5-year Survival Benefit Research Articles

Systemic therapy issues: Immunotherapy in nonmetastatic urothelial cancer.

Non-muscle-invasive bladder cancer is one of the most common malignancies. Patients with intermediate-risk or high-risk disease can be treated with intravesical Bacillus Calmette-Guerin, a vaccine against tuberculosis. However, many of these patients will experience tumor recurrence, despite appropriate treatment. 1 The standard of care in these patients is radical cystectomy (RC) with urinary diversion. 2 Patients diagnosed with muscle-invasive bladder cancer (MIBC) have traditionally faced 2 main treatment options: RC and urinary diversion, as in Bacillus Calmette-Guerin-unresponsive Non-muscle-invasive bladder cancer, or alternatively, trimodal therapy comprising maximal transurethral resection of bladder tumor plus chemoradiation. 3 For patients with MIBC and clinical (c)T2-T4a, neoadjuvant chemotherapy (NAC) preceding RC is supported by Level 1 evidence with a modest 5-year overall survival benefit of 5% with cisplatin-based regimens. 4-9 A number of factors preclude MIBC patients from standard treatment options. For example, patients with serious comorbidities might be unable to tolerate general anesthesia, while others might be unwilling to adapt to the lifestyle changes after RC. 10-12 Likewise, patients with extensive carcinoma in situ or poor bladder function might not be optimal candidates for trimodal therapy or be prepared for the ongoing risk that salvage RC might be ultimately required. Reasons for the underuse of NAC range from the fear of delaying potentially curative surgery in nonresponders to patient ineligibility to cisplatin-based NAC. 13,14 Despite best efforts, in both surgical and bladder-sparing approaches, the 5-year overall survival in treated patients with MIBC is only 35% to 50%. 3,15 Strategies to improve overall prognosis as well as to reduce the indications of RC are desperately needed. Trial results have demonstrated the unprecedented ability of immune-checkpoint inhibitors to induce durable remissions in some patients with metastatic urothelial carcinoma. 16-20 Furthermore, immune-checkpoint inhibitors have shown to be better tolerated than traditional chemotherapy. 16 These successful results have spearheaded the research on these agents in earlier curative settings, with the shared goal of improving overall outcomes, and potentially avoid surgery in patients who show complete response (pT0). Strategies to enhance the immune response by combining immunotherapy with immune sensitizers such as chemotherapy, immunotherapy, targeted therapy or radiation are on the rise.

Survival impact of adjuvant chemotherapy in patients with stage IIA colon cancer: Analysis of the National Cancer Database.

Utility of adjuvant chemotherapy for stage II cancer remains a matter of debate. Clinical guidelines suggest adjuvant chemotherapy for stage II tumors with high-risk features, in particular T4 tumors. However, limited consensus exists regarding the importance of other high-risk features (lymphovascular or perineural invasion, microsatellite instability). Our study aimed to investigate the impact of adjuvant chemotherapy for stage IIA (T3N0) colon cancer patients. Patients who underwent colectomy for stage IIA colon adenocarcinoma (2010-2015) were identified in the National Cancer Database (NCDB) and divided in two groups based on receipt of adjuvant chemotherapy vs observation. Inverse probability of treatment weighting (IPTW)-adjusted Kaplan-Meier and Cox proportional hazards regression analyses were performed to compare overall survival between the two groups. Subgroup analysis of patients with specific high-risk features LVI, PNI and MSI was performed. Among 46 688 surgical patients with stage IIA colon adenocarcinoma 5937 (12.7%) received adjuvant chemotherapy, while 40 751 (87.3%) were observed. Five-year IPTW-adjusted survival was higher in the adjuvant chemotherapy group (79.7% [95% CI 79.1, 80.2]) compared to the observation group (70.3% [95% CI 69.7, 70.9]). Patients with high-risk pathological features showed an estimated 5-year survival benefit of 11.3% (78.2% [95% CI 77.4, 79.1] vs 66.9% [95% CI 65.9, 67.8]) when treated with adjuvant chemotherapy. This NCDB analysis revealed a survival benefit for patients with stage IIA colon adenocarcinoma and high-risk features that were treated with adjuvant chemotherapy.

Neoadjuvant Chemotherapy Before Radical Cystectomy: Why We Must Adhere?

This study provides a critical literature review on state-of-the-art and novel strategies in the field of neoadjuvant treatments for muscle-invasive bladder cancer (MIBC). A nonsystematic literature review was performed using PubMed, Scopus and Clinical Trials.gov to retrieve papers related to neoadjuvant treatments for MIBC over the past 15 years. Prospective and retrospective studies were included. Platinum-based treatment is the gold standard and mainly consists of a combination of cisplatin with vinblastine, methotrexate, doxorubicin, gemcitabine, adriamycin or even epirubicin. The 5- year absolute overall survival benefit of MVAC is 5% and the absolute disease-free survival improves by 9%. CMV treatment is associated with a 10-year overall survival improving from 30% to 36% and a 16% reduction in mortality. Gemcitabine and cisplatin regimen provides complete response in 20% of cases, with non-inferior oncological outcomes compared to MVAC regimen. Recent prospective trials investigating neoadjuvant immunotherapy show a high rate of complete response, from 29% with atezolizumab to 39.5% with pembrolizumab. The tyrosine kinase inhibitor pathway is being explored and could offer an interesting strategy to improve survival outcomes. Available evidence suggests better oncological outcomes for MIBC patients receiving neoadjuvant treatment before radical cystectomy. While MVAC remains the standard of care in cisplatin eligible patients, novel strategies are under development for cisplatin-ineligible patients, whereby immunotherapy seems to hold great promise.

Impact of Lymph Node Yield on Survival in Surgically Treated Oropharyngeal Squamous Cell Carcinoma.

(1) To estimate the association between neck dissection lymph node yield (LNY) and survival among patients with surgically treated human papilloma virus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC). (2) To identify a clinically relevant quality metric for surgical treatment of HPV-related OPSCC. Retrospective cohort study. National Cancer Database. From the National Cancer Database, 4130 patients were identified with HPV-associated OPSCC treated with primary surgery from 2010 to 2016. Based on prior literature, an adequate neck dissection LNY was defined as ≥18 lymph nodes. To determine whether LNY is associated with survival, univariable and multivariable Cox proportional hazards regression was performed. Analysis was stratified by adjuvant therapy regimen. A total of 2113 patients (51.2%) underwent surgery with or without adjuvant radiation (S ± RT), and 2017 patients (48.8%) underwent surgery with adjuvant chemoradiation. LNY ≥18 was associated with a 5-year survival benefit of 7.15% (91.7% for LNY ≥18, 84.5% for LNY <18, P = .004) for the S ± RT cohort on unadjusted survival analysis. For the S ± RT group, LNY ≥18 was associated with decreased hazard of death (hazard ratio, 0.45; 95% CI, 0.29-0.70; P < .001) after adjustment for patient characteristics, TNM staging, surgical margins, extranodal extension, and treating facility characteristics. For surgery with adjuvant chemoradiation, the adjusted hazard ratio estimate for LNY ≥18 was 0.64 (95% CI, 0.41-1.00), but the result was not statistically significant (P = .052). An adequate LNY from a neck dissection may affect survival when HPV-related OPSCC is treated with up-front surgery.

84P Actual 5-year survival of dose-dense sequential adjuvant chemotherapy in early breast cancer (BC) patients treated in the post-trastuzumab era: A pooled analysis of 3 clinical trials

The addition of trastuzumab (T) in dose-dense (dd) sequential (s) chemotherapy (CT) has been found to improve the outcome of patients (pts) with HER2(+) BC. We aimed to evaluate the 5-year survival benefit of dds-CT in pts treated in the post-trastuzumab era. We analyzed 3,026 pts diagnosed with operable BC between 2005 and 2013, treated with dds-CT within one randomized and two observational HeCOG trials. Pts with HER2(+) disease had received T for 1 year. Hormonal and radiation therapy were administered, as indicated.The primary endpoints were disease-free survival (DFS) and overall survival (OS). In total, 59.7% of pts had Hormone receptor (HR)(+)/HER2(-)(luminal) tumors, 25.5% had HER2(+) disease, and 14.5% had triple-negative breast cancer (TNBC). T was administered in 95.5% of pts with HER2(+) disease. At a median follow-up of 7.4 years, the 5-year DFS rate of pts with HER2(+) and luminal tumors was 88%, respectively, as compared to 83% for those with TNBC. The 5-year OS rate was 93% for pts with HER2(+) disease, 92% for luminal and 87% for TNBC. Pts with luminal disease had the greatest 5-year DFS rates both among women with positive and negative nodes (86% and 95%, respectively), followed by pts with HER2(+) BC (83% and 94%, respectively) and TNBC (76% and 89%, respectively).The 5-year OS rate of pts with HER2(+) and luminal disease was 91%, respectively among pts with positive nodes and 97%, respectively in pts with node-negative BC. The 5-year OS rate of TNBC pts with node-negative disease was 92%. Trastuzumab is a part of one of success stories in Oncology, as its use dramatically improved the prognosis of HER2(+) pts. In this study, the outcomes of pts with HER2(+) BC were similar to those with luminal tumors, while TNBC remained the most unfavorable group.

Prospective, randomized, single-blinded, multi-center phase II trial of two HER2 peptide vaccines, GP2 and AE37, in breast cancer patients to prevent recurrence

PurposeAE37 and GP2 are HER2 derived peptide vaccines. AE37 primarily elicits a CD4+ response while GP2 elicits a CD8+ response against the HER2 antigen. These peptides were tested in a large randomized trial to assess their ability to prevent recurrence in HER2 expressing breast cancer patients. The primary analyses found no difference in 5-year overall disease-free survival (DFS) but possible benefit in subgroups. Here, we present the final landmark analysis.MethodsIn this 4-arm, prospective, randomized, single-blinded, multi-center phase II trial, disease-free node positive and high-risk node negative breast cancer patients enrolled after standard of care therapy. Six monthly inoculations of vaccine (VG) vs. control (CG) were given as the primary vaccine series with 4 boosters at 6-month intervals. Demographic, safety, immunologic, and DFS data were evaluated.Results456 patients were enrolled; 154 patients in the VG and 147 in CG for AE37, 89 patients in the VG and 91 in CG for GP2. The AE37 arm had no difference in DFS as compared to CG, but pre-specified exploratory subgroup analyses showed a trend towards benefit in advanced stage (p = 0.132, HR 0.573 CI 0.275–1.193), HER2 under-expression (p = 0.181, HR 0.756 CI 0.499–1.145), and triple-negative breast cancer (p = 0.266, HR 0.443 CI 0.114–1.717). In patients with both HER2 under-expression and advanced stage, there was significant benefit in the VG (p = 0.039, HR 0.375 CI 0.142–0.988) as compared to CG. The GP2 arm had no significant difference in DFS as compared to CG, but on subgroup analysis, HER2 positive patients had no recurrences with a trend toward improved DFS (p = 0.052) in VG as compared to CG.ConclusionsThis phase II trial reveals that AE37 and GP2 are safe and possibly associated with improved clinical outcomes of DFS in certain subgroups of breast cancer patients. With these findings, further evaluations are warranted of AE37 and GP2 vaccines given in combination and/or separately for specific subsets of breast cancer patients based on their disease biology.

Efficacy of Primary Surgical Versus Medical Intervention for Treatment of Left-Sided Infective Endocarditis

Left-sided staphylococcal, streptococcal, and enterococcal infective endocarditis (IE) is associated with poor clinical outcomes. Our primary aim is to compare clinical outcomes of staphylococcal, streptococcal, and enterococcal IE patients who undergo valve replacement surgery and outcomes of patients who are treated solely with antibiotics. All patients were treated medically or surgically for left-sided staphylococcal, streptococcal, or enterococcal IE at our institution from 1998 to 2014 and were retrospectively studied. The primary outcome of interest was 30-day and 1-year mortality, and secondary outcomes included posttreatment septic shock, embolic events, stroke, and end-stage renal disease at 30 days. Inverse probability treatment weights, derived from propensity scores, were used to balance the medical and surgical cohorts across clinical risk factors, The Society of Thoracic Surgeon scores, and pathogens. Outcomes were compared comprehensively and in a staphylococcal-only subanalysis. Study population consisted of 245 surgical patients and 164 medical patients. Mortality at 30 days was higher in the medical cohort, both in aggregate and for staphylococcal only (all, 7% vs 16%, P < .001; staphylococcal only, 7% vs 22%, P < .001). Surgical patients had a higher incidence of septic shock and renal dysfunction; however, stroke and embolic events at 30 days were not different between cohorts. Cox survival analysis demonstrated that surgical treatment provided a 1-year survival benefit, with a hazard ratio of 0.48 (95% confidence interval, 0.36 to 0.64) that was robust regardless of pathogen. Compared with medical management, valve replacement surgery in patients with left-sided staphylococcal, streptococcal, or enterococcal IE appears to confer a survival advantage at 30 days and 1 year.

Abstract P1-18-23: Evaluating the potential utility of presenting breast cancer clinical investigator estimates for numeric treatment benefit and recommendations for the use of two anti-HER2 adjuvant therapies: HER RISK

Background: The recent introductions of pertuzumab (P) and neratinib (N) have made counseling patients with HER2-positive breast cancer (BC) regarding the potential benefits of various adjuvant systemic regimens more complex and challenging. The HER RISK initiative was conceived as a novel means to support adjuvant therapy decision-making by providing input from BC clinical investigators (CIs). Methods: 30 CIs were recruited to provide numeric estimates of the potential benefit in 5-year disease-free survival (DFS) of various adjuvant therapeutic regimens and postadjuvant N for 24 HER2-positive BC scenarios along with their likely treatment recommendations. 50 community-based oncologists (CBOs) were then recruited and asked to provide the same estimates for 4 of the scenarios evaluated. They were then shown the responses from the CIs and asked to provide their perspectives on this information and its potential value as an educational resource. A modest honorarium was provided to CI and CBO participants. Results: There was a clear relationship between projected benefit of adding P or N and use of these agents in the 4 situations evaluated (Table). More than two thirds of CIs believe P improves DFS in cases with 2 positive nodes, and most generally recommend its inclusion in adjuvant therapy. However, for the 2 node-negative cases, CIs perceived the benefit of adding P to be minimal or absent and generally did not recommend this treatment. The numeric estimates and practice patterns of the CBOs were similar to those of the CIs, but P was perceived to be somewhat more beneficial by CBOs and was used more frequently in the node-negative scenarios. In terms of the decision to recommend postadjuvant N, CI responses strongly correlated with ER and nodal status. Almost all stated that N would provide benefit for a patient with ER-positive disease and 2 positive nodes and indicated that they would generally recommend N in that setting. CIs’ perceived benefit of N in the node-negative cases was minimal or absent, with few recommending it even for the ER-positive scenarios. N is commonly recommended by CBOs in the node-positive scenario — similar to the CIs — but more of these clinicians perceive a benefit to N in the node-negative cases and recommend its use. When asked whether they obtained clinical value from reviewing these types of estimates, 48 CBOs (96%) found the information useful and 34 (68%) stated that having access to it was likely to affect their practices. 45 CBOs (90%) would share the 5-year DFS estimates and treatment recommendations from the CIs with interested patients if available in an online format. Conclusions: The numeric estimates and practice patterns of CIs and CBOs were generally similar for the scenarios presented, but both P and N were perceived to be somewhat more beneficial and were used more frequently by CBOs than CIs in node-negative cases. Even in node-positive cases, CIs and CBOs estimated the benefit of P and N to be modest but in many cases sufficient to warrant their use. For both groups, there was a clear relationship between the estimated benefit of therapy and its use. CBOs found value in the graphical presentation of the CI estimates and practice patterns and would use them as part of patient counseling. The next phase of this ongoing project will evaluate whether integrating this information into shared decision-making is feasible and beneficial for CBOs. Citation Format: Neil Love, Sara A Hurvitz, Hope S Rugo, Lowell Hart, Gloria Kelly, Kirsten Miller, Trenton Cruse, Douglas Paley, Jonathan Moss, Kathryn Ziel. Evaluating the potential utility of presenting breast cancer clinical investigator estimates for numeric treatment benefit and recommendations for the use of two anti-HER2 adjuvant therapies: HER RISK [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-18-23.

A clinicopathological analysis of bone and soft tissue sarcoma in children and young adults: Time to adapt with the rapidly changing landscape?

Context: Primary bone and soft-tissue sarcomas (STSs) are rare tumors, comprising <1% of overall adult cancers. Despite its heterogeneous molecular profile, multimodality management of these tumors has led to the 5-year overall survival (OS) benefit, from approximately 50% in 1970 to the range of 75%–80% presently, in the adolescent age group. Various hospital-based registries have tried to address the scarcity of data of bone and STSs in Indian context in the last decade, but the number is not encouraging enough to gauge the pattern of care of the disease in children and young adults. Aims: To analyze the predictive and prognostic factors of clinical outcome in bone and STS in children and young adults. Settings and Design: This was a retrospective, single-institutional study from a prospectively maintained database. Subjects and Methods: We enrolled biopsy-proven patients (aged 3–35 years) of bone and STS, attended at our outpatient department during the period of January 2015 to December 2017 and traced till November 2019. Follow-up time was defined by the period from the date of registration to the date of last attendance or death. Statistical Analysis Used: Univariate log-rank analysis and unpaired t-test were used to assess the potential prognostic factors for progression-free survival and OS and further validated by multivariate Cox regression analyses. Results: Tumor size, stage at presentation, and treatment modality were the significant prognostic factors for both bone and STS. Children had better OS with 3-year OS (89.7% vs. 71.8%). Conclusions: We recommend multidisciplinary management with emphasis on early intervention in these tumors.

Pulmonary Metastasectomy versus Continued Active Monitoring in Colorectal Cancer (PulMiCC): a multicentre randomised clinical trial

BackgroundLung metastasectomy in the treatment of advanced colorectal cancer has been widely adopted without good evidence of survival or palliative benefit. We aimed to test its effectiveness in a randomised controlled trial (RCT).MethodsMultidisciplinary teams in 13 hospitals recruited participants with potentially resectable lung metastases to a multicentre, two-arm RCT comparing active monitoring with or without metastasectomy. Other local or systemic treatments were decided by the local team. Randomisation was remote and stratified by site with minimisation for age, sex, primary cancer stage, interval since primary resection, prior liver involvement, the number of metastases, and carcinoembryonic antigen level. The central Trial Management Group were blind to patient allocation until completion of the analysis. Analysis was on intention to treat with a margin for non-inferiority of 10%.ResultsBetween December 2010 and December 2016, 65 participants were randomised. Characteristics were well-matched in the two arms and similar to those in reported studies: age 35 to 86 years (interquartile range (IQR) 60 to 74); primary resection IQR 16 to 35 months previously; stage at resection T1, 2 or 3 in 3, 8 and 46; N1 or N2 in 31 and 26; unknown in 8. Lung metastases 1 to 5 (median 2); 16/65 had previous liver metastases; carcinoembryonic antigen normal in 55/65. There were no other interventions in the first 6 months, no crossovers from control to treatment, and no treatment-related deaths or major adverse events. The Hazard ratio for death within 5 years, comparing metastasectomy with control, was 0.82 (95%CI 0.43, 1.56).ConclusionsBecause of poor and worsening recruitment, the study was stopped. The small number of participants in the trial (N = 65) precludes a conclusive answer to the research question given the large overlap in the confidence intervals in the proportions still alive at all time points. A widely held belief is that the 5-year absolute survival benefit with metastasectomy is about 35%: 40% after metastasectomy compared to < 5% in controls. The estimated survival in this study was 38% (23–62%) for metastasectomy patients and 29% (16–52%) in the well-matched controls. That is the new and important finding of this RCT.Trial registrationClinicalTrials.gov, ID: NCT01106261. Registered on 19 April 2010

Association of Transplant Center With Survival Benefit Among Adults Undergoing Heart Transplant in the United States

In the United States, the number of deceased donor hearts available for transplant is limited. As a proxy for medical urgency, the US heart allocation system ranks heart transplant candidates largely according to the supportive therapy prescribed by transplant centers. To determine if there is a significant association between transplant center and survival benefit in the US heart allocation system. Observational study of 29 199 adult candidates for heart transplant listed on the national transplant registry from January 2006 through December 2015 with follow-up complete through August 2018. Transplant center. The survival benefit associated with heart transplant as defined by the difference between survival after heart transplant and waiting list survival without transplant at 5 years. Each transplant center's mean survival benefit was estimated using a mixed-effects proportional hazards model with transplant as a time-dependent covariate, adjusted for year of transplant, donor quality, ischemic time, and candidate status. Of 29 199 candidates (mean age, 52 years; 26% women) on the transplant waiting list at 113 centers, 19 815 (68%) underwent heart transplant. Among heart transplant recipients, 5389 (27%) died or underwent another transplant operation during the study period. Of the 9384 candidates who did not undergo heart transplant, 5669 (60%) died (2644 while on the waiting list and 3025 after being delisted). Estimated 5-year survival was 77% (interquartile range [IQR], 74% to 80%) among transplant recipients and 33% (IQR, 17% to 51%) among those who did not undergo heart transplant, which is a survival benefit of 44% (IQR, 27% to 59%). Survival benefit ranged from 30% to 55% across centers and 31 centers (27%) had significantly higher survival benefit than the mean and 30 centers (27%) had significantly lower survival benefit than the mean. Compared with low survival benefit centers, high survival benefit centers performed heart transplant for patients with lower estimated expected waiting list survival without transplant (29% at high survival benefit centers vs 39% at low survival benefit centers; survival difference, -10% [95% CI, -12% to -8.1%]), although the adjusted 5-year survival after transplant was not significantly different between high and low survival benefit centers (77.6% vs 77.1%, respectively; survival difference, 0.5% [95% CI, -1.3% to 2.3%]). Overall, for every 10% decrease in estimated transplant candidate waiting list survival at a given center, there was an increase of 6.2% (95% CI, 5.2% to 7.3%) in the 5-year survival benefit associated with heart transplant. In this registry-based study of US heart transplant candidates, transplant center was associated with the survival benefit of transplant. Although the adjusted 5-year survival after transplant was not significantly different between high and low survival benefit centers, compared with centers with survival benefit significantly below the mean, centers with survival benefit significantly above the mean performed heart transplant for recipients who had significantly lower estimated expected 5-year waiting list survival without transplant.

The efficacy and feasibility of adopting intravenous chemotherapy and oral S-1 as a sequential therapy for postoperative gastric cancer patients.

Some postoperative gastric cancer patients have to terminate systemic intravenous chemotherapy early due to adverse drug reactions. We performed a retrospective study to explore the efficacy and feasibility of sequential therapy.We retrospectively analyzed 55 postoperative gastric cancer patients (Group A) who received sequential therapy (intravenous chemotherapy and S-1) and 53 patients (Group B) who received intravenous chemotherapy from January 2012 to December 2013 in our hospital. The therapeutic effect (including 1-year, 5-year tumor recurrence and survival rate) and the incidence of adverse reactions were analyzed.When death and survival for more than 5 years was regarded as the end point of follow-up, the mean follow-up period was 40.6 months (34.7–46.4) in Group A and 39.2 months (33.0–45.3) in Group B. The 1-year tumor recurrence after the operation was 23.6% (13/55, Group A) and 28.3% (15/53, Group B). The 5-year tumor recurrence was 45.5% (25/55, Group A) and 49.1% (26/53, Group B). There was no significant difference in the 1- and 5-year tumor recurrence rates between these two groups (P > .05). The 1-year survival rates of Group A and Group B were 81.8% (45/55) and 79.2% (42/53), respectively, and the 5-year survival rates of Group A and Group B were 47.3% (26/55) and 45.3% (24/53), respectively. No significant difference was observed between these two treatments at either the 1- or 5-year survival benefit (P > .05). However, the patients in Group A had a lower incidence of gastrointestinal reactions (such as nausea and vomiting), leukopenia and liver function damage (P < .05). We also found that patients who underwent sequential therapy might show lower levels of adverse reactions.Our retrospective study provided some evidence to suggest that sequential treatment is effective and safe for postoperative gastric cancer patients who are intolerant to intravenous chemotherapy.

Management of occult neck disease in metastatic squamous cell carcinoma to the parotid gland

Background: Metastatic cutaneous squamous cell carcinoma (cSCC) to the parotid gland is associated with poor prognostic outcomes. The presence of metastatic cSCC to the parotid represents at least stage III disease, and is typically treated with bimodal therapy in the form of surgery and post-operative radiation therapy. At present, there is no consensus on the optimal management of potential occult neck metastases in the parotid positive and clinically and radiologically neck negative patient. We sought to evaluate whether elective neck dissection conferred a survival benefit in this cohort, when performed in conjunction with parotidectomy. Methods: Theatre management software was interrogated to identify all patients who underwent “parotidectomy” during the study period. Histopathology reports were then reviewed to identify patients with metastatic cSCC. Chart review was undertaken to determine suitability for inclusion. Clinical charts were reviewed and coded for demographics, clinical presentation, radiologic findings, surgical notes, inpatient stay, post-operative radiation treatment, and outpatient consultations. The Western Australian Cancer Registry was interrogated for recurrence and mortality data and cross-referenced with chart review information to provide the primary end-points of disease-free and overall survival. Results: Ninety-five patients met inclusion criteria. Sixty-two of the 95 patients with metastatic cSCC to the parotid without clinical/radiological neck disease underwent elective neck dissection. Patients who underwent neck dissection were more likely to present with an active primary (21% vs. 3%), and had more advanced parotid pathology (stage 2 or more, 60% vs. 33%), as classified by the O’Brien P stage. The rate of occult neck metastases in the neck dissection group was 25.8%, mainly seen in level 2 when dissected. The 5-year disease-free survival for the cohort was 33.5%, the overall 5-year survival was 42.5%. Elective neck dissection did not confer a 5-year disease-free or overall survival benefit. Conclusions: The prognosis of metastatic cSCC to the parotid is poor. No method has been established to predict those who will have occult neck metastases, with an observed range of 15–44% across studies. Elective neck dissection remains an option for the P+N0 parotid SCC case, and may be of benefit in select cases, including those with active primary disease or more advanced parotid pathology. The extent of neck dissection to be performed also remains unclear, but levels 2 and 3 are likely beneficial. Larger controlled studies of this group are warranted given the poor survival outcomes.

PC03.01 Adjuvant Therapy for Resected NSCLC Harboring EGFR Mutation, Chemotherapy or Targeted Therapy - PROs

Lung cancer is so far the leading cause of cancer death worldwide. Complete surgical resection remains the most effective approach for patients with early-stage non-small cell lung cancer (NSCLC). Patients with completely resected stage I NSCLC could have a 5-year survival of ∼80%, whereas it fails to ∼30%. Since 2003, adjuvant chemotherapy became the standard of care showing 4% absolute 5-year survival benefit compared to surgery alone [1]. Following randomized control trials revealed similar results [2-4], yet limited survival benefit, low therapeutic completed rate plus high toxicities rate may somehow hinder its clinical applicability. In the past decade, targeted therapies had achieved tremendous success in oncogene-driven advanced NSCLC showing both high efficacy and low toxicities [5]. As a matter of course, targeted therapy had its baby steps in early-stage NSCLC. However, no positive results were found in these trials which should probably be blame for large proportion of stage IB patients and incorrect detection methods for EGFR mutation. Besides, conservative trial design without head to head comparison could not fully address toxicities issues caused by chemotherapy. Precise target population seemed to be an essential key point to adjuvant targeted therapies and ADJUVANT as well as EVAN trial came into being [6, 7]. Although overall survival (OS) was not mature enough to measure, significantly prolonged disease-free survival (DFS) was observed in both trials along with better tolerability. Indeed, questioning around adjuvant targeted therapy has never been adjourned such as the optimal duration of targeted therapies, study design and lack of OS data. Ross et al brought up with an informative comment for ADJUVANT trial bringing the concept of MRD (molecular residual disease) into adjuvant treatment [8]. Based on the ctDNA testing after standard of care adjuvant chemotherapy, patients of high risk of recurrence will be given further treatments while observation for the others. It highlighted the significant role of discriminating beneficiaries from adjuvant targeted therapies instead of simply providing more efficient treatment modalities. Previous biomarker-based studies regarding adjuvant treatment among different tumor types [9, 10] had provided inspirational examples, and as well shown clinical feasibility and urgent need for personalized adjuvant treatment after complete surgical resection. For ADJUVANT trial, we established a comprehensive signature of genetic-features (MEDUSA) to guide personalized adjuvant treatment in EGFR-mutant stage II-III NSCLC. Results would be unleashed in upcoming ESMO meeting. Through utilizing multi-omics data, we could predict whether additional treatments, adjuvant chemotherapy only or observation would be adequate for each individual and provide optimal sequential treatments. Further translational researches and corresponding trials regarding resectable NSCLC should decipher the issues. Fortunately, several trials regarding dynamic monitoring postoperative ctDNA or genomic profile of primary cancer to guide sequential treatments are ongoing and the results should be expected. 1. Arriagada R, Bergman B, Dunant A et al. Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer. N Engl J Med 2004; 350: 351-360. 2. Winton T, Livingston R, Johnson D et al. Vinorelbine plus cisplatin vs. observation in resected non-small-cell lung cancer. N Engl J Med 2005; 352: 2589-2597. 3. Strauss GM, Herndon JE, 2nd, Maddaus MA et al. Adjuvant paclitaxel plus carboplatin compared with observation in stage IB non-small-cell lung cancer: CALGB 9633 with the Cancer and Leukemia Group B, Radiation Therapy Oncology Group, and North Central Cancer Treatment Group Study Groups. J Clin Oncol 2008; 26: 5043-5051. 4. Douillard JY, Rosell R, De Lena M et al. Adjuvant vinorelbine plus cisplatin versus observation in patients with completely resected stage IB-IIIA non-small-cell lung cancer (Adjuvant Navelbine International Trialist Association [ANITA]): a randomised controlled trial. Lancet Oncol 2006; 7: 719-727. 5. Hirsch FR, Scagliotti GV, Mulshine JL et al. Lung cancer: current therapies and new targeted treatments. Lancet 2017; 389: 299-311. 6. Zhong WZ, Wang Q, Mao WM et al. Gefitinib versus vinorelbine plus cisplatin as adjuvant treatment for stage II-IIIA (N1-N2) EGFR-mutant NSCLC (ADJUVANT/CTONG1104): a randomised, open-label, phase 3 study. Lancet Oncol 2018; 19: 139-148. 7. Yue D, Xu S, Wang Q et al. Erlotinib versus vinorelbine plus cisplatin as adjuvant therapy in Chinese patients with stage IIIA EGFR mutation-positive non-small-cell lung cancer (EVAN): a randomised, open-label, phase 2 trial. Lancet Respir Med 2018; 6: 863-873. 8. Ng TL, Camidge DR. Lung cancer's real adjuvant EGFR targeted therapy questions. Lancet Oncol 2018; 19: 15-17. 9. Sparano JA, Gray RJ, Makower DF et al. Prospective Validation of a 21-Gene Expression Assay in Breast Cancer. N Engl J Med 2015; 373: 2005-2014. 10. Dienstmann R, Salazar R, Tabernero J. Personalizing colon cancer adjuvant therapy: selecting optimal treatments for individual patients. J Clin Oncol 2015; 33: 1787-1796. Adjuvant therapy, EGFR-TKI, Lung cancer

988TiP - KEYNOTE-866: Phase III study of perioperative pembrolizumab (pembro) or placebo (pbo) in combination with neoadjuvant chemotherapy in cisplatin (cis)-eligible patients (pts) with muscle-invasive bladder cancer (MIBC)

BackgroundMIBC is associated with a high rate of recurrence and poor overall prognosis despite aggressive local and systemic therapy. With standard therapy of neoadjuvant cis-based chemotherapy (CT), only a modest 5-year survival benefit is seen after radical cystectomy (RC). Recently, neoadjuvant CT and pembro showed efficacy in cis-eligible pts with MIBC (NCT02365766). Trial designKEYNOTE-866 (NCT03924856) is a randomized, multicenter, global, phase 3 trial to assess efficacy and safety of perioperative pembro + CT vs perioperative pbo + CT for pts with MIBC. Adult pts (≥18 y) with histologically confirmed MIBC (T2-T4aN0M0) with predominant (≥50%) urothelial histology, confirmed by blinded independent central review, are eligible. Pts must be previously untreated, be cis-eligible, have ECOG PS 0/1, and have tumor tissue for histology and PD-L1 analysis. About 790 pts will be randomly assigned 1:1 to receive 4 cycles of neoadjuvant pembro + CT followed by 13 cycles of adjuvant pembro after RC + pelvic lymph node dissection (PLND) or 4 cycles of neoadjuvant pbo + CT followed by 13 cycles of adjuvant pbo after RC + PLND. Neoadjuvant/adjuvant pembro 200mg will be administered every 3 weeks (Q3W); neoadjuvant CT consists of 4 cycles of gemcitabine 1000mg/m2 + cis 70mg/m2 Q3W. Pts will be stratified by PD-L1 status (combined positive score [CPS] ≥10 vs<10), disease stage (T2 vs T3/4) and region (USA vs EU vs most of world). CT/MRI will be performed ≤5 wk pre-cystectomy, 6 wk post-cystectomy, and Q12W up to 96 wk post-cystectomy imaging, and at discontinuation; then, Q24W in year 3 and beyond. Primary end points are pathologic complete response (pCR) and event-free survival (EFS) evaluated in pts whose tumors express PD-L1 (CPS ≥10) and in all pts irrespective of CPS score. Secondary end points are OS, disease-free survival, and pathologic downstaging in populations described for pCR and EFS, as well as safety, and patient-reported outcomes. Adverse events (AEs; graded per NCI CTCAE v4.0) will be monitored from randomization through 30 days after last dose of study drug (90 days for serious AEs). Clinical trial identificationNCT03924856, April 23, 2019. Editorial acknowledgementMatthew Grzywacz, PhD, of the ApotheCom pembrolizumab team (Yardley, PA, USA), funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Legal entity responsible for the studyMerck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. FundingMerck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. DisclosureA.O. Siefker-Radtke: Advisory / Consultancy, Travel / Accommodation / Expenses: Merck Sharp & Dohme; Advisory / Consultancy, Travel / Accommodation / Expenses: Janssen; Advisory / Consultancy, Travel / Accommodation / Expenses: Nektar Therapeutics; Advisory / Consultancy, Travel / Accommodation / Expenses: Seattle Genetics; Advisory / Consultancy: Bavarian Nordic. G. Steinberg: Honoraria (self), Advisory / Consultancy: Merck; Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy, Shareholder / Stockholder / Stock options: Urogen; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Janssen; Honoraria (self), Advisory / Consultancy: Boston Scientific; Honoraria (self), Advisory / Consultancy: Cold Genesys; Honoraria (self), Advisory / Consultancy: PhotoCure; Honoraria (self), Advisory / Consultancy: Aduro; Honoraria (self), Advisory / Consultancy: Asieris; Honoraria (self), Advisory / Consultancy: Ciclomed; Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self), Advisory / Consultancy: Genentech; Honoraria (self), Advisory / Consultancy: MDxHealth; Honoraria (self), Advisory / Consultancy: Ferring; Honoraria (self), Advisory / Consultancy: Fidia; Shareholder / Stockholder / Stock options: Epivax Oncology. J. Bedke: Advisory / Consultancy: BMS, Roche, MSD, Pfizer; Speaker Bureau / Expert testimony, Research grant / Funding (institution): BMS, Roche, MSD. J. Martin: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck & Co., Inc. R. Kataria: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck & Co., Inc. T.L. Frenkl: Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Full / Part-time employment: MSD. C.J. Hoimes: Advisory / Consultancy: Seattle Genetics, Merck; Speaker Bureau / Expert testimony: Bristol-Myers Squibb, Genentech. All other authors have declared no conflicts of interest.

Radiotherapy dose escalation in the primary treatment of nasopharyngeal carcinoma: a systematic review and meta-analysis

Background: Dose escalation with radiotherapy (RT) in nasopharyngeal carcinoma (NPC) remains underutilized despite significant advances in methods of radiation delivery. RT boost during primary treatment has been shown to improve local control rates, which could have an impact on survival. We summarize the currently available evidence for dose escalation in the primary treatment of NPC. Methods: Databases were systematically searched for eligible studies from the year 2000. Included studies utilized RT dose escalation (BED >70 Gy) in the form of brachytherapy, external beam RT or stereotactic RT boost after external beam RT for primary treatment of NPC. Local recurrence-free survival (LRFS), overall survival (OS), toxicities and other relevant factors for the chosen studies were then pooled and analyzed. Results: Two randomized trials and 7 retrospective cohort studies with a total of 2,145 patients were included in the final analysis. Nine hundred and eighty-eight patients received dose escalation, mainly in the form of brachytherapy (90%). Patients were mostly male, from China/Southeast Asia, had T1-T2 disease (80%), underwent RT via conventional techniques (87%). Less than half received concurrent chemotherapy. Three-year LRFS (RR 1.04; 95% CI: 0.85–1.28, P=0.71) and OS were not significantly improved with dose escalation. However, the subset of patients pooled from the retrospective studies who did not receive concurrent chemotherapy showed significant a 5-year locoregional failure-free survival (RR 1.05; 95% CI: 1.02–1.09, P=0.005) benefit. Toxicities were not significantly increased with dose escalation. Conclusions: RT dose escalation in the primary treatment of NPC does not lead to an increase in LRFS, OS, progression free-survival and disease free-survival. However, there seems to be a LRFS benefit with dose escalation using brachytherapy in patients with T1-T2 disease and in patients who did not receive concurrent chemotherapy. Dose escalation with brachytherapy is likewise not significantly associated with any increase in the rate of complications. Data for the efficacy and toxicity of EBRT and SRT boost is currently still lacking.

Real-life data on improvement of survival after perioperative chemotherapy versus surgery alone on resectable adenocarcinoma of the stomach - a single-center study.

In the last decade, neoadjuvant chemotherapy has become the standard of care also for curatively resectable advanced gastric cancer. Prospective randomized studies have shown a significant benefit in disease free and overall survival rate after perioperative chemotherapy as compared to immediate surgery. However, data in the "real-life" setting are rare. In our retrospective study, we wanted to clarify the question whether this benefit is achievable under real-life conditions. A total of 81 patients with resected adenocarcinoma of the stomach or distal esophagogastric junction (AEG III) clinical stage II-IIIc according to UICC (eighth edition) were enrolled. Forty-two patients received perioperative chemotherapy (cohort 1) and 39 patients were operated on immediately (cohort 2). Chemotherapy was carried out according to the ECF, EOX, or FLOT protocols. Overall 5-year survival was 35.7 % in cohort 1 and 23.7 % in cohort 2. Thus, the relative 5-year overall survival benefit was 51 %, and 12 % in absolute numbers (p = 0.083). For patients receiving perioperative chemotherapy per protocol (n = 20), a more marked absolute improvement in 5-year overall survival of 16.3 % as compared to immediately operated on patients was achieved (p = 0.05). Progression-free survival in this analysis was shown to be improved by perioperative chemotherapy also without statistical significance (p = 0.03). Patients with curatively resectable gastric adenocarcinoma or type III AEG tumor benefit from perioperative chemotherapy in terms of overall survival even under real-life conditions. Moreover, a benefit in progression-free survival can be demonstrated.

Estimating the cost of radiotherapy for 5-year local control and overall survival benefit

Background and purposeEscalating health care costs have led to greater efforts directed at measuring the cost and benefits of medical treatments. The aim of this study was to estimate the costs of 5-year local control and overall survival benefits of radiotherapy for the cancer population in Australia. Materials and MethodsThe local control and overall survival benefits of radiotherapy at 5-years and optimal number of fractions per course have been estimated for 26 tumour sites for which radiotherapy is indicated. For this study, a hybrid approach that merges features from activity based costing (ABC) and relative value units costing (RVU) were used to provide cost estimates. ABC methodology was used to allocate costs to all radiotherapy activities associated with each patient’s treatment course, while the RVUs represent the cost of each radiotherapy activity relative to the average cost of all activities and were used to achieve a weighted cost allocation. A patient’s journey for the financial year was constructed by consolidating all the radiotherapy activities and their associated costs, and the average cost per activity (fraction) was determined. The cost of radiotherapy per 5-year overall survival and local control was then estimated. ResultsThe estimated population 5-year local control and overall survival benefits of radiotherapy for all cancer were 23% and 6%, respectively. The optimal number of fractions per treatment course if guidelines were followed was 19.4 fractions. The average cost per fraction for all cancer was AU$276. The estimated cost of radiotherapy was AU$23,585 per 5-year local control and AU$86,480 per 5-year overall survival (equivalent to 5 life years) for all cancer. ConclusionThe cost of AU$86,480 per 5-year overall survival would translate to AU$17,296 1-year overall survival. Therefore, the cost of radiotherapy is inexpensive if delivered optimally. Policy implications from this study include knowledge about cost to deliver radiotherapy to allow one to quantify the expected benefit at a population level.

A Pairwise Meta-Analysis of Induction Chemotherapy in Nasopharyngeal Carcinoma.

Locoregionally advanced nasopharyngeal carcinoma has high risk of distant metastasis and mortality. Induction chemotherapy is commonly administrated in clinical practice, but the efficacy was quite controversial in and out of randomized controlled trials. We thus conducted this pairwise meta-analysis. Trials that randomized patients to receive radiotherapy or concurrent chemoradiotherapy with or without induction chemotherapy were identified via searches of PubMed, MEDLINE, and ClinicalTrials.gov. A total of ten trials (2,627 patients) were included. The pooled hazard ratios (HRs) based on fixed effect model were 0.68 (95% confidence interval [CI] 0.56-0.80, p < .001) for overall survival (OS) and 0.70 (95% CI 0.61-0.79, p < .001) for progression-free survival (PFS), which strongly favored the addition of induction chemotherapy. The absolute 5-year survival benefits were 8.47% in OS and 10.27% in PFS, respectively. In addition, based on the available data of eight trials, induction chemotherapy showed significant efficacy in reducing locoregional failure rate (risk ratio [RR] = 0.81, 95% CI 0.68-0.96, p = .017) and distant metastasis rate (RR = 0.69, 95% CI 0.58-0.82, p < .001). This pairwise meta-analysis confirms the benefit in OS, PFS, and locoregional and distant controls associated with the addition of induction chemotherapy in nasopharyngeal carcinoma. According to the results of this meta-analysis of ten trials, induction chemotherapy can prolong overall survival and progression-free survival and improve locoregional and distant controls for nasopharyngeal carcinoma.

Evidence-based pharmacotherapies used in the postdischarge phase are associated with improved one-year survival in senior patients hospitalized with heart failure.

Hospitalized heart failure (HF) patients have a poor prognosis postdischarge. We determined whether renin-angiotensin system inhibitors (RASI) and β-blockers dispensed to patients within 60days post-HF hospital discharge are associated with improved 1-year survival. A retrospective population-based study was conducted in 4897 seniors, aged 65-84years, alive at 60days postindex HF hospitalization in Western Australia over 2003-2008. Dispensing of RASI and β-blocker dispensing was identified from the Pharmaceutical Benefits Scheme claims database linked to hospital admission and death records. At 1-year posthospital discharge, the all-cause mortality and all-cause death or HF rehospitalization rate was 13.5% (n=663) and 24.4% (n=1193), respectively. Postdischarge RASI and β-blocker were dispensed in 77.4% and 53.0% of patients, respectively. Their use was associated with a lower inverse probability treatment weighted (IPTW) HR for 1-year mortality of 0.70, 95% CI 0.61-0.81 and 0.79, 95% CI 0.68-0.92, respectively (both P<0.0001), with a survival advantage most evident in the subgroup (70.1%) of patients with ischemic HF. In the overall cohort, these therapies were also associated with reduced IPTW HRs for all-cause death or HF rehospitalization (both P<0.005) but not for HF rehospitalization exclusively. Use of a β-blocker was associated with a reduced IPTW HR for HF rehospitalization in the ischemic HF subgroup only. In a cohort of senior patients hospitalized with HF, dispensing of a RASI or β-blocker within 60days postdischarge is associated with a 1-year survival benefit. Early postdischarge support programs after recent HF hospitalization should include measures to optimize adherence to evidence-based medications.