Pathologic Lymph Node Regression After Neoadjuvant Chemotherapy Predicts Recurrence and Survival in Esophageal Adenocarcinoma: A Multicenter Study in the United Kingdom.

PURPOSE: There is limited evidence regarding the prognostic effects of pathologic lymph node (LN) regression after neoadjuvant chemotherapy for esophageal adenocarcinoma, and a definition of LN response is lacking. This study aimed to evaluate how LN regression influences survival after surgery for esophageal adenocarcinoma. METHODS: Multicenter cohort study of patients with esophageal adenocarcinoma treated with neoadjuvant chemotherapy followed by surgical resection at five high-volume centers in the United Kingdom. LNs retrieved at esophagectomy were examined for chemotherapy response and given a LN regression score (LNRS)-LNRS 1, complete response; 2, <10% residual tumor; 3, 10%-50% residual tumor; 4, >50% residual tumor; and 5, no response. Survival analysis was performed using Cox regression adjusting for confounders including primary tumor regression. The discriminatory ability of different LN response classifications to predict survival was evaluated using Akaike information criterion and Harrell C-index. RESULTS: In total, 17,930 LNs from 763 patients were examined. LN response classified as complete LN response (LNRS 1 ≥1 LN, no residual tumor in any LN; n = 62, 8.1%), partial LN response (LNRS 1-3 ≥1 LN, residual tumor ≥1 LN; n = 155, 20.3%), poor/no LN response (LNRS 4-5; n = 303, 39.7%), or LN negative (no tumor/regression; n = 243, 31.8%) demonstrated superior discriminatory ability. Mortality was reduced in patients with complete LN response (hazard ratio [HR], 0.35; 95% CI, 0.22 to 0.56), partial LN response (HR, 0.72; 95% CI, 0.57 to 0.93) or negative LNs (HR, 0.32; 95% CI, 0.25 to 0.42) compared with those with poor/no LN response. Primary tumor regression and LN regression were discordant in 165 patients (21.9%). CONCLUSION: Pathologic LN regression after neoadjuvant chemotherapy was a strong prognostic factor and provides important information beyond pathologic TNM staging and primary tumor regression grading. LN regression should be included as standard in the pathologic reporting of esophagectomy specimens.

Association of dynamic contrast-enhanced MRI and 18F-Fluorodeoxyglucose PET/CT parameters with neoadjuvant therapy response and survival in esophagogastric cancer.

INTRODUCTION: Better predictive markers are needed to deliver individualized care for patients with primary esophagogastric cancer. This exploratory study aimed to assess whether pre-treatment imaging parameters from dynamic contrast-enhanced MRI and 18F-fluorodeoxyglucose (18F-FDG) PET/CT are associated with response to neoadjuvant therapy or outcome. MATERIALS AND METHODS: Following ethical approval and informed consent, prospective participants underwent dynamic contrast-enhanced MRI and 18F-FDG PET/CT prior to neoadjuvant chemotherapy/chemoradiotherapy ± surgery. Vascular dynamic contrast-enhanced MRI and metabolic 18F-FDG PET parameters were compared by tumor characteristics using Mann Whitney U test and with pathological response (Mandard tumor regression grade), recurrence-free and overall survival using logistic regression modelling, adjusting for predefined clinical variables. RESULTS: 39 of 47 recruited participants (30 males; median age 65 years, IQR: 54, 72 years) were included in the final analysis. The tumor vascular-metabolic ratio was higher in patients remaining node positive following neoadjuvant therapy (median tumor peak enhancement/SUVmax ratio: 0.052 vs. 0.023, p = 0.02). In multivariable analysis adjusted for age, gender, pre-treatment tumor and nodal stage, peak enhancement (highest gadolinium concentration value prior to contrast washout) was associated with pathological tumor regression grade. The odds of response decreased by 5% for each 0.01 unit increase (OR 0.95; 95% CI: 0.90, 1.00, p = 0.04). No 18F-FDG PET/CT parameters were predictive of pathological tumor response. No relationships between pre-treatment imaging and survival were identified. CONCLUSION: Pre-treatment esophagogastric tumor vascular and metabolic parameters may provide additional information in assessing response to neoadjuvant therapy.

Metabolic tumour and nodal response to neoadjuvant chemotherapy on FDG PET-CT as a predictor of pathological response and survival in patients with oesophageal adenocarcinoma.

OBJECTIVES: 2-deoxy-2[18F]Fluoro-D-glucose (FDG) PET-CT has an emerging role in assessing response to neoadjuvant therapy in oesophageal cancer. This study evaluated FDG PET-CT in predicting pathological tumour response (pTR), pathological nodal response (pNR) and survival. METHODS: Cohort study of 75 patients with oesophageal or oesophago-gastric junction (GOJ) adenocarcinoma treated with neoadjuvant chemotherapy then surgery at Guy's and St Thomas' NHS Foundation Trust, London (2017-2020). Standardised uptake value (SUV) metrics on pre- and post-treatment FDG PET-CT in the primary tumour (mTR) and loco-regional lymph nodes (mNR) were derived. Optimum SUVmax thresholds for predicting pathological response were identified using receiver operating characteristic analysis. Predictive accuracy was compared to PERCIST (30% SUVmax reduction) and MUNICON (35%) criteria. Survival was assessed using Cox regression. RESULTS: Optimum tumour SUVmax decrease for predicting pTR was 51.2%. A 50% cut-off predicted pTR with 73.5% sensitivity, 69.2% specificity and greater accuracy than PERCIST or MUNICON (area under the curve [AUC] 0.714, PERCIST 0.631, MUNICON 0.659). Using a 30% SUVmax threshold, mNR predicted pNR with high sensitivity but low specificity (AUC 0.749, sensitivity 92.6%, specificity 57.1%, p = 0.010). pTR, mTR, pNR and mNR were independent predictive factors for survival (pTR hazard ratio [HR] 0.10 95% confidence interval [CI] 0.03-0.34; mTR HR 0.17 95% CI 0.06-0.48; pNR HR 0.17 95% CI 0.06-0.54; mNR HR 0.13 95% CI 0.02-0.66). CONCLUSIONS: Metabolic tumour and nodal response predicted pTR and pNR, respectively, in patients with oesophageal or GOJ adenocarcinoma. However, currently utilised response criteria may not be optimal. pTR, mTR, pNR and mNR were independent predictors of survival. KEY POINTS: • FDG PET-CT has an emerging role in evaluating response to neoadjuvant therapy in patients with oesophageal cancer. • Prospective cohort study demonstrated that metabolic response in the primary tumour and lymph nodes was predictive of pathological response in a cohort of patients with adenocarcinoma of the oesophagus or oesophago-gastric junction treated with neoadjuvant chemotherapy followed by surgical resection. • Patients who demonstrated a response to neoadjuvant chemotherapy in the primary tumour or lymph nodes on FDG PET-CT demonstrated better survival and reduced rates of tumour recurrence.

Exercise prehabilitation during neoadjuvant chemotherapy may enhance tumour regression in oesophageal cancer: results from a prospective non-randomised trial.

BACKGROUND: There is increasing evidence for the use of exercise in cancer patients and data supporting enhanced tumour volume reduction following chemotherapy in animal models. To date, there is no reported histopathological evidence of a similar oncological benefit in oesophageal cancer. METHODS: A prospective non-randomised trial compared a structured prehabilitation exercise intervention during neoadjuvant chemotherapy and surgery versus conventional best-practice for oesophageal cancer patients. Biochemical and body composition analyses were performed at multiple time points. Outcome measures included radiological and pathological markers of disease regression. Logistic regression calculated ORs with 95% CI for the likelihood of pathological response adjusting for chemotherapy regimen and chemotherapy delivery. RESULTS: Comparison of the Intervention (n=21) and Control (n=19) groups indicated the Intervention group had higher rates of tumour regression (Mandard TRG 1-3 Intervention n=15/20 (75%) vs Control n=7/19 (36.8%) p=0.025) including adjusted analyses (OR 6.57; 95% CI 1.52 to 28.30). Combined tumour and node downstaging (Intervention n=9 (42.9%) vs Control n=3 (15.8%) p=0.089) and Fat Free Mass index were also improved (Intervention 17.8 vs 18.7 kg/m2; Control 16.3 vs 14.7 kg/m2, p=0.026). Differences in markers of immunity (CD-3 and CD-8) and inflammation (IL-6, VEGF, INF-y, TNFa, MCP-1 and EGF) were observed. CONCLUSION: The results suggest improved tumour regression and downstaging in the exercise intervention group and should prompt larger studies on this topic. TRIAL REGISTRATION NUMBER: NCT03626610.

Effect of peri-operative chemotherapy regimen on survival in the treatment of locally advanced oesophago-gastric adenocarcinoma - A comparison of the FLOT and 'MAGIC' regimens.

BACKGROUND: Peri-operative chemotherapy improves survival in patients with locally advanced oesophago-gastric adenocarcinoma. Two regimens with proven survival benefits are epirubicin, cisplatin plus capecitabine or fluorouracil (Medical Research Council Adjuvant Gastric Infusional Chemotherapy, MAGIC) and fluorouracil plus leucovorin, oxaliplatin, and docetaxel (FLOT). This study aimed to compare the effect of these regimens on survival (primary aim) and pathological response, surgical complications, adverse events and chemotherapy completion rates. METHODS: Cohort study including 946 patients treated with FLOT (n = 257) or MAGIC (n = 689) who underwent surgical resection for oesophageal (n = 743) or gastric (n = 203) adenocarcinoma between 2002 and 2021 at St Thomas' Hospital or The Royal Marsden Hospital, London, UK. Survival analysis was performed using multivariable Cox regression, providing hazard ratios (HRs) with 95% confidence intervals (CIs) adjusted for age, sex, clinical T-stage, clinical N-stage, tumour grade and presence of signet ring cells. RESULTS: Patients treated with FLOT had better overall survival (HR = 0.69, 95% CI 0.50-0.94) and disease-free survival (HR = 0.75, 95% CI 0.58-0.98) than MAGIC. Patients treated with FLOT were more likely to have a complete pathological response (9.5% FLOT versus 5.5% MAGIC, p = 0.027) and were less likely to have a positive resection margin (19.1% FLOT versus 32.2% MAGIC, p < 0.001). The stratified analysis revealed similar results for oesophageal and gastric tumours. Rates of surgical complications, chemotherapy-associated adverse events and completion were similarly distributed between treatment groups. CONCLUSIONS: Patients with oesophageal or gastric adenocarcinoma treated with peri-operative FLOT had better survival and pathological response than those treated with peri-operative MAGIC. Rates of surgical complications, adverse events and chemotherapy completion were comparable.

Predicting response to neoadjuvant chemotherapy in patients with oesophageal adenocarcinoma.

BACKGROUND: Neoadjuvant chemotherapy is often used prior to surgical resection for oesophageal adenocarcinoma but remains ineffective in a high proportion of patients. The histological Mandard tumour regression grade is used to determine chemoresponse but is not available at the time of treatment decision-making. The aim of this cohort study was to identify factors that predict chemotherapy response prior to surgery. METHODS: A prospectively collected database of patients undergoing surgical resection for oesophageal adenocarcinoma from a high-volume UK institution was used. Patients were subcategorised using pathological tumour response into 'responders' (Mandard grade 1-3) and 'non-responders' (Mandard grade 4 and 5). Multivariable logistic regression analysis was performed to calculate crude and adjusted odds ratios (OR) with 95% confidence intervals (CI) for responder status adjusting for a variety of parameters. Receiver operating characteristic (ROC) curves were calculated. RESULTS: Among 315 patients included, 102 (32%) were responders and 213 (68%) non-responders. A decrease in radiological tumour volume (OR 1.92 95%CI 1.02-3.62; p = 0.05), a 'partial response' RECIST score (OR 7.16 95%CI 1.49-34.36; p = 0.01), a clinically improved dysphagia score (OR 2.79 95%CI 1.05-7.04; p = 0.04) and lymphovascular invasion (OR 0.06 95%CI 0.02-0.13; p = 0.000) influenced responder status. ROC curve analysis for responder status utilising all available parameters had an area under the curve (AUC) of 0.86. CONCLUSION: This study has highlighted the potential for using pre-defined factors to identify those patients who have responded to neoadjuvant chemotherapy, prior to surgical resection, potentially facilitating a more individualised therapeutic approach.

Incidence and relevance of clinically indeterminate nonregional lymph nodes in the treatment of oesophageal cancer.

OBJECTIVES: Metastatic involvement of nonregional supraclavicular or superior mediastinal lymph nodes in distal oesophageal cancer is rare but has important implications for prognosis and management. The management of nonregional lymph nodes which appear indeterminate on CT and FDG PET-CT (subcentimeter nodes or those with preserved normal morphology, but increased FDG avidity) can present a diagnostic dilemma. This study investigates the incidence, work-up and clinical significance of nonregional clinically indeterminate FDG avid lymph nodes. METHODS: A single-centre retrospective review of all FDG PET-CT scans conducted over 5 years was conducted. Patients with mid- or distal oesophageal cancer with nonregional FDG avid nodes were identified. Subsequent work-up, management and outcomes were retrieved from electronic health records. RESULTS: Reports for 1189 PET-CT scans were reviewed. A total of 79 patients met the inclusion criteria. Of these, 18 (23%) were deemed to have disease and performance status potentially amenable to radical surgery and underwent further assessment. The indeterminate lymph nodes were successfully sampled via endobronchial ultrasound (EBUS) or ultrasound-guided fine-needle aspiration (US-FNA) in 100% of cases. 15/18 (83.3%) of samples were benign and proceeded to surgery. Outcomes for patients who proceeded to surgery were similar to other cohorts. None had pathology suggesting false-negative lymph node sampling. CONCLUSIONS: EBUS and US-FNA are effective means of sampling clinically indeterminate nonregional lymph nodes, and can significantly impact prognosis, and management. Further investigations in this context are of value in this cohort and should be pursued. Nonregional clinically indeterminate lymph nodes represent a diagnostic dilemma in oesophageal cancer staging. Additional investigations in the form of endobronchial ultrasound are effective at providing additional staging information, and can substantially influence patient care.

The role of surgery after prolonged primary chemotherapy for advanced oesophageal adenocarcinoma.

BACKGROUND: Most patients presenting with oesophageal cancer do so with advanced disease not suitable for surgery. However, there are examples of encouraging survival following surgery in highly selected patients who respond well to chemotherapy. METHODS: This was a retrospective cohort study of patients who presented with advanced but nonvisceral metastatic oesophageal cancer. Consecutive patients on a prolonged primary chemotherapy pathway who underwent surgical resection following a favourable response to chemotherapy were included. Survival and recurrence rates were analysed using Cox regression, providing hazard ratios (HRs) with 95% confidence intervals (CIs). RESULTS: A total of 57 patients included in the cohort operated between 2007 and 2015, the overall median survival was 44 months and the 5-year survival was 42%. Prechemotherapy cN0/cN1 (HR: 0.27, 95% CI: 0.12-0.62) conferred an independent survival advantage compared to cN2 and cN3 disease. Poor differentiation (HR: 2.46, 95% CI: 1.11-5.42), R1 resection (HR: 2.43, 95% CI: 1.14-5.19) and advanced nodal status (HR: 3.28, 95% CI: 1.44-7.47) predicted worse survival on univariable analysis. Poor differentiation (HR: 3.93, 95% CI: 1.62-9.56) was independently associated with poor survival when adjusted for other variables. CONCLUSION: Patients who present with advanced inoperable oesophageal cancer who have a favourable response to chemotherapy represent a limited group of patients who may benefit from surgery.

Nivolumab in gastric/gastroesophageal junction cancer: real-world data from UK Early Access to Medicines Scheme.

Aim: This study provides real-world insight into patient profile, clinical effectiveness and health-related quality of life among patients with advanced gastric/gastroesophageal junction (GEJ) adenocarcinoma treated with nivolumab. Materials & methods: Data were collected from medical records of patients with advanced GEJ adenocarcinoma treated with nivolumab in a UK Early Access to Medicines Scheme and from the patient-reported EuroQoL five dimensions questionnaire. Results: Evaluable patients (n = 113; median age 62 years) were predominantly male (76.1%), White (87.4%) and with GEJ adenocarcinoma (61.9%). Median follow-up was 2.8 months. The 6-month progression-free survival and overall survival were 31.6 and 56.7%, respectively. Mean EuroQoL five dimensions questionnaire index utility scores at baseline, 8, 16 and 24 weeks were 0.795, 0.831, 0.870 and 0.793, respectively. Conclusion: Progression-free survival was consistent with trial results and health-related quality of life remained stable over time.

Lay abstract This study looked at the characteristics and quality of life (QoL) of patients who were taking the drug, nivolumab, and how well it works for advanced gastric/gastroesophageal junction (GEJ) adenocarcinoma. GEJ adenocarcinoma is a rare type of cancer that starts in the GEJ, the area where the esophagus and stomach join. Information was collected from the medical records of patients who had advanced GEJ adenocarcinoma and were treated with nivolumab as part of a UK program that gives people access to new treatments that are not yet licensed. Patients also filled out a questionnaire called the EuroQoL five dimensions questionnaire that focuses on a patient's quality of life (QoL). In total, 113 patients were a part of the study. The midpoint of all patients' ages was 62 years and they were mostly males (76.1%), Whites (87.4%) and with GEJ adenocarcinoma (61.9%). The midpoint of follow-up time was 2.8 months. The percentages of patients meeting progression-free survival for 6 months, a period when a patient lives with GEJ adenocarcinoma but it does not get worse, and overall survival were 31.6 and 56.7%, respectively. Mean EuroQoL five dimensions questionnaire index scores (comprised between zero and one, the higher the better) at treatment start, 8, 16 and 24 weeks were 0.795, 0.831, 0.870 and 0.793, respectively. Progression-free survival was similar to clinical trial results and QoL was constant over time.

Efficacy of Reduced-Intensity Chemotherapy With Oxaliplatin and Capecitabine on Quality of Life and Cancer Control Among Older and Frail Patients With Advanced Gastroesophageal Cancer: The GO2 Phase 3 Randomized Clinical Trial.

Importance: Older and/or frail patients are underrepresented in landmark cancer trials. Tailored research is needed to address this evidence gap. Objective: The GO2 randomized clinical trial sought to optimize chemotherapy dosing in older and/or frail patients with advanced gastroesophageal cancer, and explored baseline geriatric assessment (GA) as a tool for treatment decision-making. Design, Setting, and Participants: This multicenter, noninferiority, open-label randomized trial took place at oncology clinics in the United Kingdom with nurse-led geriatric health assessment. Patients were recruited for whom full-dose combination chemotherapy was considered unsuitable because of advanced age and/or frailty. Interventions: There were 2 randomizations that were performed: CHEMO-INTENSITY compared oxaliplatin/capecitabine at Level A (oxaliplatin 130 mg/m2 on day 1, capecitabine 625 mg/m2 twice daily on days 1-21, on a 21-day cycle), Level B (doses 0.8 times A), or Level C (doses 0.6 times A). Alternatively, if the patient and clinician agreed the indication for chemotherapy was uncertain, the patient could instead enter CHEMO-BSC, comparing Level C vs best supportive care. Main Outcomes and Measures: First, broad noninferiority of the lower doses vs reference (Level A) was assessed using a permissive boundary of 34 days reduction in progression-free survival (PFS) (hazard ratio, HR = 1.34), selected as acceptable by a forum of patients and clinicians. Then, the patient experience was compared using Overall Treatment Utility (OTU), which combines efficacy, toxic effects, quality of life, and patient value/acceptability. For CHEMO-BSC, the main outcome measure was overall survival. Results: A total of 514 patients entered CHEMO-INTENSITY, of whom 385 (75%) were men and 299 (58%) were severely frail, with median age 76 years. Noninferior PFS was confirmed for Levels B vs A (HR = 1.09 [95% CI, 0.89-1.32]) and C vs A (HR = 1.10 [95% CI, 0.90-1.33]). Level C produced less toxic effects and better OTU than A or B. No subgroup benefited from higher doses: Level C produced better OTU even in younger or less frail patients. A total of 45 patients entered the CHEMO-BSC randomization: overall survival was nonsignificantly longer with chemotherapy: median 6.1 vs 3.0 months (HR = 0.69 [95% CI, 0.32-1.48], P = .34). In multivariate analysis in 522 patients with all variables available, baseline frailty, quality of life, and neutrophil to lymphocyte ratio were independently associated with OTU, and can be combined in a model to estimate the probability of different outcomes. Conclusions and Relevance: This phase 3 randomized clinical trial found that reduced-intensity chemotherapy provided a better patient experience without significantly compromising cancer control and should be considered for older and/or frail patients. Baseline geriatric assessment can help predict the utility of chemotherapy but did not identify a group benefiting from higher-dose treatment. Trial Registration: isrctn.org Identifier: ISRCTN44687907.

Adjuvant therapy following neoadjuvant chemotherapy and surgery for oesophageal adenocarcinoma in patients with clear resection margins.

BACKGROUND: The role of adjuvant therapy in patients with oesophagogastric adenocarcinoma treated by neoadjuvant chemotherapy (NAC) and surgery is contentious. In UK practice, surgical resection margin status is often used to classify patients into receiving adjuvant treatment. This study aimed to assess any survival benefit of adjuvant therapy in patients with clear resection margins. METHODS: This was a retrospective collaborative cohort study combining two prospectively collected UK institutional databases of patients with oesophageal adenocarcinoma. Multivariable Cox regression and propensity matched analyses were used to compare overall and recurrence-free survival according to the adjuvant treatment. RESULTS: Of 374 patients with clear resection margins, 221 patients (59%) had no adjuvant treatment, 137 patients (37%) had adjuvant chemotherapy and 16 patients (4%) had adjuvant chemoradiotherapy. For patients who had received NAC (290, 76%), when adjuvant chemotherapy was compared to no adjuvant treatment, hazard ratios (HRs) favoured adjuvant chemotherapy but did not reach independent significance (overall survival [OS] HR 0.65 95% confidence interval [CI] 0.40-1.06; p .0.087). Responders to NAC (Mandard 1-3) were seemingly more likely to demonstrate a survival benefit from adjuvant chemotherapy (HR 0.42 95% CI 0.15-1.11; p .1.081). CONCLUSIONS: Although no independent survival benefit was observed, the point estimates favoured adjuvant treatment, predominantly in patients with chemo-responsive tumours.

Tumor stage after neoadjuvant chemotherapy determines survival after surgery for adenocarcinoma of the esophagus and esophagogastric junction.

PURPOSE: Neoadjuvant chemotherapy is established in the management of most resectable esophageal and esophagogastric junction adenocarcinomas. However, assessing the downstaging effects of chemotherapy and predicting response to treatment remain challenging, and the relative importance of tumor stage before and after chemotherapy is debatable. METHODS: We analyzed consecutive resections for esophageal or esophagogastric junction adenocarcinomas performed at two high-volume cancer centers in London between 2000 and 2010. After standard investigations and multidisciplinary team consensus, all patients were allocated a clinical tumor stage before treatment, which was compared with pathologic stage after surgical resection. Survival analysis was conducted using Kaplan-Meier analysis and Cox regression analysis. RESULTS: Among 584 included patients, 400 patients (68%) received neoadjuvant chemotherapy. Patients with downstaged tumors after neoadjuvant chemotherapy experienced improved survival compared with patients without response (P < .001), and such downstaging (hazard ratio, 0.43; 95% CI, 0.31 to 0.59) was the strongest independent predictor of survival after adjusting for patient age, tumor grade, clinical tumor stage, lymphovascular invasion, resection margin status, and surgical resection type. Patients downstaged by chemotherapy, compared with patients with no response, experienced lower rates of local recurrence (6% v. 13%, respectively; P = .030) and systemic recurrence (19% v. 29%, respectively; P = .027) and improved Mandard tumor regression scores (P = .001). Survival was strongly dictated by stage after neoadjuvant chemotherapy, rather than clinical stage at presentation. CONCLUSION: The stage of esophageal or esophagogastric junction adenocarcinoma after neoadjuvant chemotherapy determines prognosis rather than the clinical stage before neoadjuvant chemotherapy, indicating the importance of focusing on postchemotherapy staging to more accurately predict outcome and eligibility for surgery. Patients who are downstaged by neoadjuvant chemotherapy benefit from reduced rates of local and systemic recurrence.

Assessment of sarcopenia and changes in body composition after neoadjuvant chemotherapy and associations with clinical outcomes in oesophageal cancer.

OBJECTIVES: Sarcopenia and changes in body composition following neoadjuvant chemotherapy (NAC) may affect clinical outcome. We assessed the associations between CT body composition changes following NAC and outcomes in oesophageal cancer. METHODS: A total of 35 patients who received NAC followed by oesophagectomy, and underwent CT assessment pre- and post-NAC were included. Fat mass (FM), fat-free mass (FFM), subcutaneous fat to muscle ratio (FMR) and visceral to subcutaneous adipose tissue ratio (VA/SA) were derived from CT. Changes in FM, FFM, FMR, VA/SA and sarcopenia were correlated to chemotherapy dose reductions, postoperative complications, length of hospital stay (LOS), circumferential resection margin (CRM), pathological chemotherapy response, disease-free survival (DFS) and overall survival (OS). RESULTS: Nine (26 %) patients were sarcopenic before NAC and this increased to 15 (43 %) after NAC. Average weight loss was 3.7 % ± 6.4 (SD) in comparison to FM index (-1.2 ± 4.2), FFM index (-4.6 ± 6.8), FMR (-1.2 ± 24.3) and VA/SA (-62.3 ± 12.7). Changes in FM index (p = 0.022), FMR (p = 0.028), VA/SA (p = 0.024) and weight (p = 0.007) were significant univariable factors for CRM status. There was no significant association between changes in body composition and survival. CONCLUSIONS: Loss of FM, differential loss of VA/SA and skeletal muscle were associated with risk of CRM positivity. KEY POINTS: • Changes in CT body composition occur after neoadjuvant chemotherapy in oesophageal cancer. • Sarcopenia was more prevalent after neoadjuvant chemotherapy. • Fat mass, fat-free mass and weight decreased after neoadjuvant chemotherapy. • Changes in body composition were associated with CRM positivity. • Changes in body composition did not affect perioperative complications and survival.

A randomised phase III trial of the pharmacokinetic biomodulation of irinotecan using oral ciclosporin in advanced colorectal cancer: results of the Panitumumab, Irinotecan & Ciclosporin in COLOrectal cancer therapy trial (PICCOLO).

BACKGROUND: The main toxicity of irinotecan in advanced colorectal cancer (CRC) is delayed diarrhoea. Intestinal SN-38, released by deconjugation of the parent glucuronide excreted into the bile or produced in situ by intestinal carboxylesterase, is toxic to the intestinal epithelium. The canalicular transport of irinotecan and SN-38G is mediated by ABCC2 (MRP2) and ABCB1 (MDR1) which are both inhibited by ciclosporin. We tested whether irinotecan and ciclosporin was non-inferior for anti-cancer efficacy and superior for toxicity compared with single-agent irinotecan. METHODS: Six hundred and seventy-two patients with advanced, measurable CRC following prior fluoropyrimidine-containing chemotherapy were randomised to either irinotecan 3-weekly 350 mg/m(2) (or 300 mg/m(2) if age >70 or performance status (PS)=2) or 3-weekly irinotecan at 140 mg/m(2) (120 mg/m(2) if age >70 or PS=2) with ciclosporin 3mg/kg t.d.s. for three days by mouth starting on the morning before irinotecan. The primary end-point was the proportion of patients alive and progression-free at 12 weeks. The key secondary end-point was the incidence of grade ≥3 diarrhoea within 12 weeks of randomisation. RESULTS: The proportion of patients progression-free at 12 weeks with irinotecan was 53.4% compared to 47.2% with irinotecan plus ciclosporin (difference=-6.3%, 95% confidence interval (CI) [-13.8%, 1.3%]). Since the lower limit of the 95% CI crossed the pre-specified non-inferiority margin of -10.6%, non-inferiority of irinotecan plus ciclosporin compared to irinotecan alone was not statistically demonstrated. 15.0% patients developed severe diarrhoea on irinotecan compared to 13.8% on irinotecan plus ciclosporin, a non-significant difference. INTERPRETATION: The pharmacokinetic biomodulation of irinotecan using oral ciclosporin does not improve the therapeutic index of irinotecan in advanced CRC. FUNDING: The trial was funded by Cancer Research UK and supported by Amgen Pharma.

Panitumumab and irinotecan versus irinotecan alone for patients with KRAS wild-type, fluorouracil-resistant advanced colorectal cancer (PICCOLO): a prospectively stratified randomised trial.

BACKGROUND: Therapeutic antibodies targeting EGFR have activity in advanced colorectal cancer, but results from clinical trials are inconsistent and the population in which most benefit is derived is uncertain. Our aim was to assess the addition of panitumumab to irinotecan in pretreated advanced colorectal cancer. METHODS: In this open-label, randomised trial, we enrolled patients who had advanced colorectal cancer progressing after fluoropyrimidine treatment with or without oxaliplatin from 60 centres in the UK. From December, 2006 until June, 2008, molecularly unselected patients were recruited to a three-arm design including irinotecan (control), irinotecan plus ciclosporin, and irinotecan plus panitumumab (IrPan) groups. From June 10, 2008, in response to new data, the trial was amended to a prospectively stratified design, restricting panitumumab randomisation to patients with KRAS wild-type tumours; the results of the comparison between the irinotcan and IrPan groups are reported here. We used a computer-generated randomisation sequence (stratified by previous EGFR targeted therapy and then minimised by centre, WHO performance status, previous oxaliplatin, previous bevacizumab, previous dose modifications, and best previous response) to randomly allocate patients to either irinotecan or IrPan. Patients in both groups received 350 mg/m(2) intravenous irinotecan every 3 weeks (300 mg/m(2) if aged ≥70 years or a performance status of 2); patients in the IrPan group also received intravenous panitumumab 9 mg/kg every 3 weeks. The primary endpoint was overall survival in KRAS wild-type patients who had not received previous EGFR targeted therapy, analysed by intention to treat. Tumour DNA was pyrosequenced for KRASc.146, BRAF, NRAS, and PIK3CA mutations, and predefined molecular subgroups were analysed for interaction with the effect of panitumumab. This study is registered, number ISRCTN93248876. RESULTS: Between Dec 4, 2006, and Aug 31, 2010, 1198 patients were enrolled, of whom 460 were included in the primary population of patients with KRASc.12-13,61 wild-type tumours and no previous EGFR targeted therapy. 230 patients were randomly allocated to irinotecan and 230 to IrPan. There was no difference in overall survival between groups (HR 1·01, 95% CI 0·83-1·23; p=0·91), but individuals in the IrPan group had longer progression-free survival (0·78, 0·64-0·95; p=0·015) and a greater number of responses (79 [34%] patients vs 27 [12%]; p<0·0001) than did individuals in the irinotecan group. Grade 3 or worse diarrhoea (64 [29%] of 219 patients vs 39 [18%] of 218 patients), skin toxicity (41 [19%] vs none), lethargy (45 [21]% vs 24 [11%]), infection (42 [19%] vs 22 [10%]) and haematological toxicity (48 [22%] vs 27 [12%]) were reported more commonly in the IrPan group than in the irinotecan group. We recorded five treatment-related deaths, two in the IrPan group and three in the irinotecan group. INTERPRETATION: Adding panitumumab to irinotecan did not improve the overall survival of patients with wild-type KRAS tumours. Further refinement of molecular selection is needed for substantial benefits to be derived from EGFR targeting agents. FUNDING: Cancer Research UK, Amgen Inc.

Anti-epidermal growth factor receptor antibodies in the treatment of metastatic colorectal cancer.

Targeting the epidermal growth factor receptor (EGFR), an important component in carcinogenesis, is an attractive therapeutic option for selective anticancer therapy. Several EGFR inhibitors, mostly monoclonal antibodies and tyrosine kinase inhibitors are under investigation in the treatment of colorectal cancer. Although there has been some progress in the treatment of colorectal cancer with combination chemotherapy, the repertoire of active agents is still limited. More recently the anti-EGFR drugs cetuximab and panitumumab have made an impact in the treatment of metastatic disease but with variable response rates. Although the appearance of a skin rash confers a higher response rate, immunohistochemical staining of EGFR at baseline does not. Several studies have now focused on identifying predictive biological markers at a molecular level. Exciting data has demonstrated KRAS mutation status to be the first predictive marker of response to anti-EGFR monoclonal antibodies (mAbs) and has led a new era in the development of targeted therapies in colorectal malignant disease. The aim of this review is to evaluate the impact of anti-EGFR therapies in the treatment of metastatic colorectal cancer; and to present the current data on predictive markers including KRAS status, PTEN expression and germinal gene polymorphisms. The relevant patents are discussed.

Tumor necrosis factor alpha as a new target for renal cell carcinoma: two sequential phase II trials of infliximab at standard and high dose.

PURPOSE: Tumor necrosis factor alpha (TNF-alpha) may play a role in renal cell carcinoma (RCC). We performed two sequential phase II studies of infliximab, an anti-TNF-alpha monoclonal antibody, in patients with immunotherapy-resistant or refractory RCC. PATIENTS AND METHODS: Patients progressing after cytokine therapy were treated with intravenous infliximab as follows: study 1 (19 patients), 5 mg/kg at weeks 0, 2, and 6, and then every 8 weeks; study 2 (18 patients), 10 mg/kg at weeks 0, 2, and 6, and then every 4 weeks. Treatment continued until disease progression (PD). Response was assessed according to Response Evaluation Criteria in Solid Tumors. Plasma levels of TNF-alpha, CCL2, and interleukin-6 (IL-6) were measured before and during treatment. RESULTS: TNF-alpha and its receptors were detected in malignant cells in RCC biopsies. In study 1, three patients (16%) achieved partial response (PR) and three patients (16%) achieved stable disease (SD). Median duration of response (PR + SD) was 7.7 months (range, 5.0 to 40.5+ months). In study 2, 11 patients (61%) achieved SD. Median duration of response was 6.2 months (range, 3.5 to 24+ months). One patient developed grade 3 hypersensitivity and another died as a result of pulmonary infection/sepsis. Enzyme-linked immunosorbent assay analysis of plasma revealed that higher levels of TNF-alpha at baseline and higher levels of CCL2 during treatment were associated with PD. There were also correlations between higher levels of TNF-alpha, IL-6, and CCL2 and poor survival (< 12 months). CONCLUSION: This is the first direct clinical evidence suggesting that TNF-alpha may be a therapeutic target in RCC. Plasma levels of TNF-alpha, IL-6, and CCL2 may have predictive and prognostic significance.

Antitumor necrosis factor (TNF-a) antibodies in the treatment of renal cell cancer.

The kinase inhibitors sorafinib and sunitinib have demonstrated significant activity in renal cell carcinoma (RCC), and are now approved by the FDA for use in advanced disease. There still remains a need for novel therapies. Our group were the first to demonstrate activity of thalidomide in RCC, believed to be in part related to the modulation of tumor necrosis factor (TNF-a), a cytokine secreted by RCC with a number of tumor promoting properties. We subsequently conducted a phase II trial of the TNF-a monoclonal antibody infliximab in patients with previously treated advanced RCC. The drug was well tolerated. The response rate was 16% and stability was achieved in a further 16% of patients. Anti-TNF-a therapy may represent an important approach in the treatment of this disease.