Gene polymorphisms predict toxicity to neoadjuvant therapy in patients with rectal cancer

BACKGROUND

Toxicity from neoadjuvant chemoradiation therapy (NT) increases morbidity and limits therapeutic efficacy in patients with rectal cancer. The objective of this study was to determine whether specific polymorphisms in genes associated with rectal cancer response to NT were correlated with NT‐related toxicity.

METHODS

One hundred thirty‐two patients with locally advanced rectal cancer received NT followed by surgery. All patients received 5‐fluorouracil (5‐FU) and radiation (RT), and 80 patients also received modified infusional 5‐FU, folinic acid, and oxaliplatin chemotherapy (mFOLFOX‐6). Grade ≥3 adverse events (AEs) that occurred during 5‐FU/RT and during combined 5‐FU/RT + mFOLFOX‐6 were recorded. Pretreatment biopsy specimens and normal rectal tissues were collected from all patients. DNA was extracted and screened for 22 polymorphisms in 17 genes that have been associated with response to NT. Polymorphisms were correlated with treatment‐related grade ≥3 AEs.

RESULTS

Overall, 27 of 132 patients (20%) had grade ≥3 AEs; 18 patients had a complication associated only with 5‐FU/RT, 3 patients experienced toxicity only during mFOLFOX‐6, and 6 patients had grade ≥3 AEs associated with both treatments before surgery. Polymorphisms in the genes x‐ray repair complementing defective repair in Chinese hamster cells 1 (XRCC1), xeroderma pigmentosum group D (XPD), and tumor protein 53 (TP53) were associated with grade ≥3 AEs during NT (P < .05). Specifically, 2 polymorphisms—an arginine‐to‐glutamine substitution at codon 399 (Q399R) in XRCC1 and a lysine‐to‐glutamine substitution at codon 751 (K751Q) in XPD—were associated with increased toxicity to 5‐FU/RT (P < .05), and an arginine‐to‐proline substitution at codon 72 (R72P) in TP53 was associated with increased toxicity to mFOLFOX‐6 (P = .008).

CONCLUSIONS

Specific polymorphisms in XRCC1, XPD, and TP53 were associated with increased toxicity to NT in patients with rectal cancer. The current results indicated that polymorphism screening may help tailor treatment for patients by selecting therapies with the lowest risk of toxicity, thus increasing patient compliance. Cancer 2013. © 2012 American Cancer Society.     

全程新辅助治疗在直肠癌治疗中的意义

跟随时代变迁的脚步,结直肠癌（CRC）的发病率呈现出多差异性和新龄化。在CRC总发病率中直肠癌占比约1/2,且绝大数患者初诊时多为局部晚期直肠癌（LARC）。术前放化疗（NCRT）联合全直肠系膜切除术（TME）+辅助化疗（ACT）是LARC标准治疗方案,这种诊疗模式使局部复发率有了可观的控制。然而,远处转移仍是这部分患者死亡的重要原因。NCRT和术后辅助化疗在临床上虽被普遍推荐,但由于依从性差和生存率不一,ACT这一全身治疗的价值仍是个谜团。因此,目前大量全球试验的研究主题偏向于直肠癌术前化疗的潜力,其中全程新辅助治疗（TNT）就应时而生。该模式体现了新辅助化疗具有更优的病理缓解率（pCR）、降期率、安全性等优势。     

直肠癌的新辅助治疗

近年来,直肠癌发病率逐年上升,随着新辅助治疗的提出与应用,直肠癌的疗效得到提升,引起国内外学者的关注。新辅助治疗包括术前放疗、术前化疗和术前同步放化疗。其中术前放疗方式可分为短程放疗和常规放疗,通过比较T降期率、保肛率、完全缓解率等指标,对两种方式的临床效果进行了评价。尽管单纯术前化疗的经验还不够丰富,但其仍在降低肿瘤分期等方面具有优势。目前,临床应用最多的为术前同步放化疗,且国内外学者均认为该方式在治疗直肠癌时具有明显优势,同时,三维放疗技术可使靶区分布更为均匀,对病灶治疗更为精准。但直肠癌的新辅助治疗在国内却尚未广泛应用于临床,对其临床效果的确定仍需进一步的理论支持,本文就直肠癌的新辅助治疗做一综述。     

直肠癌新辅助治疗进展

近年来新辅助治疗已成为局部晚期中低位直肠癌的标准治疗,目前常用的方案为长程同步放化疗与短程放疗。全新辅助治疗也是可行的新辅助治疗方案,临床完全缓解后等待观察的临床研究也在进行中。本文就直肠癌新辅助治疗的现状与研究进展进行综述。     

Association of beclin 1 expression with response to neoadjuvant chemoradiation therapy in patients with locally advanced rectal carcinoma

Beclin 1 is an essential regulator of autophagy that is induced in response to cellular stress and serves to maintain cell survival in established tumors. We recently demonstrated that Beclin 1 suppression can sensitize colorectal cancer cells to radiation‐induced DNA damage and apoptosis. Therefore, we hypothesized that the level of Beclin 1 expression may be associated with radiation sensitivity in vivo. We determined the association of Beclin 1 expression in pretreatment rectal cancer tissues with response to neoadjuvant chemoradiation in surgical resection specimens. Stages II and III (n = 96) rectal adenocarcinoma patients were treated with neoadjuvant chemoradiation followed by surgical resection with curative intent. Beclin 1 was analyzed by immunohistochemistry and the expression level was dichotomized at the median value with categorization into low and high groups. We identified 56 (58.3%) and 40 (41.7%) patients whose tumors had high‐ versus low‐level Beclin 1 expression, respectively. Rectal cancers with high versus low Beclin 1 expression were significantly less likely to be downstaged after chemoradiation treatment (45% [25/55] vs. 58% [22/38]; p = 0.02). In a multivariable analysis adjusted for age, sex, histological grade and baseline tumor node metastasis (TNM) stage, the impact of Beclin 1 expression on tumor downstaging remained statistically significant (p = 0.03). The association of the level of Beclin 1 expression with the rate of tumor downstaging after chemoradiation is consistent with in vitro data, and suggests that Beclin 1 may be a predictive biomarker for the efficacy of chemoradiation in patients with rectal cancer.     

直肠癌的辅助放化疗的临床研究

直肠癌是常见的消化道恶性肿瘤，手术是直肠癌的主要治疗手段，放化疗对可手术直肠癌是重要的辅助治疗手段。无论术前或术后放疗均可提高局部控制，术前放疗可增加保肛的机率，放疗的方式以常规分割较佳。术后放疗在中度复发危险的患者中对生存的影响与化疗相似，但需要两者对局控的资料。本文综述的是术前放疗、术后放疔以及术前与术后放疗的比较。     

Total neoadjuvant therapy for rectal cancer

While outcomes for patients with locally advanced disease have improved considerably with combined modality therapy, there is now an emphasis on developing risk-adapted treatment strategies. Moreover, the primary cause of death from locally advanced rectal cancer is related to distant progression, which now exceeds the rate of local failure. Thus, the necessity to optimally address micrometastatic disease has led to increasing interest in delivering chemotherapy in the neoadjuvant setting rather than in the postoperative setting. This review critically appraises the emerging literature on the options for sequencing of therapy, focusing on the total neoadjuvant therapy paradigm as well as emerging options for omitting components of multimodality therapy.     

Inflammatory fibroblasts mediate resistance to neoadjuvant therapy in rectal cancer

1. Download : Download high-res image (242KB)
2. Download : Download full-size image

     

Neorectal hyposensitivity after neoadjuvant therapy for rectal cancer

Background and purpose

Preoperative radiotherapy for rectal cancer has a detrimental effect on long-term anorectal function and quality of life, additional to that observed after rectal resection. The exact physiological mechanisms for the excess impairment remain unknown. We aimed to investigate neorectal and anal sphincter properties in patients treated with neoadjuvant therapy (NT) prior to total mesorectal excision (TME).

Material and methods

Sixteen patients (NT+ patients) were examined by multimodal neorectal stimulation and standard anorectal physiological testing. Data were compared to the results of 23 patients, who underwent TME without NT (NT− patients).

Results

NT+ patients had elevated sensory thresholds to heat (median temperature, 60 vs. 55 °C; p < 0.01) and mechanical distension (median tension, 2513 vs. 1521 mmHg mm; p = 0.05) in the fasting state, and altered perception of the sensory response to heat (p = 0.01) and cold (p = 0.01) compared to NT− patients. No differences in the biomechanical properties of the neorectal wall were detected. Anal resting pressure was lower in NT+ patients compared to NT− patients (median pressure, 31 vs. 45 cm H₂O; p = 0.05).

Conclusions

Pelvic radiotherapy causes neorectal hyposensitivity to mechanical and thermal stimuli in patients receiving NT prior to TME surgery for rectal cancer, possibly due to impaired afferent nerve function.     

直肠癌新辅助治疗后临床完全缓解的评估

新辅助治疗已成为局部晚期直肠癌的标准治疗模式。新辅助治疗后对肿瘤反应进行评估及再分期对于制定患者后续的治疗策略和预测肿瘤的预后至关重要。有一部分患者在新辅助治疗后能达到临床完全缓解甚至病理完全缓解,而在病理未明确之前如何评估临床缓解一直是目前国内外专家关注的焦点。本文就直肠癌新辅助治疗后的最佳评估时间和评估方法的进展进行综述。     

术前同步放化疗在局部晚期直肠癌治疗中的价值

目的 探讨术前放化疗联合手术治疗局部晚期直肠癌的临床价值。方法 对22 例术前应用放疗（剂量45Gy/5周）和mFOLFOX 方案（奥沙利铂130mg/m2,dl,静脉滴注;甲酞四氢叶酸钙200mg, dl～d3,静脉滴注;氟尿嘧啶500mg/m2, dl～d3,静脉滴注;每3 周重复,共行2 个周期）进行新辅助治疗的局部晚期直肠癌患者资料进行分析。结果 低位前切除术16 例,保肛率72.7%,腹会阴联合切除6例。肿瘤完全消退3例（13.6 %),肿瘤部分缓解10例（45.5%),治疗有效率为59.1% (13/22。肿瘤分期降低13例,降期率为59.1％。结论 对局部晚期直肠癌采用新辅助治疗可使肿瘤不同程度消退,分期降低,提高保肛率。     

新辅助放化疗后低位直肠癌术后吻合口漏危险因素分析

目的:探讨接受新辅助放化疗的患者行腹腔镜直肠癌低位前切除术(low anterior resection,LAR)术后发生吻合口漏的危险因素.方法:采用回顾性病例对照研究方法.收集2010年01月至2019年12月南通大学附属东台医院、苏州大学附属第一医院收治的146例cT3-4期和(或)N1-2期低位直肠癌患者临床资...     

新辅助治疗在进展期低位直肠癌术前的应用

背景与目的提高进展期低位直肠癌的根切率和保肛率是一个难题,本研究探讨术前联合放化疗(新辅助治疗)在进展期低位直肠癌中的疗效。方法23例进展期低位直肠癌患者,按术前评价均需行腹-会阴联合切除术的患者进行术前联合放化疗。放疗每周5d,每次200cGy,共4周20次,总剂量4000cGy。化疗的给药方式以放疗期间持续静脉滴注,采用草酸铂(Oxa)130mg/(m2·d1),5-FU500mg/(m2·d1-5),加CF300mg/(m2·d1-5),休息4~6周进行手术。结果15例的病例肿瘤分期降级,施行了保留肛门的直肠癌根治术,保肛率达65%(15/23),其中82%的患者肛门括约肌功能良好。结论进展期低位直肠癌的患者在接受新辅助治疗后,能使肿瘤降期,切除率增加,提高保肛率,同时副反应轻,患者依顺性较好。     

同步放化疗治疗肛门癌

手术曾经是肛门癌的治愈手段,但是不能保留患者的肛门功能.多项Ⅲ期前瞻性随机分组研究表明,同步放化疗可以取得与手术相同的疗效,同时保留了患者的肛门功能,提高了生活质量,成为肛门癌的标准治疗手段.目前更深入的前瞻性随机分组研究正在进行,旨在探讨以铂为主的同步放化的疗疗效和新辅助化疗在肛门癌治疗中的作用.     

Patient‐derived organoids as a preclinical platform for precision medicine in colorectal cancer

Patient‐derived organoids are being considered as models that can help guide personalized therapy through in vitro anticancer drug response evaluation. However, attempts to quantify in vitro drug responses in organoids and compare them with responses in matched patients remain inadequate. In this study, we investigated whether drug responses of organoids correlate with clinical responses of matched patients and disease progression of patients. Organoids were established from 54 patients with colorectal cancer who (except for one patient) did not receive any form of therapy before, and tumor organoids were assessed through whole‐exome sequencing. For comparisons of in vitro drug responses in matched patients, we developed an ‘organoid score’ based on the variable anticancer treatment responses observed in organoids. Very interestingly, a higher organoid score was significantly correlated with a lower tumor regression rate after the standard‐of‐care treatment in matched patients. Additionally, we confirmed that patients with a higher organoid score (≥ 2.5) had poorer progression‐free survival compared with those with a lower organoid score (< 2.5). Furthermore, to assess potential drug repurposing using an FDA‐approved drug library, ten tumor organoids derived from patients with disease progression were applied to a simulation platform. Taken together, organoids and organoid scores can facilitate the prediction of anticancer therapy efficacy, and they can be used as a simulation model to determine the next therapeutic options through drug screening. Organoids will be an attractive platform to enable the implementation of personalized therapy for colorectal cancer patients.