Capecitabine and Temozolomide in Patients with Advanced Pulmonary Carcinoid Tumours.

BACKGROUND: Temozolomide and capecitabine (CAPTEM) chemotherapy is known to be active in patients with pancreatic neuroendocrine tumours. OBJECTIVE: This retrospective analysis set out to describe the efficacy and toxicity of CAPTEM in patients with advanced pulmonary carcinoids (PCs). METHODS: Patients were included with advanced PC who had been treated with a maximum of 6 cycles of oral temozolomide 200 mg/m2 on days 10-14 and capecitabine 750 mg/m2 b.i.d. on days 1-14, repeated every 28 days, -followed by monthly intramuscular injection of octreotide 30 mg long-acting release as maintenance treatment. RESULTS: Of the 33 patients, all with well-differentiated PC, 61% had atypical carcinoid, 36% had Ki-67 index >10% and 42% had ≥3 organs involved by metastasis. CAPTEM was administered as first-line treatment in 42% of patients, and 17% had received prior somatostatin analogue treatment. Six patients (18%) achieved a partial response, 19 (58%) had stable disease and 8 (24%) developed progressive disease. After a median time of follow-up of 34.8 months, median progression-free survival (PFS) was 9.0 months and median overall survival 30.4 months. Median duration of disease response was 21.7 months and median duration of disease control 9.7 months. Patients with multi-organ metastasis had shorter PFS, but only when treated as second or third line with CAPTEM (p = 0.023). CONCLUSIONS: CAPTEM induced a modest response and PFS rate, comparable to other studies with temozolomide in patients with advanced PC. The efficacy of CAPTEM should be compared to that of monotherapy with temozolomide in a prospective clinical trial.

Early recognition of anorexia through patient-generated assessment predicts survival in patients with oesophagogastric cancer.

Cancer cachexia is common in patients with oesophagogastric cancer (OG) and is linked to overall survival (OS). One of the key components of cachexia is anorexia; it is not known whether anorexia impacts on OS and there is no method of routine screening in current practice. Diagnosis relies on patients describing the symptoms, clinicians diagnosing anorexia and acting upon it. Patients with oesophageal/gastroesophageal junction or gastric cancer were assessed using the Functional Assessment of Anorexia Cachexia Therapy Anorexia/Cachexia Subscale (FAACT A/CS). FAACT A/CS includes 12 questions validated previously to diagnose anorexia in patients with cancer. Of the 182 patients included, 69% scored ≤37/48 and were considered to be anorexic; FAACT A/CS was a better predictor of OS in metastatic patients than body mass index or weight loss in the six months prior to cancer diagnosis. The median OS of patients with FAACT A/CS scores of >37 was longer than patients with scores of ≤37 (19.3 months vs 6.7 months, Hazard Ratio [HR] 2.9, 95% Confidence Interval [CI] 1.4-6.0, p<0.0001). Patients with performance status (PS) 0-2 and FAACT A/CS >37 had substantially longer OS than those with PS 0-2 and FAACT A/CS ≤37 (18.7 months vs 7.9 months, HR 2.5 (95% CI 1.2-5.1, P<0.0001). The FAACT A/CS questionnaire allows clinicians to identify patients with anorexia who may benefit from early nutrition interventions. Importantly, this is the first study to show the association between anorexia and survival in patients with metastatic OG cancers. This will form the basis of future interventional studies to improve patient outcomes.

Prognostic significance of positive circumferential resection margin post neoadjuvant chemotherapy in patients with esophageal or gastro-esophageal junction adenocarcinoma.

BACKGROUND: The aim of the present study was to assess the prognosis of patients with esophageal or gastroesophageal junction (E/GEJ) adenocarcinoma extending beyond the muscularis propria layer (≥ypT3) and positive circumferential resection margin (CRM), post neoadjuvant chemotherapy. METHODS: 177 patients were retrospectively studied. The majority (94.9%) received ECX (epirubicin, cisplatin, capecitabine), and all had clear proximal/distal resection margins. CRM was defined as positive (CRM+) when it was directly infiltrated (infiltrated CRM) or when tumor cells were detected within 1 mm from CRM (close CRM) and as negative (CRM-) when tumor cells were found in a distance > 1 mm from CRM. RESULTS: CRM+ was found in 83 patients (46.9%). Of them, infiltrated CRM was recorded in 36 (20.3%) and close CRM in 47 (26.6%). Adjuvant chemotherapy was administered to 132 patients (74.6%). Lymphovascular invasion and primary site in the lower esophagus were independently associated with higher risk of CRM+. Patients with infiltrated CRM, compared to those with close CRM and those CRM-, had the shortest median time-to-relapse (11.4 vs. 15.6 vs. 22.1 months, respectively, p = 0.005) and overall survival (18.7 vs. 23.1 vs. 38.8 months, respectively, p = 0.001). However, CRM status was not an independent predictor of poor outcome. Symptomatic isolated locoregional recurrences were rare in both CRM+ and CRM-patients (4/56 [7.1%] vs. 5/52 [9.6%], p = 0.736), as well as in infiltrated vs. non-infiltrated CRM (CRM- and close CRM) (0/26 [0%] vs. 9/82 [11.0%], p = 0.110). CONCLUSION: Although CRM status is associated with poor outcome, it does not represent an independent prognostic factor. The status of CRM did not significantly influence the pattern of cancer relapse.

Carboplatin in Combination with Oral or Intravenous Etoposide for Extra-Pulmonary, Poorly-Differentiated Neuroendocrine Carcinomas.

BACKGROUND: Carboplatin-etoposide (CarboEtop) is a 1st-line option for patients with advanced extra-pulmonary (EP), poorly-differentiated (PD) neuroendocrine carcinoma (NEC). Different schedules are used in clinical practice and randomised evidence is lacking. OBJECTIVES: To provide real-life outcomes of carboplatin combined with oral or intravenous (IV) etoposide (Etop) in advanced EP-PD-NEC, from 2 specialist centres. METHODS: Activity/efficacy/toxicity data of CarboEtop were collected retrospectively and analysed. RESULTS: We identified 113 patients; median age: 65.8 years; male: 64%; gastro-entero-pancreatic origin: 54%; stage IV: 90%; median Ki-67: 70%; median follow-up: 11.5 months. A total of 123 courses of CarboEtop (oral: 45%; IV: 55%) were administered; 106 (86%) 1st-line, 16 (13%) 2nd-line, and 1 (1%) 3rd-line. Disease control rate: 74.5% in 1st-line and 69.2% in 2nd/3rd-line, with no significant difference between oral and IV Etop in 1st-line (69.8 vs. 80.8%, p = 0.237). Median progression-free survival (PFS): 6.0 and 4.5 months in 1st-line and 2nd/3rd-line, respectively. Overall survival (OS): 11.5 and 12.5 months in 1st-line and 2nd/3rd-line, respectively. The schedule (oral versus IV Etop) did not impact on 1st-line PFS (5.6 vs. 6.2 months, p = 0.179), although there was a trend towards shorter OS (8.9 vs. 12.1 months, p = 0.069). Liver metastases correlated with worse 1st-line PFS (p = 0.015) and 1st-line OS (p < 0.001) on multivariable analysis. The commonest grade 3-4 adverse event was myelosuppression (49%), with comparable toxicity between oral and IV Etop, except for venous thromboembolism (12.5 vs. 1.7%, p = 0.04). CONCLUSIONS: CarboEtop for advanced EP-PD-NEC is active, effective, and well-tolerated. Oral and IV Etop schedules are associated with comparable toxicity; activity should be compared in larger cohorts.

The Role of Continuing Perioperative Chemotherapy Post Surgery in Patients with Esophageal or Gastroesophageal Junction Adenocarcinoma: a Multicenter Cohort Study.

PURPOSE: The aim of this cohort study was to assess the benefit that patients with lower esophageal or gastroesophageal junction (E/GEJ) adenocarcinoma receive by continuing perioperative chemotherapy post-surgery. METHODS: Three hundred twelve patients underwent radical tumor surgical resection after preoperative chemotherapy. Chemotherapy was mainly ECX (epirubicin, cisplatin, capecitabine). Propensity score matching (PSM) was used to compare continuation of chemotherapy post-surgery vs. no postoperative treatment. RESULTS: Two hundred ten patients (67.3%) had GEJ and 102 (32.7%) lower esophageal adenocarcinoma. Microscopically clear surgical margins (R0), according to the Royal College of Pathologists, were achieved in 208 patients (66.7%). In total, 225 patients (72.1%) continued perioperative chemotherapy post-surgery. PSM was used to create two patient groups, well-balanced for basic epidemiological, clinical, and histopathological characteristics. The first included 148 patients who continued perioperative chemotherapy after surgery and the second 86, who did not receive postoperative treatment. The first group had non-significantly different median time-to-relapse (TTR 22.2 vs. 25.7 months, p = 0.627), overall survival (OS 46.1 vs. 36.7 months, p = 0.199), and post-relapse survival (15.3 vs. 8.7 months, p = 0.122). Subgroup analysis showed that only patients with microscopically residual disease after surgery (R1 resection) benefited from continuation of chemotherapy post-surgery for both TTR (hazard ratio [HR] 0.556, 95% CI 0.330-0.936, p = 0.027) and OS (HR 0.530, 95% CI 0.313-0.898, p = 0.018). CONCLUSIONS: Continuation of perioperative chemotherapy post-surgery was not associated with improved outcome in patients with E/GEJ adenocarcinoma. Patients with microscopically residual disease post-surgery might receive a potential benefit from adjuvant chemotherapy.

Predictive factors of thromboembolic complications in patients with esophagogatric adenocarcinoma undergoing preoperative chemotherapy.

BACKGROUND: Thromboembolic events (TEEs) represent a significant treatment and disease complication for cancer patients. In the present study we assessed the incidence of TEEs in patients receiving preoperative chemotherapy for esophagogastric adenocarcinoma. The risk factors for TEE development and their impact on prognosis were further analyzed. MATERIAL AND METHODS: Data from 590 patients with esophagogastric adenocarcinoma, who received preoperative epirubicin-cisplatin with capecitabine (ECX) or 5-fluorouracil (ECF) between 2009 and 2016 in three UK hospitals were retrospectively collected. RESULTS: Twenty-one percent had stomach primary and 98% received ECX chemotherapy. In total, 52 patients (9%) had a venous and 22 (4%) an arterial event. Of those patients with venous TEEs (vTTEs), 39 had pulmonary embolism and 13 deep vein thrombosis, whereas in patients with arterial TEEs (arTTEs), 7 developed a myocardial infarct, 8 developed limb ischemia, 4 developed cerebrovascular accidents and 3 developed superior mesenteric artery thrombosis. ArTEEs were associated with a much higher inoperability rate compared to cases without TEE or with vTEE (77% vs. 20% vs. 31%, respectively, p < .001). Independent risk factors of vTEEs were primary site being the stomach (Odds ratio [OR] 3.24, 95%CI 1.72-6.12, p < .001), being overweight (OR 3.11, 95%CI 1.33-7.26, p = .009) or obese (OR 4.52, 95%CI 1.85-11.09, p = .001) and the presence of central venous access device (OR 3.40, 95%CI 1.00-11.55, p = .050). In contrast, anticoagulant treatment was independently associated with a lower risk of vTEE (OR 0.22, 95%CI 0.06-0.83, p = .026). Khorana score of 4-5 was an independent risk factor of arTEE (OR 6.38, 95%CI 1.85-22.04, p = .003). Finally, arTEEs were an independent poor prognostic factor for OS, when adjusted for baseline patient, tumor and treatment characteristics (Hazard ratio 3.02, 95%CI 1.85-4.95, p < .001). CONCLUSION: Preoperative ECX/ECF chemotherapy for patients with resectable esophagogastric adenocarcinoma was associated with relatively high incidence of TEEs. However, only arTEEs affected patient survival outcomes.

Significance of baseline FDG-PET/CT scan as a method of staging regional lymph nodes in patients with operable distal oesophageal or gastroesophageal junction adenocarcinoma.

BACKGROUND: The new American Joint Committee on Cancer eighth edition (AJCC8) staging is the first to describe separate clinical and pathology staging systems, but still has low performance to predict prognosis in patients with oesophageal/gastroesophageal junction (O/GOJ) adenocarcinoma, who are candidates for surgery. Recent studies have demonstrated that O/GOJ cancer patients with 18F-fluorodeoxyglucose (FDG) avid regional lymph nodes (RLNs) may have poor prognosis. The aim of our study was to examine whether the baseline assessment of the FDG uptake of RLN improves the prognostic accuracy of the new AJCC8 staging. PATIENTS AND METHODS: This single-centre retrospective study included patients with operable FDG avid O/GOJ adenocarcinoma treated with perioperative chemotherapy. All patients were reclassified according to the new AJCC8 clinical staging. Prognostic factors for time-to-progression (TTP) and overall survival (OS) were explored. RESULTS: Of 430 patients included in the study, 180 (41.9%) had FDG avid RLN at baseline PET/CT scan before starting perioperative chemotherapy. The presence of FDG avid RLN was significantly and independently associated with shorter TTP and OS, especially in clinical stage III patients (p < .001 in both cases). Stage III patients with FDG avid RLN had similar TTP and OS to those with stage IVA. Classifying stage III patients with FDG avid RLN into stage IVA led to a significant improvement of the prognostic accuracy of the new AJCC8 clinical staging system (Harrell's concordance index improved from 0.555 to 0.588, p < .001). Of 430 patients starting perioperative chemotherapy, 332 underwent radical tumour resection. The presence of FDG avid RLN before starting perioperative chemotherapy could additionally predict a significantly shorter postoperative time-to-relapse and OS (p < .001 in both cases). CONCLUSIONS: We propose that the incorporation of RLN status (by FDG PET/CT scan) into the AJCC8 staging system of O/GOJ adenocarcinoma improves its prognostic accuracy and may also improve treatment stratification.