M.C. Roach

Treatment of Peripheral Non-Small Cell Lung Carcinoma with Stereotactic Body Radiation Therapy

Stereotactic body radiation therapy (SBRT) is an effective and well-tolerated noninvasive treatment for medically inoperable patients with peripheral non–small cell lung carcinoma. The term “peripheral” refers to lesions that lie 2 cm or more from the mediastinum and proximal bronchial tree and was instituted based on results from a specific dose and fractionation schedule. Improvements in immobilization, respiratory motion management, and image guidance have allowed for SBRT’s highly conformal and accurate delivery of large radiation doses per fraction. Results from prospective and retrospective studies suggest that lung SBRT has superior outcomes when compared with conventionally fractionated treatments and is comparable with surgical resection. Investigations into the optimal SBRT dosing regimen for peripheral lesions are ongoing, with recent trials suggesting comparable efficacy between single and multiple fraction schedules. Chest wall toxicity after peripheral treatment is common, but it usually resolves with conservative management. Pneumonitis is less often observed after treatment of peripheral lesions, and changes in pulmonary function tests are minimal. Studies in the frail and elderly suggest that neither baseline pulmonary function tests nor age should preclude treatment. Recent technical developments have reduced delivery time and resulted in more conformal treatments. This review is on behalf of the IASLC Advanced Radiation Technology Committee.

It’s never too late: Smoking cessation after stereotactic body radiation therapy for non-small cell lung carcinoma improves overall survival

PURPOSE As stereotactic body radiation therapy (SBRT) has emerged as a quick, effective, and well-tolerated treatment for early stage non-small cell lung carcinoma (NSCLC), it can be difficult to convince patients to quit smoking in follow-up. We evaluated whether there was a survival benefit to smoking cessation after SBRT. METHODS AND MATERIALS Patients with early-stage NSCLC treated from 2004 to 2013 who were still smoking tobacco at the time of SBRT were identified from a prospective institutional review board-approved registry. Peripheral tumors were treated to 54 Gy in 3 fractions and central tumors to 50 Gy in 5 fractions. Patients were reviewed for overall survival (OS) and disease progression. The log-rank and Cox regression tests were used to identify factors predictive of OS. RESULTS Thirty-two patients (27%) quit smoking after SBRT, and 87 (73%) continued smoking. Median follow-up was 22 months (range, 2-87). On multivariate analysis, smoking status (hazard ratio, 2.1; 95% confidence interval, 1.02-4.2; P = .045), increasing age-adjusted Charlson comorbidity score and larger tumor size were predictive of worse OS. The prior number of cigarette pack-years was not significant (P = .62). In a Kaplan-Meier comparison, smoking cessation after SBRT was associated with improved 2-year OS, 78% versus 69% (P = .014). There was no significant difference in 2-year progression-free survival (75% vs 55%, P = .23) or local control (97% vs 88%, P = .63). CONCLUSION OS is significantly improved in patients who stop smoking after SBRT for early-stage NSCLC, no matter their previous smoking history. Encouraging smoking cessation should be an important part of every posttreatment visit.

Treatment utilization and outcomes in elderly patients with locally advanced esophageal carcinoma: A review of the National Cancer Database

For elderly patients with locally advanced esophageal cancer, therapeutic approaches and outcomes in a modern cohort are not well characterized. Patients ≥70 years old with clinical stage II and III esophageal cancer diagnosed between 1998 and 2012 were identified from the National Cancer Database and stratified based on treatment type. Variables associated with treatment utilization were evaluated using logistic regression and survival evaluated using Cox proportional hazards analysis. Propensity matching (1:1) was performed to help account for selection bias. A total of 21,593 patients were identified. Median and maximum ages were 77 and 90, respectively. Treatment included palliative therapy (24.3%), chemoradiation (37.1%), trimodality therapy (10.0%), esophagectomy alone (5.6%), or no therapy (12.9%). Age ≥80 (OR 0.73), female gender (OR 0.81), Charlson–Deyo comorbidity score ≥2 (OR 0.82), and high‐volume centers (OR 0.83) were associated with a decreased likelihood of palliative therapy versus no treatment. Age ≥80 (OR 0.79) and Clinical Stage III (OR 0.33) were associated with a decreased likelihood, while adenocarcinoma histology (OR 1.33) and nonacademic cancer centers (OR 3.9), an increased likelihood of esophagectomy alone compared to definitive chemoradiation. Age ≥80 (OR 0.15), female gender (OR 0.80), and non‐Caucasian race (OR 0.63) were associated with a decreased likelihood, while adenocarcinoma histology (OR 2.10) and high‐volume centers (OR 2.34), an increased likelihood of trimodality therapy compared to definitive chemoradiation. Each treatment type demonstrated improved survival compared to no therapy: palliative treatment (HR 0.49) to trimodality therapy (HR 0.25) with significance between all groups. Any therapy, including palliative care, was associated with improved survival; however, subsets of elderly patients with locally advanced esophageal cancer are less likely to receive aggressive therapy. Care should be taken to not unnecessarily deprive these individuals of treatment that may improve survival.

Cardiac dose is associated with immunosuppression and poor survival in locally advanced non-small cell lung cancer

PURPOSE Studies have associated increased radiation therapy (RT) heart dose with cardiac toxicity. Others have correlated RT-related immunosuppression with worsened survival. Given the large vascular volumes irradiated during locally advanced non-small cell lung cancer (LA-NSCLC) treatment, we hypothesized an association between increased heart dose and immunosuppression. METHODS We identified 400 LA-NSCLC patients treated with definitive RT ± chemotherapy between 2001 and 2016. Absolute lymphocyte counts (ALC), absolute neutrophil counts (ANC), and neutrophil-to-lymphocyte ratio (NLR = ANC/ALC) were analyzed pre-RT, during RT, and post-RT. Multivariable analysis (MVA) was performed to correlate Clinical factors with both hematologic toxicity and overall survival. An upper tertile threshold to increase specificity of NLR was chosen to dichotomize continuous hematologic variables. RESULTS Median follow up was 17 months (range 0.2-174 months) in all patients and 46 months (range 0.2-161 months) in survivors. A total of 94% of patients had stage III disease and 77% received concurrent chemo radiation. Two-year overall survival (OS), freedom from local recurrence (FFLR), and freedom from distant metastases (FFDM) was 42%, 60% and 45%, respectively. Median survival was 18 months. On MVA for OS (n = 207), male gender (Hazard Ratio [HR] 1.7; 95% CI 1.2-2.3), RT alone (HR 2.1; 95% CI 1.9-4.0), the percentage of heart receiving ≥50 Gy (V50) (HR 1.02; 95% CI 1.01-1.03), and higher NLR at 4 months (HR 1.02, 95% CI 1.01-1.03) were associated with reduced OS. ALC nadir was not associated with treatment outcomes. NLR >10.5 was associated with decreased OS (p < 0.001) and decreased FFDM (p = 0.04). On MVA evaluating factors associated with hematological toxicity (n = 247), adjuvant chemotherapy (HR 2.6; 95% CI 1.3-5.0; p = 0.006), RT alone (HR 3.6; 95% CI 1.1-12; p = 0.04), and heart V50 >25% (HR 2.0; 95% CI 1.1-3.5; p = 0.02) were associated with a NLR >10.5 4 months post-RT. CONCLUSION RT related immunosuppression is associated with worse patient outcomes, and may represent a source of increased mortality beyond cardiac toxicity alone.

Defining Optimal Comorbidity Measures for Patients with Early Stage Non-small Cell Lung Cancer (NSCLC) Treated with Stereotactic Body Radiation Therapy (SBRT)

PURPOSE Comparison of overall survival (OS) between stereotactic body radiation therapy (SBRT) and other treatments for early-stage non-small cell lung cancer is confounded by differences in age, performance status, and medical comorbidity. We sought to define the most robust measurement for this population among 5 indices: age, Eastern Cooperative Oncology Group performance status, Adult Comorbidity Evaluation 27, Charlson Comorbidity Index (CCI), and age-adjusted CCI (CCIa). METHODS AND MATERIALS A total of 548 patients with stage I non-small cell lung cancer treated with SBRT were analyzed. Patients were divided into high- and low-risk groups for OS for each index using the log-rank test. Continuous and dichotomized models were compared via Akaike information criterion and the Vuong test. Multivariate Cox regression modeling was used with demographic information to determine the independent prognostic value of the continuous and dichotomized versions of the indices. The best was used to stratify the patients into as many significantly different cohorts as possible. RESULTS Optimal cut-points between high-risk and low-risk OS groups for age, Eastern Cooperative Oncology Group status, Adult Comorbidity Evaluation 27, CCI, and CCIa were ≥75 years, ≥1, ≥3, ≥3, and ≥6 with hazard ratios for death of 1.23 (95% confidence interval, 1.00-1.50), 1.66 (1.28-2.15), 1.37 (1.12-1.67), 1.43 (1.17-1.76), and 1.47 (1.20-1.80), respectively. Dichotomizing did not result in a significant loss of prognostic power. Although there was no significant difference in prognostic power among the indices, CCIa best predicted OS. CCIa divided the patients into 3 cohorts with median OS of 42 months, 33 months, and 23 months for scores of ≤5, 6 to 7, and ≥8, respectively. CONCLUSIONS CCIa was the best indicator of OS in every model employed with no loss of prognostic power with dichotomization. Dichotomization of CCIa (≥6) could be implemented in future comparisons of SBRT with OS. No cohort could be identified with a median survival of less than a year, for which treatment could be deemed futile.

Local control for clinical stage I non-small cell lung cancer treated with 5-fraction stereotactic body radiation therapy is not associated with treatment schedule

PURPOSE Clinical concern remains regarding the relationship between consecutive (QD) versus nonconsecutive (QoD) lung stereotactic body radiation therapy (SBRT) treatment schedules and outcomes for clinical stage I non-small cell lung cancer (NSCLC). We examined a multi-institutional series of patients receiving 5-fraction lung SBRT to compare the local failure rates and overall survival between patients receiving QD versus QoD treatment. METHODS AND MATERIALS Lung SBRT databases from 2 high-volume institutions were combined, and patients receiving 5-fraction SBRT for a solitary stage I NSCLC were identified. QD treatment was defined as completing SBRT in ≤7 days, whereas QoD treatment was defined as completing treatment in >7 days. To control for patient characteristics between the 2 institutions, a 1:1 propensity-matched analysis was performed. Multivariable logistic regression was performed to identify variables independently associated with local failure, and Cox proportional hazards modeling to identify variables independently associated with increased mortality. RESULTS From 2005 through 2016, 245 clinical stage I NSCLC patients receiving 5-fraction SBRT were identified. A total of 117 (47.8%) patients received QD treatment and 128 (52.2%) patients received QoD treatment. On propensity-matched analysis, no association was seen between QD treatment and local failure (odds ratio [OR] for QD treatment, 0.48; 95% confidence interval [CI], 0.12-1.99; P = .5). On multivariable logistic regression, central tumors were independently associated with increased likelihood of local recurrence (OR, 5.2; 95% CI, 1.11-24.2; P = .04). Kaplan-Meier analysis identified no difference in median overall survival between QD versus QoD treatments (38.0 vs 38.0 months, log-rank P = .7), respectively. QD treatment was not associated with an increased mortality hazard (hazard ratio, 1.08; 95% CI, 0.67-1.75; P = .75). CONCLUSIONS This analysis demonstrated no association between QD versus QoD treatment scheduling and local control or overall survival for early-stage NSCLC.

Stereotactic Body Radiation Therapy for Central Early-Stage NSCLC: Results of a Prospective Phase I/II Trial

Introduction: We report results from a prospective phase I/II trial for patients with centrally located, early‐stage NSCLC receiving stereotactic body radiation therapy. Methods: Eligible patients were medically inoperable with biopsy‐proven NSCLC within 2 cm of the proximal bronchial tree or 5 mm of the mediastinal pleura or parietal pericardium. Phase I had four dose levels using 5 fractions: 9, 10, 11, and 12 Gy per fraction. The primary phase II objective was to determine if the maximum tolerated dose in phase I achieved local control greater than 80% at 2 years. Results: Seventy‐four patients were enrolled; 23 to phase I and 51 to phase II. Two phase I patients treated with 10 Gy × 5 fractions developed unrelated acute grade 3 lung toxicities which resolved. The phase II dose level selected was 11 Gy × 5 fractions. The median follow‐up for living phase II patients was 27 months (range, 9 to 58 months). Two‐year local control using 11 Gy × 5 fractions was 85% (95% confidence interval [CI]: 62%–95%). Two‐year overall survival was 43% (95% CI: 28%–57%). Three patients (6%, 95% CI: 1%–17%) experienced acute grade 3 and 4 cardiac or pulmonary toxicities. Of the 41 patients evaluable for late cardiac and pulmonary toxicity, 11 (27%, 95% CI: 14%–43%) developed grade 3, 5 (12%, 95% CI: 4%–26%) developed grade 4, and 1 (4%, 95% CI: 0%–13%) died of grade 5 toxicity. Conclusion: Stereotactic body radiation therapy for central NSCLC using 11 Gy × 5 fractions is tolerable and has excellent local control, but is associated severe late toxicity in some patients.

P3.17-02 Increasing Radiation Dose to Central Structures is Associated with Worse Survival Following Thoracic Proton Reirradiation

Background: Historically, thoracic reirradiation has been associated with high rates of toxicity from cumulative doses delivered to organs at risk (OARs). Conformal treatment in the form of proton therapy (PT) offers the opportunity to deliver definitive doses of radiotherapy with limited dose to surrounding OARs. We performed dosimetric analyses of patients undergoing thoracic re-irradiation with PT to identify parameters associated survival outcomes.Method:We identified patients with complete clinical and dosimetric information who received thoracic re-irradiation with PT on an IRB-approved prospective patient registry. Prior radiation courses were fused with PT plans to create composite plans, which were recalculated to an equivalent dose of 200 cGy per fraction (EQD2) using an a/b of 3. Toxicity was retrospectively assessed using CTCAE v4.0. Toxicity, disease control, and survival were estimated with the Kaplan-Meier method. The Cox proportional hazards model was used to estimate hazard ratios for univariate analysis (UVA), and significant dosimetric parameters were further assessed using cutpoint analysis. Patients were dichotomized based on these cutpoints, and survival differences were assessed using the log-rank test. Result: A total of 25 patients were included with a median age of 64 years (range 26-89). The majority of patients had non-small cell lung cancer (84%). Median PT re-irradiation dose was 6000 CGE (range 4000-6250) in 30 fractions (range 5-30 fractions). At a median followup of 17.5 months (range 1-34), one-year rates of local control, distant control, and overall survival, were 70.9%, 55.6%, and 71.2% respectively. No grade 4/5 toxicities were observed, and there were 5 late grade 3 events (2 non-malignant pleural effusions, 2 episodes of hemoptysis, 1 one esophageal stricture) with an estimated rate of 21% at 1 year. UVA revealed worse survival in patients with increasing maximum dose to the esophagus, carina, heart, pulmonary artery, and spinal cord, and increasing mean dose to the esophagus (p<0.05 for each). Patients who received a cumulative point max dose of 7500 cGy to the esophagus, 11620 cGy to the heart, 12000 cGy to the pulmonary artery, or 3250 mean dose to the esophagus had significantly worse survival than those who did not (all p<0.05). Conclusion: PT re-irradiation is a viable treatment option for patients with thoracic recurrences and offers excellent outcomes with limited toxicity. In this study, we identified dosimetric parameters associated with worse survival that can be used in treatment planning for recurrent disease.

Practical Implications of Ferromagnetic Artifacts in Low-field MRI-guided Radiotherapy

Fractionated radiotherapy presents a new challenge in the screening of patients undergoing magnetic resonance imaging-guided radiotherapy (MR-IGRT). In our institution, patients are evaluated at the time of consult, simulation, and first fraction using a thorough MRI questionnaire identical to the one used for diagnostic radiology patients. For each subsequent fraction, the therapists are trained to inquire about any procedures the patient may have had between the last and current fractions. Patients are also advised to avoid food and fluid intake at least two but not beyond four hours prior to treatment. Despite these screening efforts, we have observed several non-permanent imaging artifacts that, while not harmful to the patient, prevent the accurate delivery of MR-IGRT when using online adaptive radiotherapy due to interference with the identification of relevant anatomy. Two such cases are presented here: (1) an imaging artifact due to iron-enriched breakfast cereal that precluded treatment for that day, and (2) an imaging artifact due to an iron-containing multivitamin that necessitated a creative solution to enable the accurate visualization of the area to be treated.

Magnetic Resonance Image-Guided Radiotherapy (MRIgRT): A 4.5-Year Clinical Experience

AIMS Magnetic resonance image-guided radiotherapy (MRIgRT) has been clinically implemented since 2014. This technology offers improved soft-tissue visualisation, daily imaging, and intra-fraction real-time imaging without added radiation exposure, and the opportunity for adaptive radiotherapy (ART) to adjust for anatomical changes. Here we share the longest single-institution experience with MRIgRT, focusing on trends and changes in use over the past 4.5 years. MATERIALS AND METHODS We analysed clinical information, including patient demographics, treatment dates, disease sites, dose/fractionation, and clinical trial enrolment for all patients treated at our institution using MRIgRT on a commercially available, integrated 0.35 T MRI, tri-cobalt-60 device from 2014 to 2018. For each patient, factors including disease site, clinical rationale for MRIgRT use, use of ART, and proportion of fractions adapted were summated and compared between individual years of use (2014-2018) to identify shifts in institutional practice patterns. RESULTS Six hundred and forty-two patients were treated with 666 unique treatment courses using MRIgRT at our institution between 2014 and 2018. Breast cancer was the most common disease, with use of cine MRI gating being a particularly important indication, followed by abdominal sites, where the need for cine gating and use of ART drove MRIgRT use. One hundred and ninety patients were treated using ART in 1550 fractions, 67.6% (1050) of which were adapted. ART was primarily used in cancers of the abdomen. Over time, breast and gastrointestinal cancers became increasingly dominant for MRIgRT use, hypofractionated treatment courses became more popular, and gastrointestinal cancers became the principal focus of ART. DISCUSSION MRIgRT is widely applicable within the field of radiation oncology and new clinical uses continue to emerge. At our institution to date, applications such as ART for gastrointestinal cancers and accelerated partial breast irradiation (APBI) for breast cancer have become dominant indications, although this is likely to continue to evolve.