Chemotherapy followed by surgery versus surgery alone in patients with resectable oesophageal squamous cell carcinoma: Long-term results of a randomized controlled trial

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Download date: 01 Jul 2019 R E S E A R C H A R T I C L E Open Access Chemotherapy followed by surgery versus surgery alone in patients with resectable oesophageal squamous cell carcinoma: Longterm results of a randomized controlled trial Abstract Background: This is a randomized, controlled trial of preoperative chemotherapy in patients undergoing surgery for oesophageal squamous cell carcinoma (OSCC). Patients were allocated to chemotherapy, consisting of 2-4 cycles of cisplatin and etoposide, followed by surgery (CS group) or surgery alone (S group). Initial results reported only in abstract form in 1997, demonstrated an advantage for overall survival in the CS group. The results of this trial have been updated and discussed in the timeframe in which this study was performed. Methods: This trial recruited 169 patients with OSCC, 85 patients assigned to preoperative chemotherapy and 84 patients underwent immediate surgery. The primary study endpoint was overall survival (OS), secondary endpoints were disease free survival (DFS) and pattern of failure. Survival has been determined from Kaplan-Meier curves and treatment comparisons made with the log-rank test. Results: There were 148 deaths, 71 in the CS and 77 in the S group. Median OS time was 16 months in the CS group compared with 12 months in the S group; 2-year survival rates were 42% and 30%; and 5-year survival rates were 26% and 17%, respectively. Intention to treat analysis showed a significant overall survival benefit for patients in the CS group (P = 0.03, by the log-rank test; hazard ratio [HR] 0.71; 95%CI 0.51-0.98). DFS (from landmark time of 6 months after date of randomisation) was also better in the CS-group than in the S group (P = 0.02, by the logrank test; HR 0.72; 95%CI 0.52-1.0). No difference in failure pattern was observed between both treatment arms. Conclusions: Preoperative chemotherapy with a combination of etoposide and cisplatin significantly improved overall survival in patients with OSCC. Background Oesophageal squamous cell carcinoma (OSCC) accounts for most cases of oesophageal cancer worldwide The potential benefits of preoperative chemotherapy include increasing the likelihood of curative resection by downstaging the tumour and rapidly improving tumourrelated symptoms. It is also been thought that systemic chemotherapy could contribute to the eradication of micro-metastases and circulating tumour cells. More recently, the importance of systemic disease control has been emphasized by new insights in the metastasizing process of cancer Methods All eligible patients had histologically confirmed squamous cell carcinoma of the intra-thoracic ooesophagus. Patients were deemed resectable if the disease was clinically limited to the locoregional area (tumour stage 1, 2 or 3; any nodal stage and no metastases). Patients with carcinoma of the distal oesophagus and suspected celiac lymph nodes involvement (M1a) were also considered eligible for surgery. Patients had to be below 80 years of age, in adequate physical condition (Karnofsky score >70) to undergo surgery and had to have adequate hepatic, renal and bone marrow function. Exclusion criteria were synchronous cancer, tumour localization in the cervical ooesophagus (upper border, <18 cm from the incisor teeth), severe cardiovascular or pulmonary disease. Patients with previous malignancies were eligible if more than 5 years had elapsed from diagnosis without evidence of tumour recurrence; exceptions were made for adequately treated basal cell cancer of the skin or carcinoma in situ of the cervix. Preoperative work-up included clinical examination, oesophago-gastroscopy with biopsies, chest radiography, external ultrasonography of the cervical and upper abdominal region and computed tomography (CT) of the chest and abdomen. Radionuclide bone scans were performed if indicated. Bronchoscopy was performed when the primary tumour was adjacent to the trachea or main stem bronchus and invasion was suspected. Central randomisation took place at the Erasmus University Medical Center in Rotterdam (by trial coordinator TCK). Random assignment was stratified by age (<50; 51-60; >60), gender (male; female), weight loss (kg) in the past four months (0-5; 6-10; >10) and length of the tumour (cm) as measured by oesophago-gastroscopy (1-3; 4-6; 7-10; >10). Patients assigned to preoperative chemotherapy were treated with two cycles, followed by a clinical response evaluation. Response evaluation was done three to four weeks after the last cycle of chemotherapy. Clinical response after chemotherapy was evaluated by oesophago-gastroscopy and CT of the chest and abdomen. Tumour responses were assessed according to the World Health Organisation (WHO) criteria Chemotherapy Cisplatin, at a dose of 80 mg/m 2 , was given intravenously over 4 hours on day one of each cycle preceded and followed by adequate hydration. Etoposide, at a dose of 100 mg/m 2 , was administered intravenously over 2 hours on day 1 (before cisplatin) and day 2, followed by etoposide 200 mg/m 2 orally on days 3 and 5. This course was repeated in week 4. In case of clinical response, two subsequent courses of chemotherapy were administered in week 8 and 11. All patients received prophylactic anti-nausea treatment with 5-HT 3 receptor antagonists during chemotherapy. Treatment related toxicities were measured according to the WHO recommendations Surgery and pathological examination For carcinomas of the upper half of the intra-thoracic ooesophagus a right-sided thoracotomy was performed. For carcinomas of the lower half of the intra-thoracic ooesophagus a transhiatal oesophagectomy was done. The tumour and its adjacent lymph nodes were dissected en bloc. The left gastric artery was transected at its origin, with resection of local lymph nodes. The continuity of the digestive tract was restored by means of gastric tube reconstruction or colonic interposition with a cervical anastomosis. The tumour stage after resection Boonstra et al. BMC Cancer 2011, 11:181 http://www.biomedcentral.com/1471-2407/11/181 Page 2 of 10 was classified according to the TNM classification of the International Union Against Cancer Follow-up All patients were followed at an interval of three to four months during the first year, every six months for the second year, and annually for up to 5 years post surgery. After 5 years, follow-up data were obtained by telephone from the patient or his/her family practitioner. Recurrence of disease was diagnosed on clinical grounds. However, whenever a relapse was suspected, radiologic, endoscopic, or histologic confirmation was sought for. Loco-regional disease recurrence was defined as relapse at the primary site including the anastomosis or in regional lymph nodes. Distant disease recurrence was defined as distant lymph node sites or involvement of distant organs including lung, liver, bone, and subcutaneous tissue. Statistical analysis The planned number of patients to be entered in the study was 80 for each treatment arm. With these numbers of patients the statistical power should be sufficient (power = 0.8; significance 0.05) to detect an increase of the median survival from 10 to 18 months. Overall survival (OS) was calculated from the date of random assignment to date of death from any cause and surviving patients were censored at the date they were last known to be alive. Disease-free survival (DFS) was calculated from a landmark time of 6 months after date of randomisation to allow for the difference in timing of surgery between the two treatment groups Statistical analyses were performed using the SPSS statistical package (SPSS Inc., Chicago, IL, USA). Hazard ratios (HR) were calculated with the use of a Cox regression model including treatment alone (primary analysis) and after adjustment for baseline stratification factors. Categorical data were compared with the use of chi-square test or Fisher's exact test, with a test for trend over ordered categories. All statistical comparisons were made with two-tailed tests and P values < 0.05 were reported as significant. Results Between January, 1989, and January, 1996, 169 patients from six Dutch University Hospitals (Rotterdam, Amsterdam, Utrecht, Groningen, Nijmegen and Maastricht) were randomly assigned to either chemotherapy followed by surgery (CS group, N = 85) or surgery alone (S group, N = 84; Chemotherapy Of the 85 patients assigned to preoperative chemotherapy, 80 (94%) received chemotherapy; 75 (88%) patients had two or more cycles and 5 patients (13%) received one cycle. The reasons why no chemotherapy or only one cycle was given were patient's refusal (N = 3), death (N = 1), tumour bleeding (N = 3) and renal toxicity grade III (N = 1). Two patients allocated to preoperative chemotherapy, were directly lost to follow-up after randomization. Tracing back the original patient's files was impossible; therefore, it is not clear if these two patients truly received chemotherapy followed by surgery. Clinical response evaluation after two cycles of chemotherapy showed 43 patients with stable or progressive disease. Partial response to chemotherapy was observed in 32 patients. Of these, 30 patients received two additional cycles of chemotherapy; one received one additional cycle and one had three additional cycles of chemotherapy. Clinical response evaluation after the additional cycles of chemotherapy showed six patients with complete response; 20 patients had partial response; five showed stable disease and one had progressive disease. Detailed data on chemotherapy related toxicity is not available. In the prior phase II trial a high rate of grade III and IV nausea (38%) and vomiting (20%) was observed, probably due to the fact that 5-HT3 receptor blockers were rarely given throughout the study period Outcome of surgery Surgery was performed in 76 CS and 82 S patients Data on postoperative complications was available of 67/76 (88%) of patients in the CS group and 75/82 (91%) patient in the S group. The frequency of nonfatal postoperative events was closely similar in both groups Oesophagectomy was performed in 91% (69/76) in the CS-group and 85% (70/82) in the S-group. In the CS group, six patients did not receive an oesphagectomy because of tumour growth in adjacent structures (aorta or bronchial tree) and one had tumour positive celiac lymph nodes at laparotomy. In the S group, seven patients did not undergo surgical resection because of tumour encasement of the aorta or the bronchial tree and five due to tumour positive celiac lymph nodes at laparotomy. Of the 69 patients in the CS group who underwent surgical resection, 71% had R0 resections, 25% had R1 resections, and 4% had R2 resections. Of the 70 patients in the S group who underwent surgical resection, 57% had R0 resections, 29% had R1 resections, and 14% had R2 resections. Although more patients in the CS group had R0 resections as compared with the S group, no significant differences was observed (P = 0.09). However, there was a significant difference between the number of R2 resections in both treatment arm (P = 0.04). Also the number of patients with lymph node involvement (N1 or M1a) did not differ between both treatment arms (43 and 46% in the CS group and S group, respectively). In the CS group, the pathological complete response rate (pT0N0M0) was 7%. Pattern of failure The outcomes of treatments were considered according to findings at operation and to patterns of disease progression (first disease-free survival event; Overall and disease-free survival At the time of analysis, the median follow-up was 15 months in the CS group and 14 months in the S group. In an intention-to-treat survival analysis, two patients that were directly lost to follow-up were censored one month after the date of randomization. OS on intention to treat basis is shown in Overall survival according clinical response to preoperative chemotherapy showed that patients with clinical partial or complete response (those who received three or more cycles of therapy) had significantly better overall survival then those with stable or progressive disease (P = <0.001, by log-rank test; HR 0.38; 95%CI 0.23-0.65). Discussion The long-term results of this randomized controlled trial demonstrated a survival benefit for preoperative chemotherapy followed by surgery in patients with OSCC, when compared with surgery alone. This study has only been reported in abstract form, which hampers interpretation of our findings in context of other randomized trial

Endoglin and squamous cell carcinomas

Despite the fact that the role of endoglin on endothelial cells has been extensively described, its expression and biological role on (epithelial) cancer cells is still debatable. Especially its function on squamous cell carcinoma (SCC) cells is largely unknown. Therefore, we investigated SCC endoglin expression and function in three types of SCCs; head and neck (HNSCC), esophageal (ESCC) and vulvar (VSCC) cancers. Endoglin expression was evaluated in tumor specimens and 14 patient-derived cell lines. Next to being expressed on angiogenic endothelial cells, endoglin is selectively expressed by individual SCC cells in tumor nests. Patient derived HNSCC, ESCC and VSCC cell lines express varying levels of endoglin with high interpatient variation. To assess the function of endoglin in signaling of TGF-β ligands, endoglin was overexpressed or knocked out or the signaling was blocked using TRC105, an endoglin neutralizing antibody. The endoglin ligand BMP-9 induced strong phosphorylation of SMAD1 independent of expression of the type-I receptor ALK1. Interestingly, we observed that endoglin overexpression leads to strongly increased soluble endoglin levels, which in turn decreases BMP-9 signaling. On the functional level, endoglin, both in a ligand dependent and independent manner, did not influence proliferation or migration of the SCC cells. In conclusion, these data show endoglin expression on individual cells in the tumor nests in SCCs and a role for (soluble) endoglin in paracrine signaling, without directly affecting proliferation or migration in an autocrine manner.</p

Low risk of local recurrence after a successful en bloc Endoscopic Submucosal Dissection for non-invasive colorectal lesions with positive horizontal resection margins(R-ESD study)

BACKGROUND : During endoscopic submucosal dissection (ESD), the normal mucosa is cut under constant optical control. We studied whether a positive horizontal resection margin after a complete en bloc ESD predicts local recurrence. METHODS:  In this European multicenter cohort study, patients with a complete en bloc colorectal ESD were selected from prospective registries. Cases were defined by a horizontal resection margin that was positive or indeterminate for dysplasia (HM1), whereas controls had a free resection margin (HM0). Low risk lesions with submucosal invasion (T1) and margins free of carcinoma were analyzed separately. The main outcome was local recurrence. RESULTS:  From 928 consecutive ESDs (2011-2020), 354 patients (40 % female; mean age 67 years, median follow-up 23.6 months), with 308 noninvasive lesions and 46 T1 lesions, were included. The recurrence rate for noninvasive lesions was 1/212 (0.5 %; 95 %CI 0.02 %-2.6 %) for HM0 vs. 2/96 (2.1 %; 95 %CI 0.57 %-7.3 %) for HM1. The recurrence rate for T1 lesions was 1/38 (2.6 %; 95 %CI 0.14 %-13.5 %) for HM0 vs. 2/8 (25 %; 95 %CI 7.2 %-59.1 %) for HM1. CONCLUSION:  A positive horizontal resection margin after an en bloc ESD for noninvasive lesions is associated with a marginal nonsignificant increase in the local recurrence rate, equal to an ESD with clear horizontal margins. This could not be confirmed for T1 lesions

Active surveillance of oesophageal cancer after response to neoadjuvant chemoradiotherapy:dysphagia is uncommon

BACKGROUND: Active surveillance is being investigated as an alternative to standard surgery after neoadjuvant chemoradiotherapy for oesophageal cancer. It is unknown whether dysphagia persists or develops when the oesophagus is preserved after neoadjuvant chemoradiotherapy. The aim of this study was to assess the prevalence and severity of dysphagia during active surveillance in patients with an ongoing response. METHODS: Patients who underwent active surveillance were identified from the Surgery As Needed for Oesophageal cancer ('SANO') trial. Patients without evidence of residual oesophageal cancer until at least 6 months after neoadjuvant chemoradiotherapy were included. Study endpoints were assessed at time points that patients were cancer-free and remained cancer-free for the next 4 months. Dysphagia scores were evaluated at 6, 9, 12, and 16 months after neoadjuvant chemoradiotherapy. Scores were based on the European Organisation for Research and Treatment of Cancer oesophago-gastric quality-of-life questionnaire 25 (EORTC QLQ-OG25) (range 0-100; no to severe dysphagia). The rate of patients with a (non-)traversable stenosis was determined based on all available endoscopy reports. RESULTS: In total, 131 patients were included, of whom 93 (71.0 per cent) had adenocarcinoma, 93 (71.0 per cent) had a cT3-4a tumour, and 33 (25.2 per cent) had a tumour circumference of greater than 75 per cent at endoscopy; 60.8 to 71.0 per cent of patients completed questionnaires per time point after neoadjuvant chemoradiotherapy. At all time points after neoadjuvant chemoradiotherapy, median dysphagia scores were 0 (interquartile range 0-0). Two patients (1.5 per cent) underwent an intervention for a stenosis: one underwent successful endoscopic dilatation; and the other patient required temporary tube feeding. Notably, these patients did not participate in questionnaires. CONCLUSION: Dysphagia and clinically relevant stenosis are uncommon during active surveillance.</p

Active surveillance of oesophageal cancer after response to neoadjuvant chemoradiotherapy:dysphagia is uncommon

BACKGROUND: Active surveillance is being investigated as an alternative to standard surgery after neoadjuvant chemoradiotherapy for oesophageal cancer. It is unknown whether dysphagia persists or develops when the oesophagus is preserved after neoadjuvant chemoradiotherapy. The aim of this study was to assess the prevalence and severity of dysphagia during active surveillance in patients with an ongoing response. METHODS: Patients who underwent active surveillance were identified from the Surgery As Needed for Oesophageal cancer ('SANO') trial. Patients without evidence of residual oesophageal cancer until at least 6 months after neoadjuvant chemoradiotherapy were included. Study endpoints were assessed at time points that patients were cancer-free and remained cancer-free for the next 4 months. Dysphagia scores were evaluated at 6, 9, 12, and 16 months after neoadjuvant chemoradiotherapy. Scores were based on the European Organisation for Research and Treatment of Cancer oesophago-gastric quality-of-life questionnaire 25 (EORTC QLQ-OG25) (range 0-100; no to severe dysphagia). The rate of patients with a (non-)traversable stenosis was determined based on all available endoscopy reports. RESULTS: In total, 131 patients were included, of whom 93 (71.0 per cent) had adenocarcinoma, 93 (71.0 per cent) had a cT3-4a tumour, and 33 (25.2 per cent) had a tumour circumference of greater than 75 per cent at endoscopy; 60.8 to 71.0 per cent of patients completed questionnaires per time point after neoadjuvant chemoradiotherapy. At all time points after neoadjuvant chemoradiotherapy, median dysphagia scores were 0 (interquartile range 0-0). Two patients (1.5 per cent) underwent an intervention for a stenosis: one underwent successful endoscopic dilatation; and the other patient required temporary tube feeding. Notably, these patients did not participate in questionnaires. CONCLUSION: Dysphagia and clinically relevant stenosis are uncommon during active surveillance.</p

Outcome of Completion Surgery after Endoscopic Submucosal Dissection in Early-Stage Colorectal Cancer Patients

T1 colorectal cancers (T1CRC) are increasingly being treated by endoscopic submucosal dissection (ESD). After ESD of a T1CRC, completion surgery is indicated in a subgroup of patients. Currently, the influence of ESD on surgical morbidity and mortality is unknown. The aim of this study was to compare 90-day morbidity and mortality of completion surgery after ESD to primary surgery. The completion surgery group consisted of suspected T1CRC patients from a multicenter prospective ESD database (2014–2020). The primary surgery group consisted of pT1CRC patients from a nationwide surgical registry (2017–2019). Patients with rectal or sigmoidal cancers were selected. Patients receiving neoadjuvant therapy were excluded. Propensity score adjustment was used to correct for confounders. In total, 411 patients were included: 54 in the completion surgery group (39 pT1, 15 pT2) and 357 in the primary surgery group with pT1CRC. Adverse event rate was 24.1% after completion surgery and 21.3% after primary surgery. After completion surgery 90-day mortality did not occur, though one patient died in the primary surgery group. After propensity score adjustment, lymph node yield did not differ significantly between the groups. Among other morbidity-related outcomes, stoma rate (OR 1.298 95%-CI 0.587-2.872, p = 0.519) and adverse event rate (OR 1.162; 95%-CI 0.570-2.370, p = 0.679) also did not differ significantly. A subgroup analysis was performed in patients undergoing rectal surgery. In this subgroup (37 completion and 136 primary surgery), these morbidity outcomes also did not differ significantly. In conclusion, this study suggests that ESD does not compromise morbidity or 90-day mortality of completion surgery

Chemotherapy followed by surgery versus surgery alone in patients with resectable oesophageal squamous cell carcinoma: Long-term results of a randomized controlled trial

Background: This is a randomized, controlled trial of preoperative chemotherapy in patients undergoing surgery for oesophageal squamous cell carcinoma (OSCC). Patients were allocated to chemotherapy, consisting of 2-4 cycles of cisplatin and etoposide, followed by surgery (CS group) or surgery alone (S group). Initial results reported only in abstract form in 1997, demonstrated an advantage for overall survival in the CS group. The results of this trial have been updated and discussed in the timeframe in which this study was performed.Methods: This trial recruited 169 patients with OSCC, 85 patients assigned to preoperative chemotherapy and 84 patients underwent immediate surgery. The primary study endpoint was overall survival (OS), secondary endpoints were disease free survival (DFS) and pattern of failure. Survival has been determined from Kaplan-Meier curves and treatment comparisons made with the log-rank test.Results: There were 148 deaths, 71 in the CS and 77 in the S group. Median OS time was 16 months in the CS group compared with 12 months in the S group; 2-year survival rates were 42% and 30%; and 5-year survival rates were 26% and 17%, respectively. Intention to treat analysis showed a significant overall survival benefit for patients in the CS group (P = 0.03, by the log-rank test; hazard ratio [HR] 0.71; 95%CI 0.51-0.98). DFS (from landmark time of 6 months after date of randomisation) was also better in the CS-group than in the S group (P = 0.02, by the log-rank test; HR 0.72; 95%CI 0.52-1.0). No difference in failure pattern was observed between both treatment arms.Conclusions: Preoperative chemotherapy with a combination of etoposide and cisplatin significantly improved overall survival in patients with OSCC

Endoscopic full-thickness resection of T1 colorectal cancers:a retrospective analysis from a multicenter Dutch eFTR registry

Background Complete endoscopic resection and accurate histological evaluation for T1 colorectal cancer (CRC) are critical in determining subsequent treatment. Endoscopic full-thickness resection (eFTR) is a new treatment option for T1 CRC<2cm. We aimed to report clinical outcomes and short-term results. Methods Consecutive eFTR procedures for T1 CRC, prospectively recorded in our national registry between November 2015 and April 2020, were retrospectively analyzed. Primary outcomes were technical success and R0 resection. Secondary outcomes were histological risk assessment, curative resection, adverse events, and short-term outcomes. Results We included 330 procedures: 132 primary resections and 198 secondary scar resections after incomplete T1 CRC resection. Overall technical success, R0 resection, and curative resection rates were 87.0% (95% confidence interval [CI] 82.7%-90.3%), 85.6% (95%CI 81.2%-89.2%), and 60.3% (95%CI 54.7%-65.7%). Curative resection rate was 23.7% (95%CI 15.9%-33.6%) for primary resection of T1 CRC and 60.8% (95%CI 50.4%-70.4%) after excluding deep submucosal invasion as a risk factor. Risk stratification was possible in 99.3%. The severe adverse event rate was 2.2%. Additional oncological surgery was performed in 49/320 (15.3%), with residual cancer in 11/49 (22.4%). Endoscopic follow-up was available in 200/242 (82.6%), with a median of 4 months and residual cancer in 1 (0.5%) following an incomplete resection. Conclusions eFTR is relatively safe and effective for resection of small T1 CRC, both as primary and secondary treatment. eFTR can expand endoscopic treatment options for T1 CRC and could help to reduce surgical overtreatment. Future studies should focus on long-term outcomes

Functional Polymorphisms Associated with Disease-Free Survival in Resected Carcinoma of the Esophagus

Purpose: The aim of this study was to determine whether clinical outcome after surgical resection of esophageal adenocarcinoma (EAC) or esophageal squamous cell carcinoma (ESCC) could be predicted by functional polymorphisms in different proto-oncogenes and tumor suppressor genes. Experimental De

Correction: Predicting procedure duration of colorectal endoscopic submucosal dissection at Western endoscopy centers

[This corrects the article DOI: 10.1055/a-2122-0419.]