K.W. Merrell

Improving Outcomes for Esophageal Cancer using Proton Beam Therapy

Radiation therapy (RT) plays an essential role in the management of esophageal cancer. Because the esophagus is a centrally located thoracic structure there is a need to balance the delivery of appropriately high dose to the target while minimizing dose to nearby critical structures. Radiation dose received by these critical structures, especially the heart and lungs, may lead to clinically significant toxicities, including pneumonitis, pericarditis, and myocardial infarction. Although technological advancements in photon RT delivery like intensity modulated RT have decreased the risk of such toxicities, a growing body of evidence indicates that further risk reductions are achieved with proton beam therapy (PBT). Herein we review the published dosimetric and clinical PBT literature for esophageal cancer, including motion management considerations, the potential for reirradiation, radiation dose escalation, and ongoing esophageal PBT clinical trials. We also consider the potential cost-effectiveness of PBT relative to photon RT.

Multi-institutional analysis of radiation modality use and postoperative outcomes of neoadjuvant chemoradiation for esophageal cancer

PURPOSE Relative radiation dose exposure to vital organs in the thorax could influence clinical outcomes in esophageal cancer (EC). We assessed whether the type of radiation therapy (RT) modality used was associated with postoperative outcomes after neoadjuvant chemoradiation (nCRT). PATIENTS AND METHODS Contemporary data from 580 EC patients treated with nCRT at 3 academic institutions from 2007 to 2013 were reviewed. 3D conformal RT (3D), intensity modulated RT (IMRT) and proton beam therapy (PBT) were used for 214 (37%), 255 (44%), and 111 (19%) patients, respectively. Postoperative outcomes included pulmonary, GI, cardiac, wound healing complications, length of in-hospital stay (LOS), and 90-day postoperative mortality. Cox model fits, and log-rank tests both with and without Inverse Probability of treatment Weighting (IPW) were used to correct for bias due to non-randomization. RESULTS RT modality was significantly associated with the incidence of pulmonary, cardiac and wound complications, which also bore out on multivariate analysis. Mean LOS was also significantly associated with treatment modality (13.2days for 3D (95%CI 11.7-14.7), 11.6days for IMRT (95%CI 10.9-12.7), and 9.3days for PBT (95%CI 8.2-10.3) (p<0.0001)). The 90day postoperative mortality rates were 4.2%, 4.3%, and 0.9%, respectively, for 3D, IMRT and PBT (p=0.264). CONCLUSIONS Advanced RT technologies (IMRT and PBT) were associated with significantly reduced rate of postoperative complications and LOS compared to 3D, with PBT displaying the greatest benefit in a number of clinical endpoints. Ongoing prospective randomized trial will be needed to validate these results.

Stereotactic body radiation therapy of liver tumors: post-treatment appearances and evaluation of treatment response: a pictorial review.

Stereotactic body radiation therapy (SBRT) is a noninvasive treatment technique for selected patients with primary liver tumors and liver-confined oligometastatic disease. Recently, SBRT has emerged as an alternative treatment option in non-surgical candidates and in whom percutaneous treatment methods are not possible or contraindicated. The experience with SBRT continues to grow. There are currently no imaging guidelines for assessment of tumor response and follow-up schedule following SBRT. SBRT produces characteristic radiation-induced changes in the treated tumor and surrounding liver parenchyma. Knowledge of these changes is essential in the interpretation of follow-up imaging and assessment of treatment response. In this review, we will describe the CT, MRI, and PET imaging findings following SBRT of both the targeted liver tumor and surrounding hepatic parenchyma.

Utility of 18F-FDG PET for Predicting Histopathologic Response in Esophageal Carcinoma following Chemoradiation

Introduction: For patients with esophageal cancer undergoing neoadjuvant chemoradiation (CRT) followed by surgical resection, complete histopathologic response (pCR) is associated with favorable overall survival (OS). The aim of this study was to evaluate the correlation between 18F‐fluorodeoxyglucose positron emission tomography (FDG PET) response to neoadjuvant CRT and pCR. Methods: Maximum standardized uptake values and standardized uptake ratios (SURs) were measured before and after CRT. SUR was normalized to liver uptake and mediastinal blood pool uptake. FDG PET complete response was defined as metabolic activity normalization to hepatic and blood pool activity. The correlation between FDG PET parameters and pCR was examined through logistic regression analyses. Results: In total, 193 patients were monitored for a median of 3.6 years after initiation of CRT. Most tumors were adenocarcinoma (85%) and stage T3 (75%). Complete FDG PET response and pCR occurred in 27% and 34% of patients, respectively. Histologic findings, chemotherapy type, tumor stage, and radiation dose were not significantly associated with complete radiographic response. The rates of pCR in patients with and without radiographic complete response were 42% and 31% (p = 0.17), respectively. No predictive correlation was found between pCR and change in maximum standardized uptake value (p = 0.25), in SUR normalized to blood pool uptake (p = 0.20), or in SUR normalized to liver uptake (p = 0.15). The 5‐year OS rate was 46% for patients with a complete FDG PET response versus 44% without a complete response (p = 0.78). The 5‐year OS rate of patients who achieved pCR was 49% versus 43% for patients with residual tumor (p = 0.04). Conclusion: For patients with esophageal cancer who received neoadjuvant chemoradiation, pretreatment and posttreatment FDG PET parameters did not correlate with pCR or OS.

Spot-scanned pancreatic stereotactic body proton therapy: A dosimetric feasibility and robustness study

PURPOSE We explored the dosimetric potential of spot-scanned stereotactic body proton therapy (SBPT) for pancreatic cancer. METHODS We compared SBPT to stereotactic body intensity-modulated radiotherapy (SB-IMRT) in 10 patients. We evaluated 3 variables in SBPT planning: (1) 4 and 6 mm spot size; (2) single vs. multi-field optimization (SFO vs. MFO); and (3) optimization target volume (OTV) expansion. Robustness analysis was performed with unidirectional isocenter shifts of ±3 mm in x, y, and z and ±3% stopping power uncertainties. RESULTS SBPT plans had lower V10Gy for the stomach and small and large bowels. Under static robustness, a 5 mm OTV and SFO-6 mm spot size represented the best compromise between target and normal structure. A 4-mm spot-size and 3 mm OTV resulted in significant target underdosing with deformable dose accumulation analysis. CONCLUSIONS This study provides a critical basis for clinical translation of spot size, optimization technique, and OTV expansion for pancreatic SBPT.

Predictors of Locoregional Failure and Impact on Overall Survival in Patients With Resected Exocrine Pancreatic Cancer

PURPOSE Resection of exocrine pancreatic cancer is necessary for cure, but locoregional and distant relapse is common. We evaluated our institutional experience to better understand risk factors for locoregional failure (LRF) and its impact on overall survival (OS). METHODS AND MATERIALS We reviewed 1051 consecutive patients with nonmetastatic exocrine pancreatic cancer who underwent resection at our institution between March 1987 and January 2011. Among them, 458 had adequate follow-up and evaluation for study inclusion. All patients received adjuvant chemotherapy (n=80 [17.5%]) or chemoradiation therapy (n=378 [82.5%]). Chemotherapy and chemoradiation therapy most frequently consisted of 6 cycles of gemcitabine and 50.4 Gy in 28 fractions with concurrent 5-fluorouracil, respectively. Locoregional control (LRC) and OS were estimated with the Kaplan-Meier method. Univariate and multivariate analyses were performed with Cox proportional hazards regression models incorporating propensity score. RESULTS Median patient age was 64.5 years (range: 29-88 years). Median follow-up for living patients was 84 months (range: 6-300 months). Extent of resection was R0 (83.8%) or R1 (16.2%). Overall crude incidence of LRF was 17% (n=79). The 5-year LRC for patients with and without radiation therapy was 80% and 68%, respectively (P=.003; hazard ratio [HR]: 0.45; 95% confidence interval [CI]: 0.28-0.76). Multivariate analysis, incorporating propensity score, indicated radiation therapy (P<.0001; HR: 0.23; 95% CI: 0.12-0.42) and positive lymph node ratio of ≥0.2 (P=.02; HR: 1.78; 95% CI: 1.10-2.9) were associated with LRC. In addition, LRF was associated with worse OS (P<.0001; HR: 5.0; 95% CI: 3.9-6.3). CONCLUSIONS In our analysis of 458 patients with resected pancreatic cancer, positive lymph node ratio of ≥0.2 and no adjuvant chemoradiation therapy were associated with increased LRF risk. LRF was associated with poor OS. Radiation therapy should be considered as adjuvant locoregional treatment following pancreatic cancer resection.

FDG-PET parameters as predictors of pathologic response and nodal clearance in patients with stage III non-small cell lung cancer receiving neoadjuvant chemoradiation and surgery

OBJECTIVE Pathologic complete response (pCR) following neoadjuvant chemoradiation (CRT) is associated with improved outcomes in stage III non-small cell lung cancer. Conflicting results exist regarding the value of 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) in predicting pCR. This study evaluated the association between post-CRT FDG-PET and pCR using novel FDG-PET parameters. METHODS AND MATERIALS This retrospective study included patients treated with CRT and resection. All underwent pre- and post-CRT FDG-PET imaging. Maximum standard uptake value (SUVmax), standard uptake ratio (SUR), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) were measured. RESULTS In total, 44 patients were included for review. The majority had cT2 disease (59.0%). Median radiation dose was 60 Gy (45-70.2 Gy). Rate of pCR and near-pCR within the primary lesion was 29.5% and 45.5%, respectively. Average reduction in SUVmax was 9.2, whereas SUR normalized to mediastinum and liver showed mean reductions of 4.7 and 3.5, respectively. No association was found between pCR and either MTV or TLG. Reduction in SUVmax and SUR were significantly associated with increased rate of pCR (P ≤ .02). A threshold of >75% decrease in SUR-liver showed significant association with near-pCR (diagnostic odds ratio [DOR]: 8.3; P = .007). No correlation was found between nodal FDG-PET parameters and nodal pCR. CONCLUSIONS Our results indicate SUV and SUR have utility in predicting pCR after neoadjuvant CRT. SUR parameters trended toward higher DORs, suggesting improved predictive utility compared with SUVmax. Notably, no association was found with nodal pCR. Furthermore, MTV and TLG changes were not predictive, potentially resulting from inflammation after full-dose radiation, but this warrants further investigation.

Recurrence Risk Stratification After Preoperative Chemoradiation of Esophageal Adenocarcinoma

Objective: To discern recurrence risk stratification and investigate its influence on postoperative surveillance in patients with esophageal adenocarcinoma (EAC) after neoadjuvant chemoradiotherapy (CRT). Background: Reports documenting recurrence risk stratification in EAC after neoadjuvant CRT are scarce. Methods: Between 1998 and 2014, 601 patients with EAC who underwent neoadjuvant CRT followed by esophagectomy were included for analysis. The pattern, site, timing, and frequency of the first recurrence and potential prognostic factors for developing recurrences were analyzed. This cohort was used as the training set to propose a recurrence risk stratification system, and the stratification was further validated in another cohort of 172 patients. Results: A total of 150 patients (25.0%) achieved pathologic complete response (pCR) after neoadjuvant CRT and the rest were defined as the non-pCR group (n = 451) in the training cohort. After a median follow-up of 63.6 months, the pCR group demonstrated a significantly lower locoregional (4.7% vs 19.1%) and distant recurrence rate (22.0% vs.44.6%) than the non-pCR group (P < 0.001). Based on independent prognostic factors, patients were stratified into 4 recurrence risk categories: pCR with clinical stage I/II, pCR with clinical stage III, non-pCR with pN0, and non-pCR with pN+, with corresponding 5-year recurrence-free survival rates of 88.7%, 65.8%, 55.3%, and 33.0%, respectively (P < 0.001). The risk stratification was reproducible in the validation cohort. Conclusions: We proposed a recurrence risk stratification system for EAC patients based on pathologic response and pretreatment clinical stage. Risk-based postoperative surveillance strategies could be developed for different risk categories.

Predictors of relapse and evaluation of the role of postoperative radiation therapy in a modern series of patients with surgically resected stage III (N2) non–small cell lung cancer

Purpose For patients with stage III (N2) non–small cell lung cancer (NSCLC) treated with surgical resection, postoperative chemotherapy improves overall survival (OS), but the role of postoperative radiation therapy (PORT) is controversial. The purpose of this study was to evaluate risk factors for local-regional recurrence and to evaluate the impact of PORT on local-regional control (LRC) and OS in a modern series of patients with surgically resected stage III (N2) NSCLC. Methods and materials A retrospective review was performed of patients with Stage III (N2) NSCLC who underwent curative intent resection at our institution between February 1999 and January 2012. OS, LRC, and metastasis-free survival were estimated from the date of surgery using the Kaplan Meier method. Results A total of 71 patients were included in the study. Patient median age was 63 years. Histology was adenocarcinoma in 69% of patients. Pretreatment positron emission tomography/computed tomography staging was performed for 90% of patients, and preoperative chemotherapy was administered in 23%. The rate of R0 resection was 96%. Forty-one patients (58%) received PORT and the median PORT dose was 50 Gy (range, 41.4-60 Gy). The median follow-up time for living patients was 5.0 years. Five-year OS for all patients was 66%. OS at 5 years for patients who received PORT compared with patients who did not receive PORT was 71% versus 60%, respectively (hazard ratio [HR], 0.61; 95% CI, 0.30-1.44; P = .28). LRC at 5 years for patients who received PORT compared with patients who did not receive PORT was 89% versus 76%, respectively (HR, 0.44; 95% CI, 0.13-1.45; P = .17). Factors associated with decreased LRC were male sex (P = .011) and primary tumor (pT) stage (pT3/4 vs. pT1/2, P = .006). Metastasis-free survival at 5 years for patients who received PORT compared with those who did not receive PORT was 62% versus 63%, respectively (HR, 1.07; 95% CI, 0.51-2.40; P = .86). Conclusions In this modern series of patients with resected stage III (N2) NSCLC, patients who received PORT had higher rates of OS and LRC, but these differences were not statistically significant.

Radiation Optic Neuropathy

Radiation-induced retinopathy and radiation-induced optic neuropathy (RION) are rare and disabling late-onset complications of ocular irradiation. Radiation-induced retinopathy is characterized by progressive, occlusive vasculopathy, leading to subsequent retinal inflammation, edema, ischemia, and neovascular proliferation. These changes ultimately lead to retinal hemorrhage, maculopathy, and gradual decline in visual acuity. In contrast, optic neuropathy involves the optic nerve or chiasm and may present with sudden onset of visual changes. Both can lead to profound and irreversible vision loss and substantial disability and are thus critically important to consider in the treatment of any intracranial or base of skull disease.