Genomic Landscape of Adenocarcinomas Across the Gastroesophageal Junction: Moving on from the Siewert Classification.

OBJECTIVE: To investigate how the Siewert classification of gastroesophageal junction adenocarcinomas correlates with genomic profiles. SUMMARY/BACKGROUND DATA: Current staging and treatment guidelines recommend that tumors with an epicenter less than 2 cm into the gastric cardia be treated as esophageal cancers, while tumors with epicenter greater than 2 cm into the cardia be staged and treated as gastric cancers. To date, however, few studies have compared the genomic profiles of the 3 Siewert classification groups to validate this distinction. METHODS: Using targeted tumor sequencing data on patients with adenocarcinoma of the gastroesophageal junction previously treated with surgery at our institution, we compared genomic features across Siewert classification groups. RESULTS: A total of 350 patients were included: 121 had Siewert type I, 170 type II, and 59 type III. Comparisons by Siewert location revealed that Siewert type I and II were primarily characterized as the chromosomal instability (CIN) molecular subtype and displayed Barrett's metaplasia and p53 and cell cycle pathway dysregulation. Siewert type III tumors, by contrast, were more heterogeneous, including higher proportions of microsatellite instability (MSI) and genomically stable (GS) tumors and more frequently displayed ARID1A and somatic CDH1 alterations, signet ring cell features, and poor differentiation. Overall, Siewert type I and II tumors demonstrated greater genomic overlap with lower esophageal tumors, while Siewert type III tumors shared genomic features with gastric tumors. CONCLUSIONS: Overall, our results support recent updates in treatment and staging guidelines. Ultimately, however, molecular rather than anatomic classification may prove more valuable in determining staging, treatment, and prognosis.

Penile-scrotal erythrodysesthesia among rectal cancer patients receiving fluoropyrimidine-based chemoradiation: a case report series.

BACKGROUND: Palmar-plantar erythrodysesthesia (PPE) is a slowly developing cutaneous reaction commonly experienced by patients treated with fluoropyrimidines. While erythrodysesthesia normally presents in a palmar-plantar distribution, it can also present with genital involvement, but this presentation is likely underreported and incorrectly attributed to an acute reaction from radiation therapy. This article aims to define erythrodysesthesia of the penis and scrotum as a rare but significant side effect of capecitabine. CASE PRESENTATION: We identified five cases of moderate to severe penis and scrotal erythrodysesthesia over a 2-year period at a large tertiary cancer center, representing an estimated incidence of 3.6% among male patients with rectal cancer who were treated with fluoropyrimidine-based chemoradiation within our institution. CONCLUSIONS: Improved understanding of erythrodysesthesia involving the penis and scrotum can facilitate early identification and treatment of symptoms, and possibly prevent the discontinuation or delay of cancer treatment in patients treated with capecitabine and similar drugs. These clinical advances would improve and prolong patient quality of life during cancer treatment and prevent complications that result in hospitalization.

Incidence and management of esophageal cancer recurrence to regional lymph nodes after curative esophagectomy.

Up to 50% of patients treated with curative esophagectomy for esophageal cancer will develop recurrence, contributing to the dismal survival associated with this disease. Regional recurrence may represent disease that is not yet widely metastatic and may therefore be amenable to more-aggressive treatment. We sought to assess all patients treated with curative esophagectomy for esophageal cancer who developed regional recurrence. We retrospectively identified all patients who underwent esophagectomy for esophageal adenocarcinoma and esophageal squamous cell carcinoma at a single institution from January 2000 to August 2019. In total, 1626 patients were included in the study cohort. As of June 2022, 595 patients had disease recurrence, which was distant or systemic in 435 patients (27%), regional in 125 (7.7%) and local in 35 (2.2%). On multivariable analysis, neoadjuvant chemoradiation with a total radiation dose <45 Gy (hazard ratio [HR], 3.5 [95% CI, 1.7-7.3]; P = .001), pathologic node-positive disease (HR, 1.9 [95% CI, 1.3-3.0]; P = .003) and lymphovascular invasion (HR, 1.6 [95% CI, 1.0-2.5]; P = .049) were predictors of isolated nodal recurrence, whereas increasing age (HR, 0.97 [95% CI, 0.96-0.99]; P = .001) and increasing number of excised lymph nodes (HR, 0.98 [95% CI, 0.95-1.00]; P = .021) were independently associated with decreased risk of regional recurrence. Patients treated with a combination of local and systemic therapies had better survival outcomes than patients treated with systemic therapy alone (P < .001). In patients with recurrence of esophageal cancer limited to regional lymph nodes, salvage treatment may be possible. Higher radiation doses and more-extensive lymphadenectomy may reduce the risk of regional recurrence.

Induction FOLFOX and PET-Directed Chemoradiation for Locally Advanced Esophageal Adenocarcinoma.

OBJECTIVE: To compare the efficacy and safety of induction FOLFOX followed by PET-directed nCRT, induction CP followed by PET-directed nCRT, and nCRT with CP alone in patients with EAC. SUMMARY OF BACKGROUND DATA: nCRT with CP is a standard treatment for locally advanced EAC. The results of cancer and leukemia group B 80803 support the use of induction chemotherapy followed by PET-directed chemo-radiation therapy. METHODS: We retrospectively identified all patients with EAC who underwent the treatments above followed by esophagectomy. We assessed incidences of pathologic complete response (pCR), near-pCR (ypN0 with ≥90% response), and surgical complications between treatment groups using Fisher exact test and logistic regression; disease-free survival (DFS) and overall survival (OS) were estimated by the Kaplan-Meier method and evaluated using the log-rank test and extended Cox regression. RESULTS: In total, 451 patients were included: 309 (69%) received induction chemotherapy before nCRT (FOLFOX, n = 70; CP, n = 239); 142 (31%) received nCRT with CP. Rates of pCR (33% vs. 16%, P = 0.004), near-pCR (57% vs. 33%, P < 0.001), and 2-year DFS (68% vs. 50%, P = 0.01) were higher in the induction FOLFOX group than in the induction CP group. Similarly, the rate of near-pCR (57% vs. 42%, P = 0.04) and 2-year DFS (68% vs. 44%, P < 0.001) were significantly higher in the FOLFOX group than in the no-induction group. CONCLUSIONS: Induction FOLFOX followed by PET-directed nCRT may result in better histopathologic response rates and DFS than either induction CP plus PET-directed nCRT or nCRT with CP alone.

Waiting to Operate: The Risk of Salvage Esophagectomy.

OBJECTIVE: To assess postoperative morbidity, disease-free survival (DFS), and overall survival (OS) in patients treated with salvage esophagectomy (SE). BACKGROUND DATA: A shift toward a "surgery as needed" approach for esophageal cancer has emerged, potentially resulting in delayed esophagectomy. METHODS: We identified patients with clinical stage I-III esophageal adenocarcinoma or squamous cell carcinoma who underwent chemoradiation followed by esophagectomy from 2001 to 2019. SE was defined as esophagectomy performed >90 days after chemoradiation ("for time") and esophagectomy performed for recurrence after curative-intent chemoradiation ("for recurrence"). The odds of postoperative serious complications were assessed by multivariable logistic regression. The relationship between SE and OS and DFS were quantified using Cox regression models. RESULTS: Of 1137 patients identified, 173 (15%) underwent SE. Of those, 61 (35%) underwent SE for recurrence, and 112 (65%) underwent SE for time. The odds of experiencing any serious complication [odds ratio, 2.10 (95% CI, 1.37-3.20); P =0.001] or serious pulmonary complication [odds ratio, 2.11 (95% CI, 1.31-3.42); P =0.002] were 2-fold higher for SE patients; SE patients had a 1.5-fold higher hazard of death [hazard ratio, 1.56 (95% CI, 1.25-1.94); P <0.0001] and postoperative recurrence [hazard ratio, 1.43 (95% CI, 1.16-1.77); P =0.001]. Five-year OS for nonsalvage esophagectomy was 45% [(95% CI, 41.6%-48.6%) versus 26.5% (95% CI, 20.2%-34.8%) for SE (log-rank P <0.001)]. Five-year OS for SE for time was 27.1% [(95% CI, 19.5%-37.5%) versus 25.2% (95% CI, 15.3%-41.5%) for SE for recurrence ( P =0.611)]. CONCLUSIONS: SE is associated with a higher risk of serious postoperative complications and shorter DFS and OS.

Durvalumab and PET-Directed Chemoradiation in Locally Advanced Esophageal Adenocarcinoma: A Phase Ib/II Study.

OBJECTIVE: To determine the safety and efficacy of adding the anti-PD-L1 antibody durvalumab to induction FOLFOX and preoperative chemotherapy in locally advanced esophageal adenocarcinoma. BACKGROUND: Neoadjuvant induction FOLFOX followed by positron emission tomography (PET) directed chemoradiation has demonstrated improved survival for esophageal adenocarcinoma. There is clear benefit now for the addition of immune checkpoint inhibitors both in early and advanced stage disease. Given these results we investigated the safety and efficacy of adding durvalumab to induction FOLFOX and preoperative chemoradiotherapy. METHODS: Patients with locally advanced resectable esophageal/gastroesophageal junction adenocarcinoma received PET-directed chemoradiation with durvalumab before esophagectomy. Patients who had R0 resections received adjuvant durvalumab 1500 mg every 4 weeks for 6 treatments. The primary endpoint of the study was pathologic complete response. RESULTS: We enrolled 36 patients, 33 of whom completed all preoperative treatment and underwent surgery. Preoperative treatment was well tolerated, with no delays to surgery nor new safety signals. Pathologic complete response was identified in 8 [22% (1-sided 90% lower bound: 13.3%)] patients with major pathologic response in 22 [61% (1-sided 90% lower bound: 50%)] patients. Twelve and 24-month overall survival was 92% and 85%, respectively. CONCLUSIONS: The addition of durvalumab to induction FOLFOX and PET-directed chemoradiotherapy before surgery is safe, with a high rate of pathologic response, as well as encouraging survival data.

A More Extensive Lymphadenectomy Enhances Survival After Neoadjuvant Chemoradiotherapy in Locally Advanced Esophageal Adenocarcinoma.

OBJECTIVE: We sought to determine the extent of lymphadenectomy that optimizes staging and survival in patients with locally advanced EAC treated with neoadjuvant chemoradiotherapy followed by esophagectomy. SUMMARY OF BACKGROUND DATA: Several studies have found that a more extensive lymphadenectomy leads to better disease-specific survival in patients treated with surgery alone. Few studies, however, have investigated whether this association exists for patients treated with neoadjuvant chemoradiotherapy. METHODS: We examined our prospective database and identified patients with EAC treated with neoadjuvant chemoradiotherapy followed by esophagectomy between 1995 and 2017. Overall survival (OS) and DFS were estimated using Kaplan-Meier methods, and a multivariable Cox proportional hazards model was used to identify independent predictors of OS and DFS. The relationship between the total number of nodes removed and 5-year OS or DFS was plotted using restricted cubic spline functions. RESULTS: In total, 778 patients met the inclusion criteria. The median number of excised nodes was 21 (interquartile range, 16-27). A lower number of excised lymph nodes was independently associated with worse OS and DFS (OS: hazard ratio, 0.98; confidence interval, 0.97-1.00; P = 0.013; DFS: hazard ratio, 0.99; confidence interval, 0.98-1.00; P = 0.028). Removing 25 to 30 lymph nodes was associated with a 10% risk of missing a positive lymph node. Both OS and DFS improved with up to 20 to 25 lymph nodes removed, regardless of treatment response. CONCLUSIONS: The optimal extent of lymphadenectomy to enhance both staging and survival after chemoradiotherapy, regardless of treatment response, is approximately 25 lymph nodes.

Survival After Trimodality Therapy in Patients With Locally Advanced Esophagogastric Adenocarcinoma: Does Only a Complete Pathologic Response Matter?

OBJECTIVE: To evaluate whether pCR exclusively defines major pathologic response to treatment with improved survival. SUMMARY BACKGROUND DATA: pCR after trimodality therapy for EAC is infrequent but associated with improved prognosis. Yet most clinical trials and correlative studies designate pCR as the primary endpoint. METHODS: We analyzed our prospectively maintained database for patients who underwent trimodality therapy for locally advanced esophageal adeno-carcinoma between 1995 and 2017. Overall survival (OS) was examined by percentage TR in the primary tumor bed and pathologic nodal stage (ypN0) using Kaplan-Meier plots. Optimal thresholds of TR for differentiating patients in terms of OS were investigated with descriptive plots using restricted cubic spline functions; associations were quantified using Cox multivariable analysis. RESULTS: Among 788 patients, median follow-up was 37.5 months (range, 0.4210.6); median OS was 48.3 months (95% CI, 42.2-58.8). Absence of residual nodal disease was independently associated with improved survival ( P < 0.001). Survival curves for 90% to 99% TR and 100% TR were similar, and a change in probability of improved OS was observed at 90% TR. On multivariable analysis, combining 90% to 99% and 100% TR was independently associated with improved OS, compared with 50% to 89% and <50% TR. CONCLUSIONS: ypN0 status is the strongest indicator of major pathologic response to trimodality therapy, in addition to >90% TR in the primary tumor bed. These findings may allow the definition of major pathologic response to be expanded, from pCR to > 90% TR and ypN0. This has meaningful implications for future clinical trials and correlative studies.

Survival After Induction Chemotherapy and Chemoradiation Versus Chemoradiation and Adjuvant Chemotherapy for Locally Advanced Rectal Cancer.

BACKGROUND: Total neoadjuvant therapy (TNT) improves tumor response in locally advanced rectal cancer (LARC) patients compared to neoadjuvant chemoradiotherapy alone. The effect of TNT on patient survival has not been fully investigated. MATERIALS AND METHODS: This was a retrospective case series of patients with LARC at a comprehensive cancer center. Three hundred and eleven patients received chemoradiotherapy (chemoRT) as the sole neoadjuvant treatment and planned adjuvant chemotherapy, and 313 received TNT (induction fluorouracil and oxaliplatin-based chemotherapy followed by chemoradiotherapy in the neoadjuvant setting). These patients then underwent total mesorectal excision or were entered in a watch-and-wait protocol. The proportion of patients with complete response (CR) after neoadjuvant therapy (defined as pathological CR or clinical CR sustained for 2 years) was compared by the χ2 test. Disease-free survival (DFS), local recurrence-free survival, distant metastasis-free survival, and overall survival were assessed by Kaplan-Meier analysis and log-rank test. Cox regression models were used to further evaluate DFS. RESULTS: The rate of CR was 20% for chemoRT and 27% for TNT (P=.05). DFS, local recurrence-free survival, metastasis-free survival, and overall survival were no different. Disease-free survival was not associated with the type of neoadjuvant treatment (hazard ratio [HR] 1.3; 95% confidence interval [CI] 0.93-1.80; P = .12). CONCLUSIONS: Although TNT does not prolong survival than neoadjuvant chemoradiotherapy plus intended postoperative chemotherapy, the higher response rate associated with TNT may create opportunities to preserve the rectum in more patients with LARC.

Treatment planning and outcomes effects of reducing the preferred mean esophagus dose for conventionally fractionated non-small cell lung cancer radiotherapy.

Based on an analysis of published literature, our department recently lowered the preferred mean esophagus dose (MED) constraint for conventionally fractionated (2 Gy/fraction in approximately 30 fractions) treatment of locally advanced non-small cell lung cancer (LA-NSCLC) with the goal of reducing the incidence of symptomatic acute esophagitis (AE). The goal of the change was to encourage treatment planners to achieve a MED close to 21 Gy while still permitting MED to go up to the previous guideline of 34 Gy in difficult cases. We compared all our suitable LA-NSCLC patients treated with plans from one year before through one year after the constraint change. The primary endpoint for this study was achievability of the new constraint by the planners; the secondary endpoint was reduction in symptomatic AE. Planners were able to achieve the new constraint in statistically significantly more cases during the year following its explicit implementation than in the year before (P = 0.0025). Furthermore, 38% of patients treated after the new constraint developed symptomatic AE during their treatment as opposed to 48% of the patients treated before. This is a clinically desirable endpoint although the observed difference was not statistically significant. A subsequent power calculation suggests that this is due to the relatively small number of patients in the study.

Hypofractionated vs. conventional radiation therapy for stage III non-small cell lung cancer treated without chemotherapy.

Background: Patients with unresectable locally advanced NSCLC who refuse or are not candidates for chemotherapy often receive radiation therapy (RT) alone. Hypofractionated RT (HFRT) regimens are becoming increasingly common. An analysis of the National Cancer Database (NCDB) was performed to evaluate the practice patterns and outcomes of HFRT vs. conventionally fractionated RT (CFRT) in patients with stage III NSCLC undergoing definitive RT alone.Material and methods: The NCDB was queried for all patients with stage III NSCLC diagnosed between 2004 and 2014 who received RT alone. CFRT was defined as patients treated to a total dose of 60-80 Gy in 1.8-2 Gy daily fractions. HFRT was defined as patients treated to a total dose of 50-80 Gy in 2.25-4 Gy fractions. Logistic regression, univariable and multivariable analyses (MVAs) for overall survival (OS) and propensity score matched analyses (PSMAs) were performed.Results: A total of 6490 patients were evaluated: 5378 received CFRT and 1112 received HFRT. Median CFRT dose was 66 Gy in 2 Gy fractions vs. 58.5 Gy in 2.5 Gy fractions for HFRT. HFRT was associated with older age, lower biological effective dose (BED10), academic facility type, higher T-stage and lower N-stage. On initial analysis, HFRT was associated with inferior OS (median 9.9 vs. 11.1 months, p<.001), but after adjusting for the imbalance in covariates such as age, BED10, T-stage and N-stage using PSMA, the difference in survival was no longer significant (p=.1).Conclusions: In the appropriate clinical context, HFRT can be an option for patients with locally advanced NSCLC who are not candidates for chemotherapy or surgical resection. HFRT needs to be further studied in prospective trials to evaluate toxicity and tumor control.

Clinical evaluation of 4D MRI in the delineation of gross and internal tumor volumes in comparison with 4DCT.

PURPOSE: To evaluate clinical utility of respiratory-correlated (RC) four-dimensional magnetic resonance imaging (4DMRI) for lung tumor delineation and motion assessment, in comparison with the current clinical standard of 4D computed tomography (4DCT). METHODS AND MATERIALS: A prospective T2-weighted (T2w) RC-4DMRI technique was applied to acquire coronal 4DMRI images for 14 lung cancer patients (16 lesions) during free breathing (FB) under an IRB-approved protocol, together with a breath-hold (BH) T1w 3DMRI and axial 4DMRI. Clinical simulation CT and 4DCT were acquired within 2 h. An internal navigator was applied to trigger amplitude-binned 4DMRI acquisition whereas a bellows or real-time position management (RPM) was used in the 4DCT reconstruction. Six radiation oncologists manually delineated the gross and internal tumor volumes (GTV and ITV) in 399 3D images using programmed clinical workflows under a tumor delineation guideline. The ITV was the union of GTVs within the breathing cycle without margin. Average GTV and motion range were assessed and ITV variation between 4DMRI and 4DCT was evaluated using the Dice similarity index, mean distance agreement (MDA), and volume difference. RESULTS: The mean tumor volume is similar between 4DCT (GTV4DCT  = 1.0, as the reference) and T2w-4DMRI (GTVT2wMR  = 0.97), but smaller in T1w MRI (GTVT1wMR  = 0.76), suggesting possible peripheral edema around the tumor. Average GTV variation within the breathing cycle (22%) in 4DMRI is slightly greater than 4DCT (17%). GTV motion variation (-4 to 12 mm) and ITV variation (∆VITV =-25 to 95%) between 4DCT and 4DMRI are large, confirmed by relatively low ITV similarity (Dice = 0.72 ± 0.11) and large MDA = 2.9 ± 1.5 mm. CONCLUSION: Average GTVs are similar between T2w-4DMRI and 4DCT, but smaller by 25% in T1w BH MRI. Physician training and breathing coaching may be necessary to reduce ITV variability between 4DMRI and 4DCT. Four-dimensional magnetic resonance imaging is a promising and viable technique for clinical lung tumor delineation and motion assessment.

Evaluation of respiratory motion-corrected cone-beam CT at end expiration in abdominal radiotherapy sites: a prospective study.

BACKGROUND: Cone beam computed tomography (CBCT) for radiotherapy image guidance suffers from respiratory motion artifacts. This limits soft tissue visualization and localization accuracy, particularly in abdominal sites. We report on a prospective study of respiratory motion-corrected (RMC)-CBCT to evaluate its efficacy in localizing abdominal organs and improving soft tissue visibility at end expiration. MATERIAL AND METHODS: In an IRB approved study, 11 patients with gastroesophageal junction (GEJ) cancer and five with pancreatic cancer underwent a respiration-correlated CT (4DCT), a respiration-gated CBCT (G-CBCT) near end expiration and a one-minute free-breathing CBCT scan on a single treatment day. Respiration was recorded with an external monitor. An RMC-CBCT and an uncorrected CBCT (NC-CBCT) were computed from the free-breathing scan, based on a respiratory model of deformations derived from the 4DCT. Localization discrepancy was computed as the 3D displacement of the GEJ region (GEJ patients), or gross tumor volume (GTV) and kidneys (pancreas patients) in the NC-CBCT and RMC-CBCT relative to their positions in the G-CBCT. Similarity of soft-tissue features was measured using a normalized cross correlation (NCC) function. RESULTS: Localization discrepancy from the end-expiration G-CBCT was reduced for RMC-CBCT compared to NC-CBCT in eight of eleven GEJ cases (mean ± standard deviation, respectively, 0.21 ± 0.11 and 0.43 ± 0.28 cm), in all five pancreatic GTVs (0.26 ± 0.21 and 0.42 ± 0.29 cm) and all ten kidneys (0.19 ± 0.13 and 0.51 ± 0.25 cm). Soft-tissue feature similarity around GEJ was higher with RMC-CBCT in nine of eleven cases (NCC =0.48 ± 0.20 and 0.43 ± 0.21), and eight of ten kidneys (0.44 ± 0.16 and 0.40 ± 0.17). CONCLUSIONS: In a prospective study of motion-corrected CBCT in GEJ and pancreas, RMC-CBCT yielded improved organ visibility and localization accuracy for gated treatment at end expiration in the majority of cases.

Stereotactic body radiation therapy (SBRT) improves local control and overall survival compared to conventionally fractionated radiation for stage I non-small cell lung cancer (NSCLC).

BACKGROUND: Stereotactic body radiotherapy (SBRT) has been adopted as the standard of care for inoperable early-stage non-small cell lung cancer (NSCLC), with local control rates consistently >90%. However, data directly comparing the outcomes of SBRT with those of conventionally fractionated radiotherapy (CONV) is lacking. MATERIAL AND METHODS: Between 1990 and 2013, 497 patients (525 lesions) with early-stage NSCLC (T1-T2N0M0) were treated with CONV (n = 127) or SBRT (n = 398). In this retrospective analysis, five endpoints were compared, with and without adjusting for clinical and dosimetric factors. Competing risks analysis was performed to estimate and compare the cumulative incidence of local failure (LF), nodal failure (NF), distant failure (DF) and disease progression. Overall survival (OS) was estimated by the Kaplan-Meier method and compared by the Cox regression model. Propensity score (PS) matched analysis was performed based on seven patient and clinical variables: age, gender, Karnofsky performance status (KPS), histology, T stage, biologically equivalent dose (BED), and history of smoking. RESULTS: The median dose delivered for CONV was 75.6 Gy in 1.8-2.0 Gy fractions (range 60-90 Gy; median BED = 89.20 Gy) and for SBRT 48 Gy in four fractions (45-60 Gy in three to five fractions; median BED = 105.60 Gy). Median follow-up was 24.4 months, and 3-year LF rates were 34.1% with CONV and 13.6% with SBRT (p < .001). Three-year OS rates were 38.9 and 53.1%, respectively (p = .018). PS matching showed a significant improvement of OS (p = .0497) for SBRT. T stage was the only variable correlating with all five endpoints. CONCLUSION: SBRT compared to CONV is associated with improved LF rates and OS. Our data supports the continued use and expansion of SBRT as the standard of care treatment for inoperable early-stage NSCLC.

Evaluation of automatic contour propagation in T2-weighted 4DMRI for normal-tissue motion assessment using internal organ-at-risk volume (IRV).

PURPOSE: The purpose of this study was to evaluate the quality of automatically propagated contours of organs at risk (OARs) based on respiratory-correlated navigator-triggered four-dimensional magnetic resonance imaging (RC-4DMRI) for calculation of internal organ-at-risk volume (IRV) to account for intra-fractional OAR motion. METHODS AND MATERIALS: T2-weighted RC-4DMRI images were of 10 volunteers acquired and reconstructed using an internal navigator-echo surrogate and concurrent external bellows under an IRB-approved protocol. Four major OARs (lungs, heart, liver, and stomach) were delineated in the 10-phase 4DMRI. Two manual-contour sets were delineated by two clinical personnel and two automatic-contour sets were propagated using free-form deformable image registration. The OAR volume variation within the 10-phase cycle was assessed and the IRV was calculated as the union of all OAR contours. The OAR contour similarity between the navigator-triggered and bellows-rebinned 4DMRI was compared. A total of 2400 contours were compared to the most probable ground truth with a 95% confidence level (S95) in similarity, sensitivity, and specificity using the simultaneous truth and performance level estimation (STAPLE) algorithm. RESULTS: Visual inspection of automatically propagated contours finds that approximately 5-10% require manual correction. The similarity, sensitivity, and specificity between manual and automatic contours are indistinguishable (P > 0.05). The Jaccard similarity indexes are 0.92 ± 0.02 (lungs), 0.89 ± 0.03 (heart), 0.92 ± 0.02 (liver), and 0.83 ± 0.04 (stomach). Volume variations within the breathing cycle are small for the heart (2.6 ± 1.5%), liver (1.2 ± 0.6%), and stomach (2.6 ± 0.8%), whereas the IRV is much larger than the OAR volume by: 20.3 ± 8.6% (heart), 24.0 ± 8.6% (liver), and 47.6 ± 20.2% (stomach). The Jaccard index is higher in navigator-triggered than bellows-rebinned 4DMRI by 4% (P < 0.05), due to the higher image quality of navigator-based 4DMRI. CONCLUSION: Automatic and manual OAR contours from Navigator-triggered 4DMRI are not statistically distinguishable. The navigator-triggered 4DMRI image provides higher contour quality than bellows-rebinned 4DMRI. The IRVs are 20-50% larger than OAR volumes and should be considered in dose estimation.

Chemotherapy and intensity-modulated radiation therapy for locally advanced pancreatic cancer achieves a high rate of R0 resection.

BACKGROUND: To assess local control, survival and conversion to resectability among locally advanced pancreatic cancer (LAPC) patients treated with induction chemotherapy (ICT) followed by chemoradiotherapy treatment using intensity-modulated radiation therapy (IMRT). MATERIAL AND METHODS: Between 2007 and 2012, 134 LAPC patients were treated with ICT followed by IMRT. After chemoradiotherapy, 40 patients received maintenance chemotherapy. RESULTS: With a median follow-up of 20 months, median overall survival (OS) was 23 months. One- and two-year OS was 85% and 47%, respectively. On multivariate analysis, progression of disease after IMRT was associated with worse OS. Cumulative incidence of local failure was 10% at one year and 36% at two years. Twenty-six patients (19%) underwent resection after chemoradiotherapy including 22 patients (85%) with negative margins. On multivariate analysis, response to IMRT was associated with surgery (p = .01). Acute grade 3-4 hematologic and non-hematologic toxicity rates were 26% and 4.5%, respectively. CONCLUSION: IMRT is safe in patients with LAPC. Patients with non-progressive LAPC after ICT and who received IMRT had high rates of local control and prolonged survival.

Stereotactic body radiation vs. intensity-modulated radiation for unresectable pancreatic cancer.

BACKGROUND: Stereotactic body radiation therapy (SBRT) is an emerging treatment option for unresectable pancreatic cancer, and is postulated to be more effective and less toxic than conventionally fractionated intensity modulated radiation therapy (IMRT). MATERIAL AND METHODS: We retrospectively reviewed unresectable stage I-III pancreatic adenocarcinoma treated from 2008 to 2016 at our institution with SBRT (five fractions, 30-33 Gy) or IMRT (25-28 fractions, 45-56 Gy with concurrent chemotherapy). Groups were compared with respect to overall survival (OS), local and distant failure, and toxicity. Log-rank test and Cox proportional hazards regression model, and competing risks methods were used for univariate and multivariate analysis. RESULTS: SBRT patients (n = 44) were older than IMRT (n = 226) patients; otherwise there was no significant difference in baseline characteristics. There was no significant difference in OS or local or distant failure. There was no significant difference in rates of subsequent resection (IMRT =17%, SBRT =7%, p = .11). IMRT was associated with more acute grade 2+ gastrointestinal toxicity, grade 2+ fatigue, and grade 3+ hematologic toxicity (p = .008, p < .0001, p = .001, respectively). CONCLUSIONS: In this analysis, SBRT achieves similar disease control outcomes as IMRT, with less acute toxicity. This suggests SBRT is an attractive technique for pancreatic radiotherapy because of improved convenience and tolerability with equivalent efficacy. However, the lack of observed advantages in disease control with this moderate-dose SBRT regimen may suggest a role for increasing SBRT dose, if this can be accomplished without significant increase in toxicity.

Change in chemotherapy during concurrent radiation followed by surgery after a suboptimal positron emission tomography response to induction chemotherapy improves outcomes for locally advanced esophageal adenocarcinoma.

BACKGROUND: A positron emission tomography (PET) scan after induction chemotherapy before preoperative chemoradiation and surgery for esophageal adenocarcinoma predicts outcomes. Some patients with progression on PET after induction chemotherapy had long-term overall survival (OS) when they were changed to alternative chemotherapy during radiation. METHODS: This study retrospectively reviewed esophageal adenocarcinoma patients who received induction chemotherapy and chemoradiation before planned surgery; all had undergone a PET scan before and after induction chemotherapy. RESULTS: There were 201 patients, and 113 (56%) were PET responders (≥35% decrease in the maximum standardized uptake value of the tumor). All PET responders received the same chemotherapy during radiation, whereas 38 of the 88 PET nonresponders (43%) changed chemotherapy. Among the 152 patients who underwent surgery, the pathologic complete response rate was 15% for PET responders and 3% for PET nonresponders who did not change chemotherapy (P = .046). The median progression-free survival (PFS; 18.9 vs 10.0 months, P < 0.01) and OS (37 vs 25.3 months, P = .02) were significantly better for PET responders versus PET nonresponders who did not change chemotherapy. The median PFS for PET nonresponders who changed chemotherapy was 17.9 months, and it was superior to the median PFS for PET nonresponders who did not change chemotherapy (P = .01). For PET nonresponders, the 5-year OS rates were 37% for those who changed chemotherapy and 25% for those who did not change chemotherapy (P = .18). CONCLUSIONS: A PET scan after induction chemotherapy predicts outcomes for locally advanced esophageal adenocarcinoma patients who undergo chemoradiation and surgery. The median PFS is improved, and trends toward improved OS appear possible in PET nonresponders who change chemotherapy during radiation. The fully accrued Cancer and Leukemia Group B 80803 study (NCT01333033) is evaluating this strategy. Cancer 2016;122:2083-90. © 2016 American Cancer Society.

Distance to the anal verge is associated with pathologic complete response to neoadjuvant therapy in locally advanced rectal cancer.

BACKGROUND AND OBJECTIVES: Achieving a pathologic complete response (pCR) after neoadjuvant therapy has been associated with better prognosis in rectal cancer patients. The objective of this study was to investigate the relationship between distance to the anal verge (DTAV) and pCR. METHODS: Review of a prospectively maintained database of patients with locally advanced rectal cancer who received neoadjuvant treatment was completed. Uni- and multivariate analysis assessed the association between DTAV and pCR after neoadjuvant therapy. RESULTS: Of 827 included patients, 20% had a pCR. We found that pCR rates were 11% for tumors <4 cm, 24% for tumors 4-6 cm, 30% for tumors at 6-8 cm, 17% for tumors 8-10 cm, and 14% for tumors >10 cm from the anal verge (P = 0.002). Multivariate analysis also showed a strong association between DTAV and pCR (P = 0.008). The bimodal distribution of pCR resulted in a lower odds ratio of pCR for tumors <4 and >8 cm from the anal verge. CONCLUSIONS: Patients with low tumors (<4 cm) and higher tumors (>8 cm), were less likely to have a pCR. Further investigation is warranted to determine if these observations are related to tumor biology or possibly differences in radiation technique. J. Surg. Oncol. 2016;114:637-641. © 2016 Wiley Periodicals, Inc.

Predictors of acute toxicities during definitive chemoradiation using intensity-modulated radiotherapy for anal squamous cell carcinoma.

PURPOSE: To identify clinical and dosimetric factors associated with acute hematologic and gastrointestinal (GI) toxicities during definitive therapy using intensity-modulated radiotherapy (IMRT) for anal squamous cell carcinoma (ASCC). MATERIALS AND METHODS: We retrospectively analyzed 108 ASCC patients treated with IMRT. Clinical information included age, gender, stage, concurrent chemotherapy, mitomycin (MMC) chemotherapy and weekly hematologic and GI toxicity during IMRT. From contours of the bony pelvis and bowel, dose-volume parameters were extracted. Logistic regression models were used to test associations between toxicities and clinical or dosimetric predictors. RESULTS: The median age was 59 years, 81 patients were women and 84 patients received concurrent MMC and 5-fluorouracil (5FU). On multivariate analysis (MVA), the model most predictive of Grade 2 + anemia included the maximum bony pelvis dose (Dmax), female gender, and T stage [p = 0.035, cross validation area under the curve (cvAUC) = 0.66]. The strongest model of Grade 2 + leukopenia included V10 (percentage of pelvic bone volume receiving ≥ 10 Gy) and number of MMC cycles (p = 0.276, cvAUC = 0.57). The model including MMC cycle number and T stage correlated best with Grade 2 + neutropenia (p = 0.306, cvAUC = 0.57). The model predictive of combined Grade 2 + hematologic toxicity (HT) included V10 and T stage (p = 0.016, cvAUC = 0.66). A model including VA45 (absolute bowel volume receiving ≥ 45 Gy) and MOH5 (mean dose to hottest 5% of bowel volume) best predicted diarrhea (p = 0.517, cvAUC = 0.56). CONCLUSION: Dosimetric constraints to the pelvic bones should be integrated into IMRT planning to reduce toxicity, potentially reducing treatment interruptions and improving disease outcomes in ASCC. Specifically, our results indicate that Dmax should be confined to ≤ 57 Gy to minimize anemia and that V10 should be restricted to ≤ 87% to reduce incidence of all HT.