Induction Chemoradiation Therapy Research Articles

Induction Immune Checkpoint Inhibitors and Chemotherapy Before Definitive Chemoradiation Therapy for Patients With Bulky Unresectable Stage III Non-Small Cell Lung Cancer

In the era of immunotherapy, the treatment for bulky, locally advanced non-small cell lung cancer (LA-NSCLC) remains challenging. This study explored the feasibility of induction immune checkpoint inhibitors (ICIs) plus chemotherapy before definitive chemoradiation therapy (CRT) for bulky LA-NSCLC. Patients with bulky, unresectable stage III NSCLC (primary tumor ≥5 cm in greatest dimension or metastatic lymph nodes ≥2 cm in shortest diameter) receiving ICIs and chemotherapy before CRT from 2018 to 2022 were identified. Survival outcomes and toxic effects were analyzed. Radiation therapy plans on computed tomography images before and after 2 cycles of induction chemoimmunotherapy were simulated to evaluate dosimetric outcomes. Seventy-five patients were included. One- and 2-year overall-survival (OS) rates were 91.5% (95% CI, 85.2%-98.3%) and 75.1% (95% CI, 64.1%-88.0%), respectively. One- and 2-year progression-free-survival (PFS) rates were 85.8% (95% CI, 78.0%-94.4%) and 64.2% (95% CI, 52.5%-78.6%), respectively. Median OS was not reached (NR). Median PFS was 30.6 months (95% CI, 25.9 months to NR). Grade 2 and ≥3 pneumonitis occurred in 26.7% and 9.3% of patients, respectively. Grade ≥3 pneumonitis was significantly associated with poorer OS (P=.003) and PFS (P=.018). Treatment discontinuation was significantly associated with shorter OS (P=.023) and PFS (P=.047). Patients with consolidation ICIs exhibited numerically better OS than those without consolidation ICIs (2-year OS, 85.8% vs 64.2%; P=.170). The objective response rate was 76.1% for induction treatment and 86.7% for induction treatment plus CRT. The disease control rate after 2 cycles of induction therapy was significantly greater than after 4 (P=.046) or more cycles (P=.025). Simulated radiation plans indicated that all target volumes, mean lung dose, and volume of lung parenchyma receiving ≥5 Gy, ≥20 Gy, and ≥30 Gy significantly decreased after 2 cycles (all P < .005). Two cycles of induction ICIs plus chemotherapy before definitive CRT were feasible for bulky LA-NSCLC, with significant tumor reduction and normal lung protection. Further investigations on CRT combined with induction and consolidation ICIs are warranted.

Assessment of erectile and ejaculatory functions after bladder-sparing therapy against muscle-invasive bladder cancer

ABSTRACT Introduction Radical cystectomy (RC) is still gold standard for muscle invasive bladder cancer (MIBC). Whereas, bladder-sparing therapy with transurethral resection of bladder tumor (TUR) and chemoradiation therapy (CRT) has been recognized as an alternative treatment to RC for selected patients with MIBC. We have developed and implemented tetra-modality bladder-sparing therapy (TeMT) incorporating partial cystectomy (PC) in addition to maximal TUR and induction CRT to overcome local recurrence after bladder-sparing therapy (Kageyama et al. Am J Clin Oncol 2003, Koga et al. BJU Int 2012, Kijima et al. BJU Int 2019). There are few studies on erectile and ejaculatory functions after bladder-sparing therapy. Objective To cross-sectionally survey erectile and ejaculatory functions after TeMT in patients with MIBC. Methods Of the total 117 male patients with MIBC who completed TeMT between 2006 and 2019, 70 patients were set as the target to distribute the questionnaires after excluding patients lost to follow up as of February 2020, patients with local recurrence of MIBC or additional prostate cancer treatment. Erectile function was assessed using the International Index of Erectile Function short form (IIEF-5), and ejaculatory function using Male Sexual Health Questionnaire Ejaculatory Dysfunction short form (MSHQ-EjD-SF). Attending physicians handed the questionnaires to the patients at the first regular outpatient visit after February 2020 and had the patients complete them outside the office. Results Of 44 patients received the questionnaires between February and August 2020, 35 completed the questionnaires. The median age (range) of the eligible patients was 70 (50-87) years old, and the median time from the date of PC to the date of response was 5.2 (0.35-14) years. The results of IIEF-5 showed that 3 (9%) had no erectile dysfunction (ED) (22-25 points), 9 (26%) had mild ED (17-21 points), 4 (11%) had mild to moderate ED (12-16 points), 4 (11%) had moderate ED (8-11 points), and 15 (43%) had severe ED (5-7 points). Based on the results of MSHQ-EjD-SF, 23 patients (66%) responded that they could ejaculate. Of those, 5 patients (14%) scored 4 or higher on all questions 1-3 of MSHQ-EjD-SF, suggesting that they did not have ejaculatory dysfunction. Conclusions Preservation of erectile and ejaculatory functions was observed in MIBC patients treated with bladder-sparing therapy. Along with that of lower urinary tract function, preservation of male sexual function in bladder-sparing therapy, especially ejaculatory function which is inevitably lost by RC, is considered to be an advantage over RC. Disclosure Work supported by industry: no.

Patterns and influence of nodal metastases after neoadjuvant chemoradiation and R0 resection in esophageal adenocarcinoma

ObjectiveLittle is known about the pattern of nodal metastases in patients with esophageal adenocarcinoma who have received neoadjuvant chemoradiation and undergone surgery. We sought to assess this pattern and evaluate its association with prognosis. MethodsAll patients with esophageal adenocarcinoma who underwent neoadjuvant chemoradiation and R0 esophagectomy between 2010 and 2018 at our institution were included (n = 537). The primary objective was to evaluate the association of sites of lymph node metastases with disease-free survival. The number of nodal stations and individual sites of nodal metastases were evaluated first in univariable then in separate multivariable Cox regression models adjusted for clinical factors. ResultsOf 537 patients, 193 (36%) had pathologic nodal metastases at the time of surgery; 153 (28%) had single-station disease, 32 (6.0%) had 2-station disease, and 8 (1.5%) had 3-station disease. The majority of patients with multiple positive nodal stations had positive nodes in the paraesophageal (93%) and/or left gastric stations (60%). Multivariable models controlling for clinical factors showed that an increasing number of positive nodal stations (hazard ratio, 1.59; 95% CI, 1.35-1.84; P < .01)—in particular, the subcarinal (hazard ratio, 2.78; 95% CI, 1.54-5.03; P < .01) and paraesophageal stations (hazard ratio, 2.0; 95% CI, 1.58-2.54; P < .01)—was associated with increased risk of recurrence. ConclusionsOne-third of patients who have undergone R0 resection for esophageal adenocarcinoma following induction chemoradiation therapy have metastatic lymph nodes. An increasing number of nodal stations, particularly paraesophageal and subcarinal metastases, were associated with increased risk of recurrence.

Importance of tumor size in resectable stage III-N2 non–small cell lung cancer

ObjectiveThe 8th TNM edition classifies stage III-N2 disease as IIIA and IIIB based on a tumor size cutoff of 5 cm. However, the importance of tumor size on survival in patients with resectable stage III-N2 disease has not been analyzed systematically. MethodsSurvival analysis based on tumor size (>5 cm vs ≤ 5 cm) for 255 consecutive patients with nonbulky (maximal lymph node diameter of 1.5 cm) stage III-N2 non–small cell lung cancer treated with surgery in our institution. ResultsNinety patients (35.3%) underwent induction chemoradiation therapy (n = 72, 28%) or induction chemotherapy (n = 18, 7%), and 165 patients underwent primary surgery followed by adjuvant chemotherapy (n = 52, 32%), adjuvant chemoradiation therapy (n = 47, 29%), or adjuvant radiation therapy (n = 14, 13.2%). After a median follow-up of 6.5 years, the overall survival was 46.5% at 5 years and 28.9% at 10 years. In tumors 5 cm or less, there was no difference in survival between patients treated with induction or adjuvant therapy. However, in tumors greater than 5 cm, the survival was significantly better after induction therapy compared with adjuvant therapy or surgery alone. Pathologic multi-station N2 disease was more frequently detected in tumors greater than 5 cm (31% vs 18% in tumors ≤5 cm, P = .042), and the rate of R1 resection was lower after induction therapy (2.2% vs 8.5% in primary surgery, P = .048). ConclusionsThese results support the redefinition of tumors greater than 5 cm with resectable N2 disease to stage IIIB. This change should help to refine the multimodality approach for stage III-N2 lung cancer.

Salvage Surgery Compared to Surgery After Induction Chemoradiation Therapy for Advanced Lung Cancer

BackgroundSalvage surgery is performed for selected patients with relapses of locally advanced lung cancer after definitive chemoradiation therapy (CRT), and it seems to be effective. To assess the feasibility of salvage surgery after definitive CRT, this study compared clinical outcomes of surgery after definitive CRT with those of surgery after induction CRT. MethodsMedical records of patients who underwent surgery from January 2000 to January 2018 were reviewed. The study compared patients with salvage anatomic pulmonary resection after definitive CRT with patients with surgery after induction CRT in terms of perioperative and long-term outcomes. ResultsA total of 23 patients underwent salvage surgery after definitive CRT for locally advanced lung cancer (salvage group), and 36 underwent surgery after induction CRT for cN2 stage III non-small cell lung cancer (induction CRT group). The surgical procedures in the salvage group were 2 segmentectomies, 13 lobectomies, 1 bilobectomy, and 7 pneumonectomies, and those in the induction CRT group were 34 lobectomies and 2 bilobectomies. There was no 30-day or 90-day mortality in either group. The 5-year overall survival was 44.7% for the salvage group and 58.6% for the induction CRT group. The 5-year progression-free interval was 42.2% for the salvage group and 47.7% for the induction CRT group. ConclusionsSalvage anatomic pulmonary resection after definitive CRT for locally advanced lung cancer is feasible, with acceptable morbidity and prognosis in highly selected patients.

855 OPTIMIZATION OF SURGICAL DELAY AFTER INDUCTION CHEMORADIATION FOR ESOPHAGEAL CANCER: 10 YEARS RETROSPECTIVE MULTI-CENTER STUDY

Abstract The treatment of esophageal cancer is in constant evolution. Most of the esophageal cancer receive induction chemoradiation therapy. Surgical delay has been studied but the optimal timing has not been clarified. Through the years, surgical delay has been modified by surgeons in our institutions, going from an average of 6 weeks delay to an average of 10 weeks delay. It is time to ask if this change has a real positive impact on our patient. Methods In this retrospective multi-center study, we combined data from two center in Quebec city that performs oncologic esophagectomy. The surgical delay went from 6 to 10 weeks around 2014. All surgeons changed their practice at that moment. We retrospectively analysed 5 years before and after the change of practice and created two cohorts of patients. Our primary outcome compared complete pathologic response rate. Our secondary outcomes were surgical complications, anastomotic leak, disease free survival and overall survival. Results Thirty-eight patients had surgery under 8 weeks (mean: 6 weeks) after their induction chemoradiation compared to 64 patients that had surgery after 8 weeks (mean: 10 weeks). There was no statistical significant difference between groups for the complete pathologic response (32% vs 25%, p = 0,16). Important complications were similar, with a rate of 24% vs 28% (p = 0,69). Anastomotic leaks were less frequent in the less than 8 weeks group, but no statistical significance was obtained (13% vs 27%, p = 0,14).No difference in the disease-free survival rate and overall survival rate was noted (DFS 40% vs 55% (p = 0,32), OS 38% vs 38% (p = 0,29)). Conclusion The treatment of esophageal cancer is in constant evolution, induction therapy and surgical technics involve over time. Surgical delay has no impact on complete pathologic response, complication and overall survival. There is no advantage to wait longer before surgery.

854 OPTIMIZATION OF SURGICAL DELAY AFTER INDUCTION CHEMORADIATION FOR ESOPHAGEAL CANCER: 10 YEARS RETROSPECTIVE MULTI-CENTER STUDY

Abstract The treatment of esophageal cancer is in constant evolution. Most of the esophageal cancer receive induction chemoradiation therapy. Surgical delay has been studied but the optimal timing has not been clarified. Through the years, surgical delay has been modified by surgeons in our institutions, going from an average of 6 weeks delay to an average of 10 weeks delay. It is time to ask if this change has a real positive impact on our patient. Methods In this retrospective multi-center study, we combined data from two center in Quebec city that performs oncologic esophagectomy. The surgical delay went from 6 to 10 weeks around 2014. All surgeons changed their practice at that moment. We retrospectively analysed 5 years before and after the change of practice and created two cohorts of patients. Our primary outcome compared complete pathologic response rate. Our secondary outcomes were surgical complications, anastomotic leak, disease free survival and overall survival. Results Thirty-eight patients had surgery under 8 weeks (mean: 6 weeks) after their induction chemoradiation compared to 64 patients that had surgery after 8 weeks (mean: 10 weeks). There was no statistical significant difference between groups for the complete pathologic response (32% vs 25%, p = 0,16). Important complications were similar, with a rate of 24% vs 28% (p = 0,69). Anastomotic leaks were less frequent in the less than 8 weeks group, but no statistical significance was obtained (13% vs 27%, p = 0,14). No difference in disease-free survival rate and overall survival rate was noted (DFS 40% vs 55% (p = 0,32), OS 38% vs 38% (p = 0,29)). Conclusion The treatment of esophageal cancer is in constant evolution, induction therapy and surgical technics involve over time. Surgical delay has no impact on complete pathologic response, complication and overall survival. There is no advantage to wait longer before surgery.

Lobectomy with bronchoplasty and pulmonary arterial angioplasty for lung cancer after correction of contralateral partial anomalous pulmonary venous connection

BackgroundThere have been few reports on surgically treated primary lung cancer accompanied by contralateral partial anomalous pulmonary venous connection (PAPVC). In such cases, repair of the PAPVC might be necessary to avoid postoperative right-heart failure due to the increased flow of the left-to-right shunt.Case presentationWe herein report a case of lung adenocarcinoma treated by left-upper lobectomy with bronchoplasty and pulmonary arterial angioplasty after induction chemoradiation therapy followed by surgical correction of the PAPVC in the right-upper lobe. The patient is alive without recurrence of lung cancer or any symptoms of heart failure 17 months after pulmonary resection.ConclusionWhen considering performing major pulmonary resection for lung tumor, thoracic surgeons should pay close attention to the presence of a PAPVC not only on the ipsilateral side of the lung tumor, but also the contralateral side, although it is a rare phenomenon.

National trends and perioperative outcomes of robotic oesophagectomy following induction chemoradiation therapy: a National Cancer Database propensity-matched analysis.

Oesophagectomy following induction chemoradiation therapy (CRT) is technically challenging. To date, little data exist to describe the feasibility of a robotic approach in this setting. In this study, we assessed national trends and outcomes of robotic oesophagectomy following induction CRT compared to the traditional open approach. The National Cancer Database was queried for patients who underwent oesophagectomy following induction CRT (2010-2014). Trends of robotic utilization were assessed by a Mantel-Haenszel test of trend. Propensity matching controlled for differences in age, gender, comorbidity, stage, histology and tumour location between the robotic and open groups. Overall survival was estimated by Kaplan-Meier analysis and compared by a log-rank test. Oesophagectomy following induction CRT was performed in 6958 patients. Of them, 555 patients (8%) underwent robotic surgery (5% converted to an open approach). Between 2010 and 2014, utilization of a robotic approach increased from 3% to 11% (Mantel-Haenszel, P < 0.001) and the number of hospitals performing at least 1 robotic oesophagectomy increased from 23 to 57. Compared to the traditional open approach, robotic oesophagectomy was used more frequently at academic hospitals (76% vs 60%, P < 0.001), and in patients living in metropolitan areas (85% vs 77%, P < 0.001) and those living in the Midwest (41% vs 33%, P < 0.001). In the matched groups, a robotic approach was associated with shorter median hospital stay (9 vs 10 days, P = 0.004) and dissection of more lymph nodes (median, 16 vs 12, P < 0.001). However, there were no differences in rates of positive margin resection (5% for both groups, P = 0.95), 30-day readmissions (5% vs 7%, P = 0.18), 30-day mortality (2.5% vs 4%, P = 0.79), 90-day mortality (9% vs 8.5%, P = 0.89) or 5-year overall survival (42% vs 39%, P = 0.19) between patients undergoing robotic and open surgery, respectively. Robotic oesophagectomy after induction CRT is feasible and associated with shorter hospitalization compared to an open approach, and does not compromise the adequacy of oncological resection, perioperative outcomes or long-term survival.

ES23.02 Which N2 Patients Are Candidates to Surgery in the Era If I/O?

The role of surgery in patients with pre-resection documented N2 disease remains a subject of controversy. In some institutions, any clinical N2 disease identified preoperatively is considered non-surgical and these patients are offered upfront definitive chemoradiation therapy (DefCRT) without planned resection. In other institutions, a selective approach to N2 patients will consider surgery as part of a multimodality approach where surgery may be offered first followed by adjuvant cytotoxic chemotherapy (AC) with or without sequential post-operative radiation therapy (PORT), or where surgery will be offered after induction chemotherapy or induction chemoradiation therapy. Due to variability in N2 disease presentation, factors determining this selective approach vary between institutions and may include the bulk of N2 nodal involvement (size), extent of N2 involvement (single vs multistation, microscopic vs macroscopic), the presence or absence of extracapsular nodal involvement, the need to perform a pneumonectomy or not, and mediastinal sterilization after induction therapy. Historically, response to induction therapy with clearance of N2 nodal involvement following induction therapy has been shown to bode for a better prognosis after surgical resection. Unfortunately, even after complete resection following induction therapy, many patients develop distant metastases, with brain metastases prevailing. In 2018, the PACIFIC trial showed that adding an immune checkpoint inhibitor (IO) durvalumab for up to one year after completion of DefCRT in non-surgical stages cIIIa and cIIIB patients led to a significant and unprecedented overall survival in this population of patients. (Antonia, NEJM 2018) In patients with resectable NSCLC (cIIIA and less), recent small phase I clinical trials of either single-agent induction IO (Forde, NEJM 2018) or concurrent induction chemoimmunotherapy (Provencio, JTO abst. 2018) given before surgery have demonstrated feasibility, acceptable toxicity, and unprecedented pathological response rates. It remains to be seen if these pathologic responses will translate into improved overall survival in this patient population. Extrapolating from these early observations, one may think that induction IO (likely with concurrent cytotoxic chemotherapy) may possibly allow us to offer surgery to a larger proportion of patients with clinical N2 disease in the future as we observe higher response rates to induction therapies which may translate in better survival. Others may want to extrapolate from the Pacific trial results and hypothesize that surgery followed by adjuvant IO may become a desirable option. Though encouraging, there is a paucity of data to help guide us in the incorporation of IO therapy perioperatively for patients with clinical N2 disease. As such, the role for IO in multimodality treatment for N2 disease remains undefined. Unknown are the true impacts of periop IOs in this patient population and what is the optimal combination and timing of these multimodality treatments. There are more unanswered questions than established guidelines: (1) whether “IO first then surgery” is superior to “surgery first then adjuvant IO”, (2) whether an induction IO strategy followed by resection would be superior to DefCRT followed by IO in this population of potentially resectable cN2 IIIA patients, (3) if induction IO is shown to be superior, how many cycles preop, (4) do we need to continue IOs post op, if so, for how long, (5) whether there will be a role for surgery after major response to IO, and (6) how will we select patients for resection when major pathological response rates will be in the 80% range (7) do we need to utilize biomarkers, tumor mutation burden, or genotyping in patient selection, (8) What is the best biomarker to predict response, among other questions . The easy answer at this stage is to treat these patients on trials where the impact of IOs can be rigorously studied. Ideally, I personally would want to compare: (1) Induction vs adjuvant IOs for surgical patients with cN+ disease, (2) Induction IO followed by resection vs DefCRT followed by IO. The duration of periop IO also needs to be evaluated and these studies should include cost analysis as well. For the surgeons, as systemic treatments improve, our duty is to perform sound oncological surgery with minimal morbidity and minimal to absent mortality. I believe that preop IO may allow us to consider surgical resection for a larger proportion of cIIIA N2 patients in the future. Immunotherapy, stage IIIA NSCLC, surgery

ES22.02 A Milestone in Locally Advanced NSCLC

Stage III NSCLC encompasses locally advanced tumours with infiltration of locoregional nodes and central thoracic structures and accounts for about a third of newly diagnosed NSCLC[1]. It represents the most advanced stage of NSCLC in which treatment is delivered with curative intent, but eventually more than 60% of patients die from their disease. Stage III NSCLC patients must strictly be discussed in a multidisciplinary tumor board, whereat the definition of resectability suffers from a certain heterogeneity across centers. Resectability is usually defined by the degree of invasion of lymph nodes, most often excluding multilevel or bulky N2 and N3 disease as well as invasion of the oesophagus, aorta and myocardium. Controversy exists on the role of surgery in stage III NSCLC since two large randomized trials investigated either induction chemoradiation therapy followed by resection versus radiotherapy[2], or induction chemotherapy followed by resection versus radiotherapy[3]. Both studies failed to demonstrate a difference in survival[2-5], however these treatment strategies are evidence-based and can be pursued in restectable NSCLC[6]. In the surgical scenario, randomised trials and meta-analyses have consistently shown that either adjuvant or neoadjuvant chemotherapy added to surgery results, with a better survival than surgery alone[7,8]. Adding preoperative radiotherapy to chemotherapy in patients with stage IIIA/N2 NSCLC did not improve the clinical outcome in a phase 3 randomised trial[9]. The role of adjuvant radiotherapy in stage IIIA/N2 after neoadjuvant chemotherapy followed by surgery has been evaluated in a unique randomized trial with awaited results (Lung ART, NCT00410683). Early NSCLC stages offer a theoretical unique curative scenario for the development of immunotherapy strategies, with limited disease volumes, a relative immune system preservation as well as unique opportunities for the investigation and assessment of new biomarkers. Perspectives, rational, hopes and ongoing attempts to combine immunotherapy in the surgical setting or alternatively complementary to chemoradiation will be discussed, with a focus on locally advanced disease. 1. Detterbeck FC. The eighth edition TNM stage classification for lung cancer: What does it mean on main street? J Thorac Cardiovasc Surg 2018;155:356-9. 2. Albain KS, Swann RS, Rusch VW, et al. Radiotherapy plus chemotherapy with or without surgical resection for stage III non-small-cell lung cancer: a phase III randomised controlled trial. Lancet 2009;374:379-86. 3. van Meerbeeck JP, Kramer GW, Van Schil PE, et al. Randomized controlled trial of resection versus radiotherapy after induction chemotherapy in stage IIIA-N2 non-small-cell lung cancer. J Natl Cancer Inst 2007;99:442-50. 4. O'Rourke N, Roque IFM, Farre Bernado N, Macbeth F. Concurrent chemoradiotherapy in non-small cell lung cancer. Cochrane Database Syst Rev 2010:CD002140. 5. Auperin A, Le Pechoux C, Rolland E, et al. Meta-analysis of concomitant versus sequential radiochemotherapy in locally advanced non-small-cell lung cancer. J Clin Oncol 2010;28:2181-90. 6. Postmus PE, Kerr KM, Oudkerk M, et al. Early and locally advanced non-small-cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2017;28:iv1-iv21. 7. Group NM-aC. Preoperative chemotherapy for non-small-cell lung cancer: a systematic review and meta-analysis of individual participant data. Lancet 2014;383:1561-71. 8. Group NM-aC, Arriagada R, Auperin A, et al. Adjuvant chemotherapy, with or without postoperative radiotherapy, in operable non-small-cell lung cancer: two meta-analyses of individual patient data. Lancet 2010;375:1267-77. 9. Pless M, Stupp R, Ris HB, et al. Induction chemoradiation in stage IIIA/N2 non-small-cell lung cancer: a phase 3 randomised trial. Lancet 2015;386:1049-56. Stage III NSCLC , chemoradiation, neo-adjuvant immunotherapy

P692Chemoradiation therapy to patients with lung cancer exacerbates thoracic aortic calcification

Abstract Introduction Development of chemoradiation therapy (CRT) has improved mortality in patients with cancer. Whereas, it is emerging problem that cancer-survivors suffer from cardiovascular diseases, and the association between modern CRT and the increase in future cardiovascular events is suggested. Meanwhile, previous studies showed that thoracic aortic calcification (TAC) detected by computed tomography (CT), a marker of atherosclerosis, was associated with all-cause mortality and cardiovascular events. However, the influence of CRT on TAC progression remains unclear. Purpose The purpose of this study was to evaluate whether CRT would exacerbate TAC. Methods A total of 68 patients who treated lung cancer at our hospital between 2011 and 2015 were retrospectively analyzed (mean 62 year-old, male 78%): 35 patients underwent surgical treatment after induction CRT (CRT group) and 33 patients underwent surgical treatment alone (control group), extracted by propensity score matching by age, sex, smoking status, and diseased side. The volume of TAC between 2nd and 12th thoracic vertebrae was quantitatively measured with CT imaging, at baseline and at 1 year follow-up. The annual percent change in TAC was compared between the CRT and the control group. Moreover, the independent relationship between implementation of CRT and the progression of TAC was assessed by multivariate logistic regression analysis, adjusting for age, gender, conventional atherosclerotic risk factors and baseline aortic calcification volume. Results Patients in the CRT group received radiation (mean 47.3±4.0 Gy) and chemotherapy: 2 courses of cisplatin with docetaxel (34 cases) or vinorelbine (1 case). The prevalence of dyslipidemia, taking statins and diabetes drugs were significantly higher in the control groups (17% vs. 39%; p=0.041, 11% vs. 33%; p=0.029, 3% vs. 18%; p=0.044, respectively). Baseline C-reactive protein level was significantly higher in the CRT group (0.255 vs. 0.115; p=0.034). In univariate analysis, the annual percent change in TAC volume was significantly increased in the CRT group compared with the control group (37.6% vs. 23.3%; p=0.006). Multivariate logistic regression analysis demonstrated that CRT was an independent factor associated with the progression of TAC volume, even after adjustment for baseline calcification volume and coronary risk factors (OR, 3.90; 95% CI, 1.32–11.47; p=0.014). Conclusion CRT to patients with lung cancer exacerbates thoracic aortic calcification, which may result in future cardiovascular events.

Tumor Remission and Tumor-Infiltrating Lymphocytes During Chemoradiation Therapy: Predictive and Prognostic Markers in Locally Advanced Esophageal Squamous Cell Carcinoma

Clinical tools are unavailable for accurate prediction of pathologic responses to chemoradiation therapy (CRT) among patients with esophageal squamous cell carcinoma (ESCC) before surgery. We evaluated tumor remission and tumor-infiltrating lymphocytes (TILs) during CRT as predictors of pathologic response and prognostic markers for patients with locally advanced ESCC treated with neoadjuvant CRT (neo-CRT) or definitive CRT. We analyzed patients with locally advanced ESCC (N = 164) who underwent neo-CRT (N = 48) or definitive CRT (N = 116). Patients underwent endoscopic ultrasonography and biopsies when induction CRT finished. Tumor remission characteristics were designated minor (-/+) to excellent remission (ER) (+++). TILs were determined in 10% increments. Tumor remission, TILs, or both were associated with pathologic complete response (pCR) and survival in the neo-CRT group and then analyzed in the definitive CRT group. ER and lymphocyte-predominant ESCC (LPE; ≥60% TILs) were identified according to the pCR rate and disease-free survival. We built a prediction model for pCR incorporating ER and LPE. The area under the receiver operating characteristic curve was 0.877, and sensitivity and specificity were 86.7% and 90.9%, respectively. Furthermore, this model identified pathologic response with an excellent calibration. Disease-free survival of patients with ER and LPE tumors was significantly longer than that of other patients. When we included tumor remission and TILs during CRT, our model predicted pCR with high probability and helped stratify prognostic subgroups, thereby guiding future therapy decisions for patients with locally advanced ESCC. Validation of this model in larger, prospective, multicenter studies is essential.

Induction chemoradiation is associated with improved survival in chest wall invasion lung cancer.

To determine if induction chemotherapy with concurrent high-dose radiation followed by resection is associated with improved survival in patients with nonsuperior sulcus lung cancer with chest wall invasion. We performed a retrospective review of clinical T3 (chest wall invasion) N0/N1 patients with non-small cell lung cancer who underwent surgical resection between January 1, 1992, and January 31, 2017. Exclusion criteria included superior sulcus tumors and resection performed for palliation/recurrence. Patients undergoing induction chemoradiation followed by surgical resection were compared to those undergoing resection first or those receiving induction radiation followed by resection. Overall survival was calculated using the Kaplan-Meier method. Thirty-four patients were included in the analysis, with 5-year overall survival (OS) of 30%. By clinical stage, 31 (91%) were IIB (T3N0) and 3 (9%) were IIIA (T3N1). Sixteen patients (47%) received induction chemoradiation before surgery. Of the remaining 18 patients, 5 (15%) received induction radiation followed by surgery, and 13 (38%) underwent surgery as the first treatment. Three patients belonging to the group not receiving induction chemoradiation died within 30 days after surgery and were excluded from survival analysis. In the remaining 31 patients, induction chemoradiation was associated with improved 5-year OS (53% for induction chemoradiation vs 7% for others; P<0.01). Disease recurrence was evident in 9 cases, 2 (12.5%) in the induction chemoradiation group and 7 (46.6%) in the others (median disease-free time 103.0 months for induction chemoradiation group vs 8.0 months for others; P<0.01). In patients with nonsuperior sulcus lung cancer with chest wall invasion, induction chemoradiation therapy followed by resection is associated with improved OS.

Adjuvant chemotherapy for patients with pathologic node-positive esophageal cancer after induction chemotherapy is associated with improved survival

ObjectivesThe study objectives were to identify variables associated with the use of adjuvant chemotherapy among patients with node-positive esophageal cancer who received induction therapy and to evaluate its relationship with overall survival. MethodsTreatment data for patients with esophageal cancer receiving induction chemotherapy ± radiotherapy and esophagectomy were abstracted from the National Cancer Data Base. Pathologic node-positive patients were dichotomized by whether they received 2 or more cycles of adjuvant chemotherapy or none. Kaplan–Meier survival curves were generated, and a Cox proportional hazards model was done to identify factors associated with overall survival. ResultsFrom 2006 to 2012, 3100 patients had pathologic positive nodes after induction therapy and esophagectomy. A total of 2625 patients (84.7%) did not receive adjuvant chemotherapy, and 475 patients (15.3%) did. N3 nodal stage was associated with an increased likelihood of receiving adjuvant chemotherapy (reference: N1, odds ratio, 1.82, 95% confidence interval, 1.15-2.97, P = .01), whereas increasing age (by year, odds ratio, 0.97, confidence interval, 0.96-0.98, P < .001), induction chemoradiation therapy (reference: induction chemotherapy, odds ratio, 0.39, confidence interval, 0.30-0.52, P < .001), and increasing inpatient length of stay after esophagectomy (per day: odds ratio, 0.98, confidence interval, 0.97-0.99, P = .007) were associated with a decreased likelihood. Patients receiving adjuvant chemotherapy had improved overall survival at each pathologic nodal stage: 31.6 months versus 22.7 months for N1 disease (P < .001), 32.4 months versus 19.2 months for N2 disease (P = .035), and 19.5 months versus 10.4 months for N3 disease (P < .001). Adjuvant therapy was independently associated with decreased mortality hazard (hazard ratio, 0.69, 95% confidence interval, 0.57-0.83, P < .001). ConclusionsPatients receiving adjuvant chemotherapy after induction therapy and esophagectomy show a survival benefit at all positive nodal stages. Prospective studies may help further delineate this benefit.

Impact of Immunohistochemistry-Based Subtypes in Muscle-Invasive Bladder Cancer on Response to Chemoradiation Therapy

A bladder-sparing strategy is a useful option for patients with muscle-invasive bladder cancer (MIBC), in which the response to chemoradiation therapy (CRT) is primarily important in achieving favorable oncologic outcomes. Our objective is to evaluate the impact of immunohistochemistry (IHC)-based subtyping in MIBC on prediction of CRT response. Treatment protocol consisted of induction CRT followed by partial or radical cystectomy as consolidative surgery; 118 eligible patients with nonmetastatic MIBC were retrospectively analyzed. Of these patients, 92 eventually underwent partial or radical cystectomy after CRT. We applied the IHC-based subtyping model developed by Lund University, which classifies patients into urobasal (Uro), genomically unstable (GU), and squamous cell cancer-like (SCCL) subtypes. GU and SCCL cancers are supposed to be highly aggressive and to have worse prognoses than Uro. Correlations of subtypes with CRT response were analyzed clinically in all patients and pathologically in 92 cystectomized patients. The impact of each subtype on cancer-specific mortality (CSM) was also analyzed. Of all patients, 26 (22%), 61 (52%), and 31 (26%) were classified into Uro, GU, and SCCL subtypes, respectively. Clinical complete response (CR) was achieved in 42% of patients overall after CRT, with a significantly higher proportion in GU patients (52%) and SCCL patients (45%) than in Uro patients (15%; P<.001 and P=.01, respectively). On multivariate analysis, the GU/SCCL subtype was a significant predictor of clinical CR, as was absence of hydronephrosis or concomitant carcinoma in situ. Analyses for pathologic CR in the cystectomized patients revealed analogous findings. Five-year CSM of Uro, GU, and SCCL patients was 16%, 23%, and 28% overall, respectively, and 19%, 22%, and 23% in cystectomized patients, respectively, with no significant difference among the subtypes. CR status after CRT was significantly and independently correlated with low CSM in both clinical and pathologic evaluations. GU and SCCL cancers showed significantly more favorable CRT response than did Uro cancers. IHC-based subtyping may improve clinical decisions about the indication of CRT for MIBC patients.

Prognosis of multi-level N2-positive non-small cell lung cancer according to lymph node staging using endobronchial ultrasound-transbronchial biopsy.

BackgroundThe optimal treatment for stage IIIA‐N2 non‐small cell lung cancer (NSCLC) remains controversial, and multidisciplinary team approaches are needed. Downstaging after induction therapy is a good prognostic factor in surgical patients; however, re‐evaluation of nodal status before surgery is challenging. The aim of this study was to evaluate the prognosis of patients with multi‐level N2 NSCLC who received surgery or chemoradiation therapy (CRT) according to restaging using endobronchial ultrasound‐transbronchial aspiration (EBUS‐TBNA).MethodsThis was a single center, prospective study that included 16 patients with biopsy‐proven multi‐level N2 disease on initial EBUS‐TBNA that was restaged using EBUS‐TBNA after induction therapy. Cases downstaged after rebiopsy were treated surgically. Three‐year progression‐free survival (PFS) and locoregional PFS were determined using Kaplan–Meier analysis.ResultsOf the 16 patients (median age 58 years, male 63%), eight had persistent N2 disease and eight showed N2 clearance on restaging using EBUS‐TBNA. Ten patients underwent surgery, including two patients without N2 clearance. Recurrence and locoregional recurrence occurred in eight and five patients, respectively. The three‐year PFS was longer in patients with N2 clearance than in those with N2 persistent disease (57.1% vs. 37.5%). Patients with N2 clearance also had longer three‐year locoregional PFS than those with N2 persistent disease (71.4% vs. 62.5%).ConclusionsEBUS‐TBNA could be an effective diagnostic method for restaging in multi‐level N2 NSCLC patients after induction CRT. As this was a pilot study, further large‐scale randomized studies are needed.

P1.05-013 Induction Chemoradiation Is Associated with Improved Survival in Resected Non-Pancoast Lung Cancer with Chest Wall Invasion

Induction chemo-radiation therapy has shown an increase in 5-year survival in patients with superior sulcus tumors and complete surgical resection. We hypothesized that induction chemo-radiation therapy followed by surgical resection is associated with improved survival in patients with non-superior sulcus lung cancer with chest wall invasion.

P.4.a.003 - Neural substrates of fear conditioning are modulated by GLRB allelic variation: converging evidence from an independent replication

A bladder-sparing strategy is a useful option for patients with muscle-invasive bladder cancer (MIBC), in which the response to chemoradiation therapy (CRT) is primarily important in achieving favorable oncologic outcomes. Our objective is to evaluate the impact of immunohistochemistry (IHC)-based subtyping in MIBC on prediction of CRT response.Treatment protocol consisted of induction CRT followed by partial or radical cystectomy as consolidative surgery; 118 eligible patients with nonmetastatic MIBC were retrospectively analyzed. Of these patients, 92 eventually underwent partial or radical cystectomy after CRT. We applied the IHC-based subtyping model developed by Lund University, which classifies patients into urobasal (Uro), genomically unstable (GU), and squamous cell cancer-like (SCCL) subtypes. GU and SCCL cancers are supposed to be highly aggressive and to have worse prognoses than Uro. Correlations of subtypes with CRT response were analyzed clinically in all patients and pathologically in 92 cystectomized patients. The impact of each subtype on cancer-specific mortality (CSM) was also analyzed.Of all patients, 26 (22%), 61 (52%), and 31 (26%) were classified into Uro, GU, and SCCL subtypes, respectively. Clinical complete response (CR) was achieved in 42% of patients overall after CRT, with a significantly higher proportion in GU patients (52%) and SCCL patients (45%) than in Uro patients (15%; P < .001 and P = .01, respectively). On multivariate analysis, the GU/SCCL subtype was a significant predictor of clinical CR, as was absence of hydronephrosis or concomitant carcinoma in situ. Analyses for pathologic CR in the cystectomized patients revealed analogous findings. Five-year CSM of Uro, GU, and SCCL patients was 16%, 23%, and 28% overall, respectively, and 19%, 22%, and 23% in cystectomized patients, respectively, with no significant difference among the subtypes. CR status after CRT was significantly and independently correlated with low CSM in both clinical and pathologic evaluations.GU and SCCL cancers showed significantly more favorable CRT response than did Uro cancers. IHC-based subtyping may improve clinical decisions about the indication of CRT for MIBC patients.

Trimodality therapy for Pancoast tumors: T4 is not a contraindication to radical surgery.

This study aims to evaluate the impact of T stage and extended surgery on the outcome of patients with Pancoast tumors after induction chemoradiation therapy. Forty-six consecutive patients who underwent chemoradiation therapy (platin-based, 45-66 Gy) followed by surgery between 1998 and 2013 were retrospectively reviewed and analyzed. In 28 (61%) patients with T4 tumors, extended procedures (more than rib resection) were performed. There were 37 (80%) lobectomies, 6 (13%) pneumonectomies, and 3 (7%) sublobar resections. A total of 44 (96%) patients had R0 resection. About 30-day mortality was 0%, major surgical complications occurred in 9 (19.6%) patients. Overall survival (OS) at 5-years was 63%. Disease-free survival (DFS) at 5-years was 45%. At multivariate cox regression analysis adjusted for clinical factors, T factor (T3/T4) and extended surgical procedures did not impact survival. However, pathological positive N stage had a negative impact on OS and lack of pathological response negatively impacted both OS and DFS. Trimodality treatment including radical resection for Pancoast tumors provides good surgical outcome and favorable long-term results. Survival of patients with T4 tumors and extended surgical procedures comparable to that of patients with T3 tumors undergoing rib resection only.