Efficacy and cost of high-frequency IGRT in elderly stage III non-small-cell lung cancer patients.

BACKGROUND: High-frequency image-guided radiotherapy (hfIGRT) is ubiquitous but its benefits are unproven. We examined the cost effectiveness of hfIGRT in stage III non-small-cell lung cancer (NSCLC). METHODS: We selected stage III NSCLC patients ≥66 years old who received definitive radiation therapy from the Surveillance, Epidemiology, and End-Results-Medicare database. Patients were stratified by use of hfIGRT using Medicare claims. Predictors for hfIGRT were calculated using a logistic model. The impact of hfIGRT on lung toxicity free survival (LTFS), esophageal toxicity free survival (ETFS), cancer-specific survival (CSS), overall survival (OS), and cost of treatment was calculated using Cox regressions, propensity score matching, and bootstrap methods. RESULTS: Of the 4,430 patients in our cohort, 963 (22%) received hfIGRT and 3,468 (78%) did not. By 2011, 49% of patients were receiving hfIGRT. Predictors of hfIGRT use included treatment with intensity-modulated radiotherapy (IMRT) (OR = 7.5, p < 0.01), recent diagnosis (OR = 51 in 2011 versus 2006, p < 0.01), and residence in regions where the Medicare intermediary allowed IMRT (OR = 1.50, p < 0.01). hfIGRT had no impact on LTFS (HR 0.97; 95% CI 0.86-1.09), ETFS (HR 1.05; 95% CI 0.93-1.18), CSS (HR 0.94; 95% CI 0.84-1.04), or OS (HR 0.95; 95% CI 0.87-1.04). Mean radiotherapy and total medical costs six months after diagnosis were $17,330 versus $15,024 (p < 0.01) and $71,569 versus $69,693 (p = 0.49), respectively. CONCLUSION: hfIGRT did not affect clinical outcomes in elderly patients with stage III NSCLC but did increase radiation cost. hfIGRT deserves further scrutiny through a randomized controlled trial.

Dynamic Changes in Circulating Tumor DNA During Chemoradiation for Locally Advanced Lung Cancer.

PURPOSE: Concurrent chemoradiation therapy (CRT) is the principal treatment modality for locally advanced lung cancer. Cell death due to CRT leads to the release of cell-free DNA (cfDNA) and circulating tumor DNA (ctDNA) into the bloodstream, but the kinetics and characteristics of this process are poorly understood. We hypothesized that there could be clinically meaningful changes in cfDNA and ctDNA during a course of CRT for lung cancer. METHODS AND MATERIALS: Multiple samples of plasma were obtained from 24 patients treated with CRT for locally advanced lung cancer to a mean dose of 66 Gy (range, 58-74 Gy) at the following intervals: before CRT, at weeks 2 and 5 during CRT, and 6 weeks after treatment. cfDNA was quantified, and a novel next generation sequencing (NGS) technique using enhanced tagged/targeted-amplicon sequencing was performed to analyze ctDNA. RESULTS: Patients for whom specific mutations in ctDNA were undetectable at the baseline time point had improved survival, and potentially etiologic driver mutations could be tracked throughout the course of CRT via NGS in multiple patients. We quantified the levels of cfDNA from patients before CRT, at week 2, week 5, and at 6 weeks after treatment. No differences were observed at weeks 2 and 5 of therapy, but we noted a significant increase in cfDNA in the posttreatment follow-up samples compared with samples collected before CRT (P = .05). CONCLUSIONS: Dynamic changes in both cfDNA and ctDNA were observed throughout the course of CRT in patients with locally advanced lung cancer. Specific mutations with therapeutic implications can be identified and tracked using NGS methodologies. Further work is required to characterize the changes in cfDNA and ctDNA over time in patients treated with CRT and to assess the predictive and prognostic potential of this powerful technology.

Impact of estrogen monotherapy on survival in women with stage III-IV non-small cell lung cancer.

OBJECTIVES: Women with lung cancer have better survival than men. The reasons are unknown, but estrogen is hypothesized to improve survival. Our objective was to examine the association between estrogen monotherapy and cancer-specific and overall survival in elderly women with non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: We used the SEER-Medicare database to identify women ≥65 years old who were diagnosed with stage III or IV NSCLC. Estrogen monotherapy (EM) was defined as at least one estrogen claim without any progesterone claims 6 months prior to diagnosis. To assess cancer-specific survival and overall survival, we used Kaplan-Meier and multivariate Cox modeling with propensity score adjustments. As an exploratory analysis, we also examined the effect of combined estrogen and progesterone hormonal therapy on survival using Cox modeling. RESULTS: We identified 6958 women in our initial cohort: 283 used EM (4%) and 6675 (96%) did not. The median follow-up time was 46.5 months in the EM patients and 49.5 months in the non-EM patients. In a Kaplan-Meier analysis, median overall survival was 8.2 months in patients who receive EM and 6.2 months in those who did not (p = 0.004). In our 1:4 propensity-matched cohort, median follow-up was 46.5 in the EM group and 50.6 in the non-EM group; median overall survival was 8.0 months in the EM group and 6.4 months in the non-EM group (p = 0.02). In a multivariate Cox regression of the matched cohort, EM was significantly associated with overall survival (HR 0.84; 95% CI 0.73 - 0.97). All results were similar for cancer-specific survival. In our exploratory analysis, combined Estrogen-Progesterone did significantly impact overall survival (HR 0.84; 95% CI 0.71-0.99, p = 0.04) but did not appear to effect cancer-specific survival (HR 0.91; 95% CI 0.77-1.09, p = 0.30). CONCLUSION: EM was associated with a significant improvement in cancer-specific survival and overall survival in women with late stage NSCLC.

Five-year Long-term Outcomes of Stereotactic Body Radiation Therapy for Operable Versus Medically Inoperable Stage I Non-small-cell Lung Cancer: Analysis by Operability, Fractionation Regimen, Tumor Size, and Tumor Location.

BACKGROUND: Stereotactic body radiation therapy (SBRT) is standard for medically inoperable stage I non-small-cell lung cancer (NSCLC) and is emerging as a surgical alternative in operable patients. However, limited long-term outcomes data exist, particularly according to operability. We hypothesized long-term local control (LC) and cancer-specific survival (CSS) would not differ by fractionation schedule, tumor size or location, or operability status, but overall survival (OS) would be higher for operable patients. PATIENTS AND METHODS: All consecutive patients with stage I (cT1-2aN0M0) NSCLC treated with SBRT from June 2009 to July 2013 were assessed. Thoracic surgeon evaluation determined operability. Local failure was defined as growth following initial tumor shrinkage or progression on consecutive scans. LC, CSS, and OS were calculated using Cox proportional hazards regression. RESULTS: A total of 186 patients (204 lesions) were analyzed. Most patients were inoperable (82%) with Eastern Cooperative Oncology Group performance status of 1 (59%) or 2 (26%). All lesions received biological effective doses ≥ 100 Gy most commonly (94%) in 3 to 5 fractions. The median follow-up was 4.0 years. LC at 2 and 5 years were 95.6% (95% confidence interval, 92%-99%) and 93.7% (95% confidence interval, 90%-98%), respectively. Compared with operable patients, inoperable patients did not have significant differences in 5-year LC (93.1% vs. 96.7%; P = .49), nodal failure (31.4% vs. 11.0%; P = .12), distant failure (12.2% vs. 10.4%; P = .98), or CSS (80.6% vs. 91.0%; P = .45) but trended towards worse OS (34.2% vs. 45.3%; P = .068). Tumor size, location, and fractionation did not significantly influence outcomes. CONCLUSIONS: SBRT has excellent, durable LC and CSS rates for early-stage NSCLC, although inoperable patients had somewhat lower OS than operable patients, likely owing to greater comorbidities.

Rectal balloon use limits vaginal displacement, rectal dose, and rectal toxicity in patients receiving IMRT for postoperative gynecological malignancies.

Pelvic radiotherapy for gynecologic malignancies traditionally used a 4-field box technique. Later trials have shown the feasibility of using intensity-modulated radiotherapy (IMRT) instead. But vaginal movement between fractions is concerning when using IMRT due to greater conformality of the isodose curves to the target and the resulting possibility of missing the target while the vagina is displaced. In this study, we showed that the use of a rectal balloon during treatment can decrease vaginal displacement, limit rectal dose, and limit acute and late toxicities. Little is known regarding the use of a rectal balloon (RB) in treating patients with IMRT in the posthysterectomy setting. We hypothesize that the use of an RB during treatment can limit rectal dose and acute and long-term toxicities, as well as decrease vaginal cuff displacement between fractions. We performed a retrospective review of patients with gynecological malignancies who received postoperative IMRT with the use of an RB from January 1, 2012 to January 1, 2015. Rectal dose constraint was examined as per Radiation Therapy Oncology Group (RTOG) 1203 and 0418. Daily cone beam computed tomography (CT) was performed, and the average (avg) displacement, avg magnitude, and avg magnitude of vector were calculated. Toxicity was reported according to RTOG acute radiation morbidity scoring criteria. Acute toxicity was defined as less than 90 days from the end of radiation treatment. Late toxicity was defined as at least 90 days after completing radiation. Twenty-eight patients with postoperative IMRT with the use of an RB were examined and 23 treatment plans were reviewed. The avg rectal V40 was 39.3% ± 9.0%. V30 was65.1% ± 10.0%. V50 was 0%. Separate cone beam computed tomography (CBCT) images (n = 663) were reviewed. The avg displacement was as follows: superior 0.4 + 2.99 mm, left 0.23 ± 4.97 mm, and anterior 0.16 ± 5.18 mm. The avg magnitude of displacement was superior/inferior 2.22 ± 2.04 mm, laterally 3.41 ± 3.62 mm, and anterior/posterior 3.86 ± 3.45 mm. The avg vector magnitude was 6.60 ± 4.14 mm. For acute gastrointestinal (GI) toxicities, 50% experienced grade 1 toxicities and 18% grade 2 GI toxicities. For acute genitourinary (GU) toxicities, 21% had grade 1 and 18% had grade 2 toxicities. For late GU toxicities, 7% had grade 1 and 4% had grade 2 toxicities. RB for gynecological patients receiving IMRT in the postoperative setting can limit V40 rectal dose and vaginal displacement. Although V30 constraints were not met, patients had limited acute and late toxicities. Further studies are needed to validate these findings.

Survival Benefit of Adjuvant Radiation Therapy in Node-positive Vulvar Cancer.

BACKGROUND: Adjuvant radiation therapy improves overall survival in patients with vulvar cancer with 2+ positive lymph nodes, but its benefit remains uncertain for 1 positive lymph node. METHODS: Using the Surveillance, Epidemiology, and End Results (SEER) database, we identified node-positive, American Joint Committee on Cancer version 6-staged women with squamous cell vulvar carcinoma treated with and without radiation following surgery. The Kaplan-Meier approach assessed overall and cause-specific survival. Propensity score-based, multiply imputed Cox modeling accounted for missing data and selection bias. RESULTS: From 2004 to 2013, 488 versus 206 women did and did not receive adjuvant radiation after surgery. Patient characteristics were well balanced, including home county, index tumor diameter, number of nodes excised, provider type, race, and surgery type (P>0.05). Unbalanced covariates-including median age, grade, number of positive nodes, N-stage-were adjusted using Cox regression. At a median follow-up of 36 months, adjuvant radiation was associated with improved median overall survival across all node-positive patients (54 vs. 24 mo; P<0.01). This survival benefit persisted in women with just one (not reached vs. 39 mo; P<0.01) and 2+ (26 vs. 16 mo; P<0.01) positive lymph nodes. Likewise, all node-positive groups saw a cause-specific survival benefit with adjuvant radiation (all P<0.02). On multivariable Cox regression, adjuvant radiation, age, tumor diameter, number of positive nodes, race, and N-stage associated with survival (P<0.05). CONCLUSIONS: All node positive vulvar cancer patients should benefit from and thus should receive adjuvant radiation, including those with one positive node.

Velocity-based Adaptive Registration and Fusion for Fractionated Stereotactic Radiosurgery Using the Small Animal Radiation Research Platform.

PURPOSE: To implement Velocity-based image fusion and adaptive deformable registration to enable treatment planning for preclinical murine models of fractionated stereotactic radiosurgery (fSRS) using the small animal radiation research platform (SARRP). METHODS AND MATERIALS: C57BL6 mice underwent 3 unique cone beam computed tomography (CBCT) scans: 2 in the prone position and a third supine. A single T1-weighted post-contrast magnetic resonance imaging (MRI) series of a murine metastatic brain tumor model was selected for MRI-to-CBCT registration and gross tumor volume (GTV) identification. Two arms were compared: Arm 1, where we performed 3 individual MRI-to-CBCT fusions using rigid registration, contouring GTVs on each, and Arm 2, where the authors performed MRI-to-CBCT fusion and contoured GTV on the first CBCT followed by Velocity-based adaptive registration. The first CBCT and associated GTV were exported from MuriPlan (Xstrahl Life Sciences) into Velocity (Varian Medical Systems, Inc, Palo Alto, CA). In Arm 1, the second and third CBCTs were exported similarly along with associated GTVs (Arm 1), while in Arm 2, the first (prone) CBCT was fused separately to the second (prone) and third (supine) CBCTs, performing deformable registrations on initial CBCTs and applying resulting matrices to the contoured GTV. Resulting GTVs were compared between Arms 1 and 2. RESULTS: Comparing GTV overlays using repeated MRI fusion and GTV delineation (Arm 1) versus those of Velocity-based CBCT and GTV adaptive fusion (Arm 2), mean deviations ± standard deviation in the axial, sagittal, and coronal planes were 0.46 ± 0.16, 0.46 ± 0.22, and 0.37 ± 0.22 mm for prone-to-prone and 0.52 ± 0.27, 0.52 ± 0.36, and 0.68 ± 0.31 mm for prone-to-supine adaptive fusions, respectively. CONCLUSIONS: Velocity-based adaptive fusion of CBCTs and contoured volumes allows for efficient fSRS planning using a single MRI-to-CBCT fusion. This technique is immediately implementable on current SARRP systems, facilitating advanced preclinical treatment paradigms using existing clinical treatment planning software.

Definitive dose thoracic radiation therapy in oligometastatic non-small cell lung cancer: A hypothesis-generating study.

PURPOSE: A subset of patients with minimal extrathoracic disease may benefit from aggressive primary tumor treatment. We report comparative outcomes in oligometastatic non-small cell lung cancer (NSCLC) treated with and without definitive, conventionally fractionated thoracic radiation therapy. METHODS AND MATERIALS: We identified consecutive patients with stage IV NSCLC who had an Eastern Cooperative Oncology Group performance status ≤2 and ≤4 total sites of metastatic disease and who had been prescribed ≥50 Gy of thoracic radiation. RESULTS: Twenty-nine patients with oligometastatic NSCLC were identified between January 2004 and August 2010. Median survival was 22 months from diagnosis. Four patients (14%) experienced pneumonitis greater than or equal to grade 3; 6 (21%) had esophagitis greater than or equal to grade 3. Local control was associated with improved survival (P = .02). In matched subset analysis, median survival was 9 months (P < .01) in patients who received chemotherapy alone. Median time to local failure was 18 versus 6 months (P = .01). On multivariable analysis, radiation (P < .01; odds ratio [OR], 0.33), fewer metastases (P < .01; OR, 2.14), and female sex (P < .01; OR, 0.41) were associated with improved survival. CONCLUSIONS: Definitive dose radiation therapy may improve survival in a select subset of patients with minimal extrathoracic disease in whom local progression is of primary concern. Prospective trials are needed to further evaluate the role of local control in oligometastatic NSCLC.

Stage migration in planning PET/CT scans in patients due to receive radiotherapy for non-small-cell lung cancer.

INTRODUCTION: This study examined rates of tumor progression in treatment-naive patients with non-small-cell lung cancer (NSCLC) as determined by repeat treatment-planning fluorine-18 ((18)F) fluorodeoxyglucose positron emission tomography/computed tomography ((18)F-FDG PET/CT). METHODS AND MATERIALS: This study assessed patients who underwent PET/CT simulation for NSCLC stage II/III, radiation-naive, nonmetastatic NSCLC. It compared planning PET/CT with previous PET/CT images. Patients were analyzed for change in stage, treatment intent, or both. Progression was defined as a change in TNM status leading to upstaging, and standardized uptake value (SUV) velocity was defined as [(SUVscan2 - SUVscan1)/interscan interval in days]. RESULTS: Of 149 consecutive patients examined between April 2009 and April 2011, 47 had prior PET/CT scans and were included. The median age was 68 years. New nodal disease or metastatic disease was identified in 24 (51%) of 47 patients. Fourteen (30%) had evidence of extrathoracic metastatic disease; the remaining 10 (21%) had new nodal disease that required substantial alteration of treatment fields. At a scan interval of 20 days, the rate of upstaging was 17%. SUV velocity was analyzed in the subset of patients who had their studies on the identical PET/CT scanner (n = 14). Nonupstaged patients had a mean SUV velocity of 0.074 units per day, compared with 0.11 units per day in patients that were upstaged by their second PET/CT scan (P = .020). CONCLUSION: Radiation treatment planning with hybrid PET/CT scans repeated within 120 days of an initial staging PET/CT scan identified significant upstaging in more than half of patients. For a subset of patients who underwent both scans on the same instrument, SUV velocity predicts upstaging, and the difference between those upstaged and those not was statistically significant.

Impact of PET staging in limited-stage small-cell lung cancer.

INTRODUCTION: Although positron emission tomography computed tomography (PET-CT) has been widely used for small-cell lung cancer (SCLC) staging, no study has examined the clinical impact of PET staging in limited-stage (LS) SCLC. METHODS: We identified patients with LS-SCLC treated definitively with concurrent chemoradiation. Outcomes were assessed using the Kaplan-Meier approach, Cox regression, and competing risks method. RESULTS: We treated 54 consecutive LS-SCLC patients with concurrent chemoradiation from January 2002 to August 2010. Forty underwent PET, 14 did not, and all underwent thoracoabdominopelvic CT and magnetic resonance imaging neuroimaging. Most patient characteristics were balanced between the comparison groups, including age, race, sex, bone scanning, median dosage, and performance status. More number of PET-staged patients presented with nodal metastases (p = 0.05). Median follow-up was similar for PET-staged and non-PET-staged patients (p = 0.59). Median overall survival from diagnosis in PET-staged patients was 32 versus 17 months in patients staged without PET (p = 0.03), and 3-year survival was 47% versus 19%. Median time-to-distant failure was 29 versus 12 months (p = 0.04); median time-to-local failure was not reached versus 16 months (p = 0.04). On multivariable analysis, PET staging (odds ratio [OR] = 0.24; p = 0.04), performance status (OR = 1.89; p = 0.05), and N-stage (OR = 4.94; p < 0.01) were associated with survival. CONCLUSION: LS-SCLC patients staged with PET exhibited improved disease control and survival when compared with non-PET-staged LS-SCLC patients. Improved staging accuracy and better identification of intrathoracic disease may explain these findings, underscoring the value of PET-CT in these patients.