Prediction of histological response by PET-CT after 2 weeks of neoadjuvant chemo-radiotherapy for rectal cancer: a prospective clinical trial

Introduction

For patients with locally advanced rectal cancer (LARC; stage II–III), trimodality treatment consisting of neoadjuvant chemoradiotherapy (nCRT) followed by total mesorectal excision (TME) is considered standard, improving local control and facilitating tumor downstaging (1-3). Only 13–30% of patients reach pathological complete response (pCR) after nCRT, a finding associated with more favorable long-term outcomes (4). More recently, total neoadjuvant treatment (TNT) has become widely adopted as standard practice for LARC, with randomized trials demonstrating higher rates of pCR and improvements in disease-free and overall survival compared to nCRT alone (5-7). The ability to identify early which patients are likely or unlikely to achieve pCR has important implications: it may allow de-escalation to a watch-and-wait strategy in complete responders (8-11), earlier surgical resection in poor responders, or chemotherapy intensification before surgery in selected cases.

Metabolic imaging with ¹⁸F-fluorodeoxyglucose (¹⁸FDG)-positron emission tomography (PET)-computed tomography (CT) has been explored as a potential tool in this setting. Several studies have demonstrated associations between reductions in metabolic activity during nCRT, reflected by different ¹⁸FDG-PET-CT parameters, and histological response in LARC (12-14). However, results across studies remain inconsistent because of heterogeneity in PET methodologies, including variation in imaging timing, quantitative parameters, and response thresholds.

To address this question, we initiated a prospective clinical trial evaluating the correlation between interim ¹⁸FDG-PET-CT performed at different time points during nCRT and subsequent histological response. We previously reported findings from the first cohort, which suggested that a decrease in maximum standardized uptake value (SUV-max) after 1 week of nCRT was associated with pCR (14), as well as the results of a separate validation cohort that did not reproduce this association (15). In the present report, we describe the results of the second cohort, in which interim imaging was performed after 2 weeks of nCRT. We present this article in accordance with the STARD reporting checklist (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2026-1-0104/rc).

Methods

Patients

This prospective study included patients with LARC who received standard nCRT followed by radical surgery at a tertiary cancer center between January 2009 and February 2016. Eligibility criteria included histologically confirmed primary LARC, defined as uT3–4NxM0 or uTxN+M0-disease according to the American Joint Committee on Cancer (AJCC) version 7 (16). All patients underwent staging at baseline, which included rigid proctorectoscopy, endoscopic ultrasound (EUS), and whole body ¹⁸FDG-PET-CT. Inclusion criteria also included Eastern Cooperative Oncology Group (ECOG) performance status 0–1, FDG-avid tumor, and no chronic renal or hepatic failure. Exclusion criteria included personal history of other malignancy (other than non-melanoma skin cancer and cervical carcinoma in situ) within the past 5 years prior to study inclusion, prior chemotherapy or pelvic radiotherapy, and history of surgery for rectal cancer. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Rabin Medical Center Helsinki Committee (approval: November 2008; No. 0239–07-RMC), and all participants provided written informed consent to participate in it.

nCRT

The neoadjuvant treatment consisted of continuous oral fluoropyrimidine-based chemotherapy given with concurrent radiotherapy. Radiotherapy included a total pelvic dose of 45 Gy delivered in 1.8 Gy daily fractions, 5 times per week, and a boost dose of 5.4 Gy to the tumor. The dose was prescribed to the isodose encompassing the primary tumor and the internal iliac nodes using 6 or 18 MV photons. Radiation planning techniques employed either three-dimensional conformal radiotherapy (3DCRT) or intensity modulated radiation therapy (IMRT). Chemotherapy, consisting of either capecitabine 825 mg/m² twice daily or uracil-tegafur (UFT) 300 mg/m² daily, both administered on radiotherapy days , started on the first day of radiotherapy and continued until its completion.

¹⁸FDG-PET-CT protocol, imaging, and analysis

Patients underwent whole-body ¹⁸FDG-PET-CT at baseline (within 2 weeks prior to initiation of nCRT) and a pelvic limited ¹⁸FDG-PET-CT scan 2 weeks after the initiation of nCRT, with 24-hour confidence margins for the timing of the second scan. All patients fasted for a minimum of 4 hours prior to the injection of ¹⁸F-FDG. Patients were required to drink oral contrast fluid (300 mg Telebrix with 1,000 cc of water). Images were obtained 60 minutes later using an integrated eighty-section PET-CT scanner (Discovery ST; GE Medical Systems, Milwaukee, WI, USA). Iodine contrast medium (Ultravist 300) was administered intravenously during the CT scan to all patients, unless they had an iodine allergy, impaired renal function, or refused. PET was performed immediately after CT. The acquisition time for emission scans was 2 minutes per bed position, with a one-section overlap CT data used for attenuation correction. Images were reconstructed with a standard iterative algorithm.

Image analysis was done visually and semi-quantitatively. SUV-max, mean standardized uptake value (SUV-mean), and metabolic tumor volume (MTV) were calculated for the rectal lesion at baseline and after 2 weeks of neoadjuvant therapy. The difference between the two time points was depicted as the percentage of SUV-max, SUV-mean, and MTV reduction (ΔSUV-max%, ΔSUV-mean%, ΔMTV%, respectively). Two expert nuclear-medicine radiologists (H.B. and D.G.) evaluated the PET-CT scans separately. Both were blinded to any clinical information regarding the patients as well as to the timing of the study in the course of nCRT. Final results were the calculated average of their readings.

Surgery

Surgery, TME in all cases, was planned to take place 6–10 weeks after the completion of nCRT, and was to be either low anterior resection (LAR) or abdominoperitoneal resection (APR). Prior to surgery, all patients underwent restaging with rigid proctorectoscopy, PET-CT, and EUS.

Histological evaluation of tumor response

All surgical specimens were evaluated at the Department of Pathology in RMC by a single expert pathologist (S.M.) who was blinded to the PET-CT findings. Two measures of treatment response were assessed: pCR, defined as the absence of residual tumor in the rectal wall (pT0) and in the regional lymph nodes (pN0), and tumor regression grade (TRG), as defined by Mandard et al. (17). The non-pCR group included all patients who did not achieve a pCR. TRG was categorized from I, indicating no residual cancer, to V, indicating no evidence of regressive changes within the tumor. Response categorization was determined for each patient individually. For additional analysis, TRG I–II was grouped as major response and TRG III–V was grouped as non major response.

Statistical analysis

This was an exploratory, hypothesis-generating study, and the sample size was not formally powered to detect small differences in metabolic parameters. MTV, SUV-max, and SUV-mean were measured at baseline and at the 2-week PET-CT. The percentage change from baseline was calculated for each parameter. Differences in absolute values and percentage reductions between patients who achieved pCR and those who did not, as well as between histologic responders and non-responders according to TRG, were evaluated using the Mann Whitney test. For variables demonstrating statistically significant differences between response groups, receiver operating characteristic (ROC) analysis was performed in order to identify cutoff values that maximized sensitivity and specificity. The optimal cutoff value for each variable was determined using the Youden index (J = sensitivity + specificity − 1), which maximizes the difference between the true positive rate and the false positive rate. All statistical analyses were conducted in R (version 4.2.1) and were two-sided, with a significance level of 5%.

Results

Patients

Twenty-one patients were included in this study (Figure 1). Baseline patient and tumor characteristics as well as treatment details are summarized in Table 1. The median age was 61 years (range, 50 to 82 years), and 65% were males. Most tumors (90%) were located at least 5 cm from the anal verge. Clinical stage II disease was more common than stage III (67% vs. 33%). The majority of patients had cT3 tumors (95%), and no cases of cT4 or cN2 disease were observed.

Figure 1 Patient flow chart. PET, positron emission tomography.

Treatment

All patients received standard nCRT, with the concurrent chemotherapy consisting of capecitabine in 95% of cases. Patients underwent surgery within a median of 8.1 weeks (range, 4.6–12.9 weeks) after completing nCRT. One patient declined surgery after nCRT, despite a clinical evidence for persistent disease, and subsequently experienced disease progression and underwent resection 360 days after completing radiotherapy. For the purposes of this analysis, this patient was classified as a non-responder (non-pCR and TRG III–IV). All patients underwent curative intent (R0) resection, and 86% underwent sphincter-preserving LAR. On histopathologic evaluation, 6 patients (29%) achieved pCR and 8 (38%) demonstrated TRG I–II and were therefore categorized as having a major response. No tumors were classified as TRG V, indicating that all patients exhibited some degree of treatment response.

PET-CT evaluation

The mean SUV-max at baseline was 16.2 (range, 4–43.9) and the mean SUV-max at the second scan was 9.5 (range, 0–26.2). A reduction in SUV-max was observed during the first 2 weeks of nCRT in 19 patients, with a mean decrease of 40.5% (range, 100% decrease to 40.9% increase). The mean SUV-mean at baseline was 9.6 (range, 2.5–28) and the mean SUV-mean at the second scan was 5.6 (range, 0–16.4). A reduction in SUV-mean was observed in 17 patients, with a mean decrease of 40.8% (range, 100% decrease to 34.4% increase). The mean MTV at baseline and after 2 weeks were 24.9 (range, 7.3–107) and 16.9 (range, 0–39.3), respectively. Reduction of MTV was observed in 19 patients with a mean decrease of 29% (range, 100% decrease to 25.9% increase). Two patients achieved a complete metabolic response at the interim PET-CT evaluation.

Correlation between metabolic parameters and histological response

At baseline, SUV-max and SUV-mean were significantly higher in patients who did not achieve pCR compared with those who did (P=0.04 and P=0.03, respectively), while MTV showed a non-significant trend in the same direction (P=0.09) (Figure 2 and Table 2). At 2 weeks after initiation of nCRT, significant differences between pCR and non-pCR patients were observed in SUV-max and MTV (P=0.043 and P=0.03, respectively), with a trend for SUV-mean (P=0.051) (Figure 2 and Table 2). When stratified by TRG, baseline SUV-max and SUV-mean were significantly higher in non-responders (TRG III–IV) compared with responders (TRG I–II) (P=0.043 and P=0.03, respectively), whereas no significant differences were observed at 2 weeks (P=0.13 and P=0.11, respectively). MTV demonstrated a trend toward higher values in non-responders at both time points (P=0.11 at baseline and P=0.055 at 2 weeks).

Figure 2 Distribution of metabolic values according to histological response. SUV-max at baseline and after 2 weeks of nCRT by pCR (A) and TRG (B), SUV-mean at baseline and 2 weeks by pCR (C) and TRG (D) and MTV at baseline and 2 weeks by pCR (E) and TRG (F). MTV, metabolic tumor volume; nCRT, neoadjuvant chemoradiotherapy; pCR, pathological complete response; SUV-max, maximum standardized uptake value; SUV-mean, mean standardized uptake value; TRG, tumor regression grade.

The association between the degree of metabolic reduction after 2 weeks of nCRT (∆SUV-max%, ∆SUV-mean%, and ∆MTV%) and histologic response was then evaluated. No significant differences were observed between patients who achieved pCR and those who did not (P=0.26, P=0.28, and P=0.33, respectively) (Figure 3 and Table 2). Two patients with pCR demonstrated a complete metabolic response on interim PET-CT, compared with none in the non-pCR group. Early metabolic reduction was also not associated with response per TRG, with P=0.54, P=0.47, and P=0.33 for ∆SUV-max%, ∆SUV-mean%, and ∆MTV%, respectively, between major responders (TRG I–II) and non-responders (TRG III–IV) (Figure 3 and Table 2).

Figure 3 Distribution of change in metabolic values between baseline and after 2 weeks of nCRT according to histological response. ΔSUV-max% by pCR (A) or TRG (B), ΔSUV-mean% by pCR (C) or TRG (D) and ΔMTV% by pCR (E) or TRG (F). MTV, metabolic tumor volume; nCRT, neoadjuvant chemoradiotherapy; pCR, pathological complete response; SUV-max, maximum standardized uptake value; SUV-mean, mean standardized uptake value; TRG, tumor regression grade.

Prediction of histological response

As only absolute values of SUV-max, SUV-mean at baseline and SUV-max and MTV at 2 weeks were associated with pCR, ROC analysis was performed on these parameters to identify cutoffs that could predict histological response (Table 3). ROC analyses for SUV-max and SUV-mean at baseline demonstrated moderate discrimination, with area under the curve (AUC) values of 0.81 [95% confidence interval (CI): 0.59 to 1.0] and 0.82 (95% CI: 0.61 to 1.0), respectively. A cutoff of 7.8 for SUV-mean at baseline identified patients who achieved pCR with a sensitivity of 83% and a specificity of 73%. Using a cutoff of 12.8 for SUV-max at baseline, sensitivity and specificity for predicting pCR were 83% and 80%, respectively.

ROC analyses for SUV-max and MTV at 2 weeks also demonstrated moderate discrimination, with AUC values of 0.79 (95% CI: 0.56 to 1.0) and 0.81 (95% CI: 0.57 to 1.0), respectively. Using a cutoff of 5.35 for SUV-max at 2 weeks of nCRT, sensitivity and specificity for predicting pCR were 87% and 67%, respectively. A cutoff of 11.25 for MTV at 2 weeks identified patients who achieved a pCR with sensitivity of 83.3% and specificity of 86.7%

Discussion

In this study, early metabolic response assessed by interim PET-CT performed two weeks after initiation of nCRT did not correlate with pCR or TRG, with no significant differences in ∆SUV-max, ∆SUV-mean, or ∆MTV values between histologic response groups. In contrast, absolute SUV-max and SUV-mean values at baseline and absolute SUV-max and MTV at 2 weeks demonstrated moderate to high discriminatory ability for predicting pCR.

Given that absolute SUV-max and SUV-mean at baseline already demonstrated significant predictive value for pCR, and the interim metabolic changes did not, the results of this study suggest that an interim PET-CT performed at the 2-week mark may not provide enough additional clinical utility to justify its routine use outside of a clinical trial setting. When considering the associated costs and radiation exposure, a high-quality baseline assessment may be sufficient for early response prediction in this patient population.

Findings in the literature regarding the predictive value of interim PET-CT during nCRT for LARC are heterogeneous and sometimes conflicting (Table 4). Studies differ in the timing of the interim scan, PET-derived parameters examined, quantitative thresholds applied, and histological endpoints used. Sample sizes have generally been small, often with heterogeneous clinical and pathological characteristics, limiting statistical power and external validity. Although multiple studies and small prospective trials have reported some degree of predictive value (30), interim PET-CT has not been adopted into routine clinical practice, reflecting the inconsistency of available evidence and the lack of standardized methodology. Only two studies, including one from our group, have attempted validation in an independent cohort (15,31), underscoring the limited robustness of existing data and the need for reproducibility in this field.

The heterogeneity in methodology across studies extends to analytic approaches, including the use of non-standard PET metrics such as total lesion glycolysis (TLG) and visual response scoring (22), as well as attempts to correct for partial volume effects. No consensus has emerged regarding the optimal metabolic parameter (25), the most informative imaging time point, or the most appropriate histological comparator. These inconsistencies, combined with small sample sizes in most reports, limit the ability to draw firm conclusions regarding the clinical utility of interim PET-CT in guiding response-adapted therapy.

In our study, tumors with lower SUV-max and SUV-mean at baseline were more likely to achieve pCR, and a similar trend was observed for MTV. Findings in the literature regarding baseline metabolic PET parameters are heterogeneous overall, with many studies reporting limited predictive value for baseline SUV-max, and some suggesting that volumetric metrics such as MTV or TLG may offer improved discrimination in selected cohorts (18,21,22,24,29,32,33). In several retrospective series evaluating metabolic predictors of treatment response, baseline SUV-max did not consistently differentiate responders, whereas MTV showed a stronger association with pathologic outcomes (15,34-36). Conversely, a larger study of 151 LARC cases reported no significant association between baseline SUV-max, MTV, or TLG and Mandard TRG or pCR rates (37).

Our study also found that absolute PET parameters at the 2-week interim time point, specifically SUV-max and MTV, with a similar trend for SUV-mean, were associated with pCR. This association between 2-week absolute metabolic and volumetric values and pCR has not been consistently reported in prior studies, which have emphasized early change in PET parameters. Considered together with our baseline findings, these results most likely indicate that tumors with lower baseline metabolic activity and tumor burden are more likely to achieve histological response.

The present findings should be interpreted in the context of several limitations. The small cohort size and low number of pCR events restrict statistical power, raising the possibility that our negative findings regarding interim metabolic changes represent a Type II error. However, even if a larger sample size were to yield statistical significance, the substantial overlap in ΔSUV% and ΔMTV% values observed between the pCR and non-pCR groups suggests that these parameters would likely remain clinically uninformative. Such extensive overlap makes it difficult to establish robust, high-confidence cutoffs for individual patient management. This trial was designed as an exploratory, hypothesis-generating phase within a broader research program evaluating several interim PET-CT intervals to identify the optimal window for metabolic assessment. Preliminary signals from these cohorts led our group to prioritize the 1-week time point for a larger, recently published prospective validation study (15). Tumor-related factors, such as low FDG avidity or inflammation within areas of necrosis, and patient-related factors, including background rectal inflammation, may alter FDG uptake independent of treatment effect. Treatment-related inflammation from radiotherapy, which may be more pronounced at the 2-week imaging time point, can further attenuate metabolic decline and increase the risk of false negative assessments, a phenomenon described in other studies (18). The discrepancy between the predictive value observed in our earlier 1-week cohort and the current 2-week results further suggests that there may be a narrow window for early metabolic assessment. While imaging at 1 week may capture initial chemo- and radiosensitivity, imaging at 2 weeks may coincide with the onset of radiation-induced inflammatory FDG uptake, which can mask the true metabolic response of the tumor and contribute to the variability observed across different imaging time points. Because of the small sample size, multivariable analyses were not feasible, and ROC-derived cutoffs should be interpreted cautiously given the limited number of outcome events. Additionally, the staging for this cohort relied on EUS and PET-CT rather than modern pelvic magnetic resonance imaging (MRI). Consequently, high-resolution data on circumferential resection margin (CRM) involvement was not available for analysis in this study. Finally, the study was conducted before the widespread adoption of TNT, and the relevance of early PET-CT findings to modern treatment algorithms remains uncertain.

Methods for predicting pCR early in the course of treatment are rapidly evolving. Early MRI assessment, alone or integrated with PET-CT, may enhance the accuracy of response prediction (32,38). Radiomics, which extracts high-dimensional quantitative features from MRI and CT images for machine learning-based analysis, is also under active investigation and has shown promising early results (39). Circulating tumor DNA (ctDNA) and circulating tumor cells (CTCs), establishing their role as excellent surrogates for microscopic residual disease in multiple cancer types, are being studied in this setting and have shown promise in predicting treatment response and surgery outcomes (40,41). Gene expression profiling may further enable identification of tumors with intrinsic resistance to nCRT even before treatment onset (42-44). These approaches differ from strategies that rely on defining cCR at the end of nCRT or TNT; instead, they aim to predict histological response early during therapy, with the goal of guiding treatment adaptation and improving patient outcomes.

For early PET-CT to have meaningful clinical utility, its predictive performance must be sufficiently high. In a systematic review by Maffione et al. (30), interim PET-CT during nCRT demonstrated pooled specificity and sensitivity of 85% and 82%, respectively, across ten studies. However, the specificity and sensitivity depend on the cut-off chosen and can be adjusted depending on the test’s aim. As noted in a previous study from our group (14) one might maximize the positive predictive value at the expense of sensitivity to lower false positive results (for example, if one wishes to intensify treatment but not to overtreat patients with good responses) or maximize the negative predictive value to lower false negative results at the expense of specificity (for example if one wishes to follow a “wait and see” policy).

The treatment algorithm of LARC has changed since the initiation of this study, with the wide adoption of the TNT approach after the publication of the OPRA (10), RAPIDO (5), and PRDIGE-23 (6) trials. With TNT becoming the preferred approach for most LARCs and the incorporation of “watch and wait” for complete responders into clinical guidelines (45), the importance of predictive factors for pCR becomes even more significant. Standard post-treatment evaluation typically includes rectal MRI, physical examination, and endoscopy to assess for residual disease. Although this multimodal approach does not achieve perfect accuracy, most patients who experience local regrowth under watch-and-wait protocols can still undergo successful salvage surgery. A drawback of assessing response only at the end of TNT is that some patients may be overtreated and might have achieved pCR with nCRT alone, thereby avoiding additional chemotherapy. Specifically, in induction TNT frameworks, interim PET during nCRT could serve to identify tumors demonstrating early metabolic resistance to concurrent chemoradiotherapy despite previous chemotherapy exposure. Conversely, in consolidation TNT, early metabolic markers could potentially identify ‘excellent responders’ who might safely omit or reduce the duration of subsequent chemotherapy in favor of a ‘watch-and-wait’ approach. Early predictive markers could help identify such patients, reduce unnecessary toxicity, and expand organ-preservation strategies. Future trials of interim PET-CT should therefore be embedded within TNT frameworks to determine their ability to guide treatment de-escalation or intensification, use standardized imaging and histological endpoints, determine optimal imaging timing, and validate findings in larger and more robust cohorts.

Conclusions

In summary, this study failed to show a correlation between early metabolic response as evaluated using interim PET-CT conducted 2 weeks after the initiation of nCRT for LARC and the achievement of pCR or TRG. It did demonstrate the potential of baseline PET-CT to predict the histological response. This strategy is now being further evaluated by our group.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STARD reporting checklist. Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2026-1-0104/rc

Data Sharing Statement: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2026-1-0104/dss

Peer Review File: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2026-1-0104/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2026-1-0104/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Rabin Medical Center Helsinki Committee (approval: November 2008; No. 0239–07-RMC), and informed consent was obtained from all individual participants.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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