Total neoadjuvant therapy vs standard therapy of locally advanced rectal cancer with high-risk factors for failure

BACKGROUNDFor locally advanced rectal cancer (LARC), standard therapy [consisting of neoadjuvant chemoradiotherapy (CRT), surgery, and adjuvant chemotherapy (ChT)] achieves excellent local control. Unfortunately, survival is still poor due to distant metastases, which remains the leading cause of death among these patients. In recent years, the concept of total neoadjuvant treatment (TNT) has been developed, whereby all systemic ChT-mainly affecting micrometastases-is applied prior to surgery.AIMTo compare standard therapy and total neoadjuvant therapy for LARC patients with high-risk factors for failure.METHODSIn a retrospective study, we compared LARC patients with high-risk factors for failure who were treated with standard therapy or with TNT. High-risk for failure was defined according to the presence of at least one of the following factors: T4 stage; N2 stage; positive mesorectal fascia; extramural vascular invasion; positive lateral lymph node. TNT consisted of 12 wk of induction ChT with capecitabine and oxaliplatin or folinic acid, fluorouracil and oxaliplatin, CRT with capecitabine, and 6-8 wk of consolidation ChT with capecitabine and oxaliplatin or folinic acid, fluorouracil and oxaliplatin prior to surgery. The primary endpoint was pathological complete response (pCR). In total, 72 patients treated with standard therapy and 89 patients treated with TNT were included in the analysis.RESULTSCompared to standard therapy, TNT showed a higher proportion of pCR (23% vs 7%; P = 0.01), a lower neoadjuvant rectal score (median: 8.43 vs 14.98; P < 0.05), higher T-and N-downstaging (70% and 94% vs 51% and 86%), equivalent R0 resection (95% vs 93%), shorter time to stoma closure (mean: 20 vs 33 wk; P < 0.05), higher compliance during systemic ChT (completed all cycles 87% vs 76%; P < 0.05), lower proportion of acute toxicity grade ≥ 3 during ChT (3% vs 14%, P < 0.05), and equivalent acute toxicity and compliance during CRT and in the postoperative period. The pCR rate in patients treated with TNT was significantly higher in patients irradiated with intensity-modulated radiotherapy/volumetric-modulated arc radiotherapy than with 3D conformal radiotherapy (32% vs 9%; P < 0.05).CONCLUSIONCompared to standard therapy, TNT provides better outcome for LARC patients with high-risk factors for failure, in terms of pCR and neoadjuvant rectal score.     

Nucleic acid-based markers of response to neoadjuvant chemoradiotherapy in locally advanced rectal cancer

The progress that has been made in the treatment of rectal cancer has mostly resulted from multimodality strategy approach that combines surgery, chemotherapy and radiotherapy. In locally advanced rectal cancer (LARC), surgery remains the primary treatment, while neoadjuvant chemoradiotherapy (nCRT) is used to downsize or downstage the tumor before surgical resection. Highly variable response to nCRT observed in LARC patients raises the need for biomarkers to enable prediction and evaluation of treatment response in a more efficient and timely manner than currently available tools. The search for predictive biomarkers continues beyond blood proteins, which have failed in subsequent validation studies. This review presents nucleic acids-based markers and their predictive potential in LARC patients. Most of the candidate biomarkers come from relatively small single-institution studies. The only candidate biomarker that emerged as relevant in more than a single study was elevated levels of Fusobacterium nucleatum nucleic acids in tumor tissue. Considering that this marker is easily accessible through non-invasive analysis of faecal samples, its predictive potential is worth further validation. The other candidate nucleic acid-based biomarkers require more consistent studies on larger cohorts before they can be considered for use in clinical setting.     

Total pelvic exenteration for locally advanced and locally recurrent rectal cancer in the elderly

Background

Total pelvic exenteration (TPE) is a radical approach for locally advanced rectal cancer (LARC) and locally recurrent rectal cancer (LRRC) in case of tumour invasion into the urogenitary tract. The aim of this study is to assess surgical and oncological outcomes of TPE for LARC and LRRC in elderly patients compared to younger patients.

Metastases in locally advanced rectal cancer undergoing curatively intended treatment

BackgroundThe main cause of mortality in locally advanced rectal cancer (LARC) is metastatic progression. The aim of the present study was to describe frequency, pattern and outcome of metastatic disease in a cohort of LARC patients after curative resection.MethodsThis was a single-centre cohort study of 628 LARC cases after neoadjuvant chemoradiotherapy/radiotherapy (CRT/RT) and surgery. Data, including the first site of metastasis, was registered in an institutional database linked to the National Cancer Registry.ResultsMetastases were diagnosed in 270 patients (43.0%) with liver and lungs as the first site in 113 and 96 cases, respectively. Involved resection margins, high tumour stage and poor response to CRT/RT were associated with metastasis development and inferior overall survival (OS). Metastasectomy was performed in 76 (67.3%) patients with liver metastases and 28 (29.2%) patients with lung metastases. Five-year OS was 89% in patients without metastases and 32% in metastatic cases. In patients selected for metastasectomy, 5-year OS was 69% and 53% for lung and liver metastases, respectively. Corresponding numbers without metastasectomy were 12% and 0%.ConclusionIn this large LARC cohort undergoing curatively intended treatment, liver and lung metastases occurred at similar frequencies. Liver as the first metastatic site was associated with inferior long-term outcome, while selection for metastasectomy was associated with better OS, with more than half of the resected patients being alive five years after LARC surgery. Our results show that the presence of resectable metastatic disease at diagnosis should not exclude a curative therapeutic approach in LARC.     

Stepwise neoadjuvant chemoradiotherapy in the management of mid-low locally advanced rectal cancer

BackgroundThis study aimed to compare the treatment response, complications and prognosis in mid-low locally advanced rectal cancer (LARC) patients who underwent stepwise neoadjuvant chemoradiotherapy (SCRT) or traditional neoadjuvant chemoradiotherapy (CRT).MethodsThe medical records of patients with mid-low rectal cancer who underwent SCRT or CRT were retrospectively analyzed. Differences in the treatment response, pathologic complete response (pCR), R0 resection, local recurrence, anastomotic leakage, presacral infection, anal preservation, defunctioning stoma, treatment-emergent adverse events (TEAEs), overall survival (OS) and disease-free survival (DFS) between patients who underwent SCRT and CRT were compared.ResultsA total of 430 medical records were investigated, including 194 patients in the SCRT group and 236 patients in the CRT group. There was no significant difference in the rates of treatment response, pCR, R0 resection, local recurrence, anastomotic leakage, presacral infection, anal preservation or TEAEs between the two groups. However, the rate of defunctioning stoma in the SCRT group was significantly lower than that in the CRT group (20.1% vs. 44.1%, respectively, P < 0.01). Moreover, the median OS time of the SCRT and CRT groups was 44.0 and 50.5 months, respectively (P = 0.17). The median DFS time of the SCRT and CRT groups was 41.0 and 46.8 months, respectively (P = 0.32).ConclusionCompared with the CRT group, the SCRT group had a similar treatment response, local control and long-term prognosis, and more importantly, a portion of the patients in the SCRT group were exempted from excessive radiation.     

Intensified concurrent chemoradiotherapy with 5-fluorouracil and irinotecan as neoadjuvant treatment in patients with locally advanced rectal cancer

This study aimed to evaluate the feasibility and efficacy of neoadjuvant chemoradiotherapy intensified with irinotecan in patients with locally advanced rectal cancer. Eligible patients had nonmetastatic disease at a locally advanced stage that made R0 resection and sphincter preservation uncertain. They received preoperative radiation over 6 weeks to 45 Gy and boost of 5.4 Gy and concurrent continuous infusion 5-fluorouracil 250 mg m(-2) day(-1) and weekly irinotecan 40 mg m(-2). In all, 37 patients entered the study. T stage at baseline as determined by ultrasound was T2/T3/T4 in 2/19/16 patients; 31 patients had lymph node involvement. The predominant toxicity was diarrhoea (grade 3/4 in 10/2 patients). Haematologic toxicity and surgical complications were moderate. Among 36 patients undergoing surgery, 32 (89%) had R0 resection and 23 (64%) sphincter preservation. Pathologic complete response (pCR) was achieved in eight (22%) of 36 patients, and 10 patients (28%) had only microscopic residual disease. At 4 years, overall survival was 66%, disease-free survival 73%, local relapse rate 7%, and distant failure rate 24%. Extent of resection and postoperative nodal status were significant predictors of overall and disease-free survival. Intensified neoadjuvant chemoradiotherapy with irinotecan can be safely administered and results in a high pCR rate.     

Preoperative radiotherapy combined with 5 days per week capecitabine chemotherapy in locally advanced rectal cancer

There is increasing evidence supporting the use of preoperative chemoradiotherapy in patients with locally advanced rectal cancer in an attempt to facilitate complete surgical resection with clear margins. We describe our experience of using a 5-day per week regime of preoperative capecitabine chemoradiotherapy. Between November 2004 and September 2006, 70 patients with MRI-defined locally advanced rectal cancer were selected for treatment. Capecitabine was given at a dose of 900 mg m(-2) for 5 days per week combined with 45 Gy of radiotherapy in 25 doses. This regime was well tolerated with 89% of our patients receiving the full dose of chemotherapy and 96% receiving the full dose of radiotherapy. Ninety-three per cent proceeded to macroscopically complete surgical resection. The pathological complete response rate was 9.2% with a node-negative rate of 66%. A negative circumferential margin was achieved by 79% of the patients who underwent resection. Compared to studies using a 7-day per week capecitabine schedule, our results show increased compliance and less dose reductions with comparable pathological outcome.     

局部晚期低位直肠癌术前同步放化疗的疗效观察

目的 探讨术前同步放化疗治疗局部晚期低位直肠癌的安全性和有效性.方法 对临床分期属T3/T4低位直肠癌患者分为A组和B组.A组28例患者,给予术前放疗,同步口服卡培他滨.B组26例患者直接给予手术.结果 A组和B组根治术率分别为82.1％和50.0％ (P ＜0.01),保肛率分别为64.3％和26.9％ (P＜0.0...     

The efficacy and safety of different radiotherapy doses in neoadjuvant chemoradiotherapy for locally advanced rectal cancer

BackgroundThis study aimed to evaluate efficacy and adverse effects of different radiotherapy (RT) doses in neoadjuvant chemoradiotherapy for locally advanced rectal cancer.MethodsFifty-nine patients with locally advanced rectal cancer who underwent neoadjuvant chemoradiotherapy in hospital between January 2015 and May 2017 were enrolled in retrospective analysis. The patients were divided into the 56-Gy group and the 50-Gy group. The concurrent chemotherapy regimen was based on capecitabine. All patients received one cycle of oxaliplatin combined with capecitabine induction chemotherapy. All patients completed neoadjuvant chemoradiotherapy and received radical surgery.ResultsOf the patients in this study, 29 patients and 30 patients received a radiation dose of 56- and 50-Gy, respectively. All clinical characteristics were matched between the two groups. All patients received surgery 6 to 8 weeks after completing RT. The therapeutical effective rate in the 56-Gy group was 93.10% (27/29), compared with 66.67% in the 50-Gy group (20/30); the difference between the two groups was statistically significant (χ²=6.36, P=0.01). The pathological complete remission (pCR) rate in the 56-Gy group (37.93%, 11/29) was statistically significantly higher than that in the 50-Gy group (13.33%, 4/30) (χ²=4.71, P=0.030). The anal preservation rate in the 56-Gy group (65.5%, 19/29) was statistically significantly higher than that in the 50-Gy group (33.33%, 10/30) (χ²=6.11, P=0.01). The 56-Gy group had a local recurrence rate of 0% (0/29) and a distant metastasis rate of 10.34% (3/29), while the 50-Gy group had a local recurrence rate of 6.67% (2/30) and a distant metastasis rate of 16.67% (5/30); no significant difference existed between the two groups (χ²=2.00, 0.50, P=0.16, 0.48). The incidence of adverse reactions (gastrointestinal reactions, bone marrow suppression, and perianal skin reactions) in the 56-Gy group was not significantly different from that in the 50-Gy group (P>0.05).ConclusionsIncreasing the radiation dose can significantly improve the anal preservation and pCR rates of patients with locally advanced rectal cancer, thus improving their life quality. Moreover, it does not increase the rates of recurrence or adverse reactions. Our findings have certain clinical significance, but further prospective study is needed.     

Abdominosacral resection: Long-term outcome in 86 patients with locally advanced or locally recurrent rectal cancer

Aims

The purpose of this study is to evaluate the outcome of abdominosacral resections (ASR) in patients with locally advanced or recurrent rectal cancer.

Methods

From 1994 until 2012 patients with locally advanced rectal cancer (LARC) and locally recurrent rectal cancer (LRRC) underwent a curative ASR and were enrolled in a database. The postoperative complication rates, predictive factors on oncological outcome and survival rates were registered.

Results

Seventy-two patients with LRRC (mean age 63; 44 male, 28 female) and 14 patients with LARC (mean age 65; 6 male, 8 female) underwent ASR. R0 resection was achieved in 37 patients with LRRC and 11 patients with LARC. Twenty-seven patients underwent an R1 resection (3 in the LARC group). Eight patients had an R2 resection, compared to no patients in the LARC group. In respectively 26 and 1 patients of the LRRC and LARC groups a grade 3 or 4 complication occurred and the 30-days mortality rate was respectively 3% and 7%. The 5-years overall survival was 28% and 24% respectively.

Conclusion

En bloc radical resection remains the primary goal in the treatment of dorsally located (recurrent) rectal cancer. After thorough patient selection, ASR is a safe procedure to perform, shows acceptable morbidity rates and leads to a good oncological outcome.     

Role of radiation therapy in neoadjuvant era in patients with locally advanced rectal cancer

Surgery remains the primary determinant of cure in patients with localized rectal cancer, and total mesorectal excision is now widely accepted as standard of care. The widespread implementation of neoadjuvant shortcourse radiotherapy (RT) or long-course chemoradiotherapy (CRT) has reduced local recurrence rates from 25% to 40% to less than 10%; Preoperative RT in resectable rectal cancer has a number of potential advantages, most importantly reducing local recurrence, and down-staging effect. In this article making a comprehensive literature review searching the reliable medical data bases of PubMed and Cochrane we present all available information on the role of radiation therapy alone or in combination with chemotherapy in preoperative setting of rectal cancer. Data reported show that in locally advanced rectal cancer the addition of radiation therapy or CRT pre surgically has significantly improved sphincter prevention surgery. Moreover, the addition of chemotherapy to radiation therapy in preoperative setting has significantly improved pathologic complete response rate and loco-regional control rate without improvement in sphincter preserving surgery. Finally, the results of recently published randomized trials have shown a significant improvement of prevs postoperative CRT on local control; however, there was no effect on overall survival.     

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。     

Indications for neoadjuvant treatment based on risk factors for poor prognosis before and after neoadjuvant chemotherapy alone in patients with locally advanced rectal cancer

IntroductionThe oncological benefit of neoadjuvant chemotherapy (NAC) alone for locally advanced rectal cancer (LARC) remains controversial. The aim of this study was to clarify the clinical risk factors for poor prognosis before and after NAC for decision making regarding additional treatment in patients with LARC.Materials and methodsWe examined a total of 96 patients with MRI-defined poor-risk locally advanced mid-low rectal cancer treated by NAC alone between 2006 and 2018. Survival outcomes and clinical risk factors for poor prognosis before and after NAC were analyzed.ResultsIn the median follow-up duration after surgery of 60 months (3–120), the rates of 5-year overall survival (OS), relapse-free survival (RFS), and local recurrence (LR) were 83.6%, 78.4%, and 8.2%, respectively. In the multivariate analyses, patients with cT4 disease had a significantly higher risk of poor OS (HR; 6.10, 95% CI; 1.32–28.15, P = 0.021) than those with cT3 disease. After NAC, ycN+ was significantly associated with a higher risk of poor OS (HR; 5.92, 95% CI; 1.27–27.62, P = 0.024) and RFS (HR; 2.55, 95% CI; 1.01–6.48, P = 0.048) than ycN-. In addition, patients with CEA after NAC (post-CEA) ≥ 5 ng/ml had a significantly higher risk LR (HR; 5.63, 95% CI; 1.06–29.93, P = 0.043).ConclusionNAC alone had an insufficient survival effect on patients with cT4 disease, ycN+, or an elevated post-CEA level. In contrast, NAC alone is a potential treatment for other patients with LARC.     

Updated systematic review of the approach to pelvic exenteration for locally advanced primary rectal cancer

ObjectivesTo review the evidence regarding surgical advances in the management of primary locally advanced rectal cancer.BackgroundThe management of rectal cancer has evolved significantly in recent decades, with improved (neo)adjuvant treatment strategies and enhanced perioperative protocols. Centralization of care for complex, advanced cases has enabled surgeons in these units to undertake more ambitious surgical procedures.MethodsA Pubmed, Ovid, Embase and Cochrane database search was conducted according to the predetermined search strategy. The review protocol was prospectively registered with PROSPERO (CRD42021245582).Results14 studies were identified which reported on the outcomes of 3,188 patients who underwent pelvic exenteration (PE) for primary rectal cancer. 50% of patients had neoadjuvant radiotherapy. 24.2% underwent flap reconstruction, 9.4% required a bony resection and 34 patients underwent a major vascular excision. 73.9% achieved R0 resection, with 33.1% experiencing a major complication. Median length of hospital stay ranged from 13 to 19 days. 1.6% of patients died within 30 days of their operation. Five-year overall survival (OS) rates ranged 29%–78%.LimitationsThe studies included in our review were mostly single-centre observational studies published prior to the introduction of modern neoadjuvant treatment regimens. It was not possible to perform a meta-analysis on the basis that most were non-randomized, non-comparative studies.ConclusionsPelvic exenteration offers patients with locally advanced rectal cancer the chance of long-term survival with acceptable levels of morbidity. Increased experience facilitates more radical procedures, with the introduction of new platforms and/or reconstructive options.     

肿瘤体积对局部进展期直肠癌预后的影响

目的:探讨肿瘤体积(gross tumor volume,GTV)对接受新辅助放化疗(neoadjuvant chemoradiotherapy,NCRT)和全直肠系膜切除术(total mesorectal excision,TME)后,局部进展期直肠癌(locally advanced rectal cancer,LARC)患者的预后影响。方法:回顾性分析2011年1月至2016年9月湖南省肿瘤医院收治的128例初治直肠癌患者的临床资料,均接受术前同步放化疗+TME。采用受试者工作特征曲线(receiver-operating characteristic,ROC)分析GTV截点值,用Kaplan-Meier生存分析和Cox比例风险回归模型进行预后分析。结果:行NCRT后T分期降期率为58.6%,N分期降期率为69.5%,总体降期率为77.3%,病理完全缓解(pathologi-cal complete response,p CR)率为16.4%,总体保肛率为57.03%。GTV的截点为79.31 m L,GTV≥79.31 m L与GTV<79.31 m L患者的3年总生存...     

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.     

直肠癌的新辅助治疗

为了保留肛门、减少复发、延长生存,新辅助化放疗已成为直肠癌治疗的重要组成部分.本文详细论述了直肠癌新辅助治疗的发展和现状.探讨了新辅助放疗、新辅助放化疗与单纯手术及辅助化放疗相比的优劣.     

Patterns of local recurrence in locally advanced rectal cancer after intra-operative radiotherapy containing multimodality treatment

Background and purpose

The purpose of this study is to analyze the patterns of local recurrence (LR) after intra-operative radiotherapy (IORT) containing multimodality treatment of locally advanced rectal carcinoma (LARC).

Methods and materials

Two hundred and ninety patients with LARC who underwent multimodality treatment between 1994 and 2006 were studied. For patients who developed LR, the subsite was classified into presacral, postero-lateral, lateral, anterior, anastomotic or perineal. Patient and treatment characteristics were related to subsite of LR.

Results

After 5 years, 34 patients (13.2%) developed LR. The most prominent subsite of LR was the presacral subsite. 47% of the local recurrences occurred outside the IORT field. Most recurrences developed when IORT was given dorsally, while least occurred when IORT was given ventrally. Especially after dorsal IORT a high amount of infield recurrences were observed (6 of 8; 75%). In multi-variate analysis tumor distance of more than 5 cm from the anal verge and a positive circumferential margin were associated with presacral local recurrence.

Conclusions

Multimodality treatment is effective in the prevention of local recurrence in LARC. IORT application to the area most at risk is feasible and seems effective in the prevention of local recurrence. Dorsal tumor location results in unfavourable oncologic results.