A. Warner

An Individual Patient Data Metaanalysis of Outcomes and Prognostic Factors After Treatment of Oligometastatic Non-Small-Cell Lung Cancer.

INTRODUCTION/BACKGROUNDnAn individual patient data metaanalysis was performed to determine clinical outcomes, and to propose a risk stratification system, related to the comprehensive treatment of patients with oligometastatic NSCLC.nnnMATERIALS AND METHODSnAfter a systematic review of the literature, data were obtained on 757 NSCLC patients with 1 to 5 synchronous or metachronous metastases treated with surgical metastectomy, stereotactic radiotherapy/radiosurgery, or radical external-beam radiotherapy, and curative treatment of the primary lung cancer, from hospitals worldwide. Factors predictive of overall survival (OS) and progression-free survival were evaluated using Cox regression. Risk groups were defined using recursive partitioning analysis (RPA). Analyses were conducted on training and validating sets (two-thirds and one-third of patients, respectively).nnnRESULTSnMedian OS was 26 months, 1-year OS 70.2%, and 5-year OS 29.4%. Surgery was the most commonly used treatment for the primary tumor (635 patients [83.9%]) and metastases (339 patients [62.3%]). Factors predictive of OS were: synchronous versus metachronous metastases (P < .001), N-stage (P = .002), and adenocarcinoma histology (P = .036); the model remained predictive in the validation set (c-statistic = 0.682). In RPA, 3 risk groups were identified: low-risk, metachronous metastases (5-year OS, 47.8%); intermediate risk, synchronous metastases and N0 disease (5-year OS, 36.2%); and high risk, synchronous metastases and N1/N2 disease (5-year OS, 13.8%).nnnCONCLUSIONnSignificant OS differences were observed in oligometastatic patients stratified according to type of metastatic presentation, and N status. Long-term survival is common in selected patients with metachronous oligometastases. We propose this risk classification scheme be used in guiding selection of patients for clinical trials of ablative treatment.

Predictive parameters of symptomatic radiation pneumonitis following stereotactic or hypofractionated radiotherapy delivered using volumetric modulated arcs.

PURPOSEnTo identify dosimetric factors that predict development of radiation pneumonitis (RP) following stereotactic or hypofractionated radiotherapy for lung tumors.nnnMETHODSnSeventy-nine consecutive patients with either a planning target volume (PTV)>100 cm(3) (n=69) or prior pneumonectomy or bi-lobectomy (n=13) were identified. Radiation doses (range: 5-50 Gy, with 5 Gy increments) were converted to equivalent doses (EQD(2 Gy)) (α/β=3). Total lung (TL), ipsilateral (IL) and contralateral lung (CL) volumes minus PTV, receiving 5 Gy (V5) up to 50 Gy (V50) and mean lung dose (MLD) were analyzed. Predictors of grade ≥3 RP (CTCAEv4.03) were identified with concordance-statistics (C-statistic) and p-values used to quantify the performance of the model. Factors found to be significant were entered into a recursive partitioning analysis (RPA).nnnRESULTSnMedian PTV was 150 cm(3). Grade ≥3 RP was observed in 8 patients (10%). In univariable analysis, CL-MLD, CL-V5-15, TL-MLD, TL-V5-V10 and ITV size were predictive of RP (p<0.05). In multivariable analysis, contralateral MLD (p=.007) and ITV (p=.063) were the strongest predictors of grade ≥3 RP, with excellent discrimination (C-statistic: 0.868).nnnCONCLUSIONnContralateral MLD and ITV size are both strong predictors of grade ≥3 RP post treatment. Planning constraints should aim to keep contralateral MLD below 3.6 Gy.

A Phase 1/2 Trial of Brief Androgen Suppression and Stereotactic Radiation Therapy (FASTR) for High-Risk Prostate Cancer

PURPOSEnTo initiate a phase 1/2 trial to examine the tolerability of a condensed combined-modality protocol for high-risk prostate cancer.nnnMETHODS AND MATERIALSnMen scoring ≥3 on the Vulnerable Elderly Scale (VES) or refusing conventionally fractionated treatment for high-risk prostate cancer were eligible to participate. Androgen suppression was delivered for 12 months, and radiation therapy was delivered using 25 Gy to pelvic nodes delivered synchronously with 40 Gy to the prostate given as 1 fraction per week over 5 weeks. The phase 1 component included predetermined stopping rules based on 6-month treatment-related toxicity, with trial suspension specified if there were ≥6 of 15 patients (40%) or ≥3 of 15 (20%) who experienced grade ≥2 or ≥3 gastrointestinal (GI) or genitourinary (GU) toxicity, respectively.nnnRESULTSnSixteen men were enrolled, with 7 men meeting the criteria of VES ≥3 and 9 men having a VES <3 but choosing the condensed treatment. One man was not treated owing to discovery of a synchronous primary rectal cancer. Four patients (26%) experienced grade ≥2 toxicity at 6 weeks after treatment. There were 9 of 15 (60%) who experienced grade ≥2 GI or GU toxicity and 4 of 15 (26%) grade ≥3 GI or GU toxicity at 6 months, and 5 of 15 (30%) grade ≥2 GI and GU toxicity at 6 months. A review of the 15 cases did not identify any remedial changes, thus the phase 1 criteria were not met.nnnCONCLUSIONnThis novel condensed treatment had higher than anticipated late toxicities and was terminated before phase 2 accrual. Treatment factors, such as inclusion of pelvic lymph node radiation therapy, planning constraints, and treatment margins, or patient factors related to the specific frail elderly population may be contributing.

Predicting Overall Survival After Stereotactic Ablative Radiation Therapy in Early-Stage Lung Cancer: Development and External Validation of the Amsterdam Prognostic Model.

PURPOSEnA prognostic model for 5-year overall survival (OS), consisting of recursive partitioning analysis (RPA) and a nomogram, was developed for patients with early-stage non-small cell lung cancer (ES-NSCLC) treated with stereotactic ablative radiation therapy (SABR).nnnMETHODS AND MATERIALSnA primary dataset of 703 ES-NSCLC SABR patients was randomly divided into a training (67%) and an internal validation (33%) dataset. In the former group, 21 unique parameters consisting of patient, treatment, and tumor factors were entered into an RPA model to predict OS. Univariate and multivariate models were constructed for RPA-selected factors to evaluate their relationship with OS. A nomogram for OS was constructed based on factors significant in multivariate modeling and validated with calibration plots. Both the RPA and the nomogram were externally validated in independent surgical (n = 193) and SABR (n = 543) datasets.nnnRESULTSnRPA identified 2 distinct risk classes based on tumor diameter, age, World Health Organization performance status (PS) and Charlson comorbidity index. This RPA had moderate discrimination in SABR datasets (c-index range: 0.52-0.60) but was of limited value in the surgical validation cohort. The nomogram predicting OS included smoking history in addition to RPA-identified factors. In contrast to RPA, validation of the nomogram performed well in internal validation (r(2) = 0.97) and external SABR (r(2) = 0.79) and surgical cohorts (r(2) = 0.91).nnnCONCLUSIONSnThe Amsterdam prognostic model is the first externally validated prognostication tool for OS in ES-NSCLC treated with SABR available to individualize patient decision making. The nomogram retained strong performance across surgical and SABR external validation datasets. RPA performance was poor in surgical patients, suggesting that 2 different distinct patient populations are being treated with these 2 effective modalities.

Radiation-induced lung injury after concurrent neoadjuvant chemoradiotherapy for locally advanced breast cancer

Outcomes for women with locally advanced breast cancer (LABC) remain poor, with a fi ve-year survival of approximately 50%, despite aggressive treatment with a combination of chemotherapy, surgery and radiotherapy, all delivered sequentially [1,2]. Achieving a pathological complete response (pCR) to neoadjuvant systemic therapy (defi ned as no residual disease in the breast or axilla at surgery) is a major favorable prognostic factor [3 – 5]; however, rates of pCR are low: a large meta-analysis demonstrated that 17% of women, on average, achieve a pCR after neoadjuvant treatment [3]. In LABC, concurrent chemoradiotherapy has been associated with higher rates of pCR [4,6]. In an attempt to improve the pCR rate for LABC, a phase II trial was launched to evaluate the effi cacy of a regimen consisting of neoadjuvant docetaxel con-current with locoregional radiotherapy. At the rec-ommendation of the data safety monitoring committee, the trial closed early due to a higher-than-anticipated rate of symptomatic radiation pneumonitis (RP). The goal of this study was to evaluate predictors of symptomatic RP and CT-based radiation-induced lung injury (RILI) in a unique cohort of breast cancer patients treated with concurrent neoadjuvant chemoradiation therapy.

A comparison between accelerated hypofractionation and stereotactic ablative radiotherapy (SABR) for early-stage non-small cell lung cancer (NSCLC): Results of a propensity score-matched analysis

BACKGROUND AND PURPOSEnStereotactic ablative radiotherapy (SABR) has become standard for inoperable early-stage non-small cell lung cancer (NSCLC). However, there is no randomized evidence demonstrating benefit over more fractionated radiotherapy. We compared accelerated hypofractionation (AH) and SABR using a propensity score-matched analysis.nnnMATERIALS AND METHODSnFrom 1997-2007, 119 patients (T1-3N0M0 NSCLC) were treated with AH (48-60 Gy, 12-15 fractions). Prior to SABR, this represented our institutional standard. From 2008-2012, 192 patients (T1-3N0M0 NSCLC) were treated with SABR (48-52 Gy, 4-5 fractions). A total of 114 patients (57 per cohort) were matched (1:1 ratio, caliper: 0.10) using propensity scores.nnnRESULTSnMedian follow-up (range) for the AH cohort was 36.3 (2.5-109.1) months, while that for the SABR group was 32.5 (0.3-62.6)months. Three-year overall survival (OS) and local control (LC) rates were 49.5% vs. 72.4% [p=0.024; hazard ratio (HR): 2.33 (1.28, 4.23), p=0.006] and 71.9% vs. 89.3% [p=0.077; HR: 5.56 (1.53, 20.2), p=0.009], respectively. On multivariable analysis, tumour diameter and PET staging were predictive for OS, while the only predictive factor for LC was treatment cohort.nnnCONCLUSIONSnOS and LC were improved with SABR, although OS is more closely related to non-treatment factors. This represents one of the few studies comparing AH to SABR for early-stage lung cancer.

Extreme hypofractionation for high-risk prostate cancer: Dosimetric correlations with rectal bleeding

PURPOSEnWe explored the association of dosimetric parameters with late rectal bleeding among high-risk prostate cancer patients treated with hypofractionated simultaneous in-field boost (H-SIB) to prostate with nodal treatment.nnnMETHODS AND MATERIALSnRectal toxicity results and dose-volume histogram (DVH) information from patients treated on FASTR and SATURN were combined. Patients in both trials received long-term androgen deprivation and H-SIB with prescription dose 40 Gy to the prostate and proximal seminal vesicles and 25 Gy to the lymph nodes delivered over 5 weekly fractions using image guidance with cone beam computed tomography. Mean rectal DVH values at 5-Gy intervals and mean DVH curves were compared between patients with rectal bleeding (B) versus no bleeding (NB).nnnRESULTSnThere were 12 B and 33 NB patients in the pooled group. Rectal bleeding was more frequent and of higher grade among FASTR patients (8/15, 5 grade 2 or higher) than among SATURN patients (4/30, all grade 1). For any bleeding (grade ≥1), individual dose-volume points in the 20 to 40 Gy range were significantly different (2-sided P < .05) between the B and NB groups, with the 40 Gy point being the most significant (B: V40 = 1.53%, standard deviation (SD), 1.32; NB: V40 = 0.69%, SD, 1.46; P = .006). For grade ≥2 bleeding, the V20 Gy was most significant (B: 68.4%, SD, 4.76; NB: 40.45%, SD, 13.9; P < .001).nnnCONCLUSIONSnThe higher relative dose volumes to the rectum (V20-V40) were most strongly associated with clinically significant bleeding in this analysis and are consistent with findings of series that used H-SIB to treat prostate only. Differences in the prostate target volumes and planning margins likely account for the differences in the rates and grades of rectal bleeding observed between trials.

Estimating Survival After Salvage Surgery for Recurrent Oral Cavity Cancer

Importance Locoregional recurrence of oral cavity squamous cell carcinoma (OCSCC) continues to be a life-threatening and difficult clinical situation. Salvage surgery can result in significant morbidities, and survival following recurrence is poor. Objective To outline prognostic factors influencing overall survival (OS) following salvage surgery for OCSCC to guide management of treatment for patients with locoregionally recurrent disease. Design, Setting, and Participants The medical records of 293 patients presenting to the London Health Sciences Center with locoregionally recurrent OCSCC between October 5, 1999, and May 2, 2011, were retrospectively reviewed. The primary outcome was OS from salvage treatment to last follow-up or death. Univariate analyses were carried out using the Cox proportional hazards regression model. A recursive partitioning analysis was used to create risk groups based on prognosis. Analysis was conducted from December 8, 2015, to February 26, 2016. Results Of the 293 patients evaluated, 59 (20%) had recurrence identified after their initial OCSCC treatment; 39 (66%) were men, and the mean (SD) age at diagnosis was 62.2 (11.8) years. Thirty-nine (66%) of these patients underwent salvage surgery for locoregional recurrence with curative intent. Five-year OS from the time of salvage surgery was 43%. Recursive partitioning analysis identified 3 risk groups: (1) high risk (patients who received adjuvant chemoradiotherapy or radiotherapy after initial surgery) with 5-year OS rate of 10% (hazard ratio [HR], 9.41; 95% CI, 2.68-33.04), (2) intermediate risk (previous surgery alone, age ≥62 years) with a 5-year OS rate of 39% (HR, 2.95; 95% CI, 0.86-10.09), and (3) low risk (previous surgery alone, age <62 years) with 5-year OS rate of 74%. Conclusions and Relevance This recursive partitioning analysis identified 3 prognostic groups in patients undergoing salvage surgery for recurrent OCSCC. The marked differences in survival between these groups should be taken into consideration when counselling and managing treatment for patients with locoregionally recurrent disease.

The role of adjuvant therapy in stage IA serous and clear cell uterine cancer: A multi-institutional pooled analysis

OBJECTIVEnAs the optimal adjuvant management of stage IA serous or clear cell endometrial cancer is controversial, a multi-institutional review was conducted with the objective of evaluating the appropriateness of various strategies including observation.nnnMETHODSnRetrospective chart reviews for 414 consecutive patients who underwent hysterectomy for FIGO stage IA endometrial cancer with serous, clear cell or mixed histology between 2004 and 2015 were conducted in 6 North American centers. Time-to-event outcomes were analyzed by Kaplan-Meier estimates, log-rank test, univariable and multivariable cox proportional hazard regression models.nnnRESULTSnPost-operative management included observation (50%), chemotherapy and radiotherapy (RT) (27%), RT only (16%) and chemotherapy only (7%). The 178 RT patients received external beam (EBRT, 16%), vaginal vault brachytherapy (VVB, 56%) or both (28%). Among patients without any adjuvant treatment, 5-year local control (LC), disease free survival (DFS) and cancer-specific survival (CSS) were 82% (95% confidence interval: 74-88), 70% (62-78) and 90% (82-94), respectively. CSS in patients without adjuvant treatment was improved with adequate surgical staging (100% vs. 87% (77-92), log-rank p=0.022). Adjuvant VVB was associated with improved LC (5-year 96% (91-99) vs. 84% (76-89), log-rank p=0.007) and DFS (5-year 79% (66-88) vs. 71% (63-77), log-rank p=0.033). Adjuvant chemotherapy was associated with better LC (5-year 96% (90-98) vs. 84% (77-89), log-rank p=0.014) and DFS (5-year 84% (74-91) vs. 69% (61-76), log-rank p=0.009). On multivariable analysis, adjuvant chemotherapy and VVB were associated with improved LC while adjuvant chemotherapy and age were significant for DFS.nnnCONCLUSIONSnIn stage IA serous or clear cell uterine cancer, adjuvant RT and chemotherapy were associated with better LC and DFS. Observation may be appropriate in patients who have had adequate surgical staging.

Evaluation of a new predictor of heart and left anterior descending artery dose in patients treated with adjuvant radiotherapy to the left breast

BackgroundHeart-sparing techniques arexa0time and resource intensive, although not all patients require the use of these strategies. This study evaluates the performance of different distance metrics in predicting the need for breath-hold radiotherapy in left-sided breast cancer patients receiving adjuvant radiotherapy.MethodsFifty left-sided breast cancer patients treated with breast conserving surgery and adjuvant radiotherapy to the breast from a single institution were retrospectively studied. The left breast and organs at risk were contoured in accordance to guidelines and a plan with tangents was obtained using the free-breathing CT in supine position. Heart (mean heart dose (MHD), heart V25xa0Gy) and left anterior descending artery dosimetry were computed and compared against distance metrics under investigation (Contact Heart, 4th Arch and 5th Arch). Recursive partitioning analysis (RPA) was used to determine optimal cut-points for distance metrics for dosimetric end points. Receiver operating characteristic curves and Pearson correlation coefficients were used to evaluate the association between distance metrics and dosimetric endpoints. Univariable and multivariable logistic regression analysis was performed to identify significant predictors of dosimetric end points.ResultsThe mean MHD and heart V25xa0Gy were 2.3xa0Gy and 10.4xa0cm3, respectively. With tangents, constraints for MHD (<u20091.7xa0Gy and V25xa0Gyu2009<u200910xa0cm3) were unattainable in 80% and 46% of patients, respectively. Optimal RPA thresholds included: Contact Heart (73xa0mm), 4th Arch (7xa0mm) and 5th Arch (41xa0mm). Of these, the 4th Arch had the highest overall accuracy, sensitivity, concordance index and correlation coefficient. All metrics were statistically significant predictors for MHDu2009≥u20091.7xa0Gy based on univariable logistic regression. Fifth Arch did not reach significance for heart V25xa0Gyu2009≥u200910xa0cm3. Fourth Arch was the only predictor to remain statistically significant after multivariable analysis.ConclusionsWe propose a novel “4th Arch” metric as an accurate and practical tool to determine the need for breath-hold radiotherapy for left-sided breast cancer patients undergoing adjuvant radiotherapy with standard tangents. Further validation in an external cohort is necessary.