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Treatment outcomes regarding the addition of targeted agents in the therapeutic portfolio for stage II-III rectal cancer undergoing neoadjuvant chemoradiation.

ABSTRACT: To evaluate the impact of targeted agents in stage II-III rectal cancer undergoing neoadjuvant concurrent chemoradiation therapy (CCRT).A retrospective study was performed in 124 consecutive patients with clinically T3N0-2M0-staged rectal cancer incorporating targeted agents in CCRT.Pathologic complete response was detected in 34.2% (n=26) of bevacizumab+FOLFOX-treated patients (n=76), which was significantly higher (p=0.019, post-hoc statistical power =35.87%) than that (n=10, 20.8%) of the cetuximab+FOLFOX-treated patients (n=48). Patients receiving cetuximab+FOLFOX therapy tended to develop severe liver toxicity (91.7%, n=44 versus 17.1%, n=13, p<0.0001), as evaluated by morphologic grading of hepatic steatosis and sinusoidal dilatation in laparoscopy. In the 57 patients with morphologically severe liver toxicity, 36 (63.2%) retained a normal liver function; for the remaining 21 patients with an abnormal liver function, the abnormality was self-limited in 19 patients, whereas 2 cetuximab-treated patients progressed to hepatic failure and mortality. A subset analysis within bevacizumab+FOLFOX-treated patients with either wild-type (n=36) or mutant (n=40) K-ras status indicated K-ras status did not significantly influence the treatment outcomes.The addition of bevacizumab instead of cetuximab to FOLFOX in the neoadjuvant settings for T3N0-2M0-staged rectal cancer could induce a promising rate of pathologic complete response and lesser hepatotoxicity.

SUBMITTER: Liang JT

PROVIDER: S-EPMC5731917 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundCurrent guidelines recommend neoadjuvant therapy for patients with stage II or III rectal cancer. The addition of platinum derivatives to fluoropyrimidine-based chemoradiotherapy has been frequently investigated, but their role in this setting remains controversial.MethodsPubMed, Cochrane Library, and Web of Science were systematically searched for randomized trials comparing chemoradiotherapy with or without platinum agents in stage II or III rectal cancer. Main outcome parameters were overall and disease-free survival, additional outcomes included pathological complete response, isolated local recurrence, distant recurrence, toxicity, and perioperative morbidity. Time-to-event data were pooled as hazard ratios (HRs) by the inverse variance method and binary outcomes as odds ratios (ORs) by the Peto method with their respective 95% confidence interval (CI). All statistical tests were two-sided.ResultsTen randomized controlled trials with data on 5599 patients were included in the meta-analysis. Platinum derivatives did not statistically significantly improve overall survival (HR = 0.93, 95% CI = 0.82 to 1.05, P?=?.23), disease-free survival (HR = 0.91, 95% CI = 0.83 to 1.01, P?=?.07), or local recurrence (OR = 0.83, 95% CI = 0.66 to 1.05, P?=?.12). However, it led to a statistically significant increase of pathological complete response (OR = 1.31, 95% CI = 1.10 to 1.55, P?=?.002) and a statistically significant reduction of distant recurrence (OR = 0.78, 95% CI = 0.66 to 0.92, P?=?.004). Benefits were accompanied by higher rates of grade 3 or 4 toxicities.ConclusionsIntensified neoadjuvant chemoradiotherapy with the addition of platinum derivatives cannot be recommended routinely because it did not improve overall or disease-free survival and was associated with increased toxicity. It needs to be elucidated whether the benefits in distant recurrence and pathological complete response may be advantageous for selected high-risk patients.

Project description:The neutrophil-lymphocyte ratio (NLR) has been proposed as an indicator of systemic inflammatory response and may predict the clinical outcome in some cancers, such as head and neck cancer and gastric cancer. However, the value of this ratio is variable in different cancers. Studies of the relationship between NLR and both survival and response to chemoradiation have been limited with respect to locally advanced rectal cancer.From 2006 to 2011, 199 consecutive locally advanced rectal cancer patients who were treated with neoadjuvant chemoradiation in the Shanghai Cancer Center were enrolled and analysed retrospectively. Tumor response was evaluated by pathological findings. The baseline total white blood cell count (WBC) and the neutrophil, lymphocyte, platelet counts were recorded. The neutrophil-lymphocyte ratio (NLR) and the relationship with clinical outcomes such as overall survival (OS) and disease-free survival (DFS) was analyzed.With ROC analysis, the baseline NLR value was found to significantly predict prognosis in terms of OS well in locally advanced rectal cancer patients. A multivariate analysis identified that a cut-off value of NLR???2.8 could be used as an independent factor to indicate decreased OS (HR, 2.123; 95% CI, 1.140-3.954; P?=?0.018). NLR???2.8 was also associated with worse DFS in univariate analysis (HR, 1.662; 95% CI, 1.037-2.664; P?=?0.035), though it was not significant in the multivariate analysis (HR, 1.363; 95% CI, 0.840-2.214; P?=?0.210). There was no observed significant correlation of mean value of NLR to the response to neoadjuvant chemoradiation. The mean NLR in the ypT0-2 N0 group was 2.68?±?1.38, and it was 2.77?±?1.38 in the ypT3-4/N+ group, with no statistical significance (P?=?0.703). The mean NLR in the TRG 0-1 group was 2.68?±?1.42, and it was 2.82?±?1.33 in the TRG 2-3 group with no statistical significance (P?=?0.873).An elevated baseline NLR is a valuable and easily available prognostic factor for OS in addition to tumor response after neoadjuvant therapy. Baseline NLR could be a useful candidate factor for stratifying patients and making treatment decisions in locally advanced rectal cancer.

Project description:The purpose of this prospective pilot study was to determine the efficacy of preoperative chemotherapy with six cycles of FOLFOX 6 (without radiation therapy) followed by radical surgery followed by six additional cycles of FOLFOX 6 for patients with stage II/III rectal cancer.From January 2010 to January 2014, patients with locally advanced rectal cancer who met the eligibility criteria were enrolled in this study. Patients received FOLFOX 6 chemotherapy comprising oxaliplatin and leucovorin calcium i.v. over 2 hours on day 1, then bolus, and then continuous fluorouracil i.v. over 46 hours on days 1 and 2. Treatment was repeated every 14 days for 6 courses followed by radical surgery followed by additional 6 cycles of FOLFOX 6.In total, 45 patients were enrolled in this study. In the preoperative re-evaluation, the overall response rate was 68.8% (clinical complete response was 4.4%, and the partial response was 64.4%). There were 14 cases (31.2%) of stable disease. No patients had progressive disease. Postoperatively, the pathologic complete response rate was 8 of 45 (17.8%; 95% confidence interval [CI]: 8.9%-28.9%). The median follow-up was 29 months (range 9-54 months). The actuarial 3-year overall survival and disease-free survival rates for all patients were 80.8% (standard error, 1.877; 95% CI: 69.3%-92.3%) and 67.9% (standard error, 2.319; 95% CI: 54.3%-81.5%), respectively.Neoadjuvant chemotherapy (FOLFOX) without radiotherapy is active and safe but cannot be considered a standard of care until the results of prospective randomized phase III trials are available.Neoadjuvant radiotherapy of rectal cancer represents the current standard of care. However, its use is also associated with short-term toxicity and long-term morbidity. With the increasing use of total mesorectal resection resulting in better local control and advances in systemic therapy for colorectal cancer, this study highlights the question of whether radiation is a necessary component of neoadjuvant therapy for all patients with rectal cancer or whether select patients could be spared the additional toxicities and inconvenience of radiotherapy. This study suggests that neoadjuvant FOLFOX without radiotherapy is active and safe, but it could not be considered a standard of care till now.

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Treatment outcomes regarding the addition of targeted agents in the therapeutic portfolio for stage II-III rectal cancer undergoing neoadjuvant chemoradiation.

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