipi and SRS appears to be well tolerated. Concurrent delivery of Ipi and SRS is associated with favorable locoregional control and possibly longer survival. It may also cause a temporary increase in tumor size, possibly because of an enhanced immunomodulatory effect.
To report the incidence and predictors of treatment-related toxicity at 10 years after three-dimensional conformal radiotherapy (3D-CRT) and intensity-modulated radiotherapy (IMRT) for localized ...prostate cancer.
Between 1988 and 2000, 1571 patients with stages T1-T3 prostate cancer were treated with 3D-CRT/IMRT with doses ranging from 66 to 81 Gy. The median follow-up was 10 years. Posttreatment toxicities were all graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events.
The actuarial likelihood at 10 years for the development of Grade>or=2 GI toxicities was 9%. The use of IMRT significantly reduced the risk of gastrointestinal (GI) toxicities compared with patients treated with conventional 3D-CRT (13% to 5%; p<0.001). Among patients who experienced acute symptoms the 10-year incidence of late toxicity was 42%, compared with 9% for those who did not experience acute symptoms (p<0.0001). The 10-year incidence of late Grade>or=2 genitourinary (GU) toxicity was 15%. Patients treated with 81 Gy (IMRT) had a 20% incidence of GU symptoms at 10 years, compared with a 12% for patient treated to lower doses (p=0.01). Among patients who had developed acute symptoms during treatment, the incidence of late toxicity at 10 years was 35%, compared with 12% (p<0.001). The incidence of Grade 3 GI and GU toxicities was 1% and 3%, respectively.
Serious late toxicity was unusual despite the delivery of high radiation dose levels in these patients. Higher doses were associated with increased GI and GU Grade 2 toxicities, but the risk of proctitis was significantly reduced with IMRT. Acute symptoms were a precursor of late toxicities in these patients.
Spinal stereotactic radiosurgery (SRS) is increasingly used to manage spinal metastases. However, target volume definition varies considerably and no consensus target volume guidelines exist. This ...study proposes consensus target volume definitions using common scenarios in metastatic spine radiosurgery.
Seven radiation oncologists and 3 neurological surgeons with spinal radiosurgery expertise independently contoured target and critical normal structures for 10 cases representing common scenarios in metastatic spine radiosurgery. Each set of volumes was imported into the Computational Environment for Radiotherapy Research. Quantitative analysis was performed using an expectation maximization algorithm for Simultaneous Truth and Performance Level Estimation (STAPLE) with kappa statistics calculating agreement between physicians. Optimized confidence level consensus contours were identified using histogram agreement analysis and characterized to create target volume definition guidelines.
Mean STAPLE agreement sensitivity and specificity was 0.76 (range, 0.67-0.84) and 0.97 (range, 0.94-0.99), respectively, for gross tumor volume (GTV) and 0.79 (range, 0.66-0.91) and 0.96 (range, 0.92-0.98), respectively, for clinical target volume (CTV). Mean kappa agreement was 0.65 (range, 0.54-0.79) for GTV and 0.64 (range, 0.54-0.82) for CTV (P<.01 for GTV and CTV in all cases). STAPLE histogram agreement analysis identified optimal consensus contours (80% confidence limit). Consensus recommendations include that the CTV should include abnormal marrow signal suspicious for microscopic invasion and an adjacent normal bony expansion to account for subclinical tumor spread in the marrow space. No epidural CTV expansion is recommended without epidural disease, and circumferential CTVs encircling the cord should be used only when the vertebral body, bilateral pedicles/lamina, and spinous process are all involved or there is extensive metastatic disease along the circumference of the epidural space.
This report provides consensus guidelines for target volume definition for spinal metastases receiving upfront SRS in common clinical situations.
Systematic literature review.
To determine the options, indications, and outcomes for conventional radiotherapy and radiosurgery for metastatic spine disease.
Three research questions were determined ...through a consensus among a multidisciplinary panel of spine oncology experts. A systematic review of the literature was conducted regarding radiotherapy and radiosurgery for metastatic spine disease using PubMed, Embase, the Cochrane Evidence Based Medicine Database, and a review of bibliographies of reviewed articles.
1. What are the clinical outcomes of the current indications for conventional radiotherapy alone and stereotactic radiosurgery for metastatic spine disease? 2. What are the current dose recommendations and fractionation schedules for conventional spine radiotherapy and stereotactic radiosurgery for metastatic spine disease? 3. What are the current known patterns of failure and complications after conventional spine radiation and stereotactic radiosurgery for metastatic spine disease?
For conventional radiotherapy, the initial literature search yielded a total of 531 potentially relevant abstracts. Each of these abstracts was reviewed for relevance, and 62 were selected for in-depth review. Forty-nine studies met all the inclusion criteria. References from the articles included in the analysis and review articles were also examined for potential inclusion in the study. For conventional radiotherapy, 3 randomized trials (high-quality evidence), 4 prospective studies (moderate-quality evidence), and over 40 nonprospective data sets (low- or very-low-quality evidence) that included over 5000 patients in the literature were included in this review. Drawing from the same databases, a systematic search for radiosurgery yielded 195 abstracts, of which 29 met all inclusion criteria. They all represented single-institution reports (low- or very-low-quality data). No randomized data are available for spine radiosurgery.
A systematic review of the available evidence suggests that conventional radiotherapy is safe and effective with good symptomatic response and local control, particularly for radiosensitive histologies. A strong recommendation can be made with moderate quality evidence that conventional fractionated radiotherapy is an appropriate initial therapy option for patients with spine metastases in cases in which no relative contraindication exists. A systematic review of the available evidence suggests that radiosurgery is safe and provides an incremental benefit over conventional radiotherapy with more durable symptomatic response and local control independent of histology, even in the setting of prior fractionated radiotherapy. A strong recommendation can be made with low-quality evidence that radiosurgery should be considered over conventional fractionated radiotherapy for the treatment of solid tumor spine metastases in the setting of oligometastatic disease and/or radioresistant histology.
Background.
Spinal metastases frequently arise in patients with cancer. Modern oncology provides numerous treatment options that include effective systemic, radiation, and surgical options. We ...delineate and provide the evidence for the neurologic, oncologic, mechanical, and systemic (NOMS) decision framework, which is used at Memorial Sloan‐Kettering Cancer Center to determine the optimal therapy for patients with spine metastases.
Methods.
We provide a literature review of the integral publications that serve as the basis for the NOMS framework and report the results of systematic implementation of the NOMS‐guided treatment.
Results.
The NOMS decision framework consists of the neurologic, oncologic, mechanical, and systemic considerations and incorporates the use of conventional external beam radiation, spinal stereotactic radiosurgery, and minimally invasive and open surgical interventions. Review of radiation oncology and surgical literature that examine the outcomes of treatment of spinal metastatic tumors provides support for the NOMS decision framework. Application of the NOMS paradigm integrates multimodality therapy to optimize local tumor control, pain relief, and restoration or preservation of neurologic function and minimizes morbidity in this often systemically ill patient population.
Conclusion.
NOMS paradigm provides a decision framework that incorporates sentinel decision points in the treatment of spinal metastases. Consideration of the tumor sensitivity to radiation in conjunction with the extent of epidural extension allows determination of the optimal radiation treatment and the need for surgical decompression. Mechanical stability of the spine and the systemic disease considerations further help determine the need and the feasibility of surgical intervention.
摘要
背景. 癌症患者经常会发生肿瘤脊柱转移。现代肿瘤学提供了众多治疗方案，包括有效的系统治疗、放射治疗和手术治疗。我们描述并提供了解释神经病变学、肿瘤学、机械力学、以及系统（neurologic，oncologic，mechanical and systemic），NOMS决策框架的证据，该框架在斯隆‐凯特琳纪念癌症中心用于制定脊柱转移瘤患者的最佳治疗方案。
方法. 我们对以NOMS框架为基础的主要出版文献进行了文献综述，报告系统实施NOMS指导治疗的结果。
结果. NOMS决策框架包括对神经病变学、肿瘤学、机械力学以及系统原因的考量，综合应用常规外照射治疗、脊髓立体定向放射外科治疗、微创及开放性手术治疗。旨在调查脊柱转移瘤治疗结果的放射肿瘤学和外科学文献的综述为NOMS决策框架提供了支持。NOMS范例应用时综合多学科治疗以优化局部肿瘤控制、疼痛缓解，恢复或保留神经功能，并将此类容易系统性患病的患者人群的发病率降至最低。
结论. NOMS范例提供一种决策框架，该框架可汇总脊柱转移瘤治疗中的前哨决策点。针对肿瘤对放射治疗的敏感性结合肿瘤硬膜外侵犯程度的考量，可确定最佳放射治疗方案并符合外科减压手术的需求。针对脊柱的机械稳定性和系统性疾病的考虑更进一步有助于确定外科手术治疗的需求及其可行性。The Oncologist 2013;18:744–751
Spinal metastases frequently arise in patients with cancer. This article describes the neurologic, oncologic, mechanical, and systemic decision framework used at Memorial Sloan‐Kettering Cancer Center to determine the optimal therapy for patients with spinal metastases.
Brain metastases are the most common intracranial tumors in adults, accounting for more than 50% of all such cases. The approach to and management of brain metastases have evolved significantly in ...recent years due to several reasons. These include advances in neurosurgical and radiotherapeutic techniques, improved systemic therapy options offering better systemic and intracranial disease control and prolongation of survival as a result of these improvements, making side-effects of proposed therapies (e.g. neurocognitive decline from whole brain radiotherapy) an important consideration. In this article, we review the the primary therapeutic approaches to the management of brain metastases, namely, surgery, stereotactic radiosurgery, and whole brain radiation therapy and the primary factors dictating choice.
The abscopal effect is a phenomenon in which local radiotherapy is associated with the regression of metastatic cancer at a distance from the irradiated site. The abscopal effect may be mediated by ...activation of the immune system. Ipilimumab is a monoclonal antibody that inhibits an immunologic checkpoint on T cells, cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4). We report a case of the abscopal effect in a patient with melanoma treated with ipilimumab and radiotherapy. Temporal associations were noted: tumor shrinkage with antibody responses to the cancer-testis antigen NY-ESO-1, changes in peripheral-blood immune cells, and increases in antibody responses to other antigens after radiotherapy. (Funded by the National Institutes of Health and others.).
Systematic literature review.
To assess the toxicity, common radiation doses, and local control (LC) rates of radiation therapy for chordoma of the spine and sacrum and identify the difference in LC ...and toxicity between adjuvant, salvage, and primary therapy using radiation.
Chordoma of the spine is typically a low-grade malignant tumor thought to be relatively radioresistant with a high rate of local recurrence and the potential for metastases. Improved results of modern radiation therapy in the treatment of chordoma support exploration of its role in the management of primary/de novo chordoma or recurrent chordoma.
We conducted a systematic literature review using PubMed and Embase databases to assess information available regarding the toxicity, LC rates, and overall survival (OS) rates for adjuvant, salvage, and primary radiation therapy for spinal and sacral chordoma.
A total of 40 articles were reviewed. Evidence quality was low or very low. The highest rates of LC and OS were with early adjuvant RT for primary/de novo disease. Salvage RT for recurrent disease has very small cohorts and thus strong conclusions were not able be made.
The use of pre- and/or post-operative photon image-guided radiotherapy (IGRT), proton or carbon ion therapy should be considered for patients undergoing surgery for the treatment of primary and recurrent chordomas in the mobile spine and sacrum, since these RT modalities may improve local control. Preoperative evaluation by the surgeon and radiation oncologist should be used to formulate a cohesive treatment plan.The use of photon IGRT or carbon ion therapy as the primary treatment of chordoma, when currently in its developmental stage, shows promise and requires clear delineation of toxicity profile and long-term local control.
2.
Conventional radiation treatment (20-40 Gy in 5-20 fractions, 2-5 Gy per fraction) for sarcoma metastatic to the spine provides subtherapeutic doses, resulting in poor durable local control (LC) ...(50%-77% at 1 year). Hypofractionated (HF) and/or single-fraction (SF) image-guided stereotactic radiosurgery (IG-SRS) may provide a more effective means of managing these lesions.
Patients with pathologically proven high-grade sarcoma metastatic to the spine treated with HF and SF IG-SRS were included. LC and overall survival (OS) were analyzed by the use of Kaplan-Meier statistics. Univariate and multivariate analyses were performed by the use of Cox regression with competing-risks analysis; all confidence intervals are 95%. Toxicities were assessed according to Common Terminology Criteria for Adverse Events, version 4.0.
From May 2005 to November 11, 2012, 88 patients with 120 discrete metastases received HF (3-6 fractions; median dose, 28.5 Gy; n=52, 43.3%) or SF IG-SRS (median dose, 24 Gy; n=68, 56.7%). The median follow-up time was 12.3 months. At 12 months, LC was 87.9% (confidence interval CI, 81.3%-94.5%), OS was 60.6% (CI, 49.6%-71.6%), and median survival was 16.9 months. SF IG-SRS demonstrated superior LC to HF IG-SRS (12-month LC of 90.8% CI, 83%-98.6% vs 84.1% CI, 72.9%-95.3% P=.007) and retained significance on multivariate analysis (P=.030, hazard ratio 0.345; CI, 0.132-0.901. Treatment was well tolerated, with 1% acute grade 3 toxicity, 4.5% chronic grade 3 toxicity, and no grade >3 toxicities.
In the largest series of metastatic sarcoma to the spine to date, IG-SRS provides excellent LC in the setting of an aggressive disease with low radiation sensitivity and poor prognosis. Single-fraction IG-SRS is associated with the highest rates of LC with minimal toxicity.
This prospective phase 3 randomized trial was designed to test whether ultra high single-dose radiation therapy (24 Gy SDRT) improves local control of oligometastatic lesions compared to a standard ...hypofractionated stereotactic body radiation therapy regimen (3 × 9 Gy SBRT). The secondary endpoint was to assess the associated toxicity and the impact of ablation on clinical patterns of metastatic progression.
Between November 2010 and September 2015, 117 patients with 154 oligometastatic lesions (≤5/patient) were randomized in a 1:1 ratio to receive 24 Gy SDRT or 3 × 9 Gy SBRT. Local control within the irradiated field and the state of metastatic spread were assessed by periodic whole-body positron emission tomography/computed tomography and/or magnetic resonance imaging. Median follow-up was 52 months.
A total of 59 patients with 77 lesions were randomized to 24 Gy SDRT and 58 patients with 77 lesions to 3 × 9 Gy SBRT. The cumulative incidence of local recurrence for SDRT-treated lesions was 2.7% (95% confidence interval CI, 0%-6.5%) and 5.8% (95% CI, 0.2%-11.5%) at years 2 and 3, respectively, compared with 9.1% (95% CI, 2.6%-15.6%) and 22% (95% CI, 11.9%-32.1%) for SBRT-treated lesions (P = .0048). The 2- and 3-year cumulative incidences of distant metastatic progression in the SDRT patients were 5.3% (95% CI, 0%-11.1%), compared with 10.7% (95% CI, 2.5%-18.8%) and 22.5% (95% CI, 11.1%-33.9%), respectively, for the SBRT patients (P = .010). No differences in toxicity were observed.
The study confirms SDRT as a superior ablative treatment, indicating that effective ablation of oligometastatic lesions is associated with significant mitigation of distant metastatic progression.
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