|Ahead of print
The role of MRI and 18F-FDG PET/CT with respect to evaluation of pathological response in the rectal cancer patients after neoadjuvant chemoradiotherapy
Gulhan Guler Avci, Ipek Pinar Aral
Department of Radiation Oncology, Tokat Gaziosmanpasa University, Merkez, Tokat, Turkey
|Date of Submission||31-Jan-2020|
|Date of Decision||01-Feb-2020|
|Date of Acceptance||25-Jul-2020|
|Date of Web Publication||19-Sep-2021|
Gulhan Guler Avci,
Department of Radiation Oncology, Tokat Gaziosmanpasa University, Merkez, Tokat
Source of Support: None, Conflict of Interest: None
Background: We aimed to evaluate the role of magnetic resonance imaging (MRI) and 18F-fluorodeoxyglucose (FDG) positron emission tomography–computed tomography (PET-CT) in determining the correct stage and predicting the pathological response.
Methods: Seventy one patients with pathologic proven rectal adenocarcinoma, clinical stage IIA-IVA, and neoadjuvant chemoradiotherapy (CRT) were evaluated retrospectively. Radiotherapy was delivered 45–50 Gy in 25 fractions with concomitant oral capecitabine. Pelvic MRI, colonoscopy, and 18F-FDG PET-CT were performed before the neoadjuvant treatment (NAT). After NAT, MRI and PET-CT were performed for re-evaluation.
Results: The median follow-up time was 25 months (range: 3–57 months). Of the 71 patients who underwent NAT, 57 patients underwent surgery. Downstaging was recorded in 48 (84.2%) of 57 patients who underwent surgery. There was no statistically significant difference between both MRI and PET-CT with pathology results in terms of response evaluation. As a result of the comparison of MRI and PET-CT with pathological results; sensitivity and specificity were 91.6% (44/48) and 22.2% (2/9) for MRI, and 100% (47/47) and 12.5% (1/8) for PET-CT, respectively.
Conclusion: PET-CT and MRI are effective in predicting response to NAT and predictive for the pathological response. A more accurate response can be judged when both PET-CT and MRI are executed together in restaging after NAT.
Keywords: MRI, 18F-FDG PET-CT, neoadjuvant treatment, radiotherapy, rectal cancer
Key Message: Results of evaluation after neoadjuvant therapy in locally advanced rectal cancer 18-fluorodeoxyglucose positron emission tomography and magnetic resonance imaging response predict pathological response.
|How to cite this URL:|
Avci GG, Aral IP. The role of MRI and 18F-FDG PET/CT with respect to evaluation of pathological response in the rectal cancer patients after neoadjuvant chemoradiotherapy. Indian J Cancer [Epub ahead of print] [cited 2022 May 25]. Available from: https://www.indianjcancer.com/preprintarticle.asp?id=326250
| » Introduction|| |
Although surgical resection is the main treatment modality for rectal cancer, surgery alone can be sufficient only in very early stage patients. In locally advanced rectal cancers (LARC), enhancement in local control and survival have been reported with the addition of radiotherapy (RT) and chemotherapy (CT)., LARC means that mesorectal involvement and T3, T4, and N+ (presence of metastatic lymph node). In the last 10 years, the standard treatment approach for LARC is neoadjuvant chemoradiotherapy (CRT) followed by surgery (total mesorectal excision), followed by adjuvant chemotherapy or follow-up. After 1990, total mesorectal excision (TME) was applied as a surgical procedure; in the 2000s, preoperative CRT efficacy was demonstrated with the German study and then chemotherapy with oxaliplatin added to treatment. As a result, local recurrence and distant metastasis decreased in LARC.,,
Preoperative CRT can reduce nodal disease and primary tumor size and regress the tumor stage and perform radical surgery on unresectable/borderline resectable tumors, and protect the sphincter in lower rectum tumors. In addition to all these advantages, it has disadvantages such as increasing postoperative complications, exposure of small intestine to radiation, causing fibrosis and adhesions in the RT area. Preoperative evaluation of patients and accurate clinical staging are essential to avoid overtreatment.,,
After neoadjuvant treatment (NAT), the surgeon needs to re-stage to map the road. As it is known, local recurrence in rectal cancer is directly related to circumferential surgical margin., In patients with lower rectum, the patient should be re-evaluated preoperatively to preserve the sphincter and to obtain negative surgical margins.
In recent studies, organ protection approaches have come to the forefront. Surgery was omitted in patients who responded well to NAT with a "wait and see" policy. Thus, the quality of life was increased due to both the reduction of morbidity caused by surgery and the absence of permanent stoma, and consequently increased the overall and disease-free survival as a result of these studies.,
Considering all these topics, clinically accurate staging after NAT is the key point. Today, endorectal ultrasound, magnetic resonance imaging (MRI), thoracic/abdominal tomography or 18F-fluorodeoxyglucose (FDG) positron emission tomography-computed tomography (PET-CT) are used for clinical staging. Endorectal ultrasound is particularly sensitive in determining the T stage in early stage disease. Currently, pelvic MRI is the most favorable evaluation of T and N stages. In the literature, the studies are examining the relationship between 18F-FDG PET-CT and pathological tumor response and predicting pathological response using the maximum standardized uptake value (SUVmax) change., In our study, we examined the efficacy of both MRI and 18F-FDG PET-CT in the evaluation of pathological response in the same group of patients.
| » Patients and Methods|| |
The study was conducted in accordance with the Declaration of Helsinki and was approved by the ethics committee of the Tokat Gaziosmanpasa University on 24 September 2019 with the number 83116987-596.
Seventy one patients with rectal adenocarcinoma were evaluated retrospectively from August 2014 to March 2019 in Gaziosmanpaşa University, Radiation Oncology Clinic. Patient interview information, patient files, and electronic system data were used for the study. Demographic status, tumor localization, clinical, and pathological stage of the disease, anal sphincter involvement, hematological values, treatment modality, treatment response, and final status were noted. Patients with pathologically-proven rectal adenocarcinoma, clinical stage IIA-IVA according to American Joint Committee on Cancer (AJCC) 8th edition, with all available information and received neoadjuvant CRT were included in the study. Patients with incomplete file and follow-up information, who received palliative or adjuvant or short-term RT, were excluded from the study.
External RT was administered with intensity modulated radiotherapy (IMRT) with simultaneous integrated boost (SIB) technique as a total dose of 45–50 Gy in 25 fractions with 1.8–2 Gy doses per day in the majority of patients (91.5%). Concomitant capecitabine was given to 90% of the patients at a dose of 825 mg/m2 twice daily.
Pelvic MRI, colonoscopy, and 18F-FDG PET-CT were performed in order to evaluate the clinical stage before the NAT decision. Both MRI and PET-CT were re-conducted with the aim of accurately assessing the treatment response and restaging before the surgical plan after NAT. PET-CT images were performed with intravenous administration of 8-11 mCi 18F-FDG after 6 hours of fasting by using Siemens Biograph 2 slice PET-CT device. In the PET-CT evaluation, both the shrinkage of tumor diameter and decrease in SUVmax were considered as a response. All patients underwent the multiparametric MRI imaging according to rectal cancer protocols. In addition to the conventional MRI, high-resolution dynamic and diffusion imaging were performed for each patient. Finally, pathological staging and real response status were evaluated.
According to tumor location and intraoperative conditions low anterior resection (LAR) or abdominopelvic resection (APR) were performed with total mesorectal excision.
Descriptive statistics for continuous (quantitative) variables are expressed as mean, standard deviation, range, and median values, while categorical variables are expressed as number (n) and ratio (%). Compliance of the variables to the normal distribution was evaluated by visual and analysis methods, and parametric tests were used for the data matching the normal distribution, and non-parametric tests were used for the non-matching data. Categorical demographic characteristics of the patients were calculated by Chi-square and Fisher's exact test. Analyzes were performed with IBM SPSS version 24.0 (IBM Corporation, Armonk, NY, USA). Statistical significance level was considered as P < 0.05.
The primary endpoint of the study was to evaluate the role of MRI and 18F-FDG PET-CT in determining the correct stage and predicting the pathological response. The correlation between clinical and pathological staging was examined. Complete response (CR), partial response (PR), unresponsive (NoR) are defined as an absence of lesion, regression from the clinical stage before NAT, the same stage or progression of the tumor, respectively. Sensitivity/specificity of NAT in response evaluation was examined together with pathological results.
| » Results|| |
The median age was 63 (range: 42–86) years, and 47 (66%) of patients were men [Table 1]. Majority of patients presented with stage 3 (n=57, 80%). The median tumor size was 5 (range: 3–13) cm. Sphincter preservation was achieved in 13 of 24 patients with tumors located in the lower rectum, only 10 patients underwent APR. The median time between completion of RT and second PET-CT was 49 (range: 25–90) days.
Median follow-up time was 25 (range: 3–57) months. Fifty-seven (80.3%) patients underwent surgery but 14 patients (19.7%) refused surgery for various reasons (advanced age, regression in their complaints, avoid the morbidity of surgery, etc.). Five patients had the complete pathological response (pCR) to NAT. A total of 12 (17.6%) patients died, 7 (9.9%) had local recurrence and 28 (39.4%) had distant metastasis. Ten (14.1%) patients were radiologically unresponsive, while 61 (85.9%) were responsive to NAT treatment. Downstaging was recorded in 48 (84.2%) of 57 patients who underwent surgery. Demographic data and treatment details of the patients are summarized in [Table 1].
Relationship between MRI and pathological response
According to MRI scans after NAT of operated patients (n: 57), 6 (10.5%) had no treatment response and 3 (5.3%) had complete radiological response, and the remaining 48 (84.2%) had PR. Nine (15.8%) of the patients were pathologically unresponsive, whereas 6 (10.5%) of the patients were unresponsive according to MRI. Forty-eight (84.2%) of the patients were evaluated as PR on MRI. In fact, according to pathological results 43 (75.4%) patients had PR. According to MRI and pathology, CR detected in 3 (5.3%) and 5 (8.8%) patients, respectively.
There was no statistically significant difference between MRI and pathology results in terms of response evaluation (P= 0.237). On comparing pathological results with MRI response data, sensitivity and specificity was 91.6% (44/48) and 22.2% (2/9), respectively. The positive (PPV) and negative predictive value (NPV) for MRI were 86.2% (44/51) and 33.3% (2/6), respectively. [Table 2] shows the correlation between MRI and pathological response after NAT.
|Table 2: Relationship between MRI response and pathologic response after neoadjuvant treatment|
Click here to view
Relationship between 18F-FDG PET-CT and pathological response
Fifty-five of 57 operated patients underwent two consecutive FDG PET-CT before and after RT. According to PET-CT after RT, while only 1 (1.8%) patient was unresponsive, PR or CR was observed in 54 (98.2%) patients. Complete and partial response was reported in 5 (9.1%) patients and 49 (89.1%) patients, respectively.
In the study, 9 (15.8%) of the patients who had 18F-FDG PET-CT and underwent surgery were pathologically unresponsive; however, according to PET-CT only one (1.8%) was unresponsive. 18F-FDG PET-CT revealed PR and CR in 49 (89.1%) and 5 (9.1%) patients, respectively. In fact, pathologically, 43 (75.4%) and 5 (8.8%) patients had PR and CR, respectively.
There was no statistically significant difference between 18F-FDG PET-CT and pathology results in terms of response evaluation (P= 0.14). When 18F-FDG PET-CT adequacy in response evaluation is evaluated together with pathological results, sensitivity and specificity was 100% (47/47) and 12.5% (1/8), respectively. The PPV and NPV for 18F-FDG PET-CT were 87% (47/54) and 100% (1/1), respectively. [Table 3] shows the correlation between 18F-FDG PET-CT and pathological response after NAT.
|Table 3: Relationship between PET-CT response and pathologic response after neoadjuvant treatment|
Click here to view
| » Discussion|| |
In the present study, we evaluated the predictive value of MRI and PET-CT after NAT in 71 patients with advanced rectal cancer. This study is especially important for predictive comparison of both PET-CT and MRI at the same time in a single study in the same study group. Of the 71 patients who underwent NAT, 57 patients underwent surgery. Downstaging was recorded in 48 (84.2%) of 57 patients who underwent surgery. Sphincter was preserved in 13 of 24 patients with tumors located in the lower rectum. There was no statistically significant difference between both MRI and PET-CT with pathology results in terms of response evaluation. As a result of the comparison of MRI and PET-CT with pathological results, sensitivity and specificity were 91.6% and 22.2% for MRI and 100% and 12.5% for PET-CT, respectively. The PPV was similar for PET-CT and MRI (86.2% versus 87%), while the NPV was 33.3% for MRI and 100% for PET-CT.
After the 2000s, the importance of preoperative neoadjuvant CRT in LARC was demonstrated by the German study. The superiority of preoperative CRT over postoperative adjuvant CRT has been emphasized in two large randomized trials., The first of these is the National Surgical Adjuvant Breast and Bowel Project (NSABP) R-03 study. While 900 patients were planned to be included in this study, the study was closed early at 267 patients because of poor patient participation. In the study, cT3-T4 tumors were included, and some patients underwent local excision without the requirement of TME. As a result of this study which was terminated at the end of 6 years, no significant difference was found in preoperative versus postoperative CRT arms in terms of survival, local control, and sphincter protection. The study demonstrating the superiority of preoperative CRT over postoperative CRT was the CAO/ARO/A10-94 coded study of the German Rectal Cancer Group (GRCG). In the study of GRCG, 50.4 Gy doses of pelvic RT were administered simultaneously with 5-Fluorouracil (5-FU) in both arms and 5.4 Gy of boost was added in the postoperative arm. Four cycles of adjuvant chemotherapy were applied to both arms. It was reported that preoperative CRT showed significantly downstaging, increased local control, less acute-late toxicity, and increased sphincter preservation rates in distal localized tumors compared to postoperative treatment. However, there was no significant difference in overall survival (OS) between the two randomization arms. The German study, after its publication, has been widely accepted all over the world and preoperative CRT has become the standard treatment for LARC.
Pathological complete response to NAT is predictive and prognostic factor for OS and disease-free survival (DFS) in many studies.,,,, Currently, there is no randomized trial to implement a "wait and see" policy in selected patients with clinical complete response (cCR). In order to do this, the cCR must be determined with very good reliability. MRI is the most commonly used clinical staging for this purpose. So as to do this, the cCR must be established with very good reliability. MRI is the most commonly used clinical staging for this purpose. Endorectal ultrasound is particularly sensitive in determining the T stage in early stage disease, but it is technically insufficient for bulky and stenotic lesions. It is also an operator-dependent examination. Unfortunately, the accuracy of restaging is reduced due to inflammation-fibrosis after NAT on MRI. Accuracy of restaging after NAT increases markedly with T2-weighted sequences of MRI and diffusion-weighted MRI (accuracy increases from 87.9% to 99.6%)., In the present study, although we found high PPV for MRI, NPV was low. This demonstrates that MRI cannot reveal the absence of the disease when the disease actually disappears. This problem could be solved with the combined use of PET-CT and MRI. In current study, the results showed that NPV was 33% for MRI and 100% for PET-CT in the same patient group.
There is no clear consensus on the optimal timing of MRI restaging after CRT. Recent literature suggests that re-staging is carried out 8 weeks after the completion of CRT but the clinical response rate elavates with increasing interval., In our study, MRI and PET-CT were performed for restaging at median 7 weeks after the end of CRT. In a similar study by Elmashad et al., 68 patients with LARC who underwent standard 5-week radiochemotherapy were subjected to MRI for staging before and after CRT. Correlations between MRI and pathological findings were investigated. They conducted LARC in 40% of the patients and APR in the rest. When MRI and pathological response were compared, they found 100% sensitivity and 78.7% specifity. Contrary to the present trial, they exhibited as 100% NPV, accuracy 80.9% with MRI.
In a study from Italy, 29 patients with LARC underwent dynamic contrast enhanced MRI (DCE-MRI) and diffusion-weighted imaging (DW-MRI) before and after NAT. The accuracy of both DCE-MRI and DW-MRI response to NAT was investigated. DW-MRI and T2 weighted MRI were superior to DW-MRI in prediction of response. Sensitivity and specificity were 86% and 93% for DCE-MRI, 64% and 94% for DW-MRI, respectively. We also found that the sensitivity of MRI was similar to that of DCE-MRI but the specificity was lower.
MRI is the standard for clinical staging of advanced rectal cancer, while PET-CT is not. Nevertheless, the use of PET-CT with MRI may improve accuracy in clinical response evaluation after CRT. With this in mind, in our study, 65 of 71 patients underwent both MRI and PET-CT to evaluate the clinical response accurately. The sensitivity and specificity for PET-CT and MRI were similar, while the NPV for PET-CT was higher than MRI. In the study of Capirci et al., 87 patients with LARC underwent PET-CT twice, before neoadjuvant CRT and 5–6 weeks after the end of CRT. While 40 of 81 patients responded well to NAT (TRG1-2), mean percentage of SUVmax difference (response index-RI) was significantly higher in patients with good response. They indicated the sensitivity, specificity, PPV, and NPV for PET-CT as 84.5%, 80%, 81.4%, and 84.2%, respectively.
Leccisotti et al., investigated the predictive value of PET-CT in 126 LARC patients, and pCR was accomplished in 22% of the patients. They illustrated that PET-CT had a sensitivity of 83% and a specificity of 65%. In the other study, 88 patients with stage II and III rectal cancer underwent neoadjuvant CRT. Colonoscopy, MRI, and PET-CT were conducted preoperatively. Five-year OS and DFS were 83% and 73%, respectively. In multivariate analysis, only two parameters were found to be independent prognostic predictors for both OS and DFS — the first is the pathological stage and the other is the PET-CT findings after CRT. Five-year OS was 91% and 72% for patients with non-reactive and reactive PET after CRT, respectively (P= 0.024). It was concluded that the prognosis is better in patients with good response to CRT via PET-CT and the predictive importance of PET-CT for survival was emphasized. In the present study, sensitivity of PET-CT were found to be better than other studies in the literature (sensitivity= 100%), on the other hand, its specificity was lower.,
There are a number of limitations of this study. Firstly, the study is retrospective and single-centered. Only 71 patients were included in the study, and 57 of them were operated. Median follow-up time was 25 months.
As shown in many studies in the literature, the use of PET-CT for CRT response assessment and restaging is becoming widespread. PET-CT and MRI are effective in predicting response to NAT and predictive for the pathological response. A more accurate response can be judged when both PET-CT and MRI are executed together in restaging after NAT. Nevertheless, randomized trials with more patients are needed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| » References|| |
Dahlberg M, Glimelius B, Påhlman L. Improved survival and reduction in local failure rates after preoperative radiotherapy: Evidence for the generalizability of the results of Swedish Rectal Cancer Trial. Ann Surg 1999;229:493-7.
Folkesson J, Birgisson H, Pahlman L, Cedermark B, Glimelius B, Gunnarsson U. Swedish rectal cancer trial: Long lasting benefits from radiotherapy on survival and local recurrence rate. J Clin Oncol 2005;23:5644-50.
Sauer R, Becker H, Hohenberger W, Rùdel C, Wittekind C, Fietkau R, et al
. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 2004;351:1731-40.
Bujko K, Nowacki MP, Nasierowska-Guttmejer A. Sphincter preservation following preoperative radiotherapy for rectal cancer: Report of a randomized trial comparing short-term radiotherapy vs. conventionallyfractionated radiochemotherapy. Radiother Oncol 2004;72:15-24.
Bujko K, Nowacki MP, Kepka L, Oledzki J, Bebenek M, Kryj M. Postoperative complications in patients irradiated pre-operatively for rectal cancer: Report of a randomized trial comparing short-term radiotherapy vs. chemoradiation. Colorectal Dis 2005;7:410-6.
Adam IJ, Mohamdee MO, Martin IG, Scott N, Finan PJ, Johnston D, et al
. Role of circumferential margin involvement in the local recurrence of rectal cancer. Lancet 1994;344:707-11.
Quirke P, Durdey P, Dixon MF, Williams NS. Local recurrence of rectal adenocarcinoma due to inadequate surgical resection: Histopathological study of lateral tumor spread and surgical excision. Lancet 1986;2:996-9.
Habr-Gama A, Gama-Rodrigues J, São Julião GP, Proscurshim I, Sabbagh C, Lynn PB, et al
. Local recurrence after complete clinical response and watch and wait in rectal cancer after neoadjuvant chemoradiation: İmpact of salvage therapy on local disease control. Int J Radiat Oncol Biol Phys 2014;88:822-8.
van der Valk MJM, Hilling DE, Bastiaannet E, Meershoek-Klein Kranenbarg E, Beets GL, Figueiredo NL, et al
. Long-term outcomes of clinical complete responders after neoadjuvant treatment for rectal cancer in the International Watch & Wait Database (IWWD): An international multicentre registry study. Lancet 2018;391:2537-45.
Magri KD, Bin FC, Formiga FB, Manzione Tda S, Gomes CM, Candelári Pde A, et al
. Impact of neoadjuvant therapy in downstaging of lower rectal adenocarcinoma and the role of pelvic magnetic resonance in staging. Rev Col Bras Cir 2016;43:102-9.
Capirci C, Rubello D, Pasini F, Galeotti F, Bianchini E, Del Favero G, et al
. The role of dual-time combined 18-fluorodeoxyglucose positron emission tomography and computed tomography in the staging and restaging workup of locally advanced rectal cancer, treated with preoperative chemoradiation therapy and radical surgery. Int J Radiat Oncol Biol Phys 2009;74:1461-9.
Leccisotti L, Gambacorta MA, de Waure C, Stefanelli A, Barbaro B, Vecchio FM, et al
. The predictive value of 18F-FDG PET/CT for assessing pathological response and survival in locally advanced rectal cancer after neoadjuvant radiochemotherapy. Eur J Nucl Med Mol Imaging 2015;42:657-66.
Roh MS, Colangelo LH, O'Connell MJ, Yothers G, Deutsch M, Allegra CJ, et al
. Preoperative multimodality therapy improves disease-free survival in patients with carcinoma of the rectum: NSABP R-03. J Clin Oncol 2009;27:5124-30.
Foti PV, Privitera G, Piana S, Palmucci S, Spatola C, Bevilacqua R, et al
. Locally advanced rectal cancer: Qualitative and quantitative evaluation of diffusion-weighted MR imaging in the response assessment after neoadjuvant chemo-radiotherapy. Eur J Radiol Open 2016;3:145-52.
De Felice F, Magnante AL, Musio D, Ciolina M, De Cecco CN, Rengo M, et al
. Diffusion-weighted magnetic resonance imaging in locally advanced rectal cancer treated with neoadjuvant chemoradiotherapy. Eur J Surg Oncol 2017;43:1324-9.
Sloothaak DA, Geijsen DE, van Leersum NJ, Punt CJ, Buskens CJ, Bemelman WA, et al
. Dutch surgical colorectal audit. Optimal time interval between neoadjuvant chemoradiotherapy and surgery for rectal cancer. Br J Surg 2013;100:933-9.
West MA, Dimitrov BD, Moyses HE, Kemp GJ, Kemp GJ, Loughney L, et al
. Timing of surgery following neoadjuvant chemoradiotherapy in locally advanced rectal cancer—a comparison of magnetic resonance imaging at two time points and histopathological responses. Eur J Surg Oncol 2016;42:1350-8.
Elmashad NM, Hamisa MF, Ziada DH, Abdel Fatah ON, Arafat W. Role of MRI in rectal carcinoma after chemo irradiation therapy with pathological correlation. Alex J Med 2016;52:1-8.
Petrillo M, Fusco R, Catalano O, Sansone M, Sansone M, Avallone A, et al
. MRI for assessing response to neoadjuvant therapy in locally advanced rectal cancer using DCE-MR and DW-MR data sets: A preliminary report. Biomed Res Int 2015;2015:514740.
Capirci C, Rubello D, Chierichetti F, Crepaldi G, Fanti S, Mandoliti G, et al
. Long-term prognostic value of 18F-FDG PET in patients with locally advanced rectal cancer previously treated with neoadjuvant radiochemotherapy. AJR Am J Roentgenol 2006;187:202-8.
[Table 1], [Table 2], [Table 3]