Triggering daily online adaptive radiotherapy in the pelvis: Dosimetric effects and procedural implications of trigger parameter-value selection.

BACKGROUND: Online adaptive radiotherapy (ART) can address dosimetric consequences of variations in anatomy by creating a new plan during treatment. However, ART is time- and labor-intensive and should be implemented in a resource-conscious way. Adaptive triggers composed of parameter-value pairs may direct the judicious use of online ART. PURPOSE: This work analyzed our clinical experience using CBCT-based daily online ART to demonstrate how a conceptual framework based on adaptive triggers affects the dosimetric and procedural impact of ART. METHODS: Sixteen patients across several pelvic sites were treated with CBCT-based daily online ART. Differences in standardized dose metrics were compared between the original plan, the original plan recalculated on the daily anatomy, and an adaptive plan. For each metric, trigger values were analyzed in terms of the proportion of treatments adapted and the distribution of metric values. RESULTS: Target coverage metrics were compromised due to anatomic variation with the average change per treatment ranging from -0.90 to -0.05 Gy, -0.47 to -0.02 Gy, -0.31 to -0.01 Gy, and -12.45% to -2.65% for PTV D99%, PTV D95%, CTV D99%, and CTV V100%, respectively. These were improved using the adaptive plan (-0.03 to 0.01 Gy, -0.02 to 0.00 Gy, -0.03 to 0.00 Gy, and -4.70% to 0.00%, respectively). Increasingly strict triggers resulted in a non-linear increase in the proportion of treatments adapted and improved the distribution of metric values with diminishing returns. Some organ-at-risk (OAR) metrics were compromised by anatomic variation and improved using the adaptive plan, but changes in most OAR metrics were randomly distributed. CONCLUSIONS: Daily online ART improved target coverage across multiple pelvic treatment sites and techniques. These effects were larger than those for OAR metrics, suggesting that maintaining target coverage was our primary benefit of CBCT-based daily online ART. Analyses like these can determine online ART triggers from a cost-benefit perspective.

Setup Accuracy in Craniospinal Irradiation: Implications for Planning Treatment Volume Margins.

PURPOSE: Craniospinal irradiation (CSI) using tomotherapy has advantages over standard 3-dimensional techniques. However, there is a paucity of published data on craniospinal setup reproducibility to guide appropriate planning treatment volume (PTV) margins. We sought to evaluate the setup accuracy of patients undergoing CSI to optimize PTV margins. METHODS AND MATERIALS: We measured residual setup deviation between simulation computed tomography (CT) and daily megavoltage CT after couch shifts made by therapists after megavoltage CT-based image registration for 10 patients who completed CSI at our institution. Translational displacement values were recorded at the sella, top of T1, and top of L5 in the anteroposterior (AP) and lateral planes. Systematic and random error were calculated from displacement values. Using z score analysis, we calculated minimal PTV margins to encompass 90% of recorded fractions at each level. We evaluated whether patient characteristics predict for increased setup error using standard statistical techniques. RESULTS: The mean setup deviation in the AP plane across all treatments was 2.49, 3.40, and 3.83 mm at the sella, T1, and L5, respectively. Mean lateral setup error was 2.86, 4.02, and 5.46 mm at the sella, T1, and L5, respectively. Systematic error ranged from 0.75 to 1.01 mm at the sella, 1.09 to 1.37 mm at T1, and 1.30 to 1.50 mm at L5. Random error ranged from 1.35 to 1.41 mm at the sella, 1.48 to 1.73 mm at T1, and 2.26 to 2.37 mm at L5. The minimum margin to cover 90% of the treatments was 6.4, 8.2, and 10.5 mm at the sella, T1, and L5, respectively. There appeared to be a correlation between older age and lateral setup error in the L spine approaching statistical significance (R, 0.629; P = .052). CONCLUSIONS: Setup error increases in the caudal direction of the spine and is greater in the lateral plane compared with the AP plane. We recommend a PTV margin of 5 to 7 mm in the brain and 10 mm in the spine.

Palliative Radiation for Cancer Pain Management.

Bone metastases are the most common cause of cancer-related pain. Radiation therapy (RT) is a very common and effective treatment to relieve pain. Conventionally fractionated RT typically consists of the following regimens: 8 Gy in a single treatment, 20 Gy in five fractions, 24 Gy in six fractions, or 30 Gy in ten fractions. All treatment regimens have similar rates of pain relief (range 50-80%), with single-fraction treatment often requiring retreatment. While many painful bony metastases can be managed with RT alone, some may be more complex, often requiring multidisciplinary management, including the need for surgical stabilization or augmentation prior to RT. There are multiple assessment tools including the neurologic, oncologic, mechanical, and systemic (NOMS) decision framework, which allows clinicians to assess the proper course of treatment for these patients. For patients with good prognosis, oligometastatic disease, or those presenting with more radioresistant tumors, stereotactic body radiotherapy (SBRT) may be another option, which offers ablative doses of radiation delivered over several treatments. This chapter reviews the fundamentals of RT for palliation.

Factors predictive of 90-day mortality after surgical resection for oral cavity cancer: Development of a recursive partitioning analysis for risk stratification.

BACKGROUND: Factors that influence postoperative mortality (POM) have been identified, but a predictive model to guide clinicians treating oral cavity cancer (OCC) has not been well established. METHODS: Patients with OCC undergoing upfront surgical resection were included. Primary outcome was 90-day POM (90dPOM). RESULTS: 33 845 were identified using the National Cancer Database. Rate of 90dPOM was 3.2%. Predictors of higher 90dPOM include older age, higher comorbidity scores, nonprivate insurance, lower income, treatment in an academic facility, higher T- and N-classification, radical excision, and presence of positive margins. On RPA, two high-risk (90dPOM > 10%) patient subsets were identified: patients ≥80 years of age with T3-4 disease and patients <80 years, with any comorbidity and T3-4, N2-3 disease. CONCLUSIONS: We identified a subset of patients in this cohort who are at high risk for 90dPOM. These patients may warrant additional perioperative and postoperative monitoring in addition to better preoperative assessment and screening.

Dosimetric comparison of multiple vs single isocenter technique for linear accelerator-based stereotactic radiosurgery: The Importance of the six degree couch.

PURPOSE: Single isocenter technique (SIT) for linear accelerator-based stereotactic radiosurgery (SRS) is feasible. However, SIT introduces the potential for rotational error which can lead to geographical miss. Additional planning treatment volume (PTV) margin is required when using SIT. With the six degrees of freedom (6DoF) couch, rotational error can be minimized. We sought to evaluate the effect of the 6DoF couch on the dosimetry of patients with multiple brain metastases treated with SIT. MATERIALS AND METHODS: Ten consecutive patients treated with SRS to ≥3 metastases were identified. Original treatments had MIT plans (MITP). The lesions were replanned using SIT. Lesions 5-10 cm from isocenter had an additional 1mm of margin. Patients were replanned with these additional margins to account for inability to correct rotational error (SITPM). Multiple dosimetric variables and time metrics were evaluated. Dosimetry planning time (DPT) and patient treatment time (PTT) were evaluated. Statistics were calculated using the Wilcoxon signed-rank test. RESULTS: A total of 73 brain metastases receiving SRS, to a median of 6 lesions per patient, were identified. MITPs treated 73 lesions with 63 isocenters. On average, MITPs had a 19.2% higher brain V12 than SITPs (P = 0.017). For creation of SITPM, 30 lesions required 1 mm of additional margin, while none required 2 mm of margin. This increased V12 by 47.8% on average per patient (P = 0.008) from SITP to SITPM. DPT was 5.5 hours for SITP, while median for MITP was 12.5 hours (P = 0.005) PTT was 30 minutes for SITP, while median for MITP was 144 minutes (P = 0.005). CONCLUSIONS: SITPs are comparable to MITPs if rotational error can be corrected with the use of a 6DoF couch. Increasing margin to account for rotational error leads to a nearly 50% increase in V12, which could result in higher rates of radiation necrosis. Time savings are significant using SIT.

Disparate outcomes in nonsmall cell lung cancer by immigration status.

OBJECTIVE: The purpose of this study was to evaluate overall survival (OS) outcomes by race, stratified by country of origin in patients diagnosed with NSCLC in California. METHODS: We performed a retrospective analysis of nonsmall cell lung cancer (NSCLC) patients diagnosed between 2000 and 2012. Race/ethnicity was defined as White (W), Black (B), Hispanic (H), and Asian (A) and stratified by country of origin (US vs. non-US [NUS]) creating the following patient cohorts: W-US, W-NUS, B-US, B-NUS, H-US, H-NUS, A-US, and A-NUS. Three multivariate models were created: model 1 adjusted for age, gender, stage, year of diagnosis and histology; model 2 included model 1 plus treatment modalities; and model 3 included model 2 with the addition of socioeconomic status, marital status, and insurance. RESULTS: A total of 68,232 patients were included. Median OS from highest to lowest were: A-NUS (15 months), W-NUS (14 months), A-US (13 months), B-NUS (13 months), H-US (11 months), W-US (11 months), H-NUS (10 months), and B-US (10 months) (p < 0.001). In model 1, B-US had worse OS, whereas A-US, W-NUS, B-NUS, H-NUS, and A-NUS had better OS when compared to W-US. In model 2 after adjusting for receipt of treatment, there was no difference in OS for B-US when compared to W-US. After adjusting for all variables (model 3), all race/ethnicity profiles had better OS when compared to W-US; B-NUS patients had similar OS to W-US. CONCLUSION: Foreign-born patients with NSCLC have decreased risk of mortality when compared to native-born patients in California after accounting for treatments received and socioeconomic differences.

Dosimetric Predictors of Genitourinary Toxicity From a Phase I Trial of Prostate Bed Stereotactic Body Radiation Therapy.

PURPOSE: Our purpose was to analyze dose-volume parameters associated with genitourinary (GU) toxicity from a phase I clinical trial of prostate bed stereotactic body radiation therapy. METHODS AND MATERIALS: Patients were treated in escalating dose levels of 35, 40, and 45 Gy, over 5 fractions. Data from all 26 patients enrolled in the protocol were analyzed using multiple dose-volume cut points for multiple GU organs at risk. Univariate logistical regression and Fisher exact test were used to assess statistical significance associated with incidence of toxicity. RESULTS: The median follow-up was 36 months for all patients. Acute GU toxicity was mild and resolved spontaneously. Eight out of 26 patients (30.7%) developed late GU toxicity of grade 2 or higher. Two patients developed grade 3 ureteral stenosis, 1 in the 35 Gy arm and the other in the 45 Gy arm. Three patients developed grade 2 or higher hematuria/cystitis, and 3 developed grade 2 or higher incontinence. Incidence of grade 3 ureteral stenosis was related to the absolute volume of bladder wall receiving greater than 20, 25, and 30 Gy (P < .01). Grade 2 cystitis and hematuria were related to the volume of bladder wall receiving 20 Gy less than 34% and 35 Gy less than 25% (18.8% vs 60% and 23.8% vs 80%, respectively, P < .05). Incontinence was related to mean urethral dose less than 35 Gy and 25 Gy (4.3% vs 66.7% and 0% vs 37.5%, respectively, P < .05) and volume of urethra receiving 35 Gy less than 24% (8.3% vs 50%, P < .05). CONCLUSIONS: This is the first analysis to report dose-volume thresholds associated with late GU toxicity in patients receiving prostate bed stereotactic body radiation therapy. We recommend limiting the bladder wall receiving 25 Gy to less than 18 cubic centimeters to reduce the risk for late grade 3 ureteral stenosis.

Machine Learning-Based Interpretation and Visualization of Nonlinear Interactions in Prostate Cancer Survival.

PURPOSE: Shapley additive explanation (SHAP) values represent a unified approach to interpreting predictions made by complex machine learning (ML) models, with superior consistency and accuracy compared with prior methods. We describe a novel application of SHAP values to the prediction of mortality risk in prostate cancer. METHODS: Patients with nonmetastatic, node-negative prostate cancer, diagnosed between 2004 and 2015, were identified using the National Cancer Database. Model features were specified a priori: age, prostate-specific antigen (PSA), Gleason score, percent positive cores (PPC), comorbidity score, and clinical T stage. We trained a gradient-boosted tree model and applied SHAP values to model predictions. Open-source libraries in Python 3.7 were used for all analyses. RESULTS: We identified 372,808 patients meeting the inclusion criteria. When analyzing the interaction between PSA and Gleason score, we demonstrated consistency with the literature using the example of low-PSA, high-Gleason prostate cancer, recently identified as a unique entity with a poor prognosis. When analyzing the PPC-Gleason score interaction, we identified a novel finding of stronger interaction effects in patients with Gleason ≥ 8 disease compared with Gleason 6-7 disease, particularly with PPC ≥ 50%. Subsequent confirmatory linear analyses supported this finding: 5-year overall survival in Gleason ≥ 8 patients was 87.7% with PPC < 50% versus 77.2% with PPC ≥ 50% (P < .001), compared with 89.1% versus 86.0% in Gleason 7 patients (P < .001), with a significant interaction term between PPC ≥ 50% and Gleason ≥ 8 (P < .001). CONCLUSION: We describe a novel application of SHAP values for modeling and visualizing nonlinear interaction effects in prostate cancer. This ML-based approach is a promising technique with the potential to meaningfully improve risk stratification and staging systems.

Temporal Trends of Resident Experience in External Beam Radiation Therapy Cases: Analysis of ACGME Case Logs from 2007 to 2018.

PURPOSE: We sought to characterize temporal trends of radiation oncology resident-reported external beam radiation therapy (EBRT) case experience with respect to various disease sites, including trends in stereotactic radiosurgery and stereotactic body radiation therapy cases. METHODS AND MATERIALS: Summarized, deidentified case logs for graduating radiation oncology residents between 2007 and 2018 were obtained from the Accreditation Council for Graduate Medical Education national summary data report. Mean number of cumulative cases and standard deviations per graduating resident by year were evaluated. Cases were subdivided into 12 disease-site categories using the Accreditation Council for Graduate Medical Education classification. Analysis of variance was used to determine significant differences, and strength of association was evaluated using Pearson correlation. RESULTS: The number of graduating residents per year increased by 66% from 114 in 2007 to 189 in 2018 (P < .001, r = 0.88). The overall mean number of EBRT cases per graduating resident decreased by 13.2% from 521.9 in 2007 to 478.5 in 2018, with a decrease in the ratio of nonmetastatic to metastatic cases per graduating resident. There was significant variation among the disease categories analyzed; however, the largest proportionate decreases were seen in hematologic, lung, and genitourinary malignancies. Stereotactic radiosurgery volume per graduating resident increased from an average of 27.9 cases in 2007 to 50.3 in 2018 (P < .001, r = 0.96). Stereotactic body radiation therapy volume per graduating resident increased as well, from a mean of 6 cases in 2007 to 55.6 cases in 2018 (P < .001, r = 0.99). CONCLUSIONS: We report a longitudinal summary of resident-reported experience in EBRT cases. These findings have implications for future efforts to optimize residency training programs and requirements.

Resident experience in brachytherapy: An analysis of Accreditation Council for Graduate Medical Education case logs for intracavitary and interstitial brachytherapy from 2007 to 2018.

PURPOSE: We sought to characterize temporal trends of radiation oncology resident-reported case experience with intracavitary brachytherapy (ICBT) and interstitial brachytherapy (ISBT). METHODS AND MATERIALS: Summarized, deidentified case logs for graduating radiation oncology residents (GRORs) between 2007 and 2018 were obtained from the Accreditation Council for Graduate Medical Education national summary data report. Cases were subdivided based on the site of treatment. Analysis of variance was used to determine differences, and strength of association was evaluated using the Pearson correlation. RESULTS: The number of GRORs increased by 66% from 114 in 2007 to 189 in 2018 (p < 0.001). Average number of gynecologic ICBT cases per GROR increased, from 39.6 in 2007 to 48.7 in 2018 (p < 0.005). Average number of ISBT cases per GROR decreased, from 34.5 to 20.6 (p < 0.001), due to decreasing prostate volume, from 21.5 to 12 (p < 0.001). Experience with gynecologic ISBT cases remained low at an average of 4.5 cases per year. CONCLUSIONS: The average number of ICBT cases per GROR has increased, although this does not differentiate between cylinder and tandem-based insertions currently. There has been a steady decline in ISBT experience. These findings may have implications for the development of Accreditation Council for Graduate Medical Education case minimums for residency programs.

Impact of Surgical Resection on Survival Outcomes After Chemoradiotherapy in Anal Adenocarcinoma.

BACKGROUND: Anal adenocarcinoma is a rare malignancy with a poor prognosis, and no randomized data are available to guide management. Prior retrospective analyses offer differing conclusions on the benefit of surgical resection after chemoradiotherapy (CRT) in these patients. We used the National Cancer Database (NCDB) to analyze survival outcomes in patients undergoing CRT with and without subsequent surgical resection. METHODS: Patients with adenocarcinoma of the anus diagnosed in 2004 through 2015 were identified using the NCDB. Patients with metastatic disease and survival <90 days were excluded. We analyzed patients receiving CRT and stratified by receipt of surgical resection. Logistic regression was used to evaluate predictors of use of surgery and to form a propensity score-matched cohort. Overall survival (OS) was compared between treatment strategies using Cox proportional hazards regression. RESULTS: We identified 1,747 patients with anal adenocarcinoma receiving CRT, of whom 1,005 (58%) received surgery. Predictors of increased receipt of surgery included age <65 years, private insurance, overlapping involvement of the anus and rectum, N0 disease, and external-beam radiation dose ≥4,000 cGy. With a median follow-up of 3.5 years, 5-year OS was 61.1% in patients receiving CRT plus surgery compared with 39.8% in patients receiving CRT alone (log-rank P<.001). In multivariate analysis, surgery was associated with significantly improved OS (hazard ratio, -0.59; 95% CI, 0.50-0.68; P<.001). This survival benefit persisted in a propensity score-matched cohort (log-rank P<.001). CONCLUSIONS: In the largest series of anal adenocarcinoma cases to date, treatment with CRT followed by surgery was associated with a significant survival benefit compared with CRT alone in propensity score-matching analysis. Our findings support national guideline recommendations of neoadjuvant CRT followed by resection for patients with anal adenocarcinoma.

A proposal for a new classification of "unfavorable risk criteria" in patients with stage I endometrial cancer.

BACKGROUND: Randomized trials describe differing sets of high-intermediate risk criteria. OBJECTIVE: To use the National Cancer Database to compare the impact of radiation therapy in patients with stage I endometrial cancer meeting different criteria, and define a classification of "unfavorable risk." METHODS: Patients with stage I endometrial cancer between January 2010 and December 2014 were identified in the National Cancer Database and stratified into two cohorts: (1) patients meeting Gynecologic Oncology Group (GOG)-99 criteria only for high-intermediate risk, but not Post-Operative Radiation Therapy in Endometrial Carcinoma (PORTEC)-1 criteria and (2) those meeting PORTEC-1 criteria only. High-risk stage I patients with both FIGO stage IB (under FIGO 2009 staging) and grade 3 disease were excluded. In each cohort, propensity score-matched survival analyses were performed. Based on these analyses, we propose a new classification of unfavorable risk. We then analyzed the association of adjuvant radiation with survival, stratified by this classification. RESULTS: We identified 117,272 patients with stage I endometrial cancer. Of these, 11,207 patients met GOG-99 criteria only and 5,920 patients met PORTEC-1 criteria only. After propensity score matching, adjuvant radiation therapy improved survival (HR=0.73; 95% CI 0.60 to 0.89; p=0.002) in the GOG-99 only cohort. However, there was no benefit of adjuvant radiation (HR=0.89; 95% CI 0.69 to 1.14; p=0.355) in the PORTEC-1 only cohort. We, therefore, defined unfavorable risk stage I endometrial cancer as two or more of the following risk factors: lymphovascular invasion, age ≥70, grade 2-3 disease, and FIGO stage IB. Adjuvant radiation improved survival in stage I patients with adverse risk factors (HR=0.74; 95% CI 0.68 to 0.80; p<0.001), but not in other stage I patients (HR=1.02; 95% CI 0.91 to 1.15; p=0.710; p interaction <0.001). CONCLUSION: Our study showed that adjuvant radiation was associated with an overall survival benefit in patients meeting GOG-99 criteria only; however, no survival benefit was seen in patients meeting PORTEC-1 criteria only. We propose a definition of unfavorable risk stage I endometrial cancer: ≥2 risk factors from among lymphovascular invasion, age ≥70, grade 2-3 disease, and FIGO stage IB disease.

The evolving role of radiation therapy for resectable and unresectable gastric cancer.

Gastric cancer is a common malignancy worldwide, and treatment of localized disease has shifted from surgery alone to the addition of chemotherapy at various stages in treatment. The role of radiation in the management of gastric cancer has evolved significantly since the seminal publication of INT 0116 demonstrated a survival advantage to adjuvant chemoradiation. In this review, we summarize multiple landmark studies discussing the role of radiation in non-metastatic gastric cancer, both in resectable and unresectable patients. This review will additionally discuss the evidence for pre-operative chemoradiation, as the benefit has already been demonstrated in esophageal and rectal cancer.

Role of Locoregional Treatment in Vulvar Cancer With Pelvic Lymph Node Metastases: Time to Reconsider FIGO Staging?

BACKGROUND: Vulvar cancer with pelvic nodal involvement is considered metastatic (M1) disease per AJCC staging. The role of definitive therapy and its resulting impact on survival have not been defined. PATIENTS AND METHODS: Patients with pelvic lymph node-positive vulvar cancer diagnosed in 2009 through 2015 were evaluated from the National Cancer Database. Patients with known distant metastatic disease were excluded. Logistic regression was used to evaluate use of surgery and radiation therapy (RT). Overall survival (OS) was evaluated with log-rank test and Cox proportional hazards modeling (multivariate analysis [MVA]). A 2-month conditional landmark analysis was performed. RESULTS: A total of 1,304 women met the inclusion criteria. Median follow-up was 38 months for survivors. Chemotherapy, RT, and surgery were used in 54%, 74%, and 62% of patients, respectively. Surgery was associated with prolonged OS (hazard ratio [HR], 0.58; P<.001) but had multiple significant differences in baseline characteristics compared with nonsurgical patients. In patients managed nonsurgically, RT was associated with prolonged OS (HR, 0.66; P=.019) in MVA. In patients undergoing surgery, RT was associated with better OS (3-year OS, 55% vs 48%; P=.033). Factors predicting use of RT were identified. MVA revealed that RT was associated with prolonged OS (HR, 0.75; P=.004). CONCLUSIONS: In this cohort of women with vulvar cancer and positive pelvic lymph nodes, use of RT was associated with prolonged survival in those who did not undergo surgery. Surgery followed by adjuvant RT was associated with prolonged survival compared with surgery alone.

Analyzing the impact of neoadjuvant radiation dose on pathologic response and survival outcomes in esophageal and gastroesophageal cancers.

BACKGROUND: The optimal neoadjuvant radiation therapy (RT) dose prior to esophagectomy is unknown. We compared patients receiving lower-dose RT (LD-RT) of 41.4-45 Gy versus those receiving higher-dose RT (HD-RT) of 50-54 Gy. METHODS: Patients with non-metastatic esophageal or gastroesophageal cancer diagnosed from 2004 to 2015 who underwent neoadjuvant chemoradiation (CRT) followed by esophagectomy were identified using the National Cancer Database (NCDB) and divided into LD-RT and HD-RT groups. Logistic regression was used to evaluate predictors of HD-RT utilization and propensity score matching. Overall survival (OS) was compared between HD-RT and LD-RT groups using Cox regression. Logistic regression was performed with respect to pathologic complete response (pCR), positive surgical margins, postoperative mortality, and readmission rates. RESULTS: We identified 7,996 patients meeting inclusion criteria, of which 5,732 (71.7%) received HD-RT. At median follow-up of 3.3 years, 3-year OS was 48.7% for HD-RT versus 48.4% for LD-RT (P=0.734). pCR rates were 20.3% with HD-RT versus 16.3% with LD-RT [odds ratio (OR) 1.24; 95% CI: 1.06-1.44; P=0.006]. There were no statistically significant differences between HD-RT and LD-RT with respect to positive margins, 90-day postoperative mortality, or readmission rates. In a separate analysis of patients treated with CRT alone and no subsequent esophagectomy, HD-RT was associated with improved OS (HR 0.83; 95% CI: 0.78-0.88; P<0.001). CONCLUSIONS: Our analysis suggests that 41.4-45 and 50-54 Gy dose regimens are similar in survival and postoperative outcomes. However, in cases of equivocal resectability, a higher RT dose of 50-54 Gy may be preferred.

Radiation-Related Toxicities Using Organ Sparing Total Marrow Irradiation Transplant Conditioning Regimens.

PURPOSE: Toxicities after organ sparing myeloablative total marrow irradiation (TMI) conditioning regimens have not been well characterized. The purpose of this study is to report pulmonary, renal, thyroid, and cataract toxicities from a prospective trial monitoring patients up to 8 years after TMI. METHODS AND MATERIALS: A total of 142 patients with primarily multiple myeloma or acute leukemia undergoing hematopoietic cell transplantation were evaluated. Follow-up included pulmonary function tests, serum creatinine, glomerular filtration rate, thyroid panel, and ophthalmologic examinations performed at 100 days, 6 months, and annually. Median TMI dose was 14 Gy (10-19 Gy) delivered at 1.5 to 2.0 Gy twice per day at a dose-rate of 200 cGy/min. RESULTS: Median age was 52 years (range 9-70). Median follow-up (range) for all patients was 2 years (0-8) and for patients alive at the time of last follow-up (n = 50), 5.5 years (0-8). Mean organ doses in Gy were lung 7.0, kidneys 7.1, thyroid 6.7, and lens 2.8. The crude incidence of radiation pneumonitis (RP) was 1 of 142 (0.7%). The cumulative incidence of infection and RP (I/RP) was 22.7% at 2 years post-TMI. Mean lung dose ≤8 Gy predicted for significantly lower rates of I/RP (2-year cumulative incidence 20.8% vs 31.8%, P = .012). No radiation-induced renal toxicity was noted. Hypothyroidism occurred in 6.0% and cataract formation in 7.0% of patients. CONCLUSIONS: TMI delivered with intensity modulated radiation therapy results in lower organ doses and was associated with fewer toxicities compared with historical cohorts treated with conventional total body irradiation. Keeping the mean lung dose to 8 Gy or less was associated with lower pulmonary complications. Further evaluation in clinical trials of intensity modulated radiation therapy to deliver TMI, total marrow and lymphoid irradiation, and organ sparing conformal total body irradiation is warranted.

The role of sequential radiation following adjuvant chemotherapy in resected pancreatic cancer.

BACKGROUND: Optimal adjuvant therapy for resectable pancreatic cancer remains controversial. The Radiation Therapy Oncology Group (RTOG) 0848 is evaluating adjuvant chemotherapy (CT) with or without sequential chemoradiation in the absence of disease progression. In the absence of completed RTOG 0848 data, we addressed the question through a retrospective analysis. METHODS: The National Cancer Database was queried for non-metastatic, histologically-confirmed pancreatic carcinoma status post resection and adjuvant CT. Patients receiving neoadjuvant therapy were excluded. Multivariable logistic regression was performed to identify factors associated with receipt of sequential radiation therapy (RT) starting at least 4 months after CT, with generation of propensity scores. Log-rank analysis assessed univariate overall survival (OS), while multivariable Cox proportional hazards modeling examined multivariate OS. Six-month landmark analysis was performed to allow for completion of all planned adjuvant therapy. RESULTS: Of 15,661 patients, 14,167 (90.5%) underwent CT alone, and 1,494 (9.5%) received RT. Patients receiving RT had nodal disease and R+ resection more often (P<0.05). Median follow-up was 53.6 months. Sequential RT after adjuvant CT improved outcomes compared to adjuvant CT alone (3-year OS 44.6% vs. 35.3%; P<0.001). On multivariate analysis, sequential RT continued to improve OS (HR =0.68; 95% CI, 0.63-0.73; P<0.001). After propensity score adjustment, the benefit of sequential RT was maintained (HR =0.68, P<0.001). CONCLUSIONS: Sequential RT after adjuvant CT for resected pancreatic cancer was associated with improved survival. The final results of RTOG 0848 are eagerly awaited to provide definitive evidence in this clinical scenario.

The Effect of Time to Postoperative Radiation Therapy on Survival in Resected Merkel Cell Carcinoma.

OBJECTIVES: Delays from surgery to adjuvant radiation therapy (aRT) are associated with poorer prognosis in multiple neoplasms. Presently, no data exist for Merkel cell carcinoma (MCC). The authors sought to assess the time interval from surgery to aRT and effect on outcomes in MCC. MATERIALS AND METHODS: The National Cancer Database was queried for histologically confirmed nonmetastatic MCC status post resection and aRT diagnosed between 2004 and 2015 who received aRT within 24 weeks of surgery. Kaplan-Meier analysis assessed univariate overall survival (OS); multivariable Cox proportional hazards modeling assessed multivariate OS; χ and logistic regression assessed differences in baseline characteristics and predictors of delayed aRT. RESULTS: Of 5952 patients meeting criteria, 13% commenced aRT within 4 weeks, 48% between 4 and 7 weeks, 23% between 8 and 11 weeks, 11% between 12 and 15 weeks, and 6% between 16 and 24 weeks. There were no differences in OS on the basis of the surgery-aRT interval (P=0.99). Predictors of worse OS on the multivariate analysis included advanced age, greater comorbidities, male sex, lower regional income, earlier year of diagnosis, more advanced tumor and nodal staging, positive margins, head and neck location, and treatment at community facilities (P<0.05 for all). Factors predictive of delayed aRT were identified. Subset analyses on these factors, such as receipt of chemotherapy or positive lymph nodes, did not demonstrate that the timing of aRT affected survival (P≥0.37). CONCLUSION: This study of a contemporary national database revealed that delays from resection to aRT were not associated with survival in MCC, somewhat discordant from other malignancies such as squamous cell carcinoma.