The TNT strategy may also improve DFS and OS and reduce the risk of distant metastasis. Total neoadjuvant therapy: Fact, fantasy, or fallacy? National Library of Medicine https://doi.org/10.1016/S1470-2045(13)70599-0. Can diet and exercise reverse prediabetes? The primary difference is their timing in the overall treatment schedule. Cookies policy. Local recurrence rate is the main long-term endpoint. Please enable it to take advantage of the complete set of features! Because a considerable reduction in the bulk of the tumor with a TNT approach might result in more and more patients adopting a nonoperative watch-and-wait strategy in the future, accurate determination of CCR in addition to PCR is imperative. An alternative strategy known as total neoadjuvant therapy (TNT) involves administration of CRT plus neoadjuvant chemotherapy before surgery with the goal of delivering uninterrupted systemic therapy to eradicate micrometastases. Total Neoadjuvant Therapy (TNT) versus Standard Neoadjuvant Chemoradiotherapy for Locally Advanced Rectal Cancer: A Systematic Review and MetaAnalysis - PMC Back to Top Skip to main content An official website of the United States government Here's how you know The .gov means it's official. the contents by NLM or the National Institutes of Health. Taking into account the outcomes from these studies (Garcia-Aguilar et al9 described a 5-year disease-free survival whereas Markovina et al10 and Conroy et al12 reported a 3-year disease-free survival) generated an OR of 2.07 (95% CI, 1.20-3.56; I2=49%) (Figure 5) favoring improved disease-free survival among those who received TNT.7,8,10. complete pathologic response, downstaging, neoadjuvant rectal score, rectal cancer, survival, total neoadjuvant treatment. 2023 Jun 26;15(13):3345. doi: 10.3390/cancers15133345. Ankylosing Spondylitis Pain: Fact or Fiction, https://www.cancer.gov/publications/dictionaries/cancer-terms/def/adjuvant-therapy, https://www.cancer.org/cancer/breast-cancer/treatment/chemotherapy-for-breast-cancer.html, https://www.cancer.org/treatment/treatments-and-side-effects/treatment-types/chemotherapy/chemotherapy-side-effects.html, https://academic.oup.com/jncimono/article/2015/51/36/945910, https://www.cancer.org/treatment/treatments-and-side-effects/treatment-types/hormone-therapy.html, https://www.cancer.gov/publications/dictionaries/cancer-terms/def/neoadjuvant-therapy, https://academic.oup.com/jncics/article/1/1/pkx004/4210673, https://www.cancer.org/treatment/treatments-and-side-effects/treatment-types/radiation/effects-on-different-parts-of-body.html, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7299787/, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7564362/, https://jamanetwork.com/journals/jamaoncology/fullarticle/2330620, https://onlinelibrary.wiley.com/doi/abs/10.1002/jso.26305, Dementia: Olive oil could boost brain health, according to new study, 2 glasses of 'non-alcoholic' wine a day may help improve aging skin. 2011;4(2):23944. Google Scholar. Several randomized clinical trials (RCTs) compared total neoadjuvant treatment (TNT) vs. standard neoadjuvant chemoradiotherapy (CRT) with inconsistent results. Two meta-analysis confirmed no statistically significant differences in TNT and standard arm for what concern the rate of negative resection margins [32, 46]. Kong JC, Soucisse M, Michael M, Tie J, Ngan SY, Leong T, McCormick J, Warrier SK, Heriot AG. The landscape of total neoadjuvant therapy for locally advanced rectal cancers looks promising, and the RAPIDO protocol is likely to be the new standard of care, especially in resource-limited settings and the current climate of the COVID-19 pandemic, when fewer visits to health-care centres are desirable. On the contrary, meta-analyses comparing TNT to the standard of care, report homogeneous results regarding DFS improvement in patients undergoing TNT [27, 28, 32, 45, 46]. Would you like email updates of new search results? For this reason, using the available evidence, we propose an interesting minireview which is also novel, ethical and relevant on this particularly complex intervention with the scope of summarizing the body of research to evaluate sources of heterogeneity. Received 2020 Jul 15; Accepted 2020 Oct 25. 2019;37(34):321222. Annals of Surgery276(6):e819-e824, December 2022. Rdel C, Martus P, Papadoupolos T, et al.. Prognostic significance of tumor regression after preoperative chemoradiotherapy for rectal cancer. LDC can be pictured as a composite of different endpoints. Several ongoing studies are analyzing whether this new approach could improve oncological outcomes. Body mass index and complications following major gastrointestinal surgery: a prospective, international cohort study and meta-analysis. Most of these studies were single institutional and retrospective [2]. Postoperative oncologic outcomes of curative resection after neoadjuvant chemotherapy were compared with those of upfront surgery. Neoadjuvant therapy may also serve as a tool for determining the patients response to treatment. 2021;16(1):14. https://doi.org/10.1186/s13062-021-00298-3. An atlas of inter- and intra-tumor heterogeneity of apoptosis competency in colorectal cancer tissue at single-cell resolution. How many different models of cell death? TNT increases AEs but does not appear to influence overall survival. https://doi.org/10.1016/S1470-2045(20)30555-6. GUID:59B7A38F-A214-4724-AE23-0CAD57250CEB. Surgical outcomes, including rates of sphincter-preserving surgery and ileostomy, did not significantly differ among the 2 populations. Forest plots for survival endpoints. A randomized phase 2 trial of consolidation chemotherapy after preoperative chemoradiation therapy versus chemoradiation therapy alone for locally advanced rectal cancer: KCSG CO 14-03. Total neoadjuvant therapy vs standard therapy of locally advanced ; Collaborative investigators . Thus, these data will need validation before being fully applicable to patients at high risk of cancer progression. Kasi A, Abbasi S, Handa S, Al-Rajabi R, Saeed A, Baranda J, Sun W. Total neoadjuvant therapy vs standard therapy in locally advanced rectal cancer: a systematic review and meta-analysis. Can diet help improve depression symptoms? Of note, pCR improvement is particularly evident in the three most recent trials, perhaps due to progress in TNT regimens [30, 31, 36]. Kim JK, Marco MR, Roxburgh CSD, Chen CT, Cercek A, Strombom P, Temple LKF, Nash GM, Guillem JG, Paty PB, Yaeger R, Stadler ZK, Gonen M, Segal NH, Reidy DL, Varghese A, Shia J, Vakiani E, Wu AJ, Romesser PB, Crane CH, Gollub MJ, Saltz L, Smith JJ, Weiser MR, Patil S, Garcia-Aguilar J. Oncologist. J Clin Oncol. Colorectal Dis. eTable 1 in the Supplement presents baseline characteristics of the studies included for analysis. JAMA Oncol. Multiple ongoing TNT trials are now including the neoadjuvant rectal score as a primary or secondary end point.32,37 In the CAO/ARO/AIO-04 trial,41 the neoadjuvant rectal score was found to be an independent predictor for disease-free, overall, and distant metastasisfree survival as well as local recurrence; however, a recent Netherlands Cancer Registrybased study including more than 6500 patients42 found the neoadjuvant rectal score to be poorly concordant with the true end point when compared with a simple Cox proportional hazards regression model using the same 3 criteria included in the neoadjuvant rectal score formula. 2012;23(6):152530. Likewise, insufficient data were available to calculate a pooled overall survival. This treatment protocol is also likely . One such surrogate end point for prognostication in patients treated with TNT is the neoadjuvant rectal score. Hupkens BJP, Martens MH, Stoot JH, et al.. Quality of life in rectal cancer patients after chemoradiation: watch-and-wait policy versus standard resectiona matched-controlled study. Epub 2017 Jun 27. 2022 Nov 4;17(11):e0276599. Because we might be moving toward an era of a watch-and-wait approach in patients who are able to demonstrate sustained CCR, several questions, such as the reliability with which patients with a CCR can be identified, the optimal diagnostic test for monitoring of these patients in terms of imaging or gene expression profiling, and the appropriate follow-up duration, remain to be answered. Doctors may prescribe both neoadjuvant and adjuvant therapies. In particular, the meta-analysis of Riesco-Martinez et al. Out of 8,548 patients, 36% received TNT and 64% nCRT. 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. put an alert on consolidation regimens because they may threaten local control [27] however, this was not confirmed by the short-term results of the OPRA trial [39]. BCL-XL is crucial for progression through the adenoma-to-carcinoma sequence of colorectal cancer. https://doi.org/10.1038/s41418-021-00815-x. ; EORTC Radiation Oncology Group . Fluorouracil-based adjuvant chemotherapy after preoperative chemoradiotherapy in rectal cancer: long-term results of the EORTC 22921 randomised study. Feasibility of Perineal Defect Reconstruction with Simplified Fasciocutaneous Inferior Gluteal Artery Perforator (IGAP) Flaps after Tumor Resection of the Lower Rectum: Incidence and Outcome in an Interdisciplinary Approach. The two therapies differ largely in when they are given and why. Of the 8 RCT, four reported on induction and four on consolidation TNT. 2018 Mar;17 (1):1-12. doi: 10.1016/j.clcc.2017.06.008. Resection limits were available for 2268 patients reported by 6 RCTs showing comparable R0 resections rates. Gold standard in the treatment of rectal cancer is a multimodality approach, aiming at a good control of the local disease. OConnell E, Reynolds IS, McNamara DA, Prehn JHM, Burke JP. Outcomes of SCRT vs CRT are controversial. Total 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. Bosset JF, Calais G, Mineur L, Maingon P, Stojanovic-Rundic S, Bensadoun RJ, Bardet E, Beny A, Ollier JC, Bolla M, Marchal D, Van Laethem JL, Klein V, Giralt J, Clavre P, Glanzmann C, Cellier P, Collette L, EORTC Radiation Oncology Group. Adjuvant vs. neoadjuvant chemotherapy: What to know - Medical News Today Despite the adoption of adjuvant postoperative chemotherapy, patients are more than twice as likely to present with a distant recurrence rather than tumor regrowth at the primary site.2,3 This situation emphasizes the urgency of devising upfront treatment strategies aimed at controlling obscure micrometastases. Pellino G, Espn-Basany E. Bowel decontamination before colonic and rectal surgery. Lymphovascular and perineural invasion (PNI) are extremely important to tailor patient treatment due to the increased risk of both local recurrence and metastatic disease. Long-term outcomes of clinical complete responders after neoadjuvant treatment for rectal cancer in the International Watch & Wait Database (IWWD): an international multicentre registry study. However, it is not clear whether pCR improvement is due to the administration of TNT or to the prolonged interval. Phase II study of durvalumab plus total neoadjuvant therapy (TNT) in locally advanced rectal cancer: the GEMCAD-1703 DUREC trial, Short-term results of VOLTAGE-A: nivolumab monotherapy and subsequent radical surgery following preoperative chemoradiotherapy in patients with microsatellite stable and microsatellite instability-high locally advanced rectal cancer. N Engl J Med. Locally advanced rectal cancer (LARC) is a relatively common disease, with a poor prognosis because of its high metastatic potential. Overall, TNT does not seem to induce significant nodal down staging. In the RAPIDO trial reported compliance to TNT was 84%, consistent with data present in literature, while compliance to CRT and aCT were 93% and 58% respectively. In fact, induction-type TNT, which is given before neoadjuvant RT, allows an early systemic disease control, slowing occult micro metastasis growth, thus potentially reducing distant failure rates, but could determine local growth of previously resectable cancers. The appropriate Medical Subject Heading (MeSH) terms were combined in the search builder. Doctors use these additional therapies to ensure all cancer cells are targeted, including those that do not show up on scans and those that have spread to distant parts of the body. Cancers | Free Full-Text | Impact of Total Neoadjuvant Therapy vs Data regarding the first author, publication year, location, sample size, and rates of PCR, sphincter-preserving surgery, ileostomy, and disease-free and overall survival were extracted using Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines and pooled using a random-effects model. https://clinicaltrials.gov/ct2/show/NCT04246684#contacts ClinicalTrials.gov Identifier: NCT04246684. 2019;270(5):74754. R0 was achieved in 1102 out of 1225 patients (90%) in the experimental arm and 959 out of 1043 patients (92%) in the control arm. Sica GS, Fiorani C, Stolfi C, Monteleone G, Candi E, Amelio I, Catani V, Sibio S, Divizia A, Tema G, Iaculli E, Gaspari AL. 2012;30(16):192633. Considering that all kinds of TNT importantly prolong time from diagnosis to radical surgery (which remains the mainstay of rectal cancer curative treatment) and may result in overtreatment for non-responders, it seems reasonable to focus upcoming studies on identifications of factors capable of predicting response to TNT and consequentially to tailor the best treatment for each patient. Preferred reporting items for systematic, Preferred reporting items for systematic reviews and metaanalysis flowchart. The present study has used organ preservation as a secondary end point and compared induction and consolidation chemotherapy against historic controls of chemoradiation alone in a pick the winner design. Benson AB, Venook AP, Al-Hawary MM, et al.. Rectal Cancer, version 2.2018, NCCN clinical practice guidelines in oncology. Retrospective study of total neoadjuvant therapy for locally advanced Adjuvant chemotherapy refers to chemotherapy that people receive after another cancer treatment, such as surgery. Preferred reporting items for systematic reviews and metaanalysis flowchart. Adoption of total neoadjuvant therapy for locally advanced rectal cancer. Data regarding cTNM reported by all RCTs did not show any difference between experimental and standard arms. Federal government websites often end in .gov or .mil. PubMed Central Total neoadjuvant therapy appears to be a promising treatment strategy that has been reported in several trials. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. However, long-term results in terms of 3-years disease free survival (DFS) from the phase 2 randomized OPRA trial are still awaited. Neoadjuvant and adjuvant therapies are often used to treat breast cancer, colon cancerand lung cancer, and may include chemotherapy, hormone therapy, radiation therapy, immunotherapy and targeted therapy. Studies beyond the inclusion criteria or originally published in a language other than English were excluded. Front Surg. Randomized clinical trials or prospective/retrospective cohort studies comparing outcomes in patients with locally advanced rectal cancer who received TNT vs CRT plus A. PubMed Patients in all studies underwent surgery apart from Cercek et al,8 in which a subset of patients who attained a clinical complete response (CCR) was observed. https://doi.org/10.1016/S2468-1253(20)30075-3. The most advantageous timing of surgery following RT is not clear. However, its efficacy and safety remain controversial in randomized controlled trials (RCTs). Distant recurrences are the major cause of mortality. 2015;40(8):42534. No significant difference was found in rates of sphincter-preserving surgery or ileostomy requirements between the 2 approaches. Objective & background: Total neoadjuvant therapy (TNT) is a novel approach for locally advanced rectal cancer (LARC), which attempts to deliver both systemic chemotherapy and neoadjuvant. As reported by almost all the RCTs, TNT does not appear to increase incidence of overall or severe post-operative complications (Clavien-Dindo) [32, 44, 45]. This site needs JavaScript to work properly. A cumulative metric of PCR for those who underwent surgery and sustained CCR (no evidence of local recurrence at 12 months) for those who did not undergo surgery was used. Radioimmunotherapy in colorectal cancer treatment: present and future. Find out more. The site is secure. The best timing for surgery following RT is not clear; a minimum of 10weeks seems an appropriate period to assess pCR and consolidation TNT may allow for extended durations between radiotherapy and surgery. PubMed Central It seems therefore, important to identify factors predictive of a good response to TNT. The publication year ranged from 2011 to 2021. We conducted this meta-analysis to assess such concerns. 1. However, its efficacy and safety remain controversial in randomized controlled trials (RCTs). 5FU/Folinic Acid, Irinotecan and Oxaliplatin, Near-Complete Pathological Complete Response. Guida, A.M., Sensi, B., Formica, V. et al. 2021;28(9):267389. The National Comprehensive Cancer Network guidelines already endorse the use of TNT; however, given that the current evidence is only preliminary, we sought to consolidate the evidence by performing a meta-analysis of relevant studies. Methods: We reviewed our experience in BR/LA patients undergoing resection . Total neoadjuvant therapy versus standard neoadjuvant chemoradiotherapy They can then make adjustments for future treatment protocols. In separate models, both pCR and a NAR score <8 were associated with improved OS. Keeping in mind the importance of distant recurrence on patient prognosis [22], consolidation-type TNT regimens appear to be the preferable therapeutic option. Owing to a more intensive neoadjuvant chemotherapy regimen, grade 3 or 4 toxic effects, such as neutropenia and lymphopenia, were more commonly reported in the TNT cohorts in 2 of the 7 studies.9,10 However, this did not translate into increased treatment discontinuation or dose reduction in the TNT cohorts. Colorectal Dis. The median age for the patients receiving TNT ranged from 57 to 69 years, with 58% to 73% being male. Background: Total 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. Its important to know, though, that neoadjuvant and adjuvant therapies may cause side effects, such as the nausea and fatigue that often accompany chemotherapy. PubMed Significance of pCR is well established due to its correlation with long-term oncological outcomes. Mammarella E, Zampieri C, Panatta E, Melino G, Amelio I. NUAK2 and RCan2 participate in the p53 mutant pro-tumorigenic network. Total Neoadjuvant Therapy versus Standard Neoadjuvant Chemoradiation in Patients with Locally Advanced Rectal Cancer A Comparison of Short- and Long-term Oncologic Outcomes Goffredo, Paolo MD *; Khan, Adil MD ; Mott, Sarah L. MS ; Jensen, Christine MD, MPH *; Madoff, Robert MD *; Gaertner, Wolfgang MD *; You, Nancy MD ; Hassan, Imran MD A 2015 review noted that neoadjuvant therapy could increase the likelihood of survival for people with certain cancers. Background: Neoadjuvant chemotherapy (NACT) with human epidermal growth factor receptor 2 (HER2) blockade is the preferred approach for treating early and locally advanced HER2-positive breast cancer. 2021;12(1):27. https://doi.org/10.1007/s12672-021-00422-9;). Total Neoadjuvant Therapy vs Standard Therapy in Locally Advanced Some error has occurred while processing your request. preoperative treatment sequencing for BR/LA PDA is unknown. Total 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. Head-to-head phase II/III RCTs were searched in Embase, PubMed, Web of Science, and the Cochrane Library, as well as other sources. The total neoadjuvant therapy (TNT) and chemoradiotherapy followed by surgery and adjuvant chemotherapy (CRT plus A) groups were compared. CAS None of these studies reported sub-analysis investigating whether these preoperative factors could be predictive of TNT response. Keywords: Nevertheless, data are still insufficient to establish whether TNT could improve systemic control disease. Romesser PB, Holliday EB, Phillip T, et al.. A multicenter phase Ib/II study of DNA-PK inhibitor peposertib (M3814) in combination with capecitabine and radiotherapy in patients with locally advanced rectal cancer. However, while it destroys cancer cells, it can also have adverse effects. Liang W, Mo C, Wei J, Chen W, Gong W, Shi J, Hou X, Li C, Deng Y, Ou M. FAM65A as a novel prognostic biomarker in human tumors reveal by a pan-cancer analysis. The GCR-3 and the POLISH II trial did not show any statistically significant difference between the experimental and standard arm [13, 37]. eTable 1. 2021;12(1):60. https://doi.org/10.1007/s12672-021-00456-z. In: ClinicalTrials.gov. Liu S, Jiang T, Xiao L, Yang S, Liu Q, Gao Y, Chen G, Xiao W. Total neoadjuvant therapy (TNT) versus standard neoadjuvant chemoradiotherapy for locally advanced rectal cancer: a systematic review and meta-analysis. Despite several efforts and the use of a multimodality approach, distant recurrences are still significant and represent the leading cause of mortality for rectal cancer patients [18,19,20]. In multivariable analysis, as compared to nCRT, TNT demonstrated numerically higher pCR rates ( P = 0.05) but had similar incidence of positive CRM ( P = 0.11). Oncotarget. Department of Surgery, Minimally Invasive Unit, University of Rome Tor Vergata, 00133, Rome, Italy, Andrea M. Guida,Bruno Sensi,Piero Rossi&Giuseppe S. Sica, Department of Systems Medicine, Medical Oncology Unit, Policlinico Tor Vergata, Rome, Italy, Department of Biomedicine and Prevention, Radiation Oncology, University of Rome Tor Vergata, 00133, Rome, Italy, Department of Systems Medicine, Gastroenterology Unit, University of Rome Tor Vergata, 00133, Rome, Italy, Department of Colorectal Surgery, Colorectal Surgery Unit, Campus Bio-Medico University, 00128, Rome, Italy, Department of Surgery, Policlinico Tor Vergata, University of Rome, Tor Vergata, Viale Oxford 81, 00133, Rome, Italy, You can also search for this author in Dengler MA, Gibson L, Adams JM. Cercek A, Roxburgh CSD, Strombom P, et al.. Benson AB, Venook AP, Al-Hawary MM, Cederquist L, Chen YJ, Ciombor KK, Cohen S, Cooper HS, Deming D, Engstrom PF, Grem JL, Grothey A, Hochster HS, Hoffe S, Hunt S, Kamel A, Kirilcuk N, Krishnamurthi S, Messersmith WA, Meyerhardt J, Mulcahy MF, Murphy JD, Nurkin S, Saltz L, Sharma S, Shibata D, Skibber JM, Sofocleous CT, Stoffel EM, Stotsky-Himelfarb E, Willett CG, Wuthrick E, Gregory KM, Gurski L, Freedman-Cass DA. Furthermore, TNT could impact on patient performance status, thus reducing the number of patients able to tolerate surgery. Although reported in only 3 studies,9,10,12 TNT was associated with a significantly longer disease-free survival. CAS Cell Death Differ. 2021;28(12):327081. In recent years, the concept of total neoadjuvant treatment (TNT) has been developed, whereby all systemic ChT-mainly affecting micrometastases-is applied prior to surgery. Short course chemotherapy followed by concomitant chemoradiotherapy and surgery in locally advanced rectal cancer: a randomized multicentric phase II study. Google Scholar. Objective Total neoadjuvant therapy (TNT) versus standard neoadjuvant https://doi.org/10.1200/JCO.18.02309. All RCTs were included for descriptive analysis. After adjusting for confounders, OS was comparable between the 2 groups. A recently published systemic review and meta-analysis [1] identified 7 unique studies with 1206 patients receiving total neoadjuvant terapy (TNT) and surgery and 1210 patients treated with chemoradiotherapy (CRT), surgery, and adjuvant chemotherapy (CRT plus A). The Holy Plane of rectal surgery. Extracted variables were the following: general study characteristics (e.g., author, name of the study, country of recruitment, year of last publication, study design, number of patients, treatment arms and primary end point), treatment protocols (RT regimens, CT agents, timing of CT administration, timing of surgery, aCT), local disease control outcomes (pCR, nodal down staging, resection, lymphovascular and perinervous invasion, local recurrence rate), distant disease control outcomes (DFS, OS, distant recurrence rate), toxicity and complications (chemo-related adverse effect, surgical complications, compliance), and predictors of disease control.