James D. Murphy

A dosimetric model of duodenal toxicity after stereotactic body radiotherapy for pancreatic cancer

INTRODUCTION Dose escalation for pancreas cancer is limited by the tolerance of adjacent normal tissues, especially with stereotactic body radiotherapy (SBRT). The duodenum is generally considered to be the organ at greatest risk. This study reports on the dosimetric determinants of duodenal toxicity with single-fraction SBRT. METHODS AND MATERIALS Seventy-three patients with locally advanced unresectable pancreatic adenocarcinoma received 25 Gy in a single fraction. Dose-volume histogram (DVH) endpoints evaluated include V(5) (volume of duodenum that received 5 Gy), V(10), V(15), V(20), V(25), and D(max) (maximum dose to 1 cm(3)). Normal tissue complication probability (NTCP) was evaluated with a Lyman model. Univariate and multivariate analyses were conducted with Kaplan-Meier and Cox regression models. RESULTS The median time to Grade 2-4 duodenal toxicity was 6.3 months (range, 1.6-11.8 months). The 6- and 12-month actuarial rates of toxicity were 11% and 29%, respectively. V(10)-V(25) and D(max) all correlated significantly with duodenal toxicity (p<0.05). In particular, V(15)≥9.1 cm(3) and V(15)<9.1 cm(3) yielded duodenal toxicity rates of 52% and 11%, respectively (p=0.002); V(20)≥3.3 cm(3) and V(20)<3.3 cm(3) gave toxicity rates of 52% and 11%, respectively (p=0.002); and D(max)≥23 Gy and D(max)<23 Gy gave toxicity rates of 49% and 12%, respectively (p=0.004). Lyman NTCP model optimization generated the coefficients m=0.23, n=0.12, and TD(50)=24.6 Gy. Only the Lyman NTCP model remained significant in multivariate analysis (p=0.001). CONCLUSIONS Multiple DVH endpoints and a Lyman NTCP model are strongly predictive of duodenal toxicity after SBRT for pancreatic cancer. These dose constraints will be valuable in future abdominal SBRT studies.

Colon cancer, version 1.2017: Clinical practice guidelines in oncology

This selection from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Bladder Cancer focuses on systemic therapy for muscle-invasive urothelial bladder cancer, as substantial revisions were made in the 2017 updates, such as new recommendations for nivolumab, pembrolizumab, atezolizumab, durvalumab, and avelumab. The complete version of the NCCN Guidelines for Bladder Cancer addresses additional aspects of the management of bladder cancer, including non-muscle-invasive urothelial bladder cancer and nonurothelial histologies, as well as staging, evaluation, and follow-up.

Validation that metabolic tumor volume predicts outcome in head-and-neck cancer.

PURPOSE We have previously reported that metabolic tumor volume (MTV) obtained from pretreatment (18)F-fluorodeoxydeglucose positron emission tomography (FDG PET)/ computed tomography (CT) predicted outcome in patients with head-and-neck cancer (HNC). The purpose of this study was to validate these results on an independent dataset, determine whether the primary tumor or nodal MTV drives this correlation, and explore the interaction with p16(INK4a) status as a surrogate marker for human papillomavirus (HPV). METHODS AND MATERIALS The validation dataset in this study included 83 patients with squamous cell HNC who had a FDG PET/CT scan before receiving definitive radiotherapy. MTV and maximum standardized uptake value (SUV(max)) were calculated for the primary tumor, the involved nodes, and the combination of both. The primary endpoint was to validate that MTV predicted progression-free survival and overall survival. Secondary analyses included determining the prognostic utility of primary tumor vs. nodal MTV. RESULTS Similarly to our prior findings, an increase in total MTV of 17 cm(3) (difference between the 75th and 25th percentiles) was associated with a 2.1-fold increase in the risk of disease progression (p = 0.0002) and a 2.0-fold increase in the risk of death (p = 0.0048). SUV(max) was not associated with either outcome. Primary tumor MTV predicted progression-free (hazard ratio [HR] = 1.94; p < 0.0001) and overall (HR = 1.57; p < 0.0001) survival, whereas nodal MTV did not. In addition, MTV predicted progression-free (HR = 4.23; p < 0.0001) and overall (HR = 3.21; p = 0.0029) survival in patients with p16(INK4a)-positive oropharyngeal cancer. CONCLUSIONS This study validates our previous findings that MTV independently predicts outcomes in HNC. MTV should be considered as a potential risk-stratifying biomarker in future studies of HNC.

Approach to patients with pancreatic cancer without detectable metastases.

The poors outcomes associated with pancreatic cancer clearly reflect the advanced stage of disease at diagnosis for most patients. Through this lens, it is easy to lose sight of the fact that roughly 50% of patients with pancreatic cancer have no clinically detectable metastases at presentation. Herein, we discuss how patients with localized pancreatic cancer are currently managed. The primary goal of care for patients with resectable and borderline-resectable tumors is cure, facilitated by achieving margin-negative resection of the primary disease and delivering effective adjuvant and/or neoadjuvant therapy. For patients with locally advanced disease, the focus is on limiting local progression and outgrowth of metastatic disease and maintaining quality of life. Although it was once a centerpiece of therapy for localized pancreatic cancer, the value and place of radiation therapy in the treatment algorithm is now under increased scrutiny. In contrast, given its value as demonstrated in multiple prospective trials, chemotherapy is an established part of the treatment paradigm for all patients. With the demonstration that cytotoxic combinations such as fluorouracil, leucovorin, irinotecan, and oxaliplatin as well as gemcitabine/nab-paclitaxel are active in the metastatic setting, these agents are now being studied in patients with localized disease. The neoadjuvant setting provides a particularly favorable setting for evaluating new systemic strategies. Given the array of new targets, including immunomodulatory approaches, there is reason for optimism that we can markedly improve survival for all patients with pancreatic cancer and enter an era in which surgery with curative intent actually fulfills this goal on a much more regular basis.

Postradiation metabolic tumor volume predicts outcome in head-and-neck cancer.

PURPOSE To explore the prognostic value of metabolic tumor volume measured on postradiation (18)F-fluorodeoxyglucose positron emission tomography (PET) imaging in patients with head-and-neck cancer. METHODS AND MATERIALS Forty-seven patients with head-and-neck cancer who received pretreatment and posttreatment PET/computed tomography (CT) imaging along with definitive chemoradiotherapy were included in this study. The PET/CT parameters evaluated include the maximum standardized uptake value, metabolic tumor volume (MTV(2.0)-MTV(4.0); where MTV(2.0) refers to the volume above a standardized uptake value threshold of 2.0), and integrated tumor volume. Kaplan-Meier and Cox regression models were used to test for association between PET endpoints and disease-free survival and overall survival. RESULTS Multiple postradiation PET endpoints correlated significantly with outcome; however, the most robust predictor of disease progression and death was MTV(2.0). An increase in MTV(2.0) of 21 cm(3) (difference between 75th and 25th percentiles) was associated with an increased risk of disease progression (hazard ratio [HR] = 2.5, p = 0.0001) and death (HR = 2.0, p = 0.003). In patients with nonnasopharyngeal carcinoma histology (n = 34), MTV(2.0) <18 cm(3) and MTV(2.0) ≥18 cm(3) yielded 2-year disease-free survival rates of 100% and 63%, respectively (p = 0.006) and 2-year overall survival rates of 100% and 81%, respectively (p = 0.009). There was no correlation between MTV(2.0) and disease-free survival or overall survival with nasopharyngeal carcinoma histology (n = 13). On multivariate analysis, only postradiation MTV(2.0) was predictive of disease-free survival (HR = 2.47, p = 0.0001) and overall survival (HR = 1.98, p = 0.003). CONCLUSIONS Postradiation metabolic tumor volume is an adverse prognostic factor in head-and-neck cancer. Biomarkers such as MTV are important for risk stratification and will be valuable in the future with risk-adapted therapies.

Epidemiology of Gastrointestinal Stromal Tumors in the Era of Histology Codes: Results of a Population-Based Study

To date, all population-based epidemiologic data on gastrointestinal stromal tumor (GIST) in the United States predate the 2001 implementation of GIST-specific histology coding. As such, results from previous studies were limited because of inclusion of non-GIST abdominal or gastrointestinal sarcomas. We used a national cancer registry with modern day histologic codes to gain greater insight into the true epidemiology of GIST in the United States. We identified 6,142 patients diagnosed with GIST between 2001 and 2011 in the Surveillance, Epidemiology, and End Results database. Incidence, survival, demographic risk factors, and prognostic factors were analyzed. Annual age-adjusted incidence rose from 0.55/100,000 in 2001 to 0.78/100,000 in 2011 and increased with age, peaking among 70- to 79-year-olds (3.06/100,000). GIST was also more common in males than females [rate ratio (RR), 1.35], non-Hispanics than Hispanics (RR, 1.23), and blacks (RR, 2.07) or Asians/Pacific Islanders (RR, 1.50) than whites. The study period had 5-year overall and GIST-specific survival rates of 65% and 79%, respectively. The 5-year overall survival rates for those with localized, regional, and metastatic disease at diagnosis were 77%, 64%, and 41%, respectively. Multivariate analyses demonstrated that older age at diagnosis, male sex, black race, and advanced stage at diagnosis were independent risk factors for worse overall survival. Multivariate analysis also showed the four aforementioned characteristics, along with earlier year of diagnosis, to be independent risk factors for worse GIST-specific survival. As the first population-based, epidemiologic study of histologically confirmed disease, our findings provide a robust representation of GIST in the era of immunohistochemical diagnoses. Cancer Epidemiol Biomarkers Prev; 24(1); 298–302. ©2014 AACR.

A Population-Based Comparative Effectiveness Study of Radiation Therapy Techniques in Stage III Non-Small Cell Lung Cancer

PURPOSE Concerns have been raised about the potential for worse treatment outcomes because of dosimetric inaccuracies related to tumor motion and increased toxicity caused by the spread of low-dose radiation to normal tissues in patients with locally advanced non-small cell lung cancer (NSCLC) treated with intensity modulated radiation therapy (IMRT). We therefore performed a population-based comparative effectiveness analysis of IMRT, conventional 3-dimensional conformal radiation therapy (3D-CRT), and 2-dimensional radiation therapy (2D-RT) in stage III NSCLC. METHODS AND MATERIALS We used the Surveillance, Epidemiology, and End Results (SEER)-Medicare database to identify a cohort of patients diagnosed with stage III NSCLC from 2002 to 2009 treated with IMRT, 3D-CRT, or 2D-RT. Using Cox regression and propensity score matching, we compared survival and toxicities of these treatments. RESULTS The proportion of patients treated with IMRT increased from 2% in 2002 to 25% in 2009, and the use of 2D-RT decreased from 32% to 3%. In univariate analysis, IMRT was associated with improved overall survival (OS) (hazard ratio [HR] 0.90, P=.02) and cancer-specific survival (CSS) (HR 0.89, P=.02). After controlling for confounders, IMRT was associated with similar OS (HR 0.94, P=.23) and CSS (HR 0.94, P=.28) compared with 3D-CRT. Both techniques had superior OS compared with 2D-RT. IMRT was associated with similar toxicity risks on multivariate analysis compared with 3D-CRT. Propensity score matched model results were similar to those from adjusted models. CONCLUSIONS In this population-based analysis, IMRT for stage III NSCLC was associated with similar OS and CSS and maintained similar toxicity risks compared with 3D-CRT.

Importance of Radiation Oncologist Experience Among Patients With Head-and-Neck Cancer Treated With Intensity-Modulated Radiation Therapy

PURPOSE Over the past decade, intensity-modulated radiation therapy (IMRT) has replaced conventional radiation techniques in the management of head-and-neck cancers (HNCs). We conducted this population-based study to evaluate the influence of radiation oncologist experience on outcomes in patients with HNC treated with IMRT compared with patients with HNC treated with conventional radiation therapy. METHODS We identified radiation providers from Medicare claims of 6,212 Medicare beneficiaries with HNC treated between 2000 and 2009. We analyzed the impact of provider volume on all-cause mortality, HNC mortality, and toxicity end points after treatment with either conventional radiation therapy or IMRT. All analyses were performed by using either multivariable Cox proportional hazards or Fine-Gray regression models controlling for potential confounding variables. RESULTS Among patients treated with conventional radiation, we found no significant relationship between provider volume and patient survival or any toxicity end point. Among patients receiving IMRT, those treated by higher-volume radiation oncologists had improved survival compared with those treated by low-volume providers. The risk of all-cause mortality decreased by 21% for every additional five patients treated per provider per year (hazard ratio [HR], 0.79; 95% CI, 0.67 to 0.94). Patients treated with IMRT by higher-volume providers had decreased HNC-specific mortality (subdistribution HR, 0.68; 95% CI, 0.50 to 0.91) and decreased risk of aspiration pneumonia (subdistribution HR, 0.72; 95% CI, 0.52 to 0.99). CONCLUSION Patients receiving IMRT for HNC had improved outcomes when treated by higher-volume providers. These findings will better inform patients and providers when making decisions about treatment, and emphasize the critical importance of high-quality radiation therapy for optimal treatment of HNC.

Intensity-modulated radiotherapy for oral cavity squamous cell carcinoma: Patterns of failure and predictors of local control

PURPOSE Few studies have evaluated the use of intensity-modulated radiotherapy (IMRT) for squamous cell carcinoma (SCC) of the oral cavity (OC). We report clinical outcomes and failure patterns for these patients. METHODS AND MATERIALS Between October 2002 and June 2009, 37 patients with newly diagnosed SCC of the OC underwent postoperative (30) or definitive (7) IMRT. Twenty-five patients (66%) received systemic therapy. The median follow-up was 38 months (range, 10-87 months). The median interval from surgery to RT was 5.9 weeks (range, 2.1-10.7 weeks). RESULTS Thirteen patients experienced local-regional failure at a median of 8.1 months (range, 2.4-31.9 months), and 2 additional patients experienced local recurrence between surgery and RT. Seven local failures occurred in-field (one with simultaneous nodal and distant disease) and two at the margin. Four regional failures occurred, two in-field and two out-of-field, one with synchronous metastases. Six patients experienced distant failure. The 3-year actuarial estimates of local control, local-regional control, freedom from distant metastasis, and overall survival were 67%, 53%, 81%, and 60% among postoperative patients, respectively, and 60%, 60%, 71%, and 57% among definitive patients. Four patients developed Grade ≥ 2 chronic toxicity. Increased surgery to RT interval predicted for decreased LRC (p = 0.04). CONCLUSIONS Local-regional control for SCC of the OC treated with IMRT with or without surgery remains unsatisfactory. Definitive and postoperative IMRT have favorable toxicity profiles. A surgery-to-RT interval of < 6 weeks improves local-regional control. The predominant failure pattern was local, suggesting that both improvements in target delineation and radiosensitization and/or dose escalation are needed.

Cost-Effectiveness of Modern Radiotherapy Techniques in Locally Advanced Pancreatic Cancer

Radiotherapy may improve the outcome of patients with pancreatic cancer but at an increased cost. In this study, the authors evaluated the cost‐effectiveness of modern radiotherapy techniques in the treatment of locally advanced pancreatic cancer.