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Role of [18F]FDG-PET/CT in Evaluation of Tumor Response to Chemoradiation Therapy for Advanced Colorectal Cancer
Address for correspondence: Dr. Chandan Jyoti Das, Department of Radio-Diagnosis and Interventional Radiology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi - 110 029, India. E-mail: docchandan17@gmail.com
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Received: ,
Accepted: ,
This article was originally published by Wolters Kluwer - Medknow and was migrated to Scientific Scholar after the change of Publisher.
Abstract
Objectives:
The objective is to evaluate the efficacy of 18F-fluorodeoxyglucose positron emission tomography (18F-FDG-PET) computed tomography (CT) in the evaluation of tumor response to preoperative/palliative chemoradiotherapy (CRT) for advanced colorectal cancer; including metastatic cancer at primary presentation and recurrent cancers with local and/or distant metastasis.
Materials and Methods:
Fifty patients with advanced rectal cancer underwent two point imaging with 18 FDG PET-CT before and after 3 weeks of completion of preoperative/palliative CRT in between 2016 and 2022. Patients with locally recurrent cancer also underwent radical surgery. The assessment consisted of the evaluation of the following metabolic PET parameters: Maximum standardized uptake value (SUVmax), SUVratio, metabolic tumor volume (MTV), and total lesion glycolysis (TLG). Response was assessed among the followed patients using RECIST 1.1 criteria.
Observations and Results:
There was a significant decline in the mean post therapy SUVmax and SUVratio as compared to baseline (P = 0.0001). Twenty-six out of 50 (52%) patients were classified as responders. A significant decrease in all parameters (SUVmax, SUVratio, TLG, and MTV) from baseline was observed in responders of the study when comparing with nonresponders (P < 0.05). Besides SUVmax and SUVratio, the mean posttherapy TLG was significantly reduced in responders than nonresponders (P = 0.0065).
Conclusion:
PET-CT is a useful combined anatomic and functional imaging modality in monitoring tumor response to preoperative/palliative CRT in advanced rectal cancer, whether primary or recurrent, including metastatic cancers at presentation. Posttherapy SUV and TLG in particular are significantly associated with treatment response.
Keywords
18F-fluorodeoxyglucose positron emission tomography computed tomography
advanced colorectal cancer
recurrent colorectal cancer
Introduction
Colorectal cancer currently contributes to a significant proportion of cancer related morbidity and mortality, which is mainly attributed to a notoriously high rate (approx. 25.7%) of local and systemic recurrences.[1] Locally recurrent rectal cancer (LRRC) remains a major problem after curative resection, with reported incidences ranging in between 5% and 30% in literature.[23] Besides these, a multitude of patients have metastatic disease at the first presentation.[14] Introduction of chemoradiotherapy (CRT) has dramatically improved the survival outcomes in such cases. Chemotherapy therefore currently forms the mainstay therapy in cases with systemic spread and recurrences; along with radiotherapy and surgery which can be mainly instituted for local recurrent disease.[4]
Pathological evaluation of the resected specimen with evaluation of the pathological tumor regression grade is the gold standard for assessing treatment response of primary tumors after CRT.[56] This takes into account the proportion of residual tumor cells and fibrosis within the resected tumor specimen.[6] Surgical and treatment-related morbidity reduce the feasibility of using histopathology for response assessment in each and every patient; additionally, systemic metastasis are usually not resected or biopsied in the presence of a known primary.[7]
Imaging plays a central role in response assessment of such advanced colorectal cancers to adjuvant CRT. Although Computed tomography (CT) and pelvic magnetic resonance imaging (MRI) provide excellent anatomical evaluation of locally recurrent cancer, both are not able to differentiate between residual tumor and treatment induced fibrosis.[8] Newer MRI techniques such as diffusion weighted imaging and dynamic contrast-enhanced MRI provide valuable functional information thereby aiding in differentiation in between both.[7] MRI, however, has limited availability and suffers from cost restraints. In addition, systemic evaluation in a single sitting by these modalities is limited.[38]
18F-fluorodeoxyglucose positron emission tomography (18F-FDG-PET) with CT overcomes these limitations and allows a comprehensive evaluation of the residual tumor metabolic activity with simultaneous anatomical assessment post-CRT.[3]
FDG PET-CT has previously demonstrated encouraging results in evaluation of the tumor response to CRT in a multitude of cancers, including rectal and esophageal cancers.[3910] Maximum standardized uptake value (SUVmax), a semi-quantitative assessment parameter in particular, has demonstrated promising results in assessing treatment response in colorectal cancers.[3]
The objective of this study was to evaluate the efficacy of 18F-FDG-PET-CT in the evaluation of tumor response to chemoradiation therapy for advanced colorectal cancer, which included metastatic rectal cancer at primary presentation and recurrent cancers with local and/or distant metastasis.
Materials and Methods
This ambispective cohort study was conducted after obtaining the clearance from the Institutional Ethics Committee during January 2016–October 2022 (ID-IEC PG-621/25.11.20, RT-06/23.12.2020). Requirement of consent was waived off by the committee for the 40 retrospective cases. Due consent was obtained before imaging the prospectively included 10 patients of primary metastatic rectal cancer.
Patient population
Two groups of patients were included: (1) patients with histopathologically proven colorectal cancer with visceral and/or nodal metastasis at primary presentation, (2) patients with previously treated colorectal cancer who now presented with local and systemic recurrence. All patients were more than 18 years in age. Patients who had not received CRT or patients who had not received pre- and postoperative PET-CT evaluation were excluded from the study. Eventually, a total of 50 patients were enrolled. Median carcinoembryonic antigen (CEA) levels were obtained in 36/50 patients. The extent of the recurrent tumor was assessed by CT and MRI of abdomen and pelvis, along with colonoscopy.
Positron emission tomography computed tomography acquisition
All patients were normoglycemic (blood glucose <140 mg/dL). Patients fasted for at least 4 h before the tracer injection and avoided strenuous exercises for 6 h before the scan to maintain uniform insulin levels and metabolism. All patients voided urine immediately before the PET-CT examination to reduce bladder activity. They were then administered 296–370 MBq (8–10 mCi) of F-18-FDG intravenously and whole-body (vertex to mid-thigh) scan was acquired 45–60-min postinjection on dedicated FDG PET-CT scanners (Biograph mCT 64, Siemens Inc., Germany, and 710 Discovery, GE Healthcare, USA). Both scanners underwent regular calibration for quality assurance. A low-dose noncontrast CT scan was acquired first (80–120 keV; 150–300 mAs; CARE dose protocol) followed by PET acquisition for 1.5–2 min/bed position. Iterative reconstruction was used for postprocessing. All patients received a PET-CT scan before CRT and another scan 3 weeks after completion of palliative/preoperative CRT.
Image analysis
The images were transferred to dedicated workstations for semi-quantitative analysis. Three dimensional (3D) regions of interest (ROIs) were drawn using 40% of SUVmax uptake by the lesion as threshold around the lesion/site of interest and following metabolic PET parameters calculated: SUVmax, SUVratio, metabolic tumor volume (MTV), and total lesion glycolysis (TLG). SUVratio was calculated by dividing SUVmax of tumor with the SUV of liver. In case of multiplicity, the lesion with highest FDG uptake, i.e. with highest SUVmax was included for quantitative analysis and metabolic parameters as mentioned above derived for the same.
Chemoradiotherapy protocol
The standard chemotherapy regimen consisted of 5-fluorouracil, oxaliplatin, and folinic acid as adjuvant chemotherapy in cases of advanced colorectal cancer. Patients with wild-type KRAS will also be treated with cetuximab. Radiotherapy was given in mid and lower rectal cancer. A total dose of 45 Gy was administered in 25 daily fractions over a total time of 5 weeks, treating 5 days/week, 1 fraction/day, using 1.8 Gy/fraction with concomitant capecitabine therapy.
Response evaluation
Response was assessed among the enrolled patients using RECIST 1.1[11] criteria which were assigned on the basis of a contrast-enhanced CT of chest and abdomen which acquired as a part of routine reporting procedure before and after completion of therapy. The cases were eventually assigned to four categories – complete response, partial response, stable, and progressive disease. For the purpose of study, patients showing complete and partial response were grouped together as “responders” and those with stable disease and progressive disease were grouped together as “nonresponders.”
Statistical analysis
The analysis was performed using Stata 17 software (Stata Corp. LLC, USA) and SPSS (IBM SPSS statistics version 26, Armonk, New York, USA) with RECIST criteria 1.1 as the gold standard. Descriptive statistics were performed for all data with frequency as a measure of central tendency and deviation as appropriate (proportion for qualitative variables; mean/median and standard deviation/interquartile range of quantitative variables). Pre- and posttherapy SUVmax, SUVratio, MTV, TLG, and CEA were compared among the response groups.
Wilcoxon signed-rank test was used to compare pretherapy versus posttherapy quantitative PET parameters and pretherapy versus posttherapy CEA levels. Two sample Wilcoxon rank-sum (Mann–Whitney) test was used to correlate individual quantitative parameters among both the response groups. Wilcoxon signed-rank test was also used to compare and derive differences in quantitative PET parameters and CEA levels among the various response groups. A P < 0.05 was considered statistically significant in all comparison statistics.
Observations and Results
Patient population
A total of 50 patients were included in the study which consisted of 25 cases of primary colorectal cancer with distant metastases, 12 patients with local recurrence and 13 patients with recurrent cancer and deposits at distant sites. Among these 26 (52%) showed response with preoperative/palliative CRT. Relevant patient features are tabulated in Table 1.
| Characteristics | Total (n=50) |
|---|---|
| Sex | |
| Male | 28 |
| Female | 22 |
| Median age (years) | 46 (20–80) |
| Median CEA (ng/mL) | |
| Pre-CRT (n=36) | 9.79 (1.24–122.1) |
| Post-CRT (n=25) | 5.3 (0.9–167) |
| Observed response (RECIST) | |
| Responders | 26 |
| Nonresponders | 24 |
| Observed lesions# | |
| Recurrent/residual lesion at operating site | 12 |
| Nodal metastases | 26 |
| Liver metastases | 15 |
| Peritoneal deposits | 10 |
| Lung and bone metastases | 8 |
#Multiple metastatic sites were demonstrated in few patients. CEA: Carcinoembryonic antigen, CRT: Chemoradiotherapy
Carcinoembryonic antigen levels
CEA was done as a part of routine disease burden monitoring. Pretherapy test values of 36/50 patients and posttherapy test values of 25 patients were recovered from the institutional medical records. Ten out of 36 patients were found to have normal CEA levels (<5 ng/mL) at the time of pretherapy scans. CEA also showed an overall decline in median value posttherapy; however, it was not statistically significant [Table 2]. A significant difference was observed in pre and post therapy mean CEA levels in responders [Table 3].
| Parameter | Pretherapy | Posttherapy | P |
|---|---|---|---|
| SUVmax | 11.78 (2.32–133.82) | 7.16 (0.65–32.48) | 0.0001 |
| SUVratio | 4.99 (1.14–20.12) | 3.68 (0.26–11.48) | 0.0003 |
| MTV | 10.93 (0.25–104.45) | 7.43 (0–81.91) | 0.0213 |
| TLG | 53.80 (0.28–918.11) | 20.99 (0–805.20) | 0.0031 |
| CEA | 9.795 (1.24–122.1) | 5.3 (0.9–167) | 0.3674 |
All FDG parameters showed statistically significant reduction when the entire cohort was considered. SUVmax: Maximum standardized uptake value, SUVratio: Standard uptake value ratio (SUVmax/SUVliver), SUVliver: Average standard uptake value of liver parenchyma, MTV: Metabolic tumor volume, TLG: Total lesion glycolysis, CEA: Carcinoembryonic antigen, FDG: Fluorodeoxyglucose
| Parameter | Pretherapy (range) | Posttherapy (range) | P |
|---|---|---|---|
| SUVmax | |||
| Responders | 15.30 (4.36–133.82) | 5.14 (0.91–20.75) | 0.0001 |
| Nonresponders | 9.85 (2.32–58.18) | 12.89 (0.65–32.48) | 0.7533 |
| SUVratio | |||
| Responders | 5.66 (1.67–20.12) | 2.94 (0.41–7.02) | 0.0001 |
| Nonresponders | 3.72 (1.14–19.33) | 4.56 (0.26–11.48) | 0.6071 |
| MTV | |||
| Responders | 13.65 (1.13–104.45) | 4.97 (0–19.43) | 0.0009 |
| Nonresponders | 6.66 (0.25–76.41) | 9.09 (0–81.91) | 0.6682 |
| TLG | |||
| Responders | 76.72 (3.39–918.11) | 15.85 (0–86.624) | 0.0001 |
| Nonresponders | 34.47 (0.28–532.98) | 55.68 (0–805.200) | 0.3758 |
| CEA | |||
| Responders | 7.905 (1.24–122.1) | 2.13 (0.9–5.44) | 0.0121 |
| Nonresponders | 11.385 (2.04–73.8) | 9.4 (3.09–167) | 0.5067 |
All FDG parameters and CEA demonstrated a statistically significant decrease from baseline values in responders as compared to nonresponders. SUVmax:Maximum standardized uptake value, SUVratio: Standard uptake value ratio (SUVmax/SUVliver), SUVliver: Average standard uptake value of liver parenchyma, MTV: Metabolic tumor volume, TLG: Total lesion glycolysis, CEA: Carcinoembryonic antigen, FDG: Fluorodeoxyglucose
Fluorodeoxyglucose positron emission tomography parameters
A statistically significant decrease in all parameters, namely SUVmax (P = 0.0001), SUVratio (P = 0.0003), MTV (P = 0.0213), and TLG (P = 0.0031) was observed in posttherapy groups when considering all patients as compared to baseline [Table 2 and Figure 1].
On comparison of pretherapy and posttherapy parameters among the responders and the nonresponders, all parameters showed a statistically significant decrease from baseline values in responders [Table 3 and Figures 2-4].
When comparing the individual parameters at posttherapy among both the response groups, mean SUVmax, SUVratio, and TLG demonstrated statistically significant lower values in responders as compared to nonresponders [Table 4 and Figure 1]. Incidental differences in the pretherapy SUVratio and TLG were also seen between the responders and nonresponders, with the responders demonstrating higher pretherapy values of both SUVratio and TLG as compared to the nonresponders.
| Parameter | Responders (n=26) | Nonresponders (n=24) | P |
|---|---|---|---|
| SUVmax | |||
| Pretherapy | 15.30 (4.36–133.82) | 9.85 (2.32–58.18) | 0.0822 |
| Posttherapy | 5.14 (0.91–20.75) | 12.89 (0.65–32.48) | 0.0002 |
| SUVratio | |||
| Pretherapy | 5.66 (1.67–20.12) | 3.72 (1.14–19.33) | 0.0219 |
| Posttherapy | 2.94 (0.414–7.019) | 4.56 (0.26–11.48) | 0.0049 |
| MTV | |||
| Pretherapy | 13.65 (1.13–104.45) | 6.66 (0.25–76.41) | 0.1374 |
| Posttherapy | 4.97 (0–19.43) | 9.09 (0–81.91) | 0.1069 |
| TLG | |||
| Pretherapy | 76.72 (3.39–918.11) | 34.47 (0.28–532.98) | 0.0396 |
| Posttherapy | 15.85 (0–86.624) | 55.68 (0–805.200) | 0.0065 |
| CEA | |||
| Pretherapy (n=36) | 7.905 (1.24–122.1) | 11.385 (2.04–73.8) | 0.2935 |
| Posttherapy (n=25) | 2.13 (0.9–5.44) | 9.4 (3.09–167) | 0.0001 |
Posttherapy mean SUVmax, SUVratio and TLG along with CEA demonstrated statistically significant lower values in responders as compared to nonresponders. SUVmax:Maximum standardized uptake value, SUVratio: Standard uptake value ratio (SUVmax/SUVliver), SUVliver: Average standard uptake value of liver parenchyma, MTV: Metabolic tumor volume, TLG: Total lesion glycolysis, CEA: Carcinoembryonic antigen
In addition, posttherapy median CEA had significantly lower values (P = 0.0001) in responders as compared to nonresponders.
Discussion
Our study demonstrated a significant reduction in all metabolic PET parameters post institution of CRT in advanced and recurrent colorectal cancer. 18F-FDG is a radiolabeled glucose analogue which is widely known for its ability to assess and quantify tumor metabolic activity. CRT typically causes alteration of the metabolic response in tumors, which is assessed by 18 FDG PET-CT and typically occurs before decline in tumor volume.[12131415] Therefore, PET-CT may reliably allow earlier detection of response than conventional CT and MRI which rely on assessing the size. In addition, PET-CT allows differentiation between recurrent tumor and posttherapy fibrosis by detection of metabolic activity.[31617]
A multitude of semi-quantitative parameters have been studied previously for assessing the treatment response post-CRT especially in locally advanced rectal cancer which include SUVmax, percentage SUVmax reduction, TLG, and MTV. Among these, SUVmax remains the most extensively studied parameter for semi-quantitative analysis. This is primarily because its value remains most consistent and is independent of the ROI (in contrast to SUV mean).[312] Our study additionally demonstrated a decline in SUVratio which implied decreased radiotracer concentration at the tumor site which is reflective of the changes in metabolic activity. Another study however has previously demonstrated that TLG had the best accuracy in predicting response to preoperative CRT in locally advanced rectal cancer.[13]
A significant decrease in all parameters (SUVmax, SUVratio, TLG, and MTV) from baseline was observed in responders of the study when comparing with nonresponders which was seen irrespective of the presentation (primary or recurrent). This is in agreement with previous conducted studies which demonstrated similar results with neoadjuvant therapy in locally advanced rectal cancer.[121415181920] A relative paucity of literature seems to exist when dealing with recurrent cancers. A recent study demonstrated the usefulness of PET-CT in the assessment of tumor response to preoperative CRT in LRRC and found posttherapy-SUV to be associated with pathological response and as an independent prognostic survival indicator for such patients.[3]
In addition, we found that posttherapy mean TLG was lower in responders as compared to nonresponders besides mean SUVmax and SUVratio. Therefore, PET-CT was reliably able to differentiate responders versus nonresponders which is in accordance with and an addition to the results in previously observed studies where only SUV was analyzed.[3] A reduction in TLG and SUV primarily indicates a decrease in the number of viable tumor cells, which may lead to better prognosis.[3] Therefore, a low posttherapy SUV and TLG in advanced rectal cancers is a sign of therapeutic response.
Currently, there are no clear guidelines when considering the optimal time to perform the PET-CT for response assessment. Previous studies demonstrate conflicting evidence(s), with some advocating the usage of early PET-CT in locally advanced rectal cancer for early alteration of CRT.[21] A study on recurrent rectal cancer has, however, failed to demonstrate similar results.[3] It has been postulated that this may be explained by the relative resistance of recurrent tumor to hypoxia created by chemotherapeutic regimens.[322] Therefore, we performed the scans at 3 weeks postcompletion of CRT which was a standard time followed at the author’s institute in colorectal malignancies with the rationale of routinely performing resection after 3 weeks.
We noticed a non significant fall in CEA levels Post institution of CRT. CEA levels however were significantly found to be lower than baseline in responders and mean CEA levels were lower in responders when compared with those who did not demonstrate partial/complete response. Thus, CEA levels may be used as adjunct to differentiate between both which is in agreement with the previously conducted studies.[23]
There are a few limitations of this study. First, a sample cohort was small and large scale studies on a bigger population are warranted for validation of the results. Second, a majority of patients had metastatic disease either at presentation or at recurrence (n = 28). Unlike patients with locally recurrent cancer (n = 12), these patients did not undergo surgery and consequent histopathological analysis which remains a widely accepted gold standard for malignancies. Finally, despite the utilization of stringent measures for calibration, usage of two different PET scanners may have introduced some variability in the values of measured parameters. Both baseline and postchemotherapy scans for a patient were however conducted in the same scanner.
Conclusion
PET-CT is a useful combined anatomic and functional imaging tool in monitoring tumor response to preoperative/palliative CRT in patients with advanced rectal cancer, including recurrent disease and metastatic cancers at primary presentation. Post therapy SUV and TLG in particular are significantly associated with treatment response.
Conflicts of interest
There are no conflicts of interest.
Nil.
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