Nodal stage migration and prognosis in anal cancer: a systematic review, meta-regression, and simulation study

Background: In patients with squamous cell carcinoma of the anus (SCCA), lymph node positivity (LNP) indicates poor prognosis for survival and is central to radiotherapy planning. Over the past three decades, LNP proportion has increased, mainly reflecting enhanced detection with newer imaging modalities; a process known as nodal stage migration. If accompanied by constant T stage distributions, prognosis for both lymph node-positive and lymph node-negative groups may improve without any increase in overall survival for individual patients; a paradox termed the Will Rogers phenomenon. Here, we aim to systematically evaluate the impact of nodal stage migration on survival in SCCA and address a novel hypothesis that this phenomenon results in reduced prognostic discrimination. Methods: We did a systematic review and meta-regression to quantify changes in LNP over time and the impact of this change on survival and prognostic discrimination. We searched MEDLINE, Embase, and the Cochrane Library to identify randomised trials and observational studies in patients with SCCA published between Jan 1, 1970, and Oct 11, 2016. Studies were eligible if patients received chemoradiotherapy or radiotherapy as the main treatment, reported LNP proportions (all studies), and reported overall survival (not necessarily present in all studies). We excluded studies with fewer than 50 patients. We extracted study-level data with a standardised, piloted form. The primary outcome measure was 5-year overall survival. To investigate scenarios in which reduced prognostic discrimination might occur, we simulated varying true LNP proportions and true overall survival, and compared these with expected observed outcomes for varying levels of misclassification of true nodal state. Findings: We identified 62 studies reporting LNP proportions, which included 10 569 patients. From these, we included 45 studies (6302 patients) with whole cohort 5-year overall survival, 11 studies with 5-year survival stratified by nodal status, and 20 studies with hazard ratios in our analyses of temporal changes. In 62 studies, the LNP proportions increased from a mean estimate of 15·3% (95% CI 10·5–20·1) in 1980 to 37·1% (34·0–41·3) in 2012 (p<0·0001). In 11 studies with prognostic data, increasing LNP was associated with improved overall survival in both lymph node-positive and lymph node-negative categories, whereas the proportions with combined tumour stage T3 and T4 remained constant. In 20 studies, across a range of LNP proportions from 15% to 40%, the hazard ratios for overall survival of lymph node-positive versus lymph node-negative patients decreased significantly from 2·5 (95% CI 1·8–3·3) at 15% LNP to 1·3 (1·2–1·9; p=0·014) at 40% LNP. The simulated scenarios reproduced this effect if the true LNP proportions were 20% or 25%, but not if the true LNP proportions were 30% or greater. Interpretation: We describe a consequence of staging misclassification in anal cancer that we have termed reduced prognostic discrimination. We used this new observation to infer that the LNP proportions of more than 30% seen in modern clinical series (11 out of 15 studies with a median year since 2007) are higher than the true LNP proportion. The introduction of new staging technologies in oncology might misclassify true disease stage, spuriously informing disease management and ultimately increasing the risk of overtreatment. Funding: Bowel Disease Research Foundation

A comprehensive overview of radioguided surgery using gamma detection probe technology

The concept of radioguided surgery, which was first developed some 60 years ago, involves the use of a radiation detection probe system for the intraoperative detection of radionuclides. The use of gamma detection probe technology in radioguided surgery has tremendously expanded and has evolved into what is now considered an established discipline within the practice of surgery, revolutionizing the surgical management of many malignancies, including breast cancer, melanoma, and colorectal cancer, as well as the surgical management of parathyroid disease. The impact of radioguided surgery on the surgical management of cancer patients includes providing vital and real-time information to the surgeon regarding the location and extent of disease, as well as regarding the assessment of surgical resection margins. Additionally, it has allowed the surgeon to minimize the surgical invasiveness of many diagnostic and therapeutic procedures, while still maintaining maximum benefit to the cancer patient. In the current review, we have attempted to comprehensively evaluate the history, technical aspects, and clinical applications of radioguided surgery using gamma detection probe technology

Eight-year follow up result of the OTOASOR trial: The Optimal Treatment Of the Axilla - Surgery Or Radiotherapy after positive sentinel lymph node biopsy in early-stage breast cancer: A randomized, single centre, phase III, non-inferiority trial

INTRODUCTION: The National Institute of Oncology, Budapest conducted a single centre randomized clinical study. The OTOASOR (Optimal Treatment Of the Axilla - Surgery Or Radiotherapy) trial compares completion of axillary lymph node dissection (cALND) to regional nodal irradiation (RNI) in patients with sentinel lymph node metastasis (pN1sn) in stage I-II breast cancer. PATIENTS AND METHODS: Patients with primary invasive breast cancer (cN0 and cT </= 3 cm) were randomized before surgery for cALND (standard treatment) or RNI (investigational treatment). Sentinel lymph nodes (SN) were investigated with serial sectioning at 0.5 mm levels by hematoxylin-eosin staining. Investigational treatment arm patients received 50 Gy RNI instead of cALND. Adjuvant treatment and follow up were performed according to the actual guidelines. Between August 2002 and June 2009, 1054 patients were randomized for cALND and 1052 patients for RNI. SN was evaluated in 2073 patients and was positive in 526 patients (25.4%). 474 cases were evaluable (244 in the cALND and 230 in the RNI arm), and in the cALND group 94 of 244 patients (38.5%) who underwent completion axillary surgery has additional positive nodes. The two arms were well balanced according to the majority of main prognostic factors. Primary endpoint was axillary recurrence and secondary endpoints were overall survival (OS) and disease-free survival (DFS). RESULTS: Mean follow-up was 97 months (Q1-Q3: 80-120). Axillary recurrence was 2.0% in cALND arm vs. 1.7% in RNI arm (p = 1.00). OS at 8 years was 77.9% vs. 84.8% (p = 0.060), and DFS was 72.1% in cALND arm and 77.4% after RNI (p = 0.51). The results show that RNI is statistically not inferior to cALND treatment. CONCLUSIONS: The long term follow-up results of this prospective-randomized trial suggest that RNI without cALND does not increase the risk of axillary failure in selected patients with early-stage invasive breast cancer (cT </= 3 cm, cN0) and pN1(sn). Axillary radiotherapy should be an alternative treatment for selected patients with sentinel lymph node metastases