Clinical response assessment post neoadjuvant chemo-radiotherapy in rectal cancer: Current evidence and practices

At the outset, we like to express our admiration for Gulhan Guler Avci et al for their published clinical study on the role of MRI and 18F FDG PET/CT with respect to evaluation of pathological response in the rectal cancer patients after neoadjuvant chemoradiotherapy in view of their analysis presented in this study and clarity in answering questions.^[1]

In patients with locally advanced rectal cancer, the initial MRI scan plays a crucial role in determining the need for neoadjuvant chemoradiotherapy. This is achieved through risk stratification based on several factors, including the assessment of circumferential resection margin (CRM), T3 sub-classifications, extramural vessel invasion, nodal status, and sphincter invasion. As a result, there is a consensus among experts regarding the significance of baseline MRI in the preoperative evaluation of rectal cancer patient. Post-chemoradiotherapy MRI is commonly used as the primary method to evaluate treatment response after chemoradiotherapy. However, it remains uncertain whether post-chemoradiotherapy MRI can guide treatment decisions. Surgeons may be hesitant to change their initial treatment plan due to concerns about residual viable tumor cells, even if a patient has shown clinical complete response (following preoperative chemoradiotherapy. Additionally, the effectiveness of post-chemoradiotherapy MRI in determining whether a more extensive surgical dissection or organ-preserving strategy is required has been limited. This is because it can be difficult to differentiate between residual tumor and chemoradiotherapy-related changes like edema, necrosis, and fibrotic changes that occur after chemoradiotherapy.^[2]

Recent research has emphasized the importance of organ preservation during treatment. For patients who respond well to neoadjuvant treatment, surgery can be avoided and a “watch and wait” approach can be adopted. This not only reduces the morbidity associated with surgery but also eliminates the need for a permanent stoma. Consequently, these studies have demonstrated an improvement in both the quality of life of patients and their overall and disease-free survival rates. Habr-Gama in her study demonstrated that 49% patients achieved complete clinical response and adopted a “Watch and Wait” policy. 31% patients experienced local recurrence and salvage therapy was possible in more than 90% of these patients, resulting in 94% local disease control and 78% organ preservation.^[3] The International Watch & Wait Database (IWWD) reported outcome of the wait and watch strategy in a large-scale registry of pooled individual patient data. The 2-year cumulative rate of local regrowth was found to be 25.2%, with the first two years accounting for the detection of 88% of all local regrowth cases. Moreover, the bowel wall was identified as the location of 97% of the instances of local regrowth. Distant metastasis were identified in 8% patients. 5-year overall survival was 85% and 5-year disease-specific survival was 94% (91–96%).^[4] The National Comprehensive Cancer Network too recommends Watch and Wait approach for specific indications for complete clinical response in locally advanced rectal cancer patients post chemoradiotherapy.^[5] However, certain groups have raised concerns over this approach with regards to increased local failure in inappropriately selected cases.^[6]

Taking all of these factors into account, obtaining an accurate clinical staging after neoadjuvant treatment (NAT) is crucial. Currently, a variety of imaging techniques, such as endorectal ultrasound, magnetic resonance imaging (MRI), thoracic/abdominal tomography, and 18F-FDG Positron Emission Tomography-Computed Tomography (PET-CT), are used for clinical staging purposes.

Issues with Endorectal Ultra-sound: Endorectal ultrasound is highly effective in accurately identifying the T stage in early stage rectal cancer. However, for bulky and stenotic lesions, it may not be sufficient due to technical limitations. Additionally, it is an examination that relies heavily on the expertise of the operator performing it.

Whilst MRI is the most commonly used modality for restaging post chemoradiation therapy, it does have its own set of drawbacks. Xiaoxuan Jia and colleagues carried out a detailed analysis of the disparities in MRI for the restaging of locally advanced rectal cancer with the Pathologic Reference Standard. Their findings suggest that MRI is susceptible to overestimating the extent of the disease. The discrepancies between MRI and pathological results were predominantly due to the misinterpretation of fibrosis. In addition, inflammatory cell infiltration, pure mucin, edematous mucosa and submucosa adjacent to the tumor, and muscularis propria could also be misread as residual tumor.^[7] A meta-analysis and systematic review were conducted by Wei to assess the diagnostic accuracy of Magnetic Resonance Imaging (MRI) in the restaging of rectal cancer following preoperative chemoradiotherapy. According to the findings, Magnetic Resonance Imaging (MRI) is a reliable means of diagnosing T3-T4 stage and N stage rectal cancer; however, its sensitivity and specificity are not particularly high.^[8]

Many studies and centres across the world have attempted to use FDG PET CT as a modality of reassessment post chemoradiation therapy. In a meta-analysis conducted by Maffione et al., 34 studies comprising 1526 patients were analyzed to evaluate the effectiveness of 18F-FDG PET in predicting response to neoadjuvant therapy in rectal cancer. The results of the meta-analysis indicated that 18F-FDG PET had a good level of accuracy in both the overall cohort (with a pooled sensitivity of 73%, pooled specificity of 77%, and pooled AUC of 0.83) and supports the use of FDG PET in restaging locally advanced rectal cancer.^[9]

The esteemed authors have attempted to define the role of MRI and 18F FDG PET/CT with respect to evaluation of pathological response in the rectal cancer patients after neoadjuvant chemoradiotherapy. When comparing MRI results with pathological findings to assess the pathological response, the sensitivity was determined to be 91.6%, while the specificity was found to be 22.2%. MRI had a positive predictive value (PPV) and negative predictive value (NPV) of 86.2 % and 33.3%. For PET CT, Sensitivity and specificity was 100% and 12.5%, respectively. The PPV and NPV for 18F FDG PET CT were 87% and 100%, respectively. This study has provided meaningful insights, there are certain limitations of its retrospective nature and limited sample size.^[1] There is also a certain level of discrepancy when compared to other similar studies. Faheem et.al conducted a similar study and exhibited the subsequent results, for presence of local tumor, MRI showed 94.7% sensitivity, 100% specificity, 100% PPV, 94.1% NPV, and 97.1% overall accuracy, regarding lymph node affection, MRI showed 100% sensitivity, 76.2% specificity, 73.7% PPV, 100% NPV, and 85.7% overall accuracy. In terms of identifying the existence of a local tumor, PET CT displayed a sensitivity of 94.7%, specificity of 100%, positive predictive value (PPV) of 100%, negative predictive value (NPV) of 94.1%, and an overall accuracy of 97.1%. When it came to detecting lymph node involvement, PET CT demonstrated a sensitivity of 78.6%, specificity of 95.2%, PPV of 91.7%, NPV of 87%, and an overall accuracy of 88.6%.^[10] The accuracy of MRI and 18F-FDG PET/CT in post-preoperative concurrent chemoradiotherapy restaging of rectal cancer was assessed by Cho YB et al. in their study. Regarding the T category, MRI showed an accuracy rate of 67%, with 30% of patients being over-staged and 3% being under-staged. In terms of the N category, 75% of patients were correctly staged, while 14% were over-staged and 11% were under-staged. (18)F-FDG PET/CT showed an overall accuracy rate of 60% for the T category and 71% for the N category. In summary, when it comes to restaging rectal cancer patients following preoperative CCRT, MRI is a valuable diagnostic tool for predicting both T and N categories. On the other hand, (18)F-FDG PET/CT is useful in identifying metastases and predicting a pathologic complete response after preoperative CCR.^[11]

There is an emerging role for PET/MRI for the reassessment of rectal cancer post chemoradiation therapy. To evaluate the effectiveness of PET/CT and PET/MRI in pre surgical staging of rectal cancer, the RECTOPET study is being conducted. The study is expected to provide new insights into the usefulness of combining hybrid with conventional imaging, as well as the comparative benefits of PET/CT versus PET/MRI.^[12]

At present, no randomised trials have established any one single modality as gold standard for reassessment post chemoradiation therapy. We tend to agree with the authors with the view that both PET/CT and MRI be recommended for reassessment as each modality helps to characterize the response in an enhanced way and could guide decision making. There is need for larger prospective randomized studies and consensus guidelines for adopting uniform practises.