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。     

Prognostic value of pathologic complete response after neoadjuvant therapy in locally advanced rectal cancer: long-term analysis of 566 ypCR patients

PURPOSE: In the literature, a favorable prognosis was observed for complete pathologic response after preoperative therapy (ypCR) in patients with locally advanced rectal cancer. The aim of this study is to verify whether ypCR predicts a favorable outcome in a large series of patients. METHODS AND MATERIALS: The Gastro-Intestinal Working Group of the Italian Association of Radiation Oncology collected clinical data for 566 patients with ypCR (ypT0N0) after neoadjuvant therapy. Eligibility criteria included locally advanced rectal cancer with no evidence of metastases at the time of diagnosis, evidence of ypCR after preoperative radiotherapy +/- chemotherapy (CT). RESULTS: Median radiation dose was 50 Gy. A total of 527 patients (93%) received one of 12 different neoadjuvant CT schedules. Sphincter preservation, anteroposterior resection, and endoscopic surgery were performed in 73%, 22%, and 5% of patients, respectively. Adjuvant CT was administered to 22% of patients. Median follow-up was 46.4 months. Locoregional recurrence occurred in 7 patients (1.6%). Distant metastases occurred in 49 patients (8.9%). Overall, 5-year rates of disease-free survival, overall survival, and cancer-specific survival were 85%, 90%, and 94%, respectively. In multivariate analysis, only age and clinical stage statistically correlated with survival outcome. Adjuvant CT was still of borderline significance (worse for adjuvant CT). No relation was found between survival and neoadjuvant CT schedules. CONCLUSION: A ypCR after neoadjuvant therapy identified a favorable group of patients, even in this large series of 566 patients collected in 61 centers. Locoregional recurrence occurred only in 1.6% patients.     

Association of statin use with a pathologic complete response to neoadjuvant chemoradiation for rectal cancer

PURPOSE: To assess whether 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, or statins, might enhance the efficacy of neoadjuvant chemoradiation in rectal cancer. METHODS AND MATERIALS: Between 1996 and 2001, 358 patients with clinically resectable, nonmetastatic rectal cancer underwent surgery at Memorial Sloan-Kettering Cancer Center after neoadjuvant chemoradiation for either locally advanced tumors or low-lying tumors that would require abdominoperineal resection. We excluded 9 patients for radiation therapy dose <45 Gy or if statin use was unknown, leaving 349 evaluable patients. Median radiation therapy dose was 50.4 Gy (range, 45-55.8 Gy), and 308 patients (88%) received 5-fluorouracil-based chemotherapy. Medication use, comorbid illnesses, clinical stage as assessed by digital rectal examination and ultrasound, and type of chemotherapy were analyzed for associations with pathologic complete response (pCR), defined as no microscopic evidence of tumor. Fisher's exact test was used for categoric variables, Mantel-Haenszel test for ordered categoric variables, and logistic regression for multivariate analysis. RESULTS: Thirty-three patients (9%) used a statin, with no differences in clinical stage according to digital rectal examination or ultrasound compared with the other 324 patients. At the time of surgery, 23 nonstatin patients (7%) were found to have metastatic disease, compared with 0% for statin patients. The unadjusted pCR rates with and without statin use were 30% and 17%, respectively (p = 0.10). Variables significant univariately at the p = 0.15 level were entered into a multivariate model, as were nonsteroidal anti-inflammatory drugs (NSAIDs), which were strongly associated with statin use. The odds ratio for statin use on pCR was 4.2 (95% confidence interval, 1.7-12.1; p = 0.003) after adjusting for NSAID use, clinical stage, and type of chemotherapy. CONCLUSION: In multivariate analysis, statin use is associated with an improved pCR rate after neoadjuvant chemoradiation for rectal cancer. The low prevalence of statin use limits the power to detect a significant difference at a type I error threshold of p = 0.05 in this analysis. Although no definitive conclusions can be drawn on the basis of this retrospective study, the unusually high incidence of pCR after chemoradiation suggests that the use of statins in the treatment of rectal cancer warrants further evaluation.     

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。     

直肠癌术前新辅助治疗进展

直肠癌是人类常见的恶性肿瘤,由于发病率和复发率较高,严重影响了人们的健康。肿瘤外科学者为提高患者的生存率和生活质量,术中术后采用了很多的方法,但效果不理想。于是术前新辅助治疗被提出,经过几十年的研究探索,其在直肠癌的应用越来越受到重视。采用术前新辅助治疗已经逐渐成为一种标准疗法。     

直肠癌术前新辅助治疗进展

直肠癌是人类常见的恶性肿瘤,由于发病率和复发率较高,严重影响了人们的健康。肿瘤外科学者为提高患者的生存率和生活质量,术中术后采用了很多的方法,但效果不理想。于是术前新辅助治疗被提出,经过几十年的研究探索,其在直肠癌的应用越来越受到重视。采用术前新辅助治疗已经逐渐成为一种标准疗法。     

Comparison of pathological complete response rates after neoadjuvant short-course radiotherapy or chemoradiation followed by delayed surgery in locally advanced rectal cancer

Introduction

Patients with locally advanced rectal cancer (LARC) who are unfit for chemoradiation (CRT), are often offered short-course radiotherapy followed by delayed surgery (SCRT-delay). This entails a lower radiation dose, no chemotherapy and a shorter treatment period. This may lower their chances for complete tumor response and, as such, organ-sparing approaches. The purpose of this study was to compare the pathological complete response (pCR) rates between neoadjuvant CRT and SCRT-delay in patients with LARC in a nationwide database from the Netherlands.

Lymph node yield in rectal cancer surgery: Effect of preoperative chemoradiotherapy

Aim

Adequate lymph node resection in rectal cancer is important for staging and local control. This study aims to verify the effect of neoadjuvant chemoradiation, as well as some clinicopathological features, on the yield of lymph nodes in rectal carcinoma.

Methods

Data on consecutive patients who had total mesorectal excision for rectal adenocarcinoma at a single cancer center between January 2003 and July 2008 were reviewed. No patient had any prior pelvic surgery or radiotherapy. Patients had neoadjuvant chemoradiotherapy if they were stage II or III.

Results

A total of 116 patients were included. The mean age was 53 years (range 29–83). Fifty-nine patients (51%) received neoadjuvant therapy before resection. The mean number of lymph nodes removed was 18 (range 4–67) per specimen. There was less lymph node yield in patients who received neoadjuvant therapy (16 vs. 19, p = 0.008). Only 64% of patients who had preoperative therapy had 12 lymph nodes or more in the specimen as opposed to 88% of those who had surgery upfront (p = 0.003). Other factors associated with lower lymph node yield included: female sex (p = 0.03) and tumour location in the lower rectum (p = 0.002). Age, tumour stage and grade, type of operation and surgical delay did not affect the number of lymph nodes removed.

Conclusion

Preoperative chemoradiotherapy for rectal cancer results in reduction in lymph node yield. Female sex and lower rectal tumours are also associated with retrieval of fewer lymph nodes.     

Diffusion-weighted magnetic resonance for prediction of response after neoadjuvant chemoradiation therapy for locally advanced rectal cancer: Preliminary results of a monoinstitutional prospective study

Purpose

To evaluate diffusion-weighted imaging (DWI) for assessment of treatment response in locally advanced rectal cancer (LARC) 8 weeks after neoadjuvant chemoradiotherapy (CRT).

Methods and materials

A total of 28 patients with LARC underwent magnetic resonance imaging (MRI) prior to and 8 weeks after CRT. Tumor volume (TV) was calculated on T2-weighted MRI scans as well as the apparent diffusion coefficient (ADC) was calculated using Echo-planar DWI-sequences. All data were correlated to surgical results and histopathologic tumor regression grade (TRG), according to Mandard's classification. Post-treatment difference ADC (%ΔADC) and TV (%ΔTV) changes at 8 weeks were compared complete response (CR; TRG1) and non-complete response tumors (non-CR; TRG2–5).

Results

The mean % ADC increase of CR group was significantly higher compared to non-CR group (77.2 ± 54.63% vs. 36.0 ± 29.44%; p = 0.05). Conversely, the mean % TV reduction did not significantly differ in CR group from non-CR group (73.7% vs. 63.77%; p = 0.21). Accordingly, the diagnostic accuracy of the mean % ADC increase to discriminate CR from non-CR group was significantly higher than that of the mean % TV reduction (0.913 vs. 0.658; p = 0.022). No correlation was found between mean % TV reduction and TRG (rho = 0.22; p = 0.3037), whereas a negative correlation between mean % ADC increase and TRG was recorded (r = −0.69; p = 0.006).

Conclusion

The mean % ADC increase appears to be a reliable tool to differentiate CR from non-CR after CRT in patients with LARC.     

Evaluating mesorectal lymph nodes in rectal cancer before and after neoadjuvant chemoradiation using thin-section T2-weighted magnetic resonance imaging

PURPOSE: To apply thin-section T2-weighted magnetic resoance imaging (MRI) to evaluate the number, size, distribution, and morphology of benign and malignant mesorectal lymph nodes before and after chemoradiation treatment compared with histopathologic findings. METHODS AND MATERIALS: Twenty-five patients with poor-risk adenocarcinoma of the rectum treated with neoadjuvant chemoradiation were evaluated prospectively. Thin-section T2-weighted MR images obtained before and after chemoradiation treatment were independently reviewed in consensus by 2 expert radiologists to determine the tumor stage, nodal size, nodal distribution, and nodal stage. Total mesorectal excision surgery after chemoradiation allowed MR nodal stage to be compared with histopathology using kappa statistics. Nodal downstaging was compared using the Chi-square test. RESULTS: Before chemoradiation, 152 mesorectal nodes were visible (mean, 6.2 mm; 100 benign, 52 malignant) and 4 of 52 malignant nodes were in contact with the mesorectal fascia. The nodal staging was 7/25 N0, 10/25 N1, and 7/25 N2. After chemoradiation, only 29 nodes (mean, 4.1 mm; 24 benign, 5 malignant) were visible, and none were in contact with the mesorectal fascia. Nodal downstaging was observed: 20/25 N0 and 5/25 N1 (p < 0.01, Chi-square test). There was good agreement between MRI and pathologic T-staging (kappa = 0.64) and N-staging (kappa = 0.65) after chemoradiation. CONCLUSIONS: Neoadjuvant chemoradiation treatment resulted in a decrease in size and number of malignant- and benign-appearing mesorectal nodes on MRI. Nodal downstaging and nodal regression from the mesorectal fascia were observed after treatment. MRI is a useful tool for assessing nodal response to neoadjuvant treatment.     

Positron emission tomography as predictor of rectal cancer response during or following neoadjuvant chemoradiation

Positron emission tomography (PET) shows great promise as a tool to evaluate the effectiveness of rectal cancer neoadjuvant therapy as it has demonstrated high predictive value in several studies. Creating a standardized method of using PET has the potential to reduce ineffective treatments. However, relevant studies have been heterogenous in approach, making any unified standard difficult to establish. PET related parameters used to assess treatment response include magnitude and change of standard uptake value, total lesion glycolysis, and visual response. Finding the best evaluation interval and parameters to use for interpreting PET results in the neo-adjuvant treatment of rectal cancer needs additional study.     

Predictive factors associated with complete pathological response after neoadjuvant treatment for rectal cancer

PurposeA proportion of 10 to 30% of patients treated by chemoradiotherapy followed by total mesorectal excision surgery for a locally advanced rectal cancer can achieve a complete pathological response. We aimed to identify predictive factors associated with complete pathological response or no response and to assess the impact of each response on survival rates.Patients and methodsPatients treated with long course chemoradiotherapy for locally advanced and/or node positive rectal cancer from 2010 to 2016 were retrospectively reviewed. Statistical analysis was carried out to determine predictors of tumor regression and treatment outcomes.ResultsRecords were available on 70 patients. In the univariate analysis, clinical factors associated with complete tumor response were tumor mobility in digital rectal examination (P = 0.047), a limited parietal invasion (P = 0.001), clinically negative lymph node (P < 0.001) and a circumferential extent greater than 50% (P = 0.001). On the other hand, a T4 classification and an endoscopic tumor size greater than 6 cm were associated with no response to treatment (P = 0.049 and P = 0.017 respectively). On multivariate analysis, T2 clinical classification and N0 statement before treatment were independent predictive factors of pathologic complete response (P < 0.001 and P = 0.001) and a delayed surgery after 12 weeks was associated with no response to treatment (P = 0.001).ConclusionThe identification of predictive factors of histological response may help clinicians to predict the prognosis and to propose organ preservation for good responders.     

Current debate in the oncologic management of rectal cancer

Despite the considerable amount of research in the field, the management of locally advanced rectal cancer remains a subject to debate. To date, effective treatment centers on surgical resection with the standard approach of total mesorectal resection. Radiation therapy and chemotherapy have been incorporated in order to decrease local and systemic recurrence. While it is accepted that a multimodality treatment regimen is indicated, there remains significant debate for how best to accomplish this in regards to order, dosing, and choice of agents. Preoperative radiation is the standard of care, yet remains debated with the option for chemoradiation, short course radiation, and even ongoing studies looking at the possibility of leaving radiation out altogether. Chemotherapy was traditionally incorporated in the adjuvant setting, but recent reports suggest the possibility of improved efficacy and tolerance when given upfront. In this review, the major studies in the management of locally advanced rectal cancer will be discussed. In addition, future directions will be considered such as the role of immunotherapy and ongoing trials looking at timing of chemotherapy, inclusion of radiation, and non-operative management.     

Microsatellite instability and response to neoadjuvant chemoradiotherapy in rectal cancer: A systematic review and meta-analysis

BackgroundResponse to neoadjuvant chemoradiotherapy (CRT) in locally advanced rectal cancer is variable. Identification of biomarkers to predict response is desirable in order to provide prognostic information and targeted therapy. Several studies have investigated microsatellite instability (MSI) as a predictor of response to CRT with contradictory results. This study aims to clarify the effect of MSI status on response to CRT in locally advanced rectal cancer through systematic review and meta-analysis.MethodsA systematic search of PubMed, Embase and Cochrane databases was performed for all studies relating to MSI and response to CRT in rectal cancer using the search algorithm (Microsatellite Instability) AND (Chemoradiotherapy) AND (Rectal Cancer). From each included study the number of patients with MSI tumors and Microsatellite Stable (MSS) tumors and the numbers achieving pathological complete response (pCR) were recorded. Pooled outcome measures were determined using a random effects model and the odds ratio estimated with variance and 95% confidence interval.ResultsNine published studies were identified reporting data on MSI and its effect on outcome after CRT for locally advanced rectal cancer. Five studies describing 5,877 patients included data on MSI and the number of patients achieving pCR. There was no significant association between MSI and pCR (MSI Vs MSS: 10.1% Vs 6.6%, OR 1.38, 95% CI: 0.7–2.72, p = 0.35).ConclusionThis meta-analysis concludes that there appears to be no significant difference in pCR rate following CRT in patients with MSI versus MSS rectal tumors.     

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.     

Clinical and pathological predictors of recurrence in breast cancer patients achieving pathological complete response to neoadjuvant chemotherapy

IntroductionDespite the excellent prognosis associated with pathological complete response (pCR) to neoadjuvant chemotherapy (NAC), some patients still develop recurrence. Here, we investigated the outcomes of breast cancer patients with pCR, as well as the clinical and pathological predictors of cancer recurrence in these patients.Materials and methodsOf the 1599 breast cancer patients treated with NAC, we evaluated 394 patients who achieved pCR between January 2007 and December 2016. pCR was defined as no evidence of invasive cancer in breast. Residual in situ ductal and axillary lymph node diseases were not considered. We analyzed the outcomes using the Kaplan–Meier method. We assessed the association of clinical and pathological predictors with cancer recurrence using the cox proportional hazards regression model.ResultsThe median follow-up time was 63 months. The 5-year disease-free survival rate was 92.3%. Cancer recurrence was observed in 28 patients (7.1%): local recurrence 8 patients (2.0%), visceral metastasis 10 patients (2.5%), and brain metastasis 10 patients (2.5%). Brain metastases were found in patients with HER2 type breast cancer. The significant predictors of cancer recurrence were HER2 positivity (p = 0.04), clinical tumor size (p < 0.01), and lymph node metastasis (p < 0.01) before NAC on univariate analysis and only lymph node metastasis on multivariate analysis.ConclusionPatients achieving pCR to NAC showed excellent outcomes. Advanced clinical stage, large tumor size, presence of lymph node metastasis, and HER2 positivity before NAC were identified as significant predictors of cancer recurrence. Residual in situ ductal and lymph node diseases after NAC were not significant predictors.