Prospective randomized trial of neoadjuvant chemotherapy during the ‘wait period’ following preoperative chemoradiotherapy for rectal cancer: results of the <scp>WAIT</scp> trial

Moore, James W.; Price, Tim; Carruthers, Scott; Selva-Nayagam, Sudarsha; Luck, Andrew; Thomas, Michelle; Hewett, Peter

doi:10.1111/codi.13724

Cited by 48 publications

(78 citation statements)

References 31 publications

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“…Among them, five were updates of prior published studies, one was a secondary analysis of an already included RCT, and two were discarded for not having enough information on the main outcome. Hence, eight different RCTs comparing TNT to standard CRT were included in the present meta-analysis [7][8][9][10][11][12][13][14]. (Figure 1 A total of 2301 patients were included, of whom 1131 (49.2%) received standard neoadjuvant RT and 1170 (50.8%) TNT.…”

Section: Literature Search Results and Study Characteristicsmentioning

confidence: 99%

“…It should be noted that, despite most trials allowing the inclusion of rectal cancer patients regardless of their location, the vast majority of included patients presented mid or low rectal cancer. Indeed, only 8.3% of patients with available data on tumor location had upper rectal cancer, although two trials did not report specific information on this important matter [11,12], and one trial [7] provided only the number of patients with low rectal location. This raises the question of whether these results may apply to patients with upper rectal cancer, as data on this particular tumor site are scarce.…”

Section: Discussionmentioning

confidence: 99%

“…In the four RCTs that used induction chemotherapy [7][8][9]13], 130 of 682 (19.1%) randomized patients achieved a pCR, 84 of 339 (24.8%) in the TNT group and 46 of 343 (13.4%) in the standard arm (OR 2.13, 95% CI 1.44-3.17, p < 0.001; I 2 = 39%, p = 0.18). In the four trials that used consolidation CT in the TNT arm [10][11][12]14], 268 patients of 1481 (18.1%) achieved a pCR, 171 of 748 (22.9%) in the experimental arm and 97 of 733 (13.2%) in the standard group. (OR 1.92, 95% CI 1.46-2.53, p< 0.001; I 2 = 49%, p = 0.12).…”

Section: Pathological Complete Response Ratesmentioning

confidence: 99%

“…Six trials used CRT in the experimental and control arms (n = 827) [7][8][9][11][12][13]. In these RCTs, 149 of 827 (18%) randomized patients achieved a pCR, 94 of 408 (23.0%) in the TNT arm and 55 of 419 (13.1%) in the standard arm (OR 1.97, 95% CI 1.37-2.84, p< 0.001; I 2 = 39%, p = 0.15).…”

Section: Pathological Complete Response Ratesmentioning

confidence: 99%

“…Six RCTs reported data on the type of resection accomplished [7,8,[10][11][12]14]. In 1404 of 1646 patients (85.3%), an R0 resection was achieved, 721 of 836 (86.2%) in the experimental arm and 683 of 810 (84.3%) in the standard group.…”

Section: R0 Resection Ratesmentioning

confidence: 99%

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Impact of Total Neoadjuvant Therapy vs. Standard Chemoradiotherapy in Locally Advanced Rectal Cancer: A Systematic Review and Meta-Analysis of Randomized Trials

Martínez

Fernández-Martos

Gravalos-Castro

et al. 2020

Cancers

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Multimodality treatment is a standard of care for LARC, but the optimal sequencing of the treatment modalities remains unclear. Several randomized clinical trials (RCTs) compared total neoadjuvant treatment (TNT) vs. standard neoadjuvant chemoradiotherapy (CRT) with inconsistent results. A systematic review and meta-analysis was performed to evaluate the efficacy of TNT in terms of complete pathological response (pCR) rate, disease-free and overall survival vs. standard CRT in LARC. A systematic search was performed through MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials and meeting abstracts up to May 2020. RCTs comparing CRT vs. TNT followed by surgery in LARC were eligible for the study. Study selection and data extraction were done following PRISMA guidelines by two independent reviewers. The Mantel–Haenzel method was used to obtain a fixed-effects model of pooled odds or hazard ratios for the main outcomes. Eight RCTs, including 2301 patients, met the eligibility criteria. TNT significantly improved pCR rate (OR = 1.99, 95% confidence interval (CI) 1.59–2.49; p < 0.001), 3-year disease-free-survival (DFS) (HR = 0.82, 95%CI 0.71–0.95; p = 0.01) and 3-year overall survival (OS) (hazard ratio (HR) = 0.81, p = 0.04). Grade 3–4 adverse events were not significantly different in both strategies (OR = 1.58; p = 0.14). An improved pCR rate was documented regardless of the type of radiotherapy administered (long vs. short fractionation schedules). No significant heterogeneity was found. The results of this meta-analysis show that TNT improves pCR and survival rates vs. standard preoperative CRT in patients with LARC. TNT may become a new standard of care in LARC, although longer follow-up is needed to properly assess its long-term impact on survival.

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Section: Literature Search Results and Study Characteristicsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Pathological Complete Response Ratesmentioning

confidence: 99%

Section: Pathological Complete Response Ratesmentioning

confidence: 99%

Section: R0 Resection Ratesmentioning

confidence: 99%

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Impact of Total Neoadjuvant Therapy vs. Standard Chemoradiotherapy in Locally Advanced Rectal Cancer: A Systematic Review and Meta-Analysis of Randomized Trials

Martínez

Fernández-Martos

Gravalos-Castro

et al. 2020

Cancers

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Treatment of Locally Advanced Rectal Cancer in the Era of Total Neoadjuvant Therapy

Turri,

Ostuzzi,

Vita

et al. 2024

JAMA Netw Open

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ImportanceTreatment of locally advanced rectal cancer (LARC) involves neoadjuvant chemoradiotherapy plus total mesorectal excision and adjuvant chemotherapy. However, total neoadjuvant therapy (TNT) protocols (ie, preoperative chemotherapy in addition to radiotherapy) may allow better adherence and early treatment of distant micrometastases and may increase pathological complete response (pCR) rates.ObjectiveTo assess the efficacy and tolerability of TNT protocols for LARC.Data SourcesMEDLINE, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), and Web of Science Core Collection electronic databases and ClinicalTrials.gov for unpublished studies were searched from inception to March 2, 2024.Study SelectionRandomized clinical trials including adults with LARC who underwent rectal resection as a final treatment were included. Studies including nonoperative treatment (watch-and-wait strategy), treatments other than rectal resection, immunotherapy, or antiangiogenic agents were excluded. Among the initially identified studies, 2.9% met the selection criteria.Data Extraction and SynthesisTwo authors independently screened the records and extracted data. Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA)–compliant pairwise and network meta-analyses with a random-effects model were performed in a frequentist framework, and the certainty of evidence was assessed according to the confidence in network meta-analysis approach.Main Outcomes and MeasuresThe primary outcome was pCR, defined as the absence of residual tumor at pathological assessment after surgery. Secondary outcomes included tolerability, toxic effects, perioperative outcomes, and long-term survival.ResultsOf 925 records identified, 27 randomized clinical trials, including 13 413 adults aged 18 years or older (median age, 60.0 years [range, 42.0-63.5 years]; 67.2% male) contributed to the primary network meta-analysis. With regard to pCR, long-course chemoradiotherapy (L-CRT) plus consolidation chemotherapy (relative risk [RR], 1.96; 95% CI, 1.25-3.06), short-course radiotherapy (S-RT) plus consolidation chemotherapy (RR, 1.76; 95% CI, 1.34-2.30), and induction chemotherapy plus L-CRT (RR, 1.57; 95% CI, 1.09-2.25) outperformed standard L-CRT with single-agent fluoropyrimidine-based chemotherapy. Considering 3-year disease-free survival, S-RT plus consolidation chemotherapy (RR, 1.08; 95% CI, 1.01-1.14) and induction chemotherapy plus L-CRT (RR, 1.12; 95% CI, 1.01-1.24) outperformed L-CRT, in spite of an increased 5-year locoregional recurrence rate of S-RT plus consolidation chemotherapy (RR, 1.65; 95% CI, 1.03-2.63).Conclusions and RelevanceIn this systematic review and network meta-analysis, 3 TNT protocols were identified to outperform the current standard of care in terms of pCR rates, with good tolerability and optimal postoperative outcomes, suggesting they should be recognized as first-line treatments.

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Optimal Sequence for Total Neoadjuvant Therapy in Locally Advanced Rectal Cancer: An Evidence‐Based Review

Ghalehtaki,

Nourbakhsh,

Abyaneh

et al. 2024

Cancer Medicine

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IntroductionHistorically, multimodal therapeutic strategies involving preoperative chemoradiotherapy (CRT), surgery, and adjuvant chemotherapy (CT) have been employed to treat locally advanced rectal cancer (LARC). Total Neoadjuvant Therapy (TNT) is showing promise in improving outcomes. Despite its benefits, the optimal sequencing within TNT—whether induction chemotherapy should precede or follow chemoradiotherapy—remains a critical question. This study endeavors to explore the effects of different TNT sequencing strategies on patient outcomes, including tumor downstaging, pathological response, organ preservation, and the balance between efficacy and tolerability.MethodsOur methodology entailed a comprehensive literature review conducted on Medline, focusing on recent research, including retrospective studies, systematic reviews, and clinical trials. The review emphasized the comparison of induction chemotherapy versus consolidation chemotherapy within TNT regimens, assessing outcomes such as pathological response, organ preservation rates, and adverse effects. To ensure the selection of appropriate and high‐quality studies, specific inclusion and exclusion criteria were applied.ResultsThe analysis revealed that induction chemotherapy might lead to decreased adherence to subsequent chemoradiotherapy while offering an early intervention against micrometastasis and potentially improving overall chemotherapy compliance. Conversely, consolidation chemotherapy has been associated with higher pathological complete response (pCR) rates and improved tolerability, indicating its potential for patients requiring local symptom relief or those eligible for a nonoperative management approach. Comparative studies like CAO/ARO/AIO‐12 and the OPRA trials have significantly contributed to our understanding, suggesting that while both strategies have distinct advantages, the choice between induction and consolidation chemotherapy should be tailored based on individual patient profiles and tumor characteristics.ConclusionThis narrative review underscores the importance of a nuanced approach to TNT sequencing in locally advanced rectal cancer, highlighting the need for further research to refine treatment strategies.

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Prospective randomized trial of neoadjuvant chemotherapy during the ‘wait period’ following preoperative chemoradiotherapy for rectal cancer: results of the WAIT trial

Abstract: The addition of three cycles of 5-fluorouracil/leucovorin in a 10 week wait period after conventional chemoradiotherapy seems to result in similar pCR rates in patients with locally advanced rectal cancer based on this small randomized trial.

Cited by 48 publications

References 31 publications

Impact of Total Neoadjuvant Therapy vs. Standard Chemoradiotherapy in Locally Advanced Rectal Cancer: A Systematic Review and Meta-Analysis of Randomized Trials

Impact of Total Neoadjuvant Therapy vs. Standard Chemoradiotherapy in Locally Advanced Rectal Cancer: A Systematic Review and Meta-Analysis of Randomized Trials

Treatment of Locally Advanced Rectal Cancer in the Era of Total Neoadjuvant Therapy

Optimal Sequence for Total Neoadjuvant Therapy in Locally Advanced Rectal Cancer: An Evidence‐Based Review

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