Preoperative Chemoradiotherapy Research Articles

Modern approaches to esophageal squamous cell carcinoma therapy: paradigm shift?

Esophageal cancer (EC) is one of the most aggressive malignant neoplasms, ranking sixth among oncological causes of death. According to GLOBOCAN, more than half a million people die from this disease every year, and by 2040 this indicator is expected to increase almost twice. In most patients, esophageal cancer is diagnosed at stages III–IV of the disease. Currently, the standard of treatment for inoperable patients with EC is simultaneous chemoradiotherapy.One of the main methods of treatment of patients with non-metastatic esophageal lesion remains surgical intervention in the volume of esophagectomy with radical lymph dissection, accompanied by quite frequent serious postoperative complications. However, the results of surgical treatment of locally advanced esophageal cancer alone remain unsatisfactory, and the fiveyear survival rate is less than 20 %. In order to improve the oncological results of treatment, various combinations of drug and radiation therapy are used (preoperative chemotherapy or chemoradiotherapy, independent chemoradiotherapy). To date, recommendations for the treatment of locally advanced esophageal cancer vary from country to country. Trimodal therapy (preoperative chemoradiotherapy up to TFD – 46 Gy with 5 cycles of weekly chemotherapy according to the carboplatin + paclitaxel scheme followed by surgical treatment) is the standard in operable patients with non-metastatic squamous cell carcinoma of the esophagus in our and European countries. In Asian countries, preference is given to neoadjuvant chemotherapy, based on the data of the JCOG1109 (NExT) study, in which it was shown that the addition of docetaxel to neoadjuvant therapy with cisplatin and fluorouracil is accompanied by an improvement in overall survival and acceptable toxicity, compared with the CF regimen and chemoradiotherapy. A separate issue is the place of lifesaving esophagectomy in patients who have received a course of radical chemoradiotherapy. Unfortunately, according to several researchers, recurrent or persistent esophageal cancer remains an urgent problem with a risk of relapse of the disease in up to 60 % of cases.We have studied the data of the Russian and global literature concerning the treatment of squamous cell carcinoma of the esophagus.

Sequential Lateral Lymphatic Metastasis Shows Similar Oncologic Outcomes to Upward Spread in Advanced Rectal Cancer After Preoperative Chemoradiotherapy.

Whether lateral pelvic node metastasis should be considered as a regional or systemic disease is a long-standing debate. Although previous Japanese studies have considered it to be locoregional disease, Western countries consider it a systemic disease and do not perform lateral pelvic node dissection after preoperative chemoradiotherapy. To evaluate whether lateral pelvic node metastasis is a systemic or regional disease that is amenable to curative resection. Retrospective analysis of a prospectively collected database. This study was conducted at a tertiary cancer center. There were 616 consecutive patients who underwent curative total mesorectal excision alone or with lateral pelvic node dissection after preoperative chemoradiotherapy for locally advanced rectal cancer between 2011 and 2019. Three-year disease-free and overall survival. A total of 360 patients underwent total mesorectal excision, and 160 patients underwent total mesorectal excision with lateral pelvic node dissection. There was no difference in the 3-year disease-free survival (DFS; p = 0.844) or overall survival rates ( p = 0.921) between the groups. Patients with lateral pelvic node metastasis showed DFS similar to those with perirectal lymph node metastasis in the total mesorectal excision group. In a subgroup analysis, patients with internal iliac pelvic node metastasis showed a disease-free survival comparable to those with perirectal node involvement, and patients with other lateral pelvic node metastasis showed a DFS similar to those with intermediate node involvement. In the lateral pelvic node dissection group, the lateral pelvic node metastatic rate was 32.5%. On multivariate analysis, fewer than 8 of the unilateral harvested lateral pelvic nodes and advanced ypT stage were significantly associated with poor disease-free survival. The retrospective design. Lateral lymphatic metastasis showed oncologic outcomes similar to those of upward spread, especially perirectal lymph nodes metastasis. Large cohort studies with long-term follow-up are required to confirm these results. See Video Abstract . ANTECEDENTES:Es un debate muy antiguo si las metástasis en los ganglios pélvicos laterales deben considerarse una enfermedad regional o sistémica. Si bien estudios japoneses anteriores las consideran como una enfermedad locorregional, en los países de occidente se las considera como una enfermedad sistémica por la cual no se realiza disección de ganglios pélvicos laterales después de una radioquimioterapia preoperatoria.OBJETIVOS:Evaluar si la metástasis en los ganglios pélvicos laterales se consideran como enfermedad sistémica o enfermedad regional susceptible de resección curativa.DISEÑO:Análisis retrospectivo de una base de datos recopilada prospectivamente.AJUSTE:Este estudio se realizó en un centro oncológico terciario.PACIENTES:616 pacientes consecutivos se sometieron a excisión total del mesorrecto curativa sola o con disección de los ganglios pélvicos laterales después de radioquimioterapia preoperatoria en casos de cáncer de recto localmente avanzado entre 2011 y 2019.PRINCIPALES MEDIDAS DE RESULTADO:Sobrevida global y libre de enfermedad a 3 años.RESULTADOS:Un total de 360 pacientes se sometieron a excisión total del mesorrecto y 160 pacientes se sometieron a excisión total del mesorrecto con disección de ganglios pélvicos laterales.No hubo diferencias en la sobrevida libre de enfermedad a 3 años (p = 0,844) ni en las tasas de sobrevida general (p = 0,921) entre los grupos. Los pacientes con metástasis en los ganglios pélvicos laterales mostraron una sobrevida libre de enfermedad similar a aquellos con metástasis en los ganglios linfáticos perirrectales que se encontraban en el grupo de excisión total del mesorrecto.En el análisis de subgrupos, los pacientes con metástasis en los ganglios pélvicos ilíacos internos mostraron una sobrevida libre de enfermedad comparable a aquellos con afección de los ganglios perirrectales y los pacientes con otras metástasis en los ganglios pélvicos laterales mostraron una sobrevida libre de enfermedad similar a aquellos con afección de los ganglios intermedios.En el grupo de disección de los ganglios pélvicos laterales, la tasa de metástasis en dichos ganglios fué del 32,5%. En el análisis multivariado, < de 8 ganglios pélvicos laterales resecados unilateralmente y el estadio ypT avanzado se asociaron significativamente con una menor sobrevida libre de enfermedad.LIMITACIÓN:El diseño retrospectivo del estudio.CONCLUSIONES:Las metástasis linfáticas laterales mostraron resultados oncológicos similares a la diseminación ascendente, especialmente las metástasis en los ganglios linfáticos perirrectales. Se requieren grandes estudios de cohortes con seguimiento a largo plazo para confirmar estos resultados. (Traducción-Dr. Xavier Delgadillo ).

Incidence and risk factors of lymph node metastasis in breast cancer patients without preoperative chemoradiotherapy and neoadjuvant therapy: analysis of SEER data.

Breast cancer (BC) is the leading cause of death in the female reproductive system, often linked to lymph node involvement, indicating poor prognosis. This study investigated lymph node metastasis incidence and risk factors in M0 stage BC patients who hadn't received preoperative chemoradiotherapy or neoadjuvant therapy. We explored the influence of various factors on lymph node metastasis. We conducted a retrospective analysis using Surveillance, Epidemiology, and End Results data from BC patients diagnosed between 2010 and 2015. Binary logistic regression and propensity score matching (PSM) assessed significant factors in BC patients without preoperative treatment. We developed predictive nomograms and evaluated model performance using the concordance index, calibration curve, area under the curve, and decision curve analysis. Among 256,504 eligible BC patients, 25.57% had lymph node metastasis. Multivariate logistic regression revealed associations between lymph node metastasis and younger age, African-American ethnicity, central/nipple location, lobular carcinoma, human epidermal growth factor receptor 2 (HER2)-positive status, grade III classification, and T3 stage. PSM confirmed these findings. Interactions were identified between age, race, primary site, histology, breast subtype, grade, and T stage, all influencing lymph node metastasis. This retrospective study identified lymph node metastasis in female BC patients with distinct clinicopathological characteristics who received no preoperative treatment. We constructed valuable nomograms, revealing that: (I) young age (<35 years), African-American race, central/nipple location, infiltrating duct carcinoma, HER2 positivity, high histological grade (grade III), and larger tumor size are risk factors for regional lymph node metastasis; (II) lymph node metastasis may not solely represent the invasive nature of triple-negative BC; (III) patients with different BC subtypes in T1c-T2 stages may benefit from individualized neoadjuvant treatment strategies.

Protocol digest of a randomized controlled Phase III study comparing surgery alone versus adjuvant nivolumab versus adjuvant S-1 for locally advanced oesophageal squamous cell carcinoma with no pathological complete response after neoadjuvant chemotherapy followed by curative esophagectomy: Japan Clinical Oncology Group study JCOG2206 (SUNRISE Trial)

Abstract Although the efficacy of postoperative therapy with nivolumab after preoperative chemoradiotherapy for locally advanced oesophageal cancer has been proven in Western countries, the survival benefits of postoperative therapy after preoperative chemotherapy with docetaxel, cisplatin and 5-FU or cisplatin plus 5-FU as the Japanese standard therapy remain controversial. This randomized Phase III trial was designed to confirm the superiority of postoperative therapy with nivolumab over observation alone and S-1 over observation alone in patients with locally advanced oesophageal squamous cell carcinoma with no pathological complete response after preoperative chemotherapy followed by curative esophagectomy. A total of 450 patients will be enrolled from 56 hospitals in Japan over 5.5 years. The primary endpoint is relapse-free survival, and the secondary endpoints are disease-free survival, overall survival, adverse events and incremental cost-effectiveness ratio. This trial has been registered in the Japan Registry of Clinical Trials as jRCTs031230219 (https://jrct.niph.go.jp/latest-detail/jRCTs031230219).

Independent Stage Classification for Gastroesophageal Junction Adenocarcinoma.

In gastroesophageal junction (GEJ) adenocarcinoma cases, a prognosis based on ypTNM staging could be affected by preoperative therapy. Patients with esophageal adenocarcinoma and gastric adenocarcinoma who underwent preoperative therapy followed by surgical resection from 2006 through 2017 were identified in the National Cancer Database. To enable stage-by-stage OS comparisons, tumors were classified into four gross ypTNM groups: ypT1/2, N-negative; ypT1/2, N-positive; ypT3/4, N-negative; and ypT3/4, N-positive. Prognostic factors were examined, and an OS prediction nomogram was developed for patients with abdominal/lower esophageal and gastric cardia adenocarcinoma, representing GEJ cancers. We examined 25,463 patient records. When compared by gross ypTNM group, the abdominal/lower esophageal and gastric cardia adenocarcinoma groups had similar OS rates, differing from those of other esophageal or gastric cancers. Cox regression analysis of patients with GEJ cancers showed that preoperative chemoradiotherapy was associated with shorter OS than preoperative chemotherapy after adjustment for the ypTNM group (hazard ratio 1.31, 95% CI 1.24-1.39, p < 0.001), likely owing to downstaging effects. The nomogram had a concordance index of 0.833 and a time-dependent area under the curve of 0.669. OS prediction in GEJ adenocarcinoma cases should include preoperative therapy regimens. Our OS prediction nomogram provided reasonable OS prediction for patients with GEJ adenocarcinoma, and future validation is needed.

MRI Tumor Regression Grade Combined with T2-Weighted Volumetry May Predict Histopathological Response in Locally Advanced Rectal Cancer following Neoadjuvant Chemoradiotherapy-A New Scoring System Proposal.

Modern studies focus on the discovery of innovative methods to improve the value of post-treatment magnetic resonance imaging (MRI) in the prediction of pathological responses to preoperative neoadjuvant chemoradiotherapy (nCRT) in locally advanced rectal cancer (LARC). The aim of this study was to assess the potential benefits of combining magnetic resonance tumor regression grade (mrTRG) with T2-weighted volumetry in the prediction of pathological responses to nCRT in LARC. This was a cohort study conducted on patients with histopathologically confirmed LARC in a period from 2020 to 2022. After histopathological verification, all patients underwent initial MRI studies, while the follow-up MRI was performed after nCRT. Tumor characteristics, MRI estimated tumor regression grade (mrTRG) and tumor volumetry were evaluated both initially and at follow-up. All patients were classified into responders and non-responders according to pathological tumor regression grade (pTRG) and mrTRG. A total of 71 patients, mostly male (66.2%) were included in the study. The median tumor volume reduction rate was significantly higher in nCRT-responders compared to non-responders (79.9% vs. 63.3%) (p = 0.003). Based on ROC analysis, optimal cut-off value for tumor volume reduction rate was determined with an area under the curve (AUC) value of 0.724 (p = 0.003). Using the tumor volume reduction rate ≥75% with the addition of response to nCRT according to mrTRG, a new scoring system for prediction of pTRG to preoperative nCRT in LARC was developed. Diagnostic performance of prediction score was tested and the sensitivity, PPV, specificity, and NPV were 81.8%, 56.3%, 71.4%, and 89.7%, respectively. The combination of mrTRG and T2-weighted volumetry increases the MRI-based prediction of pTRG to preoperative nCRT in LARC. The proposed scoring system could aid in distinguishing responders to nCRT, as these patients could benefit from organ-preserving treatment and a "watch and wait" strategy.

Dual-energy computed tomography-based iodine concentration as a predictor of histopathological response to preoperative chemoradiotherapy for pancreatic cancer.

To explore predictors of the histopathological response to preoperative chemoradiotherapy (CRT) in patients with pancreatic cancer (PC) using dual-energy computed tomography-reconstructed images. This retrospective study divided 40 patients who had undergone preoperative CRT (50-60Gy in 25 fractions) followed by surgical resection into two groups: the response group (Grades II, III and IV, evaluated from surgical specimens) and the nonresponse group (Grades Ia and Ib). The computed tomography number [in Hounsfield units (HUs)] and iodine concentration (IC) were measured at the locations of the aorta, PC and pancreatic parenchyma (PP) in the contrast-enhanced 4D dual-energy computed tomography images. Logistic regression analysis was performed to identify predictors of histopathological response. Univariate analysis did not reveal a significant relation between any parameter and patient characteristics or dosimetric parameters of the treatment plan. The HU and IC values in PP and the differences in HU and IC between the PP and PC (ΔHU and ΔIC, respectively) were significant predictors for distinguishing the response (n = 24) and nonresponse (n = 16) groups (P < 0.05). The IC in PP and ΔIC had a higher area under curve values [0.797 (95% confidence interval, 0.659-0.935) and 0.789 (0.650-0.928), respectively] than HU in PP and ΔHU [0.734 (0.580-0.889) and 0.721 (0.562-0.881), respectively]. The IC value could potentially be used for predicting the histopathological response in patients who have undergone preoperative CRT.

The "Watch and Wait" Method After Chemoradiotherapy for Rectal Cancer Requiring Abdominoperineal Resection.

The present study examined the therapeutic effects of preoperative neoadjuvant chemoradiation therapy (NACRT) and predictive factors for complete clinical remission, compared the prognosis and costs of abdominoperineal resection (APR) and the "watch and wait" method (WW), and evaluated the usefulness of WW.In our department, patients with stage II-III lower rectal cancer requiring APR receive NACRT. NACRT was performed as a preoperative treatment (52Gy + S-1: 80-120mg/day × 25days). Eight weeks after the completion of NACRT, rectal examination, endoscopic, computed tomography, and magnetic resonance imaging findings were evaluated to assess its therapeutic effects. APR was indicated for patients in whom endoscopic findings suggested a residual tumor in which a deep ulcer or marginal swelling remained or lymph node metastasis. However, WW was selected for patients who refused APR after informed consent was obtained. In the APR and WW groups, 5- and 20-year treatment costs after CRT were calculated using the Medical Fee Points of Japan in 2020.No significant differences were observed in 3-year disease-free survival rates for either parameter between the two groups. Regarding expenses, treatment costs were lower in the WW group than in the APR group.Organ preservation using active surveillance with CRT for rectal cancer requiring APR is feasible with the achievement of endoluminal complete remission.

Pathologic complete response following preoperative chemotherapy vs. chemoradiotherapy in pancreatic ductal adenocarcinoma: a systematic review and meta-analysis

Pathologic complete response following preoperative chemotherapy vs. chemoradiotherapy in pancreatic ductal adenocarcinoma: a systematic review and meta-analysis

Effect of Anemia on Tumor Response to Preoperative Neoadjuvant Chemoradiotherapy for Locally Advanced Rectal Cancer

Preoperative neoadjuvant chemoradiotherapy (nCRT) and total rectal mesenteric resection (TME) are the primary treatment options for locally advanced rectal cancer (LARC), but their efficacy varies. This study aimed to investigate the impact of anemia on the tumor response of patients with LARC receiving preoperative neoadjuvant chemoradiotherapy. This study was a retrospective analysis of clinical and pathological data from patients with LARC who underwent nCRT and TME from January 2019 to May 2022 at a single institution. The tumor response was evaluated based on the tumor regression grade (TRG) and T-stage change of the primary tumor. Hemoglobin concentration was measured and graded to determine the presence of anemia. Anemia was categorized into four groups based on the hemoglobin levels: mild anemia (90-120 g/L), moderate anemia (60-90 g/L), severe anemia (30-60 g/L), and extreme anemia (less than 30 g/L). Finally, tumor response was quantified histologically using the AJCC 8th edition tumor regression grading system for rectal cancer and pre- and post-treatment T-grading. A total of 88 patients with LARC who received nCRT and TME were included in the study, with 17 females and 71 males. Of these patients, 9 were moderately anemic and 37 were mildly anemic. The radiation therapy regimen was administered at a dose of 1.8-2 Gy per fraction, five times a week, for a total dose of 45-50.4 Gy. Capecitabine chemotherapy was also administered orally (825 mg/m2, twice a day) on the days of radiation therapy. Other chemotherapy regimens included XELOX and mFOLFOX6. The TRG was significantly different in anemic patients compared to non-anemic patients (P = 0.039). Only 2 out of 46 anemic patients (4%) showed an excellent response (TRG0), while 8 out of 42 non-anemic patients (19%) showed an excellent response (p = 0.043). There was also a significant difference in the incidence of anemia between cT3 and cT4 stages (p = 0.048), with 44% of cT3 patients and 67% of cT4 patients being anemic. The number of patients with poor response (TRG2-3) decreased as the degree of anemia decreased, but no significant difference was found. The incidence of TRG3 was 11% in patients with moderate anemia and 7% in non-anemic patients (P = 0.863). There was no significant difference in postoperative pathological T-stage between anemic and non-anemic patients. 89% of anemic patients had a pathological stage of ypT3 or less after chemoradiotherapy, while 95% of non-anemic patients did (P = 0.167). The pre- and post-treatment pathological staging did not significantly differ between anemic and non-anemic patients. 67% of anemic patients had descending tumors, while 59.5% of non-anemic patients had descending tumors (p = 0.509). Patients with LARC who have normal hemoglobin concentrations during nCRT have better tumor regression compared to patients with anemia. Additionally, the incidence of anemia was higher among patients with advanced T-stage prior to treatment.

Preoperative Carbon Ion Radiotherapy (CIRT) with Chemotherapy in Resectable and Borderline Resectable Pancreatic Adenocarcinoma (PCa): A Multicenter Prospective Phase II Clinical Study (Pioppo Study NCT 03822936)

Preoperative chemoradiation and surgery may improve survival for resectable (Re) or borderline resectable (BRe) PCa. However, there is a lack of evidence regarding the feasibility of combined chemotherapy (CT) and CIRT in the neoadjuvant setting for Re/BRe PCa, especially in the Caucasian population. To assess the safety and efficacy of this challenging combination, we designed a prospective multicentric single-arm phase II trial MATERIALS/METHODS: PIOPPO trial was opened in September 2014. We prospectively treated patients with Re/BRe Pca with a neoadjuvant CT (3 cycles of FOLFIRINOX) and a short-course of CIRT (38.4 GyRBE, 8 fractions, 4 fractions per week) planned with 4D-imaging and delivered with breath-gating and rescanning. Four-6 weeks after CIRT patients (pts) received surgery followed by adjuvant-CT (FOLFIRINOX for 9 or gemcitabine for 6 cycles). After each step patients underwent a re-staging. The primary endpoint was Local Progression Free Survival (LPFS). Fourteen (47%) of the foreseen 30 pts were evaluated for enrollment. There were 4 screening failures for duodenum infiltration. Ten Caucasian pts (M = 7; 70%; F = 3;30%) with a median age of 65.5 (range:46-76) started the treatment. There were four (40%) Re and 6 (60%) BRe Pca. 100% of the Re and 50% of BRe PCa completed the planned combined treatment for a total of 7 (70%) pts. Three (30%) pts developed systemic progression after CT and underwent palliative care (2 cases) or a second line of CT (1 case). With regards to toxicities, we recorded 2 (28.6%) cases of neutropenia during CT, none acute CIRT toxicity and one (14%) case of intra-operative ulceration of the gastro-enteric anastomosis. Moreover, we reported one (14%) case of fatal liver failure due to portal vein stenosis due to the combo approach (CT+CIRT+surgery). Six (86%) pts experienced Tumor Regression Grade (TRG) = 2 according to the College of American Pathologists (CAP) and 1 (14%) a TRG = 3. At the last follow-up, among pts who completed the scheme, 2 (28%) are currently alive and disease-free at 57 and 49 months, respectively. With a median follow-up of 13 months, the median LPFS was 9.4 months (range:4.9-57), with 1 case (14%) of systemic progression and 3 cases (43%) of local recurrence + systemic progression. The study was early closed due to low accrual in August 2022. Although the small sample size limits the interpretation of the endpoints, a neoadjuvant approach combining CT and a short course of CIRT for resectable/borderline Pca seems feasible. Liver toxicity was similar to the Japanese series and needs to deepen investigation on the vascular dose constraints and surgical techniques. Considering the worse outcomes, a better selection of patients to treat also with a centralized imaging interpretation is mandatory.

Sarcopenia as a Predictor of Neoadjuvant Therapy-Related Toxicity in Esophageal Squamous Cell Carcinoma Patients

Sarcopenia, characterized by loss of muscle mass, plays a critical role in patients with esophageal squamous cell cancer (ESCC). Preoperative chemoradiotherapy and immunotherapy in ESCC patients has been reported to improve survival. Therefore, we sought to evaluate the predictive value of preoperative sarcopenia for toxicity and pathological tumor response to neoadjuvant therapy (NAT) in ESCC patients. A retrospective analysis was performed using a prospectively collected patient cohort of an academic cancer center diagnosed with cT2-4N0-3M0 ESCC between 2019-2022 and treated with neoadjuvant chemoradiotherapy ± pembrolizumab. Sarcopenia was assessed by skeletal muscle index at the third lumbar vertebra in computed tomography scans before NAT (men: 43cm²/m² for body mass index (BMI) < 25kg/m², 53cm²/m² for BMI≥25 kg/m²; women: 41cm²/m²). Logistic regression was performed to assess the association between sarcopenia and preoperative therapy-related toxicity and tumor response. The study included 59 locally advanced ESCC patients (53 male and 6 female), 48 (81.4%) in the non-sarcopenia group, and 11 (18.6%) in the sarcopenia group. Mean age at diagnosis was 62±8 years. Mean BMI at diagnosis was 22.13±2.85 kg/m². 19 patients (32.2%) were stage ⅢA, 25 patients (42.4%) were ⅢB, 15 patients (25.4%) were ⅣA. No significant differences were found between both groups regarding sex, age, BMI, and clinical stage. Acute grade ≥3 toxicity occurred significantly more frequently in the sarcopenia group (54.5% vs. 22.9%, p = 0.045), which mainly included leukopenia, neutropenia, anemia and thrombocytopenia. The discontinuation of NAT owing to toxicity occurred in 8 patients (13.5%), which was significantly associated with sarcopenia (p = 0.003). All patients proceeded to surgery and 33 patients (55.9%) had a pathological complete response (pCR). Univariate analysis revealed no significant association between sarcopenia and pCR (p = 0.071). Among patients with locally advanced EC, sarcopenia is not a predictor of poor NAT response, but it is strongly associated with discontinuation of NAT due to toxicity.

Gastric Radiotherapy in the UK – Current Practice and Opinion on Future Directions

Gastric radiotherapy (RT) is more commonly practiced in the US compared to the UK, where postoperative chemoradiotherapy (CRT) is reserved for selected high-risk patients, and preoperative CRT is not standard of care pending the results of phase 3 trials, TOPGEAR and CRITICSII. CRT for inoperable, non-metastatic gastric cancer is also not recommended in the UK, despite being listed in NCCN guidelines. Recent systematic review of definitive gastric CRT (dCRT) conducted by the authors found median overall survival of 11-26.4 months, clinical complete response rates of 8-45% and acceptable rates of ≥G3 toxicity, supporting further research. Given these promising findings and perceived low uptake of gastric RT in the UK, we set out to establish current UK practice, opinion and RT technique to inform the development of a UK gastric RT protocol and future clinical trials. A 19 question survey was developed. Following local ethical approval and pilot by 4 clinical oncologists, the final survey was distributed electronically on 13/12/22 to UK Consultant Clinical Oncologists specializing in esophago-gastric (OG) cancer. Responses were anonymous. Survey was closed 6/2/23 and data analyzed using JISC/spreadsheet software. A total of 43 clinicians completed the survey. For gastric cancer, 28.6%, 7.1% and 9.5% would agree/strongly agree with use of postoperative (postopRT), preoperative (preopRT) or definitive RT (dRT) respectively, compared to 26.2%, 45.2% and 46.6% for type III gastro-esophageal junction tumors. 93% had prescribed palliative gastric RT in the last 3 years compared to 40.5% postopRT, 16.7% dRT and 9.5% preopRT. Main reasons for infrequent use were; rarely indicated within standard UK practice 88.4%, lack of UK gastric RT protocol 53.5%, toxicity concerns 44.2%. 45Gy/25# was most commonly used for preopRT (66%) and postopRT (86%), and 50Gy/25# for dRT (58%). 96% use IMRT/VMAT, 85% CT simulation with IV/oral contrast, 69% gastric filling protocol and 54% 4DCT. When ranked out of 10 (1 = low 10 = high), clinician confidence in accurately delineating gastric volumes mean rank was 4.33 for postopRT, with 9% rating ≥8/10, and 4.52 for dCRT/preopRT with 17% rating ≥8/10. However, 48.8% were experienced in outlining upper abdominal nodes and 62.8% duodenum. 93% would find a detailed outlining protocol useful, 81.4% wanted some form of peer review, 76.7% a nodal atlas, and 74.4% a workshop with an expert. 77.6% would be supportive of a future clinical trial of dCRT, with 23.4% needing more supporting evidence. No-one would not support a future trial in this setting. Gastric RT is not often practiced in the UK, due to lacking evidence and toxicity concerns. Given the growing evidence and supportive OG community, it is time to consider a trial of dCRT in the UK, which must include detailed RT protocols, atlases and educational materials to improve clinician confidence and ensure good RT quality assurance.

KZ02 enhances the radiosensitivity of BRAF-mutated CRC in vitro and in vivo

Colorectal cancer (CRC) is a common malignant tumor with a high incidence and mortality worldwide. Preoperative chemoradiotherapy is a common treatment for patients with metastatic colorectal cancer (mCRC) as it reduces colostomy and local recurrence. The RAS (rat sarcoma)-RAF (extracellular signal-regulated kinase)-MEK (mitogen-activated protein kinase)-ERK (extracellular signal-regulated kinase) pathway regulates important cellular processes in the CRC. Abnormal ERK activation stimulates cell growth and provides a survival advantage. Our group has previously reported that the compound KZ02 has a stronger ability to inhibit tumor growth than AZD6244 (a MEK inhibitor). In this study, we evaluated the antitumor activity of KZ02 in combination with ionizing radiation (IR) and investigated its mechanism of action in BRAF-mutated colorectal cancer. Our results showed that this combination kills tumor cells better than either radiation or drugs alone, both in vivo and in vitro. Furthermore, studies have shown that KZ02 inhibits ERK overactivation. The combination resulted in a G1 phase arrest, a reduction in the radioresistant S phase, and aggravating DNA damage. It can also inhibit Pim-1 (Moloney murine leukemia virus-1), p-BAD (Bcl-2 associated agonist of cell death), Bcl-2 (B-cell lymphoma 2) and Bcl-XL (B-cell lymphoma-extra large) levels and promote apoptosis when combined with radiation. Our results suggest that KZ02 significantly increases the radiosensitivity of BRAF-mutated CRC cells by perturbing the cell cycle, increasing DNA damage, and promoting tumor apoptosis.

Mismatch Repair system protein deficiency as a resistance factor for locally advanced rectal adenocarcinoma patients receiving neoadjuvant chemo-radiotherapy.

Available data on Mismatch Repair system (MMR) deficiency are conflicting and derived from small studies. Our study aimed to evaluate the therapeutic implications of MMR status in patients with locally advanced rectal cancer (LARC). We retrospectively collected data from 318 patients affected by LARC treated in Italy at the Medical Oncology Units of the University Hospital of Cagliari, Istituto Nazionale dei Tumori Milan, and AOU Ospedali Riuniti Ancona. All patients underwent neoadjuvant chemoradiotherapy. The primary objective was major TRG while secondary objectives were pathological complete response, disease-free survival (DFS) and overall survival (OS). One hundred sixty patients (148 pMMR and 12 dMMR) were included in the exploratory cohort and 158 (146 pMMR and 12 dMMR) were included in the validation cohort. A major TRG has been shown in 42.6% and 43.1% patients with pMMR in exploratory and validation cohort, respectively; while no major TRG have been shown in dMMR patients in both cohorts. Exploratory and validation cohorts showed a statistically significant higher mDFS in pMMR patients compared to dMMR: NR vs. 14 months and NR vs. 17 months, respectively. Our results indicated an association between dMMR and poor response to preoperative chemoradiotherapy and they represent a hypothesis-generating data for new neoadjuvant strategies.

The efficacy of neoadjuvant chemoradiotherapy in signet ring cell carcinoma of the rectum: a retrospective propensity-score matched study

INTRODUCTION: there is a lack of information chemoradiotherapy (CRT) efficacy in signet ring cell carcinoma of the rectum (SRCCR). The aim of our research was to investigate the efficacy of preoperative CRT in patients with SRCCR.PATIENTS AND METHODS: we conducted a retrospective analysis of medical records from the archive of Research Institute FSBI “N.N. Blokhin Cancer Research Center” of the Ministry of Health of Russia and multicenter registry of the Russian Society of Specialists in Colorectal Cancer (RSSCC) from 2000 to 2020 and included in the study group patients with histologically confirmed primary SRCCR who received preoperative CRT. A control group with rectal adenocarcinoma was created using propensity-score matching from the institutional database 1:1 taking into account sex, age, tumor size, the cT and cN clinical stage. We estimated the rate of Dworak tumor regression grade 3-4, RECIST, 5-year overall survival (OS) and disease-free survival (DFS) rates.RESULTS: the study and control group included 22 patients each. The study group included 11 patients (50%) with cT3 and cT4 clinical stage. 10 (45,5%) patients had cT3 clinical stage and 12 (54,5%) patients had cT4 clinical stage in the control group (p = 0,763). The number of patients with cN1-2 clinical stage was 17 (77,3%) and 16 (72,7%) in the study and control group, respectively (p = 0,728). The rate of Dworak tumor regression grade 3–4 was 40,9% in the group of patients with SRCCR and 45,5% in the group of patients with rectal adenocarcinoma (p = 0,761).When assessed by RECIST scale, 9 (40,9%), 12 (54,5%) and 1 (4,5%) patients with SRCCR had partial tumor response, stabilization and progression, respectively. Partial response was observed in 18 (81,8%) patients and stabilization — in 4 (18,2%) patients with rectal adenocarcinoma (p = 0,018). Median followup was 58,8 months. The 5-year OS was 34% in the SRCCR group and 71,3% in the group with rectal adenocarcinoma (p = 0,024), and the 5-year PFS was 30,2% with SRCCR and 52,2% with adenocarcinoma (p = 0,115).CONCLUSIONS: CRT leads to comparable grade 3–4 tumor regression in SRCCR and rectal adenocarcinoma, but the objective response rate is lower. This histological subtype has significantly lower OS values.

Postchemoradiation magnetic resonance imaging circumferential resection margin predicts treatment failure after multidisciplinary directed sphincter preservation in low rectal cancer.

This study aimed to review the magnetic resonance imaging (MRI) features of patients with low rectal cancer (LRC) undergoing preoperative chemoradiotherapy (CRT) and investigate the risk factors for treatment failure after sphincter preserving surgery following preoperative CRT based on multidisciplinary approach. Patients who underwent standard CRT and sphincter preserving radical surgery for LRC between January 2000 and December 2011 were retrospectively reviewed. Sphincter preservation failure (SPF) was defined as any one of the following: positive pathologic circumferential resection margin, local recurrence, failure to repair ileostomy, or permanent stoma formation due to anastomotic complications. Among the 191 patients, there were no overall significant differences between sphincter preservation success (n = 161) and SPF (n = 30) groups. SPF group showed a higher MRI circumferential resection margins (mrCRM) positive rate before and after CRT (before CRT: 33.3% vs. 16.1%, p = 0.027; after CRT: 23.3% vs. 6.2%, p = 0.002). Multivariate analysis showed that only mrCRM after CRT was associated with SPF (hazard ratio = 4.596, p = 0.005). SPF group showed worse 5-year cancer-specific survival (51% vs. 92.7%, p < 0.001). MRI-based assessment of the tumor after CRT plays a crucial role in predicting the success and feasibility of sphincter preservation as well as oncological outcomes in patients with LRC.

Prediction model of the risk for lateral local recurrence in locally advanced rectal cancer without enlarged lateral lymph nodes: Lessons from a Japanese multicenter pooled analysis of 812 patients.

Although the oncological impact of lateral lymph node dissection on enlarged lateral lymph nodes has been gradually accepted over the last decade, that on lateral lymph nodes without swelling remains doubtful. This study aimed to develop a prediction model for the future risk of lateral local recurrence and to clarify the value of adding lateral lymph node dissection in locally advanced rectal cancer without enlarged lateral lymph nodes. This retrospective, multi-institutional study recruited 812 patients with cStage II/III low rectal cancer without enlarged lateral lymph nodes <7 mm. Total lateral local recurrence was a hypothetical value of future risk of lateral local recurrence when lateral lymph node dissection was never performed. Overall, total lateral local recurrences were observed in 67 patients (8.3%). In the multivariate analyses, the strongest risk factor for total local recurrences was no preoperative chemoradiotherapy (odds ratio [OR][95%Cl]: 33.2 [4.56-241.7], P < 0.001), followed by tumor distance ≤40 mm (OR [95%Cl]: 2.71 [1.51-4.86], P < 0.001) and lateral lymph node 5-7 mm (OR[95%Cl]: 2.38 [1.26-4.48], P = 0.007). In patients with lateral lymph nodes of 5-7 mm, the total lateral recurrence rate was 4.8% after preoperative chemoradiotherapy. Lateral lymph node dissection could reduce from a total lateral local recurrence of 21.6% to an actual lateral local recurrence of 8.0% in patients without preoperative treatment. We introduce a novel prediction model of future risk of lateral local recurrences, which has the potential to enable us to indicate lateral lymph node dissection selectively according to the patients' risks.

External validation of a nomogram predicting conditional survival after tri-modality treatment of esophageal cancer

BackgroundA conditional survival nomogram was developed at a single high-volume center to predict 5-year overall survival for esophageal cancer patients after neoadjuvant chemoradiation and esophagectomy. The aim of this study was to externally validate the nomogram in a cohort of patients with esophageal adeno- or squamous cell carcinoma from another high-volume center. MethodsConsecutive patients with an esophageal adeno- or squamous cell carcinoma who had undergone esophagectomy after being treated with preoperative chemoradiation between 2004 and 2016 were selected from a prospectively maintained institutional database. The level of discrimination for prediction of 5-year overall survival was quantified by Harrell’s C statistic. Calibration of the conditional survival nomogram was visualized by plotting predicted 5-year survival and observed 5-year survival for comparison. ResultsOf the 296 patients examined, the probability of 5-year overall survival directly after surgery was 45% and increased to 51%, 68%, 78%, and 89% for each additional year survived. The predicted 5-year overall survival differed from the observed survival, with a calibration slope of 0.54, 0.55, 0.59, 0.73, and 1.09 directly after surgery and 1, 2, 3, and 4 years of survival after surgery, respectively. The nomogram's discrimination level for 5-year survival was moderate, with a C statistic of 0.65 compared to the 0.70 reported in the original study. ConclusionThe nomogram model has moderate predictive discrimination and accuracy, supporting its applicability to external cohorts to predict conditional survival. Further validation studies should empirically assess the model for predictive performance.

GRECCAR 14 - a multicentric, randomized, phase II-III study evaluating the tailored management of locally advanced rectal carcinoma after a favourable response to induction chemotherapy: Study protocol.

Total neoadjuvant treatment (TNT) is becoming standard in patients with locally advanced rectal carcinoma (LARC). Preoperative chemoradiotherapy (CRT) has proven side effects on bowel and genitourinary function. An early tumoral response to induction chemotherapy demonstrates its high prognostic value. Tailored management could be used as an alternative to systematic CRT. The GRECCAR 14 trial will attempt to personalize treatment strategy according to the patient's early tumour response to intensive chemotherapy with the aim of achieving the best toxicity-efficiency ratio. GRECCAR 14 is a multicentric, randomized, two-arm, phase II-III noninferiority trial. Patients with mid or low LARC with a predictive circumferential resection margin ≤2 mm or T3c-d stage with extramural venous invasion will be included. Evaluation of the tumoral response will be performed after six courses of high-dose FOLFIRINOX chemotherapy. Good responders (GRs) will be defined by a 60% decrease in tumoral volume on magnetic resonance imaging. Patients will be randomized to CRT before surgery. The primary endpoints will be R0 resection for phase II and the 3-year disease-free survival (DFS) for phase III. Tailored management of LARC is becoming an exciting challenge for the modality of neoadjuvant treatment and for the type of surgery or its omission. Neoadjuvant FOLFIRINOX has established efficacy, with a significant increase in the 3-year DFS. Better control of systemic disease must be accompanied by the same locoregional control, with the lowest morbidity. Our previous GRECCAR 4 trial demonstrated the high value of the early tumoral response after induction chemotherapy and the long-term safety of tailored management for GRs. If GRECCAR 14 demonstrates the ability to tailor TNT for LARC, this could lead to changes in clinical practice.