Development and validation of an MRI-based model to predict response to chemoradiotherapy for rectal cancer

Background and purpose

To safely implement organ preserving treatment strategies for patients with rectal cancer, well-considered selection of patients with favourable response is needed. In this study, we develop and validate an MRI-based response predicting model.

局部晚期直肠癌术前短程放疗的研究进展

术前放疗提高了局部晚期直肠癌的局部控制率,可以采用常规分割同步化疗的长程方案,也可行25 Gy／5次短程放疗。前者肿瘤反应率高;后者毒副反应低,耐受性好。二者局部控制率无差异,均好于单独手术,但总生存率未见提高。短程放疗延期4～8周后手术较7天内手术提高了肿瘤反应率。近期研究又发现短程放疗联合新辅助化疗并延期手术,进一步提高了肿瘤的完全缓解率,甚至有超过长程同步放化疗的趋势,局部控制率亦不劣于长程。但是否可降低远处转移率,提高总生存率还有待长期研究。     

同期放化疗治疗局部晚期不可手术的直肠癌近期疗效观察

目的：观察同期放化疗治疗局部晚期不可手术的直肠癌患者的近期疗效及耐受性。方法：３８例经病理证实的局部晚期或局部 区域复发的直肠癌患者接受全盆腔三维适形放疗ＤＴ４６～５０Ｇｙ／２３～２５ｆ,后缩野至肿瘤区继续推量至ＤＴ６４～６６Ｇｙ／３２～３３ｆ,同期接受奥沙利铂１３０ｍｇ／ｍ^２ｄ_１,氟尿嘧啶３５０ｍｇ／ｍ^２ｄ_１～ｄ_５,甲酰四氢叶酸２００ｍｇ／ｍ^２ｄ_１～ｄ_５,４周为１周期,共２个周期。结果：获ＣＲ７例（１９.４％）,ＰＲ１６例（４４.４％）,ＳＤ６例（１６.７％）,ＰＤ７例（１９.４％）,总有效率（ＣＲ＋ＰＲ）为６３.９％;疼痛症状缓解率为１００％;全身状况好转率７２.２％;中位生存时间为２２个月,１年和２年总生存率分别为６７.７％和２１.３％。治疗相关的毒副反应以中性粒细胞减少、腹泻、恶心呕吐以及周围神经毒性反应为主,其３级毒副反应的发生率分别为１９.４％、１６.７％、１３.９％和１１.１％,均无３级以上毒副反应发生。结论：以奥沙利铂为基础的化疗同期联合放疗对局部晚期不可手术直肠癌患者具有较好的姑息治疗作用,其治疗依从性高,治疗相关毒性可以接受,值得临床进一步推广。     

Advances in organ preserving strategies in rectal cancer patients

Treatment of rectal cancer patients has been subjected to change over the past thirty years. Total mesorectal excision is considered the cornerstone of rectal cancer treatment, but is also associated with significant morbidity resulting in an impaired quality of life. The addition of neoadjuvant chemoradiotherapy to surgery has shown to improve survival and local control and may lead to a partial or even complete response (CR). This raises questions regarding the necessity for subsequent radical surgery. After careful patient selection local excision and wait-and-see approaches are explored, aiming to improve quality of life without compromising oncological outcome. A multimodality diagnostic approach for optimal staging is crucial in determining the appropriate neoadjuvant treatment regimen. Adequate endoscopic restaging of rectal tumours after multimodality treatment will aid in selecting patients who are eligible for an organ preserving approach. The role and accuracy of imaging in the detection of the primary tumour, residual rectal cancer or local recurrence seems vital. Alternative neoadjuvant regimens are currently explored to increase the rate of clinical CRs, which may support organ preserving approaches. This review aims to generate insight into the advances in diagnostics and treatment modalities in all stages of rectal cancer and will highlight future studies that may support further implementation of organ preservation treatment in rectal cancer.     

Neoadjuvant chemoradiotherapy for locally advanced rectal cancer: The debate continues

Rectal carcinoma represents the 30% of all colorectal cancers, with about 40000 new cases/years. In the past two decades, the management of rectal cancer has made important progress, highlighting the main role of a multimodality strategy approach, combining surgery, radiation therapy and chemotherapy. Nowadays, surgery remains the primary treatment and neo-adjuvant chemoradiotherapy, based on fluoropyrimidine (5-FU) continuous infusion, is considered the standard in locally advanced rectal carcinoma. The aim is to reduce the incidence of local recurrence and to perform a conservative surgery. To improve these purposes different drugs combination have been tested in the neo-adjuvant setting. At American Society of Clinical Oncology 2014 an important abstract was presented focusing on the role of adding oxaliplatin to concomitant treatment, in patients with locally advanced rectal carcinoma. Rodel et al reported on the CAO/ARO/AIO-04 randomized phase III trial that compared standard treatment with 5-FU and radiation therapy, to oxaliplatin plus 5-FU in association with radiation therapy. The addition of oxaliplatin to the neo-adjuvant treatment has been shown to improve disease-free survival from 71.2% to 75.9% (P = 0.03). This editorial was planned to clarify the optimal treatment in patients with locally advanced rectal cancer, considering the results from CAO/ARO/AIO-04 study.     

Phase I-II trial of cetuximab, capecitabine, oxaliplatin, and radiotherapy as preoperative treatment in rectal cancer

PURPOSE: To evaluate the safety and activity of preoperative radiotherapy (RT) with concurrent cetuximab, capecitabine, and oxaliplatin in rectal cancer patients. PATIENTS AND METHODS: A total of 60 patients with rectal cancer (T3-T4 or N+, M1 allowed) entered the trial at five investigator sites; the data from 58 patients were assessable. Cetuximab was given as an initial dose of 400 mg/m2 7 days before the start of RT, and then at 250 mg/m2 once weekly during RT (50.4 Gy in 28 fractions). Capecitabine and oxaliplatin were administered according to an established schedule of oxaliplatin (50 mg/m2 on Days 1, 8, 22, and 29) and capecitabine (Days 1-14 and 22-35) at three dose levels: 1,000, 1,300, and 1,650 mg/m2/d during the Phase I part of the study. The main endpoint of the Phase II was the pathologic complete response rate. RESULTS: Thirteen patients were included in the Phase I part of the study, and the maximal tolerated dose was not reached. Overall, 48 patients were treated at the recommended dose of capecitabine (1,650 mg/m2) and 45 patients (94%) underwent surgery. A pathologic complete response was observed in 4 patients (9%), and moderate (n=12), minimal (n=10), and no tumor regression (n=2) was noted in 24 (53%) of 45 patients. The mean radiation dose intensity, cetuximab, capecitabine, oxaliplatin was 98%, 95%, 94%, and 94%, respectively. The incidence of Grade 3-4 diarrhea was restricted to 19%. Postoperative complications of any grade occurred in 33% of patients. CONCLUSIONS: The results of our study have shown that cetuximab can be combined safely with capecitabine and oxaliplatin plus RT. The low pathologic complete response rate achieved should stimulate additional preclinical investigations to establish the best sequence of triple combinations.     

ctDNA on liquid biopsy for predicting response and prognosis in locally advanced rectal cancer: A systematic review

BackgroundThe management of locally advanced rectal cancer (LARC) requires a multidisciplinary approach, with an increasing interest for non-operative strategies. Liquid biopsy for obtaining circulating tumor DNA (ctDNA) can provide information on neoadjuvant chemoradiotherapy (nCRT) pathological response and cancer-specific prognosis, and therefore might be a promising guide for these treatments.MethodsA systematic review of the studies available in literature has been performed to assess the role of ctDNA as a predictive and prognostic biomarker in LARC patients.ResultsWe retrieved 21 publications, of which 17 full-text articles and 4 abstracts. Results have been labelled into two groups: predictive and prognostic. Data about the usefulness of liquid biopsy in this setting is still inconclusive. However, baseline higher levels of longer fragments of cell-free DNA and integrity index, tumor-specific mutations and certain methylated genes could predict non-responders. Also, undetectable baseline ctDNA and decrease of common rectal cancer mutations throughout treatment (dynamic monitoring) were predictive factors of pathological complete response. The continuous detection of ctDNA in different timepoints of treatment (minimal residual disease) was consistently associated with worse prognosis.ConclusionsctDNA is a promising biomarker that could assist predicting treatment response to nCRT and prognosis in patients with LARC. The ideal methods and timings for the liquid biopsy still have to be defined.     

Short-course preoperative radiotherapy with immediate surgery versus long-course chemoradiation with delayed surgery in the treatment of rectal cancer: A systematic review and meta-analysis

BackgroundLong-course chemoradiotherapy (LCRT) with delayed surgery or short-course radiotherapy (SCRT) with immediate surgery is probably the most frequent regimen in the treatment of rectal cancer. Debate is still going on whether SCRT or LCRT is more effective. So we performed this meta-analysis to evaluate the safety and efficacy of SCRT with immediate surgery versus LCRT with delayed surgery for the management of rectal cancer.MethodsLiterature were searched from PubMed, Embase, Web of science, Cochrane Library up to May, 2014. Quality of the randomized controlled trials (RCTs) was evaluated according to the Cochrane's risk of bias tool of RCT. RevMan 5.3 was used for statistical analysis. Pooled risk ratio (RR) and 95% confidence interval (CI) were calculated. Subgroup analysis and sensitivity analysis were employed to explore heterogeneity.Results16 trials were included in the qualitative systematic review. 12 trials were included in meta-analyses. 4 of them were RCTs; other 8 were non-RCTs. Meta-analysis demonstrated that there were no significant differences in overall survival (OS), disease free survival (DFS), local recurrence rate (LRR), distant metastasis rate (DMR), sphincter preservation rate, R0 resection rate and late toxicity. Compared with SCRT, LCRT obviously increased pCR rate [RR = 0.15, 95%CI (0.08, 0.28), P = 0.003], while LCRT obviously increased the grade 3–4 acute toxicity [RR = 0.13, 95%CI (0.06, 0.28), P < 0.00001].ConclusionsSCRT with immediate surgery is as effective as LCRT with delayed surgery for treatment of rectal cancer in terms of OS, DFS, LRR, DMR, Sphincter preservation rate, R0 resection rate and late toxicity. Though LCRT increased pCR rate, LCRT also increased acute toxicity compared with SCRT. SCRT is a better choice in centers with a long waiting list or lack of medical resources.     

Multicenter study of surgical and oncologic outcomes of extra-levator versus conventional abdominoperineal excision for lower rectal cancer

BackgroundThe surgical and oncological outcome of extra-levator abdominoperineal excision (ELAPE) procedure remains unclear in low rectal cancer.MethodsA total of 194 cases of rectal cancer patients underwent ELAPE or conventional abdominoperineal excision (APE) procedure were analyzed in four hospitals’ databases from January 2010 to December 2015. Clinicopathological data, overall survival (OS), disease free survival (DFS) and local recurrence free survival (LRFS) of patients were compared between two groups.ResultsThe operation time spent in perineal phase was significantly shorter in the ELAPE group than that in conventional APE procedure (P < 0.001). There were more specimens with excellent or good quality in ELAPE group compared to conventional APE group (P = 0.033). Patients whom underwent ELAPE procedures showed significantly better OS, DFS and LRFS than those underwent conventional APE procedures. Patients with preoperative stage cT3∼T4 (P = 0.033, P = 0.008, P = 0,033), cN+ (P = 0.002, P < 0.001, P = 0.006) and pathological stage III-IV (P = 0.023, P = 0.008, P = 0.016) were associated with significant benefits from ELAPE procedure in terms of OS, DFS and LRFS. DFS differed significantly between two groups of patients whom got preoperative chemoradiation therapy (P = 0.009) or postoperative chemotherapy (P = 0.029). For patients of pathological stage IIII-IV without preoperative chemoradiation, ELAPE procedures resulted in statistically better OS (P = 0.018) and DFS (P = 0.030). ELAPE procedure was an independent risk factor of OS, DFS and LRFS in multivariate analysis.ConclusionLow rectal cancer patients might benefit from ELAPE procedure on both surgical and oncological outcomes, especially in patients with relatively advanced tumors, inspite of the effects of pre-operative radio- and chemotherapy.     

Blood biomarkers are helpful in the prediction of response to chemoradiation in rectal cancer: A prospective,hypothesis driven study on patients with locally advanced rectal cancer

Purpose/objective

Chemoradiation (CRT) has been shown to lead to downsizing of an important portion of rectal cancers. In order to tailor treatment at an earlier stage during treatment, predictive models are being developed. Adding blood biomarkers may be attractive for prediction, as they can be collected very easily and determined with excellent reproducibility in clinical practice. The hypothesis of this study was that blood biomarkers related to tumor load, hypoxia and inflammation can help to predict response to CRT in rectal cancer.

Material/methods

295 patients with locally advanced rectal cancer who were planned to undergo CRT were prospectively entered into a biobank protocol (NCT01067872). Blood samples were drawn before start of CRT. Nine biomarkers were selected, based on a previously defined hypothesis, and measured in a standardized way by a certified lab: CEA, CA19-9, LDH, CRP, IL-6, IL-8, CA IX, osteopontin and 25-OH-vitamin D. Outcome was analyzed in two ways: pCR vs. non-pCR and responders (defined as ypT0-2N0) vs. non-responders (all other ypTN stages).

Results

276 patients could be analyzed. 20.7% developed a pCR and 47.1% were classified as responders. In univariate analysis CEA (p = 0.001) and osteopontin (p = 0.012) were significant predictors for pCR. Taking response as outcome CEA (p < 0.001), IL-8 (p < 0.001) and osteopontin (p = 0.004) were significant predictors. In multivariate analysis CEA was the strongest predictor for pCR (OR 0.92, p = 0.019) and CEA and IL-8 predicted for response (OR 0.97, p = 0.029 and OR 0.94, p = 0.036). The model based on biomarkers only had an AUC of 0.65 for pCR and 0.68 for response; the strongest model included clinical data, PET-data and biomarkers and had an AUC of 0.81 for pCR and 0.78 for response.

Conclusion

CEA and IL-8 were identified as predictive biomarkers for tumor response and PCR after CRT in rectal cancer. Incorporation of these blood biomarkers leads to an additional accuracy of earlier developed prediction models using clinical variables and PET-information. The new model could help to an early adaptation of treatment in rectal cancer patients.     

Impact of body mass index on treatment outcome of neoadjuvant chemoradiotherapy in locally advanced rectal cancer

Aim

To determine the effect of obesity, measured by body mass index (BMI), on tumor response and surgical outcome in patients with locally advanced rectal cancer (LARC) undergoing neoadjuvant chemoradiotherapy (nCRT) and radical surgery.

Prognostic importance of Mandard tumour regression grade following pre-operative chemo/radiotherapy for locally advanced rectal cancer

Purpose

To assess the prognostic value of the Mandard tumour regression score (TRG) following pre-operative chemo/radiotherapy in patients with locally advanced rectal cancer.

Methods and materials

The study involved 158 patients with locally advanced rectal cancer treated with pre-operative long course chemo/radiotherapy at Nottingham University Hospital between April 2001 and December 2008. Patients were treated with radiotherapy to a dose of 50 Gy in 25 fractions over 5 weeks with or without concurrent capecitabine chemotherapy at a dose of 1650 mg/m²/day. Surgery was normally performed after an interval of 6-10 weeks. The response to pre-operative treatment was carefully graded by a single pathologist using the five point Mandard score. The median follow-up was 40 months (range 3-90 months).

Results

Of the 158 patients 14% were TRG1, 41% were TRG2, 31% were TRG3, 13% were TRG4 and 1% were TRG5. The groups were combined into TRG1, TRG2 and TRG3-5 to simplify further analysis. The Mandard score was clearly related to both disease-free (p < 0.001) and overall survival (p = 0.012). On multivariate analysis perineural invasion, nodal status, TRG and circumferential resection margin status were the most powerful predictors of disease-free survival.

Conclusions

The Mandard tumour regression score is an independent prognostic factor and predicts for long-term outcome following pre-operative chemo/radiotherapy in rectal cancer.     

Proton beam therapy in rectal cancer: A systematic review and meta-analysis

IntroductionLocally advanced rectal cancer is often treated with neoadjuvant chemoradiotherapy and surgery. Radiotherapy carries significant risk of toxicity to organs at risk (OAR). Proton beam therapy (PBT) has demonstrated to be effective in other cancers, delivering equivalent dosimetric radiation but with the benefit of improved sparing of OAR. This review compares dosimetric irradiation of OAR and oncological outcomes for PBT versus conventional photon-based radiotherapy in locally advanced rectal cancer.MethodsAn electronic literature search was performed for studies with comparative cohorts receiving proton beam therapy and photon-based radiotherapy for rectal cancer.ResultsEight articles with a total of 127 patients met the inclusion criteria. There was significantly less irradiated small bowel with PBT compared to three-dimensional conformal radiation therapy (3DCRT) and intensity-modulated radiation therapy (IMRT) (MD -17.01, CI [-24.06, −9.96], p < 0.00001 and MD -6.96, CI [-12.99, −0.94], p = 0.02, respectively). Similar dosimetric results were observed for bladder and pelvic bone marrow. Three studies reported clinical and oncological results for PBT in recurrent rectal cancer with overall survival reported as 43 %, 68 % and 77.2 %, and one study in primary rectal cancer with 100 % disease free survival.ConclusionPBT treatment plans revealed significantly less irradiation of OAR for rectal cancer compared to conventional photon-based radiotherapy. Trials for recurrent rectal cancer and PBT have shown promising results. There are currently no ongoing clinical trials for primary rectal cancer and PBT. More research is required to validate its potential role in dose escalation, higher complete response rate and organ preservation without increasing toxicity.     

Chemoradiotherapy and adjuvant chemotherapy for rectal cancer

Local recurrence is an important factor in determining the outcome of patients after surgery for rectal cancer, and various attempts have been made to reduce the local recurrence rate. Randomized controlled trials have shown that radiotherapy combined with total mesorectal excision can reduce the local recurrence rate in rectal cancer patients who undergo curative surgery. Chemoradiotherapy is more effective in achieving local control than radiotherapy alone, and preoperative chemoradiotherapy is superior to postoperative chemoradiotherapy in terms of adverse events. Recent advances have led to the identification of potential therapeutic targets such as epidermal growth factor receptor, vascular endothelial growth factor, and endothelial receptors. These new agents have been used in combination with conventional chemoradiotherapy, and higher pathological complete response rates have been reported for such combinations in comparison with conventional regimens. With regard to lateral node dissection, a recent study showed that postoperative chemoradiotherapy was more effective in reducing the local recurrence rate than lateral node dissection. As for adjuvant chemotherapy, one randomized controlled trial showed that patients who received uracil and tegafur as adjuvant therapy had significantly prolonged relapse-free survival times and overall survival times. As well, one metaanalysis has shown the efficacy of oral uracil-tegafur as adjuvant chemotherapy for rectal cancer.     

直肠癌新辅助放化疗抵抗性的基因组学预测研究

目的 基于加权基因共表达网络(WGCNA)从分子水平寻找影响直肠癌放化疗抵抗的枢纽基因。方法 于基因表达数据库获得接受放化疗患者的全基因组表达数据GSE119409,分别构建放化疗病理完全缓解组与未获得病理完全缓解组的加权基因共表达网络。利用NetRep保守性评估方法综合分析网络模块各个节点基因连接度、基因显著性与网络位置属性,确定与直肠癌放化疗抵抗性密切相关的枢纽基因。结果 通过WGCNA方法共获得5个(black、blue、green、yellow、purple)与放化疗抵抗性密切相关的网络模块,筛选出5个(SLC22A14、SIDT2、CABP4、EPHB6、RAB11B)与直肠癌放化疗抵抗性相关的枢纽基因。结论 通过加权基因共表达网络分析方法共筛选出与直肠癌放化疗抵抗性相关的5个基因共表达网络模块及相应的5个枢纽基因,为寻找术前放化疗抵抗性评估分子标志物及潜在的治疗靶点提供了线索。