Expression of the DNA repair gene MLH1 correlates with survival in patients who have resected pancreatic cancer and have received adjuvant chemoradiation: NRG Oncology RTOG Study 9704.

BACKGROUND: The majority of patients with pancreatic cancer who undergo curative resection experience rapid disease recurrence. In previous small studies, high expression of the mismatch-repair protein mutL protein homolog 1 (MLH1) in pancreatic cancers was associated with better outcomes. The objective of this study was to validate the association between MLH1 expression and survival in patients who underwent resection of pancreatic cancer and received adjuvant chemoradiation. METHODS: Samples were obtained from the NRG Oncology Radiation Therapy Oncology Group 9704 prospective, randomized trial (clinicaltrials.gov identifier NCT00003216), which compared 2 adjuvant protocols in patients with pancreatic cancer who underwent resection. Tissue microarrays were prepared from formalin-fixed, paraffin-embedded, resected tumor tissues. MLH1 expression was quantified using fluorescence immunohistochemistry and automated quantitative analysis, and expression was dichotomized above and below the median value. RESULTS: Immunohistochemical staining was successfully performed on 117 patients for MLH1 (60 and 57 patients from the 2 arms). The characteristics of the participants who had tissue samples available were similar to those of the trial population as a whole. At the time of analysis, 84% of participants had died, with a median survival of 17 months. Elevated MLH1 expression levels in tumor nuclei were significantly correlated with longer disease-free and overall survival in each arm individually and in both arms combined. Two-year overall survival was 16% in patients who had low MLH1 expression levels and 53% in those who had high MLH1 expression levels (P < .0001 for both arms combined). This association remained true on a multivariate analysis that allowed for lymph node status (hazard ratio, 0.41; 95% confidence interval, 0.27-0.63; P < .0001). CONCLUSIONS: In the current sample, MLH1 expression was correlated with long-term survival. Further studies should assess whether MLH1 expression predicts which patients with localized pancreatic cancer may benefit most from aggressive, multimodality treatment. Cancer 2018;124:491-8. © 2017 American Cancer Society.

Patterns of care of radiation therapy in patients with stage IV rectal cancer: a Surveillance, Epidemiology, and End Results analysis of patients from 2004 to 2009.

BACKGROUND: According to the 2013 National Comprehensive Cancer Network guidelines, pelvic radiation therapy (RT) is one of the preferred regimens for patients with metastatic rectal cancer (mRC). The objective of this study was to analyze patterns of care and outcomes data for the receipt of RT among patients with mRC using the Surveillance, Epidemiology, and End Results (SEER) database. METHODS: Patients with stage IV rectal or rectosigmoid cancer were identified in the SEER database (2004-2009). Patients were stratified according to their primary disease site (rectum vs rectosigmoid), tumor (T) classification, and lymph node (N) classification. Treatment regimens (with or without surgical resection, with or without RT) were recorded. The Fisher exact test was used to compare RT rates based on stratified factors. Two and five-year survival rates were compared among treatment groups. RESULTS: In total, 6873 patients with stage IV rectal cancer and 3417 patients with rectosigmoid cancer were identified. Overall, 20.5% of patients with rectal cancer underwent surgery alone, whereas 38.7% received RT with or without surgery. Within the rectosigmoid group, 51.4% of patients underwent surgery alone, and 15.1% received RT with or without surgery. The use of RT differed significantly between patients with in situ (Tis) through T2 tumors versus T3/T4 tumors (P < .001) and between those with N0 disease versus N1/N2 disease (P < .001). The 2-year and 5-year survival rates differed between treatment groups, with the highest survival rates observed among those who received combined surgery and RT. CONCLUSIONS: The primary treatments for patients with mRC include RT with or without surgery. RT is used more commonly in patients with primary rectal (vs rectosigmoid) tumors, N0 disease, or Tis-T2 tumors. Treatment with combination surgery and RT is associated with prolonged survival.

Phase II Trial of Five-Fraction Accelerated Partial Breast Irradiation Using Noninvasive Image-Guided Breast Brachytherapy.

PURPOSE/OBJECTIVE(S): NIBB has potential advantages over other APBI techniques by delivering highly conformal radiation with minimal collateral dose to the heart and lung compared with external beam techniques, but unlike other brachytherapy techniques NIBB is non-invasive. Previous data has shown encouraging outcomes using a 10-fraction regimen. To improve efficiency, convenience, and cost, reduction in the fraction number is desirable. Final results of a prospective phase II trial are reported. MATERIALS/METHODS: NIBB APBI was delivered using 28.5Gy in 5 fractions daily over 1 week. Patient eligibility criteria required: invasive carcinoma ≤2.0 cm or DCIS ≤3.0 cm, ER positive (if invasive), lymph node negative, LVI absent, and lumpectomy with margins negative by 2mm. The primary endpoint was grade ≥ 2 subcutaneous fibrosis/induration <30%. Secondary endpoints included any late toxicity, cosmetic outcome, and local control. RESULTS: 40 patients were treated with a median follow-up of 59.7 months. The mean age was 67 years (50-89 years) and tumor size was 1.0cm (0.3-2.0cm). 80% had invasive carcinoma. The mean breast separation with compression was 6.7cm (3.5-8.9cm). The 5-year actuarial local control was 96.6% and overall survival was 96.9%. Grade 2 and 3 late toxicities were 15% and 0%, respectively. The rate of grade 2 subcutaneous fibrosis/induration was 2.5% (+/-2.5%) meeting the study's primary endpoint. The most common late toxicity of any grade was skin telangiectasia; 22.5% grade 1 and 15% grade 2. Only breast separation was associated with telangiectasia risk, p=0.002. Overall cosmetic outcome was excellent, good, and fair/poor in 75%, 25%, and 0%, respectively. CONCLUSIONS: NIBB APBI delivered in 5 fractions results in a low rate of late toxicity and a high rate of good/excellent cosmetic outcomes. Telangiectasia risk can be minimized by keeping breast separation ≤7.0cm. The local failure rate was appropriately low. Further investigation of this technique is warranted.

Analysis of Radiation Therapy Quality Assurance in NRG Oncology RTOG 0848.

PURPOSE: NRG/Radiation Therapy Oncology Group 0848 is a 2-step randomized trial to evaluate the benefit of the addition of concurrent fluoropyrimidine and radiation therapy (RT) after adjuvant chemotherapy (second step) for patients with resected pancreatic head adenocarcinoma. Real-time quality assurance (QA) was performed on each patient who underwent RT. This analysis aims to evaluate adherence to protocol-specified contouring and treatment planning and to report the types and frequencies of deviations requiring revisions. METHODS AND MATERIALS: In addition to a web-based contouring atlas, the protocol outlined step-by-step instructions for generating the clinical treatment volume through the creation of specific regions of interest. The planning target volume was a uniform 0.5 cm clinical treatment volume expansion. One of 2 radiation oncology study chairs independently reviewed each plan. Plans with unacceptable deviations were returned for revision and resubmitted until approved. Treatment started after final approval of the RT plan. RESULTS: From 2014 to 2018, 354 patients were enrolled in the second randomization. Of these, 160 patients received RT and were included in the QA analysis. Resubmissions were more common for patients planned with 3-dimensional conformal RT (43%) than with intensity modulated RT (31%). In total, at least 1 resubmission of the treatment plan was required for 33% of patients. Among patients requiring resubmission, most only needed 1 resubmission (87%). The most common reasons for resubmission were unacceptable deviations with respect to the preoperative gross target volume (60.7%) and the pancreaticojejunostomy (47.5%). CONCLUSION: One-third of patients required resubmission to meet protocol compliance criteria, demonstrating the continued need for expending resources on real-time, pretreatment QA in trials evaluating the use of RT, particularly for pancreas cancer. Rigorous QA is critically important for clinical trials involving RT to ensure that the true effect of RT is assessed. Moreover, RT QA serves as an educational process through providing feedback from specialists to practicing radiation oncologists on best practices.

Cost and effectiveness of radiofrequency ablation versus limited surgical resection for stage I non-small-cell lung cancer in elderly patients: is less more?

PURPOSE: To retrospectively evaluate cost and mortality in 84 patients older than 65 years of age with stage IA or IB non-small-cell lung cancer treated with radiofrequency (RF) ablation or limited surgical resection (ie, wedge resection or segmentectomy) from the perspective of the payer, Medicare. MATERIALS AND METHODS: From August 2000 to November 2009, 56 patients were treated with RF ablation and 28 with surgery who met the inclusion criteria. Patient health histories and billing charges from initial treatment to the study endpoint were collected. Charges were converted to 2009 Medicare reimbursement fees and cumulated by month. Time-event data were analyzed by using the Kaplan-Meier method. Survival functions and median survival estimates were reported with standard errors. Patient cohorts' survival functions were compared based on the Wilcoxon weighted χ(2) statistic. RESULTS: Group demographics were comparable with the exception of age, with patients treated with RF ablation an average of 4 years older (95% confidence interval, 0.85-6.76). The overall mortality rate was lower in patients treated with surgery than in those treated with RF ablation (χ(2) = 8.0225, P = .0046), with a median cost per month lived for RF ablation recipients of $620.74, versus $1,195.92 for those treated with surgery (P = .0002, Wilcoxon rank-sum test). CONCLUSIONS: Patients treated with surgery showed a significant increase in survival; however, those treated with RF ablation were significantly older. For patients who are not surgical candidates, RF ablation provides an alternative treatment option at a significantly lower cost.

Veliparib in combination with carboplatin/paclitaxel-based chemoradiotherapy in patients with stage III non-small cell lung cancer.

OBJECTIVES: Veliparib is a potent poly(ADP)-ribose polymerase (PARP) 1 and 2 inhibitor that impedes repair of DNA damage induced by cytotoxic and radiation therapies. This phase 1 study evaluated veliparib in combination with chemoradiotherapy in patients with unresectable stage III non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: Patients received veliparib orally twice daily (BID) in escalating doses (60-240 mg, Day -3 to 1 day after last dose of radiation) combined with weekly carboplatin (area under the curve [AUC] 2 mg/mL/min), paclitaxel (45 mg/m2), and daily radiation therapy (60 Gy in 30 fractions), followed by two cycles of veliparib (120-240 mg BID, Days -2 through 5 of each 21-day cycle), carboplatin (AUC 6 mg/mL/min, Day 1 of each cycle), and paclitaxel (200 mg/m2, Day 1 of each cycle) consolidation. Endpoints included veliparib maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), pharmacokinetics, safety, and efficacy. RESULTS: Forty-eight patients were enrolled. The MTD/RP2D of veliparib was 240 mg BID with chemoradiotherapy followed by 120 mg BID with consolidation. The most common any-grade adverse events (AEs) in this cohort for the whole treatment period were nausea (83%), esophagitis (75%), neutropenia (75%), and thrombocytopenia (75%). Dose-proportional pharmacokinetics of veliparib were observed. Median progression-free survival (mPFS) was 19.6 months (95% CI: 9.7-32.6). Median overall survival was estimated to be 32.6 months (95% CI: 15.0-not reached). In patients treated with the RP2D, mPFS was 19.6 months (95% CI: 3.0-not reached). CONCLUSIONS: When combined with standard concurrent chemoradiotherapy and consolidation chemotherapy in patients with stage III NSCLC, veliparib demonstrated an acceptable safety profile and antitumor activity with an mPFS of 19.6 months.

Pneumonectomy after neoadjuvant chemotherapy and radiation for advanced-stage lung cancer.

BACKGROUND: Intergroup 0139 Trial suggests an increase in mortality after pneumonectomy in patients receiving preoperative chemotherapy and radiation. We evaluate our outcomes with pneumonectomy after neoadjuvant chemotherapy and radiation. METHODS: Neoadjuvant chemotherapy and radiation consisted of cisplatin 50 mg/m2 on days 1, 8, 29, and 36 and etoposide 50 mg/m2 on days 1-5 and 29-33 given concurrently with 5,040 cGy radiation. From a prospective database, results after pneumonectomy were compared between patients receiving and not receiving neoadjuvant chemotherapy and radiation during the same time period. RESULTS: Over 7 years, 50 pneumonectomies were performed for non-small-cell carcinoma; 18 received neoadjuvant chemotherapy and radiation (group A) and 32 did not (group B). Comparing group A with group B, there was no significant difference in patient demographics, blood loss, transfusion requirements or pneumonectomy side. Group A had more patients with stage III disease [17/ 18 (94%) versus 15/32 (47%), P = 0.001] and also more often had vascularized flap for bronchial stump coverage [17/18 (94%) versus 4/32 (13%), P < 0.001]. There was no significant difference in operative morbidity or mortality. Mortality for group A was 0/18 and for group B was 2/32 (6.3%) (P = 0.530). Group A patients with IIIA(N2) disease (n = 13) had median recurrence-free survival of 12.4 months, median overall survival of 25 months, and 3- year overall survival of 22.2%. CONCLUSIONS: Using a multidisciplinary team approach at a tertiary care center, pneumonectomy can be performed successfully after neoadjuvant chemotherapy and radiation for advanced-stage lung cancer. Vascularized flap for bronchial stump coverage may be important in this regard.

Results of the NRG Oncology/RTOG 0848 Adjuvant Chemotherapy Question-Erlotinib+Gemcitabine for Resected Cancer of the Pancreatic Head: A Phase II Randomized Clinical Trial.

PURPOSE: NRG/RTOG 0848 was designed to determine whether adjuvant radiation with fluoropyrimidine sensitization improved survival following gemcitabine-based adjuvant chemotherapy for patients with resected pancreatic head adenocarcinoma. In step 1 of this protocol, patients were randomized to adjuvant gemcitabine versus the combination of gemcitabine and erlotinib. This manuscript reports the final analysis of these step 1 data. METHODS: Eligibility-within 10 weeks of curative intent pancreaticoduodenectomy with postoperative CA19-9<180. Gemcitabine arm-6 cycles of gemcitabine. Gemcitabine+erlotinib arm-gemcitabine and erlotinib 100 mg/d. Two hundred deaths provided 90% power (1-sided α=0.15) to detect the hypothesized OS signal (hazard ratio=0.72) in favor of the arm 2. RESULTS: From November 17, 2009 to February 28, 2014, 163 patients were randomized and evaluable for arm 1 and 159 for arm 2. Median age was 63 (39 to 86) years. CA19-9 ≤90 in 93%. Arm 1: 32 patients (20%) grade 4 and 2 (1%) grade 5 adverse events; arm 2, 27 (17%) grade 4 and 3 (2%) grade 5. GI adverse events, arm 1: 22% grade ≥3 and arm 2: 28%, (P=0.22). The median follow-up (surviving patients) was 42.5 months (min-max: <1 to 75). With 203 deaths, the median and 3-year OS (95% confidence interval) are 29.9 months (21.7, 33.4) and 39% (30, 45) for arm 1 and 28.1 months (20.7, 30.9) and 39% (31, 47) for arm 2 (log-rank P=0.62). Hazard ratio (95% confidence interval) comparing OS of arm 2 to arm 1 is 1.04 (0.79, 1.38). CONCLUSIONS: The addition of adjuvant erlotinib to gemcitabine did not provide a signal for increased OS in this trial.

Microwave ablation of lung malignancies: effectiveness, CT findings, and safety in 50 patients.

PURPOSE: To retrospectively evaluate effectiveness, follow-up imaging features, and safety of microwave ablation in 50 patients with intraparenchymal pulmonary malignancies. MATERIALS AND METHODS: This HIPAA-compliant study was approved by the institutional review board; informed consent was waived. From November 10, 2003, to August 28, 2006, 82 masses (mean, 1.42 per patient) in 50 patients (28 men, 22 women; mean age, 70 years) were percutaneously treated in 66 microwave ablation sessions. Each tumor was ablated with computed tomographic (CT) guidance. Follow-up contrast material-enhanced CT and positron emission tomographic (PET) scans were reviewed. Mixed linear modeling and logistic regression were performed. Time-event data were analyzed (Kaplan-Meier survival estimates and log-rank statistic). All event times were the time to a patient's first event (alpha level = .05, all analyses). RESULTS: At follow-up (mean, 10 months), 26% (13 of 50) of patients had residual disease at the ablation site, predicted by using index size of larger than 3 cm (P = .01). Another 22% (11 of 50) of patients had recurrent disease resulting in a 1-year local control rate of 67%, with mean time to first recurrence of 16.2 months. Kaplan-Meier analysis yielded an actuarial survival of 65% at 1 year, 55% at 2 years, and 45% at 3 years from ablation. Cancer-specific mortality yielded a 1-year survival of 83%, a 2-year survival of 73%, and a 3-year survival of 61%; these values were not significantly affected by index size of larger than 3 cm or 3 cm or smaller or presence of residual disease. Cavitation (43% [35 of 82] of treated tumors) was associated with reduced cancer-specific mortality (P = .02). Immediate complications included pneumothorax (Common Terminology Criteria for Adverse Events [CTCAE] grades 1 [18 of 66 patients] and 2 [eight of 66 patients]), hemoptysis (four of 66 patients), and skin burns (CTCAE grades 2 [one of 66 patients] and 3 [one of 66 patients]). CONCLUSION: Microwave ablation is effective and may be safely applied to lung tumors. (c) RSNA, 2008.

Tolerability of ADXS11-001 Lm-LLO Listeria-Based Immunotherapy With Mitomycin, Fluorouracil, and Radiation for Anal Cancer.

PURPOSE: To obtain safety and preliminary efficacy data of the combination of ADXS11-001, live attenuated Listeria monocytogenes bacterium, with mitomycin, 5-fluorouracil (5-FU), and intensity modulated radiation therapy in locally advanced anal cancer. PATIENTS AND METHODS: Eligibility included patients with previously untreated, nonmetastatic anal cancer with a primary tumor >4 cm or node-positive disease. Patients received 2 cycles of mitomycin and 5-FU concurrent with 54.0 Gy intensity modulated radiation therapy. One intravenous dose of ADXS11-001 (1 × 109 colony-forming units) was administered before chemoradiation; 3 additional monthly doses were given after chemoradiation. RESULTS: Ten patients were treated, including 1 with N2 and 4 with N3 disease. Two patients had grade 3 acute toxicities after the initial dose of ADXS11-001, including chills/rigors (n = 2), back pain (n = 1), and hyponatremia (n = 1). All ADXS11-001 toxicities occurred within 24 hours of administration. There was no apparent increase in chemoradiation toxicities or myelosuppression. One patient had a grade 5 cardiopulmonary event shortly after beginning 5-FU treatment. All 9 assessable patients had complete clinical responses by sigmoidoscopy. Eight of 9 patients (89%) are progression-free at a median follow-up of 42 months. CONCLUSIONS: Preliminary data show that ADXS11-001 can be safely administered with standard chemoradiation for anal cancer. Further studies of listeria-based immunotherapy with radiation are warranted.

Postresection CA19-9 and margin status as predictors of recurrence after adjuvant treatment for pancreatic carcinoma: Analysis of NRG oncology RTOG trial 9704.

PURPOSE: NRG Oncology RTOG 9704 was the first adjuvant trial to validate the prognostic value of postresection CA19-9 levels for survival in patients with pancreatic carcinoma. The data resulting from this study also provide information about predictors of recurrence that may be used to tailor individualized management in this disease setting. This secondary analysis assessed the prognostic value of postresection CA19-9 and surgical margin status (SMS) in predicting patterns of disease recurrence. METHODS AND MATERIALS: This multicenter cooperative trial included participants who were enrolled as patients at oncology treatment sites in the United States and Canada. The study included 451 patients analyzable for SMS, of whom 385 were eligible for postresection CA19-9 analysis. Postresection CA19-9 was analyzed at cut points of 90, 180, and continuously. Patterns of disease recurrence included local/regional recurrence (LRR) and distant failure (DF). Multivariable analyses included treatment, tumor size, and nodal status. To adjust for multiple comparisons, a P value of ≤ .01 was considered statistically significant and > .01 to ≤ .05 to be a trend. RESULTS: For CA19-9, 132 (34%) patients were Lewis antigen-negative (no CA19-9 expression), 200 (52%) had levels <90, and 220 (57%) had levels <180. A total of 188 patients (42%) had negative margins, 152 (34%) positive, and 111 (25%) unknown. On univariate analysis, CA19-9 cut at 90 was associated with increases in LRR (trend) and DF. Results were similar at the 180 cut point. SMS was not associated with an increase in LRR on univariate or multivariate analyses. On multivariable analysis, CA19-9 ≥ 90 was associated with increased LRR and DF. Results were similar at the 180 cut point. CONCLUSIONS: In this prospective evaluation, postresection CA19-9 was a significant predictor of both LRR and DF, whereas SMS was not. These findings support consideration of adjuvant radiation therapy dose intensification in patients with elevated postresection CA19-9.

Long-term outcome and toxicity in a Phase I/II trial using high-dose-rate multicatheter interstitial brachytherapy for T1/T2 breast cancer.

PURPOSE: To present an updated analysis of survival, recurrence rate, and toxicity for a cohort of women with early-stage breast cancer treated with high-dose-rate interstitial brachytherapy for accelerated partial breast irradiation. METHODS AND MATERIALS: From August 1997 to July 2001, a total of 32 women with 33 breast cancers were treated with interstitial high-dose-rate brachytherapy after breast-conserving surgery as part of a Phase I/II protocol. All patients had T1-2 tumors with < or b=3 axillary nodes positive, nonlobular histology, negative surgical margins, and no evidence of extracapsular lymph node extension. Multiple brachytherapy catheters were used and radiation was delivered with a high activity (3-10Ci) (192)Ir source placed via remote after loader. Dose was prescribed to the tumor bed plus a 2 cm margin. A total of 3400 cGy was delivered in 10 fractions of 340 cGy each given twice daily over 5 days. Toxicities (skin, subcutaneous tissue, pain, fat necrosis) were evaluated by Radiation Therapy Oncology Group criteria; cosmesis was assessed using a previously published scale. Toxicity scores were separated into four followup intervals: < or =6 months, >6 months and < or =2 years, >2 and < or =5 years, and >5 years. RESULTS: The actuarial local recurrence rate was 6.1% at 5 years with the last measured event at 70.5 months. A total of three treatment failures were observed at 25.8, 39.9, and 70.5 months of followup. All three were elsewhere failures within the treated breast. One patient died after 90.0 months of followup secondary to a subsequently diagnosed small-cell lung cancer. For the purpose of analysis, toxicity scores were assigned to each of four followup intervals: < or =6 months, >6 but < or =24 months, >24 but < or =60 months, and >60 months. Fat necrosis was not seen in the first 6 months after treatment, then appeared in 27.3% of patients from 6 to 24 months, 28.1% from 24 to 60 months, and 17.9% beyond 60 months. Skin toxicity appeared to stabilize with longer followup: the percentage of patients showing any degree of skin toxicity was 69.7%, 33.3%, 40.6%, and 28.6% at each successive time interval. Subcutaneous toxicity increased beyond 60 months: moderate to severe subcutaneous toxicity was seen in 15.2%, 18.2%, 18.8%, and 35.7% of patients successively. The percentage of patients with less than excellent cosmetic outcome improved beyond 60 months (21.2%, 21.2%, 21.9%, and 11.1% successively). Only 1 patient experienced more than mild pain at any time. The percentage of patients experiencing any degree of pain improved over time (30.3%, 33.3%, 18.8%, 17.9%). CONCLUSIONS: Our series showed a local recurrence rate of 6.1% at 5 years, which is comparable to that seen in conventional whole breast series. Fat necrosis was found in more than half the cohort. Fat necrosis, pain, and cosmesis appeared to improve with longer followup, whereas subcutaneous toxicity worsened and skin toxicity stabilized.

Role of adjuvant radiation (external beam/brachytherapy) for stage I NSCLC.

There seems to be no role for adjuvant radiation in stage I NSCLC patients treated by lobectomy. Adjuvant brachytherapy in combination with sublobar resection is a promising approach that seems to decrease local recurrence rates similar to that reported following lobectomy. If the results of the current American College of Surgeons Oncology Group randomized trial are favorable, it may be possible in the future to define subgroups of patients with stage I NSCLC who are able to be treated with this approach in preference to lobectomy. Until further data are available, lobectomy should remain the standard of care. RFA is an alternative for the high-risk patient with NSCLC who is considered too high-risk even for sublobar resection. Although long-term results are not yet available, it does seem that local recurrence is a significant problem. In a similar fashion to the approach currently being investigated with sublobar resection, the addition of radiation may improve local control after RFA. In particular, adjuvant stereotactic radiation should be investigated as a potential method of decreasing local recurrence and preserving lung function in these high-risk patients.

Patients with Long-Term Control of Systemic Disease Are a Favorable Prognostic Group for Treatment of Brain Metastases with Stereotactic Radiosurgery Alone.

BACKGROUND: Stereotactic radiosurgery (SRS) alone is an attractive option for treatment of brain metastases. SRS avoids whole-brain radiotherapy (WBRT)-associated morbidity, but is limited by regional central nervous system (CNS) failures and short survival in some patients. We evaluated a subgroup of patients with controlled systemic disease that could represent a favorable patient population for SRS alone. METHODS: All patients with brain metastases treated with SRS without WBRT at our institution between 2004 and 2014 were grouped into two cohorts: those with controlled systemic disease (CSD) for 1 year or longer before prior to presentation with brain metastases and those without (i.e., uncontrolled systemic disease [USD]). Rates of local and regional CNS failure, and overall survival were assessed with χ2 and Student t tests. Cox regression analysis was performed to evaluate independent predictors of regional control and overall survival. RESULTS: Two hundred ninety-four patients underwent SRS to 697 lesions, of which 65 patients had CSD. Median follow-up was 9.7 months. There was no difference in local control between the two cohorts (P = 0.795). Regional CNS control was significantly better for patients with CSD (68% vs. 48%; P = 0.001). Overall survival at 1 and 5 years for CSD were 65% and 13% with USD yielding 41% and 7%, respectively (P < 0.001). Multivariate analysis demonstrated that USD (relative CSD) independently predicts regional failure (hazard ratio [HR], 1.75; P = 0.008) and shorter overall survival (HR, 1.55; P = 0.007). CONCLUSIONS: Patients with brain metastases after 1 year or longer of primary and systemic disease control represent a particularly favorable cohort, with lower regional CNS failure and prolonged survival, for an approach of SRS alone.

Dose-modeling study to compare external beam techniques from protocol NSABP B-39/RTOG 0413 for patients with highly unfavorable cardiac anatomy.

PURPOSE: The aim of this study was to select patients with heart anatomy that is specifically unfavorable for tangential irradiation in whole-breast radiotherapy (WBRT), to be used as an experimental cohort to compare cardiac dosimetric and radiobiological parameters of three-dimensional conformal external beam accelerated partial breast irradiation (3D-CRT APBI) to WBRT with techniques as defined by the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-39/Radiation Therapy Oncology Group (RTOG) 0413 clinical trial. METHODS AND MATERIALS: A dosimetric modeling study that compared WBRT and 3D-CRT APBI was performed on CT planning data from 8 patients with left-sided breast cancer. Highly unfavorable cardiac anatomy was defined by the measured contact of the myocardium with the anterior chest wall in the axial and para-sagittal planes. Treatment plans of WBRT and 3D-CRT APBI were generated for each patient in accordance with NSABP B-39/RTOG 0413 protocol. Dose-volume relationships of the heart, including the V5min (minimum dose delivered to 5% of the cardiac volume), biological effective dose (BED) of the V5min, and normal tissue complication probability (NTCP) were analyzed and compared. RESULTS: Despite expected anatomic variation, significantly large differences were found favoring 3D-CRT APBI in cumulative dose-volume histograms (p < 0.01), dose to the entire heart (mean difference 3.85 Gy, p < 0.01), NTCP (median difference, 1.00 Gy; p < 0.01), V5min (mean difference, 24.53 Gy; p < 0.01), and proportional reduction in radiobiological effect on the V5min (85%, p < 0.01). CONCLUSIONS: Use of 3D-CRT APBI can demonstrate improved sparing of the heart in select patients with highly unfavorable cardiac anatomy for WBRT, and may result in reduced risk of cardiac morbidity and mortality.

Persistent seroma after intraoperative placement of MammoSite for accelerated partial breast irradiation: incidence, pathologic anatomy, and contributing factors.

PURPOSE: To investigate the incidence of, and possible factors associated with, seroma formation after intraoperative placement of the MammoSite catheter for accelerated partial breast irradiation. METHODS AND MATERIALS: This study evaluated 38 patients who had undergone intraoperative MammoSite catheter placement at lumpectomy or reexcision followed by accelerated partial breast irradiation with 34 Gy in 10 fractions. Data were collected regarding dosimetric parameters, including the volume of tissue enclosed by the 100%, 150%, and 200% isodose shells, dose homogeneity index, and maximal dose at the surface of the applicator. Clinical and treatment-related factors were analyzed, including patient age, patient weight, history of diabetes and smoking, use of reexcision, interval between surgery and radiotherapy, total duration of catheter placement, total excised specimen volume, and presence or absence of postprocedural infection. Seroma was verified by clinical examination, mammography, and/or ultrasonography. Persistent seroma was defined as seroma that was clinically detectable >6 months after radiotherapy completion. RESULTS: After a median follow-up of 17 months, the overall rate of any detectable seroma was 76.3%. Persistent seroma (>6 months) occurred in 26 (68.4%) of 38 patients, of whom 46% experienced at least modest discomfort at some point during follow-up. Of these symptomatic patients, 3 required biopsy or complete cavity excision, revealing squamous metaplasia, foreign body giant cell reaction, fibroblasts, and active collagen deposition. Of the analyzed dosimetric, clinical, and treatment-related variables, only body weight correlated positively with the risk of seroma formation (p = 0.04). Postprocedural infection correlated significantly (p = 0.05) with a reduced risk of seroma formation. Seroma was associated with a suboptimal cosmetic outcome, because excellent scores were achieved in 61.5% of women with seroma compared with 83% without seroma. CONCLUSION: Intraoperative placement of the MammoSite catheter for accelerated partial breast irradiation is associated with a high rate of clinically detectable seroma that adversely affects the cosmetic outcome. The seroma risk was positively associated with body weight and negatively associated with postprocedural infection.

Incidence, Treatment, and Survival Patterns for Sacral Chordoma in the United States, 1974-2011.

INTRODUCTION: Sacral chordomas represent one half of all chordomas, a rare neoplasm of notochordal remnants. Current NCCN guidelines recommend surgical resection with or without adjuvant radiotherapy or definitive radiation for unresectable cases. Recent advances in radiation for chordomas include conformal photon and proton beam radiation. We investigated incidence, treatment, and survival outcomes to observe any trends in response to improvements in surgical and radiation techniques over a near 40-year time period. MATERIALS AND METHODS: Three hundred forty-five microscopically confirmed cases of sacral chordoma were identified between 1974 and 2011 from the surveillance, epidemiology, and end results program of the National Cancer Institute. Cases were divided into three cohorts by calendar year, 1974-1989, 1990-1999, and 2000-2011, as well as into two groups by age ≤65 versus >65 to investigate trends over time and age via Chi-square analysis. Kaplan-Meier analyses were performed to determine effects of treatment on survival. Multivariate Cox regression analysis was performed to determine predictors of overall survival (OS). RESULTS: Five-year OS for the entire cohort was 60.0%. OS correlated significantly with treatment modality, with 44% surviving at 5 years with no treatment, 52% with radiation alone, 82% surgery alone, and 78% surgery and radiation (p < 0.001). Age >65 was significantly associated with non-surgical management with radiation alone or no treatment (p < 0.001). Relatively, fewer patients received radiation between 2000 and 2011 compared to prior time periods (p = 0.03) versus surgery, for which rates which did not vary significantly over time (p = 0.55). However, 5-year OS was not significantly different by time period. Age group and treatment modality were predictive for OS on multivariate analysis (p < 0.001). CONCLUSION: Surgery remains an important component in the treatment of sacral chordomas in current practice. Fewer patients were treated with radiation more recently despite advances in photon and proton beam radiation. OS remains unchanged. Additional analyses of margin status, radiation modality, and local control in current practice are warranted.

Management approach for recurrent brain metastases following upfront radiosurgery may affect risk of subsequent radiation necrosis.

PURPOSE: Many patients treated with stereotactic radiosurgery (SRS) alone as initial treatment require 1 or more subsequent salvage therapies. This study aimed to determine if commonly used salvage strategies are associated with differing risks of radiation necrosis (RN). METHODS AND MATERIALS: All patients treated with upfront SRS alone for brain metastases at our institution were retrospectively analyzed. Salvage treatment details were obtained for brain failures. Patients who underwent repeat SRS to the same lesion were excluded. RN was determined based on pathological confirmation or advanced brain imaging consistent with RN in a symptomatic patient. Patients were grouped according to salvage treatment and rates of RN were compared via Fisher's exact tests. RESULTS: Of 284 patients treated with upfront SRS alone, 132 received salvage therapy and 44 received multiple salvage treatments. This included 31 repeat SRS alone, 58 whole brain radiation therapy (WBRT) alone, 28 SRS and WBRT, 7 surgery alone, and 8 surgery with adjuvant radiation. With a median follow-up of 10 months, the rate of RN among all patients was 3.17% (9/284), salvaged patients 4.55% (6/132), and never salvaged patients 1.97% (3/152). Receiving salvage therapy did not significantly increase RN risk (P = .31). Of the patients requiring salvage treatments, the highest RN rate was among patients that had both salvage SRS and WBRT (delivered as separate salvage therapies) (6/28, 21.42%). RN rate in this group was significantly higher than in those treated with repeat SRS alone (0/31), WBRT alone (0/58), surgery alone (0/7), and surgery with adjuvant radiation (0/8). Comparing salvage WBRT doses <30 Gy versus ≥30 Gy revealed no effect of dose on RN rate. Additionally, among patients who received multiple SRS treatments, number of treated lesions was not predictive of RN incidence. CONCLUSION: Our results suggest that initial management approach for recurrent brain metastasis after upfront SRS does not affect the rate of RN. However, the risk of RN significantly increases when patients are treated with both repeat SRS and salvage WBRT. Methods to improve prediction of toxicity and optimize patient selection for salvage treatments are needed.

Impact of Sublobar Resection on Pulmonary Function: Long-Term Results from American College of Surgeons Oncology Group Z4032 (Alliance).

BACKGROUND: Sublobar resection (SR) in high-risk operable patients may result in a long-term decrease in pulmonary function. We previously reported 3-month pulmonary function outcomes from a randomized phase III study of SR alone compared with SR with brachytherapy in patients with non-small cell lung cancer. We now report long-term pulmonary function after SR. METHODS: Pulmonary function was measured at baseline and at 3, 12, and 24 months. A decline of 10% or more from baseline in the percentage predicted forced expiratory volume of 1 percentage or in the diffusion capacity of the lung for carbon monoxide was considered clinically meaningful. The effect of study arm, tumor location, size, approach (video-assisted thoracoscopic surgery vs thoracotomy), and SR type (wedge vs segmentectomy) on pulmonary function was assessed using a Wilcoxon rank sum test. A generalized estimating equation model was used to assess the effect of each factor on longitudinal data, including all four time points. RESULTS: Complete pulmonary function data at all time points was available in 69 patients. No significant differences were observed in pulmonary function between SR and SR with brachytherapy, thus the study arms were combined for all analyses. A decline of 10% or more (p = 0.02) in the percentage predicted forced expiratory volume in 1 second was demonstrated for lower-lobe resections at 3 months but was not at 12 or 24 months. A decline of 10% or more (p = 0.05) in the percentage predicted diffusion capacity of the lung for carbon monoxide was seen for thoracotomy at 3 months but was not at 12 or 24 months. CONCLUSIONS: Clinically meaningful declines in pulmonary function occurred after lower lobe resection and after thoracotomy at 3 months but subsequently recovered. This study suggests that SR does not result in sustained decreased pulmonary function in high-risk operable patients.

A Nomogram to Predict Recurrence and Survival of High-Risk Patients Undergoing Sublobar Resection for Lung Cancer: An Analysis of a Multicenter Prospective Study (ACOSOG Z4032).

BACKGROUND: Individualized prediction of outcomes may help with therapy decisions for patients with non-small cell lung cancer. We developed a nomogram by analyzing 17 clinical factors and outcomes from a randomized study of sublobar resection for non-small cell lung cancer in high-risk operable patients. The study compared sublobar resection alone with sublobar resection with brachytherapy. There were no differences in primary and secondary outcomes between the study arms, and they were therefore combined for this analysis. METHODS: The clinical factors of interest (considered as continuous variables) were assessed in a univariate Cox proportional hazards model for significance at the 0.10 level for their impact on overall survival (OS), local recurrence-free survival (LRFS), and any recurrence-free survival (RFS). The final multivariable model was developed using a stepwise model selection. RESULTS: Of 212 patients, 173 had complete data on all 17 risk factors. Median follow-up was 4.94 years (range, 0.04 to 6.22). The 5-year OS, LRFS, and RFS were 58.4%, 53.2%, and 47.4%, respectively. Age, baseline percent diffusing capacity of lung for carbon monoxide, and maximum tumor diameter were significant predictors for OS, LRFS, and RFS in the multivariable model. Nomograms were subsequently developed for predicting 5-year OS, LRFS, and RFS. CONCLUSIONS: Age, baseline percent diffusing capacity of lung for carbon monoxide, and maximum tumor diameter significantly predicted outcomes after sublobar resection. Such nomograms may be helpful for treatment planning in early stage non-small cell lung cancer and to guide future studies.