AIM: To assess the clinical diagnostic value of functional imaging, combining quantitative parameters of apparent diffusion coefficient (ADC) and standardized uptake value (SUV)max, before and after chemo-radiation therapy, in prediction of tumor response of patients with rectal cancer, related to tumor regression grade at histology.

METHODS: A total of 31 patients with biopsy proven diagnosis of rectal carcinoma were enrolled in our study. All patients underwent a whole body ¹⁸FDG positron emission tomography (PET)/computed tomography (CT) scan and a pelvic magnetic resonance (MR) examination including diffusion weighted (DW) imaging for staging (PET1, RM1) and after completion (6.6 wk) of neoadjuvant treatment (PET2, RM2). Subsequently all patients underwent total mesorectal excision and the histological results were compared with imaging findings. The MR scanning, performed on 1.5 T magnet (Philips, Achieva), included T2-weighted multiplanar imaging and in addition DW images with b-value of 0 and 1000 mm²/s. On PET/CT the SUVmax of the rectal lesion were calculated in PET1 and PET2. The percentage decrease of SUVmax (ΔSUV) and ADC (ΔADC) values from baseline to presurgical scan were assessed and correlated with pathologic response classified as tumor regression grade (Mandard’s criteria; TRG1 = complete regression, TRG5 = no regression).

RESULTS: After completion of therapy, all the patients were submitted to surgery. According to the Mandard’s criteria, 22 tumors showed complete (TRG1) or subtotal regression (TRG2) and were classified as responders; 9 tumors were classified as non responders (TRG3, 4 and 5). Considering all patients the mean values of SUVmax in PET 1 was higher than the mean value of SUVmax in PET 2 (P < 0.001), whereas the mean ADC values was lower in RM1 than RM2 (P < 0.001), with a ΔSUV and ΔADC respectively of 60.2% and 66.8%. The best predictors for TRG response were SUV2 (threshold of 4.4) and ADC2 (1.29 × 10^-3 mm²/s) with high sensitivity and specificity. Combining in a single analysis both the obtained median value, the positive predictive value, in predicting the different group category response in related to TRG system, presented R² of 0.95.

CONCLUSION: The functional imaging combining ADC and SUVmax in a single analysis permits to detect changes in cellular tissue structures useful for the assessment of tumour response after the neoadjuvant therapy in rectal cancer, increasing the sensitivity in correct depiction of treatment response than either method alone.

The use of pre-operative chemoradiation treatment (CRT) induces downsizing and downstaging of primary rectal tumors, yielding a pathologic complete response (pCR) in up to 24% of patients[1]. A pCR is known to be associated with a favourable oncologic outcome, in regard to both recurrence and patients survival[2].

The trend in treatment of rectal cancer, although is still controversial, to date is toward a more conservative approach in patients identified as complete responders after CRT. Generally, a pCR is determined with histopathologic examination after surgery, but, if the determination of CR before surgery may influence the subsequent treatment decision, an accurate clinical assessment of response becomes essential[3-5].

Recently, diffusion weighted magnetic resonance imaging (DW-MR) after CRT has demonstrated to be more valuable than standard morphologic MR study in differentiation between a pCR and the presence of residual disease. On DW images, the viable neoplastic remnants are more easily defined, since they appear hyperintense in comparison to the low signal intensity (SI) of the surroundings not neoplastic tissues[6,7]. Promising results have been shown with quantitative DW imaging analysis by quantifying the apparent diffusion coefficient (ADC) in the evaluation of treatment response to CRT in patients having rectal cancer[8-14].

Even positron emission tomography (PET)/computed tomography (CT) has been suggested to be an accurate imaging modality in the staging of newly diagnosed or in detection of recurrent rectal cancer. Furthermore, qualitative and quantitative assessment of fluorodeoxyglucose-PET provide helpful information regarding treatment response and prognosis of patients with rectal cancer[15,16] .

Both DWI imaging and PET-CT imaging have been used separately in different fields of tumor evaluation, such as detection, characterization and CRT response assessment. As both ADC and standardized uptake value (SUV) have been associated with biological behaviour and treatment response in various tumors types a correlation between SUV values, which reflect metabolic activity and ADC values which reflect cellular density might be found[17].

To date, there have been few comparative studies between ADC and SUVmax to evaluate the tumour response to preoperative CRT in locally advanced rectal cancer (LARC). The aim of this study was, along with brief review of literature, to evaluate the accuracy of combined ADC and SUVmax values in prediction of tumor regression grade (TRG) complete responders in LARC patients, using histological tumor regression grade as standard reference.

All patients underwent surgical excision within 8-10 wk after CRT completion, i.e., low anterior resection (n = 24), abdominoperineal resection (n = 6) and extended resection (n = 1). The surgical approach was established considering the clinical response to CRT defined at conventional restaging.

Recently, a more conservative treatment has been advocated in patients with rectal cancer showing a good or a complete response to neoadjuvant treatments. The selection of true responders is essential and the role of imaging for restaging after CRT has been the subject of several recent studies, suggesting that neither MRI nor endorectal ultrasound or FDG-PET are enough accurate for identifying the true complete responders, with an overall PPV ranging from 17% to 50%[6,19-23].

The correlation between therapy-related changes in FDG uptake and tumour response in rectal cancer has been previously reported by several groups. Despite the differences in study set-up, scan type, pathological and metabolic evaluation, the final metabolic response to CRT in rectal cancer with FDG-PET/CT have been demonstrated to correlate with the histopathological response and therefore to be a useful method for early assessment of treatment efficacy in rectal cancer. The different studies provided similar cut-off values, however the above mentioned differences make a direct comparison of the results not possible (Table 3).

Cascini et al[24] showed that early responder patients, evaluated with PET/CT 12 d after the beginning of therapy, had a higher decrease of SUV than non-responder patients (62% vs 28%, respectively; P < 0.0001). Conversely, the pre-surgical PET data did not demonstrate any statistically significant correlation between mean SUV late change and TRG findings (P = 0.2) obtaining a low correlation between overall changes and the TRG (P = 0.63).

Also Janssen et al[25] found an early significant decrease of the metabolic activity after the first week of CRT, both in SUVmean and SUVmax, that decreased from respectively 8.5 ± 2.8 (range: 4.0-15.1) and 16.4 ± 5.8 (range: 7.0-28.1) to 6.9 ± 2.2 (range: 4.3-12.7) (P < 0.001) and 13.0 ± 4.8 (range: 7.6-27.4) (P < 0.001) after the first week of combined treatment. More recently Herrmann et al[26] found in 28 patients a decrease of mean SUV uptake from 9.5 at baseline to 5.5 (P < 0.001) 14 d after the onset of preoperative radiochemotherapy and in the third PET scan (4 wk after completion of treatment), mean SUV decreased to 3.1 (P < 0.001).

Rosenberg et al[27] did not obtain the same result but reported that the percentage of early SUV reduction tended to be higher (44.3%) in responders than in non-responder patients (29.6%; P = 0.085). However after the completion of therapy, the reduction of FDG uptake was 66% in histopathologically responding tumors and 48.3% in non responding tumors (P = 0.040).

Similarly also Lambrecht et al[28] found, during CRT, a mean reduction in SUVmax of 59% in patients with histopathological complete response vs a mean reduction of SUVmax of 25% in patients without complete response (P = 0.0036). Additionally, 5 wk after the completion of CRT, a 90% SUVmax reduction in the first group vs 63% in second group (P = 0.013) was found.

Shanmugan et al[29] recently evaluated seventy patients that underwent pre- and post-CRT PET/CT followed by surgery and found that patients with pCR had a lower median post-CRT SUV compared with those without (2.7 vs 4.5, P = 0.01). Median SUV decrease was 63% (7.5%-95.5%) and predicted pCR (P = 0.002); the authors concluded that post-treatment SUV and %SUV decrease correlate with pCR.

Similar results were found by Sun et al[30] in a study group of 53 patients diagnosed with clinical T3- 4 and/or N+ rectal cancer and treated with CRT followed by radical surgery after 6-8 wk. A PET/CT scan was performed before (PET/CT1) beginning of treatment and a second scan (PET/CT2) was performed within 1 wk after the completion of CRT. Thirty-five out of 53 patients also underwent a third (PET/CT3) scan within 1 wk before surgery. When patients were regrouped as having a pCR and a non-pCR significant differences were found in the percentage difference between PET/CT1 and PET/CT3 in SUVmax [(Δ% SUVmax(1-3); 69.17% vs 57.77%)].

Also Bampo et al[31] evaluated the possible predictive role of late FDG-PET/CT for the assessment of pathological response in locally advanced rectal cancer following neoadjuvant chemoradiation in 30 patients; significant differences in late SUV value and response index were observed between complete and non-complete pathological responder (P = 0.0006 and 0.03). Furthermore, with receiver operating characteristic curve analysis, a SUV threshold of 5.4% had 81% sensitivity and 100% specificity, with 90% overall accuracy.

Nevertheless the optimal timing of the post-treatment PET scan, for a proper assessment of early response to CRT, is still unclear. Radiation-induced reduction in glucose intake occurs due to cell loss, which is a prolonged effect[32]. However, this can be confounded by two transient processes that occur soon after radiochemotherapy. The first is defined as ‘‘stunning” of tumor cells and can lead to a transient reduction in glucose metabolism, increasing false negative results[33]. The second one is the possible increase in FDG uptake due to radiogenic inflammatory processes after radiotherapy and can lead to false positive results[34]. Increasing time interval between neoadjuvant treatment and PET scan should theoretically lead to a more accurate evaluation. Alternatively, ¹⁸F-FLT PET has been tested to minimize the influence of radiation-induced inflammation[35]. In previous animal studies, FLT uptake has been shown to be in inflamed tissue as compared with FDG. However, it has not shown to be a valid tool for a proper CRT response assessment in rectal cancer patients[36].

In Lambrecht et al[28] study ROC curve analysis identified a threshold value for ΔSUVmax of 40%, for differentiating patients with a complete response after 2 wk, with a sensitivity of 100%, but a specificity of 75% and a PPV of 60%. Similarly using a threshold for ΔSUVmax of 76% after CRT and before surgery, is possible to identify complete responders with a sensitivity of 100%, a specificity of 75% and a PPV of 60%.

Considering our results, ROC curves analysis have shown that SUV2 has the best accuracy (80.7%) in predicting response to neoadjuvant treatment with a threshold value of 4.4. Interestingly, to note that in our study the PPV of SUV2 in predicting response was very high (94.4%) suggesting more conservative surgical approaches only in patients with evidence of lower glucose uptake at the end of neoadjuvant treatment.

While evaluating the correlation between the changes of ADC before and after CRT we found that before CRT, the mean tumour ADC in the responder group was (0.88 ± 0.19) × 10^-3 mm²/s, while that in the non-responder group was (0.78 ± 0.09) × 10^-3 mm²/s. At the end of combined chemoradiation therapy the mean tumor ADC value for responder patients was (1.47 ± 0.22) × 10^-3 mm²/s. For non-responder patients the mean ADC value after therapy was (1.19 ± 0.20) × 10^-3 mm²/s.

Our results are in line with the previously published by Jung et al[37]. Before neoadjuvant CRT, the mean ADC of responders and non-responders were (0.93 ± 0.09) × 10^-3 mm²/s and (1.03 ± 0.08) × 10^-3 mm²/s, respectively. After neoadjuvant CRT the mean post-CRT ADC in responders was higher than in non-responders (P = 0.009), being respectively (1.29 ± 0.13) × 10^-3 mm²/s and (1.18 ± 0.08) × 10^-3 mm²/s. Using a post-CRT ADC of 1.18 × 10^-3 mm²/s as cut-off value for discriminate between the responders and non-responders, the highest accuracy (77.1%) was obtained, with the following diagnostic predictive values: Sensitivity 91.3%, specificity 50.0%, positive predictive value 77.8%, and negative predictive value 75.0%.

Similarly Kim et al[6] reported that the mean ADC after CRT in the responders group [(1.62 ± 0.36) × 10^-3 mm²/s)] differed significantly from the one in the non-responders group [(1.04 ± 0.24) × 10^-3 mm²/s)]. Moreover, when an ADC value of 1.20 × 10^-3 mm²/s was used as cut-off, the authors obtained an accuracy of 85% with the following diagnostic predictive values: sensitivity 100%, specificity 79%, positive predictive value 65%, and negative predictive value 100%.

Recently, other studies[38-40] revealed similar data. Ha et al[38] comparing the mean post-CRT ADC for the RC group vs the non-CR group [(1.33 ± 0.25) × 10^-3 mm²/s vs (1.13 ± 0.32) × 10^-3 mm²/s] found a significant increased (P = 0.001) of ADC value. When a post-CRT ADC of 1.20 × 10^-3 mm²/s was used as a cut-off value for discriminating CR, the accuracy was 67%, sensitivity was 52.1%, specificity of 80.8%, positive predictive value of 71.4%, and negative predictive value of 64.6%.

Even the best timing to perform the follow-up MR study for the assessment of response to CRT is still debated. Some Authors performed the diffusion-MR also during the first 15 d of the combined treatment. Sun et al[12] evaluated the ADC only one week after the beginning of CRT. Before CRT the mean tumour ADC value in the down-staged group was lower than that in the nondown-staged group (1.07 × 10^-3 mm²/s ± 0.13 vs 1.19 × 10^-3 mm²/s ± 0.15, F = 6.91, P = 0.013). At the end of the first week, the mean tumour ADC increased significantly to 1.32 × 10^-3 mm²/s ± 0.16 (F = 37.63, P < 0.001) in the down-staged group, while there was no significant ADC value increase in the nondown-staged group (F = 1.18, P = 0.291).

Also Kim et al[41] reported that the mean percentage of tumour ADC change in the responder group after 2 wk of CRT was higher in comparison with that of the non-responder group, even if not statistically significant. Seierstad et al[42] found an increase in tumour ADC values on day 11 after the beginning of CRT.

Cai et al[39] obtained an increase in the mean tumour ADC during the course of neoadjuvant CRT, especially at the 2^th week (P = 0.004), with a significant increase in the mean ADC at the 2^th week of neoadjuvant therapy in the T down-stage and tumour regression group (P = 0.011; 0.004). They also found a strong negative correlation between the mean pretreatment tumour ADC and tumour regression after neoadjuvant CRT (P = 0.0021).

Hypotizing that disrupted membranes increase the extracellular volume since they demonstrated higher permeability, Authors concluded that the ADC values changes in this early phase of CRT are probably the result of irreparable radiation induced DNA damage. However considering the variability among the results obtained in the recent literature (Table 4), actual evidence suggests that DWI-MR performed early after the beginning of therapy could not provide accurate and reproducible results for the evaluation of early tumour response to CRT. Hence the attention should be focused on ADC values obtained after the end of the treatment.

As well as for SUV values, in order to evaluate the prognostic value of pretreatment MR, several authors assessed[6,7,38-40,43,44] the pre-CRT ADC, obtaining controversial results. Curvo-Semedo et al[43] demonstrated that lower pre-CRT ADC values were associated with a more aggressive tumour profile: in their study mean ADCs were significantly different for mesorectal fascia tumour free (MRF) vs MRF-invaded (P = 0.013), mrN0 vs mrNþ (P = 0.011), and for the different tumour differentiation grades at histology (P = 0.025). Particularly tumours with involved MRFs, nodal-positive disease and those of less differentiated showed lower ADC values. Furthermore, a significant positive correlation (r = 0.374; P = 0.019) between ADC values and the distance of the tumour from the MRF was found.

Jung et al[37] recently reported that the mean pre-CRT ADC obtained with a 3 Tesla MR of responders was lower than that of non-responders (P = 0.034). Other authors[39,40], obtained similar results with 1.5 T MR. For instance, in the study of Birlik et al[40], before CRT the mean tumour ADC in the responder group was significantly lower than that in the nonresponder group (P < 0.001).

Other authors, however, reported that pre-treatment ADC values were not statistically different for responders and non-responders and that may be limited in predicting treatment outcome[6,38,41,44,45]. For instance, Kim et al[41] reported that, predicting the treatment outcome based on TRG, there were no significant differences among responder and non-responder groups when comparing pre-CRT ADCs and early tumour ADC increase rates: As the tumour responds to treatment, ADC values will probably rise at first, due the initial disruption of cell membranes, and then decrease at the end of the treatment, for the post-irradiation ingrowth of fibrosis restricting water mobility.

Considering these results and according to recent literature, the best reproducibility was obtained by studies that evaluated a post-treatment cut-off value of ADC and SUV; being the most promising and precise way of applying functional techniques in the clinical practice.

Moreover, as evaluated in our series of patients, combining in a single analysis the mathematical model of median values of ADC and of SUV values, the power of both functional technique improves, gaining a strictly and significant relationship with TRG system staging by linear regression analysis with R² of 0.95 (Figure 5).

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Figure 5 Receiver operating characteristic curve of combined model with median value of standardized uptake value post and apparent diffusion coefficient post, in comparison with tumor regression grade. ROC: Receiver operating characteristic.

In the era of PET/MRI scanner, the future approach should be represented by the combination of PET imaging with MRI not only to increase anatomical resolution but also for cell and molecular imaging, improving the accuracy in the assessment of tumour response. Moreover, the synchronous acquisition of both technique is critical in order to avoid differences in patient position, organ motion, and tumor growth.

In conclusion, the combined functional analysis of MRI and PET imaging, by the quantitative analysis of ADC map on DW-MR imaging and glucose uptake by ¹⁸F-FDG-PET, can contribute to the management of patients with locally advanced rectal cancer increasing the overall accuracy and sensitivity for treatment response evaluation in one step, since they permit to detect changes in cellular tissue structures useful in prediction the different group category response in relation to TRG system.