Circulating tumor cells detected in follow-up predict survival outcomes in tri-modality management of advanced non-metastatic esophageal cancer: a secondary analysis of the QUINTETT randomized trial.

BACKGROUND: Our aim was to establish if presence of circulating tumor cells (CTCs) predicted worse outcome in patients with non-metastatic esophageal cancer undergoing tri-modality therapy. METHODS: We prospectively collected CTC data from patients with operable non-metastatic esophageal cancer from April 2009 to November 2016 enrolled in our QUINTETT esophageal cancer randomized trial (NCT00907543). Patients were randomized to receive either neoadjuvant cisplatin and 5-fluorouracil (5-FU) plus radiotherapy followed by surgical resection (Neoadjuvant) or adjuvant cisplatin, 5-FU, and epirubicin chemotherapy with concurrent extended volume radiotherapy following surgical resection (Adjuvant). CTCs were identified with the CellSearch® system before the initiation of any treatment (surgery or chemoradiotherapy) as well as at 6-, 12-, and 24-months post-treatment. The threshold for CTC positivity was one and the findings were correlated with patient prognosis. RESULTS: CTC data were available for 74 of 96 patients and identified in 27 patients (36.5%) at a median follow-up of 13.1months (interquartile range:6.8-24.1 months). Detection of CTCs at any follow-up visit was significantly predictive of worse disease-free survival (DFS;hazard ratio [HR]: 2.44; 95% confidence interval [CI]: 1.41-4.24; p=0.002), regional control (HR: 6.18; 95% CI: 1.18-32.35; p=0.031), distant control (HR: 2.93; 95% CI: 1.52-5.65;p=0.001) and overall survival (OS;HR: 2.02; 95% CI: 1.16-3.51; p=0.013). After adjusting for receiving neoadjuvant vs. adjuvant chemoradiotherapy, the presence of CTCs at any follow-up visit remained significantly predictive of worse OS ([HR]:2.02;95% [Cl]:1.16-3.51; p=0.013) and DFS (HR: 2.49;95% Cl: 1.43-4.33; p=0.001). Similarly, any observed increase in CTCs was significantly predictive of worse OS (HR: 3.14; 95% CI: 1.56-6.34; p=0.001) and DFS (HR: 3.34; 95% CI: 1.67-6.69; p<0.001). CONCLUSION: The presence of CTCs in patients during follow-up after tri-modality therapy was associated with significantly poorer DFS and OS regardless of timing of chemoradiotherapy.

The quality of life in neoadjuvant versus adjuvant therapy of esophageal cancer treatment trial (QUINTETT): Randomized parallel clinical superiority trial.

BACKGROUND: We compared the health-related quality of life (HRQOL) in patients undergoing trimodality therapy for resectable stage I-III esophageal cancer. METHODS: A total of 96 patients were randomized to standard neoadjuvant cisplatin and 5-fluorouracil chemotherapy plus radiotherapy (neoadjuvant) followed by surgical resection or adjuvant cisplatin, 5-fluorouracil, and epirubicin chemotherapy with concurrent extended volume radiotherapy (adjuvant) following surgical resection. RESULTS: There was no significant difference in the functional assessment of cancer therapy-esophageal (FACT-E) total scores between arms at 1 year (p = 0.759) with 36% versus 41% (neoadjuvant vs. adjuvant), respectively, showing an increase of ≥15 points compared to pre-treatment (p = 0.638). The HRQOL was significantly inferior at 2 months in the neoadjuvant arm for FACT-E, European Organization for Research and Treatment of Cancer quality of life questionnaire (EORTC QLQ-OG25), and EuroQol 5-D-3 L in the dysphagia, reflux, pain, taste, and coughing domains (p < 0.05). Half of patients were able to complete the prescribed neoadjuvant arm chemotherapy without modification compared to only 14% in the adjuvant arm (p < 0.001). Chemotherapy related adverse events of grade ≥2 occurred significantly more frequently in the neoadjuvant arm (100% vs. 69%, p < 0.001). Surgery related adverse events of grade ≥2 were similar in both arms (72% vs. 86%, p = 0.107). There were no 30-day mortalities and 2% vs. 10% 90-day mortalities (p = 0.204). There were no significant differences in either overall survival (OS) (5-year: 35% vs. 32%, p = 0.409) or disease-free survival (DFS) (5-year: 31% vs. 30%, p = 0.710). CONCLUSION: Trimodality therapy is challenging for patients with resectable esophageal cancer regardless of whether it is given before or after surgery. Newer and less toxic protocols are needed.

Adjuvant Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors (TKIs) in Resected Non-Small Cell Lung Cancer (NSCLC): A Systematic Review and Meta-analysis.

The role of adjuvant tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC) is not well defined. Recent randomized controlled trials showed a disease-free survival (DFS) benefit in patients harboring an epidermal growth factor receptor (EGFR) mutation. Yet, older trials on patients with any EGFR status did not demonstrate the same benefit. We aimed to assess the efficacy and safety of adjuvant TKIs in NSCLC patients. The electronic databases Medline (PubMed) and EMBASE were searched for relevant randomized controlled trials. Random effect models were used. The primary outcome was DFS measured as hazard ratio (HR). The secondary outcomes were overall survival (OS) measured as HR, 2-year DFS and toxicity expressed as risk ratio and odds ratio (OR), respectively. Subgroup analyses assessed DFS by trial design. Six trials incorporating 1860 patients were included. In patients harboring an EGFR mutation, adjuvant TKIs decreased the risk of disease recurrence by 48% (HR: 0.52, 95% confidence interval [CI]: 0.35-0.78), improved 2-year DFS (HR: 0.53, 95% CI: 0.43-0.66) but did not improve OS (HR: 0.64, 95% CI: 0.22-1.89). The risk of developing ≥grade 3 skin toxicity (OR: 6.07, 95% CI: 4.34-8.51) and diarrhea (OR: 4.05; 95% CI: 2.44-6.74) was increased. In subgroup analyses, the DFS benefit was more pronounced in trials using TKIs over chemotherapy compared with trials using TKIs postchemotherapy. In conclusion, adjuvant TKIs decrease the risk of recurrence in NSCLC patients harboring an EGFR mutation but do not improve OS. Longer follow-up is needed for a definitive assessment of OS and to define the role of adjuvant TKI for NSCLC in the clinical practice.

External validation of the ProCaRS nomograms and comparison of existing risk-stratification tools for localized prostate cancer.

INTRODUCTION: The purpose of this study was to perform a direct comparison of several existing risk-stratification tools for localized prostate cancer in terms of their ability to predict for biochemical failure-free survival (BFFS). Two large databases were used and an external validation of two recently developed nomograms on an independent cohort was also performed in this analysis. METHODS: Patients who were treated with external beam radiotherapy (EBRT) and/or brachytherapy for localized prostate cancer were selected from the multi-institutional Genitourinary Radiation Oncologists of Canada (GUROC) Prostate Cancer Risk Stratification (ProCaRS) database (n=7974) and the Centre Hospitalier de l'Université de Montréal (CHUM) validation database (n=2266). The primary outcome was BFFS using the Phoenix definition. Concordance index (C-index) reported from Cox proportional hazards regression using 10-fold cross validation and decision curve analysis (DCA) were used to predict BFFS. RESULTS: C-index identified Cancer of the Prostate Risk Assessment (CAPRA) score and ProCaRS as superior to the historical GUROC and National Comprehensive Cancer Network (NCCN) risk-stratification systems. CAPRA modeled as five and three categories were superior to GUROC and NCCN only for the CHUM database. C-indices for CAPRA score, ProCaRS, GUROC, and NCCN were 0.72, 0.72, 0.71, and 0.72, respectively, for the ProCaRS database, and 0.66, 0.63, 0.57, and 0.60, respectively, for the CHUM database. However, many of these comparisons did not demonstrate a clinically meaningful difference. DCA identified minimal differences across the different risk-stratification systems, with no system emerging with optimal net benefit. External validation of the ProCaRS nomograms yielded favourable calibrations of R2=0.778 (low-dose rate [LDR]-brachytherapy) and R2=0.868 (EBRT). CONCLUSIONS: This study externally validated two ProCaRS nomograms for BFFS that may help clinicians in treatment selection and outcome prediction. A direct comparison between existing risk-stratification tools demonstrated minimal clinically significant differences in discriminative ability between the systems, favouring the CAPRA and ProCaRS systems. The incorporation of novel prognostic variables, such as genomic markers, is needed.

Measuring the population impact of introducing stereotactic ablative radiotherapy for stage I non-small cell lung cancer in Canada.

BACKGROUND: The Cancer Risk Management Model (CRMM) was used to estimate the health and economic impact of introducing stereotactic ablative radiotherapy (SABR) for stage I non-small cell lung cancer (NSCLC) in Canada. METHODS: The CRMM uses Monte Carlo microsimulation representative of all Canadians. Lung cancer outputs were previously validated internally (Statistics Canada) and externally (Canadian Cancer Registry). We updated costs using the Ontario schedule of fees and benefits or the consumer price index to calculate 2013 Canadian dollars, discounted at a 3% rate. The reference model assumed that for stage I NSCLC, 75% of patients undergo surgery (lobectomy, sublobar resection, or pneumonectomy), 12.5% undergo radiotherapy (RT), and 12.5% undergo best supportive care (BSC). SABR was introduced in 2008 as an alternative to sublobar resection, RT, and BSC at rates reflective of the literature. Incremental cost effectiveness ratios (ICERs) were calculated; a willingness-to-pay threshold of $100,000 (all amounts are in Canadian dollars) per quality-adjusted life-year (QALY) was used from the health care payer perspective. RESULTS: The total cost for 25,085 new cases of lung cancer in 2013 was calculated to be $608,002,599. Mean upfront costs for the 4,318 stage I cases were $7,646.98 for RT, $8,815.55 for SABR, $12,161.17 for sublobar resection, $16,266.12 for lobectomy, $22,940.59 for pneumonectomy, and $14,582.87 for BSC. SABR dominated (higher QALY, lower cost) RT, sublobar resection, and BSC. RT had lower initial costs than SABR that were offset by subsequent costs associated with recurrence. Lobectomy was cost effective when compared with SABR, with an ICER of $55,909.06. CONCLUSION: The use of SABR for NSCLC in Canada is projected to result in significant cost savings and survival gains.

Adjuvant concurrent chemoradiation using intensity-modulated radiotherapy and simultaneous integrated boost for resected high-risk adenocarcinoma of the distal esophagus and gastro-esophageal junction.

PURPOSE: Multimodality therapy leads to improved outcomes for adenocarcinoma of the distal esophagus and gastroesophageal junction (GEJ) over surgery alone. At our institution, adjuvant chemoradiation (chemoRT) using IMRT and SIB is standard of care for resected high-risk disease. In this study, we review our experience with a recent cohort of patients treated in this manner. METHODS AND MATERIALS: We identified 18 patients with resected T3 and/or N1 adenocarcinoma of the distal esophagus and GEJ who received adjuvant chemoRT. A large elective volume (PTV1) and a smaller high-risk volume (PTV2) were irradiated simultaneously using IMRT and an SIB technique. All patients received concurrent chemotherapy. Relevant clinical outcomes are reported. RESULTS: The median dose to 95% of PTV1 was 3747cGy and to 95% of PTV2 was 4876cGy. All RT was given in a median of 28 daily fractions. Four patients did not complete chemotherapy. At a median follow up of 952 days from the start of RT, 7 of 18 patients were dead; of these, 3 had developed local recurrence only; 3 had developed both local and distant recurrence; 1 died of a late toxicity, without recurrence. OS was 88% at 1year, 76% at 2 years and 58% at 3 years. Freedom from local recurrence was 88% at 1 year, 82% at 2 years and 82% at 3 years. Freedom from distant recurrence was 72% at 1 year, 67% at 2 years and 56% at 3 years. Toxicity was acceptable. CONCLUSIONS: Adjuvant concurrent chemoRT with IMRT and SIB is feasible for resected high-risk adenocarcinoma of the distal esophagus and GEJ. Our results describe how modern treatment techniques can be employed as part of a treatment paradigm that is neither commonly used nor commonly described in the literature.

Accuracy of recorded tumor, node, and metastasis stage in a comprehensive cancer center.

PURPOSE: The benefits of recording the tumor, node, and metastasis (TNM) stages of cancer patients are well accepted, but little is known about how accurately this is performed. An audit was performed to determine the accuracy of recorded stage and to act as a baseline before the implementation of an education program. PATIENTS AND METHODS: All new patient referrals to Princess Margaret Hospital between July 1 and August 31, 1997, were reviewed. An audit panel composed of five health record technicians (HRTs) and 10 doctors was assembled. Each auditor reviewed 10% of the health record. If there was a discrepancy between the stage in the health record and the auditor stage, then the final stage was determined by the audit committee. Analysis of the agreement between the health record, the physician auditor, the HRT auditor, and the final stage was performed. RESULTS: A total of 855 patients were referred with a new diagnosis of a malignancy for which there was a TNM stage system; 833 patients (97.4%) had a stage assigned. There was agreement between the health record stage and final stage in 80% (95% confidence interval [CI], 77% to 82%) of cases for clinical stage, compared with 90% (95% CI, 87% to 92%) for pathologic stage. Of the major site groups, lung was the least accurately recorded. The most common major discrepancies were due to the recording of X when a definite category could be assigned. CONCLUSION: This audit demonstrates the importance of staging and provides impetus to develop staging guidelines and education programs.