Total Neoadjuvant Therapy for Rectal Cancer in the CAO/ARO/AIO-12 Randomized Phase 2 Trial: Early Surrogate Endpoints Revisited

Diefenhardt, Markus; Schlenska-Lange, Anke; Kuhnt, Thomas; Kirste, Simon; Piso, Pompiliu; Bechstein, Wolf O.; Hildebrandt, Guido; Ghadimi, Michael; Hofheinz, Ralf–Dieter; Rödel, Claus; Fokas, Emmanouil

doi:10.3390/cancers14153658

Cited by 7 publications

(4 citation statements)

References 37 publications

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“…Nor is it known if chemotherapy should be provided after radiation (consolidation) or before (induction). At least two trials indicate that CRT first results in better oncological outcome ( 93 , 94 , 98 ). It is not known whether triple chemotherapy, as used in PRODIGE-23 ( 34 ) or GRECCAR-4 ( 91 ) or a doublet as used in the other trials, is advantageous.…”

Section: Total Neoadjuvant Treatmentmentioning

confidence: 99%

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Recent advances in rectal cancer treatment – are we on the right track?

Glimelius

2024

ujms

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Background: Staging and treatment of rectal cancer have evolved over several decades with considerably fewer locoregional recurrences but no marked improved survival since systemic recurrence risks remain virtually unchanged. This development will briefly be summarised followed by a thorough discussion of two recent developments. Methods: A systematic approach towards the literature is aimed at focusing on organ preservation and the delivery of all non-surgical treatments prior to surgery or total neoadjuvant treatment (TNT). Results: Organ preservation, that is to defer surgery if the tumour happens to disappear completely after any pre-treatment given to locally advanced tumours to decrease recurrence risks has increased in popularity and is, if not universally, widely accepted. To give neo-adjuvant treatment to intentionally obtain a clinically complete remission to avoid surgery is practised in some environments but is mostly still experimental. TNT, that is to provide both radiotherapy and chemotherapy aimed at killing microscopic disease in the pelvis or elsewhere has been subject to several trials. Collectively, they show that the chance of achieving a complete response, pathologically or clinically, has approximately doubled, increasing the chance for organ preservation, and the risk of distant metastasis has decreased at least in some trials. The best schedule remains to be established. Conclusions: To obtain substantial progress and also improve survival, the systemic treatments need to be improved even if preoperative delivery is more effective and better tolerated than postoperative. The locoregional treatment may be further optimised through better risk prediction.

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Section: Total Neoadjuvant Treatmentmentioning

confidence: 99%

“…It is, thus, possible to select a group of patients whose tumours are sensitive to chemotherapy and omit CRT with its late toxicity. This may constitute an argument for starting with chemotherapy although this sequence appeared worse in two trials ( 93 , 94 , 98 ).…”

Section: Total Neoadjuvant Treatmentmentioning

confidence: 99%

Recent advances in rectal cancer treatment – are we on the right track?

Glimelius

2024

ujms

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“…Randomized phase III trials examining the addition of oxaliplatin concurrently with LCCRT provided useful data for benchmarking [5][6][7][8][9][10]26,27]. We also considered several relevant randomized phase II trials investigating NACT [18,19,[28][29][30][31][32][33][34][35][36][37][38][39][40], prospective phase II trials, and metaanalyses of varying quality examining TNT [41][42][43][44][45][46][47][48][49][50].…”

Section: Search Strategy and Selection Criteriamentioning

confidence: 99%

Selecting a TNT Schedule in Locally Advanced Rectal Cancer: Can We Predict Who Actually Benefits?

Aschele¹,

Glynne‐Jones

2023

Cancers

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Many consider the standard of care for locally advanced rectal cancer (LARC) to be preoperative chemoradiotherapy, radical surgery involving a total mesorectal excision, and post-operative adjuvant chemotherapy based on the pathology of the specimen. The poor impact on distant control is a major limitation of this strategy, with metastasis rates remaining in the 25–35% range and recovery after radical surgery leading to reluctance with prescription and inconsistent patient compliance with adjuvant chemotherapy. A second limitation is the low rate of pathologic complete response (pCR) (around 10–15%) despite multiple efforts to potentiate preoperative chemoradiation regimens, which in turn means it is less effective at achieving non-operative management (NOM). Total neoadjuvant treatment (TNT) is a pragmatic approach to solving these problems by introducing systemic chemotherapy at an early timepoint. Enthusiasm for delivering TNT for patients with LARC is increasing in light of the results of published randomized phase III trials, which show a doubling of the pCR rate and a significant reduction in the risk of subsequent metastases. However, there has been no demonstrated improvement in quality of life or overall survival. A plethora of potential chemotherapy schedules are available around the radiotherapy component, which include preoperative induction or consolidation with a range of options (FOLFOXIRI, FOLFOX, or CAPEOX,) and a varying duration of 6–18 weeks, prior to long course chemoradiation (LCCRT) or consolidation NACT following short-course preoperative radiation therapy (SCPRT) using 5 × 5 Gy or LCCRT using 45–60 Gy, respectively. The need to maintain optimal local control is a further important factor, and preliminary data appear to indicate that the RT schedule remains a crucial issue, especially in more advanced tumors, i.e., mesorectal fascia (MRF) invasion. Thus, there is no consensus as to the optimum combination, sequence, or duration of TNT. The selection of patients most likely to benefit is challenging, as clear-cut criteria to individuate patients benefiting from TNT are lacking. In this narrative review, we examine if there are any necessary or sufficient criteria for the use of TNT. We explore potential selection for the individual and their concerns with a generalized use of this strategy.

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“…As mentioned above, the timing of surgery after TNT is variable: 6-8 weeks (STELLAR), 4-12 weeks (Memorial Sloan Kettering), 2-4 weeks (RAPIDO), or 6-12 weeks (CAO/ARO/AIO-12). Therefore, the optimal timing is not established in clinical practice [9,10,12,15,22,36]. In terms of tumor resection, several studies have reported high rates of pCR, tumor downstaging, and R0 resection, whereas others have not found significant differences in R0 resection [34].…”

Section: Evaluation Of Responsementioning

confidence: 99%

Total Neoadjuvant Therapy Approach for the Treatment of Locally Advanced Rectal Cancer: Where Do We Stand?

Romero Zoghbi,

Martín Martín,

García

et al. 2023

Oncology

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Background: for the management of locally advanced rectal cancer (LARC), initial treatment with neoadjuvant chemoradiotherapy followed by surgery and chemotherapy in selected patients is considered one of the recommended options by the main international clinical guidelines. Nonetheless, the administration of all chemotherapy before definitive treatment (total neoadjuvant therapy or TNT) is an optimal alternative with a growing level of evidence that must be evaluated in multidisciplinary boards. This review summarizes the available data and controversies in this scenario. Summary: we have analyzed the characteristics of the main published studies that assess the use of TNT in patients with LARC, evaluating their inclusion criteria and distinguishing between the employed radiotherapy fractionations, systemic agents, timing, and the implications of these treatments in regard to surgery and long-term oncological results. Our aim is to describe the evidence that supports the use of a specific regime in everyday clinical practice. Key points: there is solid evidence for the use of TNT in patients with LARC. There is no data indicating the superiority of one specific TNT scheme among all the existing options. International clinical guidelines leave the door open to choose the most adequate treatment based on the clinical and pathological characteristics of each patient. This review shows the different approaches to TNT and assesses the best options based on clinical evidence.

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Total Neoadjuvant Therapy for Rectal Cancer in the CAO/ARO/AIO-12 Randomized Phase 2 Trial: Early Surrogate Endpoints Revisited

Cited by 7 publications

References 37 publications

Recent advances in rectal cancer treatment – are we on the right track?

Recent advances in rectal cancer treatment – are we on the right track?

Selecting a TNT Schedule in Locally Advanced Rectal Cancer: Can We Predict Who Actually Benefits?

Total Neoadjuvant Therapy Approach for the Treatment of Locally Advanced Rectal Cancer: Where Do We Stand?

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