Preoperative Chemoradiation In Patients Research Articles

Total neoadjuvant therapy with mFOLFIRINOX versus preoperative chemoradiation in patients with locally advanced rectal cancer: 7-year results of PRODIGE 23 phase III trial, a UNICANCER GI trial.

LBA3504 Background: We have reported that neoadjuvant chemotherapy (NACT) with FOLFIRINOX followed by chemoradiotherapy (CRT), surgery, and adjuvant chemotherapy (ACT) significantly improved outcomes in patients (pts) with locally advanced rectal cancer (LARC) compared with pts who received standard CRT, surgery, and ACT. We now report the primary and secondary endpoints with mature follow-up (F/U). Methods: PRODIGE 23 is a phase III randomized clinical trial. Eligible pts had cT3 or cT4, M0 rectal adenocarcinomas <15 cm from the anal verge, age 18-75 years, and WHO PS ≤1. Randomization was stratified by center, T stage, N status, T location, and T extramural spread. Arm A pts received preoperative CRT (50 Gy, 2 Gy/fr; 25 fr + capecitabine), surgery, then ACT for 6 months (mos). Arm B pts received 6 cycles of mFOLFIRINOX, then the same preoperative CRT, surgery and 3 mos of ACT, mFOLFOX6 or capecitabine. From 6/2012 to 6/2017, pts were randomly assigned in Arm A (n=230) and B (n=231) by 35 participating centers. Analysis was performed on intent-to-treat population. For survival outcomes, HR and 95% CI were estimated by a stratified Cox proportional hazard (PH) model. However, we observed non-PH. So we used the restricted mean survival time (RMST) to evaluate the treatment effect (Liang F & al Ann Oncol 2018, Pak K & al JAMA Oncol 2017). Results: With a median F/U of 82.2 mos, death was reported for 55 pts in arm A and 42 in Arm B. All survival endpoints were better for Arm B vs Arm A. The absolute increase in 5-year survival were 7.6% for Disease-Free Survival (DFS), 6.9% for Overall Survival (OS), 9.9% for Metastasis-Free Survival (MFS), and 5.7% for Cancer Specific Survival (CSS) in Arm B compared to Arm A. Survival results at 7 years are presented in the Table. 7-year cumulative incidence of locoregional relapses are 5.3% in arm B vs 8.1% in arm A (p= 0.38). Conclusions: NACT with mFOLFIRINOX followed by CRT, surgery, and ACT significantly improved all outcomes, including OS in pts with LARC vs those who received standard CRT, surgery, and ACT. Clinical trial information: NCT01804790 . [Table: see text]

LBA21 Neoadjuvant mFOLFIRINOX and preoperative chemoradiation (CRT) versus preoperative CRT in patients with T3-4 rectal cancer: Surgical and quality of life results of PRODIGE 23 phase III trial

LBA21 Neoadjuvant mFOLFIRINOX and preoperative chemoradiation (CRT) versus preoperative CRT in patients with T3-4 rectal cancer: Surgical and quality of life results of PRODIGE 23 phase III trial

Abstract CT234: Phase I study of epacadostat added to preoperative chemoradiation in patients with locally advanced rectal cancer

Abstract Background: Epacadostat is an orally active, potent and selective inhibitor of indoleamine 2, 3-dioxygenase 1 (IDO1). IDO1 inhibition enhances cytotoxic T cell activation by dendritic cells, and significantly decreases regulatory T cell proliferation. We developed preclinical data supporting combination of epacadostat with radiation therapy in rectal cancer. In rectal cancer samples obtained from patients who received hypofractionated radiation, IDO1 was overexpressed in tumor tissue as compensatory response after radiation in both microsatellite stable and unstable cell lines. IDO1 inhibition with epacadostat selectively reduced survival of cancer cells and enhanced radiosensitivity without impacting normal epithelial cells. Epacadostat in addition to radiation showed both increased tumor cytotoxicity and enhanced immune activation in tumor microenvironment in a syngeneic mouse model of colorectal cancer. Literature also supports the choice of high dose, hypofractionated radiation to induce a more favorable anti-tumor immune response. Therefore, we hypothesized that IDO1 expression is a mechanism of radioresistance in rectal cancer and IDO1 inhibition is a safe and well-tolerated combination therapy to enhance tumor radiosensitivity. Methods: Patients with locally advanced rectal cancer who are candidates for neoadjuvant therapy using short-course radiation and chemotherapy are included in this study. Primary objective of the study is to determine the recommended phase II dose (RP2D) of epacadostat for combination with short course radiation and chemotherapy in preoperative treatment of locally advanced rectal cancer. This study includes dose-escalation part of patients receiving epacadostat with radiation and chemotherapy (n=6-18) followed by dose-expansion (n=up to 27 including those treated at RP2D during escalation). Two dose levels of epacadostat (300mg and 600mg orally twice daily) will be explored. Epacadostat will be combined with short-course radiation (5Gy x 5 fractions) followed by 6 cycles of CAPOX chemotherapy, until the day of surgery for a total of approximately 24 weeks of therapy. Research biopsies of tumor and adjacent non-tumor tissue along with blood sample collection will be performed before and after the radiation, and at the time of surgery. Tryptophan pathway metabolites, immune checkpoint biomarkers, markers of cell death, proliferation and potentially prognostic molecular biomarkers will be measured in tumor tissues before and after radiation therapy. In addition, patient-derived organoid and xenograft models from rectal biopsy samples will be used to determine the success rate of organoid generation, to evaluate treatment response and to characterize molecular changes to identify potential predictors of response and mechanisms of resistance. Enrollment began in November 2019. NCT03516708 Citation Format: Haeseong Park, Ebunoluwa Otegbeye, Hyun Kim, Matthew Mutch, Katrina Pedersen, Manik Amin, Benjamin Tan, Nikolaos Trikalinos, Kian-Huat Lim, Olivia Aranha, Rama Suresh, Shahed Badiyan, Matthew Silviera, Lauren Henke, Paul Wise, Steven Hunt, Jonathan Mitchem, Esther Lu, Andrea Wang-Gillam, Matthew Ciorba. Phase I study of epacadostat added to preoperative chemoradiation in patients with locally advanced rectal cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT234.

Total neoadjuvant therapy with mFOLFIRINOX versus preoperative chemoradiation in patients with locally advanced rectal cancer: Final results of PRODIGE 23 phase III trial, a UNICANCER GI trial.

4007 Background: PRODIGE 23 investigated the role of neoadjuvant mFOLFIRINOX before preoperative (preop) chemoradiation (CRT), with TME-surgery and adjuvant chemotherapy (CT) in resectable locally advanced rectal cancer. Methods: PRODIGE 23 is a phase III multicenter randomized clinical trial. Eligible pts had cT3 or cT4, M0 rectal adenocarcinomas <15 cm from the anal verge, age 18-75 years, and WHO PS ≤1. Randomization was stratified by center, T stage, N status, tumor location, and perirectal fat extramural extension. Primary endpoint was 3-yr disease-free survival (DFS). Main secondary endpoints were ypT0N0 rate, overall survival (OS) and metastasis-free survival (MFS). 460 pts were required to observe 136 events to show a gain in 3-year DFS from 75% to 85% (HR=0.56) with a 2-sided α=0.05 and 90% power. HR and 95% CI were estimated by a stratified Cox proportional hazard model. Arm A pts received preop CRT (50 Gy, 2 Gy/fraction [fr]; 25 fr + capecitabine), surgery, then adjuvant CT for 6 months (mos). Arm B pts received 6 cycles of mFOLFIRINOX (oxaliplatin 85 mg/m², leucovorin 400 mg/m², irinotecan 180 mg/m² D1, and 5-FU 2.4 g/m² over 46 h) every 14 days, followed by the same preop CRT, surgery and 3 mos of adjuvant CT. Adjuvant CT consisted of mFOLFOX6 or capecitabine, depending on the centre’s choice for all pts. Imaging work-up, operative and pathology reports were centrally reviewed. Results: (ITT) Between 6/2012 and 6/2017, 230 and 231 pts were randomly assigned in Arm A/B, respectively by 35 participating centers. Pts characteristics were well balanced. Neoadjuvant mFOLFIRINOX and CRT in both arms were well tolerated. Compliance to CRT and to adjuvant CT was not hampered by neoadjuvant CT. Surgical morbidity did not differ between the 2 arms. The ypT0N0 rate was 11.7 vs 27.5% in Arm A/B (p<0.001). Median follow-up was 46.5 mos. 136 DFS events was reported. 3-yr DFS was significantly increased in arm B (HR 0.69, 95% CI 0.49-0.97, p=0.034): 68.5% (CI: 61.9-74.2) vs 75.7% (CI: 69.4-80.8) in arm A/B. The subgroup analysis showed no evidence of heterogeneity of the effect size of treatment on DFS. 3-yr MFS was also significantly higher in arm B: 71.7 in arm A vs 78.8% (HR 0.64, CI 0.44-0.93, p<0.02) in arm B. 3-yr OS was 87.7 vs 90.8% (HR 0.65, CI 0.40-1.05, p=0.077) in arm A/B, with 54.2% of the pts with recurrence being alive. Conclusions: Neoadjuvant mFOLFIRINOX plus CRT is safe, and significantly increased ypCR rate, DFS and MFS. OS data are not mature. Clinical trial information: NCT01804790 .

Efficacy of Three-Drug Induction Chemotherapy Followed by Preoperative Chemoradiation in Patients with Localized Gastric Adenocarcinoma

Background: Preoperative induction chemotherapy followed by chemoradiation yields better R0 resection rates, pathologic complete response (pCR) rates and improved survival for localized gastric adenocarcinoma (GAC). We report the effect of three-drug induction chemotherapy on a large cohort of localized GAC patients. Methods: We identified 97 patients with localized GAC who received three-drug induction chemotherapy followed by preoperative chemoradiation therapy. We assessed various endpoints (overall survival [OS], recurrence-free survival [RFS], R0 resection and pCR rate). Results: The median follow-up time was 3.5 years (range; 0.4–16.7). The induction chemotherapy regimen was a fluoropyrimidine and a platinum compound (cisplatin or oxaliplatin) with a taxane (docetaxel or paclitaxel) for 95% of patients. Seventy-three (75.3%) out of 97 patients underwent planned surgery. R0 resection and pCR rae were 93.2 and 20.6%, respectively. Pathologic partial response (<50% residual carcinoma) rate was 50.7%. The median OS was 6.4 years (95% Cl 3.3–12.4) for the entire cohort and 11.1 years (95% Cl 7.1-not estimable) for patients that underwent surgery. The estimated 2- and 5-year OS rates were 72.4% (95% CI 62.1–80.3) and 54.3% (95% CI 43.2–64.1) for the entire cohort and 83.2% (95% CI 72.3–-90.1) and 66% (95% CI 52.3–75.8) for patients that underwent surgery. Pathologic lesser stage (stage I/II vs. stage III/IV) (p = 0.001) and R0 resection (p = 0.02) were independently associated with longer RFS in the multivariate analysis. Conclusion: Our data shows that three-drug combination is feasible without providing substantial advantage compared with two-drug combination in this setting of preoperative induction chemotherapy followed by chemoradiation and surgery.

Gut Microbiome Composition Is Associated with a Pathologic Response After Preoperative Chemoradiation in Patients with Rectal Cancer

There are ongoing investigations to find promising biomarkers for predicting a complete response (CR) after concurrent chemoradiation (CCRT) in rectal cancer. We aimed to find the predictive value in the gut microbiome in terms of response after preoperative CCRT. We collected a total of 45 fecal samples from patients with rectal cancer before CCRT. Tumor response after CCRT was assessed according to the American Joint Committee on Cancer tumor regression grading system. Analysis of linear discriminant analysis effect size and MetaCyc pathway abundance predictions were performed to compare composition and metabolic function of microbiome between patients with and without CR. We also established a Bayesian network model to identify microbial networks and species to be related with CCRT response. Seven patients (15.6%) demonstrated pathologically CR, and 38 patients (84.4%) showed non-CR after preoperative CCRT. Between CR and non-CR patients, there was a significant difference in terms of β-diversity (P = .028), but no difference in α-diversity was found. Bacteroidales (Bacteroidaceae, Rikenellaceae, Bacteroides) were relatively more abundant in patients with non-CR than those with CR. Pathways related to anabolic function predominated in CR patients. According to Bayesian network analysis, Duodenibacillus massiliensis was linked with the improved CR rate. From the fecal microbiome using samples obtained before preoperative CCRT, differences in microbial community composition and functions were observed between patients with and without CR in rectal cancer. However, the finding that a specific taxon may be linked with the improved therapeutic response should be verified in a prospective setting.

Efficacy of three-drug induction chemotherapy followed by preoperative chemoradiation in patients with localized gastric adenocarcinoma (GAC).

106 Background: Preoperative induction chemotherapy followed by chemoradiation yields better R0 resection rates, pathologic complete response (pCR) rates and improved survival for localized GAC.Previous studies with two-drug induction chemotherapy showed 70-80% R0 resection rates and 20-30% pCR rates. We report the effect of three-drug induction chemotherapy on a large cohort of localized GAC patients. Methods: We identified 97 patients with localized GAC who received three-drug induction chemotherapy followed by preoperative chemoradiation therapy. We assessed various endpoints (overall survival [OS], recurrence-free survival [RFS], R0 resection and pCR rate). Results: The median follow-up time was 3.5 years (range; 0.4-16.7). Most of the patients were men (60.8%) and the median age was 60 years (range; 21-89). The induction chemotherapy regimen was a fluoropyrimidine and a platinum compound (cisplatin or oxaliplatin) with a taxane (docetaxel or paclitaxel) for 95% of patients. Seventy-three (75%) out of 97 patients underwent planned surgery. R0 resection and pCR rate were 93% and 21%, respectively. Pathologic partial response (&lt; 50% residual carcinoma) rate was 50.7%. The median OS was 6.43 years (95% Cl 3.27-12.36) for the entire cohort and 11.1 years (95% Cl 7.1-not estimable) for patients that underwent surgery. The estimated 2- and 5-year OS rates were 72% (95% CI 62-80) and 54% (95% CI 43-64) for the entire cohort and 83% (95% CI 72-91) and 66% (95% CI 53-76) for patients that underwent surgery. Pathological lesser stage (stage I/II vs. stage III/IV) (p = 0.001) and R0 resection (p = 0.019) were independently associated with longer RFS in the multivariate analysis. Conclusions: Our data show that three-drug combination is feasible without providing substantial advantage in this setting of preoperative induction chemotherapy followed by chemoradiation and surgery.

A Phase 2 Study of 5-Fluorouracil (5-FU), Ziv-Aflibercept, and Radiation for the Preoperative and Adjuvant Treatment of Patients with Stage II/III Rectal Cancer

ABSTRACTBackground: This phase II study combined aflibercept with preoperative chemoradiation for patients with stage II/III rectal cancer, followed by mFOLFOX6/aflibercept. Methods: Patients received preoperative 5-FU (days 1–43), radiation (weeks 1–6), and aflibercept (days 1–15) each 28 day cycle for 6 weeks. Six weeks following the last aflibercept dose, patients underwent surgical resection. Four cycles of mFOLFOX6 plus aflibercept began 8 weeks after surgery. Results: Common treatment-related toxicities included diarrhea, fatigue, and mucositis. The pCR rate was 23%. Discussion: Afilbercept plus 5-FU-based chemoradiation was tolerated in patients with localized rectal cancer and showed a pCR rate within range of historical data.

Neoadjuvant Treatment for Locally Advanced Rectal Cancer: New Concepts in Clinical Trial Design.

Treatment for locally advanced rectal cancer has evolved from surgery alone to surgery plus adjuvant therapy. Preoperative 5-fluorouracil- or capecitabine-based chemoradiation with standard fractionated radiation, surgery utilizing total mesorectal excision, and further chemotherapy has become the standard of care in the USA. Preoperative adjuvant chemoradiation treatment sequencing has allowed for decreased toxicity, more sphincter-sparing surgery, and improved local control rates as compared to delivering the chemoradiation postoperatively. Yet, given the heterogeneity of locally advanced disease, some patients may be over-treated with this approach, leading to unnecessary toxicity and costs, while others may have a propensity to develop distant metastases and may benefit from intensified therapy. Therefore, the trend in modern clinical trial design has been to individualize therapy. As such, current studies are examining shortening the duration of radiation, omitting preoperative chemoradiation in patients who have a robust response to induction chemotherapy alone, omitting or delaying surgery in patients who have a clinical complete response to preoperative chemoradiation, and completing all of the adjuvant treatment prior to surgery.

Prognostic Impact of Immunonutritional Status Changes During Preoperative Chemoradiation in Patients With Rectal Cancer

PurposePrevious studies have demonstrated the prognostic impact of the prognostic nutritional index (PNI), a proposed indicator of immunonutritional statuses of surgical patients, on patients with various gastrointestinal cancers. Although the prognostic impact of the PNI on patients with colorectal cancer has been well established, its value has not been studied in patients treated with preoperative chemoradiation (pCRT). This study aimed to evaluate the prognostic impact of PNI on patients receiving pCRT for locally advanced rectal cancer (LARC).MethodsPatients with LARC who underwent curative pCRT followed by surgical resection were enrolled. The PNI was measured in all patients before and after pCRT, and the difference in values was calculated as the PNI difference (dPNI). Patients were classified according to dPNI (<5, 5–10, and >10). Clinicopathologic parameters and long-term oncologic outcomes were assessed according to dPNI classification.ResultsNo significant intergroup differences were observed in clinicopathologic parameters such as age, histologic grade, tumor location, tumor-node-metastasis stage, and postoperative complications. Approximately 53% of the patients had a mild dPNI (<5); only 15% had a high dPNI (>10). Univariate and multivariate analyses identified the dPNI as an independent prognostic factor for disease-free status (P < 0.01; hazard ratio [HR], 2.792; 95% confidence interval [CI], 1.577–4.942) and for cancer-specific survival (P = 0.012; HR, 2.469; 95%CI, 1.225–4.978).ConclusionThe dPNI is predictive of long-term outcomes in pCRT-treated patients with LARC. Further prospective studies should investigate whether immune-nutritional status correction during pCRT would improve oncologic outcomes.

Prognostic Relevance of Lymph Node Regression After Neoadjuvant Chemoradiation for Esophageal Cancer

Prognostic factors after preoperative chemoradiation for patients with advanced esophageal cancer are under discussion. Treatment response measured in the primary tumor is a well-defined prognostic marker. The prognostic relevance of tumor regression in lymph nodes (LNs), eg, histomorphologic characteristics must be evaluated in a larger series of patients. From 1997-2010, 403 patients with cT3N×M0 esophageal cancer underwent preoperative chemoradiation followed by transthoracic esophagectomy. Histopathologic response of the primary tumor was graded in resected specimens as "minor" (≥10% vital residual tumor cells) or "major." The LNs of all patients without LN metastases (ypN0 n = 222, adenocarcinoma n = 129, squamous cell carcinoma n = 93) were reevaluated for central fibrosis. Univariate and multivariate analyses were performed on histomorphologic criteria of examined LNs and used to correlate these with tumor response and prognosis. The 5-year survival rate (5YSR) for all patients was 30%. Overall, 5480 LNs were reevaluated for the existence of central fibrosis in ypN0 cases. The prognostic relevance of the LN regression (LNR) grading system was confirmed for all patients with univariate (P < 0.001) and multivariate (P = 0.02) analyses. In results, the 5YSR for ypN0 patients overall was 37%, for patients with major response by the primary tumor was 42%, and for minor responders was 19% (P < 0.001). Analyzing LNR in major responders, the group with less than 3 LNs with central fibrosis (n = 52) showed significantly better prognosis (5YSR = 63%) compared to those with more (5YSR = 34%), (P = 0.016). Conclusion includes morphologic signs of metastatic LNR after chemoradiation, such as central fibrosis, are of prognostic relevance for patients with advanced esophageal cancer, especially for those with major response of the primary tumor.

Postoperative Morbidity and Mortality Rates are Not Increased for Patients with Gastric and Gastroesophageal Cancer Who Undergo Preoperative Chemoradiation Therapy.

This study aimed to determine whether postoperative morbidity and mortality rates increased after preoperative chemoradiation in patients who underwent gastrectomy. The medical records of 7404 patients with gastric or gastroesophageal cancer seen from January 1995 to August 2012 were reviewed to identify patients who underwent gastrectomy. χ (2) and logistic regression analysis were used to determine differences in the 90-day postoperative morbidity and mortality rates of patients who underwent upfront surgery (SURG), preoperative chemotherapy (CHEMO), or preoperative chemoradiation (CHEMOXRT). Of the 500 patients included in this study, 200 underwent SURG, 65 had CHEMO, and 235 had CHEMOXRT. Respectively, 33, 43, and 58 % of these patients underwent total gastrectomy (p < 0.01). Resection of other organs was performed respectively in 19, 26, and 23 % of the patients (p = 0.37). Minor complications within 90 days (Clavien-Dindo 1 or 2) occurred for 41 % of the SURG patients, 43 % of the CHEMO patients, and 45 % of the CHEMOXRT patients (p = 0.68). Major complications or death within 90 days (Clavien-Dindo 3, 4, or 5) occurred for 21, 28, and 29 % of the patients, respectively (p = 0.15). The 90-day mortality (Clavien-Dindo 5) rates were 2 % for the SURG patients, 6 % for the CHEMO patients, and 3 % for the CHEMOXRT patients (p = 0.25). The median hospital stays were respectively 12, 12, and 13 days (p = 0.09). In the multivariate analysis, male sex, gastroesophageal junction cancer, total gastrectomy, and resection of other organs were associated with increased major morbidity and mortality rates, whereas preoperative therapy was not. The CHEMOXRT patients had postoperative morbidity and mortality rates similar to those for the SURG and CHEMO patients.

Factors affecting the restaging accuracy of magnetic resonance imaging after preoperative chemoradiation in patients with rectal cancer

PurposesWe evaluated patient or tumor factors associated with the preoperative restaging accuracy of magnetic resonance imaging (MRI) for determining T and N stages as well as circumferential resection margin (CRM) involvement after chemoradiation (CRT) in patients with locally advanced rectal cancer. MethodsSeventy-seven patients with rectal cancer that were treated with preoperative CRT (50.4 Gy) followed by radical resection were included. Post-CRT MRI was performed approximately 4 weeks after preoperative CRT. ResultsThe median tumor distance from the anal verge was 6 cm, 48 (62%) of which were anterior and 29 (38%) posterior. The median tumor diameter was 3 cm. A stage-by-stage comparison showed that correct staging occurred in 62%, 43%, and 86% of patients for T staging, N staging, and CRM prediction, respectively. Shorter distance to the anal verge (<5 cm), smaller tumor diameter (<1 cm), and anterior tumor location were associated with incorrect T staging. There were no significant variables in terms of N staging accuracy. Shorter tumor distance and anterior tumor location were associated with incorrect CRM prediction. ConclusionsOur findings suggest that specific tumor factors such as small, distal, or anterior rectal tumors are closely associated with the accuracy of MRI after preoperative CRT.

Results of the baseline positron emission tomography can customize therapy of localized esophageal adenocarcinoma patients who achieve a clinical complete response after chemoradiation

BackgroundPatients with localized esophageal adenocarcinoma (EAC) who achieve a clinical complete response (clinCR) after preoperative chemoradiation (trimodality therapy; TMT) or definitive chemoradiation (bimodality therapy; BMT) live longer than those who achieve a <clinCR (Suzuki A, Xiao LC, Hayashi Y et al. Prognostic significance of baseline positron emission tomography and importance of clinical complete response in patients with esophageal or gastroesophageal junction cancer treated with definitive chemoradiotherapy. Cancer 2011; 117: 4823–4833; Cheedella NK, Suzuki A, Xiao L et al. Association between clinical complete response and pathological complete response after preoperative chemoradiation in patients with gastroesophageal cancer: analysis in a large cohort. Ann Oncol 2013; 24: 1262–1266; Ajani JA, Correa AM, Hofstetter WL et al. Clinical parameters model for predicting pathologic complete response following preoperative chemoradiation in patients with esophageal cancer. Ann Oncol 2012; 23: 2638–2642). We hypothesized that the initial standardized uptake value (iSUV) of positron emission tomography will define novel subsets of clinCR patients. MethodsWe analyzed 323 EAC patients, from our prospective database, who achieved a clinCR. Various statistical methods were used to assess the influence of iSUV on patient outcome. ResultsThe median follow-up of 323 patients was 40.8 months [95% confidence interval (CI) 35.6–47.3 months]. Two hundred six (63.8%) patients had TMT and 117 (36.2%) had BMT. If iSUV was ≥6, TMT patients had a longer median OS (94.8 months; 95% CI 66.07–NA) than BMT patients (31.4 months; 95% CI 21.7–42.1; P ≤ 0.001). However, if iSUV was <6, the median OS of TMT and BMT patients was similar (P = 0.62). iSVU did not influence the pathologic complete response rate in TMT patients (P = 0.85). ConclusionclinCR patients with iSUV of <6 are identified as a new subset that fared equally well when treated with TMT or BMT. Future esophageal preservation strategy may be best suited for this newly identified subset of EAC patients.

A phase II randomized trial of induction chemotherapy versus no induction chemotherapy followed by preoperative chemoradiation in patients with esophageal cancer

BackgroundThe contribution of induction chemotherapy (IC) before preoperative chemoradiation for esophageal cancer (EC) is not known. We hypothesized that IC would increase the rate of pathologic complete response (pathCR). MethodsTrimodality-eligibile patients were randomized to receive no IC (Arm A) or IC (oxaliplatin/FU; Arm B) before oxaliplatin/FU/radiation. Surgery was attempted ∼5–6 weeks after chemoradiation. The pathCR rate, post-surgery 30-day mortality, overall survival (OS), and toxic effects were assessed. Bayesian methods and Fisher's exact test were used. ResultsOne hundred twenty-six patients were randomized dynamically to balance the two arms for histology, baseline stage, gender, race, and age. Fifty-five patients in Arm A and 54 in Arm B underwent surgery. The median actuarial OS for all patients (54 deaths) was 45.62 months [95% confidence interval (CI), 27.63–NA], with median OS 45.62 months (95% CI 25.56–NA) in Arm A and 43.68 months (95% CI 27.63–NA) in Arm B (P = 0.69). The pathCR rate in Arm A was 13% (7 of 55) and 26% (14 of 54) in Arm B (two-sided Fisher's exact test, P = 0.094). Safety was similar in both arms. ConclusionsThese data suggest that IC produces non-significant increase in the pathCR rate and does not prolong OS. Further development of IC before chemoradiation may not be beneficial.Clinical trial no.: NCT 00525915 (www.clinicaltrials.gov).

Association between clinical complete response and pathological complete response after preoperative chemoradiation in patients with gastroesophageal cancer: analysis in a large cohort

BackgroundChemoradiation followed by surgery is the preferred treatment of localized gastroesophageal cancer (GEC). Surgery causes considerable life-altering consequences and achievement of clinical complete response (clinCR; defined as postchemoradiation [but presurgery] endoscopic biopsy negative for cancer and positron emission tomographic (PET) scan showing physiologic uptake) is an enticement to avoid/delay surgery. We examined the association between clinCR and pathologic complete response (pathCR). Patients and methodsTwo hundred eighty-four patients with GEC underwent chemoradiation and esophagectomy. The chi-square test, Fisher exact test, t-test, Kaplan–Meier method, and log-rank test were used. ResultsOf 284 patients, 218 (77%) achieved clinCR. However, only 67 (31%) of the 218 achieved pathCR. The sensitivity of clinCR for pathCR was 97.1% (67/69), but the specificity was low (29.8%; 64/215). Of the 66 patients who had less than a clinCR, only 2 (3%) had a pathCR. Thus, the rate of pathCR was significantly different in patients with clinCR than in those with less than a clinCR (P < 0.001). ConclusionsclinCR is not highly associated with pathCR; the specificity of clinCR for pathCR is too low to be used for clinical decision making on delaying/avoiding surgery. Surgery-eligible GEC patients should be encouraged to undergo surgery following chemoradiation despite achieving a clinCR.

Clinical parameters model for predicting pathologic complete response following preoperative chemoradiation in patients with esophageal cancer

Approximately 25% of patients with esophageal cancer (EC) who undergo preoperative chemoradiation, achieve a pathologic complete response (pathCR). We hypothesized that a model based on clinical parameters could predict pathCR with a high (≥60%) probability. We analyzed 322 patients with EC who underwent preoperative chemoradiation. All the patients had baseline and postchemoradiation positron emission tomography (PET) and pre- and postchemoradiation endoscopic biopsy. Logistic regression models were used for analysis, and cross-validation via the bootstrap method was carried out to test the model. The 70 (21.7%) patients who achieved a pathCR lived longer (median overall survival [OS], 79.76 months) than the 252 patients who did not achieve a pathCR (median OS, 39.73 months; OS, P = 0.004; disease-free survival, P = 0.003). In a logistic regression analysis, the following parameters contributed to the prediction model: postchemoradiation PET, postchemoradiation biopsy, sex, histologic tumor grade, and baseline (EUS)T stage. The area under the receiver-operating characteristic curve was 0.72 (95% confidence interval [CI] 0.662-0.787); after the bootstrap validation with 200 repetitions, the bias-corrected AU-ROC was 0.70 (95% CI 0.643-0.728). Our data suggest that the logistic regression model can predict pathCR with a high probability. This clinical model could complement others (biomarkers) to predict pathCR.

Long-Term Results of Surgical Resection After Preoperative Chemoradiation in Patients With Pancreatic Cancer

Long-Term Results of Surgical Resection After Preoperative Chemoradiation in Patients With Pancreatic Cancer

Pathologic complete response to standard preoperative chemoradiation in patients with locally advanced rectal cancer.

686 Background: Pathologic complete response (pCR) is associated with lower rates of recurrences and longer disease-free survival rates in locally advanced rectal cancer (LARC) patients. The purpose of this study was to evaluate clinical outcomes of neoadjuvant chemoradiation and pCR among these patients. Methods: A retrospective chart review was performed for all patients treated for LARC between August 2005 and May 2011 at St. Michael's Hospital, Toronto. Patients were stratified into pCR and no-pCR groups and compared with respect to tumor size, nodal status, and treatment characteristics. Descriptive statistics were calculated for all variables of interest. Chi-square and t-tests were conducted to test for associations between categorical and continuous variables respectively. Disease free survival was calculated as the time between diagnosis and recurrence date, censored at last follow up. Results: A total of 92 patient charts were reviewed; 21 patients had metastatic carcinoma and were excluded from analysis. 63.4% (45/71) were male, with a mean age of 61.2 years and median follow up of 15 months. 12.7% (9/71) of patients achieved a pCR, while the remaining 87.35% (62/71) were no-pCR. All pCR patients received and completed standard pre-operative chemotherapy-radiotherapy. 73.4% (52/71) of the patients had complications from chemoradiotherapy. Furthermore, there was a significant association between having a significant response to treatment and achieving a pCR; where 78% (7/9) of pCR patients had a significant response to treatment. Overall, 4/71 patients had a local recurrence, 22.2% (2/9) pCR and 3.2% (2/62) no-pCR. Those with no-pCR had a recurrence at 1 and 2.2 years post diagnosis, while those with pCR had a recurrence at 3.7 years. Conclusions: This study suggests that patients undergoing standard pre-operative chemoradiotherapy are likely to have a significant response and achieve a pCR. Based on this study, although a pCR does not prevent the risk of recurrence, it delays the onset of local recurrence. Longer follow-up is required to determine if these results are robust and to develop future studies to improve efficacy of treatment delivery in LARC patients.

Double blind randomized phase II study with radiation + 5-fluorouracil ± celecoxib for resectable rectal cancer

Purpose To assess the feasibility and efficacy of the COX-2 inhibitor celecoxib in conjunction with preoperative chemoradiation for patients with locally advanced rectal cancer in a double blind randomized phase II study. Materials and methods Thirty-five patients of the initially planned 80 patients with locally advanced rectal cancer were treated with preoperative radiation (45 Gy; 1.8 Gy/fraction, 5 days/week) combined with 5-fluorouracil (continuous infusion, 225 mg/m 2/day) and celecoxib (2 × 400 mg/day) or placebo. Pathological response and toxicity of study treatment were evaluated, as well as expression of COX-2 and Ki67 in tumor tissue and IL-6 in plasma as possible molecular correlates and predictors of response to treatment. Results Patients treated with celecoxib tended to show a better response (61%) when compared to those treated with placebo (35%), although not significant ( p = 0.13). T-downstaging and N-downstaging were also slightly higher with celecoxib. Plasma IL-6 levels and intratumoral COX2 or Ki67 were altered by chemoradiation, but were not further altered by celecoxib treatment and therefore not useful for prediction of treatment benefit. Celecoxib therapy in conjunction with chemoradiation was not associated with additional toxicity and seemed to help mitigate therapy-related pain. Conclusions Addition of celecoxib to preoperative chemoradiation is feasible for patients with locally advanced rectal cancer. To study the individual effect of COX-2 inhibitors on pathological response phase III studies are required.