Ruth Swann

BACKGROUND: Early diagnosis interventions such as symptom awareness campaigns increasingly form part of global cancer control strategies. However, these strategies will have little impact in improving cancer outcomes if the targeted symptoms represent advanced stage of disease. Therefore, we aimed to examine associations between common presenting symptoms of cancer and stage at diagnosis. METHODS: In this cross-sectional study, we analysed population-level data from the English National Cancer Diagnosis Audit 2014 for patients aged 25 years and older with one of 12 types of solid tumours (bladder, breast, colon, endometrial, laryngeal, lung, melanoma, oral or oropharyngeal, ovarian, prostate, rectal, and renal cancer). We considered 20 common presenting symptoms and examined their associations with stage at diagnosis (TNM stage IV vs stage I-III) using logistic regression. For each symptom, we estimated these associations when reported as a single presenting symptom and when reported together with other symptoms. FINDINGS: We analysed data for 7997 patients. The proportion of patients diagnosed with stage IV cancer varied substantially by presenting symptom, from 1% (95% CI 1-3; eight of 584 patients) for abnormal mole to 80% (71-87; 84 of 105 patients) for neck lump. Three of the examined symptoms (neck lump, chest pain, and back pain) were consistently associated with increased odds of stage IV cancer, whether reported alone or with other symptoms, whereas the opposite was true for abnormal mole, breast lump, postmenopausal bleeding, and rectal bleeding. For 13 of the 20 symptoms (abnormal mole, breast lump, post-menopausal bleeding, rectal bleeding, lower urinary tract symptoms, haematuria, change in bowel habit, hoarseness, fatigue, abdominal pain, lower abdominal pain, weight loss, and the "any other symptom" category), more than 50% of patients were diagnosed at stages other than stage IV; for 19 of the 20 studied symptoms (all except for neck lump), more than a third of patients were diagnosed at stages other than stage IV. INTERPRETATION: Despite specific presenting symptoms being more strongly associated with advanced stage at diagnosis than others, for most symptoms, large proportions of patients are diagnosed at stages other than stage IV. These findings provide support for early diagnosis interventions targeting common cancer symptoms, countering concerns that they might be simply expediting the detection of advanced stage disease. FUNDING: UK Department of Health's Policy Research Unit in Cancer Awareness, Screening and Early Diagnosis; and Cancer Research UK.

7014 Background: Surgery after CT/RT remains controversial for patients (pts) with stage IIIA(pN2) NSCLC. Initial analyses of INT 0139 showed significantly better progression-free survival (PFS), but not overall survival (OS), in the trimodality arm. (PASCO 2003) With longer follow-up (≥2.5 yrs per pt), new analyses of primary endpoints PFS and OS were conducted. Methods: Pts with PS 0–1 and T1–3, pN2, M0 NSCLC were randomized if resection was technically feasible. All received cisplatin 50 mg/m2 d1, 8, 29, 36 and etoposide 50 mg/m2 d1–5, d29–33 (PE) and RT to 45 Gy starting day 1. Arm 1 had resection if no progression (PD), then PE X2; Arm 2 completed RT to 61 Gy with PE X2. Intent to treat analyses used Kaplan-Meier estimates, log-rank tests and Cox multivariate models; exploratory analyses used logistic regression. All CI are 95% and p-values, 2-sided. Results: 396 eligible pts were enrolled (Arm 1, 202; Arm 2, 194; well-balanced on all factors). Treatment-related deaths: Arm 1, 16 (7.9%), of which 10 (5.0%) were within 30 days postop; Arm 2, 4 (2.1%). Deaths by type of surgery: 5/23 (22%) simple and 9/31 (29%) complex pneumonectomies, 1/98 (1%) lobectomies. Arm 1 pathology (n=164): T0N0, 29 (18%); TanyN0, 76 (46%). Arm 1 PFS is superior: median 12.8 vs 10.5 mos, p=0.017, HR 0.77 (0.62, 0.96); 5-yr 22.4% vs 11.1%. More pts on Arm 1 are alive without PD (p=0.008), but more died without PD (p=0.021). OS curves overlap for 2 yrs, but separate late favoring Arm 1: median 23.6 vs 22.2 mos, p=0.24, HR 0.87 (0.70,1.10); 5-yr 27.2% vs 20.3%, odds ratio for 5-yr survival 0.63 (0.36, 1.10, p=0.10). 96 pts are alive/censored. Independent favorable OS predictors: female, no weight loss. Arm 1 5-yr OS if pN0 at surgery was 41%; pN1–3, 24%; no surgery, 8% (p< 0.0001). Conclusions: 1) Longer follow-up of INT 0139 confirms significantly improved PFS but not OS when surgery follows CT/RT in pts with stage IIIA(pN2) NSCLC, 2) there is a trend for better 5-yr OS with trimodality therapy, 3) pN0 at surgery predicts long-term survival, 4) surgery after CT/RT can be considered in fit pts, 4) this approach may not be optimal if a pneumonectomy is needed. No significant financial relationships to disclose.

PURPOSE: Vascular endothelial growth factor (VEGF) signaling is key to tumor angiogenesis and is an important target in the development of anticancer drugs. However, VEGF receptor (VEGFR) expression in human cancers, particularly the relative expression of VEGFR-2 and VEGFR-3 in tumor vasculature versus tumor cells, is poorly defined. EXPERIMENTAL DESIGN: VEGFR-2- and VEGFR-3-specific antibodies were identified and used in the immunohistochemical analysis of human primary cancers and normal tissue. The relative vascular localization of both receptors in colorectal and breast cancers was determined by coimmunofluorescence with vascular markers. RESULTS: VEGFR-2 and VEGFR-3 were expressed on vascular endothelium but not on malignant cells in 13 common human solid tumor types (n > 400, bladder, breast, colorectal, head and neck, liver, lung, skin, ovarian, pancreatic, prostate, renal, stomach, and thyroid). The signal intensity of both receptors was significantly greater in vessels associated with malignant colorectal, lung, and breast than adjacent nontumor tissue. In colorectal cancers, VEGFR-2 was expressed on both intratumoral blood and lymphatic vessels, whereas VEGFR-3 was found predominantly on lymphatic vessels. In breast cancers, both receptors were localized to and upregulated on blood vessels. CONCLUSIONS: VEGFR-2 and VEGFR-3 are primarily localized to, and significantly upregulated on, tumor vasculature (blood and/or lymphatic) supporting the majority of solid cancers. The primary clinical mechanism of action of VEGF signaling inhibitors is likely to be through the targeting of tumor vessels rather than tumor cells. The upregulation of VEGFR-3 on tumor blood vessels indicates a potential additional antiangiogenic effect for dual VEGFR-2/VEGFR-3-targeted therapy.

BACKGROUND: Continual improvements in diagnostic processes are needed to minimise the proportion of patients with cancer who experience diagnostic delays. Clinical audit is a means of achieving this. AIM: To characterise key aspects of the diagnostic process for cancer and to generate baseline measures for future re-audit. DESIGN AND SETTING: Clinical audit of cancer diagnosis in general practices in England. METHOD: Information on patient and tumour characteristics held in the English National Cancer Registry was supplemented by information from GPs in participating practices. Data items included diagnostic timepoints, patient characteristics, and clinical management. RESULTS: Data were collected on 17 042 patients with a new diagnosis of cancer during 2014 from 439 practices. Participating practices were similar to non-participating ones, particularly regarding population age, urban/rural location, and practice-based patient experience measures. The median diagnostic interval for all patients was 40 days (interquartile range [IQR] 15-86 days). Most patients were referred promptly (median primary care interval 5 days [IQR 0-27 days]). Where GPs deemed diagnostic delays to have occurred (22% of cases), patient, clinician, or system factors were responsible in 26%, 28%, and 34% of instances, respectively. Safety netting was recorded for 44% of patients. At least one primary care-led investigation was carried out for 45% of patients. Most patients (76%) had at least one existing comorbid condition; 21% had three or more. CONCLUSION: The findings identify avenues for quality improvement activity and provide a baseline for future audit of the impact of 2015 National Institute for Health and Care Excellence guidance on management and referral of suspected cancer.