Complementary and alternative medicine in reducing radiation-induced skin toxicity.

Radiation therapy-induced acute and late effects, particularly skin toxicities, have significant impact on cancer patients' quality of life and long-term survival. To date, no effective topical agents have been routinely used in the clinical setting to prevent skin toxicity. Using SKH-hr1 hairless mice, we investigated two complementary and alternative medicine in their effects on inflammation and ionizing radiation (IR)-induced skin toxicity: Calendula officinalis (CO) and Ching Wan Hung (CWH). They were applied immediately following each IR dosing of 10 Gy/day for 4 days. Skin toxicity and inflammatory factors were evaluated at multiple time points up to 15 days post-radiation. Serum interleukin (IL)-1α, monocyte chemotactic protein-1 (MCP1), keratinocyte-derived chemokine (KC), and granulocyte colony-stimulating factor (G-CSF) were significantly induced by radiation. Both CO and CWH significantly inhibited IR-induced MCP1 (p < 0.01), KC (p < 0.05), and G-CSF (p < 0.001). IR-induced erythema and blood vessel dilation were significantly reduced by CWH (p < 0.001) but not by CO at day 10 post-IR. Both agents inhibited IR-induced IL-1α (p < 0.01), MCP1 (p < 0.05), and vascular endothelial growth factor (p < 0.05). There were continuous inhibitory effects of CWH on IR-induced skin toxicities and inflammation. In contrast, CO treatment resulted in skin reactions compared to IR alone. Our results suggest that both CO and CWH reduce IR-induced inflammation and CWH reduced IR-induced erythema. In summary, CWH showed promising effects in reducing IR-related inflammation and skin toxicities, and future proof-of-principal testing in humans will be critical in evaluating its potential application in preventing IR-induced skin toxicities.

The influence of Hispanic ethnicity on nonsmall cell lung cancer histology and patient survival: an analysis of the Survival, Epidemiology, and End Results database.

BACKGROUND: Most studies exploring ethnic/racial disparities in nonsmall cell lung cancer (NSCLC) compare black patients with whites. Currently, the effect of Hispanic ethnicity on the overall survival of NSCLC is poorly understood. Therefore, the authors carried out a large-scale, population-based analysis using the Surveillance, Epidemiology, and End Results (SEER) data base to determine the impact of Hispanic ethnicity the survival of patients with NSCLC. METHODS: The authors identified 172,398 adult patients with pathologically confirmed NSCLC from the SEER data base who were diagnosed between 1988 and 2007. A multivariate Cox proportional hazards regression analysis was used to determine the impact of race/ethnicity on overall survival. Pair-wise comparisons were used to determine whether Hispanic ethnicity influenced NSCLC histology or stage at diagnosis. RESULTS: Compared with non-Hispanic white patients, Hispanic white patients had a statistically significant better overall survival (hazard ratio [HR], 0.85; 95% confidence interval [CI], 0.83-0.87), and black patients had worse survival (HR, 1.091; 95% CI, 1.072-1.109). Within the bronchioalveolar carcinoma (BAC) subtype, Hispanic-white patients tend to be over represented (8.1% Hispanic whites vs 5.5% non-Hispanic whites vs 3.7% blacks; P < .001). CONCLUSIONS: The current study demonstrated that Hispanic-white patients with NSCLC had a decreased risk for overall mortality compared with non-Hispanic whites and blacks. Moreover, Hispanic patients were over represented within the BAC histologic subtype. Thus, the overall survival advantage of Hispanic NSCLC patients may be because of their predilection toward developing certain histologic subtypes of NSCLC. Further studies are warranted to determine the etiologies of such predilections and may reveal certain genetic, environmental, and/or epigenetic factors associated with Hispanic ethnicity.

The management of incidental low-grade gliomas using magnetic resonance imaging: systematic review and optimal treatment paradigm.

OBJECT: The discovery of incidental low-grade gliomas (LGGs) on MR imaging is rare, and currently there is no existing protocol for management of these lesions. Various studies have approached the dilemma of managing patients with incidental LGGs. While some advocate surgery and radiotherapy, others reserve surgery until there is radiological evidence of growth. For neurosurgeons and radiologists, determining the course of action after routine brain imaging poses not only a medical but also an ethical dilemma. The authors conducted a systematic review of case reports and case series in hopes of enhancing the current understanding of the management options for these rare lesions. METHODS: A PubMed search was performed to include all relevant MR imaging studies in which management of suspected incidental LGG was reported. Comparisons were made between the surgical treatment arm and the active surveillance arm in terms of outcome, mode of discovery, reasons for treatment, and histology. RESULTS: Nine studies with 72 patients were included in this study (56 in the surgical arm and 16 in the active surveillance arm). Within the surgical arm, 49% remained deficit free after treatment, 25% showed evidence of tumor progression, 13% underwent a second treatment, and 7% died. The active surveillance group resulted in no unanticipated adverse events, with serial imaging revealing no tumor growth in all cases. Lesion regression was reported in 31% of this group. The surgical arm's mortality rate was 7% compared with 0% in the active surveillance arm. CONCLUSIONS: Treatment decisions for incidental LGG should be individualized based on presenting symptoms and radiological evidence of growth. The asymptomatic patient may be monitored safely with serial MR imaging and occasionally PET scanning before treatment is initiated. In patients presenting with nonspecific symptoms or concurrent symptomatic lesions, treatment may be initiated earlier to reduce potential morbidity. All treatment decisions must be tempered by patient factors and expectations of anticipated benefit.

Identification and biological evaluation of a novel and potent small molecule radiation sensitizer via an unbiased screen of a chemical library.

For patients with solid tumors, the tolerance of surrounding tissues often limits the dose of radiation that can be delivered. Thus, agents that preferentially increase the cytotoxic effects of radiation toward tumor cells would significantly alter the therapeutic ratio and improve patient survival. Using a high-throughput, unbiased screening approach, we have identified 4'-bromo-3'-nitropropiophenone (NS-123) as a radiosensitizer of human glioma cells in vitro and in vivo. NS-123 radiosensitized U251 glioma cells in a dose-dependent and time-dependent manner, with dose enhancement ratios ranging from 1.3 to 2.0. HT-29 colorectal carcinoma and A549 lung adenocarcinoma cells were also radiosensitized by NS-123 in vitro, whereas NS-123 did not increase the radiation sensitivity of normal human astrocytes or developmental abnormalities or lethality of irradiated Zebrafish embryos. In a novel xenograft model of U251 cells implanted into Zebrafish embryos, NS-123 enhanced the tumor growth-inhibitory effects of ionizing radiation (IR) with no apparent effect on embryo development. Similar results were obtained using a mouse tumor xenograft model in which NS-123 sensitized U251 tumors to IR while exhibiting no overt toxicity. In vitro pretreatment with NS-123 resulted in accumulation of unrepaired IR-induced DNA strand breaks and prolonged phosphorylation of the surrogate markers of DNA damage H2AX, ataxia telangiectasia mutated protein, DNA-dependent protein kinase, and CHK2 after IR, suggesting that NS-123 inhibits a critical step in the DNA repair pathway. These results show the potential of this cell-based, high-throughput screening method to identify novel radiosensitizers and suggest that NS-123 and similar nitrophenol compounds may be effective in antiglioma modalities.

Adjuvant therapy for non-small cell lung cancer with mediastinal nodal involvement.

Since the publication of the meta-analysis in 1995 indicating a potential survival benefit with adjuvant cisplatin-based chemotherapy for patients with resected NSCLC, the management of patients with resected NSCLC and N2 disease involvement has evolved dramatically. The delivery of systemic therapy in the postoperative setting remains difficult, however, because tolerance for the toxicities of chemotherapy is reduced by recovery from surgery itself. Even with a proven survival benefit with adjuvant chemotherapy, cure is not guaranteed, and most patients die from relapse of their cancer. Optimization of treatment through the administration of neoadjuvant therapy, application of more modern radiotherapy techniques, and combined-modality therapy with chemoradiation or molecularly targeted agents are areas currently under active investigation. Ideally, the improvement of prediction of which patients harbor micrometastatic disease before undergoing surgical resection and the prediction of which patients would benefit from different systemic therapies may help to improve further the chance of cure for NSCLC while at the same time reducing toxicity.

Long-Term Outcomes of a Phase 2 Trial of Chemotherapy With Consolidative Radiation Therapy for Oligometastatic Non-Small Cell Lung Cancer.

PURPOSE: Recent data indicate consolidative radiation therapy improves progression-free survival (PFS) for patients with oligometastatic non-small cell lung cancer (NSCLC). Data on long-term outcomes are limited. METHODS AND MATERIALS: This prospective, multicenter, single-arm, phase 2 trial was initiated in 2010 and enrolled patients with oligometastatic NSCLC. Oligometastatic disease was defined as a maximum of 5 metastatic lesions for all disease sites, including no more than 3 active extracranial metastatic lesions. Limited mediastinal lymph node involvement was allowed. Patients achieving a partial response or stable disease after 3 to 6 cycles of platinum-based chemotherapy were treated with CRT to the primary and metastatic sites of disease, followed by observation alone. The primary endpoint was PFS, with secondary endpoints of local control, overall survival (OS), and safety. RESULTS: Twenty-nine patients were enrolled between October 2010 and October 2015, and 27 were eligible for consolidative radiation therapy. The study was closed early because of slow accrual but met its primary endpoint for success, which was PFS >6 months (P < .0001). The median PFS (95% confidence interval) was 11.2 months (7.6-15.9 months), and the median OS was 28.4 months (14.5-45.8 months). Survival outcomes were not significantly different for patients with brain metastases (P = .87 for PFS; P = .12 for OS) or lymph node involvement (P = .74 for PFS; P = .86 for OS). CONCLUSIONS: For patients with oligometastatic NSCLC, chemotherapy followed by consolidative radiation therapy without maintenance chemotherapy was associated with encouraging long-term outcomes.

Stereotactic body radiation therapy for early-stage non-small cell lung cancer: Executive Summary of an ASTRO Evidence-Based Guideline.

PURPOSE: This guideline presents evidence-based recommendations for stereotactic body radiation therapy (SBRT) in challenging clinical scenarios in early-stage non-small cell lung cancer (NSCLC). METHODS AND MATERIALS: The American Society for Radiation Oncology convened a task force to perform a systematic literature review on 4 key questions addressing: (1) application of SBRT to operable patients; (2) appropriate use of SBRT in tumors that are centrally located, large, multifocal, or unbiopsied; (3) individual tailoring of SBRT in "high-risk" clinical scenarios; and (4) SBRT as salvage therapy after recurrence. Guideline recommendations were created using a predefined consensus-building methodology supported by American Society for Radiation Oncology-approved tools for grading evidence quality and recommendation strength. RESULTS: Although few randomized trials have been completed for SBRT, strong consensus recommendations based on extensive, consistent publications were generated for several questions, including recommendations for fractionation for central tumors and surgery versus SBRT in standard-risk medically operable patients with early-stage NSCLC. Lower quality evidence led to conditional recommendations on use of SBRT for tumors >5 cm, patients with prior pneumonectomy, T3 tumors with chest wall invasion, synchronous multiple primary lung cancer, and as a salvage therapy after prior radiation therapy. These areas of moderate- and low-quality evidence highlight the importance of clinical trial enrollment as well as the role of prospective data registries. CONCLUSIONS: SBRT has an important role to play in treating early-stage NSCLC, particularly for medically inoperable patients with limited other treatment options. Shared decision-making with patients should be performed in all cases to ensure the patient understands the risks related to SBRT, the side effects, and the alternative treatments available.

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.

Inflammatory biomarker C-reactive protein and radiotherapy-induced early adverse skin reactions in patients with breast cancer.

BACKGROUND: Breast cancer is the most frequently diagnosed cancer and the second leading cause of cancer death in American women. Postsurgery adjuvant radiotherapy (RT) significantly reduced the local recurrence rate. However, many patients develop early adverse skin reactions (EASR) that impact quality of life and treatment outcomes. METHODS: We evaluated an inflammatory biomarker, C-reactive protein (CRP), in predicting RT-induced EASRs in 159 patients with breast cancer undergoing RT. In each patient, we measured pre- and post-RT plasma CRP levels using a highly sensitive ELISA CRP assay. RT-induced EASRs were assessed at weeks 3 and 6 using the National Cancer Institute Common Toxicity Criteria (v3.0). Associations between EASRs and CRP levels were assessed using logistic regression models after adjusting for potential confounders. RESULTS: RT-induced grade 2+ EASRs were observed in 8 (5%) and 80 (50%) patients at weeks 3 and 6 (end of RT), respectively. At the end of RT, a significantly higher proportion of African Americans developed grade 3 EASRs (13.8% vs. 2.3% in others); grade 2+ EASRs were significantly associated with: change of CRP > 1 mg/L [odds ratio (OR), 2.51; 95% confidence interval (CI), 1.06-5.95; P = 0.04], obesity (OR, 2.08; 95% CI, 1.03-4.21; P = 0.04), or combined both factors (OR, 5.21; 95% CI, 1.77-15.38; P = 0.003). CONCLUSION: This is the first study to demonstrate that an inflammatory biomarker CRP is associated with RT-induced EASRs, particularly combined with obesity. IMPACT: Future larger studies are warranted to validate our findings and facilitate the discovery and development of anti-inflammatory agents to protect normal tissue from RT-induced adverse effects and improve quality of life in patients with breast cancer undergoing RT.

A review of stereotactic radiosurgery practice in the management of skull base meningiomas.

Gross total resection of skull base meningiomas poses a surgical challenge due to their proximity to neurovascular structures. Once the gold standard therapy for skull base meningiomas, microsurgery has been gradually replaced by or used in combination with stereotactic radiosurgery (SRS). This review surveys the safety and efficacy of SRS in the treatment of cranial base meningiomas including 36 articles from 1991 to 2010. SRS produces excellent tumor control with low morbidity rates compared with surgery alone for asymptomatic small skull base meningiomas, patients with risk factors precluding conventional surgery, and as adjuvant therapy for recurrent or residual lesions.

ACR appropriateness Criteria® early-stage non-small-cell lung cancer.

Early-stage non-small-cell lung cancer (NSCLC) is diagnosed in about 15% to 20% of lung cancer patients at presentation. In order to provide clinicians with guidance in decision making for early-stage NSCLC patients, the American College of Radiology Appropriateness Criteria Lung Cancer Panel was recently charged with a review of the current published literature to generate up-to-date management recommendations for this clinical scenario. For patients with localized, mediastinal lymph node-negative NSCLC, optimal management should be determined by an expert multidisciplinary team. For medically operable patients, surgical resection is the standard of care, with generally no role for adjuvant therapies thereafter. For patients with medical comorbidities making them at high risk for surgery, there is emerging evidence demonstrating the availability of low toxicity curative therapies, such as stereotactic body radiotherapy, for their care. As a general statement, the American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every 2 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment.

The role of radiosurgery to the tumor bed after resection of brain metastases.

BACKGROUND: Optimal postoperative management paradigm for brain metastases remains controversial. OBJECTIVE: To conduct a systematic review of the literature to understand the role of postoperative stereotactic radiosurgery after resection of brain metastases. METHODS: We performed a MEDLINE search of the literature to identify series of patients with brain metastases treated with stereotactic radiosurgery after surgical resection. Outcomes including overall survival, local control, distant intracranial failure, and salvage therapy use were recorded. Patient, tumor, and treatment factors were correlated with outcomes through the use of the Pearson correlation and 2-way Student t test as appropriate. RESULTS: Fourteen studies involving 629 patients were included. Median survival for all studies was 14 months. Local control was correlated with the median volume treated with radiosurgery (r = -0.766, P < .05) and with the rate of gross total resection (r = .728, P < .03). Mean crude local control was 83%; 1-year local control was 85%. Distant intracranial failure occurred in 49% of cases, and salvage whole-brain radiation therapy was required in 29% of cases. Use of a radiosurgical margin did not lead to increased local control or overall survival. CONCLUSION: Our systematic review supports the use of radiosurgery as a safe and effective strategy for adjuvant treatment of brain metastases, particularly when gross total resection has been achieved. With all limitations of comparisons between studies, no increase in local recurrence or decrease in overall survival compared with rates with adjuvant whole-brain radiation therapy was found.

Adjuvant whole brain radiation following resection of brain metastases.

Brain metastasis is a common complication of systemic cancer and significant cause of suffering in oncology patients. Despite a plethora of available treatment modalities, the prognosis is poor with a median survival time of approximately one year. For patients with controlled systemic disease, good performance status, and a limited number of metastases, treatment typically entails surgical resection or radiosurgery, followed by whole brain radiotherapy (WBRT) to control microscopic disease. WBRT is known to control the progression of cancer in the brain, but it can also have toxic effects, particularly with regard to neurocognition. There is no consensus as to whether the benefit of WBRT outweighs the potential harm. We review the evidence related to the question of whether patients undergoing surgical resection of brain metastases should receive adjuvant WBRT.

ACR Appropriateness Criteria® radiation therapy for small-cell lung cancer.

The current standard of care for small cell lung cancer is combined-modality therapy, including the use of chemotherapy, surgery (in selected cases of limited stage of disease), and radiation therapy. This review will focus on the role, dose fractionation, technology and timing of thoracic radiation, and the role and dose regimen of prophylactic cranial irradiation for both limited and extensive stage of diseases. Consensus recommendation from experts is summarized in the tables for 2 typical case scenarios. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every 2 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals and the application of a well established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment.

ACR appropriateness criteria nonsurgical treatment for non-small-cell lung cancer: poor performance status or palliative intent.

Radiation therapy plays a potential curative role in the treatment of patients with non-small-cell lung cancer with locoregional disease who are not surgical candidates and a palliative role for patients with metastatic disease. Stereotactic body radiation therapy is a relatively new technique in patients with early-stage non-small-cell lung cancer. A trial from RTOG(®) reported >97% local control at 3 years. For patients with locally advanced disease, thoracic radiation to a dose of 60 Gy remains the standard of care. Sequential chemotherapy or radiation alone can be used for patients with poor performance status who cannot tolerate more aggressive approaches. Chemotherapy should be used for patients with metastatic disease. Radiation therapy is useful for palliation of symptomatic tumors, and a dose of approximately 30 Gy is commonly used. Endobronchial brachytherapy is useful for patients with symptomatic endobronchial tumors. The ACR Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every 2 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances in which evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment.

ACR Appropriateness Criteria® postoperative adjuvant therapy in non-small cell lung cancer.

Therapeutic options for postoperative adjuvant treatment for patients with non-small cell lung cancer (NSCLC) continue to evolve, and may include postoperative radiotherapy (PORT) and chemotherapy, alone or in combination. The use of platinum-based adjuvant chemotherapy has been demonstrated to confer an improvement in overall survival in patients with completely resected, stage N1 or N2 NSCLC, in several randomized trials and 2 meta-analyses. Consideration may also be given to adjuvant chemotherapy in patients with node-negative NSCLC, when the primary tumor is >4 cm, based on subset analyses of recent prospective studies. The precise role of PORT is less well defined. Older randomized studies indicated that the toxicity of PORT outweighed the potential improvement in local control, but studies using more modern radiation techniques show significantly reduced toxicity, inferring that select patients may benefit. Relative indications for PORT include the presence of mediastinal lymph nodes, positive surgical margins, and considerations with regard to the extent and type of resection. This study by the lung cancer expert panel of the American College of Radiology summarizes the recent evidence-based literature that addresses the use of postoperative adjuvant radiotherapy and chemotherapy in patients with NSCLC, illustrated with clinical scenarios. The sequencing of radiotherapy and chemotherapy is discussed, along with issues regarding radiotherapy dose and fractionation, and the appropriate use of intensity modulated radiation therapy and particle therapy.