Radical surgery with TME (total mesorectal excision) remains the main curative treatment for patients affected by LARC . The TME associated with nCRT improve outcomes by increasing 5-year survival rate . Several previous studies have demonstrated that, compared with adjuvant treatment, preoperative nCRT significantly improves loco-regional tumor recurrence and reduces toxicity compared with postoperative strategies . The early identification of pR after nCRT in rectal cancer remains an important challenge, and it could avoid surgical overtreatment without compromising local control and long-term survival . It could considerably reduce the number of surgical procedures required in the future allowing less invasive procedures, such as TAMIS (Transanal minimally invasive surgery), to be performed for initially LARC . This latter approach could also reduce rates of mortality, morbidity and other unsatisfactory functional outcomes that may occur after rectal resection. Furthermore, an early prediction in the No Responders group could provide the clinician the opportunity to evaluate the possibility of reorientation of the standard treatment by increasing number of chemotherapy cycles and radiotherapy, as well. The current conventional radiology, such as endorectal ultrasound (EU), CT scan and MRI for monitoring the tumor response, shows several limitations to assess the pR after nCRT. This is mainly due to the difficulties in discerning between disease persistence and radiation induced inflammation and fibrosis after nCRT . 18F -FDG PET-CT has a recognized validity for monitoring nCRT effects .
There are several studied that have investigated the predictive value of 18F-FDG PET-CT in the LARC and in recurrent rectal cancer, and more are likely to be produced using collaborative, international research platforms [18-27]. However, these studies have some limits mainly due to the methodological heterogeneity secondary to their multicentric nature in terms of preoperative studies, chemoradiotherapy, patients’ characteristics and PET study method (timing, technique and analysis of images). Despite these limits, it is important to observe that almost all these previous studies identify a significant correlation between tumor 18F-FDG uptake and pR, also showing correlation between OS and DFS [13,15-18].
A recent study by Niccoli-Asabella et al. was able to evaluate the prognostic value of 18F-FDG PET-CT in terms of survival in patients with LARC who have undergone surgery after nCRT. This work showed a high percentage of patients with TRG complete response (39.7%) with longer OS and DFS in responders group but without statistically significant differences .
The strength of our study relies on being one of the largest studies evaluating 18F-FDG PET-CT related to histopathological response (TRG score) at two time-points, before nCRT (early PET-CT) and after finishing CRT (late PET/CT). We found the optimal cut-off to distinguish responders patients (TRG3-TRG4) from no-responders patients (TRG0-TRG2) at of 70% of the Δ%SUV. Furthermore, our analysis showed that Δ%SUV was a stronger discriminator between the two groups with a high accuracy of 81% (34/42), with a sensitivity of 84.4%, a specificity of 80%, a positive predictive value of 81.4% and a negative predictive value of 84.2%. We were able to found correlation between Δ%SUV and OS and DFS showing a statistically significance (p<0,05), as well.
Another similar study by Leccisotti et al., found similar results They found the optimal cut-off to distinguish no-responders patients from responders patients on the early PET-CT scan as a reduction in tumor SUVmax of 61.2 % (85.4 % sensitivity, 65.2 % specificity) .
An important issue still uncleared remains the PET-CT study method (timing, technique and qualitative analysis of images). Most studies report inaccurate results due to heterogeneous methods for 18F-FDG PET-CT quantification, the correct time to perform the study and the metabolic criteria [19,20]. It is important to standardize the criteria for the correct use of 18F-FDG PET-CT in order to achieve a correct interpretation of the result. In the current literature, there is no standardized data that indicates the proper timing by which to perform the 18F-FDG PET-CT. It is well known that chemotherapy produces an inflammatory reaction that lasts one week after the beginning of treatment, while radiotherapy inflammatory reaction may last up to 6 months. Therefore, it is important choose or indicate the right time to perform 18F-FDG PET-CT after nCRT in order to standardize the correct interval being a potential source of false-positive findings on the late 18F-FDG PET-CT. The World Health Organization recommends 18F-FDG PET-CT seven weeks after nCRT and surgery one week later . This is mainly based after the trial performed by R.O Perez et al., showing a proper restaging with 18F-FDG PET-CT at 6 and 12 weeks after the completion of therapy . The present study was concomitant with this recommendation as all patients underwent FDG PET-CT six to seven weeks after the end of nCRT and surgery was performed eight weeks from the end of neoadjuvant treatment.
The main limitations are the relatively small number of patients in our cohort due to a single center enrollment. However, the unicentric nature represents also a guarantee for more homogenous data.
We believe that more technically advanced tools are important to accurately measure tumour change. Nowadays the use of quantitative analysis of PET/MRI to assess pCR following nRCT in LARC could improve outcome prediction and open the era of adaptive therapy for cancer patients [29,30].
In conclusion, the results of this analysis are promising and shown that 18F-FDG PET-CT may be an indicator in order to evaluate the pR to nCRT in patients with LARC. The decrease in 18F-FDG PET-CT uptake in the primary tumor may offer primary information in order to early identify those patients more likely to obtain a pCR to nCRT and predict those unlikely to regress significantly. Rigorous follow up and future larger prospective studies are necessary to confirm these results.