Pathological response following long-course neoadjuvant chemoradiotherapy for locally advanced rectal cancer

AIMS: To standardize the pathological analysis of total mesorectal excision specimens of rectal cancer following neoadjuvant chemoradiotherapy for locally advanced disease (T3/T4), including tumour regression. METHODS AND RESULTS: Standardized dissection and reporting was used for 60 patients who underwent total mesorectal excision following long-course chemoradiotherapy. Tumour regression was scored by two pathologists (K.S., D.G.) using both an established 5-point tumour regression grade (TRG), and a novel 3-point grade. Both scores were evaluated for interobserver variability. A complete or near-complete pathological response (3-point TRG 1) was found in 10 patients (17%). Using the 5-point TRG, there was good agreement between both pathologists (kappa = 0.64). Using the 3-point grade, agreement was excellent (kappa = 0.84). No disease recurrence has been reported in patients with a complete, or near complete pathological response (3-point TRG 1), after a mean follow-up of 22 months. CONCLUSION: Tumour regression grade is a useful method of scoring tumour response to chemoradiotherapy in rectal cancer. TRG 1 and 2 can be regarded as a complete pathological response (ypT0). A modified 3-point grade has the advantage of better reproducibility, with similar prognostic significance.     

HER2 as a limited predictor of the therapeutic response to neoadjuvant therapy in locally advanced rectal cancer

Human epidermal growth factor 2 (HER2) is a candidate therapeutic and prognostic marker for rectal cancer treated with neoadjuvant chemoradiotherapy. The specific frequency and prognostic role of HER2 protein expression and HER2 gene amplification in those rectal cancers has not been fully investigated. Pretreatment biopsied and surgically resected formalin-fixed paraffin-embedded tissues from 74 patients were retrospectively evaluated for HER2 protein expression and HER2 gene copy number using immunohistochemistry (IHC) and silver in situ hybridization (SISH), respectively. The tumor response to chemoradiation was evaluated with TNM staging and tumor regression grading (TRG) systems. Good response to chemoradiation therapy (TRG3), poor response (22 TRG1 and 19 TRG2), and TNM downstaging achieved in 33 (44.6%), 41 (55.4%), and 42 (56.8%) patients, respectively. The frequency of HER2 positivity is 17.6%, all of which were low-level HER2 gene amplification with 2.2 of median gene copy number ratio, detected in IHC0 (3/39), IHC1+ (2/18), IHC2+ (5/14) and IHC3+ (2/3). There was no association of HER2 positivity with clinicopathological parameters or survival. However, older age (≥61 years) and HER2 positivity were the independent predictive factors for non-down staging, while poorly differentiation and the papillary pattern were predictors for poor response. In multivariate analysis, good response proved as an only independent favorable prognostic factor affecting survivals. In conclusion, HER2 positivity may be predictive for a high-risk therapeutic resistance in rectal cancers. The discrepancy between IHC and gene amplification may result from the low-level amplification, which may explain lack of prognostic impact of HER2 positivity.     

A phase II study of oxaliplatin with 5-FU/folinic acid and concomitant radiotherapy as a preoperative treatment in patients with locally advanced rectal cancer

Objective:

To evaluate the activity and safety of adding oxaliplatin to a standard chemoradiotherapy schema, including 5-fluorouracil (5-FU)/folinic acid (FA), in locally-advanced rectal cancer (LARC).

Methods:

Two cycles of oxaliplatin 130 mg/m² plus FA 20 mg/m² bolus for 5 days and 5-FU 350 mg/m² continuous infusion for 5 days were given during week 1 and 4 of pelvic radiotherapy 46 Gy. Patients with a T3/4 and/or node-positive rectal tumour were eligible. Surgery was performed 4–6 weeks after radiotherapy. The primary endpoint was to determine the rate of pathological response. Secondary endpoints were to assess the rate of clinical response and the safety profile.

Results:

Between March 2005 and January 2009, a total of 35 patients were enrolled. The pathological down-staging rate was 79% with a pathological complete response rate of 17%. The overall clinical response rate (assessed by computed tomography or transrectal ultrasound) was 77%. Grade 3 diarrhoea and Grade 3 neutropaenia were reported in 14% and 11% of the patients, respectively. Eleven patients did not undergo surgery: four of them refused the operation, and seven patients were inoperable due to disease progression. In 24 patients who had surgery, a sphincter-preserving procedure could be performed in 29%. At the median follow-up time of 28.1 months, 25 patients (71%) survived with no evidence of disease.

Conclusion:

The promising results in terms of pathological response, and the associated good safety profile of a regimen of oxaliplatin plus 5-FU/FA with concomitant radiotherapy, suggest that the regimen could be used in LARC.     

新辅助放化疗间歇期巩固化疗对中低位局部进展期直肠癌的疗效及安全性

目的:探究新辅助放化疗间歇期巩固化疗对中低位局部进展期直肠癌的疗效及安全性.方法:回顾性分析2015年1月至2017年9月广西科技大学第二附属医院收治的64例中低位局部进展期直肠癌的临床资料.按新辅助治疗方案不同分为非巩固化疗组与巩固化疗组,每组32例.非巩固化疗组在行新辅助放化疗后6～8周进行手术治疗;巩固化疗组进行...     

Irreversible electroporation as treatment of locally advanced and as margin accentuation in borderline resectable pancreatic adenocarcinoma

In recent years, many local ablation technologies based on thermal damage have been used in the treatment of locally advanced pancreatic carcinoma (LAPC) and borderline resectable pancreatic carcinoma (BLRPC). However, they are associated with major complications because of possible vascular and ductal damage. Irreversible electroporation (IRE) is a nonthermal ablation technology that seems safe near vital vascular and ductal structures. IRE could be used as exclusive treatment of LAPC (en situ to IRE) after induction chemotherapy In BLRPC, surgery is not really radical in 6% of patients (microscopic residual) and local recurrences occur in 11–42% of apparent radical resections. IRE could be used as margin accentuation to increase posterior margin during radical surgery in BLRPC. Our outcomes are safety, time to progression. Secondary outcomes are overall survival, pain control and quality of life. We are performing a prospective evaluation of patients undergoing IRE for LAPC or BLRPC since July 2014. We have included patients with non-metastatic LAPC with maximum size ≤4 cm (en situ to IRE) and patients with BLRPC (complementary IRE). We have performed induction chemotherapy in both groups. After treatment, patients were evaluated on days 1, 2, 4, 7, 14, 21, 30, 60 and 90 with amylase and lipase serum and abdominal drainage test. Based on Ethics Committee’s request, follow-up imaging was performed at the 10th day for safety evaluation, at 30, 60 and 90 days for response evaluation and then every 3 months. Seven patients (two women and five men) underwent IRE. Two patients had LAPC and received en situ to IRE. In five patients affected by BLRPC we performed IRE and pancreatic head resection. In all patients, intraoperative imaging confirmed that the treatment of the whole tumor volume was complete. All seven patients demonstrated nonclinically relevant elevation of their amylase and lipase, which returned normal at 5 days postprocedure. No patient showed evidence of clinical pancreatitis or fistula. No major complications were recorded. Patients with LAPC died of distant metastases 6 month after treatment. At 3- and 6-month follow-up, all patients with BLPRC were alive and disease free. Only one patient has already reached 9-month follow-up and is alive and disease free. Our results are only preliminary. However, IRE ablation of LAPC and BLRPC seems a safe and feasible treatment.     

弥散峰度成像对局部进展期直肠癌新辅助放化疗疗效的评估价值

目的 探讨弥散峰度成像 (DKI) 定量参数和表观扩散系数(ADC)对局部进展期直肠癌患者新辅助放化疗疗效的应用价值。方法 回顾性分析。纳入2016年12月—2018年5月山西省肿瘤医院直肠癌患者108例,其中女42例、男86例,年龄42~81岁,均行新辅助放化疗,并于新辅助放化疗后4~8周接受手术治疗。根据病理结果按肿瘤退缩评级系统(TRG)进行评分分级,TRG1~2级为新辅助放化疗疗效好,TRG 3~5级为新辅助放化疗疗效差。然后利用Matlab软件测得两组治疗前后的平均弥散系数(MD)、平均峰度系数(MK)和ADC,并通过配对样本t检验、独立样本t检验、受试者操作特征(ROC)曲线和组内相关系数进行统计分析。结果 108例患者术后评估疗效好者27例(25%),其中肿瘤退缩分级评分(TRG)1级5例,TRG 2级22例;疗效差者81例(75%),其中TRG 3级41例,TRG 4级26例,TRG 5级12例。新辅助放化疗前,疗效好者ADC与MD值均低于疗效差者,MK值高于疗效差者,但差异均无统计学意义 (P值均＞0.05)。新辅助放化疗后,疗效好患者的MK值低于疗效差者,ADC与MD值显著高于疗效差者,差异均有统计学意义(P值均＜0.05),并且两组间的MD、ADC和MK比值比较差异均有统计学意义(P值均＜0.05)。ROC曲线结果提示,新辅助放化疗后的治疗后MK值较其他参数在评估新辅助放化疗疗效好的曲线下面积大(0.823),诊断效能最高,当其最佳阈值为0.635时,敏感度为76.5%,特异度为63.0%。结论 直肠癌DKI的MK、MD定量参数值和ADC值,尤其治疗后MK值,对于预测局部进展期直肠癌患者新辅助放化疗疗效有一定意义。     

Meta-analysis of FOLFIRINOX regimen as the first-line chemotherapy for locally advanced pancreatic cancer and borderline resectable pancreatic cancer

Clinical and Experimental Medicine - The study aimed to evaluate the effectiveness of the first-line chemotherapy FOLFIRINOX in treating pancreatic cancer. Pertinent studies were derived from the...     

Preoperative chemoradiotherapy in locally advanced rectal cancer: correlation of a gene expression-based response signature with recurrence

Preoperative chemoradiotherapy is recommended for locally advanced rectal cancer (UICC stage II/III). We recently demonstrated that responsive and nonresponsive tumors showed differential expression levels of 54 genes. In this follow-up study, we investigated the relationship between this gene set and disease-free (DFS) and overall survival (OS). Pretherapeutic biopsies from 30 participants in the CAO/ARO/AIO-94 trial of the German Rectal Cancer Study Group were analyzed using gene expression microarrays. Statistical analysis was performed to identify differentially expressed genes between recurrent and nonrecurrent tumors and to correlate these changes with disease recurrence and outcome. After a median follow-up of 59 months, seven of eight patients with recurrent disease was a nonresponder, and one responsive tumor recurred. Response to chemoradiotherapy was significantly correlated with an improved DFS (log rank P = 0.028), whereas OS did not differ significantly (P = 0.11). Applying a class comparison analysis, we identified 20 genes that were differentially expressed between recurrent and nonrecurrent tumors (P < 0.001). Analyzing the first two principal components of the 54 genes previously identified to predict response, we observed that this response signature correlated with an increased risk of cancer recurrence. These data suggest that the genetic basis of local response also affects the genetic basis of tumor recurrence. Genes that are indicative of nonresponse to preoperative chemoradiotherapy might also be linked to an increased risk of tumor recurrence.     

Apoptosis and tumor regression in locally advanced non-small cell lung cancer with neoadjuvant therapy

Dysregulation of apoptosis is closely associated with malignant cell transformation. On the other hand, apoptosis is induced by chemotherapy or irradiation. Therefore, in 54 patients with locally advanced non-small cell lung cancer (NSCLC, 36 squamous cell carcinomas, 18 adenocarcinomas, stage IIIA/IIIB), apoptotic indices were comparatively analysed before onset and after termination of neoadjuvant therapy. The results were compared with the response to neoadjuvant therapy (extent of therapy-induced tumour regression) as well as the survival times. A statistically significant difference could not be established between pre-therapeutically and post-surgically established apoptotic indices (mean values: 0.93% vs. 1.1%). Neither before therapy nor after surgery did the apoptotic indices show a significant predictive value concerning different overall survival times. These results suggest that neoadjuvant therapy does not modify the extent of apoptosis in lung cancer in the long term. Only a few weeks after the completion of the neoadjuvant chemoradiotherapy this contributes to a net proliferation of the residual tumour tissue which is largely equivalent to that of the untreated tumour.     

同步推量加速调强放疗联合化疗治疗局部晚期非小细胞肺癌的前瞻性研究

目的:评估同步推量加速调强放疗联合化疗治疗局部晚期非小细胞肺癌的疗效和安全性。方法:采用同步推量加速调强放疗技术联合紫杉醇和卡铂同步化疗对48例新诊断Ⅲ期局部晚期非小细胞肺癌患者进行治疗;处方剂量包括肺部原发灶PTV1为69 Gy（2.3 Gy/F）,转移淋巴结PTV2为64 Gy（2.13 Gy/F）,亚临床病灶PTV3为60 Gy（2.0 Gy/F）。对放疗计划进行剂量学分析,并观察分析生存期、无进展生存期、客观缓解率和急性毒性反应。结果:48例患者均完成放化疗,PTV1、PTV2、PTV3的Dmean分别为（70.3±2.4）、（66.5±2.1）、（64.5±3.1） Gy。中位生存期为22.0个月,中位无进展生存期为17.0个月,客观缓解率为72.9%,1年生存率为78.7%,2年生存率为45.8%;未发现严重食管炎、肺炎和心脏毒性。结论:同步推量加速调强放疗技术联合化疗治疗局部晚期非小细胞肺癌是可行的,急性毒性反应可控,但仍需要进一步的随访评估远期毒性。     

Detection of circulating tumour DNA after neoadjuvant chemoradiotherapy in patients with locally advanced oesophageal cancer

Active surveillance instead of standard surgery after neoadjuvant chemoradiotherapy (nCRT) has been proposed for patients with oesophageal cancer. Circulating tumour DNA (ctDNA) may be used to facilitate selection of patients for surgery. We show that detection of ctDNA after nCRT seems highly suggestive of major residual disease. Tumour biopsies and blood samples were taken before, and 6 and 12 weeks after, nCRT. Biopsies were analysed with regular targeted next-generation sequencing (NGS). Circulating cell-free DNA (cfDNA) was analysed using targeted NGS with unique molecular identifiers and digital polymerase chain reaction. cfDNA mutations matching pre-treatment biopsy mutations confirmed the presence of ctDNA. In total, 31 patients were included, of whom 24 had a biopsy mutation that was potentially detectable in cfDNA (77%). Pre-treatment ctDNA was detected in nine of 24 patients (38%), four of whom had incurable disease progression before surgery. Pre-treatment ctDNA detection had a sensitivity of 47% (95% CI 24–71) (8/17), specificity of 85% (95% CI 42–99) (6/7), positive predictive value (PPV) of 89% (95% CI 51–99) (8/9), and negative predictive value (NPV) of 40% (95% CI 17–67) (6/15) for detecting major residual disease (>10% residue in the resection specimen or progression before surgery). After nCRT, ctDNA was detected in three patients, two of whom had disease progression. Post-nCRT ctDNA detection had a sensitivity of 21% (95% CI 6–51) (3/14), specificity of 100% (95% CI 56–100) (7/7), PPV of 100% (95% CI 31–100) (3/3), and NPV of 39% (95% CI 18–64) (7/18) for detecting major residual disease. The addition of ctDNA to the current set of diagnostics did not lead to more patients being clinically identified with residual disease. These results indicate that pre-treatment and post-nCRT ctDNA detection may be useful in identifying patients at high risk of disease progression. The addition of ctDNA analysis to the current set of diagnostic modalities may not improve detection of residual disease after nCRT. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.     

Predictive factors in locally advanced rectal cancer treated with preoperative hyperfractionated and accelerated radiotherapy

This study examines the prognostic significance of pathologic factors in patients with primary locally advanced rectal cancer treated prospectively with preoperative radiotherapy. From 1992 to 1998, 104 patients with rectal cancer of grades T3 or T4 and any N underwent preoperative radiotherapy followed by surgical resection. Survival curves were estimated according to the Kaplan-Meier method. Correlation of outcome with clinicopathologic variables (pathologic tumor and lymph node staging, histology, radial resection margin [RRM], clearance, vessel involvement, and tumor regression grade [TRG], quantitated in 5 grades) was evaluated using the Cox proportional hazards model. None of the patients achieved a histologically confirmed complete pathologic response, but 79% of the patients showed partial tumor regression (TRG2-4) and 21% did not show any tumor regression (TRG5). Among the tumors, 22% were of a mucinous type. The RRM was free of tumor in 76% of the surgical specimens. The median clearance was 2 mm. Vascular invasion was present in 37 cases (36%). In the univariate analysis, lymph node metastases, absence of tumor regression, positive RRM, and vascular invasion were correlated with adverse overall survival and disease-free survival; absence of tumor regression, positive RRM, and clearance <2 mm were correlated with local recurrences; and advanced pT stage was correlated only with disease-free survival. However, in the multivariate analysis, only lymph node metastases and RRM were independent prognostic factors for overall survival and disease-free survival, and clearance <2 mm was an independent prognostic factor for local control. Pathologic parameters remain strong determinants of local recurrence and survival in locally advanced rectal cancer, treated preoperatively with hyperfractionated and accelerated radiotherapy. We show that patients with advanced pT, positive lymph nodes, vascular invasion, positive RRM, clearance <2 mm, or absence of tumor regression are known to have poor clinical outcome.     

4种生物学因子对局部晚期乳腺癌新辅助化疗疗效评估的价值

目的 探讨p53、ki67、nm23、表皮生长因子受体(EGFR)在局部晚期乳腺癌新辅助化疗疗效评估中的价值。 方法 选取2013年1月1日~2018年3月31日我院收治的局部晚期乳腺癌患者98例，检测新辅助化疗前后p53、ki67、nm23、EGFR的变化及其与临床疗效的关系。 结果 化疗后的p53、ki67、EGFR阳性表达均较化疗前降低，nm23阳性表达均较化疗前升高，差异均有统计学意义（P<0.05）。p53阳性者的有效率低于阴性者，差异有统计学意义（P<0.05）；ki67、nm23阳性者的有效率均高于阴性者，差异均有统计学意义（P<0.05）；EGFR阳性者与阴性者的有效率差异无统计学意义（P>0.05）。 结论 新辅助化疗能够显著改善局部晚期乳腺癌患者生物学因子p53、ki67、EGFR、nm23的表达，同时p53、ki67、nm23对评估化疗疗效具有一定价值。     

Integrated genomic profiling identifies microRNA‐92a regulation of IQGAP2 in locally advanced rectal cancer

Locally advanced rectal cancer (LARC) is treated with chemoradiation prior to surgical excision, leaving residual tumors altered or completely absent. Integrating layers of genomic profiling might identify regulatory pathways relevant to rectal tumorigenesis and inform therapeutic decisions and further research. We utilized formalin‐fixed, paraffin‐embedded pre‐treatment LARC biopsies (n=138) and compared copy number, mRNA, and miRNA expression with matched normal rectal mucosa. An integrative model was used to predict regulatory interactions to explain gene expression changes. These predictions were evaluated in vitro using multiple colorectal cancer cell lines. The Cancer Genome Atlas (TCGA) was also used as an external cohort to validate our genomic profiling and predictions. We found differentially expressed mRNAs and miRNAs that characterize LARC. Our integrative model predicted the upregulation of miR‐92a, miR‐182, and miR‐221 expression to be associated with downregulation of their target genes after adjusting for the effect of copy number alterations. Cell line studies using miR‐92a mimics and inhibitors demonstrate that miR‐92a expression regulates IQGAP2 expression. We show that endogenous miR‐92a expression is inversely associated with endogenous KLF4 expression in multiple cell lines, and that this relationship is also present in rectal cancers of TCGA. Our integrative model predicted regulators of gene expression change in LARC using pre‐treatment FFPE tissues. Our methodology implicated multiple regulatory interactions, some of which are corroborated by independent lines of study, while others indicate new opportunities for investigation. © 2016 Wiley Periodicals, Inc.     

Hypofractionated radiotherapy as local hemostatic agent in advanced cancer

Purpose:

Tumor bleeding continues to remain a challenge in an oncological setting, and radiotherapy has been studied as a local hemostatic agent. We studied the role of local radiotherapy in controlling bleeding at our center.

Materials and Methods:

We reviewed 25 treated cases (cancer urinary bladder: 12, lung cancer: 5, cervical cancer: 4, uterine cancer: 1, rectal cancer: 2, schwanoma: 1) at our center from March 2008 to December 2010. All patients had either an advanced or recurrent disease. Radiotherapy schedule was either 20 Gray in 5 fractions or 15 Gray in 5 fractions and was delivered with Cobalt 60.

Results and Conclusion:

Of 25 patients, 22 (88%) responded, and there was complete cessation of bleeding. Both 15 Gray and 20 Gray dose schedule had equal efficacy. Treatment was well tolerated without any intermission. Radiotherapy is a safe and effective option in controlling tumor bleeding.     

Survival benefits of neoadjuvant chemotherapy followed by radical surgery versus radiotherapy in locally advanced chemoresistant cervical cancer

The aim of this study was to analyze long-term survivals in patients with stage IB to IIA cervical cancer treated by neoadjuvant chemotherapy setting. Between February 1989 and January 1998, 94 women with previously untreated stage IB to IIA carcinoma of the uterine cervix who received cisplatin based neoadjuvant chemotherapy were enrolled in this study. All of patients with chemoresponse (complete response, n=15; partial response, n=47) and 16 patients with chemoresistance received radical surgery (RS group). The other 16 patients with chemoresistance received radiotherapy for definite treatment (RT group). In the RS group, the 10 yr survival estimation in patients with bulky tumors (diameter > or =4 cm, n=26) was similar to that with non-bulky tumors (83.3% vs. 89.3%, p=NS). In selected patients with chemoresistance, those treated by radiotherapy (n=16) showed significantly poorer survivals than those treated by radical surgery (n=16) (10 yr survival rates of RT (25%) vs. RS (76.4%), p=0.0111). Our results support that a possible therapeutic benefit of neoadjuvant chemotherapy plus radical surgery is only in patients with bulky stage IB to IIA cervical cancer. In cases of chemoresistance, radical surgery might be a better definite treatment option.