Signet Ring Cell Features are Associated with Poor Response to Neoadjuvant Treatment and Dismal Survival in Patients with High-Grade Esophageal Adenocarcinoma.

BACKGROUND: While the prognosis of patients with locoregional esophageal adenocarcinoma (EAC) has improved in the neoadjuvant treatment (NAT) era, high-grade histology (G3) is still associated with a limited treatment response. We sought to investigate oncologic outcomes in patients after esophagectomy for G3 EAC and to identify predictors of poor survival among these patients. METHODS: Patients with EAC who underwent resection with curative intent in 2011-2018 were divided by histologic grade (G3, G1/2) and compared for overall survival (OS). Cox regression was performed to analyze the response to NAT and the predictive role of signet ring cell (SRC) features. RESULTS: The cohort included 163 patients, 94 (57.7%) with G3 histology. NAT was administered to 69 (73.4%) patients. Following resection, OS in the G3 EAC group was 30 months (95% confidence interval [CI] 23.9-36.1). On univariate analysis, G3 disease (p = 0.050) and SRC features (p = 0.019) predicted low OS. Median survival in the G3 EAC group was worse in patients with SRC histology (18 months, 95% CI 8.6-27.4) than those without (30 months, 95% CI 23.8-36.1; p = 0.041). No patients with SRC histology were alive at 5 years of follow-up. Among all patients administered NAT, 88.2% of those with SRC showed minimal or no pathologic response and only 27.8% were downstaged. CONCLUSIONS: High-grade histology was found in most patients with EAC and predicted poor survival and treatment response. SRC features in patients with G3 disease were associated with lower OS. The benefit of NAT for G3 EAC in patients with SRC histology appears limited.

Brain metastasis in gastroesophageal adenocarcinoma and HER2 status.

The increased survival of patients with gastroesophageal adenocarcinoma (GAD) following improvements in treatment has been accompanied by a rising incidence of secondary brain metastasis. HER2 amplification/overexpression, which has been associated with an increased risk of brain metastasis in breast cancer, is found in about 20% of patients with GAD. The aim of this study was to evaluate the effect of HER2 status on brain metastasis in GAD. The database of a tertiary cancer center was searched for patients with GAD diagnosed in 2011-2015, and data were collected on clinical characteristics, brain metastasis, HER2 status, and outcome. We identified 404 patients with a confirmed diagnosis of GAD. HER2 results were available for 298: 69 (23.2%) positive and 227 negative. Brain metastasis developed in 15 patients with GAD (3.7%); HER2 results, available in 13, were positive in 6, negative in 6, and equivocal in 1. The brain metastasis rate was significantly higher in HER2-positive than HER2-negative patients with GAD (6/69, 8.7% vs. 6/227, 2.6%; RR = 3.3, 95% CI 1.1-9.9, p = 0.034). Median overall survival from diagnosis of brain metastasis was 2.3 months, with no significant difference by HER2 status. HER2 positive GAD patients may be at increased risk to develop BM. Clinicians should maintain a lower threshold for performing brain imaging in patients with HER2-positive GAD given their increased risk of brain metastasis. The role of anti-HER2 agents in the development and treatment of brain metastasis in GAD warrants further study.

Colorectal cancer in young patients: is it a distinct clinical entity?

BACKGROUND: The incidence of colorectal cancer in young patients is increasing. It remains unclear if the disease has unique features in this age group. METHODS: This was a single-center, retrospective cohort study which included patients diagnosed with colorectal cancer at age ≤40 years in 1997-2013 matched 1:2 by year of diagnosis with consecutive colorectal cancer patients diagnosed at age >50 years during the same period. Patients aged 41-50 years were not included in the study, to accentuate potential age-related differences. Clinicopathological characteristics, treatment, and outcome were compared between groups. RESULTS: The cohort included 330 patients, followed for a median time of 65.9 months (range 4.7-211). Several significant differences were noted. The younger group had a different ethnic composition. They had higher rates of family history of colorectal cancer (p = 0.003), hereditary colorectal cancer syndromes (p < 0.0001), and inflammatory bowel disease (p = 0.007), and a lower rate of polyps (p < 0.0001). They were more likely to present with stage III or IV disease (p = 0.001), angiolymphatic invasion, signet cell ring adenocarcinoma, and rectal tumors (p = 0.02). Younger patients more frequently received treatment. Young patients had a worse estimated 5-year disease-free survival rate (57.6  vs. 70 %, p = 0.039), but this did not retain significance when analyzed by stage (p = 0.092). Estimated 5-year overall survival rates were 59.1 and 62.1 % in the younger and the control group, respectively (p = 0.565). CONCLUSIONS: Colorectal cancer among young patients may constitute a distinct clinical entity. Further research is needed to validate our findings and define the optimal approach in this population.

Postoperative chemoradiotherapy in patients with locally advanced gastric cancer with poor pathologic response to neoadjuvant chemotherapy.

PURPOSE: To evaluate the effect of postoperative chemoradiotherapy (CRT) in patients with locally advanced gastric cancer (LAGC) who respond poorly to neoadjuvant chemotherapy (ChT). MATERIALS AND METHODS: The database of a tertiary medical center (2009-2020) was retrospectively reviewed for patients with LAGC in whom the initial treatment strategy consisted of perioperative ChT and surgery. Those who were subsequently referred for postoperative CRT because of a poor pathologic primary-tumor response (ypT3-4, ypN2-3, R1 resection) were selected for the study. CRT consisted of 45 Gy in 25 fractions of 1.8 Gy combined with capecitabine 825 mg/m2 twice daily on radiotherapy days or continuous infusion of 5-fluorouracil 180 mg/m2/day. RESULTS: The cohort included 26 patients of median age 61 years with LAGC (clinical stage IIA-III) after surgery with D1-D2 lymphadenectomy. R0 resection was achieved in 15 (58%). The pathological stage was III in 69% (IIA-IVA). Treatment was well tolerated. During a median follow-up time of 39 months, recurrences were documented in 14 patients (54%): 11 distant and 3 locoregional. Median progression-free survival was 23 months, and median overall survival was 65 months. Estimated 5-year survival rates were 42 and 54%, respectively. CONCLUSIONS: This small retrospective study suggests that in patients with LAGC who show a poor pathologic response to neoadjuvant ChT, a good outcome relative to reference arms in randomized trials can still be achieved with the addition of postoperative CRT. Further studies of the benefit of a tailored adaptive treatment approach to LAGC based on the response to neoadjuvant ChT are warranted.

The effect of gastric fundus radiation dose on postoperative anastomotic leakage in esophageal cancer.

Introduction: Standard-of-care treatment for locally advanced esophageal carcinoma (LAEC) includes neoadjuvant chemoradiotherapy followed by esophagectomy. A potentially catastrophic surgical complication is the development of a postoperative anastomotic leak. To date, the association with radiation dose exposure had been inconclusive. We examined the correlation between radiation exposure to the gastric fundus and risk of postoperative leakage using contemporary radiation doses and fractionation. Methods: A total of 69 consecutive patients with LAEC who underwent neoadjuvant chemoradiotherapy followed by esophagectomy in our tertiary center were prospectively followed (median, 27 months). Neoadjuvant regimen included 50.4 Gy in 28 fractions with 5-fluorouracil and cisplatin and 41.4 Gy in 23 fractions with carboplatin and paclitaxel. The gastric fundus was contoured and dosimetric and radiation technique parameters were retrospectively evaluated. Results: Of the total number of patients, 71% and 29% had esophageal and gastroesophageal junction (GEJ) tumors, respectively. Fourteen patients (20.3%) experienced anastomotic leaks within a median of 2 days postoperatively, 78.6% of whom had lower third esophagus or GEJ primaries. Mean and minimum fundus dose did not significantly differ between those with and those without leakage (p = 0.42, p = 0.51). Mean fundus V25, V30, and V35 doses were numerically but not statistically higher in those with anastomotic leak (p = 0.58, p = 0.39, and p = 0.30, respectively). No correlation with incidence of leakage was seen between 3D and IMRT treatment modalities. Conclusions: In our comparatively large prospectively collected series of patients treated for LAEC, radiation dose to the gastric fundus during neoadjuvant combination therapy prior to surgery did not correlate with the risk of postoperative anastomotic leak.

Assessment of response of brain metastases to radiotherapy by PET imaging of apoptosis with ¹8F-ML-10.

PURPOSE: Early assessment of tumor response to therapy is vital for treatment optimization for the individual cancer patient. Induction of apoptosis is an early and nearly universal effect of anticancer therapies. The purpose of this study was to assess the performance of (18)F-ML-10, a novel PET radiotracer for apoptosis, as a tool for the early detection of response of brain metastases to whole-brain radiation therapy (WBRT). MATERIALS AND METHODS: Ten patients with brain metastases treated with WBRT at 30 Gy in ten daily fractions were enrolled in this trial. Each patient underwent two (18)F-ML-10 PET scans, one prior to the radiation therapy (baseline scan), and the second after nine or ten fractions of radiotherapy (follow-up scan). MRI was performed at 6-8 weeks following completion of the radiation therapy. Early treatment-induced changes in tumor (18)F-ML-10 uptake on the PET scan were measured by voxel-based analysis, and were then evaluated by correlation analysis as predictors of the extent of later changes in tumor anatomical dimensions as seen on MRI scans 6-8 weeks after completion of therapy. RESULTS: In all ten patients, all brain lesions were detected by both MRI and the (18)F-ML-10 PET scan. A highly significant correlation was found between early changes on the (18)F-ML-10 scan and later changes in tumor anatomical dimensions (r = 0.9). CONCLUSION: These results support the potential of (18)F-ML-10 PET as a novel tool for the early detection of response of brain metastases to WBRT.

The combination of docetaxel, cisplatin, and 5-fluorouracil in advanced gastric cancer: a single-institution experience.

The addition of docetaxel to cisplatin and 5-fluorouracil was shown to confer a survival benefit in patients with advanced gastric cancer (one; AGC), although with increased toxicity. We hereby report our experience with the use of docetaxel, cisplatin, and 5-fluorouracil (DCF). Data on all consecutive patients who received first-line treatment with DCF at our institute were analyzed retrospectively. Twenty-three patients were included. The median age was 63 years. Patients received an average of 10 cycles (range, 1-24). All experienced grade ≥3 toxicity, requiring hospitalization in 35%. There was one toxic death. The median progression-free and overall survival rates were 10.0 and 12.8 months, respectively; the 2-year and 3-year survival rates were 22 and 17%, respectively. The DCF regimen is indeed associated with substantial toxicity, although manageable. Nevertheless, the observed benefit was remarkable compared with any previous report on chemotherapy in AGC, and should therefore represent a valid treatment option in AGC and a platform for future combinations.

Gastric cancer: biology and clinical manifestations in Israel.

BACKGROUND: Gastric cancer (GC) in Israel remains incompletely characterized. The aim of this study was to define the clinical and pathological characteristics of GC in Israel and to compare them to the general Western population. PATIENTS AND METHODS: This is a retrospective analysis of 461 consecutive GC patients treated at a single institution between 1995 and 2007. Epidemiological and clinical-pathological data were retrieved from the patients' medical files and the institutional electronic database and analyzed using standard statistical methods. RESULTS: Epidemiology, clinical manifestations, histopathological findings, clinical course, and prognostic factors for disease outcome were all similar to those reported in the Western literature. Findings unique to the Israeli population included: (1) rarity of GC-associated risk factors; (2) increased GC incidence in Ashkenazi Jews; (3) high incidence of second primary malignancy and family history of cancer; and (4) no dominancy of proximal GCs. CONCLUSION: There do not appear to be any major differences in the biology or clinical manifestations of GC in Israel. Western recommendations for diagnosis and treatment of GC may therefore be applied to the Israeli patient population.

Prospective phase II study of neoadjuvant therapy with cisplatin, 5-fluorouracil, and bevacizumab for locally advanced resectable esophageal cancer.

BACKGROUND: We investigated the efficacy and tolerability of cisplatin and 5-fluorouracil (5-FU) plus bevacizumab as neoadjuvant therapy for patients with locally advanced resectable esophageal cancer. PATIENTS AND METHODS: In this prospective phase II study, 22 patients with adenocarcinoma and 6 with squamous cell carcinoma received 2 4-day cycles of bevacizumab 7.5 mg/kg followed by cisplatin 80 mg/m(2) infusion on day 1 followed by 5-FU 1,000 mg/m(2) as a 96-h continuous infusion on days 1-4, separated by a 3-week interval. RESULTS: The response rate was 39%, the R0 resection rate was 43%, and the median overall survival (OS) was 17 months. The regimen was well tolerated, with the most common severe toxicities being venous thromboembolism (10%), nausea, and gastrointestinal bleeding (7% each). In 37 patients previously treated with cisplatin and 5-FU alone at our institution and thus serving as historical controls, the response rate was 30%, the R0 resection rate was 44%, and the median OS was 23 months. There was no statistically significant difference between the 2 groups of patients. CONCLUSION: Adding bevacizumab to cisplatin and 5-FU neoadjuvant chemotherapy was active and well tolerated but did not seem to improve the resection rate or OS compared with prior regimens, including the historical controls at our institution.

Proteomic analysis to identify markers for response to neoadjuvant treatment in esophageal and gastroesophageal cancer.

BACKGROUND: Esophageal cancer represents a global challenge. Despite significant evolution of treatment protocols in the past decade, recurrence rates are still high and survival rates are poor. Current treatment paradigm for localized gastroesophageal junction (GEJ) carcinoma remains to be further elucidated as for the role of neoadjuvant chemoradiation versus perioperative chemotherapy. AIM: To identify biomarkers for response to chemoradiation in esophageal and gastroesophageal cancer, we performed an in-depth proteomic analysis of esophageal and gastroesophageal tumors, to describe differences in pathway activation between patients with favorable and poor prognosis following neoadjuvant chemoradiation. METHODS: Patients with locally advanced esophageal and gastroesophageal cancer following neoadjuvant chemoradiation were included in the cohort. The study cohort was dichotomized into two groups of patients, named "favorable prognosis" and "poor prognosis" according to the postoperative disease-free interval. We performed a mass spectrometry analysis of proteins extracted from the malignant regions of surgical specimens and analyzed data from electronic medical records. Clinical data was correlated with differences in protein expression between patient with a favorable and poor prognosis using validated gene expression pathways. RESULTS: The study included 35 patients with adenocarcinoma. All patients in this cohort had esophageal adenocarcinoma. Patients median age was 62 years. Twenty-five (71.3%) patients underwent neoadjuvant chemoradiation, and 28.7% underwent neoadjuvant chemotherapy only. A proteomic analysis of our cohort identified 2885 proteins. Enrichment levels of 98 of these proteins differed significantly between favorable and poor prognosis cohorts in patients who underwent neoadjuvant chemoradiation (p < .05) but not in patients who underwent neoadjuvant chemotherapy. The favorable prognosis patients group analysis exhibited differential enrichment of 87 proteins related to cellular respiration and oxidative phosphorylation pathways as well as proteins of the RAS oncogene family. CONCLUSION: In this study we identified differential enrichment of pathways related to oxidative phosphorylation and RAS oncogene pathway in esophageal cancer patients with a favorable response to chemoradiation. Following further validation, our findings may portray potential surrogate signature of biomarkers based upon these pathways.

Tumor Lymphocyte Infiltration Is Correlated with a Favorable Tumor Regression Grade after Neoadjuvant Treatment for Esophageal Adenocarcinoma.

(1) Background: We aimed to explore the association between neoadjuvant treatment, tumor-infiltrating immune lymphocyte (TIL), and tumor-associated macrophage (TAM) and survival in patients with esophageal adenocarcinoma. (2) Methods: Patients who underwent esophagectomy were divided into three groups according to their treatment modality and tumor regression grade (TRG): (i) surgery-only group (SG), (ii) good responders (GR) group (TRG 0−1), and (iii) bad responders (BR) group (TRG 2−3). We then carried out statistical correlations of the immunofluorescence analysis of the immune infiltrate in the esophageal surgical specimens with several clinical and pathological parameters. In addition, we analyzed The Cancer Genomic Atlas (TCGA) dataset for differences in TILs, TAMs, and protein expression in immune pathways. (3) Results: Forty-three patients (SG­15, GR­13, and BR­13) were evaluated. The highest enrichment of CD3+ (p < 0.001), CD8+ (p = 0.001) and CD4+ (p = 0.009) was observed in the stroma of GR patients. On multivariate analysis, only CD8+ T cell and signet-ring features were independent prognostic factors for overall survival. In TCGA analysis, we identified overexpression of TAM and colony-stimulating factor 1 receptor (CSF-1R). (4) Conclusions: High enrichment of lymphocyte subpopulations in the microenvironment of esophageal adenocarcinoma is associated with a favorable response to neoadjuvant treatment and an improved patient outcome.

Early prediction of residual disease after neoadjuvant chemoradiotherapy and cetuximab for locally advanced esophageal cancer using 18F-FDG PET-CT imaging: a prospective cohort study.

Background: Previous studies in locally advanced esophageal cancer (LAEC) suggested that a change in the tumor's metabolic response, i.e., decrease of its interim 18F-FDG uptake compared with baseline, may predict histopathological response. We evaluated the possible predictive correlation between various PET-CT and histopathological parameters following a neoadjuvant biological-containing chemoradiotherapy (CRT) regimen. Methods: Patients with resectable LAEC received neoadjuvant cisplatin/5-fluorouracil-based CRT and cetuximab following one cycle of induction chemotherapy and cetuximab. Changes in maximum and mean standardized uptake values (ΔSUV-max and ΔSUV-mean, respectively) and metabolic tumor volume (ΔMTV), measured by PET-CT at baseline and 2 weeks after the onset of treatment, were compared with histopathological findings at surgery. Histopathological response was defined by tumor regression grade (TRG), pathological complete response (pCR) and microscopic or macroscopic residual disease (RD). Results: Of 18 patients, 13 (72%) with adenocarcinoma (AC) and 5 (28%) with squamous cell carcinoma (SCC), were included. None of the changes in the parameters of PET was associated with pCR; only ΔSUV-mean was associated with TRG in the AC cohort. In contrast, both ΔSUV-mean% and ΔSUV-max% were significantly associated with RD, both in the whole cohort and in the AC cohort. Changes in FDG-uptake predicted RD2 at surgery: only patients with less than 13% decrease in SUV-mean% or less than 29% decrease in SUV-max% had RD2, while all patients with RD0 or RD1 had greater reductions [100% specificity and 100% positive predictive value (PPV)]. Conclusions: Changes in ΔSUV-max and ΔSUV-mean after two weeks of onset of cetuximab-based neoadjuvant chemotherapy for LAEC may predict macroscopic RD but not TRG or pCR at surgery.

Is local excision after complete pathological response to neoadjuvant chemoradiation for rectal cancer an acceptable treatment option?

PURPOSE: The role of local excision in patients with good histological response to neoadjuvant chemoradiation for locally advanced rectal cancer is unclear, mainly because of possible regional nodal involvement. This study aims to evaluate the correlation between pathological T and N stages following neoadjuvant chemoradiation for locally advanced rectal cancer and the outcome of patients with mural pathological complete response undergoing local excision. METHODS: This investigation was conducted as a retrospective analysis. Between January 1997 and December 2007, 320 patients with T3 to 4Nx, TxN+ or distal (≤ 6 cm from the anus) T2N0 rectal cancer underwent neoadjuvant concurrent chemoradiation followed by surgery. Radiotherapy was standard and chemotherapy consisted of common fluoropyrimidine-based regimens. RESULTS: After chemoradiation, 93% patients had radical surgery, 6% had local excision, and 3% did not have surgery. In the 291 patients undergoing radical surgery, the pathological T stage correlated with the N stage (P = .036). We compared the outcome of patients with mural complete pathological response (n = 37) who underwent radical surgery (group I) and those (n = 14) who had local excision only (group II). With a median follow-up of 48 months, 4 patients in group I had a recurrence and none in group II had a recurrence; one patient died in group I and none died in group II. Disease-free survival, pelvic recurrence-free survival, and overall survival rates were similar in both groups. CONCLUSION: In this retrospective study, nodal metastases were rare in patients with mural complete pathological response following neoadjuvant chemoradiation (3%), and local excision did not compromise their outcome. Therefore, local excision may be an acceptable option in these patients.

Efficacy of immune-checkpoint inhibitors in metastatic gastric or gastroesophageal junction adenocarcinoma by patient subgroups: A systematic review and meta-analysis.

BACKGROUND: Efficacy of immune checkpoint inhibitors (ICIs) in metastatic gastric/gastroesophageal junction (GEJ) adenocarcinoma is inconsistent. Whether the efficacy of ICIs is comparable across different subgroups remains unknown. METHODS: We identified randomized controlled trials (RCTs) that compared standard treatment for metastatic gastric/GEJ adenocarcinoma to ICIs. Hazard ratios (HRs) and 95% confidence intervals (CI) for overall survival (OS) were extracted and pooled in a meta-analysis. Prespecified subgroups were included as follows: age at randomization (65 years), gender (female vs male), ethnicity (Asians vs non-Asians), performance-status (0 vs 1), tumor location (gastric vs GEJ), and histological subtype (diffuse vs others). OS in patients with programmed death ligand (PD-L1) positive and with microsatellite instability-high (MSI-H) were also extracted and pooled in a meta-analysis. RESULTS: Five RCTs comprising 2,264 patients were analyzed. Compared to standard therapy, ICIs did not improve OS (HR = 0.86, 95% CI 0.71-1.03, P = .10) and the effect of ICIs on OS was similar in all subgroups. Nonsignificantly greater effect sizes were seen in older patients (HR = 0.85 vs 0.88, P = .81), male (HR = 0.82 vs 0.99, P = .16), Asians (HR = 0.86 vs 0.96, P = .55), performance-status 0 (HR = 0.84 vs 0.88, P = .81), GEJ tumors (HR = 0.78 vs 0.90, P = .37), and nondiffuse subtype (HR = 0.71 vs 0.79, P = .62). ICIs were associated with significantly improved OS in patients with MSI-H (HR = 0.33, P = .001), but not in PD-L1 positive disease (HR = 0.86, P = .06). CONCLUSIONS: Compared to standard treatment, ICIs in metastatic gastric/GEJ adenocarcinoma did not improve OS. None of the evaluated subgroups has shown increased magnitude of effect to ICIs, aside of the small group with MSI-H tumors.

What is the Best Way to Plan Rectum Three-Dimensional Conformal Radiotherapy in Prone Position-Classic Anatomical Landmark, Three Dimensional Fitting the Planning Target Volume, or Volumetric Modulated Arc?

BACKGROUND: Traditionally, rectal cancer radiation therapy uses bony landmark fields to cover common lymphatic drainage sites, including the internal iliac, presacral, and perirectal lymph nodes. We aimed to investigate if bony landmark borders sufficiently cover the internal iliac nodes and to compare tumor volume and normal tissue avoidance using classic bony landmarks (c3DCRT), contoured elective clinical target volume (f3DCRT), and volumetric modulated arc therapy (VMAT) planning in locally advanced rectal cancer. METHODS: Computed tomography datasets of 11 patients with locally advanced rectal cancer who had completed treatment in the prone position on a bellyboard in c3DCRT technique. The elective clinical target volumes and organs at risk were contoured, and a f3DCRT VMAT plan generated for all patients. Planning target volume, gross tumor volume, and normal tissue dose limits were evaluated. RESULTS: The mean planning target volume 95% coverages were significantly lower for c3DCRT plans, and the lymph node coverage was better for f3DCRT. No differences were found in PTV coverages between f3DCRT and volumetric modulated arc therapy plans. No significant differences among all techniques were found for organs-at-risk constraints. The bladder dosage was higher in the VMAT plan. The c3DCRT technique missed coverage of the internal iliac lymph nodes and exposed smaller bowel, compared with the other methods. DISCUSSION AND CONCLUSION: Tumor volume coverage was improved by f3DCRT planning, without significant differences in doses to critical structures compared with c3DCRT and was noninferior to VMAT planning. It is recommended that f3DCRT be used in routine clinical practice in radiotherapy treatments for locally advanced rectal cancer.

The Financial Impact of Fractionation Scheme and Treatment Planning Method for Rectal Cancer in the United States.

BACKGROUND: Preoperative long-course chemoradiotherapy (CRT) and short-course radiotherapy (SCR) for locally advanced rectal cancer (LARC) were found to have equivalent outcomes in 3 randomized trials. SCR has not been widely adopted in the United States (US). Three-dimensional (3D) treatment planning is standard, whereas intensity-modulated radiotherapy (IMRT) is controversial. In this study, we assessed the economic impact of fractionation scheme and planning method for payers in the US. MATERIALS AND METHODS: We performed a population-based analysis of the total cost of radiotherapy for LARC in the US annually. The national annual target population was calculated using the Surveillance, Epidemiology, and End Results database. Radiotherapy costs were based on billing codes and 2018 pricing by Medicare's Hospital Outpatient Prospective Payment System. RESULTS: We estimate that 12,945 patients with LARC are treated with radiotherapy annually in the US. The cost of CRT with 3D or IMRT is US $15,882 and $23,745 per patient, respectively. With SCR, the cost with 3D or IMRT is $5,458 and $7,323 per patient, respectively. The use of SCR would lead to 53% to 77% annual savings of $106,168,871 to $232,105,727 compared with CRT. IMRT increases the total cost of treatment by 34% to 50%, and if adopted widely, would lead to an excess cost of $24,152,134 and $101,784,723 annually with SCR and CRT, respectively. CONCLUSIONS: SCR may have the potential to save approximately US $106 to t232 million annually in the US, likely without impacting outcomes. Lack of evidence showing benefit with costly IMRT should limit its use to clinical trials. It would be reasonable for public and private payers to consider which type of radiation is most suited to reimbursement.

The addition of cetuximab to preoperative chemoradiotherapy for locally advanced esophageal squamous cell carcinoma is associated with high rate of long term survival: Mature results from a prospective phase Ib/II trial.

AIM: This phase IB/II study evaluated the safety and efficacy of the addition of cetuximab to standard preoperative chemoradiotherapy (CRT) in locally advanced esophageal cancer (LAEC). METHODS: Patients (pts) with resectable LAEC (T2-3N0-1M0, T1-3N1M0 or T1-3N0-1M1A) received an induction cycle of cisplatin 100 mg/m2, day 1, and 5-fluorouracil (5-FU) 1000 mg/m2/day, days 1-5, followed 4 weeks later by radiotherapy, 50.4 Gy, given with 2 cycles of cisplatin 75 mg/m2 and escalating doses of 5-FU, days 1-4 and 29-32. Pts received 10 weekly infusions of cetuximab, 250 mg/m2, with a loading dose, 400 mg/m2. Surgery was planned 6-8 weeks after CRT. RESULTS: 64 pts were treated and 60 completed CRT. Median age was 65 years and 66% were males. Adenocarcinoma/squamous ratio was 61%/39%. Tumors were advanced: 95% T3 and 67% N1. Grade ≥3 toxicities occurred in 72%, with two (3%) toxic deaths. The 5-FU maximal tolerated dose (MTD) was 1000 mg/m2/day. Clinical complete response rate was 33%. Of the 55 operated pts, R0 resection was achieved in 51 (93%) and pathological complete response (pCR) in 18 (33%), with 8 (14%) postoperative deaths. The 5-year survival rate for all pts was 38%. Pts with squamous histology had higher pCR (55% vs 20%, p = 0.015), local control (96% vs. 74%, p < 0.001) and 5-year survival (58% vs 25%, p = 0.011) rates. CONCLUSIONS: This study suggests that the addition of cetuximab to standard preoperative CRT is feasible. R0, pCR and local control rates are encouraging. Pts with squamous cell tumors benefited more from the addition of cetuximab.

Adjuvant chemotherapy and whole abdominal irradiation for gastric carcinoma.

AIMS AND BACKGROUND: To analyze the efficacy and toxicity of adjuvant chemotherapy followed by whole abdominal irradiation in the treatment of resectable gastric cancer with positive lymph nodes. METHODS AND STUDY DESIGN: Between 1996 and 1999, 10 patients with node-positive gastric cancer underwent complete gross resection and were treated by postoperative chemoradiotherapy. The chemotherapy regimen consisted of 5-fluorouracil, 1000 mg/m2/day as a 96-hr continuous infusion on day 1, and cisplatin, 100 mg/m2 on day 2, every 21 days. Six courses were planned. Radiotherapy was administered 3 weeks after completion of the chemotherapy protocol as a single-fraction dose of 600 cGy in a two-field (anterior and posterior) configuration. RESULTS: Treatment was generally well tolerated, with no treatment-related deaths. However, 9 of the 10 patients died of recurrent disease, with a median survival of 20 months (range, 7-84). CONCLUSIONS: Adjuvant chemotherapy with whole abdominal irradiation for gastric cancer is safe and tolerable but has no apparent effect on patient outcome. Studies in larger series are needed to evaluate the role of the approach in this disease.

[Three-dimensional conformal radiation therapy concurrent with full dose Gemcitabine for locally advanced inoperable pancreatic cancer].

BACKGROUND: Gemcitabine is a potent radiosensitizer of pancreatic cancer cells. Concomitant full dose Gemcitabine and three dimensional conformal radiation to a small field is a novel approach to unresectable locally advanced pancreatic cancer. The aim of this study is to report the outcome, tolerability and toxicity of this combined therapy. METHODS: A retrospective chart review, with survival data confirmed by the population registry and statistic analysis was performed with SPSS. Radiotherapy was planned using computerized tomography, treated only the gross tumor without regional lymph nodes and was delivered in 15 fractions of 2.4 Gy to a dose of 36 Gy. Gemcitabine was administered weekly during radiation at a dose of 1000 mg/m2. Gastrointestinal toxicity was scored according to the NCI Common Toxicity Criteria. Local control was assessed by RECIST criteria, a partial response defined as a decrease of at least 30% in the longest diameter of the tumor. RESULTS: Eighteen of the 19 patients completed treatment as planned without the need for treatment break. Four patients subsequently developed severe grade III-IV gastrointestinal toxicity; 37% of patients achieved a partial response and 52% experienced significant clinical benefit. The median survival was 11.7 months. DISCUSSION: Full dose gemcitabine with conformal 3-D radiotherapy to a small field was well tolerated and was associated with a low incidence of severe gastrointestinal toxicity compared with previous studies of combination therapy using standard large radiation portals which encompass both the tumor and the regional lymph nodes. A partial response was observed in over one third of patients, non-progression of the irradiated tumor in the rest with pain relief and clinical benefit in more than half the patients. CONCLUSION: This treatment approach was well tolerated with little morbidity and achieves outcomes equal to or better than other contemporary combination modality approaches.

Baseline 18F-FDG PET/CT as predictor of the pathological response to neoadjuvant therapy in esophageal cancer: A retrospective study.

The type of pathological response to neoadjuvant chemoradiation in patients with locally advanced esophageal cancer predicts overall survival (OS).We aimed to assess early 18F-FDG positron emission tomography/computed tomography parameters in predicting the pathological response to neoadjuvant treatment.The cohort included consecutive patients with locally advanced esophageal cancer who underwent baseline 18F-FDG positron emission tomography/computed tomography between September 2006 and February 2015. Positron emission tomography variables of maximum and average standardized uptake values (SUVmax, SUVaverage), metabolic tumor volume (MTV), and total lesion glycolysis were recorded in addition to computed tomography volume. MTV was calculated using cut-off values of 42%, 50% and 60% (MTV 0.42, 0.5, and 0.6) of the tumoral SUVmax. Receiver operating characteristic (ROC) analysis was used to determine sensitivity and specificity.Sixty-one patients (44 male, 17 female) fulfilled the inclusion criteria. Only MTV values of 13.6 mL (MTV 0.42) and 7.4 mL (MTV 0.5) remained significant on ROC analysis, with an area under the curve of 0.690 (confidence interval 0.557-0.823, p = .02] and 0.664 (confidence interval 0.527-0.802, P = .048), respectively in differentiating patients with a complete (n = 44) or incomplete (n = 17) pathological response.MTV at presentation is associated with the pathological response to neoadjuvant chemoradiation in patients with locally advanced esophageal cancer.