The risk-of-bias table reveals that the quality of evidence varies considerably. Some studies, particularly prospective ones with predefined imaging and pathology protocols, scored well across domains. However, many retrospective cohorts demonstrated moderate-to-high risk of selection bias, often because healthier patients or those with better clinical response were more likely to undergo delayed surgery. Lack of comparability between groups and inconsistent outcome assessment further weaken the strength of conclusions [26-28].

A notable issue is the inconsistent quality of imaging evaluation. Several studies lacked standardized criteria for defining radiologic complete response (rCR), and in some cases, radiological assessment was performed retrospectively without blinding. Such methodological weaknesses reduce confidence in imaging as a predictor of pCR. Overall, while the evidence suggests meaningful associations between TTS, pCR, and imaging findings, the predominance of non-randomized studies with methodological limitations calls for cautious interpretation and highlights the urgent need for high-quality RCTs and standardized imaging protocols [29].

Effect of timing on pCR by tumor type

Rectal cancer (nCRT): Several cohort studies and meta-analyses reported higher rates of tumor regression and pCR when surgery occurred at longer intervals after nCRT commonly 7-12 weeks compared with shorter intervals (4-6 weeks). Randomized evidence is mixed but suggests a window around 8-11 weeks may optimize pCR without major increases in perioperative morbidity.

Esophageal/gastric cancer: Some retrospective studies report increased pCR with delayed surgery (>6-8 weeks), though evidence is heterogeneous and confounded by selection bias.

Breast cancer: Most studies do not show a consistent increase in pCR with longer TTS after completion of systemic NACT; subtype and systemic regimen (including anti-HER2 therapy) have larger effects on pCR. A few cohort analyses suggested that very long delays (>8 weeks) may be associated with adverse survival outcomes in some datasets.

NSCLC: Emerging reports suggest shorter TTS (≤4 weeks) after neoadjuvant chemo immunotherapy may improve pathological response, but data are limited.

Meta-analysis (where feasible): Pooled OR for pCR comparing longer vs shorter intervals across X studies in rectal/esophageal disease was OR= [value] (95% CI [a–b], I²= [value]). (Include forest plot in main document.)

Radiologic evaluation: accuracy and timing

Imaging modalities vary in sensitivity and specificity for predicting pCR:

ü  Breast MRI (CE-MRI and DWI): Good sensitivity for residual tumor but imperfect specificity; radiologic complete response (rCR) underestimates residual microscopic disease. Combining DWI metrics and contrast kinetics can improve AUC. Timing of MRI relative to last NACT dose affects conspicuity of residual tumor and false-negative rates.

ü  PET/CT (18F-FDG): Decreases in SUVmax correlate with pathological response in several tumor types; interval between therapy and PET affects inflammatory uptake and diagnostic accuracy.

ü  CT: Useful for gross response but limited for microscopic pCR detection.

The optimal timing of imaging to predict pCR appears to be a balance: perform imaging close enough to surgery to reflect final treatment effect while allowing time for inflammation to subside (often 2-4 weeks after last therapy), but exact timing varies by modality [30].

Discussion

Principal findings

This systematic review evaluated the influence of surgery timing after neoadjuvant chemotherapy (NACT) or chemo radiotherapy (nCRT) on pathological complete response (pCR) rates across multiple tumor types, while also considering the contribution of radiological imaging in preoperative assessment. Several important themes emerged. First, there appears to be a “window of opportunity” in certain cancers, especially rectal and esophageal malignancies treated with nCRT, where modest delays typically 6-12 weeks are associated with higher pCR rates compared with shorter intervals. Second, in breast cancer, the impact of time-to-surgery (TTS) on pCR is less consistent, with tumor biology and systemic regimen being stronger determinants of pCR than interval length [31].

Third, radiological imaging plays a vital but imperfect role in predicting pCR. While advanced modalities such as diffusion-weighted MRI (DWI), dynamic contrast-enhanced MRI, and PET/CT show promise, they cannot yet substitute for pathological assessment. Finally, extreme delays beyond 12-16 weeks are not consistently beneficial and may compromise surgical safety or oncologic outcomes.

Comparison with previous literature

The findings of this review are in line with prior meta-analyses in rectal cancer, which consistently reported that pCR rates increase as the interval between nCRT and surgery extends from 6 weeks to around 10-11 weeks. Beyond this window, further delays do not necessarily enhance response and may even increase surgical morbidity due to fibrosis and pelvic scarring. A randomized trial comparing 7 weeks versus 11 weeks after nCRT demonstrated a modest but clinically meaningful increase in pCR at the longer interval, without significantly increasing perioperative risk. These data provide the most robust support for a deliberate delay in surgery after neoadjuvant therapy [32].

In esophageal and gastric cancers, evidence is more heterogeneous. Some retrospective series show improved regression and pCR rates with delays beyond 6-8 weeks, while others demonstrate no difference. A key limitation is confounding by patient selection: patients who tolerate treatment well and recover adequately are often those for whom surgery is delayed, introducing a “healthy responder bias.” As such, the true causal impact of timing in these cancers remains uncertain [33].

Breast cancer presents a different scenario. Multiple large retrospective cohorts, including registry-based studies, suggest that pCR is predominantly determined by tumor subtype particularly triple-negative breast cancer (TNBC) and HER2-positive disease receiving targeted therapy rather than TTS. Some reports even suggest that delays beyond 8 weeks may be associated with inferior survival outcomes, although causality is difficult to establish. Therefore, in breast cancer, efforts to optimize pCR should focus on tailoring systemic regimens rather than modifying surgical timing.

In NSCLC, recent adoption of neoadjuvant chemo immunotherapy has reignited interest in TTS. Early evidence suggests that shorter intervals (≤4 weeks) may be favorable, possibly because immunologically mediated tumor clearance occurs rapidly and delays may allow for tumor regrowth. However, studies are limited and ongoing trials will be critical to clarify this issue.

Radiological evaluation in predicting pCR

Imaging is a cornerstone of assessing response after neoadjuvant therapy. Yet, the ability of imaging modalities to predict pCR varies widely across tumor types and technologies.

Breast MRI remains the most studied modality. It demonstrates high sensitivity for detecting residual disease but modest specificity, often overestimating residual tumor burden due to post-treatment enhancement or underestimating microscopic disease. Radiological complete response (rCR) on MRI correlates with but does not guarantee pCR. Addition of functional sequences such as diffusion-weighted imaging improves diagnostic accuracy, with higher apparent diffusion coefficient (ADC) values associated with favorable response [34].

PET/CT is widely used in esophageal, gastric, and lung cancers. Declines in standardized uptake value (SUVmax) after therapy correlate with pathological response. However, inflammatory uptake can confound interpretation, especially if imaging is performed too soon after therapy. Waiting several weeks before PET may improve accuracy, but excessive delay risks losing prognostic relevance.

CT and ultrasound are less reliable for detecting pCR, though they remain useful for gross assessment of tumor regression and for surgical planning. Emerging approaches such as radiomics and artificial intelligence applied to CT or MRI hold promise in extracting subtle imaging features predictive of treatment response.

Importantly, the timing of imaging is as critical as the timing of surgery. Imaging too early after therapy may exaggerate residual findings due to treatment-related inflammation, while very late imaging may not meaningfully influence surgical planning. Most studies support performing imaging 2-4 weeks after completion of therapy, providing a balance between accuracy and practicality [35].

Biological rationale for timing effect

The observed association between delayed surgery and improved pCR in some cancers has plausible biological underpinnings. Tumor cell death following cytotoxic therapy is not instantaneous; apoptosis, necrosis, and immune-mediated mechanisms may continue for weeks. This “tumor regression window” may explain why delaying surgery modestly allows maximal therapeutic benefit to manifest. Furthermore, neoadjuvant therapy may prime the tumor microenvironment for immune clearance, a process that evolves over time.

On the other hand, prolonged delays may permit tumor repopulation by resistant clones, angiogenic rebound, or epithelial mesenchymal transition, which can negate earlier treatment benefits. Additionally, therapy-induced fibrosis and desmoplastic reactions increase with time, complicating surgical dissections and potentially elevating operative risk. Thus, there is likely an optimal interval, beyond which risks outweigh benefits [36].

Clinical implications: The clinical application of these findings requires careful nuance. For rectal cancer, evidence supports a TTS of 8-11 weeks after nCRT to maximize pCR, provided patient fitness and local resources allow. For breast cancer, surgery should proceed according to standard recovery timelines (commonly 3-6 weeks) rather than being deliberately delayed for pCR purposes. In esophageal and gastric cancers, a cautious approach is warranted, with individualized decisions based on radiological response, clinical recovery, and institutional expertise. In lung cancer, current evidence suggests not prolonging intervals beyond 4-6 weeks after neoadjuvant therapy [37].

Across tumor types, radiological imaging should be integrated into the decision-making process, but clinicians must remain mindful of its limitations. Imaging can stratify responders and guide multidisciplinary discussions but should not replace pathology in confirming Pcr [38].

Limitations of the current evidence: Several limitations temper the conclusions of this review. Most included studies were retrospective and observational, introducing confounding and selection bias. Definitions of TTS varied widely, ranging from simple dichotomizations (<6 vs ≥6 weeks) to multiple interval categories, hindering comparability. Many studies did not adjust adequately for tumor biology, treatment regimen, or patient comorbidities. Additionally, radiological assessment protocols were inconsistent, with variation in modality, timing, and criteria for defining response. Few studies directly examined how imaging findings influenced surgical timing decisions [39].

Another limitation is the underrepresentation of certain tumor types, particularly lung and gastric cancers, where evidence remains sparse. Moreover, most studies reported pCR as the primary endpoint, but fewer linked TTS to long-term outcomes such as DFS and OS. This raises questions about the true clinical relevance of modest changes in pCR, especially when survival implications are uncertain.

Research recommendations: Future research should prioritize prospective randomized controlled trials (RCTs) specifically designed to evaluate different TTS intervals after standardized neoadjuvant regimens. Such trials should include central pathology review, rigorous reporting of surgical outcomes, and integration of survival endpoints. Radiological assessment must be standardized across centers, with predefined imaging protocols, response criteria, and intervals. Advanced imaging biomarkers such as DWI parameters, PET metabolic indices, and radiomics signatures should be incorporated prospectively to evaluate their ability to predict pCR and guide timing decisions [40].

Additionally, translational studies exploring the biological mechanisms underlying continued tumor regression after therapy may inform optimal timing. Integration of circulating tumor DNA (ctDNA) and other liquid biopsy markers with imaging could refine patient selection for delayed surgery or even nonoperative “watch-and-wait” strategies in selected contexts, such as rectal cancer.

Economic analyses are also warranted. Delayed surgery may incur logistical challenges, increase health system costs, and complicate scheduling. Assessing the cost-effectiveness of timing strategies, particularly in resource-limited settings, is essential for policy development [41].

Strengths of this review: This systematic review contributes by synthesizing evidence across multiple tumor types and explicitly examining the role of radiological imaging in timing decisions. By considering both biological plausibility and technological advances in imaging, it highlights the interplay between clinical practice and emerging tools. The cross-tumor comparison allows recognition of common themes (such as a potential regression window) while acknowledging disease-specific nuances. The timing of surgery after neoadjuvant chemotherapy or chemo radiotherapy significantly influences pathological complete response rates in certain cancers but not uniformly across all tumor types. Rectal and esophageal cancers appear to benefit from modestly delayed surgery (6-12 weeks), whereas breast and lung cancers show less consistent or different patterns. Radiological imaging is indispensable for evaluating treatment response and informing multidisciplinary decisions, but it remains an imperfect surrogate for pCR. Advanced imaging biomarkers and standardized protocols hold promise for enhancing predictive accuracy. Clinicians should adopt an individualized approach, balancing potential gains in pCR with risks of surgical difficulty or disease progression. Until robust randomized data become available, decisions should be guided by tumor type, neoadjuvant regimen, patient recovery, and radiological findings within multidisciplinary teams. Future trials incorporating imaging, molecular biomarkers, and survival outcomes are critical to defining evidence-based guidelines for optimal timing [42].

Conclusion

This systematic review sought to clarify the relationship between the timing of surgery after neoadjuvant chemotherapy (NACT) or chemo radiotherapy (nCRT) and the likelihood of achieving pathological complete response (pCR), while also evaluating the role of radiological imaging in guiding these decisions. Across multiple tumor types including rectal, esophageal, gastric, breast, and non-small cell lung cancer (NSCLC) the evidence demonstrates that the timing pCR relationship is both complex and tumor-specific. Importantly, radiological evaluation offers valuable but imperfect insights, emphasizing the need for multidisciplinary integration of imaging with clinical and pathological data.

The most consistent evidence emerges in rectal cancer, where several cohort studies, meta-analyses, and randomized trials suggest that extending the interval between completion of nCRT and surgery to approximately 8-11 weeks is associated with higher pCR rates compared with shorter intervals of 4–6 weeks. This observation aligns with biological rationale: tumor regression and immune-mediated clearance continue beyond the end of therapy. However, excessively prolonged delays beyond 12-16 weeks do not confer further benefits and may increase surgical technical difficulty due to fibrosis, highlighting the importance of a balanced approach.

In esophageal and gastric cancers, some studies similarly report improved tumor regression and pCR rates with modestly delayed surgery, though findings are inconsistent and frequently limited by retrospective design and patient selection bias. While a “sweet spot” around 6-8 weeks is suggested in certain cohorts, evidence is insufficient to make definitive recommendations, and individualized clinical judgment remains paramount.

Breast cancer presents a different pattern. Here, pCR is strongly determined by tumor biology such as triple-negative and HER2-positive subtypes and by systemic regimens including targeted therapies, rather than by surgical timing itself. Large registry and institutional series consistently show no clear improvement in pCR with deliberate surgical delays. Indeed, prolonged TTS beyond 8 weeks may be associated with worse survival in some cohorts, although confounding factors complicate interpretation. For breast cancer, then, timely surgery aligned with systemic treatment schedules is preferable, rather than intentionally extending the interval in pursuit of higher pCR. In NSCLC, particularly in the era of neoadjuvant chemo immunotherapy, preliminary data suggest that shorter intervals to surgery often within 4 weeks may be advantageous. This may reflect the rapid onset of immune-mediated tumor clearance and the risk of progression if surgery is delayed. However, the evidence base here is small, and ongoing trials are needed to confirm the optimal timing.

Radiological imaging is central to evaluating treatment response and influencing surgical timing decisions. Breast MRI, especially when combined with diffusion-weighted imaging, offers high sensitivity but moderate specificity for predicting pCR. PET/CT provides valuable metabolic information in esophageal, gastric, and lung cancers but is limited by inflammatory uptake if performed too soon after therapy. CT and ultrasound, though widely available, lack the accuracy required to serve as definitive predictors of pCR. Importantly, the timing of imaging itself is critical: performing scans 2-4 weeks after the end of therapy allows resolution of treatment-related changes and improves predictive performance. Despite these advances, radiological complete response (rCR) does not equate to pCR, and reliance solely on imaging is not sufficient for surgical decision-making. Taken together, these findings highlight both opportunities and challenges. Modest delays after nCRT in rectal and, to a lesser extent, esophageal or gastric cancers may enhance pCR rates and potentially long-term outcomes, but such strategies must be tailored to tumor type, regimen, and patient condition. In breast cancer and NSCLC, routine surgical delay appears unwarranted, with biology and systemic therapy being more critical determinants of response. Radiological imaging should be employed systematically but interpreted cautiously, acknowledging its predictive limitations. The quality of current evidence remains limited, as most studies are retrospective and heterogeneous in their definitions of TTS, imaging protocols, and response criteria. There is a pressing need for prospective randomized controlled trials that directly compare different surgical intervals, incorporate standardized imaging modalities, and report both pCR and survival outcomes. Future research should also integrate advanced imaging biomarkers, radiomics, and circulating tumor DNA (ctDNA) to refine prediction of pCR and personalize surgical timing.

In conclusion, the timing of surgery after neoadjuvant therapy has a measurable but context-dependent effect on pCR. For rectal and certain gastrointestinal cancers, modest delays may optimize response; for breast and lung cancers, timing exerts little influence compared with tumor biology and systemic treatment. Radiological imaging provides indispensable guidance but cannot yet replace histopathological confirmation. A nuanced, multidisciplinary approach considering tumor type, treatment modality, patient fitness, and imaging findings is essential to balance oncologic efficacy with surgical safety. By bridging biological rationale, imaging advances, and clinical evidence, future studies can better define optimal timing strategies and ultimately improve outcomes for patients undergoing multimodality cancer treatment.

 Disclosure Statement

No potential conflict of interest reported by the authors.

 Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

 Authors' Contributions

All authors contributed to data analysis, drafting, and revising of the paper and agreed to be responsible for all the aspects of this work.