Clinical parameters predicting pathologic tumor response after preoperative chemoradiotherapy for rectal cancer

PURPOSE: To identify pretreatment clinical parameters that could predict pathologic tumor response to preoperative chemoradiotherapy (CRT) for rectal cancer. METHODS AND MATERIALS: The study involved 351 patients who underwent preoperative CRT followed by surgery between October 2001 and July 2006. Tumor responses to preoperative CRT were assessed in terms of tumor downstaging and tumor regression. Statistical analyses were performed to identify clinical factors associated with pathologic tumor response. RESULTS: Tumor downstaging (defined as ypT2 or less) was observed in 167 patients (47.6%), whereas tumor regression (defined as Dworak's Regression Grades 3 or 4) was observed in 103 patients (29.3%) and complete regression in 51 patients (14.5%). Multivariate analysis found that predictors of downstaging were pretreatment hemoglobin level (p = 0.045), cN0 classification (p < 0.001), and serum carcinoembryonic antigen (CEA) level (p < 0.001), that predictors of tumor regression were cN0 classification (p = 0.044) and CEA level (p < 0.001), and that the predictor of complete regression was CEA level (p = 0.004). CONCLUSIONS: The data suggest that pretreatment CEA level is the most important clinical predictor of pathologic tumor response. It may be of benefit in the selection of treatment options as well as the assessment of individual prognosis.     

Epidermal growth factor receptor as a predictor of tumor downstaging in locally advanced rectal cancer patients treated with preoperative chemoradiotherapy

PURPOSE: To examine retrospectively whether levels of epidermal growth factor receptor (EGFR) expression can predict tumor downstaging after preoperative chemoradiotherapy in patients with locally advanced rectal cancer. METHODS AND MATERIALS: A total of 183 patients with rectal cancer (cT3-T4 or N+) were enrolled in this study. Preoperative chemoradiotherapy consisted of 50.4 Gy of pelvic radiation with concurrent 5-fluorouracil and leucovorin bolus intravenous chemotherapy in 94 patients or oral capecitabine and leucovorin in 89 patients. EGFR expression in pretreatment paraffin-embedded tumor biopsy specimens was assessed by immunohistochemistry. EGFR expression was determined from the intensity and extent of staining. Tumor downstaging was defined as a reduction of at least one T-stage level. RESULTS: Tumor downstaging occurred in 97 patients (53%), and the tumors showed a pathologic complete response in 27 patients (15%). Positive EGFR expression was observed in 140 (76%) of 183 patients. EGFR expression levels were low in 113 patients (62%) and high in 70 patients (38%). On logistic regression analysis, the significant predictive factor for increased tumor downstaging was a low level of EGFR expression and preoperative chemotherapy using oral capecitabine (odds ratio, 0.437; p = 0.012 vs. odds ratio, 3.235; p < 0.001, respectively). CONCLUSION: A high level of EGFR expression may be a significant predictive molecular marker for decreased tumor downstaging after preoperative chemoradiotherapy in locally advanced rectal cancer.     

Tumour regression grading in patients with residual rectal cancer after preoperative chemoradiation

Background and purpose

To explore the utility of tumour regression grading (TRG, the amount of residual tumour cells in relation to extension of fibrosis) after chemoradiation of rectal cancer.

Materials and methods

Of 131 patients who received preoperative chemoradiation in the frame of the randomized trial, pathological complete response (pCR, TRG0), good regression (TRG1), moderate regression (TRG2), and poor regression (TRG3) were recorded in 17%, 31%, 31%, and 22% of patients, respectively.

Results

The rates of ypN-positive category for TRG0, TRG1, TRG2, and TRG3 groups were 5%, 23%, 45%, and 46%, respectively, p = 0.001. When ypT-category and TRG were evaluated by the logistic regression analysis, only ypT-category remained significant for independent prediction of the risk for mesorectal nodal metastases, p = 0.006. The 4-year (median follow-up) disease-free survival (DFS) for TRG0, TRG1, TRG2, and TRG3 groups were 91%, 67%, 54%, and 47%. When patients with persistent disease (TRG1 vs. TRG2 vs. TRG3) were analyzed separately, TRG had no prognostic value for DFS, p = 0.402.

Conclusions

TRG in patients with residual cancer had no prognostic value for the incidence of nodal disease and for DFS. Our findings and literature data question the need for the inclusion of TRG assessment into a routine pathological report.     

Randomized, multicenter, phase IIb study of preoperative chemoradiotherapy in T3 mid-distal rectal cancer: raltitrexed + oxaliplatin + radiotherapy versus cisplatin + 5-fluorouracil + radiotherapy

PURPOSE: To prospectively compare the rates of pathologic response, acute toxicity, and sphincter preservation with two different schedules of preoperative chemoradiotherapy in patients with cT3 mid-distal rectal cancer. METHODS AND MATERIALS: Patients with cT3 and/or N+ resectable rectal carcinoma were randomized to receive one of the two following chemoradiotherapy regimens: cisplatin, 5-fluorouracil, and radiotherapy (PLAFUR) or raltitrexed, oxaliplatin, and radiotherapy (TOMOX-RT). For PLAFUR, cisplatin (60 mg/m(2)) was given on Days 1 and 29, with a prolonged infusion of 5-fluorouracil (1,000 mg/m(2)) on Days 1-4 and 29-32, plus concurrent radiotherapy (50.4 Gy in 1.8-Gy fractions daily). For TOMOX-RT, raltitrexed (3 mg/m(2)) and oxaliplatin (130 mg/m(2)) was given on Days 1, 19, and 38 with the same radiotherapy regimen as used for PLAFUR. Surgery was performed 6-8 weeks after completion of chemoradiotherapy. All pathologic specimens were reviewed by a designated expert pathologist. The primary endpoint of this study was pathologic tumor downstaging (defined as tumor regression grade 1-2). Secondary endpoints included the incidence of ypT0, clinical tumor downstaging, sphincter-saving surgery, and acute treatment-related toxicity. RESULTS: Between 2002 and 2005, 164 patients were accrued in 10 Italian centers, 83 patients in the PLAFUR arm and 81 in the TOMOX-RT arm. Overall, tumor regression grade 1-2 was observed in 76 patients (46.4%) and ypT0 in 49 (29.9%). The tumor regression grade 1-2 rate was 41.0% vs. 51.9% (p = 0.162) and the ypT0 rate was 24.1% vs. 35.8% (p = 0.102) for the PLAFUR vs. TOMOX-RT arm, respectively. The overall rate of tumor regression grade 1 and ypN+ was 4.6%. The occurrence of ypT downstaging was significantly greater in the TOMOX-RT arm (p = 0.035). Grade 3-4 acute toxicity occurred in 19 patients (11.6%): 7.1% in the PLAFUR arm vs. 16.4% in the TOMOX-RT arm. Sphincter-saving surgery was performed in 143 patients (87.2%) overall: 87.9% in the PLAFUR arm and 86.4% in the TOMOX-RT arm. CONCLUSIONS: Compared with the PLAFUR regimen, TOMOX-RT achieved a greater incidence of downstaging but was associated with a correspondingly greater rate of acute Grade 3+ toxicity. With longer follow-up, the local control and survival rates might offer additional guidance as to the choice of regimen.     

Comparison of 5-fluorouracil/leucovorin and capecitabine in preoperative chemoradiotherapy for locally advanced rectal cancer

PURPOSE: To describe our experience with a bolus injection of 5-fluorouracil and leucovorin (FL) vs. capecitabine in terms of radiologic and pathologic findings in preoperative chemoradiotherapy (CRT) for locally advanced rectal cancer. METHODS: The study enrolled 278 patients scheduled for preoperative CRT using two protocols with different chemotherapeutic regimens. Pelvic radiotherapy (50.4 Gy) was delivered concurrently with FL (n = 145) or capecitabine (n = 133). Surgery was performed 6 weeks after CRT completion. Tumor responses to CRT were measured using both radiologic and pathologic examination. Magnetic resonance volumetry was performed at the initial workup and just before surgery after completion of preoperative CRT. Post-CRT pathology tests were used to determine tumor stage and regression. RESULTS: Radiologic examination showed that tumor volume decreased by 68.2% +/- 20.5% in the FL group and 68.3% +/- 22.3% in the capecitabine group (p = 0.970). Postoperative pathologic T stage determination showed that downstaging occurred in 44.3% of FL and 49.9% of capecitabine patients (p = 0.571). The tumor regression grades after CRT were Grade 1 (minimal response) in 22.6% and 21.0%, Grade 2 (moderate response) in 53.2% and 50.0%, Grade 3 (near-complete response) in 12.9% and 12.9%, and Grade 4 (complete response) in 11.3% and 16.1% of the FL and capecitabine groups, respectively (p = 0.758). CONCLUSION: In the present study, the radiologic and pathologic findings did not reveal significant differences in short-term tumor responses between preoperative FL and capecitabine CRT for locally advanced rectal cancer. Long-term results and a prospective randomized trial are needed.     

Phase II study of preoperative chemoradiotherapy (CRT) with irinotecan plus S-1 in locally advanced rectal cancer

Background and purpose

The aim of this study is to evaluate the efficacy and safety of preoperative radiation therapy combined with S-1 and irinotecan (SI) in LARC.

Materials and methods

Patients were considered LARC if they had a T3/T4 lesion or node positive. Weekly doses of 40 mg/m² irinotecan were intravenously administered once per week during weeks 1-5 of radiotherapy. S-1 (70 mg/m²) was given from Monday to Friday in all weeks of radiotherapy. 3-D conformal radiotherapy was given at daily fractions of 1.8 Gy for 5 days for a total dose of 50.4 (45 + 5.4) Gy. Surgery was performed 4-6 weeks following the completion of chemoradiation.

Results

Between June 2006 and November 2007, 43 pts were enrolled. The stage was: cT3 24 patients, cT4 6 patients; 28 patients were cN+. Forty-one patients completed the chemoradiation and 42 patients underwent operation: a low anterior resection was performed in 36 patients, a total colectomy in 1 patient, and an abdominal perineal resection in 5 patients. T downstaging was observed in 50%; 23 N+ patients became N− (55%). The complete pathological response was observed in 9 patients (21%). The 3-year locoregional failure rate, distant failure rate, disease-free survival, and overall survival were 9.5%, 18.6%, 72.1%, and 94.3%, respectively. Only three patients experienced G3 diarrhea; one had G3 sepsis and two had septic shock. Hematological toxicity (G3-G4) was observed in five patients.

Conclusions

This study demonstrated the efficacy of preoperative CRT with S-1 and irinotecan with 21% of complete response. However, prompt recognition and management of infection is needed to use it in patients with locally advanced rectal cancer.     

局部晚期直肠癌术前含草酸铂同步放化疗Ⅱ期临床研究

目的评价术前同步放疗与草酸铂和氟尿嘧啶(5-FU)或甲酰四氢叶酸钙(CF)联合化疗治疗局部晚期直肠癌的耐受性和有效性。方法58例初诊局部晚期直肠癌(T3～T4期)患者进入该研究,疗前获病理类型,腺癌54例,印戒细胞癌4例。放疗为3个野等中心技术,盆腔照射46 Gy分23次4.5周完成。在放疗第1周和第4周同步给予2个周期化疗,草酸铂130 mg/m~2第1天,5-FU 500 mg/m~2第1～3天和CF 200 mg/m~2第1～3天。放疗结束后4～6周进行手术。结果完成术前计划并行手术者55例,手术标本总有效率为58%,其中肿瘤全消(pCR)11例,仅检出少量残存肿瘤细胞21例。3级毒副反应包括中性粒细胞减少1例,腹泻3例,放射性直肠炎4例,肝功能异常1例。结论含草酸铂方案的术前联合放化疗耐受性良好,有效率高,应进一步随访并开展Ⅲ期临床试验,以明确对局部控制率和生存率的影响。     

Phase I-II trial of concurrent capecitabine and oxaliplatin with preoperative intensity-modulated radiotherapy in patients with locally advanced rectal cancer

PURPOSE: To identify the maximal tolerated dose level of preoperative intensity-modulated radiotherapy combined with capecitabine and oxaliplatin and to evaluate the efficacy. PATIENTS AND METHODS: Patients with rectal T3-T4 and/or N0-N+ rectal cancer received capecitabine 825 mg/m(2) twice daily Monday through Friday and oxaliplatin 60 mg/m(2) intravenously on Days 1, 8, and 15, concurrently with intensity-modulated radiotherapy. The radiation dose was increased in 5.0-Gy steps in cohorts of 3 patients starting from 37.5 Gy in 15 fractions (dose level [DL] 1). DL2 and DL3 were designed to reach 42.5 Gy in 17 fractions and 47.5 Gy in 19 fractions, respectively. RESULTS: No dose-limiting toxicity was observed at DL1 or DL2. Of the 3 patients treated at DL3, 1 presented with Grade 3 diarrhea, which was considered a dose-limiting toxicity, and 3 additional patients were added. Of the 6 patients treated at DL3, no new dose-limiting toxicities were observed, and DL3 was identified as the recommended dose in this study. Eight additional patients were treated at 47.5 Gy. Grade 2 proctitis was the most frequent adverse event (40%); Grade 3 diarrhea occurred in 2 patients (10%). All patients underwent surgery, and 17 patients (85%) underwent R0 resection. Four patients (20%) presented with a histologic response of Grade 4, 11 (55%) with Grade 3+, 2 (15%) with Grade 3, and 2 patients (10%) with Grade 2. CONCLUSION: The maximal tolerated dose in this study was 47.5 Gy. The high rates of pathologic response of Grade 3+ and 4 must be confirmed through the accrual of new patients in the Phase II study.     

Accuracy of pelvic MRI in measuring tumor height in rectal cancer patients with or without preoperative chemoradiotherapy

IntroductionIn measuring tumor height for rectal cancer, rigid sigmoidoscopy (RS) is a standard modality, and the accuracy of magnetic resonance imaging(MRI) in patients with/without preoperative chemoradiotherapy (CRT) has not been fully investigated. The aim of this study was to investigate the accuracy of MRI for measuring tumor height.Materials and methodsAmong rectal cancer patients seen between July 2006 and May 2012, the initial group (RS and MRI available at initial diagnosis) and the post-CRT group (RS and MRI available after the completion of preoperative CRT) were selected. Intra-class correlation coefficient (ICC) comparison tests were performed between RS and MRI results for each group.ResultsNinety-nine and 29 patients were allocated into the initial group and the post-CRT group, respectively. The tumor heights measured by RS and MRI demonstrated a positive relationship in the scatter plot (linear regression; R² = 0.898; p < 0.001 in the initial group, R² = 0.696; p < 0.001 in the post-CRT group). With respect to difference of absolute value (DAV) between RS and MRI, the overall mean and standard deviation of DAV were 10.9 ± 10 mm in the initial group and 8 ± 6 mm in the post-CRT group. ICC comparison analysis revealed that inter-rater agreement of RS and MRI in the initial group was significantly better than that of the post-CRT group [ICC (95% CI) 0.946 (0.919–0.963) vs. 0.823 (0.621–0.917); p = 0.004)].ConclusionsMRI can be used as a viable option to measure tumor height in rectal cancer even in patients who have undergone preoperative CRT.     

Matrix metalloproteinase-9 expression correlated with tumor response in patients with locally advanced rectal cancer undergoing preoperative chemoradiotherapy

PURPOSE: To analyze whether the expression of matrix metalloproteinases (MMPs) and their tissue inhibitors are associated with tumor response to preoperative chemoradiotherapy in rectal cancer patients. METHODS AND MATERIALS: Forty-four patients who had undergone preoperative chemoradiotherapy were evaluated retrospectively. Treatment consisted of pelvic radiotherapy and two cycles of 5-fluorouracil plus leucovorin. Surgery was performed 6-8 weeks later. MMP-2, MMP-9, and tissue inhibitors of metalloproteinase-1 and -2 expression was analyzed by immunohistochemistry of the preradiation biopsy and surgical specimens. The intensity and extent of staining were evaluated separately, and a final score was calculated by multiplying the two scores. The primary endpoint was the correlation of expression with tumor response, with the secondary endpoint the effect of chemoradiotherapy on the expression. RESULTS: Preoperative treatment resulted in downstaging in 20 patients (45%) and no clinical response in 24 (55%). The pathologic tumor response was complete in 11 patients (25%), partial in 23 (52%), and none in 10 (23%). Positive MMP-9 staining was observed in 20 tumors (45%) and was associated with the clinical nodal stage (p = 0.035) and the pathologic and clinical response (p < 0.0001). The staining status of the other markers was associated with neither stage nor response. The overall pathologic response rate was 25% in MMP-9-positive patients vs. 52% in MMP-9-negative patients (p = 0.001). None of the 11 patients with pathologic complete remission was MMP-9 positive. CONCLUSIONS: Matrix metalloproteinase-9 expression correlated with a poor tumor response to preoperative chemoradiotherapy in rectal carcinoma patients.     

Predictive value of serum alpha-fetoprotein for tumor regression after preoperative chemotherapy for rectal cancer

BACKGROUNDPreoperative therapy is widely used in locally advanced rectal cancer. It can improve local control of rectal cancer. However, there are few indicators that can predict the effect of preoperative chemotherapy accurately.AIMTo investigate whether the increase in serum α-fetoprotein (AFP) can predict better efficacy of preoperative chemotherapy.METHODSThis was a retrospective study. We analyzed 125 patients admitted between 2017 and 2019 with locally advanced rectal cancer. All patients received six cycles of preoperative chemotherapy (mFOLFOX6 every 2 wk). Serum AFP of 26 patients rose slightly after three or four cycles of chemotherapy, and fell to normal again within 2 mo. The other 99 patients had a normal level of serum AFP during chemotherapy. Patients were divided into two groups (AFP risen and AFP normal). According to postoperative pathology, we compared tumor regression and complete response rate between the two groups. The primary outcome measure was the tumor regression grade (TRG) after chemotherapy. The difference in pathological complete response between the two groups was also investigated.RESULTSThere were no tumor progression and distant metastasis in both groups during preoperative chemotherapy. Patients in the AFP risen group achieved better TRG 0/1 than those in the AFP normal group (61.5% vs 39.4%). The increase in AFP was a significant predictor for better tumor regression [χ² = 4.144, odds ratio (OR) = 2.666, P = 0.04]. In the AFP risen group, the complete response rate was 30.8%, which was higher than in the AFP normal group (30.8% vs 12.1%, χ² = 4.542, OR = 3.251, P = 0.03).CONCLUSIONPatients with a slight increase in serum AFP can achieve better tumor regression during preoperative chemotherapy, and are more likely to achieve pathological complete response.     

Prognostic impact of peritonealisation in rectal cancer treated with preoperative chemoradiotherapy: Extraperitoneal versus intraperitoneal rectal cancer

Background and purpose

The oncologic outcomes of extraperitoneal (EP) rectal cancer are known to differ from those of intraperitoneal (IP) rectal cancer; however, these differences have not been studied in rectal patients treated by preoperative chemoradiotherapy (CRT). The aim of this study is to evaluate the prognostic impact of peritonealisation in rectal patients treated by preoperative CRT.

Materials and methods

This study analyzed the data of 362 patients who received preoperative CRT and underwent curative surgery for locally advanced rectal cancer at 3-9 cm above the anal verge. Patients were categorised into EP and IP groups based on whether peritonealisation was present, according to pathology reports. The oncologic outcomes between the two groups were compared.

Results

Peritonealisation was absent in 330 patients and present in 32 patients. In univariate analysis, disease-free survival was significantly worse in the EP group than in the IP group (73.0% versus 93.5%, p = 0.035). Multivariate analysis revealed the following independent risk factors for recurrence: the absence of peritonealisation (p = 0.023), ypT stage (p = 0.015) and ypN stage (p < .0001).

Conclusions

Peritonealisation of rectal cancer may be a prognostic factor of disease-free survival in patients with rectal cancer treated by preoperative CRT and surgery.     

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...     

Tumour regression grading after chemoradiotherapy for locally advanced rectal cancer: A near pathologic complete response does not translate into good clinical outcome

Background

After preoperative chemoradiotherapy (CRT) for rectal cancer, clinically undetectable residual tumour deposits or pathologic lymph nodes may remain in the mesorectum.

Aim

The aim of this study was to report histopathological effects of CRT and factors affecting outcome in a uniformly treated series of locally advanced rectal cancer (LARC) patients.

Methods

Between 2004 and 2008, 107 patients with cT3 (threatening the mesorectal fascia or <5 cm from the anal verge), cT4 or cN2 rectal cancer were treated with preoperative CRT (25 × 2 Gy with capecitabine) and TME 6–8 weeks later. Central histopathological review followed. Tumour regression grade (TRG) was scored in pCR, near-pCR, response and no response. Cox regression was performed to identify prognosticators.

Results

The 3-year distant metastasis-free interval, disease-free rate and overall survival rate were 82%, 73% and 87% (median 44 months follow-up). TRG consisted of 20% pCR, 11% near-pCR, 55% response and 14% no response. 6/21 pCR patients harboured nodal metastases. 5/12 near-pCR had ypT3 disease, while 6 harboured node metastases. 5/12 near-PCR patients developed distant metastases. ypN and TRG were powerful outcome discriminators.

Conclusion

The high number of near-pCR with ypT3 or ypN1/2 and their poor outcome demonstrates that “watch-and-wait” in LARC patients should be applied with care.     

Implications for selecting local excision in locally advanced rectal cancer after preoperative chemoradiation

Local excision may offer the possibility of organ preservation for the management of locally advanced rectal cancer after neoadjuvant chemoradiotherapy (CRT). However, the oncological outcomes of this strategy have been largely associated with the risk of nodal metastases. In this study, Surveillance, Epidemiology, and End Results Program (SEER)-registered rectal cancer patients, and patients from Fudan University Shanghai Cancer Center (FUSCC) after preoperative chemoradiation were combined to analyze the incidence of lymph node metastasis. The results showed that there was a high risk for residual lymph node metastasis among patients even with complete pathologic response of primary tumor after preoperative CRT (12.6–13.2%). However, in the selected group of patients with pre-CRT MRI staging cN0 rectal cancer, there was only one ypN+ case (3.3%) in ypT0–1 group. These results suggest that pre-CRT MRI staging cN0 patients achieved ypT0–1 of bowel wall tumor may be suitable for local resection.