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Systematic review of treatment intensification using novel agents for chemoradiotherapy in rectal cancer.

ABSTRACT: BACKGROUND:With the well established shift to neoadjuvant treatment for locally advanced rectal cancer, there is increasing focus on the use of radiosensitizers to improve the efficacy and tolerability of radiotherapy. There currently exist few randomized data exploring novel radiosensitizers to improve response and it is unclear what the clinical endpoints of such trials should be. METHODS:A qualitative systematic review was performed according to the PRISMA guidelines using preset search criteria across the PubMed, Cochrane and Scopus databases from 1990 to 2017. Additional results were generated from the reference lists of included papers. RESULTS:A total of 123 papers were identified, of which 37 were included; a further 60 articles were obtained from additional referencing to give a total of 97 articles. Neoadjuvant radiosensitization for locally advanced rectal cancer using fluoropyrimidine-based chemotherapy remains the standard of treatment. The oral derivative capecitabine has practical advantages over 5-fluorouracil, with equal efficacy, but the addition of a second chemotherapeutic agent has yet to show a consistent significant efficacy benefit in randomized clinical assessment. Preclinical and early-phase trials are progressing with promising novel agents, such as small molecular inhibitors and nanoparticles. CONCLUSION:Despite extensive research and promising preclinical studies, a definite further agent in addition to fluoropyrimidines that consistently improves response rate has yet to be found.

SUBMITTER: Clifford R

PROVIDER: S-EPMC6282533 | biostudies-other | 2018 Nov

REPOSITORIES: biostudies-other

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Systematic review of treatment intensification using novel agents for chemoradiotherapy in rectal cancer.

Clifford R R Govindarajah N N Parsons J L JL Gollins S S West N P NP Vimalachandran D D

The British journal of surgery 20181101 12

<h4>Background</h4>With the well established shift to neoadjuvant treatment for locally advanced rectal cancer, there is increasing focus on the use of radiosensitizers to improve the efficacy and tolerability of radiotherapy. There currently exist few randomized data exploring novel radiosensitizers to improve response and it is unclear what the clinical endpoints of such trials should be.<h4>Methods</h4>A qualitative systematic review was performed according to the PRISMA guidelines using pres ...[more]

PMID: 30311641

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Project description:BackgroundTotal neoadjuvant therapy (TNT) is a novel approach for locally advanced rectal cancer (LARC), which attempts to deliver both systemic chemotherapy and neoadjuvant chemoradiotherapy prior to surgery. However, its efficacy and safety remain controversial in randomized controlled trials (RCTs). We conducted this meta-analysis to assess such concerns.Materials and methodsHead-to-head phase II/III RCTs were searched in Embase, PubMed, Web of Science, and the Cochrane Library, as well as other sources. The primary endpoint was pathologic complete response (pCR). Secondary endpoints were disease-free survival (DFS), overall survival (OS), local recurrence-free survival, distant metastasis-free survival, and the R0 resection rate.ResultsEight phase II/III RCTs involving 2,196 patients with LARC were assessed. The primary analysis demonstrated a statistically significant improvement in the pCR rate for TNT treatment (odds ratio, 1.77; 95% confidence interval [CI], 1.28-2.45; p = .0005). TNT treatment also showed improvements in DFS and OS outcomes compared with standard chemoradiotherapy (hazard ratio [HR], 0.83; 95% CI, 0.72-0.96; p = .03 and HR, 0.88; 95% CI, 0.74-1.05; p = .15). In addition, TNT treatment showed significant efficacy in reducing the risk of distant metastasis (HR, 0.81; 95% CI, 0.68-0.95; p = .012).ConclusionThe overall pCR rate may be improved with TNT compared with standard treatment. The TNT strategy may also improve DFS and OS and reduce the risk of distant metastasis.Implications for practiceLocally advanced rectal cancer (LARC) is a relatively common disease, with a poor prognosis because of its high metastatic potential. The role of total neoadjuvant therapy (TNT) has always been controversial. This meta-analysis found that TNT in LARC is associated with a significant improvement in overall pathologic complete response rate, disease-free survival, overall survival, and distant metastasis-free survival compared with standard treatment. TNT is a promising strategy for LARC, especially for patients who have little desire for surgery.

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.

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Systematic review of treatment intensification using novel agents for chemoradiotherapy in rectal cancer.

Publications

Systematic review of treatment intensification using novel agents for chemoradiotherapy in rectal cancer.

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