|Year : 2019 | Volume
| Issue : 1 | Page : 9-14
To determine the utility of fluorodeoxyglucose-positron emission tomography-computed tomography scan in predicting pathological response in operated carcinoma rectum patients after initial neoadjuvant chemoradiation
Neelam Sharma1, Puneet Takkar2, Abhishek Purkayastha3, Braj Kishore Singh4
1 Department of Radiation Oncology, Army Hospital (Research and Referral), New Delhi, India
2 Department of Surgical Oncology, Military Hospital, Jabalpur, Madhya Pradesh, India
3 Department of Radiation Oncology, Command Hospital (Southern Command), Pune, Maharashtra, India
4 Department of Nuclear Medicine, Army Hospital (Research and Referral), New Delhi, India
|Date of Web Publication||13-Mar-2019|
Dr. Abhishek Purkayastha
Department of Radiation Oncology, Command Hospital (Southern Command), Pune - 411 040, Maharashtra
Source of Support: None, Conflict of Interest: None
Background: The objective of this study was to determine whether [18F]-fluorodeoxyglucose-positron emission tomography-computed tomography (FDG-PET CT) scan could predict the pathological response in carcinoma rectum patients after surgery in patients receiving neoadjuvant concurrent chemoradiotherapy (NACCRT).
Setting and Design: A prospective study was carried out from March 2015 to March 2017; 39 patients of histopathologically proven, locally advanced, potentially operable, of adenocarcinoma rectum were included in the study.
Methods: Patients had a pretreatment FDG-PET-CT scan and repeat scan after 6–8 weeks of NACCRT. The change in mean maximum standardized uptake value ([%Δ SUVmax]) was compared with the tumor regression grade (TRG) in the postoperative histology. TRG of 1 and 2 was deemed responders and 3–5 was nonresponders.
Statistical Analysis: Chi-square test, one-way ANOVA, and receiver operating characteristics curve analysis were used. All analyses were done using SPSS 17.0 version.
Results: In 61.5% responders receiving NACCRT, the SUV fell from 10.91 ± 3.70 to 4.14 ± 1.73, respectively, while in 38.5% nonresponders, SUV fell from 11.65 ± 2.66 to 4.23 ± 1.3. SUV Δ% was 63.03 ± 10.17 in nonresponders and 61.32 ± 11.81 in responders with a nonsignificant P = 0.646. The P value did not reach a statistical significance as far as reduction in SUV values pre- and post-NACCRT is concerned in both responders as well as nonresponders.
Conclusion: Hence, we concluded that assessment with FDG PET CT scan in carcinoma rectum patients' postneoadjuvant treatment cannot be the only imaging modality or assessing the response and postoperative histopathology remains the gold standard.
Keywords: Colorectal cancer, neoadjuvant chemoradiation, pathological response, positron emission tomography
|How to cite this article:|
Sharma N, Takkar P, Purkayastha A, Singh BK. To determine the utility of fluorodeoxyglucose-positron emission tomography-computed tomography scan in predicting pathological response in operated carcinoma rectum patients after initial neoadjuvant chemoradiation. J Can Res Ther 2019;15:9-14
|How to cite this URL:|
Sharma N, Takkar P, Purkayastha A, Singh BK. To determine the utility of fluorodeoxyglucose-positron emission tomography-computed tomography scan in predicting pathological response in operated carcinoma rectum patients after initial neoadjuvant chemoradiation. J Can Res Ther [serial online] 2019 [cited 2019 Aug 19];15:9-14. Available from: http://www.cancerjournal.net/text.asp?2019/15/1/9/244482
| > Introduction|| |
Colorectal cancer accounts for third most commonly diagnosed cancer in the world. In India, rectal cancer accounts for 6th most common digestive tract cancer as per cancer group projection from 2010 to 2020. The management of rectal cancer has undergone an interesting transformation over the course of the past thirty decades. The earliest procedures were mostly palliative with the first proposed resections for rectal cancer appearing in the 18th century. After that, several randomized trials have demonstrated that neoadjuvant concurrent chemoradiotherapy (NACCRT) as compared to only surgery down-staged tumors and improved local control, frequently permitting sphincter preservation in patients with low rectal tumors. NACCRT was also associated with reduced toxicity compared to postoperative CRT.,, Although downstaging is achieved in the majority of the tumors receiving long course NACCRT, the extent of downstaging may vary from patient to patient.
According to guidelines, a multimodality approach including computed tomography (CT), magnetic resonance imaging (MRI), and endoscopic ultrasonography (EUS) should be employed in the diagnostic workup of colorectal cancer patients. Advanced functional MRI techniques (for example, dynamic contrast-enhanced (CE) MRI and diffusion-weighted MRI) allows for the measurement of microcirculation, vascular permeability, and tissue cellularity and thus may be useful for determining response to neoadjuvant treatment (NAT) and restaging patients with rectal cancer.,,, The literature on the clinical use of fluorodeoxyglucose-positron emission tomography/CT (FDG-PET/CT) in colorectal cancer is fairly limited, but recent works have demonstrated some promise for optimizing the accuracy of initial staging by clarifying equivocal findings on conventional imaging in preoperative staging and evaluating response to NACCRT before surgery.,,
In addition to downstaging in the tumor, CRT produces a pathological complete response (pCR) and improves survival in selected patients., The absence of residual cancer in resected specimens follow NAT (YpT0) has led some authors to suggest “wait and watch” policy with close surveillance., However, digital rectal examination or endorectal ultrasound is unable to distinguish reliably fibrosis or scar from viable tumor cells in patients with clinical Stage T3 or T4 or node-positive rectal adenocarcinoma. MRI, despite its final resolution, is inaccurate in preoperative staging of rectal cancer after NAT. PET/CT scans are used to discriminate between benign and malignant tissue based on the increased glucose metabolism and 18F-FDG uptake in cancer cells by measuring the standardized uptake value (SUV) resection. Over the last decade, there has been increasing interest in the ability of functional imaging to predict complete response to treatment. A further correlation of pathological response to neoadjuvant regimens with the tumor regression grade (TRG) helps in identifying patients with incomplete response that may impact treatment outcome and evaluation of nodal metastases. We herein report in our study the correlation between FDG uptake using SUV before and after NACCRT and the histopathological response after surgery using TRG.
| > Methods|| |
This randomized prospective study has been carried out in 39 consecutive patients; both males and females of locally advanced adenocarcinoma of rectum involving middle and lower 1/3 from March 2015 to March 2017 at Department of Radiation Oncology of our institute after obtaining a written informed consent from the patients. All procedures performed in this study were in accordance with the ethical standards of the Institutional and/or National Research Committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.
The sample size was calculated keeping in view at the most 5% risk, with minimum 80% power and 5% significance level (significant at 95% confidence level). However, consideration of the past data, which gives idea of variation in the variables, played an important role in calculating the sample size. The sample size estimation was done by calculating intake of locally advanced rectal cancer, satisfying all inclusion criteria at our center from previous year's hospital records.
For the patients included in the study, patients with tumors of clinical stage T3–T4 or n + with no clinical evidence of metastatic spread (M0), according to the International Union against Cancer tumor-node-metastasis classification, were enrolled. Eligible patients were 18–75 years of age, had a World Health Organization performance status score of 2 or lower (on a scale of 0–5, with 0 indicating fully active, 1 unable to carry out heavy physical work, and 2 up and about more than half the day but unable to work), and had lost 10% or less of body weight. Patients also had to have adequate hematologic, renal, hepatic, and pulmonary function, as well as no history of other cancer or previous RT or chemotherapy.
Pretreatment evaluation consisted of physical and digital rectal examination and colonoscopy with biopsy. Imaging included chest X-ray or CECT of chest, abdominal ultrasound sonography, and CECT or MRI of the pelvis and 18 -FDG PET CT scan. Laboratory tests included serum chemistry and complete blood count in all patients, and testing for HIV infection in high-risk patients. A multidisciplinary team consisting of a surgeon, a radiation oncologist, and a medical oncologist decided the treatment for each patient.
With respect to administration of RT, multiple RT fields were used to include the tumor or tumor bed with a 2 or 5 cm margin, presacral nodes, and the internal iliac nodes. The external iliac nodes were included for T4 tumors involving anterior structures; inclusion of the inguinal nodes for tumors invading the distal anal canal was also considered. In long-course RT, recommended doses of RT of typically 45–50 Gy in 25–28 fractions to the pelvis were used using 3 or 4 fields by 3D-conformal technique. Any boost clinical target volumes extended to the entire mesorectum and the presacral region at the involved levels including 2 cm cephalad and caudad in the mesorectum and 2 cm on a gross tumor within the anorectum. Positioning and other techniques to minimize radiation to the small bowel were encouraged.
Either 5-fluorouracil (5-FU) (425 mg/m2) or leucovorin (25 mg/m2) was administered during the first 4 days in the 1st week and then restarted for 3 days in the 5th week of the treatment course, or capecitabine was administered concomitantly with RT at a dose of 825 mg/m2 twice daily (bid) during the whole period of RT (days 1–33) without giving weekend breaks. CA doses were given every 12 h with one of the doses administered 2 h before irradiation. If RT was interrupted, chemotherapy was not administered. Out of 39 patients, 37 received oral capecitabine concurrently to a dose of 850 mg/m2 in twice daily, while only two patients received chemotherapy in the form of 5-FU.
Postneo-adjuvant therapy evaluation
In all patients, FDG PET-CT was performed to assess the response to NAT after 6–8 weeks of NACCRT before patients were taken up for surgery. Whole body FDG PET-CT scan spanning base of skull to mid-thigh was done 45 min after intravenous (IV) injection of 370 MBq (Millibecquerel) of 18-FDG using a whole body full-ring dedicated LSO PET-CT scanner. CT images were obtained using 130 KV and 90 mAs (mean) without administration of IV or oral contrast. SUVs were determined with a small fixed-dimension region of interest (ROI), 8 mm in diameter, and the value was determined using the highest activity inside this area. SUV values were calculated after correction of radioactive decay according to the following formula: SUV = ROI activity (MBq/ml)/injected dose (MBq/body weight g). ROIs were drawn at every level where tumor tissue was detectable, and maximal SUV was the highest detectable value inside the tumor. SUV of the primary tumor was determined at baseline and after therapy. Maximal SUV of the pretreatment scan was labeled as SUV1 and the posttreatment scan SUV2. Change percentage (SUV Δ%) was expressed as ([SUV1 − SUV2]/SUV1) × 100.
Postchemoradiation at 6–8 weeks, patients were assessed by per-rectal examination, and pelvic imaging, 18 F-FDG PET CT, and surgery were planned if deemed resectable. All the eligible patients underwent laparoscopy-assisted complete total mesorectal excision with either low anterior resection or abdominoperineal resection (APR) with permanent colostomy.
Pathological specimen analysis and adjuvant chemotherapy
The postoperative specimen was analyzed in detail for tumor size, nodal stage, pathological response, margin status including circumferential resection margin, and TRG score using Mandard's scoring. Every attempt was made by the pathologist to retrieve maximum nodes possible. As per histology, the specimens were separated into two groups as per Mandard classification with or without regressive changes, while the regressive changes included the stromal changes and cytological alterations. Based on these changes, the tumor regression was classified into five histological TRGs, based on vital tumor tissue at the ratio of fibrosis: TRG 1 was defined as complete regression fibrosis without detectable tissue of tumor; TRG 2 as fibrosis with scattered tumor cells; TRG 3 was fibrosis and tumor cells with preponderance of fibrosis; TRG 4 was fibrosis and tumor cells with preponderance of tumor cells; and TRG 5 was tissue of tumor without changes of regression. Patients with TRG 1–2 were considered responders, while 3–5 were considered nonresponders. All patients were planned for adjuvant chemotherapy. If all the nodes were negative in the resected specimen, they were planned for six cycles of adjuvant chemotherapy of capecitabine alone, and for node-positive disease, six cycles of CAPOX (capecitabine 1000 mg/m2 and injection oxaliplatin) were advised.
All analysis was performed with SPSS for Windows, version 17.0, SPSS Inc., Chicago, IL, USA. All quantitative data were expressed as medians (ranges). The diagnostic accuracy of [18F]-FDG-PET-CT was calculated by the receiver operating characteristics curve (ROC) test. The area under the ROC curve (AUC) provides a measure for the accuracy of a diagnostic test. It ranges from 0.5 to 1.0. The optimum cutoff value for differentiation of responding and nonresponding tumors was defined by the point of ROC curve with minimum distance from the 0% false positive rate to 100% true positive rate. The correlation between the SUV% and TRG was determined.
| > Results|| |
The basic demographics are shown in [Table 1]. Nearly 35.9% of patients belonged to 51–60-year age group and majority 82.1% were males. In 64% of patients, disease was <5 cm from anal verge and 72% of them had locally advanced T stage and 59% had N2 nodal stage. Almost 59% of our patients underwent APR post-NACCRT. About 57% of patients showed T stage downgrading and 59% of patients had nodal downstaging also. After NACCRT, 61.5% patients were good responders according to Mandard TRG grading.
Correlation between patient factors and tumor regression grade
We tried to study the correlation between various patient factors and TRG. We did not find any statistically significant correlation between various age groups, distance of tumor from anal verge, patient being either a male or a female, and even T and N stage at presentation. However, we found a statistically significant correlation between post-NACCRT nodal staging and TRG with P = 0.031 [Table 2].
Change in standardized uptake value values postneoadjuvant treatment in responders and nonresponders
In 61.5% responders, the SUV fell from 10.91 ± 3.70 to 4.14 ± 1.73, respectively, while in 38.5% nonresponders, SUV fell from 11.65 ± 2.66 to 4.23 ± 1.3. SUV Δ% was 63.03 ± 10.17 in nonresponders and 61.32 ± 11.81 in responders with a nonsignificant P = 0.646 [Figure 1]. The P value did not reach a statistical significance as far as reduction in SUV values pre and post-NACCRT is concerned in both responders as well as nonresponders [Table 3]. This leads to a conclusion that assessment with FDG-PET-CT scan in carcinoma rectum patients post-NAT cannot be the only imaging modality for assessing the response and it definitely needs to be combined with other imaging modalities such as EUS and MRI.
Correlation between standardized uptake value% reduction and tumor regression grade
In our study, we did not find a significant correlation between the (%Δ SUV max) reduction and TRG after analyzing the data of all 39 patients' post-NACCRT with a nonsignificant value of 0.646 where correlation is significant at a value of 0.01 level (two-tailed) [Table 3].
Receiver operating characteristics curve analysis
ROC curve analysis for an AUC of 0.447 did not reach a statistical significance P = 0.583 [Figure 2].
|Figure 2: Receiver operating characteristics curve analysis for prediction of histopathological response by (%Δ maximum standardized uptake value) (maximum standardized uptake value percentage change after neoadjuvant therapy)|
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| > Discussion|| |
The utility of 18 FDG-PET CT imaging [Figure 3] to assess the response of adenocarcinoma of the rectum to neoadjuvant chemotherapy and/or radiotherapy [Figure 4] was initially demonstrated in 1992. Nonetheless, the “gold standard” of assessing response to chemoradiation is postoperative histopathology. pCR to CRT ranges from 15% to 40%. Habr-Gama et al. reported in a study of 265 patients, 71 of whom showed complete response to CRT and candidates for less extensive surgery or observation, without any significant increase in recurrence. During the past decade, numerous studies have shown that post-NAT 18-FDG uptake as measured by PET-CT scan successfully stratify patients with locally advanced rectal cancer, yet most of these provide little guidance as to how precisely use these findings in clinical practice. The pioneering articles by Calvo et al. (n = 25) and Guillem et al. (n = 15) failed to correlate SUV change after NAT with PCR using 18 FDG-PET imaging. Oku et al. found post-CCRT SUV to be the only prognostic variable for disease-free recurrence (P = 0.05). In 2006, Capirci et al. (n = 88) showed a disease-free survival of 81% in patients with a negative PET and 62% in those with a positive PET after CRT (P = 0.003).
|Figure 3: Preneoadjuvant concurrent chemoradiotherapy fluorodeoxyglucose positron emission tomography image in a case of carcinoma rectum (a) CT image and (b) fused image|
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|Figure 4: Post NACCRT FDG-PET/CT image showing partial response in the same patient (a) maximum intensity projection image; (b) CT image and (c) fused image|
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| > Conclusion|| |
In our study also we could not establish a correlation between SUVΔ% and TRG moreover we did not find a significant SUVΔ% in our patients post NACCRT leading to a conclusion that assessment with 18FDG-PET/CT scan in carcinoma rectum patients post neoadjuvant treatment cannot be the only imaging modality for assessing the response and it definitely needs to be combined with other imaging modalities like EUS and MRI. However major limitation of our study is a small sample size.
In carcinoma rectum patients with locally advanced disease who undergo NACCRT before surgery, only FDG PET CT scan is not a good imaging modality for response assessment and it has to be combined with other imaging modalities such as MRI and EUS which can give more information in addition to metabolic information given by FDG PET CT scan. At this stage according to our study, we still do not recommend observation after NACCRT in patients showing good or complete response based on imaging modalities as we have not been able to establish a correlation between SUV Δ% and TRG.
We thank all our patients for allowing us to publish the study and use their inputs. Ethical approval: Written informed consent to publication was obtained from the patient. We also like to extend our gratitude to Department of Surgical Oncology, Medical Oncology, and Pathology, Army Hospital Research and Referral, New Delhi. The manuscript has been read and approved by all the authors, the requirements for authorship have been met, and each author believes that the manuscript represents honest work.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| > References|| |
Mohandas KM, Jagannath P. Epidemiology of digestive tract cancers in India. VI. Projected burden in the new millennium and the need for primary prevention. Indian J Gastroenterol 2000;19:74-8.
Silberfein EJ, Kattepogu KM, Hu CY, Skibber JM, Rodriguez-Bigas MA, Feig B, et al.
Long-term survival and recurrence outcomes following surgery for distal rectal cancer. Ann Surg Oncol 2010;17:2863-9.
Dhadda AS, Zaitoun AM, Bessell EM. Regression of rectal cancer with radiotherapy with or without concurrent capecitabine – Optimising the timing of surgical resection. Clin Oncol (R Coll Radiol) 2009;21:23-31.
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.
van der Paardt MP, Zagers MB, Beets-Tan RG, Stoker J, Bipat S. Patients who undergo preoperative chemoradiotherapy for locally advanced rectal cancer restaged by using diagnostic MR imaging: A systematic review and meta-analysis. Radiology 2013;269:101-12.
Hötker AM, Garcia-Aguilar J, Gollub MJ. Multiparametric MRI of rectal cancer in the assessment of response to therapy: A systematic review. Dis Colon Rectum 2014;57:790-9.
Joye I, Deroose CM, Vandecaveye V, Haustermans K. The role of diffusion-weighted MRI and (18)F-FDG PET/CT in the prediction of pathologic complete response after radiochemotherapy for rectal cancer: A systematic review. Radiother Oncol 2014;113:158-65.
Lambregts DM, Rao SX, Sassen S, Martens MH, Heijnen LA, Buijsen J, et al.
MRI and diffusion-weighted MRI volumetry for identification of complete tumor responders after preoperative chemoradiotherapy in patients with rectal cancer: A Bi-institutional validation study. Ann Surg 2015;262:1034-9.
Chowdhury FU, Shah N, Scarsbrook AF, Bradley KM. [18F] FDG PET/CT imaging of colorectal cancer: A pictorial review. Postgrad Med J 2010;86:174-82.
National Institute for Health and Clinical Excellence. Manual update. London: National Institute for Health and Clinical Excellence, Improving Outcomes in Colorectal Cancer; 2004.
Poeppel TD, Krause BJ, Heusner TA, Boy C, Bockisch A, Antoch G, et al.
PET/CT for the staging and follow-up of patients with malignancies. Eur J Radiol 2009;70:382-92.
Capirci C, Valentini V, Cionini L, De Paoli A, Rodel C, Glynne-Jones R, et al.
Prognostic value of pathologic complete response after neoadjuvant therapy in locally advanced rectal cancer: Long-term analysis of 566 ypCR patients. Int J Radiat Oncol Biol Phys 2008;72:99-107.
Mignanelli ED, de Campos-Lobato LF, Stocchi L, Lavery IC, Dietz DW. Downstaging after chemoradiotherapy for locally advanced rectal cancer: Is there more (tumor) than meets the eye? Dis Colon Rectum 2010;53:251-6.
You YN, Baxter NN, Stewart A, Nelson H. Is the increasing rate of local excision for stage I rectal cancer in the United States justified? A nationwide cohort study from the National Cancer Database. Ann Surg 2007;245:726-33.
Habr-Gama A, Perez RO, Nadalin W, Sabbaga J, Ribeiro U Jr., Silva e Sousa AH Jr., et al.
Operative versus nonoperative treatment for stage 0 distal rectal cancer following chemoradiation therapy: Long-term results. Ann Surg 2004;240:711-7.
Hiotis SP, Weber SM, Cohen AM, Minsky BD, Paty PB, Guillem JG, et al.
Assessing the predictive value of clinical complete response to neoadjuvant therapy for rectal cancer: An analysis of 488 patients. J Am Coll Surg 2002;194:131-5.
Kuo LJ, Chern MC, Tsou MH, Liu MC, Jian JJ, Chen CM, et al.
Interpretation of magnetic resonance imaging for locally advanced rectal carcinoma after preoperative chemoradiation therapy. Dis Colon Rectum 2005;48:23-8.
Mandard AM, Dalibard F, Mandard JC, Marnay J, Henry-Amar M, Petiot JF, et al.
Pathologic assessment of tumor regression after preoperative chemoradiotherapy of esophageal carcinoma. Clinicopathologic correlations. Cancer 1994;73:2680-6.
Swisher SG, Hofstetter W, Wu TT, Correa AM, Ajani JA, Komaki RR, et al.
Proposed revision of the esophageal cancer staging system to accommodate pathologic response (pP) following preoperative chemoradiation (CRT). Ann Surg 2005;241:810-7.
Engenhart R, Kimmig BN, Strauss LG, Höver KH, Romahn J, Haberkorn U, et al.
Therapy monitoring of presacral recurrences after high-dose irradiation: Value of PET, CT, CEA and pain score. Strahlenther Onkol 1992;168:203-12.
Calvo FA, Domper M, Matute R, Martínez-Lázaro R, Arranz JA, Desco M, et al
. 18F-FDG positron emission tomography staging and restaging in rectal cancer treated with preoperative chemoradiation. Int J Radiat Oncol Biol Phys 2004;58:528-35.
Guillem JG, Moore HG, Akhurst T, Klimstra DS, Ruo L, Mazumdar M, et al.
Sequential preoperative fluorodeoxyglucose-positron emission tomography assessment of response to preoperative chemoradiation: A means for determining longterm outcomes of rectal cancer. J Am Coll Surg 2004;199:1-7.
Oku S, Nakagawa K, Momose T, Kumakura Y, Abe A, Watanabe T, et al.
FDG-PET after radiotherapy is a good prognostic indicator of rectal cancer. Ann Nucl Med 2002;16:409-16.
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:W202-8.
[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3]