Aspirin as a neoadjuvant agent during preoperative chemoradiation for rectal cancer

Background:

Recently, many studies have suggested a possible adjuvant role of aspirin in colorectal cancer, reporting a positive prognostic effect with its use in patients with established disease. The aim of this study was to investigate the anticancer effect of aspirin use during preoperative chemoradiation for rectal cancer.

Methods:

Two hundred and forty-one patients with stage II–III rectal cancer and candidates for chemoradiation (CRT) were selected and assigned to two groups: group 1, patients taking aspirin at the time of diagnosis, and group 2, all others. Treatment and oncological outcomes were explored.

Results:

Aspirin use was associated with a higher rate of tumour downstaging (67.6% vs 43.6%, P=0.01), good pathological response (46% vs 19% P<0.001), and a slightly, although not significant, higher rate of complete pathological response (22% vs 13% P=0.196). Aspirin use was also associated with a better 5-year progression-free survival (86.6% vs 67.1% hazard rate (HR)=0.20; 95% CI=0.07–0.60) and overall survival (90.6% vs 73.2% HR=0.21; 95% CI=0.05–0.89). Although chance of local relapse was similar (HR=0.6; 95% CI=0.06–4.5), aspirin use was associated with a lower risk of developing metastasis (HR=0.30; 95% CI=0.10–0.86).

Conclusions:

Aspirin might have anticancer activity against rectal cancer during preoperative CRT. This finding could be clinically relevant and should be further investigated with randomised trials.     

Predictors of tumor response and downstaging in patients who receive preoperative chemoradiation for rectal cancer

BACKGROUND: The objective of this study was to identify predictive factors for pathologic complete response and tumor downstaging after preoperative chemoradiation for rectal cancer. METHODS: Between 1989 and 2004, 562 patients with nonmetastatic rectal adenocarcinoma received preoperative chemoradiation and underwent mesorectal excision. The median radiation dose was 45 Gray (Gy) (range, 19.8-58.6 Gy), 77% of patients received concurrent infusional 5-fluorouracil, 20% of patients received concurrent capecitabine, and 3% of patients received other regimens. RESULTS: Nineteen percent of patients achieved a pathologic complete response (CR), whereas 20% of patients had only microscopic residual disease at surgery, and 61% of patients had macroscopic residual disease at surgery. Downstaging of the tumor stage occurred in 57% of patients. The results from a univariate analysis indicated that tumor circumferential extent>60% (P=.033) and pretreatment carcinoembryonic antigen (CEA) level>2.5 ng/mL (P=.015) were associated significantly with lower pathologic CR rates. The univariate analysis also indicated that tumor circumferential extent>60% (P=.001), pretreatment CEA level>2.5 ng/mL (P=.006), and distance from the anal verge>5 cm (P=.035) were associated significantly with lower downstaging rates. The results from a multivariate logistic regression analysis indicated that greater circumferential extent of tumor (odds ratio [OR], 0.43; P=.033) independently predicted a lower pathologic CR rate. The multivariate logistic regression analysis also indicated that greater circumferential extent of tumor (OR, 0.49; P=.020) and greater distance from the anal verge (OR, 0.46; P=.010) independently predicted a lower downstaging rate. CONCLUSIONS: Circumferential extent of tumor, CEA level, and distance from the anal verge predicted for the pathologic response to preoperative chemoradiation for patients with rectal cancer. Therefore, these factors may be used to predict outcomes for patients, to develop risk-adapted treatment strategies, and to target patients who participate in trials of newer therapies.     

The role of targeted agents in preoperative chemoradiation for rectal cancer

In the United States, randomized trials have established preoperative chemoradiation as the standard of care for patients with locally advanced rectal cancer. Pathologic complete response (pCR) rates occur in 10% to 16% of patients and have been shown to be correlated with both disease‐free and overall survival. Therefore, recent efforts incorporating newer cytotoxic and molecularly targeted agents into chemoradiotherapy regimens have reported the pCR rate to be a surrogate marker of clinical outcomes. Substitution of oral fluoropyrimidines, including capecitabine, for infusional 5‐fluorouracil reportedly generated pCR rates of up to 32% in phase 2 studies, but definitive evaluation awaits results from the National Surgical Adjuvant Breast and Bowel Project (NSABP) R‐04 trial. Similarly, regimens incorporating irinotecan generated pCR rates as high as 38%, but to the authors' knowledge have not been evaluated in randomized trials. In contrast, 2 large randomized trials reported that the addition of weekly oxaliplatin to fluoropyrimidine‐based chemoradiation led to an increase in grade 3/4 toxicity but no difference in pCR rates. Early phase trials evaluating the anti‐epidermal growth factor receptor (EGFR) antibody cetuximab in combination with chemoradiation reported modest pCR rates of 5% to 12%, and efforts have focused on identifying biomarkers of response including EGFR copy number, k‐ras mutational status, and both serum and tumor‐specific expression of EGFR ligands. Finally, incorporation of the anti‐vascular endothelial growth factor antibody bevacizumab into chemoradiation appears to be safe and feasible, with initial studies reporting a beneficial effect on vascular normalization and correlations between circulating biomarkers of angiogenesis and pathologic response. Future efforts should include prospective studies of these agents in biomarker‐defined subpopulations, as well as studies of novel agents that target angiogenesis, tumor‐stromal interaction, and the cell signaling pathways implicated in colorectal cancer. Cancer 2010. © 2010 American Cancer Society.     

Serum CEA as a predictor for the response to preoperative chemoradiation in rectal cancer

BACKGROUND AND OBJECTIVES: Recent data suggest that good responders to preoperative chemoradiation (CRT) have a favorable prognosis in rectal cancer patients. The aim of this study was to investigate the predictive value of serum carcinoembryonic antigen (CEA) levels for the tumor response to preoperative CRT in rectal cancer patients. METHODS: The study comprised 141 rectal adenocarcinoma patients who underwent preoperative radiotherapy with 5-fluorouracil (FU) based chemotherapy, followed by radical surgery. The staging workup was consisted of endorectal ultrasound, abdominopelvic computed tomography scan, or magnetic resonance imaging. The outcome parameters were cancer-specific survival and disease-free survival. Pre-CRT clinicopathologic features, including age, gender, location of the tumor, clinical tumor (cT) classification, clinical nodal (cN) classification, and serum CEA levels were investigated as possible predictors for the response to preoperative CRT. RESULTS: Pathologic complete or near complete responses (good responders, GR) occurred in 26 (19%) patients, while partial or no response (poor responders, PR) occurred in the remaining 115 (81%) patients. GR showed better cancer-specific survival (P = 0.028) and disease-free survival rates (P = 0.011) than PR. Univariate analysis revealed that positive cN and elevated (>5 ng/ml) pre-CRT serum CEA levels are associated with poor tumor response to preoperative CRT. Using logistic regression analysis, elevated pre-CRT serum CEA levels were the only significant predictor for the poor response to CRT (Odd ratio = 2.876, 95% confidence interval = 1.04-7.46, P = 0.041). CONCLUSIONS: Our data suggest that elevated pre-CRT serum CEA levels are associated with poor tumor response to CRT. Therefore, pre-CRT serum CEA levels provide useful information about tumor response to preoperative CRT in rectal cancer patients.     

Methylenetetrahydrofolate reductase genetic polymorphisms and toxicity to 5-FU-based chemoradiation in rectal cancer

Background:

There is a large degree of variation in tumour response and host toxicities associated with neoadjuvant chemoradiation for rectal cancer patients. We performed a complimentary pharmacogenetic study to investigate germline polymorphisms of genes involved in 5-fluorouracil (5-FU) and irinotecan pathways and their potential association with clinical outcomes and toxicities from neoadjuvant chemoradiation in patients with rectal cancer treated in a prospective genotype-directed study.

Methods:

The germline DNA of 131 patients was genotyped for 10 variants in TYMS, MTHFR, DPYD, UGT1A1, ABCC1 and SLCO1B1 genes. Ninety-six patients were treated with 5-FU/radiotherapy (RT) and 35 received 5-FU/RT/irinotecan. Relationships between genetic variants and adverse events, tumour response, overall and disease-free survivals were assessed.

Results:

MTHFR 1298A>C and MTHFR diplotypes (for 677C>T and 1298A>C) were associated with chemoradiation-related toxicity when 5-FU was used alone. MTHFR haplotypes (677C–1298C) and diplotypes (CA–TA and TA–TA) showed, respectively, a protective and a negative effect on the incidence of severe diarrhoea or mucositis. No association was observed between genetic markers and drug response.

Conclusion:

MTHFR polymorphisms can potentially predict toxicity in patients treated with 5-FU as a single chemotherapeutic drug.     

Improved incidence of pT0 downstaged surgical specimens in locally advanced rectal cancer (LARC) treated with induction oxaliplatin plus 5-fluorouracil and preoperative chemoradiation.

PURPOSE: To compare efficacy in terms of pathologic response in LARC patients treated with preoperative chemoradiation, with or without a short-intense course of induction oxaliplatin. PATIENTS AND METHODS: From 05/98 to 10/02, 114 patients were treated with preoperative chemoradiation (4500-5040 cGy + oral Tegafur 1200 mg/day) for cT(3)-(4)N(+/x)M(0) rectal cancer. Starting 05/01, 52 consecutive patients additionally received induction FOLFOX-4, oxaliplatin (85 mg/m(2) iv d1), 5-FU (400 mg/m(2) iv bolus d1) and 600 mg/m(2) iv continuous infusion in 22 h with leucovorin (200 mg iv) d1 and d2, every 15 days (2 cycles), followed by the previously described Tegafur chemoradiation regime. Surgery was performed in 5-6 weeks. Pathological assessment investigated post-treatment T and N status in the rectal wall and peri-rectal tissues. RESULTS: Patients, tumor and treatment characteristics were comparable between groups. Incidence of pT(0) specimens was significantly increased by induction FOLFOX-4 (P = 0.006). Total T and N downstaging were 58% versus 75% and 42% versus 40%, respectively (P = ns). T downstaging of > or =2 categories was significantly superior in FOLFOX-4 group (P = 0.029). CONCLUSIONS: Short-intense induction FOLFOX-4 significantly improves pathologic complete response in LARC patients treated with tegafur-sensitized preoperative chemoradiation. The 44% rate of pT(0)-(1) specimens observed in the oxaliplatin group should impulse innovative surgical approaches to promote ano-rectal sphincter conserving protocols.     

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...     

直肠癌新辅助放化疗敏感性预测进展

直肠癌是我国最常见的恶性肿瘤之一。近年来,直肠癌的新辅助放疗或放疗联合化疗及全直肠系膜切除的根治术已逐步成为治疗中下段进展期直肠癌的标准模式。目前已经有大量研究证实新辅助治疗的优点,但尚有一部分患者无法在其中受益。在新辅助放化疗前或其早期预测其敏感性,达到肿瘤的“个体化治疗”,目前在这方面已经进行了大量研究。本文将就预测新辅助治疗敏感性的进展进行综述。     

Tegafur and 5-fluorouracil pelvic tissue concentrations in rectal cancer patients receiving preoperative chemoradiation

Background and purpose To investigate the presence of 5-Fluorouracil (5-FU) in pelvic tissue after oral administration of tegafur. To measure tegafur and 5-FU concentrations in normal rectal mucosa, perirectal fat and residual tumor in rectal cancer patients receiving preoperative chemoradiation. To correlate drug concentrations with cancer down-staging effects. Patients and methods Three tissue samples taken from 16 surgical specimens after recto-sigmoid resection were analyzed. Tegafur and 5-FU concentrations were measured using high-performance liquid chromatography. 16 patients with locally advanced rectal cancer were treated with preoperative pelvic irradiation (45–50 Gy) sensitized with oral tegafur (400 mg for every 8 hours daily). Seven patients received a precharge dose of tegafur (400 mg oral every 8 hours) 24 hours before surgery. Results In 8 of the 9 patients who did not receive a precharge dose, detectable levels of tegafur were observed in fat tissue, normal mucosa and tumor, but detectable 5-FU levels were only observed in one patient. Mean concentrations (ranges) for tegafur in fat, normal mucosa and tumor in patients without the precharge dose were 72.19 (12.1–205.6), 179.53 (11.30–727.7) and 252.35 (27.9–874.6) ng/g, respectively; mean concentrations for 5-FU in the same samples were 0.95, 1.92 and 2.68 ng/g (1 patient), respectively. In patients receiving a tegafur precharge, both tegafur and 5-FU were present in all tissue samples with the exception of 2 fat samples, in which drug concentrations were undetectable. 5-FU levels were higher in tumor than other sites, with a median value of 68.24 ng/g (range 3.8–283.05 ng/g). Tegafur levels were also higher in tumor samples than other sites (mean 3446.53 ng/g, range 1044.5–7847.0 ng/g), except in 2 patients who had higher levels of tegafur in normal mucosa. Conclusions Tegafur and 5-FU are not always present in pelvic tissues 5 to 6 weeks after oral administration of tegafur. Both drugs were present in the tissues analyzed, in relevant concentrations, 24 hours after oral administration of tegafur. The data obtained suggest a tendency (not significant) toward a correlation between levels of 5-FU present in the residual tumor and cancer down staging. Scientifically supervised by GICOR (Grupo de Investigación Clínica en Oncología Radioterápica).     

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。     

Preoperative downstaging chemoradiation with concurrent irinotecan and capecitabine in MRI-defined locally advanced rectal cancer: a phase I trial (NWCOG-2)

Background:

The aim of this study was to investigate the safety of neoadjuvant chemoradiation using radiotherapy (RT) combined with concurrent capecitabine and irinotecan for locally advanced rectal cancer before surgery.

Methods:

Forty-six patients were recruited and treated on the basis that MRI scanning had shown poor-risk tumours with threatening (⩽1 mm) or involvement of the mesorectal fascia. Conformal RT was given using 3 or 4 fields at daily fractions of 1.8 Gy on 5 days per week to a total dose of 45 Gy. Concurrently oral capecitabine was given twice daily throughout radiotherapy continuously from days 1 to 35 and intravenous irinotecan was given once per week during weeks 1 to 4 of RT. Dose levels were gradually escalated as follows. Dose level 1: capecitabine 650 mg m⁻² b.i.d. and irinotecan 50 mg m⁻²; Dose level 2: capecitabine 650 mg m⁻² b.i.d. and irinotecan 60 mg m⁻²; Dose level 3: capecitabine 825 mg m⁻² b.i.d. and irinotecan 60 mg m²; Dose level 4: capecitabine 825 mg m⁻² b.i.d. and irinotecan 70 mg m⁻².

Results:

Diarrhoea (grade 3, no grade 4) was the main serious acute toxicity with lesser degrees of fatigue, neutropenia, anorexia and palmar-plantar erythrodysesthesia. The recommended dose for future study was dose level 2 at which 3 of 14 patients (21%) developed grade 3 diarrhoea. Postoperative complications included seven pelvic or wound infections and two anastomotic and two perineal wound dehiscences. There were no deaths in the first 30 days postoperatively. Of 41 resected specimens, 11 (27%) showed a pathological complete response (pCR) and five (12%) showed an involved circumferential resection margin (defined as ⩽1 mm). The 3-year disease-free survival (intent-to-treat) was 53.2%.

Conclusion:

In patients with poor-risk MRI-defined locally advanced rectal cancer threatening or involving the mesorectal fascia, preoperative chemoradiation based on RT at 45 Gy in 25 daily fractions over 5 weeks with continuous daily oral capecitabine at 650 mg m⁻² b.i.d. days 1–35 and weekly IV irinotecan at 60 mg m⁻² weeks 1–4, provides acceptable acute toxicity and postoperative morbidity with encouraging response and curative resection rates.     

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.     

Differences in toxicity across gender in patients treated with chemoradiation for rectal cancer

The primary objective was to prospectively investigate the efficacy and toxicity of bolus 5‐fluorouracil (5‐FU) chemotherapy compared with the infusional 5‐FU in combination with preoperative radiation in patients with locally advanced rectal cancer. Furthermore, in light of previous reports, toxicity profiles between men and women were also compared. Eighty‐four consecutive patients with rectal adenocarcinoma were prospectively treated. There were no differences in tumour response, local recurrence or survival between bolus versus infusional groups or gender groups. In locally advanced rectal cancer, preoperative infusional chemotherapy combined with radiation was found to be less toxic than bolus chemotherapy and radiotherapy. Both regimens produced more toxic effects in women compared with men.