Temporal Trends in Survival Outcomes for Patients with Esophageal Cancer Following Neoadjuvant Chemoradiotherapy: A 14-Year Analysis.

BACKGROUND: The prognosis for patients with esophageal cancer who received neoadjuvant chemoradiotherapy (nCRT) followed by surgery has shown improvement in recent years. We sought to identify the critical factors contributing to enhanced survival outcomes. PATIENTS AND METHODS: We retrospectively examined 427 patients with esophageal cancer treated with nCRT and esophagectomy across two periods: P1 (from 1 January 2004 to 31 December 2011) and P2 (from 1 January 2012 to 31 December 2017). The introduction of the CROSS regimen and total meso-esophagectomy in P2 prompted an evaluation of their effects on perioperative outcomes and overall survival (OS). RESULTS: During P2, the occurrence of recurrent laryngeal nerve palsy increased significantly from 3.9 to 16.8% (p < 0.001), while pneumonia and in-hospital mortality rates remained unchanged. The median OS improved from 19.2 to 29.2 months (p < 0.001) between P1 and P2. Multivariable analysis identified higher nodal yields and the achievement of major response as favorable prognostic factors. Conversely, an involved circumferential resection margin (CRM), an advanced ypN stage, and pneumonia were independently associated with poor outcomes. Patients treated during P2 had a lower prevalence of involved CRM (10% vs. 25.1%, p < 0.001), a higher rate of major response (52.7% vs. 34.8%, p < 0.01), and a greater nodal yield (27.8 vs. 10.9, p < 0.001). CONCLUSIONS: The clinical outcomes following nCRT and surgery have improved significantly over time. This progress can be attributed to multiple factors, with the primary drivers being the refinement of nCRT protocols and the application of radical surgery.

Adjuvant Therapy for Patients with a Tumor-Positive Resection Margin After Neoadjuvant Chemoradiotherapy and Esophagectomy.

BACKGROUND: Approximately 4-9% of patients have a tumor-positive resection margin after neoadjuvant chemoradiotherapy (nCRT) and esophagectomy. Although it is associated with decreased survival, Western guidelines do not recommend adjuvant treatment. OBJECTIVE: The aim of this study was to assess the proportion of patients who received adjuvant therapy, and to evaluate overall survival (OS) after esophagectomy in patients with a tumor-positive resection margin. METHODS: Patients diagnosed with resectable (cT2-4a/cTxN0-3/NxM0) esophageal cancer between 2015 and 2022, and treated with nCRT followed by irradical esophagectomy, were selected from the Netherlands Cancer Registry. The primary outcome was the proportion of patients with a tumor-positive resection margin who started adjuvant treatment ≤16 weeks after esophagectomy, including chemotherapy/radiotherapy, immunotherapy, or targeted therapy. OS was calculated from the date of surgery until the date of death or last day of follow-up. RESULTS: Overall, 376 patients were included in our study, of whom 357 were treated with nCRT. Of these 357 patients, 98.3% had a microscopically irradical resection and 1.7% had a macroscopically irradical resection. Approximately 72.3% of tumors showed a partial response (Mandard 2-3) and 11.8% showed little/no pathological response (Mandard 4-5) to nCRT. One of 357 patients underwent adjuvant chemoradiotherapy and 39 patients (61%) underwent adjuvant immunotherapy (nivolumab). The median and 5-year OS rate of all patients was 16.4 months (95% confidence interval 13.1-19.8) and 21%, respectively. CONCLUSION: Real-world population-level data showed that no patients with a tumor-positive resection margin underwent adjuvant therapy following nCRT and esophagectomy prior to 2021. Interestingly, 61% of patients were treated with adjuvant nivolumab in 2021-2022. OS after irradical esophagectomy is poor and long-term data will explore the added value of nivolumab.

Neoadjuvant chemotherapy combined with immunotherapy versus neoadjuvant chemoradiotherapy in patients with locally advanced esophageal squamous cell carcinoma.

BACKGROUND: To date, few studies have compared effectiveness and survival rates of neoadjuvant chemotherapy combined with immunotherapy (NACI) and conventional neoadjuvant chemoradiotherapy (NCRT) in patients with locally advanced esophageal squamous cell carcinoma (ESCC). The present study was conducted to compare therapeutic response and survival between NACI and NCRT. METHODS: The study cohort comprised patients with locally advanced ESCC treated with either NACI or NCRT followed by surgery between June 2018 and March 2021. The 2 groups were compared for treatment response, 3-year overall survival (OS), and disease-free survival (DFS). Survival curves were created using the Kaplan-Meier method, differences were compared using the log-rank test, and potential imbalances were corrected for using the inverse probability of treatment weighting (IPTW) method. RESULTS: Among 202 patients with locally advanced ESCC, 81 received NACI and 121 received conventional NCRT. After IPTW adjustment, the R0 resection rate (85.2% vs 92.3%; P = .227) and the pathologic complete response (pCR) rate (27.5% vs 36.4%; P = .239) were comparable between the 2 groups. Nevertheless, patients who received NACI exhibited both a better 3-year OS rate (91.7% vs 79.8%; P = .032) and a better 3-year DFS rate (87.4% vs 72.8%; P = .039) compared with NCRT recipients. CONCLUSIONS: NACI has R0 resection and pCR rates comparable to those of NCRT and seems to be correlated with better prognosis than NCRT. NACI followed by surgery may be an effective treatment strategy for locally advanced ESCC.

Preoperative versus postoperative chemo-radiotherapy for locally advanced gastric cancer: a multicenter propensity score-matched analysis.

BACKGROUND: Peri-operative chemo-radiotherapyplayed important rolein locally advanced gastric cancer. Whether preoperative strategy can improve the long-term prognosis compared with postoperative treatment is unclear. The study purpose to compare oncologic outcomes in locally advanced gastric cancer patients treated with preoperative chemo-radiotherapy (pre-CRT) and postoperative chemo-radiotherapy (post-CRT). METHODS: From January 2009 to April 2019, 222 patients from 2 centers with stage T3/4 and/or N positive gastric cancer who received pre-CRT and post-CRT were included. After propensity score matching (PSM), comparisons of local regional control (LC), distant metastasis-free survival (DMFS), disease-free survival (DFS) and overall survival (OS) were performed using Kaplan-Meier analysis and log-rank test between pre- and post-CRT groups. RESULTS: The median follow-up period was 30 months. 120 matched cases were generated for analysis. Three-year LC, DMFS, DFS and OS for pre- vs. post-CRT groups were 93.8% vs. 97.2% (p = 0.244), 78.7% vs. 65.7% (p = 0.017), 74.9% vs. 65.3% (p = 0.042) and 74.4% vs. 61.2% (p = 0.055), respectively. Pre-CRT were significantly associated with DFS in uni- and multi-variate analysis. CONCLUSION: Preoperative CRT showed advantages of oncologic outcome compared with postoperative CRT. TRIAL REGISTRATION: ClinicalTrial.gov NCT01291407 , NCT03427684 and NCT04062058 , date of registration: Feb 8, 2011.

Relevance of the time interval between surgery and adjuvant radio (chemo) therapy in HPV-negative and advanced head and neck carcinoma of unknown primary (CUP).

INTRODUCTION: In contrast to head and neck squamous cell carcinoma (HNSCC), the effect of treatment duration in HNSCC-CUP has not been thoroughly investigated. Thus, this study aimed to assess the impact of the time interval between surgery and adjuvant therapy on the oncologic outcome, in particular the 5-year overall survival rate (OS), in advanced stage, HPV-negative CUPs at a tertiary referral hospital. 5-year disease specific survival rate (DSS) and progression free survival rate (PFS) are defined as secondary objectives. MATERIAL AND METHODS: Between January 1st, 2007, and March 31st, 2020 a total of 131 patients with CUP were treated. Out of these, 59 patients with a confirmed negative p16 analysis were referred to a so-called CUP-panendoscopy with simultaneous unilateral neck dissection followed by adjuvant therapy. The cut-off between tumor removal and delivery of adjuvant therapy was set at the median, i.e. patients receiving adjuvant therapy below or above the median time interval. RESULTS: Depending on the median time interval of 55 days (d) (95% CI 51.42-84.52), 30 patients received adjuvant therapy within 55 d (mean 41.69 d, SD = 9.03) after surgery in contrast to 29 patients at least after 55 d (mean 73.21 d, SD = 19.16). All patients involved in the study were diagnosed in advanced tumor stages UICC III (n = 4; 6.8%), IVA (n = 27; 45.8%) and IVB (n = 28; 47.5%). Every patient was treated with curative neck dissection. Adjuvant chemo (immune) radiation was performed in 55 patients (93.2%), 4 patients (6.8%) underwent adjuvant radiation only. The mean follow-up time was 43.6 months (SD = 36.7 months). The 5-year OS rate for all patients involved was 71% (95% CI 0.55-0.86). For those patients receiving adjuvant therapy within 55 d (77, 95% CI 0.48-1.06) the OS rate was higher, yet not significantly different from those with delayed treatment (64, 95% CI 0.42-0.80; X2(1) = 1.16, p = 0.281). Regarding all patients, the 5-year DSS rate was 86% (95% CI 0.75-0.96). Patients submitted to adjuvant treatment in less than 55 d the DSS rate was 95% (95% CI 0.89-1.01) compared to patients submitted to adjuvant treatment equal or later than 55 d (76% (95% CI 0.57-0.95; X2(1) = 2.32, p = 0.128). The 5-year PFS rate of the entire cohort was 72% (95% CI 0.59-0.85). In the group < 55 d the PFS rate was 78% (95% CI 0.63-0.94) and thus not significantly different from 65% (95% CI 0.45-0.85) of the group ≥55 d; (X2(1) = 0.29, p = 0.589). CONCLUSIONS: The results presented suggest that the oncologic outcome of patients with advanced, HPV-negative CUP of the head and neck was not significantly affected by a prolonged period between surgery and adjuvant therapy. Nevertheless, oncologic outcome tends to be superior for early adjuvant therapy.

Prognostic factor for recurrence in esophagus cancer patients who underwent surgery for curative intent: A single-institution analysis.

OBJECTIVE: The purpose of this study is to analyze predisposing factors for a higher risk of recurrence in esophageal cancer patient who underwent surgery for curative intent and to do survival analysis of prognostic factors. MATERIALS AND METHODS: Between February 2018 and March 2020, we retrospectively identified 28 cases staged T1b to T4a managed electively at our institute as per multidisciplinary management plan. Demographic, clinical, radiological, operative, histopathological parameters, upfront surgery done or not, type of preoperative, and adjuvant treatment used and whether neoadjuvant or adjuvant therapy was planned along with waiting time for surgery, were assessed as potential risk factors. End point of study was to find potential risk factors for recurrence and to do their subgroup survival analysis. RESULTS: The recurrence rate in our study was 25% with a mean follow-up of 24 months. The median time of recurrence was 8.5 months, all recurrence occurred within 1 year. Overall DFS at 2 years was 72%. On univariate analysis, following prognostic factors were associated with high risk of recurrence, male sex X2 (1) =4.42, p = 0.035; histology subtype of adenocarcinoma X2 (1) = 7.07, p = 0.008; margin positive X2 (1) =3.76, p = 0.05; presence of lymph vascular invasion (LVI) X2 (1) =7.88, p = 0.005; presence of perineural invasion (PNI) X2 (1) =5.97, p = 0.015; postoperative T size >4 cm X2 (1) =3.86, p = 0.049; and nodal positivity X2 (3) =13.47, p = 0.004. CONCLUSIONS: Male sex, adenocarcinoma histological subtype, positive resected margin, presence of LVI and PNI, postoperative T size >4 cm, and high postoperative nodal positivity and whether neoadjuvant versus adjuvant therapy given (on K. M analysis) were the identified predictors of recurrence which compromised DFS.

Additional Radiotherapy With or Without Chemotherapy Following Endoscopic Resection for Stage I Esophageal Carcinoma: A Pilot Study.

Objective: To evaluate the safety and efficacy of additional radiotherapy after endoscopic resection (ER) for stage I esophageal carcinoma (EC) with high-risk factors. Materials and methods: Patients with stage cT1N0M0 EC who underwent ER and additional radiotherapy between January 2010 and August 2019 at our institution were retrospectively included. Overall survival (OS), disease-free survival (DFS), cancer-specific survival (CSS), local control rate, regional control rate, common acute toxicities, esophageal stricture, and dysphagia were analyzed. Results: Thirty-one consecutive patients were included in the study. The median age was 62 years (range, 49-78). Thirty patients (96.8%) had squamous cell carcinoma, and one patient (3.2%) had adenosquamous cell carcinoma. Twenty-six patients (83.9%) had submucosal invasion, 15 patients (48.4%) had lymphovascular invasion, and one patient (3.2%) had a venous invasion. The 1-, 3-, and 5-year OS rates were 100.0%, 86.9%, and 68.5%, respectively. The corresponding DFS rates were 100.0%, 85.2%, and 75.8%, respectively. The corresponding CSS rates were 100.0%, 89.8%, and 78.6%, respectively. The local and regional control rates were 100.0% and 93.5%, respectively. No grade 4-5 acute toxicities were observed. Fifteen patients (48.4%) were endoscopically diagnosed with esophageal strictures after ER. At the last follow-up, 28 patients (90.5%) were able to eat a regular diet, one patient (3.2%) could eat a soft diet, one needed a semifluid diet, and only one (3.2%) had to eat a fluid diet. Conclusions: For patients with stage I EC, additional radiotherapy following ER is safe and effective, with the swallowing function well-preserved. Nevertheless, prospective studies are needed to verify these results.

Evaluating disparities in delivery of neoadjuvant guideline-based chemoradiation for rectal cancer: A multicenter, propensity score-weighted cohort study.

BACKGROUND: Despite guideline recommendations, some patients still receive care inappropriate for their clinical stage of disease. Identification of factors that contribute to variation in guideline base care may help eradicate disparities in the treatment of early and locally advanced rectal cancer. METHODS: The American College of Surgeons National Cancer Database from 2010 to 2015 was analyzed with propensity score weighting to identify factors associated with delivery and omission of neoadjuvant guideline-based chemoradiation (GBC) for those with early and locally advanced rectal cancer. RESULTS: Only 74% of patients with rectal cancer received stage-appropriate neoadjuvant chemoradiation; 4544 (88%) of those with early stage disease and 8675 (68%) in locally advanced disease. Chemotherapy and radiotherapy were not planned in 27% and 34% respectively, of those who did not receive GBC. Factors associated with receipt of non-guideline-based neoadjuvant chemoradiation were age >65 years, Medicare insurance, treatment at a community facility, West-South-Central geography, having locally advanced disease, and Charlson-Deyo score >3. Receipt of ideal guideline-based neoadjuvant chemoradiation conferred a survival benefit at 5 years. CONCLUSION: Patient and non-patient factors contribute to disparities in guideline-based delivery of neoadjuvant chemoradiation in the treatment of rectal cancer. Identification of these risk factors are important to help standardize care and improve survival outcomes.

Induction versus no induction chemotherapy before neoadjuvant chemoradiotherapy and surgery in oesophageal adenocarcinoma: a multicentre randomised phase II trial (NCCTG N0849 [Alliance]).

AIM: report primary results from the first multicentre randomised trial evaluating induction chemotherapy prior to trimodality therapy in patients with oesophageal or gastro-oesophageal junction adenocarcinoma. Notably, recent data from a single-institution randomised trial reported that induction chemotherapy prolonged overall survival (OS) in patients with well/moderately differentiated tumours. METHODS: In this phase 2 trial (28 centres in the U.S. NCI-sponsored North Central Cancer Treatment Group [Alliance]), trimodality-eligible patients (T3-4N0, TanyN+) were randomised to receive induction (docetaxel, oxaliplatin, capecitabine; Arm A) or no induction chemotherapy (Arm B) followed by oxaliplatin/5-fluorouracil/radiation and subsequent surgery. The primary endpoint was the rate of pathologic complete response (pathCR). Secondary/exploratory endpoints were OS and disease-free survival (DFS). RESULTS: Of 55 patients evaluable for the primary endpoint, the pathCR rate was 28.6% (8/28) in A versus 40.7% (11/27) in B (P = .34). Given interim results indicating futility, accrual was terminated, but patients were followed. After a median follow-up of 60.4 months, a longer median OS in Arm A versus B was unexpectedly observed (3-year rates 57.1% versus 41.7%, respectively) driven by longer DFS after margin-free surgery. In posthoc analysis, induction (versus no induction) chemotherapy was associated with significantly longer OS and DFS among patients with well/moderately differentiated tumours, but not among patients with poorly/undifferentiated tumours (Pinteraction = 0.037). CONCLUSIONS: Adding induction chemotherapy prior to trimodality therapy did not improve the primary endpoint, pathCR. However, induction chemotherapy was associated with longer median OS, particularly among patients with well/moderately differentiated tumours. These findings may inform further development of curative-intent trials in this disease.

The concept and use of the neoadjuvant rectal score as a composite endpoint in rectal cancer.

There is no universally accepted instrument to use as a validated surrogate endpoint for overall survival in phase 2 and phase 3 multimodal rectal cancer trials using chemoradiotherapy. Efforts are hampered by the inaccuracy of clinical TNM staging, the variability of indications for neoadjuvant treatment, and diverse definitions of tumour regression grade. Pathological complete response is commonly used, but fails to capture information from the majority of patients. The neoadjuvant rectal score categorises response and downstaging from the entire trial population to identify whether or not a novel treatment group in a chemoradiation trial is superior by predicting overall survival outcomes. Additionally, the neoadjuvant rectal score assesses the difference between initial clinical and pathological T stage and the presence or absence of nodal involvement after treatment. The neoadjuvant rectal score has been conceptually, but incompletely, statistically validated by two independent trial datasets. However, a fundamental weakness of the score is that no preoperative phase 3 trials in locally advanced rectal cancer in the past 20 years have provided a significant benefit in overall survival to statistically validate the neoadjuvant rectal score as a surrogate endpoint for overall survival. We review the robustness, practical value, applicability, generalisability, advantages, and disadvantages of the neoadjuvant rectal score as a surrogate endpoint for overall survival and recommend how this score could be improved and be acceptable as a standard endpoint in studies investigating neoadjuvant chemotherapy and chemoradiation in patients with rectal cancer.

Role of adjuvant chemotherapy in patients with FIGO stage IB grade 3 endometrial endometrioid adenocarcinoma treated with surgery and post-operative radiotherapy.

BACKGROUND: The optimal treatment of patients with FIGO stage IB grade 3 endometrial endometrioid adenocarcinoma remains unknown. OBJECTIVE: To compare overall survival following treatment with a hysterectomy and adjuvant radiotherapy with or without chemotherapy in this group of patients. METHODS: Patients diagnosed between January 2004 and January 2016 with FIGO stage IB grade 3 endometrial endometrioid adenocarcinoma treated with hysterectomy and postoperative radiotherapy with or without adjuvant concurrent chemotherapy were identified in the National Cancer Database. Overall survival was assessed with Kaplan-Meier curves. A Cox model was constructed to evaluate survival after controlling for confounding variables. A logistic regression model was used to reveal predictors of chemotherapy use. RESULTS: A total of 2173 patients were included. The receipt of chemotherapy was associated with an increased 5-year overall survival from 67.6% to 75.6% (p=0.0313). This association trended toward statistical significance on multivariate analysis (adjusted HR (aHR) 0.80; 95% CI 0.63 to 1.01; p=0.0653). Other factors associated with improved survival were undergoing a lymphadenectomy, absence of lymphovascular space invasion, younger age, smaller tumor size, non-black race, and absence of comorbidities. Patients who underwent brachytherapy, had lymphovascular space invasion, were younger, were diagnosed in the more recent years, and were treated in higher volume centers were more likely to receive adjuvant chemotherapy. CONCLUSION: Adjuvant chemotherapy and radiation therapy were associated with an increase in survival in patients with FIGO stage IB grade 3 endometrial endometrioid adenocarcinoma compared with those treated with adjuvant radiotherapy alone.

Mismatch repair protein and MLH1 methylation status as predictors of response to adjuvant therapy in endometrial cancer.

BACKGROUND: Mismatch repair (MMR) system has been implicated in the response of mammalian cells to ionizing radiation and DNA damaging agents. We investigated the value of the MMR system in predicting response to adjuvant therapy in endometrial cancer. METHODS: This was a single institution retrospective study. MMR protein status of endometrial carcinomas was assessed by immunohistochemistry. MMR deficient (MMR-D) tumors were identified as MLH1 methylated or nonmethylated by methylation-specific multiplex ligation-dependent probe amplification. Tumors with abnormal p53 staining or polymerase ϵ exonuclease domain mutation were excluded from the MMR proficient subgroup, which was termed as "no specific molecular profile" (NSMP). Disease-specific survival analyses were adjusted for age, stage, histology and grade, depth of myometrial invasion, and lymphovascular space invasion. RESULTS: A total of 505 patients were included in the study. Median follow-up time was 81 months (range 1-136). Whole pelvic radiotherapy (adjusted hazard ratio [HR] 0.092 vs. no adjuvant therapy) and chemotherapy combined with radiotherapy (adjusted HR 0.18) were associated with improved disease-specific survival in the NSMP subgroup (n = 218). In contrast, adjuvant therapies showed no effect on disease-specific survival in the full MMR-D cohort (n = 287) or in MLH1 methylated tumors (n = 154). Whole pelvic radiotherapy (adjusted HR 25 vs. no adjuvant therapy/vaginal brachytherapy) and chemotherapy combined with whole pelvic radiotherapy (adjusted HR 32) were associated with poor disease-specific survival in MMR-D nonmethylated tumors (n = 70). CONCLUSION: MMR protein and MLH1 methylation status predict the response to adjuvant therapy in endometrial cancer. The MMR system could be utilized for selection of patients who most likely benefit from adjuvant therapy.

No benefit after neoadjuvant chemoradiation in stage IV rectal cancer: A propensity score-matched analysis on a real-world population.

BACKGROUND: Stage IV rectal cancer occurs in 25% of patients and locoregional control of primary tumor is usually poorly considered, since priority is the treatment of metastatic disease. AIMS: This study evaluates impact of neoadjuvant chemoradiation followed by surgery (nCHRTS) vs. upfront surgery on locoregional control and overall survival in stage IV rectal cancer. METHODS: All patients diagnosed with stage IV rectal carcinoma between 2009 and 2019, undergone elective surgery at the National Cancer Institute of Milan (Italy), were included. Propensity score-based matching was performed between the two study groups. Loco-regional recurrence-free survival (LRRFS) and overall survival (OS) were analysed using Kaplan-Meyer method. RESULTS: A total of 139 patients were analyzed. After propensity score matching, 88 patients were included in the final analysis. The 3-yr LRRFS rates were 80.3% for nCHRTS vs. 90.4% for upfront surgery patients (p = 0.35). The 3-yr OS rates were respectively 81.8% vs. 58% (p = 0.36). KRAS mutation (HR 2.506, p = 0.038) and extra-liver metastases (HR 4.308, p = 0.003) were both predictive of worse OS in univariate analysis. CONCLUSION: The present study failed to demonstrate a significant impact of nCHRTS on LRRFS or OS in stage IV rectal cancer.

Safety and feasibility of esophagectomy following combined immunotherapy and chemoradiotherapy for esophageal cancer.

OBJECTIVES: We sought to determine the safety and feasibility of esophagectomy after neoadjuvant immunotherapy and chemoradiotherapy in clinical trial patients with locally advanced esophageal cancer. METHODS: We retrospectively identified patients who were treated with neoadjuvant immunotherapy and chemoradiotherapy (n = 25) or chemoradiotherapy alone (n = 143) at our institution between 2017 and 2020. The primary end point was risk of 30-day major complications (Clavien-Dindo classification system grade ≥ 3), which was assessed between groups using a multivariable log-binomial regression model to obtain adjusted relative risk ratios. Secondary end points were interval to surgery, 30-day readmission rate, and 30-day mortality. RESULTS: All included patients successfully completed neoadjuvant therapy and underwent esophagectomy with negative margins. Age, sex, performance status, clinical stage, histologic subtype, procedure type, and operative approach were similar between groups. Neoadjuvant immunotherapy was not associated with a statistically significantly increased risk of developing a major pulmonary (relative risk, 1.43; 95% confidence interval, 0.53-3.84; P = .5), anastomotic (relative risk, 1.34; 95% confidence interval, 0.45-3.94; P = .6), or other complication (relative risk, 1.29; 95% confidence interval, 0.26-6.28; P = .8). Median (interquartile range) interval to surgery was 54 days (47-61 days) in the immune checkpoint inhibitor group versus 53 days (47-66 days) in the control group (P = .6). Minimally invasive approaches were successful in 72% of cases, with only 1 conversion. Thirty-day mortality and readmission rates were 0% and 17%, respectively, in the immune checkpoint inhibitor group and 1.4% and 13%, respectively, in the control group. CONCLUSIONS: On the basis of our preliminary experience, esophagectomy appears to be safe and feasible following combined neoadjuvant immunotherapy and standard chemoradiotherapy for locally advanced esophageal cancer.

Esophageal adenocarcinoma with any component of signet ring cells portends poor prognosis and response to neoadjuvant therapy.

BACKGROUND: Multiple investigations have shown inferior outcomes for esophageal cancer patients with signet ring cell (SRC) histology. Traditionally, SRC adenocarcinoma has been defined by ≥50% of the tumor composed of SRC. We hypothesized that patients with SRC even <50% would show resistance to standard multimodality therapy with poorer long-term outcomes. METHODS: Patients treated with trimodality therapy for adenocarcinoma from 2006 to 2018 were evaluated for SRC on pretreatment biopsy specimens. Available hematoxylin and eosin slides containing SRC tumors were re-reviewed by an esophageal pathologist to quantify the percent composition of SRC. RESULTS: SRC histology was identified on at least 1 pathologic specimen in 106 of 819 (13%) patients. Rates of pathologic complete response (pCR) among usual-type and SRC tumors were 25% (177/713) and 10% (11/106), respectively (P = .006). The pretreatment SRC components did not independently affect the rate of pCR (1%-10% SRC: 4% [2/46] pCR; 11%-49% SRC: 25% [7/28] pCR; 50%-100% SRC: 7% [2/30] pCR). Kaplan-Meier analysis demonstrated worse survival among patients with any degree of SRC present on pretreatment biopsy, as compared with usual-type esophageal adenocarcinoma (P < .0001). Cox multivariable analysis failed to identify a relationship between increasing SRC component and poorer survival. CONCLUSIONS: We present the only known evaluation of the percentage of SRC component in esophageal carcinoma. Our data support the hypothesis that esophageal adenocarcinoma with any component of SRC are more resistant to chemoradiation with poorer survival. Pathologic reporting of esophageal adenocarcinoma should include any component of SRC. Alternative therapies in patients with any SRC component may be indicated.

Impact of KRAS status on tumor response and survival after neoadjuvant treatment of locally advanced rectal cancer.

BACKGROUND: Mutation of the KRAS oncogene (mKRAS) in colorectal cancer has been associated with aggressive tumor biology, resistance to epidermal growth factor inhibitors, and decreased overall survival (OS). The aim of the current study was to analyze the association of mKRAS with pathologic complete response (pCR) and neoadjuvant rectal (NAR) score, and its impact on the survival of patients with locally advanced rectal cancer who were managed with multimodality therapy. METHODS: The National Cancer Database was queried for stage II-III rectal cancer patients with a known KRAS status who underwent neoadjuvant chemoradiation therapy (nCRT) and proctectomy between 2004 and 2015. RESULTS: In total, 1886 patients were identified; 12% had pCR and 36% had mKRAS. Patients with mKRAS were more likely to have advanced pathologic T stage, tumor deposits, perineural invasion, and elevated carcinoembryonic antigen levels (all p ≤ .05). After adjustment for available confounders, mKRAS status was not associated with pCR or NAR score. In multivariable analysis, patients with pCR and lower NAR score had better OS, whereas mKRAS was independently associated with a worse prognosis. CONCLUSION: In this cohort of locally advanced rectal cancer patients who underwent proctectomy after nCRT, mKRAS was not associated with lower pCR rates or NAR scores; however, these patients experienced worse survival.

Ten-year survival after pathologic complete response in rectal adenocarcinoma.

BACKGROUND: Multimodal treatment is the standard of care for rectal adenocarcinoma, with a subset of patients achieving a pathologic complete response (pCR). While pCR is associated with improved overall survival (OS), long-term data on patients with pCR is limited. METHODS: This is a single institution retrospective cohort study of all patients with clinical stages II/III rectal adenocarcinoma who underwent neoadjuvant chemoradiation therapy and operative resection (January 1, 2004-December 31, 2017). PCR was defined as no tumor identified in the rectum or associated lymph nodes by final pathology. RESULTS: Of 370 patients in this cohort, 50 had a pCR (13.5%). For pCR patients, 5-year disease-free survival (DFS) was 92%, 5-year OS was 95%. Twenty-six patients had surgery > 10 years before the study end date, of which 20 had an OS > 10 years (77%) with median OS 12.1 years and 95% alive to date (19/20). Of the 50 pCR patients, there was a single recurrence in the lung at 44.3 months after proctectomy which was surgically resected. CONCLUSION: For patients with rectal adenocarcinoma that undergo neoadjuvant chemoradiation and surgical resection, pCR is associated with excellent long-term DFS and OS. Many patients live greater than 10 years with no evidence of disease recurrence.

Perineural invasion predicts for locoregional failure in patients with oesophageal adenocarcinoma treated with neoadjuvant chemoradiotherapy.

AIM: The prognostic significance of perineural invasion (PNI) in oesophageal adenocarcinoma (EAC) is unclear. We examined the association of PNI with clinical outcomes in patients treated with neoadjuvant chemoradiotherapy (nCRT) and surgery. METHODS: We performed a single institutional retrospective study. We evaluated the association of PNI with locoregional recurrence-free survival (LRFS), distant metastasis-free survival, disease-free survival (DFS) and overall survival using log-rank and Cox proportional hazard modelling. RESULTS: 29 out of 73 patients (40%) had PNI at the time of surgery. The median follow-up was 20.1 months. The median DFS was 18.4 months for patients with PNI vs 41.3 months for patients without PNI (p<0.05). The median LRFS was 23.3 months for patients with PNI and median not reached for patients without PNI (p<0.01). In a multivariate model including age and pathological variables, PNI remained a significant independent predictor of LRFS (HR 0.20, 95% CI 0.07 to 0.60; p=0.004). CONCLUSIONS: For patients with EAC treated with nCRT, PNI found at the time of surgery is significantly associated with worse LRFS. Our data support attempts to validate this finding and perhaps testing the role of adjuvant therapy in patients with PNI.

Chemoradiotherapy after curative surgery for locally advanced pancreatic cancer: A 20-year single center experience.

INTRODUCTION: Pancreatic adenocarcinoma (PAC) is a highly malignant tumor with relevant morbidity and mortality. The role of adjuvant chemoradiotherapy (CRT) for primarily resected tumors remains controversial. We aimed to assess the outcome of patients treated at our institution with postoperative CRT for PAC. METHODS: We present a retrospective case series of patients with pancreatic adenocarcinoma at a single center in Switzerland. These patients were treated by primary surgery followed by adjuvant CRT between 1995 and 2015. The results were compared with published data. RESULTS: Median follow-up for the 60 patients was 33 months (range 19.9-193.9); median overall survival (OS) for patients undergoing a resection followed by combined CRT was 25.5 months. Overall, disease-free survival (DFS) was 15.2 months. A local recurrence occurred in 14 patients (23.3%) after a median time of 8.8 months, and in 43 patients (71.7%) distant metastasis was demonstrated with a median time to metastasis of 10.6 months. CONCLUSION: This retrospective study represents one of the sole reviews of outcome data after adjuvant CRT in resected PAC in Europe within the past years. OS was comparable to that of other institutional outcome data published previously but inferior when compared to most recent published results with an intense chemotherapy. However, not all patients are suitable to undergo such an intense chemotherapy with modified FOLFIRINOX after the extensive surgery for the PAC - these patients could benefit from adding adjuvant CRT to a less intensive chemotherapy with gemcitabine to enhance the benefit regarding locoregional recurrence-free survival.

Role of adjuvant therapy after radical hysterectomy in intermediate-risk, early-stage cervical cancer.

OBJECTIVE: Adjuvant treatment remains a controversial issue for intermediate-risk cervical cancer. The aim of this study was to compare the prognosis of patients who underwent no adjuvant treatment, pelvic radiotherapy alone, or concurrent chemoradiotherapy after radical hysterectomy for intermediate-risk, early-stage cervical cancer. METHODS: Patients with stage IB1-IIA2 (FIGO 2009) cervical squamous cell carcinoma treated with radical hysterectomy and pelvic lymph node dissection, with negative lymph nodes, surgical margins, or parametria, who had combined intermediate risk factors as defined in the Gynecologic Oncology Group trial (GOG-92; Sedlis criteria) were included in the study. Recurrence-free survival and disease-specific survival were compared. RESULTS: Of 861 patients included in the analysis, 85 patients received no adjuvant treatment, 283 patients were treated with radiotherapy, and 493 patients with concurrent chemoradiotherapy. After a median follow-up of 63 months (IQR 45 to 84), adjuvant radiotherapy or concurrent chemoradiotherapy was not associated with a survival benefit compared with no adjuvant treatment. The 5-year recurrence-free survival and corresponding disease-specific survival were 87.1%, 84.2%, 89.6% (p=0.27) and 92.3%, 87.7%, 91.4% (p=0.20) in the no adjuvant treatment, radiotherapy alone, and concurrent chemoradiotherapy groups, respectively. Lymphovascular space invasion was the only independent prognostic factor for both recurrence-free survival and disease-specific survival. Additionally, significant heterogeneity exists in Sedlis criteria: higher risk of relapse (HR=1.88; 95% CI 1.19 to 2.97; p=0.007) and death (HR=2.36; 95% CI 1.41 to 3.95; p=0.001) occurred in patients with lymphovascular space invasion and deep 1/3 stromal invasion compared with no lymphovascular space invasion, middle or deep 1/3 stromal invasion, and tumor diameter ≥4 cm. CONCLUSIONS: Radical hysterectomy alone without adjuvant treatment may achieve a favorable survival for patients with intermediate-risk cervical cancer as defined by Sedlis criteria. Criteria for adjuvant treatment in patients without high risk factors need to be further evaluated.