Achieving a Complete Clinical Response After Neoadjuvant Chemoradiation That Does Not Require Surgical Resection: It May Take Longer Than You Think!

Abstract

BACKGROUND: Patients with rectal cancer who achieve complete clinical response after neoadjuvant chemoradiation have been managed by organ-preserving strategies and acceptable long-term outcomes. Controversy still exists regarding optimal timing for the assessment of tumor response after neoadjuvant chemoradiation. OBJECTIVE: The purpose of this study was to estimate the time interval for achieving complete clinical response using strict endoscopic and clinical criteria after a single neoadjuvant chemoradiation regimen. DESIGN: This was a retrospective review of consecutive patients managed by 54-Gy and consolidation 5-fluorouracil–based chemotherapy. Assessment of response was performed at 10 weeks after radiation. Patients with suspected complete clinical response were offered watch-and-wait strategy and reassessment every 6 to 8 weeks until achievement of strict criteria of complete clinical response or overt residual cancer. SETTINGS: This study was conducted at a single tertiary care center. PATIENTS: Patients with complete clinical response who underwent a successful watch-and-wait strategy until last follow-up were eligible. Dates of radiation completion and achievement of strict endoscopic and clinical criteria (mucosal whitening, teleangiectasia, and no ulceration or irregularity) were recorded. Patients with incomplete response or with initial complete clinical response followed by local recurrence or regrowth were excluded. MAIN OUTCOMES MEASURES: The distribution of time intervals between completion of radiation and achievement of strict complete clinical response was measured. Patients who achieved early complete clinical response (≤16 wk) were compared with late complete clinical response (>16 wk). RESULTS: A total of 49 patients achieved complete clinical response and were successfully managed nonoperatively. A median interval of 18.7 weeks was observed for achieving strict complete clinical response. Only 38% of patients achieved complete clinical response between 10 and 16 weeks from radiation completion. Patients with earlier cT status (cT2/T3a) achieved a complete clinical response significantly earlier when compared with those patients with more advanced disease (T3b-d/4; 19 vs 26 wk; p = 0.03). LIMITATIONS: This was a retrospective study with a small sample size. CONCLUSIONS: Assessment at 10 to 16 weeks may detect a minority of patients who achieve complete clinical response without additional recurrence after neoadjuvant chemoradiation. Patients suspected for a complete clinical response should be considered for reassessment beyond 16 weeks before definitive management when considered for a watch and wait strategy. See Video Abstract at http://links.lww.com/DCR/A901.

Pathological complete response due to a prolonged time interval between preoperative chemoradiation and surgery in locally advanced rectal cancer: analysis from the German StuDoQ|Rectalcarcinoma registry

“…The German guidelines for colorectal cancer recommend the oncological resection 6 to 8 weeks after completed preoperative chemoradiotherapy [7]. Recent studies have shown that a prolonged interval leads to higher rates of pathological complete response (pCR) and that this my even take longer than 16 weeks [8][9][10][11]. In addition, it was shown, that additional inclusion of chemotherapy cycles in the interval between radiochemotherapy and surgery enhance complete response rate without affecting surgical morbidity [12].…”

Author response to: Should a minimum 8-week interval between preoperative radiotherapy and surgery become the standard of care? No, it shouldn't

“…We would like to thank Socha and Bujko for their close reading of our recent publication. DNA damage may occur immediately with neoadjuvant chemotherapy (nCRT), however, cellular lysis only occurs in the weeks after irradiation, and regression is time dependent. In our study, we highlighted that the analysis was limited by the inclusion of only four RCTs and that subgroup analysis of RCTs exclusively did not demonstrate an enhanced pathological complete response (pCR) rate with the increased interval (odds ratio (OR) 1·15, 95 per cent c.i.…”

“…It may facilitate appropriate selection of patients to organ‐preserving strategies, minimize the risk of performing premature and potentially avoidable surgery, while abrogating unnecessary waiting for non‐responders. As the authors suggest, a nuanced approach may be for ongoing sequential assessment of complete /near‐complete responders beyond 8 weeks before definitive management is considered, including organ‐preserving strategies. Thus, patients with a favourable course of tumour response may be considered for a watch‐and‐wait strategy or opt for radical surgery and a likely pCR with excellent long‐term outcomes, while those with radioresistant tumours could proceed to surgery after reassessment.…”

Role of tumor cell senescence in non-professional phagocytosis and cell-in-cell structure formation

“…Indeed, most malignancies require several weeks after the end of treatment to show volumetric tumor regression in clinical and imaging assessment (2,3). In rectal cancer for example, Habr-Gama et al found a median time interval of 18.7 weeks from completion of radiotherapy to complete endoscopic clinical response (4). An alternative pathway to tumor reduction is not inducing cell death but non-proliferative cells by induction of so called premature senescence (5).…”