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Addition of platinum derivatives to neoadjuvant single-agent fluoropyrimidine chemoradiotherapy in patients with stage II/III rectal cancer: protocol for a systematic review and meta-analysis (PROSPERO CRD42017073064).

ABSTRACT: Neoadjuvant (chemo-)radiation has proven to improve local control compared to surgery alone, but this improvement did not translate into better overall or disease-specific survival. The addition of oxaliplatin to fluoropyrimidine-based neoadjuvant chemoradiotherapy holds the potential of positively affecting survival in this context since it has been proven effective in the palliative and adjuvant setting of colorectal cancer. Thus, the objective of this systematic review is to assess the efficacy, safety, and quality of life resulting from adding a platinum derivative to neoadjuvant single-agent fluoropyrimidine-based chemoradiotherapy in patients with Union for International Cancer Control stage II and III rectal cancer.MEDLINE, Web of Science, and Cochrane Central Register of Controlled Trials will be systematically searched to identify all randomized controlled trials comparing single-agent fluoropyrimidine-based chemoradiotherapy to combined neoadjuvant therapy including a platinum derivative. Predefined data on trial design, quality, patient characteristics, and endpoints will be extracted. Quality of included trials will be assessed according to the Cochrane Risk of Bias Tool, and the GRADE recommendations will be applied to judge the quality of the resulting evidence. The main outcome parameter will be survival, but also treatment toxicity, perioperative morbidity, and quality of life will be assessed.The findings of this systematic review and meta-analysis will provide novel insights into the efficacy and safety of combined neoadjuvant chemoradiotherapy including a platinum derivative and may form a basis for future clinical decision-making, guideline evaluation, and research prioritization.PROSPERO CRD42017073064.

SUBMITTER: Huttner FJ

PROVIDER: S-EPMC5778669 | biostudies-other | 2018 Jan

REPOSITORIES: biostudies-other

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Addition of platinum derivatives to neoadjuvant single-agent fluoropyrimidine chemoradiotherapy in patients with stage II/III rectal cancer: protocol for a systematic review and meta-analysis (PROSPERO CRD42017073064).

Hüttner Felix J FJ Probst Pascal P Kalkum Eva E Hackbusch Matthes M Jensen Katrin K Ulrich Alexis A Büchler Markus W MW Diener Markus K MK

Systematic reviews 20180122 1

<h4>Background</h4>Neoadjuvant (chemo-)radiation has proven to improve local control compared to surgery alone, but this improvement did not translate into better overall or disease-specific survival. The addition of oxaliplatin to fluoropyrimidine-based neoadjuvant chemoradiotherapy holds the potential of positively affecting survival in this context since it has been proven effective in the palliative and adjuvant setting of colorectal cancer. Thus, the objective of this systematic review is t ...[more]

PMID: 29357929

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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:Background: Neoadjuvant chemoradiotherapy (NCRT) is the treatment of choice in advanced rectal cancer, even though there are many patients who will not benefit from it. There are still no effective methods for predicting which patients will respond or not. The present study aimed to define the genomic profile of rectal tumors and to identify alterations that are predictive of response in order to optimize therapeutic strategies. Methods: Forty-eight candidates for NCRT were recruited and their pretherapy biopsies analyzed by array Comparative Genomic Hybridization (aCGH). Pathologic response was evaluated by tumor regression grade (TRG).Results: Both Smoothing and Hidden Markov Model (HMM) approaches identified similar alterations, with a prevalence of DNA gains. Non responsive patients had a different alteration profile from responsive ones, with a higher number of genome changes mainly located on 2q21, 7q21, 7q36, 13q12, 13q32-34, 16p13, 17p12 chromosomal regions. Conclusion: This exploratory study suggests that an in depth characterization of chromosomal alterations by aCGH would provide useful predictive information about response to NCRT and help to optimize therapy in rectal cancer patients. 48 samples included in the study were analyzed on whole genome BAC arrays with the aim to characterize genomic alterations and correlate them with the tumor response to therapy. The case series was composed by 15%,81% and 4% of uT2, uT3 and uT4 tumors, respectively. At the diagnosis 56% of patients had uN0 tumors and 44% uN+. 30%,13%, 23% and 34% of patients reached/mantained respectively ypT0, ypT1, ypT2 and ypT3. With regard to response to NCRT, according to TRG criteria proposed by Dworak, two group were defined: non responders (TRG0-2= 56%) and responders (TRG3-4=44%). Clinical and pathological parameters: uT: pre-therapy stage determined by ultrasounds techniques uN: pre-therapy lymph node status determined by ultrasounds techniques ypT: pathologic stage after a neoadjuvant treatment ypN: pathologic lymph node status after a neoadjuvant treatment

Project description:BackgroundThe purpose of this study was to develop a large population-based nomogram incorporating the log odds of positive nodes (LODDS) for predicting the overall survival (OS) of stage II/III rectal cancer patients treated with neoadjuvant chemoradiotherapy (NCRT) followed by surgical resection.MethodsThe Surveillance, Epidemiology, and End Results database was used to collect information on patients diagnosed with stage II/III rectal cancer between 2010 and 2015 and treated with NCRT followed by surgical resection. The Cox regression analyses were performed to determine the independent prognostic factors. In this study, LODDS was employed instead of American Joint Committee on Cancer (AJCC) 7th N stage to determine lymph node status. Then a nomogram integrating independent prognostic factors was developed to predict the 24-, 36-, and 60-month overall survival. The receiver operating characteristic (ROC) curves and calibration curves were used to validate the nomogram. Furthermore, patients were stratified into three risk groups (high-, middle-, and low-risk) based on the total points obtained from the nomogram. And Kaplan-Meier curves were plotted to compare the OS of the three groups.ResultsA total of 3829 patients were included in the study. Race, sex, age, marital status, T stage, tumor grade, tumor size, LODDS, CEA level, and postoperative chemotherapy were identified as independent prognostic factors, based on which the prognostic nomogram was developed. The area under curve values of the nomogram for the 24-, 36-, and 60-month OS in the training cohort were 0.736, 0.720, and 0.688, respectively; and 0.691, 0.696, and 0.694 in the validation cohort, respectively. In both the validation and training cohorts, the calibration curves showed a high degree of consistency between actual and nomogram-predicted survival rates. The Kaplan-Meier curves showed that the three risk groups had significant differences in overall survival (P < 0.001).ConclusionA large population-based nomogram incorporating LODDS was developed to assist in evaluating the prognosis of stage II/III rectal cancer patients treated with NCRT followed by surgical resection. The nomogram showed a satisfactorily discriminative and stable ability to predict the OS for those patients.

Dataset Information

Addition of platinum derivatives to neoadjuvant single-agent fluoropyrimidine chemoradiotherapy in patients with stage II/III rectal cancer: protocol for a systematic review and meta-analysis (PROSPERO CRD42017073064).

Publications

Addition of platinum derivatives to neoadjuvant single-agent fluoropyrimidine chemoradiotherapy in patients with stage II/III rectal cancer: protocol for a systematic review and meta-analysis (PROSPERO CRD42017073064).

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