Palliative thoracic radiation therapy for non-small cell lung cancer: 2018 Update of an American Society for Radiation Oncology (ASTRO) Evidence-Based Guideline.

PURPOSE: To revise the recommendation on the use of concurrent chemotherapy (CC) with palliative thoracic external beam radiation therapy (EBRT) made in the original 2011 American Society for Radiation Oncology guideline on palliative thoracic radiation for lung cancer. METHODS AND MATERIALS: Based on a systematic PubMed search showing new evidence for this key question, the task force felt an update was merited. 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 clinical trials address the question of CC combined with palliative thoracic EBRT for non-small cell lung cancer (NSCLC), a strong consensus was reached among the task force on recommendations for incurable stage III and IV NSCLC. For patients with stage III NSCLC deemed unsuitable for curative therapy but who are (1) candidates for chemotherapy, (2) have an Eastern Cooperative Oncology Group PS of 0 to 2, and (3) have a life expectancy of at least 3 months, administration of a platinum-containing chemotherapy doublet concurrently with moderately hypofractionated palliative thoracic radiation therapy is recommended over treatment with either modality alone. For patients with stage IV NSCLC, routine use of concurrent thoracic chemoradiation is not recommended. CONCLUSIONS: Optimal palliation of patients with incurable NSCLC requires coordinated interdisciplinary care. Recent data establish a rationale for CC with palliative thoracic EBRT for a well-defined subset of patients with incurable stage III NSCLC. For all other patients with incurable NSCLC, data remain insufficient to support this treatment approach.

Lung metastases treated with stereotactic body radiotherapy: the RSSearch® patient Registry's experience.

OBJECTIVES: To report overall survival and local control for patients identified in the RSSearch® Patient Registry with metastatic cancer to the lung treated with SBRT. METHODS: Seven hundred two patients were identified with lung metastases in the RSSearch® Registry. Of these patients, 577 patients had SBRT dose and fractionation information available. Patients were excluded if they received prior surgery, radiation, or radiofrequency ablation to the SBRT treated area. Between April 2004-July 2015, 447 patients treated with SBRT at 30 academic and community-based centers were evaluable for overall survival (OS). Three hundred four patients with 327 lesions were evaluable for local control (LC). All doses were converted to Monte Carlo equivalents and subsequent BED Gy10 for dose response analysis. RESULTS: Median age was 69 years (range, 18-93 years). Median Karnofsky performance status (KPS) was 90 (range 25/75% 80-100). 49.2% of patients had prior systemic therapy. Median metastasis volume was 10.58 cc (range 25/75% 3.7-25.54 cc). Site of primary tumor included colorectal (25.7%), lung (16.6%), head and neck (11.4%), breast (9.2%), kidney (8.1%), skin (6.5%) and other (22.1%). Median dose was 50 Gy (range 25/75% 48-54) delivered in 3 fractions (range 25/75% 3-5) with a median BED of 100Gy10 (range 25/75% 81-136). Median OS for the entire group was 26 months, with actuarial 1-, 3-, and 5-year OS of 74.1%, 33.3, and 21.8%, respectively. Patients with head and neck and breast cancers had longer median OS of 37 and 32 months respectively, compared to colorectal (30 months) and lung (26 months) which corresponded to 3-year actuarial OS of 51.8 and 47.9% for head and neck and breast respectively, compared to 35.8% for colorectal and 31.2% for lung. The median LC for all patients was 53 months, with actuarial 1-, 3-, and 5-year LC rates of 80.4, 58.9, and 46.3%, respectively. There was no difference in LC by primary histologic type (p = 0.49). Improved LC was observed for lung metastases that received SBRT doses of BED ≥100Gy10 with 3-year LC rate of 77.1% compared to 45% for lung metastases treated with BED < 100Gy10 (p = 0.01). Smaller tumor volumes (<11 cc) had improved LC compared to tumor volumes > 11 cc. (p = 0.005) Two-year LC rates for tumor volumes < 11 cc, 11-27 cc and > 27 cc were 72.9, 64.2 and 45.6%, respectively. This correlated with improved OS with 2-year OS rates of 62.4, 60.9 and 46.2% for tumor volumes < 11 cc, 11-27 cc and > 27 cc, respectively (p = 0.0023). In a subset of patients who received BED ≥100Gy10, 2-year LC rates for tumor volumes < 11 cc, 11-27 cc and > 27 cc were 82.8, 58.9 and 68.6%, respectively (p = 0.0244), and 2-year OS rates were 66.0, 58.8 and 28.5%, respectively (p = 0.0081). CONCLUSION: Excellent OS and LC is achievable with SBRT utilizing BED ≥100Gy10 for lung metastases according to the RSSearch® Registry data. Patients with small lung metastases (volumes < 11 cc) had better LC and OS when using SBRT doses of BED ≥100Gy10. Further studies to evaluate a difference, if any, between various tumor types will require a larger number of patients.

Stereotactic body radiation therapy for the treatment of early-stage minimally invasive adenocarcinoma or adenocarcnioma in situ (formerly bronchioloalveolar carcinoma): a patterns of failure analysis.

INTRODUCTION: Ongoing prospective trials exploring stereotactic body radiation therapy (SBRT) for early stage non-small cell lung cancer (NSCLC) often exclude minimally invasive adenocarcinoma or adenocarcnioma in situ, formerly bronchioloalveolar carcinoma (BAC), due to concerns for accurate target delineation on CT. We performed a patterns of failure analysis to compare outcomes between BAC and other NSCLC subtypes. METHODS: One hundred twenty patients with early stage NSCLC were treated with SBRT from 2004-2009. Pathologic confirmation of NSCLC was obtained in 97 patients. Radiotherapy was delivered according to RTOG guidelines. The log-rank test was used to compare outcomes between BAC and other NSCLC. RESULTS: Median follow-up was 29 months. The median SBRT dose was 5400 cGy. Thirteen patients had radiographically diagnosed BAC and five patients had biopsy confirmed BAC, of which two had both. The three-year local control was 100% for biopsy-proven or radiographically diagnosed BAC (n = 18) and 86% for all other NSCLC subtypes (n = 102) (p = 0.13). Likewise, no significant difference was detected between BAC and other NSCLC for 3-year regional failure (12% vs. 20%, p = 0.45), progression-free survival (57.6% vs. 53.5%, p = 0.84) or overall survival (35% vs. 47%, p = 0.66). There was a trend towards lower three-year rates of freedom from distant failure in patients with any diagnosis of BAC compared to those without (26% vs. 38%, p = 0.053). CONCLUSIONS: Compared to other NSCLC subtypes, BAC appears to have similar patterns of failure and survival after treatment with SBRT, however there may be an increased risk of distant metastases with BAC. RTOG guideline-based target delineation provides encouraging local control rates for patients with BAC.

Patterns of failure after stereotactic body radiation therapy or lobar resection for clinical stage I non-small-cell lung cancer.

INTRODUCTION: The purpose of this study was to compare patterns of failure between lobar resection (lobectomy or pneumonectomy) and stereotactic body radiation therapy (SBRT) for patients with clinical stage I non-small-cell lung cancer (NSCLC). METHODS: From January 2004 to January 2008, 338 patients underwent definitive treatment for pathologically confirmed clinical stage I NSCLC with lobar resection (n = 260) or SBRT (n = 78). Most surgical patients underwent lobectomy (n = 237). SBRT patients received a biologically effective dose of at least 100 Gy10. Lobar resection patients were younger, healthier, and had superior pulmonary function, whereas most of the patients in the SBRT group had T1 tumors. Final pathology upstaged 32.7% of surgery patients, and 20.0% received adjuvant chemotherapy. No SBRT patients received adjuvant chemotherapy. RESULTS: In an unmatched comparison, 4-year lobar local control (98.7% versus 93.6%, p = 0.015) was greater for lobar resection versus SBRT, respectively, though primary tumor (98.7% versus 95.3%, p = 0.088), regional (82.9% versus 78.1%, p = 0.912), and distant control (76.1% versus 54.0%, p = 0.152) were similar. Overall survival (OS, 63.5% versus 29.6%, p < 0.0001) was greater for lobar resection, though cause-specific survival (CSS, 81.3% versus 75.3%, p = 0.923) was similar. In a T-stage matched comparison of 152 patients, there was no significant difference in patterns of failure or CSS, whereas OS favored surgery. CONCLUSION: Lobectomy/pneumonectomy or SBRT results in comparable patterns of failure for clinical stage I NSCLC. In this retrospective comparison, OS was superior for surgery, though CSS was similar. Randomized trials are necessary to control for fundamental differences in comorbidity, which impact interpretation of both tumor control and survival.

Thyroid carcinoma uptake of 18F-fluorodeoxyglucose in patients with elevated serum thyroglobulin and negative 131I scintigraphy.

PURPOSE: To determine if FDG-PET results can predict for outcome in thyroid cancer patients with elevated Tg and negative I-131 imaging. MATERIALS AND METHODS: We conducted a retrospective review of 76 patients who had elevated serum Tg and negative (131)I scintigraphy and who underwent FDG-PET. After FDG-PET, patients underwent neck dissection or radiation. RESULTS: The 51 patients with positive FDG-PET had a 5-year survival of 63% compared to 100% (p<0.049) for the 25 patients with negative PET. Patients with FDG-avid disease isolated to the lymph nodes had 5-year CSS of 91% compared to 32% (p=0.0033) for those with disease outside the regional lymph nodes. Twenty-nine patients with disease isolated to the regional lymph nodes underwent salvage neck dissection and 22 remain NED after 28 months. CONCLUSIONS: Negative FDG-PET with elevated Tg predicts an excellent outcome. FDG-avid disease isolated to the regional lymph nodes had a low likelihood of death due to thyroid cancer.

Dosimetric predictors of chest wall pain after lung stereotactic body radiotherapy.

PURPOSE: To identify risk factors for the development of chest wall (CW) pain after thoracic stereotactic body radiotherapy (SBRT). METHODS AND MATERIALS: A registry of patients with lung lesions treated with lung SBRT was explored to identify patients treated with 54 Gy in three fractions or 50 Gy in five fractions. One hundred and forty-six lesions in 140 patients were identified; complete electronic treatment plans were available on 86 CWs. The CW was contoured as a 3 cm outward expansion from the involved lung. Univariate and multivariate analyses were used to correlate patient, tumor, and dosimetric factors to the development of CW toxicity. RESULTS: CW pain occurred in 22 patients (15.7%). The Kaplan-Meier estimated risk of CW pain at 2 years was 20.1% (95% C.I., 13.2-28.8%). On univariate analysis of patient factors, elevated BMI (p=0.026) and connective tissue disease (p=0.036) correlated with CW pain. The percent of CW receiving 30, 35, or 40 Gy was most predictive of CW pain on multivariate analysis using logistic regression, while V40 alone was predictive using Cox regression. A V30 threshold of 0.7% and V40 threshold of 0.19% was correlated with a 15% risk of CW pain. CONCLUSIONS: We have described patient and dosimetric parameters that correlate with CW pain after lung SBRT. The risk of CW pain may be mitigated by attempting to reduce the relative proportion of CW receiving 30-40 Gy during treatment planning.

Radioactive iodine therapy decreases recurrence in thyroid papillary microcarcinoma.

Background. The most appropriate therapy for papillary microcarcinoma (PMC) is controversial. Methods. We reviewed the therapy and outcome of 407 patients with PMC. Results. Three hundred-eighty patients underwent total thyroidectomy, and 349 patients received I-131 therapy. The median followup was 5.3 years. Forty patients developed recurrent disease. On univariate analysis, development of disease recurrence was correlated with histological tumor size > 0.8 cm (P = 0.0104), age < 45 years (P = 0.043), and no I-131 therapy (P < 0.0001). On multivariate analysis, histological tumor size > 0.8 cm, positive lymph nodes, and no I-131 therapy were significant. The 5-year RFS for patients treated with I-131 was 95.0% versus 78.6% (P < 0.0001) for patients not treated with I-131. Patients with lymph node metastasis who did not receive I-131 had a 5-year RFS of 42.9% versus 93.2% (P < 0.0001) for patients who received I-131. Conclusions. Recommend I-131 remnant ablation for patients with PMC, particularly patients with lymph node metastasis.

Stereotactic body radiation therapy in the treatment of multiple primary lung cancers.

BACKGROUND AND PURPOSE: Patients with multiple primary lung cancers (MPLC) present a therapeutic dilemma, particularly when they are at high risk for surgical resection. We evaluated the role of stereotactic body radiation therapy (SBRT) in the treatment of MPLC. MATERIALS AND METHODS: A prospective thoracic SBRT registry was explored for patients with either synchronous or metachronous MPLC treated with SBRT for one or both of their tumors. Sixty-three patients were identified and clinical data were analyzed. RESULTS: Fifteen patients had synchronous lesions and 48 patients had metachronous lesions. Seventy-six lesions were treated with SBRT. Median follow-up was 24 months for living patients. Median progression-free survival (PFS) and overall survival (OS) for the entire cohort was 15.5 and 20 months, respectively. Patients with metachronous MPLC had a significantly higher 2 year PFS (53.3% vs. 0%, p=0.0466) compared to patients with synchronous MPLC. Likewise, 2 year OS was also superior for patients with metachronous versus synchronous MPLC (68.1% vs. 27.5%, p=0.0014). Six tumors (7.9%) recurred within the radiation field. There were no grade ≥3 toxicities. CONCLUSIONS: SBRT for patients with MPLC appears to be a safe and effective local treatment alternative to surgery, particularly for medically inoperable patients. Patients with metachronous MPLC have encouraging survival rates, and thus local therapy appears justified. However, patients with synchronous MPLC have poor OS and PFS despite having excellent local control, and thus the utility of local therapy in this population requires further study.

Oligodendrogliomas in children.

Oligodendrogliomas are rare central nervous system (CNS) tumors in children. The purpose of this study was to identify prognostic factors for progression free survival (PFS) and overall survival (OS) in pediatric patients with oligodendrogliomas. We retrospectively analyzed clinical data on 37 pediatric patients with oligodendroglial tumors treated at Washington University. Kaplan-Meier method was used to calculate survival rates. Log-rank was used to detect the difference between survival curves. The median age was 11.1 years (range 10 months-18 years), and median follow-up was 4.5 years (range 2 months-30.5 years). The 5-year PFS and OS were 66.4 and 93.4%, respectively. Mixed histology was associated with worse OS compared to patients with pure oligodendroglioma, 5-year OS 77.6 versus 100% (P < 0.01). Patients who underwent gross total resection (GTR) experienced an improved 5-year PFS of 100% compared to 28.8% (P = 0.03) in patients treated with subtotal resection (STR) or biopsy alone. Age >3 years at diagnosis correlated with improved 5-year PFS, 33.3 versus 69.8% (P = 0.01). Neither post-operative chemotherapy nor radiation therapy correlated with improved outcome. GTR and age >3 years at diagnosis remained significant for improved PFS on multivariate analysis. There were no factors correlated with improved overall survival on multivariate analysis. Pediatric oligodendroglial tumors are associated with excellent OS; however, a third of patients developed progressive disease. Our data demonstrate that patients with less than GTR and <3 years at diagnosis are at increased risk for progression and may benefit from more aggressive therapy.

Combined PET/CT image characteristics for radiotherapy tumor response in lung cancer.

BACKGROUND AND PURPOSE: Prediction of local failure in radiotherapy patients with non-small cell lung cancer (NSCLC) remains a challenging task. Recent evidence suggests that FDG-PET images can be used to predict outcomes. We investigate an alternative multimodality image-feature approach for predicting post-radiotherapy tumor progression in NSCLC. MATERIAL AND METHODS: We analyzed pre-treatment FDG-PET/CT studies of twenty-seven NSCLC patients for local and loco-regional failures. Thirty-two tumor region features based on SUV or HU, intensity-volume-histogram (IVH) and texture characteristics were extracted. Statistical analysis was performed using Spearman's correlation (rs) and multivariable logistic regression. RESULTS: For loco-regional recurrence, IVH variables had the highest univariate association. In PET, IVH-slope reached rs=0.3426 (p=0.0403). Motion correction slightly improved correlation of texture features. In CT, coefficient of variation had the highest association rs=-0.2665 (p=0.0871). Similarly for local failure, a CT-IVH parameter reached rs=0.4530 (p=0.0105). For loco-regional and local failures, a 2-parameter model of PET-V(80) and CT-V(70) yielded rs=0.4854 (p=0.0067) and rs=0.5908 (p=0.0013), respectively. Addition of dosimetric variables provided improvement in cases of loco-regional but not local failures. CONCLUSIONS: We proposed a feature-based approach to evaluate radiation tumor response. Our study demonstrates that multimodality image-feature modeling provides better performance compared to existing metrics and holds promise for individualizing radiotherapy planning.

Dose-response for stereotactic body radiotherapy in early-stage non-small-cell lung cancer.

PURPOSE: To compare the efficacy of three lung stereotactic body radiotherapy (SBRT) regimens in a large institutional cohort. METHODS: Between 2004 and 2009, 130 patients underwent definitive lung cancer SBRT to a single lesion at the Mallinckrodt Institute of Radiology. We delivered 18 Gy × 3 fractions for peripheral tumors (n = 111) and either 9 Gy × 5 fractions (n = 8) or 10 Gy × 5 fractions (n = 11) for tumors that were central or near critical structures. Univariate and multivariate analysis of prognostic factors was performed using the Cox proportional hazard model. RESULTS: Median follow-up was 11, 16, and 13 months for the 9 Gy × 5, 10 Gy × 5, and 18 Gy × 3 groups, respectively. Local control statistics for Years 1 and 2 were, respectively, 75% and 50% for 9 Gy × 5, 100% and 100% for 10 Gy × 5, and 99% and 91% for 18 Gy × 3. Median overall survival was 14 months, not reached, and 34 months for the 9 Gy × 5, 10 Gy × 5, and 18 Gy × 3 treatments, respectively. No difference in local control or overall survival was found between the 10 Gy × 5 and 18 Gy × 3 groups on log-rank test, but both groups had improved local control and overall survival compared with 9 Gy × 5. Treatment with 9 Gy × 5 was the only independent prognostic factor for reduced local control on multivariate analysis, and increasing age, increasing tumor volume, and poor performance status predicted independently for reduced overall survival. CONCLUSION: Treatment regimens of 10 Gy × 5 and 18 Gy × 3 seem to be efficacious for lung cancer SBRT and provide superior local control and overall survival compared with 9 Gy × 5.

Management of cervical nodal metastasis detected on I-131 scintigraphy after initial surgery of well-differentiated thyroid carcinoma.

BACKGROUND: The purpose of this study was to evaluate the outcome of patients with differentiated thyroid carcinoma whose posttherapy imaging demonstrated I-131 uptake in cervical lymph nodes. METHODS: In this prospective cohort study, 95 patients who underwent surgery for well-differentiated thyroid carcinoma had evidence of persistent cervical lymph node metastasis on posttherapy I-131 scintigraphy. These patients were evaluated by subsequent I-131 scintigraphy, and treated with additional I-131 therapy or surgical excision of cervical lymph nodes as clinically indicated. Patients were followed for a mean of 6.8 years. RESULTS: Patients received a total of one to three I-131 administrations (median dosage, 235 mCi). Surveillance I-131 scintigraphy was performed to evaluate disease activity. I-131 uptake was eliminated from the thyroid bed in all patients. Persistent disease was detected in cervical lymph nodes in 9 (9%) of 95 patients, and these 9 patients underwent lymph node excision (1 patient later had recurrent disease and was treated with additional I-131 therapy). All patients subsequently had negative I-131 imaging and undetectable serum thyroglobulin. Of the 95 patients in the study, 9 (9%) developed recurrent disease in cervical lymph nodes. Of these 9 patients, 2 also had distant metastases; 6 of these patients underwent surgical excision of cervical adenopathy, and 3 received additional I-131 therapy. There were no grade >3 toxicities attributable to I-131. At last follow-up, 93 (98%) of the 95 patients were free of disease. CONCLUSION: Most patients (82%) in the study with cervical lymph node metastases detected on initial posttherapy I-131 scintigraphy were rendered free of disease with I-131 therapy. Surgical reintervention was required in 15% of patients (15/95). The use and timing of additional I-131 therapy versus surgical intervention in this group of patients needs to be further evaluated.

Fiducial placement for stereotactic radiation by using EUS: feasibility when using a marker compatible with a standard 22-gauge needle.

BACKGROUND: Stereotactic radiation by using fiducial markers permits higher doses of radiation while reducing the exposure of uninvolved, adjacent structures. EUS has been used to deploy fiducials, although a 19-gauge needle has traditionally been required. OBJECTIVE: To report a new technique and the feasibility of deploying a fiducial compatible with a 22-gauge needle under EUS guidance. DESIGN: Single-center, case series. SETTING: Tertiary care referral center. PATIENTS: Thirteen patients with primary or metastatic cancer referred for stereotactic radiation. INTERVENTIONS: EUS-guided placement of a single fiducial marker that is compatible with a 22-gauge EUS-FNA needle. MAIN OUTCOME MEASUREMENTS: Technical success and complications. RESULTS: Thirteen patients referred for EUS-guided placement of a fiducial marker were identified in the endoscopic database. Targeted lesions measured 27 +/- 13 mm (range 8-50) x 21 +/- 10 mm (range 6-42). All fiducials were successfully deployed, 9 using a transgastric and 4 using a transduodenal approach. There were no EUS-associated complications. Two patients did not proceed to radiation therapy as a result of interval peritoneal metastasis. However, all fiducials were visible on the roentogram. Eleven of 13 patients (85%) required placement of 1 fiducial, whereas 2 patients (15%) required 2 fiducials. LIMITATIONS: Uncontrolled feasibility study with limited sample size and follow-up. CONCLUSION: EUS-guided placement of a fiducial using a 22-gauge needle is technically feasible and may permit greater access compared with the 19-gauge needle technique.

Radiotherapy for extramedullary plasmacytoma of the head and neck.

PURPOSE: To define the effectiveness of radiotherapy in the treatment of patients with extramedullary plasmacytoma of the head and neck (EMPHN). METHODS AND MATERIALS: We searched the Mayo Clinic Rochester Department of Radiation Oncology electronic Tumor Registry and identified 18 consecutive patients with a diagnosis of solitary EMPHN. Sixteen patients were treated with radiotherapy at initial diagnosis and 2 received salvage radiotherapy for local failure after surgery. Median dose administered was 50.4 Gy. Median follow-up was 6.8 years. RESULTS: One patient (6%) developed a marginal recurrence 12 months after treatment. Six patients (33%) developed multiple myeloma (2 patients) or plasmacytomas at distant sites (4 patients) at a median of 3.1 years after diagnosis (range, 0.02 to 9.6 years). Median and 5- and 10-year overall survival rates from the date of diagnosis are 12.5 years, 88%, and 55%, respectively. Two patients (11%) developed a radiation-induced malignancy at 6.5 and 6.9 years after treatment. CONCLUSIONS: Radiotherapy provides excellent local and regional tumor control and survival in patients with EMPHN. To the best of our knowledge, this is the first report of presumed radiation-induced malignancy in this patient population.

Zinc induces ERK-dependent cell death through a specific Ras isoform.

The effect of Zn on p53-independent cell death was examined in IIC9 embryonic fibroblasts. Despite the fact that these cells are p53-minus, Zn-mediated death occurs via an apoptotic mechanism. Death is facilitated by the presence of the Zn ionophore, pyrithione, indicating that intracellular Zn initiates the death response. Our investigations of the mechanism of Zn action demonstrate that Zn induces the death of IIC9 cells in a manner that is ERK-dependent. Expression of dn-(dominant negative)Ras attenuates ERK1/2 activation by Zn, and correspondingly reduces its cytotoxic effects. Raf-RBD pull-down experiments confirm that Zn treatment activates Ras and identified H-Ras as the specific isoform activated. This contrasts the activation of N-Ras that occurs when IIC9 cells are stimulated with thrombin. Thus, although the prolonged activation of the Ras/ERK pathway by Zn is similar to that seen when induced by mitogen, the distinguishing feature appears to be the isoform specificity of Ras activation.