Pathologic Complete Response, Total Neoadjuvant Therapy and the Survival Paradox in Locally Advanced Rectal Cancer.

BACKGROUND: Pathologic complete response (pCR) after preoperative chemoradiation (nCRT) correlates with improved overall survival for patients with locally advanced rectal cancers (LARCs). Escalation protocols including total neoadjuvant therapy (TNT), which delivers multi-agent chemotherapy and chemoradiation before surgery, are associated with increased complete response rates. However, TNT is not associated with improved overall survival. The authors hypothesized that the route to pCR may be an important predictor of oncologic outcome. METHODS: Adults with LARC between 2006 and 2017 were identified in the National Cancer Database. The cohort was limited to those who received neoadjuvant radiation (45-70 Gy) and underwent proctectomy. RESULTS: Of 25,880 patients, 16 % received TNT and 84 % had nCRT followed by either multi-agent (27 %), single-agent (14 %), or no adjuvant chemotherapy (44 %). Overall, 18 % achieved pCR, with higher rates in the TNT cohort than in the nCRT (18 %) or multi-agent (14 %) chemotherapy cohorts. With control for covariates, the OS in the pCR cohort was similar for the patients that received single-agent therapy and those that received multi-agent adjuvant therapy, and superior to the TNT and no adjuvant therapy cohorts. Conversely, among the patients who did not achieve pCR, those who received single-agent chemotherapy had OS comparable with those who had multi-agent adjuvant therapy and TNT, which was better than no adjuvant therapy. CONCLUSION: Patients achieving pCR after TNT had worse OS than those who had CRT alone, suggesting that the neoadjuvant route by which pCR is achieved is prognostically relevant. Therefore, in the era of neoadjuvant therapy escalation, pCR does not necessarily portend a uniformly favorable prognosis.

Survival Outcomes in Patients with Resectable Gastric Cancer Treated with Total Neoadjuvant Therapy.

BACKGROUND: Perioperative chemotherapy has become the standard of care for locally advanced gastric cancer. Total neoadjuvant therapy (TNT), including both chemotherapy and chemoradiation, is utilized in other gastrointestinal malignancies. We determined survival in a contemporary cohort of gastric cancer patients treated with TNT. METHODS: Using a prospective institutional database, patients diagnosed with cT2-4 or cN+ gastric adenocarcinoma (January 2012 to June 2022) who underwent staging laparoscopy, received TNT, and underwent gastrectomy were identified. Overall survival (OS) and disease-specific survival (DSS) were determined using standard statistical methods. RESULTS: The study included 203 patients. The most common TNT sequence was induction chemotherapy followed by chemoradiation (n = 186 [91.6%]). A total of 195 (96.1%) patients completed planned neoadjuvant treatments. Surgery included total gastrectomy in 108 (53.2%), extended (D1+/D2) lymphadenectomy in 193 (95.1%), and adjacent organ resection in 19 (9.4%) patients. Pathologic complete response (pCR) was achieved in 32 (15.8%) patients. The 5-year OS rate was 65.2% (95% confidence interval [CI] 57.8-73.5%), and the 5-year DSS rate was 70.8% (95% CI 63.6-78.9%) in the study cohort. Among patients with pCR, the 5-year OS rate was 89.1% (95% CI 78.1-100.0%), and the 5-year DSS rate was 96.9% (95% CI 91-100%). Posttreatment pathologic N and M stages were the strongest prognostic indicators associated with both OS and DSS. CONCLUSIONS: Total neoadjuvant therapy for resectable gastric cancer is associated with a high rate of treatment completion and promising survival outcomes. Prospective comparisons with perioperative treatment are needed to identify patients most likely to benefit from TNT.

A systematic review and meta-analysis of pathologic complete response rates for patients with cholangiocarcinoma treated on liver transplant protocols.

BACKGROUND AND OBJECTIVES: Many heterogenous orthotopic liver transplant (OLT) protocols exist for patients with unresectable cholangiocarcinoma. Little is known about the incidence, predictors for, and the significance of achieving a pathologic complete response (pCR). METHODS: We performed a systematic review through September 2022 of the PubMed, Embase, and Web of Science databases. A random-effect meta-analysis was conducted to pool data across studies with reported pCR rates. Heterogeneity between treatment protocols was assessed via subgroup analysis. The pCR and 1-, 3-, and 5-year recurrence-free survival (RFS) and overall survival (OS) rates were extracted as outcomes of interest. RESULTS: A total of 15 studies reported pCR rates and were grouped by use of the Mayo protocol (4/15), stereotactic body radiation therapy (2/15), and an Other category (9/15). The pooled pCR rate among all studies was 32%. Both radiation technique and duration of CHT showed no significant association with pCR (p = 0.05 and 0.13, respectively). Pooled 1-year RFS and OS after any neoadjuvant therapy and OLT was 80% (95% confidence interval [CI], 0.61-0.91), and 91% (95% CI, 0.87-0.94), respectively. There was no 1-year OS difference detected among the three groups. pCR was not associated with OS in the meta-regression. Pooled 3- and 5-year OS among all studies was 72% and 61%, respectively. CONCLUSIONS: The pooled incidence of pCR was 32%. Differences in radiation technique did not appear to influence pCR rates and upon meta-regression, pCR was not a surrogate marker for survival.

Impact of neoadjuvant therapy on nodal harvest in clinical stage III rectal cancer: Establishing optimum cut-offs by disease response.

INTRODUCTION: A minimum lymph node harvest (LNH) of 12 is the current standard for appropriate nodal staging in resectable rectal cancer. However, the rise of neoadjuvant chemoradiation (NCRT) and total neoadjuvant therapy (TNT) has been associated with decreasing number of LNH. We hypothesize that as tumor response to neoadjuvant therapy increases, the optimum for LNH to achieve appropriate nodal staging should decrease. METHODS: Patients with clinical stage III rectal adenocarcinoma who underwent NCRT/TNT followed by resection were identified from the National Cancer Database. A JoinPoint regression analysis was used to determine the LNH for each tumor regression grade (TRG) category beyond which the rate of positive nodes does not significantly change. RESULTS: Thirteen thousand four hundred and twenty-six patients met inclusion criteria. Of these, 2406 (17.9%) achieved TRG 0 or ypT0 and 8210 (61.2%) achieved ypN0. Collectively, 2043 patients (15.2%) were reported to have a pathologic complete response (ypT0 ypN0). Positive pathologic nodes were found in 15%, 23%, 31%, 54%, and 53% as ypT stage increased from ypT0 to ypT4, respectively. Similarly, ypN+ rates were 15%, 36%, 41%, and 55% in TRG 0-3. No JoinPoint was identified for TRG 0, whereas inflection points were found at 6-10 nodes for TRG1 (p = 0.002) and TRG 2 (p = 0.016), and at 11-15 nodes for TRG 3. CONCLUSION: The benchmark of retrieving 12 nodes in resectable stage III rectal cancer is not consistently achieved after NCRT/TNT. We demonstrate that the LNH requirement to establish accurate pathologic nodal staging can vary depending on the tumor response to neoadjuvant therapies.

Penile-scrotal erythrodysesthesia among rectal cancer patients receiving fluoropyrimidine-based chemoradiation: a case report series.

BACKGROUND: Palmar-plantar erythrodysesthesia (PPE) is a slowly developing cutaneous reaction commonly experienced by patients treated with fluoropyrimidines. While erythrodysesthesia normally presents in a palmar-plantar distribution, it can also present with genital involvement, but this presentation is likely underreported and incorrectly attributed to an acute reaction from radiation therapy. This article aims to define erythrodysesthesia of the penis and scrotum as a rare but significant side effect of capecitabine. CASE PRESENTATION: We identified five cases of moderate to severe penis and scrotal erythrodysesthesia over a 2-year period at a large tertiary cancer center, representing an estimated incidence of 3.6% among male patients with rectal cancer who were treated with fluoropyrimidine-based chemoradiation within our institution. CONCLUSIONS: Improved understanding of erythrodysesthesia involving the penis and scrotum can facilitate early identification and treatment of symptoms, and possibly prevent the discontinuation or delay of cancer treatment in patients treated with capecitabine and similar drugs. These clinical advances would improve and prolong patient quality of life during cancer treatment and prevent complications that result in hospitalization.

Relevance of shrinkage versus fragmented response patterns in rectal cancer.

AIMS: Partial response to neoadjuvant chemoradiotherapy (CRT) presents with one of two main response patterns: shrinkage or fragmentation. This study investigated the relevance of these response patterns in rectal cancer, correlation with other response indicators, and outcome. METHODS AND RESULTS: The study included a test (n = 197) and a validation cohort (n = 218) of post-CRT patients with rectal adenocarcinoma not otherwise specified and a partial response. Response patterns were scored by two independent observers using a previously developed three-step flowchart. Tumour regression grading (TRG) was established according to both the College of American Pathologists (CAP) and Dworak classifications. In both cohorts, the predominant response pattern was fragmentation (70% and 74%), and the scoring interobserver agreement was excellent (k = 0.85). Patients with a fragmented pattern presented with significantly higher pathological stage (ypTNM II-IV, 78% versus 35%; P < 0.001), less tumour regression with Dworak (P = 0.004), and CAP TRG (P = 0.005) compared to patients with a shrinkage pattern. As a predictor of prognosis, the shrinkage pattern outperformed the TRG classification and stratified patients better in overall (fragmented pattern, hazard ratio [HR] 2.04, 95% confidence interval [CI] 1.19-3.50, P = 0.008) and disease-free survival (DFS; fragmented pattern, HR 2.50, 95% CI 1.23-5.10, P = 0.011) in the combined cohorts. The multivariable regression analyses revealed pathological stage as the only independent predictor of DFS. CONCLUSIONS: The heterogeneous nature of tumour response following CRT is reflected in fragmentation and shrinkage. In rectal cancer there is a predominance of the fragmented pattern, which is associated with advanced stage and less tumour regression. While not independently associated with survival, these reproducible patterns give insights into the biology of tumour response.

The differential effect of neoadjuvant chemotherapy and chemoradiation on nodal downstaging in pancreatic adenocarcinoma.

BACKGROUND/OBJECTIVES: Neoadjuvant chemotherapy (NCT) and chemoradiotherapy (NCRT) enhance resectability in patients with pancreatic adenocarcinoma (PDAC). This study compares the effect of NCT and NCRT on lymph nodal downstaging and survival. METHODS: The 2004-2016 National Cancer Database Pancreas Participant User File was used to identify patients who underwent surgery for PDAC. Fisher's exact, Wilcoxon rank-sum, multivariate logistic regression, and log-rank were used. Downstaging was defined as clinically node-positive patients who demonstrated node-negativity on pathology. RESULTS: Of 42,545 patients meeting criteria, 3311 received NCT and 1511 received NCRT. After surgery for clinically node-positive disease, 23.3% of NCT patients and 41.3% of NCRT patients demonstrated nodal downstaging. Younger age and lower tumor grade independently predicted downstaging. Downstaging after neoadjuvant therapy was associated with improved survival versus no nodal treatment response (29.8 vs. 22.8 months, p < 0.001). Downstaging by NCT was associated with improved overall survival versus downstaging by NCRT (37.5 vs. 26.6 months, p = 0.001). No survival difference existed between those with no nodal response after NCT or NCRT (p = 0.101). CONCLUSIONS: Although nodal downstaging is more likely post-NCRT, survival is superior in those downstaged post-NCT. Overall survival is determined by the systemic burden of disease. Post-therapy histologic analysis may be less prognostic post-NCRT.

Pretreatment MRI-detected extramural venous invasion as a prognostic and predictive biomarker for neoadjuvant chemoradiotherapy in non-metastatic rectal cancer: a propensity score matched analysis.

OBJECTIVES: This study evaluated pretreatment magnetic resonance imaging (MRI)-detected extramural venous invasion (pmrEMVI) as a predictor of survival after neoadjuvant chemoradiotherapy (nCRT) in patients with locally advanced rectal cancer (LARC). MATERIALS AND METHODS: Medical records of 1184 patients with rectal adenocarcinoma who underwent TME between January 2011 and December 2016 were reviewed. MRI data were collected from a computerized radiologic database. Cox proportional hazards analysis was used to assess local, systemic recurrence, and disease-free survival risk based on pretreatment MRI-assessed tumor characteristics. After propensity score matching (PSM) for pretreatment MRI features, nCRT therapeutic outcomes according to pmrEMVI status were evaluated. Cox proportional hazards analysis was used to identify risk factors for early recurrence in patients receiving nCRT. RESULTS: Median follow-up was 62.8 months. Among all patients, the presence of pmrEMVI was significantly associated with worse disease-free survival (DFS; HR 1.827, 95% CI 1.285-2.597, p = 0.001) and systemic recurrence (HR 2.080, 95% CI 1.400-3.090, p < 0.001) but not local recurrence. Among patients with pmrEMVI, nCRT provided no benefit for oncological outcomes before or after PSM. Furthermore, pmrEMVI( +) was the only factor associated with early recurrence on multivariate analysis in patients receiving nCRT. CONCLUSIONS: pmrEMVI is a poor prognostic factor for DFS and SR in patients with non-metastatic rectal cancer and also serves as a predictive biomarker of poor DFS and SR following nCRT in LARC. Therefore, for patients who are positive for pmrEMVI, consideration of alternative treatment strategies may be warranted. CLINICAL RELEVANCE STATEMENT: This study demonstrated the usefulness of pmrEMVI as a predictive biomarker for nCRT, which may assist in initial treatment decision-making in patients with non-metastatic rectal cancer. KEY POINTS: • Pretreatment MRI-detected extramural venous invasion (pmrEMVI) was significantly associated with worse disease-free survival and systemic recurrence in patients with non-metastatic rectal cancer. • pmrEMVI is a predictive biomarker of poor DFS following nCRT in patients with LARC. • The presence of pmrEMVI was the only factor associated with early recurrence on multivariate analysis in patients receiving nCRT.

Nodal staging with MRI after neoadjuvant chemo-radiotherapy for locally advanced rectal cancer: a fast and reliable method.

OBJECTIVES: In patients with locally advanced rectal carcinoma (LARC), negative nodal status after neoadjuvant chemoradiotherapy (nCRT) may allow for rectum-sparing protocols rather than total mesorectal excision; however, current MRI criteria for nodal staging have suboptimal accuracy. The aim of this study was to compare the diagnostic accuracy of different MRI dimensional criteria for nodal staging after nCRT in patients with LARC. MATERIALS AND METHODS: Patients who underwent MRI after nCRT for LARC followed by surgery were retrospectively included and divided into a training and a validation cohort of 100 and 39 patients, respectively. Short-, long-, and cranial-caudal axes and volume of the largest mesorectal node and nodal status based on European Society of Gastrointestinal Radiology consensus guidelines (i.e., ESGAR method) were assessed by two radiologists independently. Inter-reader agreement was assessed in the training cohort. Histopathology was the reference standard. ROC curves and the best cut-off were calculated, and accuracies compared with the McNemar test. RESULTS: The study population included 139 patients (median age 62 years [IQR 55-72], 94 men). Inter-reader agreement was high for long axis (κ = 0.81), volume (κ = 0.85), and ESGAR method (κ = 0.88) and low for short axis (κ = 0.11). Accuracy was similar (p > 0.05) for long axis, volume, and ESGAR method both in the training (71%, 74%, and 65%, respectively) and in the validation (83%, 78%, and 75%, respectively) cohorts. CONCLUSION: Accuracy of the measurement of long axis and volume of the largest lymph node is not inferior to the ESGAR method for nodal staging after nCRT in LARC. CLINICAL RELEVANCE STATEMENT: In MRI restaging of rectal cancer, measurement of the long axis or volume of largest mesorectal lymph node after preoperative chemoradiotherapy is a faster and reliable alternative to ESGAR criteria for nodal staging. KEY POINTS: • Current MRI criteria for nodal staging in locally advanced rectal cancer after chemo-radiotherapy have suboptimal accuracy and are time-consuming. • Measurement of long axis or volume of the largest mesorectal lymph node on MRI showed good accuracy for assessment of loco-regional nodal status in locally advanced rectal cancer. • MRI measurement of the long axis and volume of largest mesorectal lymph node after chemo-radiotherapy could be a faster and reliable alternative to ESGAR criteria for nodal staging.

Diagnostic accuracy of state-of-the-art rectal MRI sequences for the diagnosis of extramural vascular invasion in locally advanced rectal cancer after preoperative chemoradiotherapy: dos or maybes?

OBJECTIVES: The aim of this study was to determine the accuracy of three state-of-the-art MRI sequences for the detection of extramural venous invasion (EMVI) in locally advanced rectal cancer (LARC) patients after preoperative chemoradiotherapy (pCRT). METHODS: This retrospective study included 103 patients (median age 66 years old [43-84]) surgically treated with pCRT for LARC and submitted to preoperative contrast-enhanced pelvic MRI after pCRT. T2-weighted, DWI, and contrast-enhanced sequences were evaluated by two radiologists with expertise in abdominal imaging, blinded to clinical and histopathological data. Patients were scored according to the probability of EMVI presence on each sequence using a grading score ranging from 0 (no evidence of EMVI) to 4 (strong evidence of EMVI). Results from 0 to 2 were ranked as EMVI negative and from 3 to 4 as EMVI positive. ROC curves were drawn for each technique, using histopathological results as reference standard. RESULTS: T2-weighted, DWI, and contrast-enhanced sequences demonstrated an area under the ROC curve (AUC) respectively of 0.610 (95% CI: 0.509-0.704), 0.729 (95% CI: 0.633-0.812), and 0.624 (95% CI: 0.523-0.718). The AUC of DWI sequence was significantly higher than that of T2-weighted (p = 0.0494) and contrast-enhanced (p = 0.0315) sequences. CONCLUSIONS: DWI is more accurate than T2-weighted and contrast-enhanced sequences for the identification of EMVI following pCRT in LARC patients. CLINICAL RELEVANCE STATEMENT: MRI protocol for restaging locally advanced rectal cancer after preoperative chemoradiotherapy should routinely include DWI due to its higher accuracy for the diagnosis of extramural venous invasion compared to high-resolution T2-weighted and contrast-enhanced T1-weighted sequences. KEY POINTS: • MRI has a moderately high accuracy for the diagnosis of extramural venous invasion in locally advanced rectal cancer after preoperative chemoradiotherapy. • DWI is more accurate than T2-weighted and contrast-enhanced T1-weighted sequences in the detection of extramural venous invasion after preoperative chemoradiotherapy of locally advanced rectal cancer. • DWI should be routinely included in the MRI protocol for restaging locally advanced rectal cancer after preoperative chemoradiotherapy.

Neoadjuvant therapy use and association with postoperative outcomes and overall survival in patients with extrahepatic cholangiocarcinoma.

BACKGROUND AND OBJECTIVES: Evidence for neoadjuvant therapy (NAT) in extrahepatic cholangiocarcinoma (eCCA) is limited. Our objectives were to: (1) characterize treatment trends, (2) identify factors associated with receipt of NAT, and (3) evaluate associations between NAT and postoperative outcomes. METHODS: Retrospective cohort study of the National Cancer Database (2004-2017). Multivariable logistic regression assessed associations between NAT and postoperative outcomes. Stratified analysis evaluated differences between surgery first, neoadjuvant chemotherapy, and neoadjuvant chemoradiation (CRT). RESULTS: Among 8040 patients, 417 (5.2%) received NAT. NAT increased during the study period 2.9%-8.4% (p < 0.001). Factors associated with receipt of NAT included age <50 (vs. >75, odds ratio [OR] 4.32, p < 0.001) and stage 3 disease (vs. 1, OR 1.68, p = 0.01). Compared with surgery first, patients who received NAT had higher odds of R0 resection (OR 1.49, p = 0.01) and lower 30-day mortality (OR 0.51, p = 0.04). On stratified analysis, neoadjuvant chemotherapy was not associated with differences in any outcomes. However, neoadjuvant CRT was associated with improvement in R0 resection (OR 3.52, <0.001) and median survival (47.8 vs. 25.3 months, log-rank < 0.001) compared to surgery first. CONCLUSIONS: NAT, particularly neoadjuvant CRT, was associated with improved postoperative outcomes. These data suggest expanding the use of neoadjuvant CRT for eCCA.

Health-related quality of life following neoadjuvant chemoradiotherapy versus perioperative chemotherapy and esophagectomy for esophageal cancer: a European multicenter study.

Curative treatment for locally advanced esophageal cancer consists of (neo)adjuvant treatment followed by esophagectomy. Both neoadjuvant chemoradiotherapy and perioperative chemotherapy improve the 5-year overall survival rate compared with surgery alone. However, it is unknown whether these treatment strategies are associated with differences in long-term health-related quality of life (HRQL). The aim of this study is to compare long-term HRQL in patients after esophagectomy treated with neoadjuvant chemoradiotherapy or perioperative chemotherapy. Disease-free cancer patients having undergone esophagectomy and (neo)adjuvant treatment in one of the participating lasting symptoms after esophageal resection (LASER) study centers between 2010 and 2016, were identified from the LASER study dataset. Included patients completed the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30), EORTC QLQ-OG25, and LASER questionnaires at least 1 year after the completion of treatment. Long-term HRQL was compared between patients treated with neoadjuvant chemoradiotherapy or perioperative chemotherapy, using univariable and multivariable regression and presented as differences in mean score. Among the 565 included patients, 349 (61.8%) received neoadjuvant chemoradiotherapy, and 216 (38.2%) perioperative chemotherapy. Patients treated with perioperative chemotherapy reported more symptomatology for diarrhea (difference in means 5.93), reflux (difference in means 7.40), and odynophagia (difference in means 4.66). The differences did not exceed the 10 points to be of clinical relevance. No significant differences for the LASER key symptoms were observed. The observed differences in long-term HRQL are in favor of patients treated with neoadjuvant chemoradiotherapy compared with patients treated with perioperative chemotherapy; however, the differences were small. Patients need to be informed about long-term HRQL when considering allocation of (neo)adjuvant treatment.

Treatment burden and cost-effectiveness analysis of the neoadjuvant CROSS regimen in esophageal squamous cell carcinoma: a multicenter retrospective study.

High-quality evidence indicated that both neoadjuvant carboplatin/paclitaxel (CROSS) and cisplatin/5-fluorouracil (PF) regimens in combination with radiotherapy improve survival outcomes compared to surgery alone in patients with esophageal cancer. It is not yet known whether they may differ in terms of treatment burden and healthcare costs. A total of 232 Taiwanese patients with esophageal squamous cell carcinoma who had undergone neoadjuvant chemoradiotherapy (nCRT) with either the CROSS (n = 153) or the PF (n = 79) regimens were included. Hospital encounters and adverse events were assessed for determining treatment burden. Cost-effectiveness analysis was undertaken using the total costs incurred over 3 years in relation to overall survival (OS) and progression-free survival (PFS). Compared with PF, the CROSS regimen was associated with a lower treatment burden: shorter inpatient days on average (4.65 ± 10.05 vs. 15.14 ± 17.63 days; P < 0.001) and fewer admission requirements (70% of the patients were never admitted vs. 20% in the PF group; P < 0.001). Patients in the CROSS group experienced significantly less nausea, vomiting, and diarrhea. While the benefits observed in the CROSS group were associated with additional nCRT-related expenditures (1388 United States dollars [USD] of added cost per patient), this regimen remained cost-effective. At a willingness-to-pay threshold of 50,000 USD per life-year, the probability of the CROSS regimen to be more cost-effective than PF was 94.1% for PFS but decreased to 68.9% for OS. The use of the CROSS regimen for nCRT in patients with ESCC was associated with a lower treatment burden and was more cost-effective than PF.

Early versus delayed surgery following neoadjuvant chemoradiation for esophageal cancer: a systematic review and meta-analysis.

BACKGROUND: Neoadjuvant chemoradiotherapy (nCRT) followed by surgery, is the mainstay of managing locally advanced esophageal cancer. However, the optimal timing of surgery after neoadjuvant therapy is not defined clearly. METHODS: A systematic search of PubMed, Embase and Cochrane databases was conducted. 6-8 weeks were used as a cut-off to define early and delayed surgery groups. Overall Survival (OS) was the primary outcome, whereas pathological complete resolution (pCR), R0 resection, anastomotic leak, perioperative mortality, pulmonary complications, and major complication (> Clavien-Dindo grade 2) rates were secondary outcomes. Cohort studies and national registry bases studies were analysed separately. Survival data were pooled as Hazard Ratio (HR) and the rest as Odds Ratio (OR). According to heterogeneity, fixed-effect or random-effect models were used. RESULTS: Twelve retrospective studies, one RCT, and six registry-based studies (13,600 participants) were included. Pooled analysis of cohort studies showed no difference in OS (HR 1.03, CI 0.91-1.16), pCR (OR 0.98, CI 0.80-1.20), R0 resection (OR 0.90, CI 0.55-I.45), mortality (OR 1.03, CI 0.59-1.77), pulmonary complications (OR 1.26, CI 0.97-1.64) or major complication rates (OR 1.29, CI 0.96-1.73). Delayed surgery led to increased leak (OR 1.48, CI 1.11-1.97). Analysis of registry studies showed that the delayed group had a better pCR rate (OR 1.12, CI 1.01-1.24), with no improvement in survival (HR 1.01, CI 0.92-1.10). Delayed surgery was associated with increased mortality (OR 1.35, CI 1.07-1.69) and major complication rate (OR 1.55, CI 1.20-2.01). Available RCT reported surgical outcomes only. CONCLUSION: National registry-based studies' analysis shows that delay in surgery is riskier and leads to higher mortality and major complication rates. Further, well-designed RCTs are required.

Up-regulated FNDC1 accelerates stemness and chemoradiation resistance in colorectal cancer cells.

Neoadjuvant chemoradiation (nCRT) followed by radical surgery is the preferred option for locally advanced colorectal cancer (CRC) treatment. However, chemo/radio-resistance remains a main obstacle in CRC therapy. In the study, we analyzed the mRNA expression profiling of CRC patients and revealed that the aberrant expression of fibronectin type III domain containing 1 (FNDC1) was associated with disease progression and poor prognosis in CRC. FNDC1 expression was consistently increased in multiple independent cohorts of CRC. Upregulated FNDC1 in pretreated primary tumor tissues predicted a poor response to nCRT, recurrence, and poor disease-free survival in nCRT-treated CRC patients. FNDC1 overexpression accelerated CRC cell survival on 5-FU or radiation treatment both in vitro and in vivo, whereas FNDC1 inhibition sensitized CRC cells to chemoradiation. In addition, FNDC1 accelerated stem cell-like properties of CRC cells. Furthermore, tumor tissues from non-responders exhibited higher activation of PI3K/Akt signaling than those from responders. FNDC1 depletion repressed 5-FU or irradiation-induced activation of PI3K/AKT in CRC cells. More importantly, pharmacological inhibition of PI3K/Akt signaling effectively decreased the effect of FNDC1 on chemoradiation resistance. Taken together, our study reveals the potential function of FNDC1 as a biomarker to predict nCRT sensitivity in CRC and a therapeutic target in CRC treatment.

FOXO transcriptional activity is associated with response to chemoradiation in EAC.

In this study we aimed to investigate signaling pathways that drive therapy resistance in esophageal adenocarcinoma (EAC). Paraffin-embedded material was analyzed in two patient cohorts: (i) 236 EAC patients with a primary tumor biopsy and corresponding post neoadjuvant chemoradiotherapy (nCRT) resection; (ii) 66 EAC patients with resection and corresponding recurrence. Activity of six key cancer-related signaling pathways was inferred using the Bayesian inference method. When assessing pre- and post-nCRT samples, lower FOXO transcriptional activity was observed in poor nCRT responders compared to good nCRT responders (p = 0.0017). This poor responder profile was preserved in recurrences compared to matched resections (p = 0.0007). PI3K pathway activity, inversely linked with FOXO activity, was higher in CRT poor responder cell lines compared to CRT good responders. Poor CRT responder cell lines could be sensitized to CRT using PI3K inhibitors. To conclude, by using a novel method to measure signaling pathway activity on clinically available material, we identified an association of low FOXO transcriptional activity with poor response to nCRT. Targeting this pathway sensitized cells for nCRT, underlining its feasibility to select appropriate targeted therapies.

Shrinkage versus fragmentation response in neoadjuvantly treated oesophageal adenocarcinoma: significant prognostic relevance.

AIMS: No consensus exists on the clinical value of tumour regression grading (TRG) systems for therapy effects of neoadjuvant chemoradiotherapy (nCRT) in oesophageal adenocarcinoma. Existing TRG systems lack standardization and reproducibility, and do not consider the morphological heterogeneity of tumour response. Therefore, we aim to identify morphological tumour regression patterns of oesophageal adenocarcinoma after nCRT and their association with survival. METHODS AND RESULTS: Patients with oesophageal adenocarcinoma, who underwent nCRT followed by surgery and achieved a partial response to nCRT, were identified from two Dutch upper-gastrointestinal (GI) centres (2005-18; test cohort). Resection specimens were scored for regression patterns by two independent observers according to a pre-defined three-step flowchart. The results were validated in an external cohort (2001-17). In total, 110 patients were included in the test cohort and 115 in the validation cohort. In the test cohort, two major regression patterns were identified: fragmentation (60%) and shrinkage (40%), with an excellent interobserver agreement (κ = 0.87). Here, patients with a fragmented pattern had a significantly higher pathological stage (stages III/IV: 52 versus 16%; P < 0.001), less downstaging (48 versus 91%; P < 0.001), a higher risk of recurrence [risk ratio (RR) = 2.9, 95% confidence interval (CI) = 1.5-5.6] and poorer 5-year overall survival (30 versus 80% respectively, P = 0.001). CONCLUSIONS: The validation cohort confirmed these findings, although had more advanced cases (case-stages = III/IV 91 versus 73%, P = 0.005) and a higher prevalence of fragmented-pattern cases (80 versus 60%, P = 0.002). When combining the cohorts in multivariate analysis, the pattern of response was an independent prognostic factor [hazard ratio (HR) = 1.76, 95% CI = 1.0-3.0]. In conclusion, we established an externally validated, reproducible and clinically relevant classification of tumour response.

Response prediction of neoadjuvant chemoradiation therapy in locally advanced rectal cancer using CT-based fractal dimension analysis.

OBJECTIVES: There are individual variations in neo-adjuvant chemoradiation therapy (nCRT) in patients with locally advanced rectal cancer (LARC). No reliable modality currently exists that can predict the efficacy of nCRT. The purpose of this study is to assess if CT-based fractal dimension and filtration-histogram texture analysis can predict therapeutic response to nCRT in patients with LARC. METHODS: In this retrospective study, 215 patients (average age: 57 years (18-87 years)) who received nCRT for LARC between June 2005 and December 2016 and underwent a staging diagnostic portal venous phase CT were identified. The patients were randomly divided into two datasets: a training set (n = 170), and a validation set (n = 45). Tumor heterogeneity was assessed on the CT images using fractal dimension (FD) and filtration-histogram texture analysis. In the training set, the patients with pCR and non-pCR were compared in univariate analysis. Logistic regression analysis was applied to identify the predictive value of efficacy of nCRT and receiver operating characteristic analysis determined optimal cutoff value. Subsequently, the most significant parameter was assessed in the validation set. RESULTS: Out of the 215 patients evaluated, pCR was reached in 20.9% (n = 45/215) patients. In the training set, 7 out of 37 texture parameters showed significant difference comparing between the pCR and non-pCR groups and logistic multivariable regression analysis incorporating clinical and 7 texture parameters showed that only FD was associated with pCR (p = 0.001). The area under the curve of FD was 0.76. In the validation set, we applied FD for predicting pCR and sensitivity, specificity, and accuracy were 60%, 89%, and 82%, respectively. CONCLUSION: FD on pretreatment CT is a promising parameter for predicting pCR to nCRT in patients with LARC and could be used to help make treatment decisions. KEY POINTS: • Fractal dimension analysis on pretreatment CT was associated with response to neo-adjuvant chemoradiation in patients with locally advanced rectal cancer. • Fractal dimension is a promising biomarker for predicting pCR to nCRT and may potentially select patients for individualized therapy.

Adjuvant chemotherapy after neoadjuvant chemoradiation and proctectomy improves survival irrespective of pathologic response in rectal adenocarcinoma: a population-based cohort study.

BACKGROUND: This study sought to determine whether adjuvant chemotherapy (AC) compared to no AC (noAC) after neoadjuvant chemoradiation (CRT) and resection for rectal adenocarcinoma prolongs survival. Current guidelines from expert groups are conflicting, and data to support administering AC to patients who received neoadjuvant CRT are lacking. METHODS: A total of 19,867 patients met inclusion/exclusion criteria. Mean age was 58.6 ± 12.0 years, and 12,396 (62.4%) were males. Complete response (CR) was documented in 3801 (19.1%) patients and 8167 (41.1%) received AC. The cohort was stratified into pathological complete (pCR, N = 3801) and incomplete (pIR, N = 16,066) subgroups, and pIR further subcategorized into ypN0 (N = 10,191) and ypN + (N = 5875) subgroups. After propensity score matching, AC was associated with improved OS in the pCR subgroups (mean 139.1 ± 1.9 vs. 134.0 ± 2.2 months; p < 0.001), in pIR ypN0 subgroup (141.6 ± 1.5 vs. 129.9 ± 1.2 months, p < 0.001), and in pIR ypN + subgroup (155.9 ± 5.4 vs. 126.5 ± 7.6 months; p < 0.001). RESULTS: AC was associated with improved OS in patients who received neoadjuvant CRT followed by proctectomy for clinical stages II and III rectal adenocarcinoma. This effect persisted irrespective of pathological response status. CONCLUSIONS: AC following neoadjuvant CRT and surgery is associated with improved OS in patients with rectal adenocarcinoma. These findings warrant adoption of AC after neoadjuvant CRT and surgery for clinical stage II and III rectal adenocarcinoma.

Optimized tools and timing of response reassessment after neoadjuvant chemoradiation in rectal cancer.

PURPOSE: Reassessment tools of response to long-course neoadjuvant chemoradiation treatment (nCRT) in patients with locally advanced rectal cancer (LARC) are important in predicting complete response (CR) and thus deciding whether a wait-and-watch strategy can be implemented in these patients. Choosing which routine reassessment tools are optimal and when to use them is still unclear and will be researched in the study. METHODS: Altogether, 250 patients with LARC who received nCRT from 2013 to 2021 and were followed up were retrospectively reviewed. Common reassessment tools of response included digital rectal examination (DRE), clinical examination and symptoms, endoscopy, biopsy, magnetic resonance imaging (MRI), and blood biomarkers. RESULTS: Overall, 27.20% (68/250) patients had a complete response and 72.80% (182/250) did not. The combination of MRI, endoscopy, and biopsy showed the best performance in terms of accuracy of 74% and area under the curve (AUC, 0.714, 95% CI 0.546-0.882). Reassessing through DRE and presence of symptoms failed to improve the efficacy of response reassessment. After 100 days, biopsy as an assessment tool would obtain a substantial rise in accuracy from 51.28 to 100% (p = 0.003). CONCLUSION: The combination of MRI, endoscopy, and biopsy is suitable as the reassessment tool of response for applying a wait-and-watch strategy after long-course nCRT in patients with LARC. The accuracy of biopsy as reassessment tools would be improved if they were used over 100 days after nCRT in patients with rectal cancer.