Justin K. Smit

A comparison of carboplatin and paclitaxel with cisplatinum and 5-fluorouracil in definitive chemoradiation in esophageal cancer patients

BACKGROUND In esophageal cancer (EC) patients who are not eligible for surgery, definitive chemoradiation (dCRT) with curative intent using cisplatinum with 5-fluorouracil (5-FU) is the standard chemotherapy regimen. Nowadays carboplatin/paclitaxel is also often used. In this study, we compared survival and toxicity rates between both regimens. PATIENTS AND METHODS This multicenter study included 102 patients treated in five centers in the Northeast Netherlands from 1996 till 2008. Forty-seven patients received cisplatinum/5-FU (75 mg/m(2) and 1 g/m(2)) and 55 patients carboplatin/paclitaxel (AUC2 and 50 mg/m(2)). RESULTS Overall survival (OS) was not different between the cisplatinum/5-FU and carboplatin/paclitaxel group {[P = 0.879, hazard ratio (HR) 0.97 [confidence interval (CI) 0.62-1.51]}, with a median survival of 16.1 (CI 11.8-20.5) and 13.8 months (CI 10.8-16.9). Median disease-free survival (DFS) was comparable [P = 0.760, HR 0.93 (CI 0.60-1.45)] between the cisplatinum/5-FU group [11.1 months (CI 6.9-15.3)] and the carboplatin/paclitaxel group [9.7 months (CI 5.1-14.4)]. Groups were comparable except clinical T stage was higher in the carboplatin/paclitaxel group (P = 0.008). High clinical T stage (cT4) was not related to OS and DFS in a univariate analysis (P = 0.250 and P = 0.201). A higher percentage of patients completed the carboplatin/paclitaxel regimen (82% versus 57%, P = 0.010). Hematological and nonhematological toxicity (≥grade 3) in the carboplatin/paclitaxel group (4% and 18%) was significantly lower than in the cisplatinum/5-FU (19% and 38%, P = 0.001). CONCLUSIONS In this study, we showed comparable outcome, in terms of DFS and OS for carboplatin/paclitaxel compared with cisplatinum/5-FU as dCRT treatment in EC patients. Toxicity rates were lower in the carboplatin/paclitaxel group together with higher treatment compliance. Carboplatin/paclitaxel as an alternative treatment of cisplatinum/5-FU is a good candidate regimen for further evaluation.BACKGROUND In esophageal cancer (EC) patients who are not eligible for surgery, definitive chemoradiation (dCRT) with curative intent using cisplatinum with 5-fluorouracil (5-FU) is the standard chemotherapy regimen. Nowadays carboplatin/paclitaxel is also often used. In this study, we compared survival and toxicity rates between both regimens. PATIENTS AND METHODS This multicenter study included 102 patients treated in five centers in the Northeast Netherlands from 1996 till 2008. Forty-seven patients received cisplatinum/5-FU (75 mg/m2 and 1 g/m2) and 55 patients carboplatin/paclitaxel (AUC2 and 50 mg/m2). RESULTS Overall survival (OS) was not different between the cisplatinum/5-FU and carboplatin/paclitaxel group {[P = 0.879, hazard ratio (HR) 0.97 [confidence interval (CI) 0.62-1.51]}, with a median survival of 16.1 (CI 11.8-20.5) and 13.8 months (CI 10.8-16.9). Median disease-free survival (DFS) was comparable [P = 0.760, HR 0.93 (CI 0.60-1.45)] between the cisplatinum/5-FU group [11.1 months (CI 6.9-15.3)] and the carboplatin/paclitaxel group [9.7 months (CI 5.1-14.4)]. Groups were comparable except clinical T stage was higher in the carboplatin/paclitaxel group (P = 0.008). High clinical T stage (cT4) was not related to OS and DFS in a univariate analysis (P = 0.250 and P = 0.201). A higher percentage of patients completed the carboplatin/paclitaxel regimen (82% versus 57%, P = 0.010). Hematological and nonhematological toxicity (≥grade 3) in the carboplatin/paclitaxel group (4% and 18%) was significantly lower than in the cisplatinum/5-FU (19% and 38%, P = 0.001). CONCLUSIONS In this study, we showed comparable outcome, in terms of DFS and OS for carboplatin/paclitaxel compared with cisplatinum/5-FU as dCRT treatment in EC patients. Toxicity rates were lower in the carboplatin/paclitaxel group together with higher treatment compliance. Carboplatin/paclitaxel as an alternative treatment of cisplatinum/5-FU is a good candidate regimen for further evaluation.

Prediction of response to radiotherapy in the treatment of esophageal cancer using stem cell markers

BACKGROUND AND PURPOSE In this study, we investigated whether cancer stem cell marker expressing cells can be identified that predict for the response of esophageal cancer (EC) to CRT. MATERIALS AND METHODS EC cell-lines OE-33 and OE-21 were used to assess in vitro, stem cell activity, proliferative capacity and radiation response. Xenograft tumors were generated using NOD/SCID mice to assess in vivo proliferative capacity and tumor hypoxia. Archival and fresh EC biopsy tissue was used to confirm our in vitro and in vivo results. RESULTS We showed that the CD44+/CD24- subpopulation of EC cells exerts a higher proliferation rate and sphere forming potential and is more radioresistant in vitro, when compared to unselected or CD44+/CD24+ cells. Moreover, CD44+/CD24- cells formed xenograft tumors faster and were often located in hypoxic tumor areas. In a study of archival pre-neoadjuvant CRT biopsy material from EC adenocarcinoma patients (N=27), this population could only be identified in 50% (9/18) of reduced-responders to neoadjuvant CRT, but never (0/9) in the complete responders (P=0.009). CONCLUSION These results warrant further investigation into the possible clinical benefit of CD44+/CD24- as a predictive marker in EC patients for the response to chemoradiation.

Prognostic factors and patterns of recurrence in esophageal cancer assert arguments for extended two-field transthoracic esophagectomy

BACKGROUND High recurrence rates determine the dismal outcome in esophageal cancer. We reviewed our experiences and defined prognostic factors and patterns of recurrences after curatively intended transthoracic esophagectomy. METHODS Between January 1991 and December 2005, 212 consecutive patients underwent a radical transthoracic esophagectomy with extended 2-field lymphadenectomy. Recurrence rates, survival, and prognostic factors were analyzed (minimal follow-up period, 2 y). RESULTS Radicality was obtained in 85.6%. The median follow-up period was 26.6 months. The overall recurrence rate at 1, 3, and 5 years was 28%, 44%, and 64%, respectively, and locoregional recurrence rate was 17%, 27%, and 43%, respectively. Overall survival rates, including postoperative deaths, were 45% and 34% at 3 and 5 years, respectively. pT stage and lymph node (LN) ratio greater than .20 were independent prognostic factors for survival and recurrences. Radicality was most prognostic for survival, and for N+ greater than 4 positive LN for recurrences. CONCLUSIONS Radicality and LN ratio are strong prognostic factors. High radicality and adequate nodal assessment are guaranteed by an extended transthoracic approach.

Residual Tumor After Neoadjuvant Chemoradiation Outside the Radiation Therapy Target Volume: A New Prognostic Factor for Survival in Esophageal Cancer

PURPOSE/OBJECTIVE(S) The aim of this study was to analyze the accuracy of gross tumor volume (GTV) delineation and clinical target volume (CTV) margins for neoadjuvant chemoradiation therapy (neo-CRT) in esophageal carcinoma at pathologic examination and to determine the impact on survival. METHODS AND MATERIALS The study population consisted of 63 esophageal cancer patients treated with neo-CRT. GTV and CTV borders were demarcated in situ during surgery on the esophagus, using anatomical reference points to provide accurate information regarding tumor location at pathologic evaluation. To identify prognostic factors for disease-free survival (DFS) and overall survival (OS), a Cox regression analysis was performed. RESULTS After resection, macroscopic residual tumor was found outside the GTV in 7 patients (11%). Microscopic residual tumor was located outside the CTV in 9 patients (14%). The median follow-up was 15.6 months. With multivariate analysis, only microscopic tumor outside the CTV (hazard ratio [HR], 4.96; 95% confidence interval [CI], 1.03-15.36), and perineural growth (HR, 5.77; 95% CI, 1.27-26.13) were identified as independent prognostic factors for OS. The 1-year OS was 20% for patients with tumor outside the CTV and 86% for those without (P<.01). For DFS, microscopic tumor outside the CTV (HR, 5.92; 95% CI, 1.89-18.54) and ypN+ (HR, 3.36; 95% CI, 1.33-8.48) were identified as independent adverse prognostic factors. The 1-year DFS was 23% versus 77% for patients with or without tumor outside the CTV (P<.01). CONCLUSIONS Microscopic tumor outside the CTV is associated with markedly worse OS after neo-CRT. This may either stress the importance of accurate tumor delineation or reflect aggressive tumor behavior requiring new adjuvant treatment modalities.

CD44, SHH and SOX2 as novel biomarkers in esophageal cancer patients treated with neoadjuvant chemoradiotherapy.

BACKGROUND AND PURPOSE Neoadjuvant chemoradiotherapy (nCRT) improves survival in esophageal cancer (EC) patients, but the response to treatment is heterogeneous and little is known regarding prognostic and predictive markers in these patients. CD44, SOX2 and SHH have been implicated in resistance to CRT, possibly through an association with a cancer stem cell phenotype. MATERIAL AND METHODS 101 EC patients treated with nCRT and surgery were included. Sufficient pre-treatment biopsy material was present in 71 patients, of which 53 patients were non-complete responders on nCRT (nCR). Protein expression was examined using immunohistochemistry (IHC). Prognostic factors were determined using Cox regression analysis for disease free survival (DFS) and cause specific survival (CSS) in the complete cohort, the pre-treatment biopsies group and post-treatment nCR group. RESULTS Low CD44 expression in the nCR group was an independent prognostic factor for both DFS and CSS (DFS HR 2.81, p=0.002 and CSS HR 3.48, p=0.002). Absent SOX2 expression in pretreatment biopsies was related to systemic recurrence (p=0.029) while low SHH in pretreatment biopsies was an independent prognostic factor for a poor DFS (HR 2.27, p=0.036). No relation between marker expression and response to nCRT was observed. CONCLUSIONS Low expression of CD44 and SHH are associated with a poor survival outcome in EC patients treated with nCRT.

Prejunctional histamine H3-receptors inhibit electrically evoked endogenous noradrenaline overflow in the portal vein of freely moving rats

Abstract The effects of intra-arterial injection of different doses of the selective histamine H3-receptor agonist R-α-methylhistamine and the selective histamine H3-receptor antagonist thioperamide on basal and electrically evoked noradrenaline overflow in the portal vein as well as on mean arterial pressure (MAP) and heart rate (HR) were investigated in permanently instrumented freely moving rats. R-α-Methylhistamine (0.01, 0.1 and 1 μmol/kg) inhibited the evoked noradrenaline overflow up to 43%, the ED50 value being 0.013 μmol/kg. Thioperamide (0.1, 0.5 and 1.0 μmol/kg) antagonized the effect of 1.0 μmol/kg R-α-methylhistamine dose-dependently, evoked overflow returning to control values at 1.0 μmol/kg of the antagonist; thioperamide alone had no effect on electrically evoked noradrenaline overflow. Basal noradrenaline levels, blood pressure and heart rate were not at all influenced by R-α-methylhistamine and thioperamide, alone or in combination. The results clearly show the presence of prejunctional histamine H3-receptors inhibiting the electrically evoked noradrenaline overflow from vascular sympathetic nerve terminals in the portal vein of freely moving rats.

Evaluation of progression prior to surgery after neoadjuvant chemoradiotherapy with computed tomography in esophageal cancer patients

BACKGROUND The risk of tumor progression during neoadjuvant chemoradiotherapy (CRT) in esophageal cancer (EC) is around 8% to 17%. We assessed the efficacy of computed tomography (CT) to identify these patients before esophagectomy. METHODS Ninety-seven patients with locally advanced EC treated with Carboplatin/Paclitaxel and 41.4 Gy neoadjuvantly were restaged with CT. Two radiologists reviewed pre- and post-CRT CT images. The primary outcome was detection of clinically relevant progressive disease. Missed metastases were defined as metastatic disease found during surgery or within 3 months after post-CRT CT. RESULTS Progressive disease was detected in 9 patients (9%). Both radiologists detected 5 patients with distant metastases (liver, n = 4; lung metastasis, n = 1), but missed progressive disease in 4 cases. One radiologist falsely assessed 2 metastatic lesions, but after agreement progressive disease was detected with sensitivity and specificity of 56% and 100%, respectively. CONCLUSION CT is effective in detecting clinically relevant progressive disease in EC patients, after neoadjuvant treatment.

Neoadjuvant therapy reduces the incidence of nodal micrometastases in esophageal adenocarcinoma

BACKGROUND We evaluated the impact of neoadjuvant chemoradiotherapy (CRT) on nodal micrometastases (NMMs) in esophageal adenocarcinoma (EAC) patients with histologically negative nodes ([y]pN0). METHODS Of 48 consecutively treated patients with neoadjuvant CRT, we selected 20 EAC ypN0 patients (group 1). These patients were matched with 20 pN0 EAC patients who had surgery alone (group 2). Harvested (y)pN0 lymph nodes were examined immunohistochemically (anti-CK8/18 [CAM 5.2]) according to a validated sentinel node protocol. A 3rd group (n = 11) staged as ypN1 after neoadjuvant CRT was used as the control group. RESULTS Upstaging to NMM+ occurred in 2 patients (10%) in group 1 and in 8 patients (40%) in group 2 (P = .028). Disease-free and overall survival rates in NMM+ patients in group 1 were worse compared with NMM- patients (P = .014 and P = .003, respectively) but comparable with ypN1 patients (n = 11). CONCLUSIONS A 30% reduction of NMM+ was obtained after neoadjuvant treatment in (y)pN0 patients. NMM+ after CRT had a negative impact on survival in ypN1 patients. These data warrant further investigation in larger prospective datasets.

Non responders to neoadjuvant chemoradiation for esophageal cancer: why better prediction is necessary

BACKGROUND Patients with pathologic limited or no response (pNR) to neoadjuvant chemoradiation (nCRT) are subjected to curative intended esophagectomy with subsequent perioperative morbidity and mortality, but potentially only harm from nCRT. The primary aim of this study was to compare the overall survival (OS) of patients with pNR and patients who underwent primary esophagectomy to evaluate potentially benefits of nCRT in these patients. The secondary aim was to identify predictive clinicopathologic factors for pNR and pathologic complete response (pCR) to nCRT with the goal to preselect these patients before the start of treatment. METHODS From the period 2005 to 2016, 206 esophageal cancer (EC) patients treated with Carboplatin/Paclitaxel and radiotherapy with complementary esophagectomy were included in this cohort. OS of patients with pNR was compared with a historical cohort of primary surgically treated patients (n=218) after a propensity score matching resulting in a group of 68 patients with pNR after nCRT versus a group of 68 primary esophagectomy patients. RESULTS The OS in the pNR group and the primary esophagectomy group was comparable (P=0.986). No predictive factors were found in this cohort for pNR. Female gender (OR 2.5, 95% CI 1.2-5.3) and squamous cell carcinoma (SCC) (OR 2.6, 95% CI 1.3-5.3) were identified as independent predictive factors for pCR. CONCLUSIONS Patients with a pNR do not benefit from nCRT followed by resection. These patients had a similar OS as those who had a primary esophagectomy alone. Although this indicates that nCRT does not negatively impact the OS of patients with pNR, patients still have an increased morbidity because of nCRT. Hence, it is important to identify factors that predict pNR. The ability to predict pNR (and pCR) will enable tailored and personalized care preventing unnecessary nCRT with increased morbidity.

Evaluation of esophageal carcinoma for a radioresistant subpopulation with cancer stem cell characteristics.

36 Background: Neo-adjuvant chemoradiation is considered as standard treatment in esophageal cancer (EC). However, a significant proportion of these tumors do not respond well to radiotherapy. Here, we investigated the presence of radioresistant cells in EC with cancer stem cell characteristics. METHODS EC OE-33 adenotype and OE-21 squamous cell carcinoma cell-lines and fresh tumor material of EC patients were analyzed for common CSC-markers with Fluorecence Activated Cell Sorting (FACS) and immunohistochemistry. Subpopulations were tested for clonogenic survival to determine radioresistance. Non-adherent 3D sphere-cultures and xenograft tumors generated in NOD/SCID mice were performed to investigate stem cell properties. RESULTS Both cell lines lacked expression of CD133 and CD90, whereas the expression of EpCam overlapped with CD44 in OE-33. In sub-confluent cultures the expression of CD44+/CD24- was 5.6% SD ± 2.3 and 35.1% SD ± 1.3 in OE-33 and OE-21, respectively. In a clonogenic survival assay the CD44+/CD24- cells showed up to a 2-fold lower radiosensitivity compared to CD44+/CD24+ cells in both the OE-33 (p = 0.02) and the OE-21 cell line (p = 0.01). The CD44+/CD24- subpopulation had a 2.2-fold higher sphere-forming capacity compared to the CD44+/CD24+ subset (p = 0.01) in OE-33. Analysis of the spheres showed an enrichment in the CD44+/CD24- phenotype from 5.6% to 56.4% (p = 0.01) after 4 days of culturing as measured by FACS, but differentiated to a higher percentage of CD44+/CD24+ in time. Furthermore, CD44+/CD24- cells exhibited a greater in vivo tumor initiating capacity, shorter latency time and faster growth speed compared with unsorted or CD44+/CD24+ cells. Importantly, a clear CD44+/CD24- population could be identified in fresh EC biopsies of patients. CONCLUSIONS EC appear to contain a radioresistant CD44+/CD24- subpopulation. This phenotype displays some CSC characteristics in vitro and in vivo and is present in human EC tumors. This marker could be used in future trials to predict tumor response. No significant financial relationships to disclose.