Is There a Benefit of Oxaliplatin in Combination with Neoadjuvant Chemoradiotherapy for Locally Advanced Rectal Cancer? An Updated Meta-Analysis

Background: Neoadjuvant fluoropyrimidine (5FU or capecitabine)-based chemoradiotherapy (CRT) has been considered the standard of care for locally advanced rectal cancer (LARC). Whether addition of oxaliplatin (OXP) will further improve clinical outcomes is still unclear. Methods: To identify clinical trials combining oxaliplatin in preoperative CRT or perioperative chemotherapy for LARC published until March 2021, we searched PubMed and the Cochrane Library. We also searched for relevant ASCO conference abstracts. The primary endpoint was disease-free survival (DFS). Data were extracted from every study to perform a meta-analysis using Review Manager (version 5.3). Results: A total of seven randomized clinical trials (ACCORD-12, CARO-AIO-04, FOWARC, JIAO, NSABP, PETACC-6, and STAR-01) with 5782 stage II or III rectal cancer patients were analyzed, including 2727 patients with OXP + 5FU regimen and 3055 patients with 5FU alone. Compared with the 5FU alone group, the OXP + 5FU regimen improved DFS (HR = 0.90, 95% CI: 0.81–0.99, p = 0.03) and pathologic complete response (pCR) (OR = 1.21, 95% CI: 1.07–1.37, p = 0.002). Patients treated with the OXP + 5FU regimen had significantly less metastatic progression (OR = 0.79; 95% CI, 0.67 to 0.94; p = 0.007). Considering adverse events (AEs), there was more grade 3–4 diarrhea with OXP + 5FU (OR = 2.41, 95% CI: 1.74–3.32, p < 0.00001). However, there were no significant differences grade 3–4 hematologic AEs (OR = 1.16, 95% CI: 0.87–1.57, p = 0.31). Conclusions: Our meta-analysis with long-term results from the randomized studies showed a benefit of the addition of OXP + 5FU regiment in terms of DFS, metastatic progression, and pCR rate that did not translate to improved OS.

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Is there a benefit of oxaliplatin in neoadjuvant treatment of locally advanced rectal cancer? An updated meta-analysis.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.4098 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. 4098-4098

Author(s):

Gaetan Des Guetz ◽

Thierry Landre ◽

Anne Larrouy ◽

Yves Panis ◽

Jean F. Morere ◽

...

Keyword(s):

Rectal Cancer ◽

Clinical Trials ◽

Meta Analysis ◽

Locally Advanced ◽

Pathologic Complete Response ◽

Advanced Rectal Cancer ◽

Locally Advanced Rectal Cancer ◽

Cochrane Library ◽

Perioperative Chemotherapy ◽

Grade 3

4098 Background: Neoadjuvant fluoropyrimidine (5FU or capecitabine)-based chemoradiotherapy (CRT) has been considered the standard of care for locally advanced rectal cancer (LARC). Whether addition of oxaliplatin (OXP) will further improve clinical outcomes is still unclear. Methods: To identify clinical trials combining oxaliplatin in preoperative CRT or perioperative chemotherapy for LARC published until December 2019, we searched PubMed, the Cochrane Library. We also search for relevant ASCO conferences. Primary endpoint was Disease-Free-Survival (DFS). Data were extracted from every study to perform a meta-analysis using Review Manager (version 5.3). Results: A total of 7 Randomized Clinical Trials (ACCORD-12, CARO-AIO-04, FOWARC, JIAO, NSABP, PETACC-6 and STAR-01) with 5782 stage II or III rectal cancer patients were analysed, including 2727 patients with OXP + 5FU regimen and 3055 patients with 5FU alone regimen. Compared with 5FU-based regimen group, OXP-based regimen group improved DFS (HR = 0.90, 95% CI: 0.81−0.99, P = 0.03) and increased pathologic Complete Response (OR = 1.21, 95% CI: 1.07−1.37, P = 0.002). Patients treated with OXP-regimen had significantly less metastatic disease (OR = 0.79; 95% CI, 0.67 to 0.94; p = 0.007). Considering Adverse Events (AEs), there was more grade 3-4 diarrhoea with OXP (OR = 2.41, 95% CI: 1.74−3.32, P < 0.00001). However, there were no significant differences grade 3-4 haematologic AEs (OR = 1.16, 95% CI: 0.87−1.57, P = 0.31). Conclusions: Combining oxaliplatin with capecitabine or 5FU in preoperative chemoradiotherapy or perioperative chemotherapy seems beneficial significantly and improved DFS. It remains necessary to identify which patients benefit most from the addition of oxaliplatin.

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Adjuvant Second-Dose Chemotherapy before Surgery for Patients with Locally Advanced Rectal Malignancy Is Not Beneficial: A Systematic Review and Meta-Analysis

Gastroenterology Research and Practice ◽

10.1155/2017/1373092 ◽

2017 ◽

Vol 2017 ◽

pp. 1-8

Author(s):

Min Chen ◽

Xue Song ◽

Liang-zhou Chen ◽

Lin Xu ◽

Yi-pu Lu ◽

...

Keyword(s):

Rectal Cancer ◽

Combination Chemotherapy ◽

Meta Analysis ◽

Locally Advanced ◽

Neoadjuvant Chemoradiotherapy ◽

Advanced Rectal Cancer ◽

Preoperative Chemoradiotherapy ◽

Locally Advanced Rectal Cancer ◽

Cochrane Library ◽

Controlled Trials

Background. Preoperative chemoradiotherapy is the standard treatment for patients with locally advanced rectal cancer, although tumor responses vary widely; some patients may achieve a pathologic complete response rate (pCR) after chemoradiotherapy. Controversy exists with regard to the efficacy of different preoperative combination chemotherapy regimens and neoadjuvant chemoradiotherapy, compared with chemoradiotherapy alone. Methods. PubMed, the Cochrane Library, and Embase databases were searched for comparative studies of patients with locally advanced rectal cancer that were published between January 1991 and January 2016. Efficacies of different preoperative combination chemotherapy regimens and neoadjuvant chemoradiotherapy (group A) were compared with chemoradiotherapy alone (group B) in a meta-analysis using Review Manager v5.2. Results. Three prospective randomized controlled trials and two prospective nonrandomized controlled trials comprising 444 cases were eligible for analysis. No significant difference was detected in the rate of pCR (50/223, 22.4% versus 35/223, 15.7%; relative risk, RR: 1.42 [95% confidence interval, CI: 0.97–2.09], p=0.07) between the two groups. The rate of tumor regression was similar for both groups (122/203, 60.1% versus 111/203, 54.7%; RR: 1.11 [95% CI: 0.94–1.29], p=0.22). Conclusions. Adjuvant chemotherapy with preoperative chemoradiotherapy did not significantly improve the rate of pCR nor the rate of T and N downstaging.

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Utility of restaging patients with stage II/III rectal cancer following neoadjuvant chemo/XRT: A systematic review.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.4_suppl.495 ◽

2019 ◽

Vol 37 (4_suppl) ◽

pp. 495-495

Author(s):

Leah E. Hendrick ◽

Renee L Levesque ◽

David Shibata ◽

Nathan M Hinkle ◽

Justin J Monroe ◽

...

Keyword(s):

Rectal Cancer ◽

Treatment Plan ◽

Meta Analysis ◽

Systemic Disease ◽

Clinical Stage ◽

Locally Advanced ◽

Advanced Rectal Cancer ◽

Locally Advanced Rectal Cancer ◽

Stage Ii ◽

Cochrane Library

495 Background: In the US, patients with clinical stage II/III rectal cancer typically receive neoadjuvant chemoradiation (chemo/XRT) over 5-6 weeks followed by a 6-10 week break before proctectomy. As this chemotherapy is delivered at radio-sensitizing doses, there is essentially a 3-month window during which potential systemic disease is untreated. Evidence regarding the utility of restaging patients prior to proctectomy is limited. Methods: PubMed, Scopus, Web of Science, and the Cochrane Library were searched for studies evaluating the utility of restaging patients with locally advanced rectal cancer after completion of long course chemo/XRT, and reporting changes in management after restaging. Studies that were non-English, included < 50 patients, or examining the diagnostic accuracy of specific imaging modalities were excluded. Study quality was evaluated using the modified Newcastle Ottawa Scale. Results: Eight studies were identified including a total of 1251 patients restaged between completion of chemo/XRT and proctectomy. All studies were retrospective (6 single institution, 2 multi-institution). Restaging identified new metastatic disease in 72 (6.0%) patients, with 4 studies reporting specific sites: liver (n = 28), lung (n = 8), adrenal (n = 1), bone (n = 1), and multiple sites (n = 7). Overall, progression (distant or local) was detected in 85 (6.8%) patients and resulted in a reported change in management in 71 (5.7%) patients. One study identified an association of high-grade tumors with progression (p ≤ 0.05), however, this was not reported in any other study. Moreover, tumor-related prognostic characteristics were inconsistently reported among studies, precluding meta-analysis. Conclusions: Although restaging between completion of neoadjuvant chemo/XRT and proctectomy detects disease progression in only a small percentage of patients, findings may alter the treatment plan. A multi-institutional collaboration with analysis of well-defined prognostic variables may better identify a group of patients most likely to benefit from restaging.

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Outcome of preoperative chemotherapy (POC) in locally advanced rectal cancer (LARC): Meta-analysis of randomized clinical trials (RCT)

Journal of Clinical Oncology ◽

10.1200/jco.2008.26.15_suppl.4085 ◽

2008 ◽

Vol 26 (15_suppl) ◽

pp. 4085-4085

Author(s):

E. Tamburini ◽

D. Tassinari ◽

M. Papi ◽

G. Oliverio ◽

S. Nicoletti ◽

...

Keyword(s):

Rectal Cancer ◽

Clinical Trials ◽

Preoperative Chemotherapy ◽

Randomized Clinical Trials ◽

Meta Analysis ◽

Locally Advanced ◽

Advanced Rectal Cancer ◽

Locally Advanced Rectal Cancer

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Neoadjuvant chemoradiation for locally advanced rectal cancer with fluoropyrimidine alone or intensified with oxaliplatin: A systematic review and meta-analysis.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.4_suppl.678 ◽

2017 ◽

Vol 35 (4_suppl) ◽

pp. 678-678 ◽

Cited By ~ 1

Author(s):

Ashlie Nadler ◽

Elizabeth Handorf ◽

Elin R. Sigurdson ◽

Joshua E. Meyer ◽

Crystal Shereen Denlinger ◽

...

Keyword(s):

Rectal Cancer ◽

Resection Margin ◽

Meta Analysis ◽

Locally Advanced ◽

Advanced Rectal Cancer ◽

Locally Advanced Rectal Cancer ◽

Neoadjuvant Chemoradiation ◽

Significant Heterogeneity ◽

Short Term ◽

Grade 3

678 Background: Improved outcomes have been demonstrated with the use of neoadjuvant fluoropyrimidine-based chemoradiotherapy and total mesorectal excision for locally advanced rectal cancer. The addition of oxaliplatin in the adjuvant setting has also resulted in improved disease-free survival (DFS). A meta-analysis was performed to evaluate DFS and overall survival (OS) with the addition of oxaliplatin to standard neoadjuvant chemoradiation for locally advanced rectal cancer. Methods: A systematic literature review was performed. Randomized-controlled trials (RCTs) comparing the addition of oxaliplatin in the neoadjuvant setting (oxaliplatin group) to fluoropyrimidine-based chemoradiation (standard group) were included. The primary outcomes were DFS and OS; secondary outcomes were short-term surgical results, morbidity, and mortality. Results were combined using meta-analysis via linear mixed-effects models. Calculations were performed using R. Results: Of 73 studies identified, 4 reported DFS (n=3829) and 3 reported OS (n=2680). There was no difference in DFS between the standard and oxaliplatin groups amongst RCTs [HR 0.90 (0.64-1.26), p=0.5313]. There was no difference in OS [HR 0.93 (0.59-1.47), p=0.9894]. There was no significant heterogeneity between RCTs for primary outcomes. There was also no difference in pathologic complete response rate [OR 0.93 (0.77-1.14), p=0.4923), resection margin (R0) status [OR 1.01 (0.59-1.72), p=0.9846], circumferential resection margin status [OR 0.84 (0.50-1.41), p=0.5079], sphincter saving surgery rate [OR 0.87 (0.74-1.03), p=0.1103], grade 3-4 toxicity [OR 1.60 (0.88-2.92), p=0.1251], and 60-day mortality [OR 1.27 (0.50-3.25), p=0.6148]. There was significant heterogeneity between RCTs for R0 status, circumferential margin status, and grade 3-4 toxicity. Adjuvant treatment varied across studies. Conclusions: There are no short-term or long-term survival benefits with the addition of oxaliplatin to fluoropyrimidine-based chemoradiation in the neoadjuvant setting for locally advanced rectal cancer.

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