Esophageal adenocarcinoma with any component of signet ring cells portends poor prognosis and response to neoadjuvant therapy.

BACKGROUND: Multiple investigations have shown inferior outcomes for esophageal cancer patients with signet ring cell (SRC) histology. Traditionally, SRC adenocarcinoma has been defined by ≥50% of the tumor composed of SRC. We hypothesized that patients with SRC even <50% would show resistance to standard multimodality therapy with poorer long-term outcomes. METHODS: Patients treated with trimodality therapy for adenocarcinoma from 2006 to 2018 were evaluated for SRC on pretreatment biopsy specimens. Available hematoxylin and eosin slides containing SRC tumors were re-reviewed by an esophageal pathologist to quantify the percent composition of SRC. RESULTS: SRC histology was identified on at least 1 pathologic specimen in 106 of 819 (13%) patients. Rates of pathologic complete response (pCR) among usual-type and SRC tumors were 25% (177/713) and 10% (11/106), respectively (P = .006). The pretreatment SRC components did not independently affect the rate of pCR (1%-10% SRC: 4% [2/46] pCR; 11%-49% SRC: 25% [7/28] pCR; 50%-100% SRC: 7% [2/30] pCR). Kaplan-Meier analysis demonstrated worse survival among patients with any degree of SRC present on pretreatment biopsy, as compared with usual-type esophageal adenocarcinoma (P < .0001). Cox multivariable analysis failed to identify a relationship between increasing SRC component and poorer survival. CONCLUSIONS: We present the only known evaluation of the percentage of SRC component in esophageal carcinoma. Our data support the hypothesis that esophageal adenocarcinoma with any component of SRC are more resistant to chemoradiation with poorer survival. Pathologic reporting of esophageal adenocarcinoma should include any component of SRC. Alternative therapies in patients with any SRC component may be indicated.

Preoperative Nomogram to Risk Stratify Patients for the Benefit of Trimodality Therapy in Esophageal Adenocarcinoma.

PURPOSE: To develop a nomogram that estimates 1-year recurrence-free survival (RFS) after trimodality therapy for esophageal adenocarcinoma and to assess the overall survival (OS) benefit of esophagectomy after chemoradiotherapy (CRT) on the basis of 1-year recurrence risk. METHODS: In total, 568 consecutive patients with potentially resectable esophageal adenocarcinoma who underwent CRT were included for analysis, including 373 patients who underwent esophagectomy after CRT (trimodality therapy), and 195 who did not undergo surgery (bimodality therapy). A nomogram for 1-year RFS was created using a Cox regression model. The upper tertile of the nomogram score was used to stratify patients in low-risk and high-risk groups for 1-year recurrence. The 5-year OS was compared between trimodality and bimodality therapy in low-risk and high-risk patients after propensity score matching, respectively. RESULTS: Median follow-up for the entire cohort was 62 months. The 5-year OS in the trimodality and bimodality treatment groups was 56.3% (95% confidence interval [CI] 47.9-64.7) and 36.9% (95% CI 31.4-42.4), respectively. The final nomogram for the prediction of 1-year RFS included male gender, poor histologic grade, signet ring cell adenocarcinoma, cN1, cN2-3, and baseline SUVmax, with accurate calibration and reasonable discrimination (C-statistic: 0.66). Trimodality therapy was associated with improved 5-year OS in low-risk patients (p = 0.003), whereas it showed no significant survival benefit in high-risk patients (p = 0.302). CONCLUSIONS: The proposed nomogram estimates early recurrence risk. The addition of surgery to CRT provides a clear OS benefit in low-risk patients. The OS benefit of surgery in high-risk patients is less pronounced.

Influence of induction chemotherapy in trimodality therapy-eligible oesophageal cancer patients: secondary analysis of a randomised trial.

BACKGROUND: A randomised phase 2 trial of trimodality with or without induction chemotherapy (IC) in oesophageal cancer (EC) patients showed no advantage in overall survival (OS) or pathologic complete response rate. To identify subsets that might benefit from IC, a secondary analysis was done. METHODS: The trial had accrued 126 patients (NCT 00525915). Recursive partitioning and proportional hazards regression with interactions were performed. RESULTS: The median follow-up of surviving patients was 6.7 years and the median OS duration was 3.8 years (95% confidence interval (CI), 2.6-5.8 years). OS was associated with tumour length (P=0.03), cT (P=0.02), cN (P=0.04), clinical stage (P=0.01), and tumour grade (P<0.001). The effect of IC differed according to tumour grade. Among patients with well or moderately differentiated (WMD) ECs (n=59), the 5-year survival rate was 74% with IC and 50% without IC, P=0.001. IC had no effect on OS of patients with poorly differentiated (PD) ECs (31% and 28%, respectively; interaction, P=0.04; IC, P=0.03). In the multivariate reduced model, WMD with IC was an independent prognosticator for better OS (HR=0.41, 95% CI, 0.25-0.67; P=<0.001). The following four EC phenotypes emerged for OS: (1) very high risk (PD, cN2/N3), (2) high risk (PD, cN0/N1, stage cIII), (3) moderate risk (PD, cN0/N1, stage cI/II or WMD without IC), and (4) low risk (WMD with IC). The 5-year survival rates were 11%, 27%, 48%, and 74%, respectively (P<0.001). CONCLUSIONS: Our data show that IC significantly prolonged OS of WMD EC patients who undergo trimodality; prospective evaluation is needed.

Nuclear expression of Gli-1 is predictive of pathologic complete response to chemoradiation in trimodality treated oesophageal cancer patients.

BACKGROUND: Predictive biomarkers or signature(s) for oesophageal cancer (OC) patients undergoing preoperative therapy could help administration of effective therapy, avoidance of ineffective ones, and establishment new strategies. Since the hedgehog pathway is often upregulated in OC, we examined its transcriptional factor, Gli-1, which confers therapy resistance, we wanted to assess Gli-1 as a predictive biomarker for chemoradiation response and validate it. METHODS: Untreated OC tissues from patients who underwent chemoradiation and surgery were assessed for nuclear Gli-1 by immunohistochemistry and labelling indices (LIs) were correlated with pathologic complete response (pathCR) or

Adjuvant chemotherapy with FOLFOX for primary colorectal cancer is associated with increased somatic gene mutations and inferior survival in patients undergoing hepatectomy for metachronous liver metastases.

OBJECTIVE: We hypothesized that metachronous colorectal liver metastases (CLM) have different biology after failure of oxaliplatin (FOLFOX) compared to 5-fluorouracil (5-FU) or no chemotherapy for adjuvant treatment of colorectal cancer (CRC). BACKGROUND: It is unclear whether patients treated with liver resection for metachronous CLM after adjuvant FOLFOX for CRC have worse outcomes than those who received 5-FU or no chemotherapy. METHODS: We identified 341 patients who underwent hepatectomy for metachronous CLM (disease-free interval ≥12 months, 1993-2010). Mass-spectroscopy genotyping for somatic gene mutations in CLM was performed in a subset of 129 patients. RESULTS: Adjuvant treatment for primary CRC was FOLFOX in 77 patients, 5-FU in 169 patients, and no chemotherapy in 95 patients. Node-positive primary was comparable between FOLFOX and 5-FU but lower in the no-chemotherapy group (P < 0.0001). Median metastasis size was smaller in the FOLFOX group (2.5 cm) than in the 5-FU (3.0 cm) or no-chemotherapy (3.5 cm) groups, (P = 0.008) although prehepatectomy chemotherapy utilization, metastases number, and carcinoembryonic antigen levels were similar. Disease-free survival (DFS) and overall survival (OS) rates after hepatectomy were worse in patients treated with adjuvant FOLFOX [DFS at 3 years: 14% vs 38% (5-FU) vs 45% (no-chemo), OS at 3 years: 58% vs 70% (5-FU) vs 84% (no-chemo)]. On multivariate analysis, adjuvant FOLFOX was associated with worse DFS (P < 0.0001) and OS (P < 0.0001). Mutation analysis revealed ≥1 mutations in 57% of patients (27/47) after FOLFOX, 29% (12/41) after 5-FU, and 32% (13/41) after no chemotherapy (P = 0.011). CONCLUSIONS: Adjuvant FOLFOX for primary CRC is associated with a high rate of somatic mutations in liver metastases and inferior outcomes after hepatectomy for metachronous CLM.

Trimodality therapy without a platinum compound for localized carcinoma of the esophagus and gastroesophageal junction.

BACKGROUND: : The use of platinum-based chemoradiation for esophageal cancer is routine, but it is unclear which class of cytotoxic are optimum. It was hypothesized that chemoradiotherapy with fluoropyrimidine, taxane, and camptothecin would have preserved or improved efficacy with no compromise in safety. METHODS: : Patients with histologically confirmed, resectable esophageal carcinoma were eligible. In addition to other tests, a baseline endoscopic ultrasonography (EUS) was obtained. Patients were medically fit and had near-normal organ functions. Patients received docetaxel and irinotecan, plus 5-fluorouracil as induction therapy and then the same cytotoxics with 50.4 grays of radiotherapy followed by an attempted surgery. Pathologic complete response (pathCR) at a rate of > or =20% was the primary endpoint. The pathCR and R0 resection were correlated with overall survival (OS). Safety was documented. RESULTS: : Fifty-five patients were enrolled. Seven were women, and the median age was 56 years. Fifty-three (96%) patients had EUST3, and 41 (75%) had EUSN1 disease. Forty-three (78%) patients underwent surgery, 20% achieved a pathCR, and 76.4% underwent an R0 resection. The median survival (n = 55 patients) was 43.3 months (range, 19-75 months). Baseline clinical parameters were not found to be predictive of OS; however, patients with a pathCR (P = .005) and who underwent R0 resection (P < or = .0001) had an improved OS. There was 1 treatment-related postsurgical death reported. Grade 3 or 4 toxicity (graded according to the National Cancer Institute Common Toxicity Criteria [version 2.0]) was observed in 62% of patients. CONCLUSIONS: : The results of the current study documented that this 3-drug, noncisplatin-based chemoradiotherapy was feasible, safe, and active but not better than the published cisplatin-based chemoradiotherapy. A fluoropyrimidine and another cytotoxic (from any class) may be adequate to establish a baseline chemoradiotherapy regimen to combine biologics. Cancer 2010. (c) 2010 American Cancer Society.

Phase II trial of neoadjuvant bevacizumab, capecitabine, and radiotherapy for locally advanced rectal cancer.

PURPOSE: We designed this Phase II trial to assess the efficacy and safety of the addition of bevacizumab to concurrent neoadjuvant capecitabine-based chemoradiation in locally advanced rectal cancer. METHODS: Between April 2004 and December 2007, 25 patients with clinically staged T3N1 (n = 20) or T3N0 (n = 5) rectal cancer received neoadjuvant therapy with radiotherapy (50.4 Gy in 28 fractions over 5.5 weeks), bevacizumab every 2 weeks (3 doses of 5 mg/kg), and capecitabine (900 mg/m(2) orally twice daily only on days of radiation), followed by surgical resection a median of 7.3 weeks later. RESULTS: Procedures included abdominoperineal resection (APR; 6 patients), proctectomy with coloanal anastamosis (8 patients), low anterior resection (10 patients), and local excision (1 patient). Eight (32%) of 25 patients had a pathologic complete response, and 6 (24%) of 25 had <10% viable tumor cells in the specimen. No patient had Grade 3 hand-foot syndrome, gastrointestinal toxicity, or significant hematologic toxicity. Three wound complications required surgical intervention (one coloanal anastamostic dehiscence requiring completion APR and two perineal wound dehiscences after initial APR). Five minor complications occurred that resolved without operative intervention. With a median follow-up of 22.7 months (range, 4.5-32.4 months), all patients were alive; one patient has had a recurrence in the pelvis (2-year actuarial rate, 6.2%) and 3 had distant recurrences. CONCLUSIONS: The addition of bevacizumab to neoadjuvant chemoradiation resulted in encouraging pathologic complete response without an increase in acute toxicity. The impact of bevacizumab on perineal wound and anastamotic healing due to concurrent bevacizumab requires further study.