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.

Long-term clinical outcomes of endoscopic submucosal dissection in rectal neuroendocrine tumors based on resection margin status: a real-world study.

BACKGROUND: Endoscopic submucosal dissection (ESD) has been widely adopted in treating rectal neuroendocrine tumors (NETs). However, clinical outcomes in rectal NETs after ESD with different resection margin status remain scanty, particularly in patients with positive resection margins. This study aimed to evaluate the long-term clinical outcomes of ESD in rectal NET based on the resection margin status. METHODS: This retrospective study included 436 patients diagnosed with rectal NET who had undergone ESD. Clinical data, including age, sex, tumor size, stage, invasion, and the resection margin status, were collected. Further, the patients were assessed for complications, recurrence, distant metastasis, and long-term outcomes. RESULTS: Among all 436 patients, 395 patients had their primary ESD in our hospital. Complete resection was achieved in 319 patients. Patients who did not achieve complete resection opted for follow-up (n = 73), salvage surgery (n = 1) and salvage ESD (n = 2). Another 41 had their primary ESD in other hospital with incomplete resection and had salvage ESD in our hospital. All 436 patients had a median follow-up period of 61.4 months (range 33.4-125.3 months). During the follow-up period, two patients developed recurrences, while three patients developed metastasis. There were no significant differences in the 5-year progression-free survival and overall survival between patients with incomplete resection opting for follow-up compared to the other two groups (P = 0.5/0.8). However, the complication rates were significantly higher in patients who received salvage ESD. CONCLUSION: This study demonstrated that positive resection margins have no influence on survival in patients with rectal NET treated using ESD.

Risk factors and oncological impact of positive resection margins in gastrectomy for cancer: are they salvaged by an additional resection?

BACKGROUND: The situation of positive resection margins (PRMs) varies notably between Western and Asian countries. In the West, PRMs are associated with advanced disease and R1, whereas in Asia, PRMs are also considered in early disease because stomach preservation was recently prioritized. Furthermore, PRMs are usually resected to obtain R0. However, the oncological impact of PRMs and additional resection remains unclear. The aim of this study is to evaluate the oncological impact of PRMs in laparoscopic gastrectomy (LG) for clinical stage (cStage) I gastric cancer. METHODS: A total of 2121 patients who underwent LG for cStage I gastric cancer between 2007 and 2015 were enrolled. Survival outcomes were compared between patients with PRMs (group P) and those without (group N). Furthermore, prognostic factors were analyzed using multivariate analysis. RESULTS: Twenty-seven patients (1.3%) had PRMs. Patients in group P had upper and more advanced disease, and the 5-year relapse-free survival (RFS) rate was worse in group P compared with group N (76.3% vs. 95.1%, P = 0.003). The 5-year RFS of patients with pT2 or deeper (pT2-4) disease in group P was significantly worse than that of patients in group N (66.7% vs. 89.5%, P = 0.030) although that of patients with pT1 was not. Likelihood ratio tests showed that there was a significant interaction between pT status and PRM (P = 0.005). CONCLUSION: PRM in cStage I gastric cancer is associated with advanced upper disease. It remains an independent prognostic factor in pT2-4 disease even after an additional resection to obtain R0.

Clinical significance of positive resection margin for patients with rectal neuroendocrine tumors within 20 mm following initial endoscopic resection: A multi-center study.

BACKGROUND: The incidence of rectal neuroendocrine tumors (RNETs) has witnessed a significant surge, with a notable proportion being amenable to endoscopic removal. However, the clinical significance of positive resection margin for RNETs patients following endoscopic resection remain unknown, resulting in a lack of consensus regarding the appropriateness of implementing salvage treatment. METHODS: In this large, multicenter, retrospective cohort study, we analyzed the medical records of individuals who underwent endoscopic resection for RNETs and classified them into two groups: the positive resection margin and the negative resection margin group. The overall survival (OS) and disease-free survival (DFS) were compared among two group. The independent variables were identified using univariate and multivariate logistic regression analyses to predict positive resection margin. Then, the model was established to predict the patients with positive resection margin using multivariate logistic regression. RESULTS: 181 RNETs patients (34.3 %) represented positive margin after endoscopic resection. Following a median follow-up period of 72 months, tumor recurrence manifested in 12 out of 527 patients (2.2 %) and the presence of positive resection margin was associated with worse DFS. Independent factors correlating with positive resection margin included endoscopic resection method choice, RNETs located in the low rectum, NLR >4.44 and tumor size exceeding 14.89 mm. A prediction model was therefore established with high predictive accuracy and excellent clinical applicability determined by calibration curves and DCA curve. Among RNETs patients with positive margin following endoscopic resection, implementing salvage treatment was beneficial for improving DFS and salvage endoscopic resection offer equal efficiency compared with salvage radical resection. CONCLUSIONS: Positive resection margin following endoscopic resection may indicate negative prognosis. Salvage treatment can improve the prognosis of RNETs patients with positive resection margin. Notably, salvage local resection exhibited similar efficacy compared with radical surgery in term of survival benefit.

Adequate gross resection margin length ensuring pathologically complete resection in gastrectomy for gastric cancer: A systematic review and meta-analysis.

Aim: A positive resection margin (RM) is associated with poor survival after gastrectomy for gastric cancer (GC). However, the adequate RM length to avoid a positive RM remains controversial. We performed a systematic review to examine the RM length required to avoid a positive RM in gastrectomy for GC. Methods: This systematic review involved all relevant articles identified in PubMed, the Cochrane Library, Web of Science, and ClinicalTrials.gov until August 2023. The incidence of a positive RM related to the RM length and the possible incidence of a positive RM estimated from the discrepancy between the gross and pathological RM length were evaluated. The Newcastle-Ottawa Scale was used to quantify study quality. Results: Thirteen studies involving 8983 patients were analyzed. Investigation of the incidence of a positive RM in relation to the RM length showed that a proximal RM length of 6 cm guaranteed a negative RM in gastrectomy. Analyses of the possible incidence of a positive RM revealed that a negative RM would be guaranteed if the proximal RM length was 6 cm in distal gastrectomy, if the esophageal resection length was 2 cm in total gastrectomy for GC without esophageal invasion and 2.5 cm in total or proximal gastrectomy for GC with esophageal invasion or esophagogastric junction cancer, and if the distal RM length was 4 cm in proximal gastrectomy for early GC. Conclusions: The adequate RM lengths to ensure a pathologically negative RM in each type of gastrectomy for GC were herein suggested.

Initial negative resection margin versus revised negative resection margin in patients who underwent surgery without adjuvant therapy for early-stage oral tongue squamous cell carcinoma.

BACKGROUND: In cases of positive resection margin (RM), re-resection is generally recommended. There has been controversy about the oncologic impact of revised negative RMs after re-resection. The aim of this study was to investigate the oncologic impact of revised negative RM in patients who underwent surgery without adjuvant therapy for early-stage (pT1-2/N0) oral tongue squamous cell carcinoma (OSCC). METHODS: We retrospectively analyzed patients with pT1-2 N0 OSCC who did not receive adjuvant therapy (N=441). These patients were classified into an initial negative RM (R0, n = 380) group and a revised negative RM (R1-R0, n = 61) group. Demographic and clinical data (T stage, tumor length, depth of invasion [DOI], lymphovascular invasion [LVI], perineural invasion [PNI], and recurrence) were compared between the R0 and R1-R0 groups. RESULTS: Age, sex, T stage, DOI, LVI, PNI, and SUVmax were not significantly different between the two groups. Local recurrence was more frequent (P=0.045) in the R1-R0 group (13.1 %) than in the R0 group (5.5 %). Local recurrence-free survival was better in the R0 group than in the R1-R0 group (P=0.046). There was no significant difference in overall recurrence or overall survival. On multivariate analysis, initial positive RM was the independent significant risk factor (hazard ratio, 2.249; 95 % confidence interval, 1.025-4.935; P=0.043) for local recurrence. CONCLUSION: A revised clear RM after initial cut-through margin is a risk factor for local recurrence in early-stage OSCC. Cautious should be considered in early-stage OSCC patients with revised clear RM.

Prevention and treatment of a positive proximal margin after gastrectomy for cardia cancer.

A tumour-positive proximal margin (PPM) after extended gastrectomy for oesophagogastric junction (OGJ) adenocarcinoma is observed in approximately 2-20% of patients. Although a PPM is an unfavourable prognostic factor, the clinical relevance remains unclear as it may reflect poor tumour biology. This narrative review analyses the most relevant literature on PPM after gastrectomy for OGJ cancers. Awareness of the risk factors and possible measures that can be taken to reduce the risk of PPM are important. In patients with a PPM, surgical and non-surgical treatments are available but the effectiveness remains unclear.

Peritumoral Delivery of Docetaxel-TIPS Microparticles for Prostate Cancer Adjuvant Therapy.

Recurrence of prostate cancer after radical prostatectomy is a consequence of incomplete tumor resection. Systemic chemotherapy after surgery is associated with significant toxicity. Improved delivery methods for toxic drugs capable of targeting positive resection margins can reduce tumor recurrence and avoid their known toxicity. This study evaluates the effectiveness and toxicity of docetaxel (DTX) release from highly porous biodegradable microparticles intended for delivery into the tissue cavity created during radical prostatectomy to target residual tumor cells. The microparticles, composed of poly(dl-lactide-co-glycolide) (PLGA), are processed using thermally induced phase separation (TIPS) and loaded with DTX via antisolvent precipitation. Sustained drug release and effective toxicity in vitro are observed against PC3 human prostate cells. Peritumoral injection in a PC3 xenograft tumor model results in tumor growth inhibition equivalent to that achieved with intravenous delivery of DTX. Unlike intravenous delivery of DTX, implantation of DTX-TIPS microparticles is not accompanied by toxicity or elevated systemic levels of DTX in organ tissues or plasma. DTX-TIPS microparticles provide localized and sustained release of nontoxic therapeutic amounts of DTX. This may offer novel therapeutic strategies for improving management of patients with clinically localized high-risk disease requiring radical prostatectomy and other solid cancers at high risk of positive resection margins.

An individual patient data meta-analysis on the effect of chemotherapy on survival in patients with craniofacial osteosarcoma.

Chemotherapy improves the survival of patients with long bone osteosarcomas. However, the benefits of chemotherapy in the treatment of craniofacial osteosarcoma (CFOS) are still controversial. We searched PubMed and EMBASE from February 1997 to December 2016 to identify studies on CFOS. The individual patient data of these studies were pooled into a meta-analysis. Univariate and multivariate survival analyses were performed. Thirteen studies with a total of 184 patients met our inclusion criteria. Positive resection margin was a poor prognostic factor for CFOS in the univariate and multivariate survival analyses. Chemotherapy improved overall survival (OS) and disease-specific survival (DSS) in patients with CFOS who had tumors in the maxilla, positive resection margins, or high-grade tumors. Patients with local tumor recurrence had better OS and DSS when treated with chemotherapy. Chemotherapy improves survival in patients with CFOS with adverse factors, such as tumors with positive margins, high-grade tumors, and recurrent tumors.

Salivary gland carcinoma (SGC) with perineural spread and/or positive resection margin - high locoregional control rates after photon (chemo) radiotherapy - experience from a monocentric analysis.

BACKGROUND: The aim was to evaluate the outcome, especially locoregional control of patients with locally advanced salivary gland carcinoma (SGC) with perineural spread (Pn1) and/or positive resection margins (R1/2) after postoperative photon (chemo) radiotherapy in a single centre. METHODS: We retrospectively reviewed data of 65 patients with newly diagnosed locally advanced SGC without distant metastases who underwent radio (chemo) therapy in the department of radiation oncology of the university hospital of Erlangen from January 2000 until April 2017. Kaplan Meier method was used to calculate survival and recurrence rates. In univariate analysis the log-rank test was used to correlate patient-/tumor- and treatment-related parameters to survival and recurrence rates. RESULTS: Median follow-up was 45 months (range: 6; 215). After 1, 3, 5 years cumulative incidence of local and locoregional failure was 3.1, 7.0, 7.0% and 3.1, 9.7, 12.9%, whereas cumulative incidence of distant metastases (DM) was 15.6, 36.0, 44.0%. After 1,3, 5 years cumulative Overall (OS) and Disease-free survival (DFS) was 90.5, 74.9, 63.9% and 83.0, 54.8, 49.4%. The only significant predictor for decreased local and locoregional control was a macroscopic resection margin(R2) (p = 0.002 and p = 0.04). High-grade histology (p = 0.006), lymph node metastases with extracapsular spread (p = 0.044) and an advanced T-stage (p = 0.031) were associated with an increased rate of DM. High-grade histology was the only factor predicting for a decreased DFS (p = 0.014). CONCLUSION: Photon radiotherapy leads to high local and locoregional control rates in a high-risk patient population with SGC with microscopically positive resection margins and/or perineural spread. The most common site of disease recurrence was distant metastases. Therefore the real challenge for the future should be to prevent distant metastases.

Tumor Resection Margin Definitions in Breast-Conserving Surgery: Systematic Review and Meta-analysis of the Current Literature.

Worldwide, various guidelines recommend what constitutes an adequate margin of excision for invasive breast cancer or for ductal carcinoma-in-situ (DCIS). We evaluated the use of different tumor resection margin guidelines and investigated their impact on positive margin rates (PMR) and reoperation rates (RR). Thirteen guidelines reporting on the extent of a positive margin were reviewed along with 31 studies, published between 2011 and 2016, reporting on a well-defined PMR. Studies were categorized according to the margin definition. Pooled PMR and RR were determined with random-effect models. For invasive breast cancer, most guidelines recommend a positive margin of tumor on ink. However, definitions of reported positive margins in the clinic vary from more than focally positive to the presence of tumor cells within 3 to 5 mm from the resection surface. Within the studies analyzed (59,979 patients), pooled PMRs for invasive breast cancer ranged from 9% to 36% and pooled RRs from 77% to 99%. For DCIS, guidelines vary between no DCIS on the resection surface to DCIS cells found within a distance of 2 mm from the resection edge. Pooled PMRs for DCIS varied from 4% to 23% (840 patients). Given the differences in tumor margin definition between countries worldwide, quality control data expressed as PMR or RR should be interpreted with caution. Furthermore, the overall definition for positive resection margins for both invasive disease and DCIS seems to have become more liberal.

Positive esophageal proximal resection margin: an important prognostic factor for esophageal cancer that warrants adjuvant therapy.

BACKGROUND: Positive esophageal proximal resection margin (ERM+) following esophagectomy was considered as incomplete or R1 resection. The clinicopathological data and long-term prognosis of esophageal cancer (EC) patients with ERM+ after esophagectomy were still unknown. Therefore, the aim of this study was to assess the clinical significance of ERM+ and its therapeutic option. METHODS: From November 2008 to December 2014, 3,594 patients with histologically confirmed EC underwent radical resection in our department. Among them there were 37 patients (1.03%) who had ERM+. ERM+ was defined as carcinoma or atypical hyperplasia (severe or moderate) at the residual esophageal margin in our study. For comparison, another 74 patients with negative esophageal proximal resection margin (ERM-) were propensity-matched at a ratio of 1:2 as control group according to sex, age, tumor location and TNM staging. The relevant prognostic factors were investigated by univariate and multivariate regression analysis. RESULTS: In this large cohort of patients, the rate of ERM+ was 1.03%. The median survival time was 35.000 months in patients with ERM+, significantly worse than 68.000 months in those with ERM- (Chi-square =4.064, P=0.044). Survival in patients with esophageal residual atypical hyperplasia (severe or moderate) was similar to those with esophageal residual carcinoma. Survival rate in stage I-II was higher than that in stage III-IV (Chi-square =27.598, P=0.000) in ERM-; But there was no difference between the two subgroups of patients in ERM+. Furthermore, in those patients with ERM+, survival was better in those who having adjuvant therapy, compared to those without adjuvant therapy (Chi-square =5.480, P=0.019). And the average survival time which was improved to a well situation for ERM+ patients who have adjuvant therapy was 68.556 months which is comparable to average survival time (65.815 months) of ERM- for those patients who are at earlier stages. CONCLUSIONS: ERM+ after esophagectomy nowadays is of low incidence but still an important prognostic factor for patients with EC. Survival of ERM+ patients who have adjuvant therapy was improved to a well situation which is comparable to overall survival (OS) rate of ERM- for those patients who are at earlier stages.

Relevant risk factors for positive lateral margin after en bloc endoscopic submucosal dissection for early gastric adenocarcinoma.

OBJECTIVE: This study aimed to systematically assess the relevant risk factors of positive lateral margin (LM) after en bloc resection of early gastric adenocarcinoma. METHODS: A total of 242 patients who had undergone endoscopic submucosal dissection (ESD) due to early gastric lesions from January 2009 to March 2015 were included in the study. Clinicopathological features of the lesions and the risk factors related to positive LM were analyzed. RESULTS: The curative rate was 82.2% and positive LM was found in 12.4% of the lesions. Univariate analysis showed that positive LM was significantly associated with the tumor location (at the upper third of the stomach), size (>3 cm), histological findings, the presence of lymphovascular invasion and deeper invasion depth. Moreover, positive LM had a higher incidence of recurrent or residual tumors. A multivariate analysis showed that the location, tumor size and histological classification of tumors were independent risk factors for positive LM. CONCLUSIONS: Positive LM is closely related to the upper third of stomach, a tumor larger than 3 cm and a mixed-type carcinoma. Additionally, positive LM has a predilection for recurrent or residual tumors.

Clinical importance and surgical decision-making regarding proximal resection margin for gastric cancer.

Because of the intramural spread of gastric cancer, a sufficient length of a resection margin has to be attained to ensure complete excision of the tumor. There has been debate on an adequate length of proximal resection margin (PRM) and its related issues. Thus, the objective of this article is to review several studies on PRM and to summarize the current evidence on the subject. Although there is some discrepancy in the recommended values for PRM between authors, a PRM of more than 2-3 cm for early gastric cancer and 5-6 cm for advanced gastric cancer is thought to be acceptable. Once the margin is confirmed to be clear, however, the length of PRM measured in postoperative pathologic examination does not affect the patient's survival, even when it is shorter than the recommended values. Hence, the recommendations for PRM length should be applied only to intraoperative decision-making to prevent positive margins on the final pathology. Given that a negative resection margin is the ultimate goal of determining an adequate PRM, development and improvement of reliable methods to confirm a negative resection margin intraoperatively would minimize the extent of surgery and offer a better quality of life to more patients. In the same context, special attention has to be paid to patients who have advanced stage or diffuse-type gastric cancer, because they are more likely to have a positive margin. Therefore, a wider excision with intraoperative frozen section (IFS) examination of the resection margin is necessary. Despite all the attempts to avoid positive margins, there is still a certain rate of positive-margin cases. Since the negative impact of a positive margin on prognosis is mostly obvious in low N stage patients, aggressive further management, such as extensive re-operation, is required for these patients. In conclusion, every possible preoperative and intraoperative evaluation should be thoroughly carried out to identify in advance the patients with a high risk of having positive margins; these patients need careful management with a wider excision or an IFS examination to confirm a negative margin during surgery.