Whether to Fused PET/CT or CECT in Post-Therapeutic Colorectal Cancer Assessments: A Study of the Efficacy of the Modality of Choice among Egyptian Patients

One of the most common cancers, colorectal cancer accounts for several tumor-related mortalities; its high recurrence rates either as a local recurrence of the disease or as a distant metastatic disease (up to 35-40%) have been reported in the treated patients within the first two years following surgery. There has been heated debate over the modality of choice for imaging the primary colorectal cancer.This study investigates the diagnostic performance of fused Positron Emission Tomography/ Computed Tomography (PET/CT) in comparison to Contrast-enhanced Computed Tomography(CECT) as a follow-up and restaging imaging tool for post-therapeutic colorectal cancers. Data were collected from 84 Egyptian patients (26 females and 58 males, age ranges from 35 to 80) who were treated from colorectal cancers. They were referred to a private imaging center for evaluation of their disease recurrence by fused PET/CT.Disease recurrence was categorized as operative bed recurrence/residual (incomplete therapeutic response), nodal, and distal metastases.With reference to histopathology reports, the fused PET\CT had sensitivity, specificity, positive predictive value, negative predictive value, and an overall accuracy of 93.33%, 83.33%, 93.33%, 83.33% & 90.48% respectively as compared to CECT(73.33%, 58.33%, 81.48%, 46.67%, 69. 05% respectively).Our findings indicate that fused PET\CT may be more effective than the CECT regarding the detection of operative bed recurrent disease and incomplete therapeutic responses. PET\CT may also offer a cost-effective whole-body scan for restaging the recurrent diseases through an accurate detection of the nodal and distant metastases.

diagnostic performance of fused Positron Emission Tomography/ Computed Tomography (PET/CT) in comparison to Contrast-enhanced Computed Tomography(CECT) as a follow-up and restaging imaging tool for post-therapeutic colorectal cancers. Data were collected from 84 Egyptian patients (26 females and 58 males, age ranges from 35 to 80) who were treated from colorectal cancers. They were referred to a private imaging center for evaluation of their disease recurrence by fused PET/CT.Disease recurrence was categorized as operative bed recurrence/residual (incomplete therapeutic response), nodal, and distal metastases.With reference to histopathology reports, the fused PET\CT had sensitivity, specificity, positive predictive value, negative predictive value, and an overall accuracy of 93.33%, 83.33%, 93.33%, 83.33% & 90.48% respectively as compared to CECT(73.33%, 58.33%, 81.48%, 46.67%, 69. 05% respectively).Our findings indicate that fused PET\CT may be more effective than the CECT regarding the detection of operative bed recurrent disease and incomplete therapeutic responses. PET\CT may also offer a cost-effective whole-body scan for restaging the recurrent diseases through an accurate detection of the nodal and distant metastases.

Background
Colorectal cancer is one of the most common cancers that affect human beings and account for several tumor-related mortalities; high recurrence rates either as a local 3 recurrence of the disease or as a distant metastatic disease (up to 35-40%) have been reported in the treated patients within the first two years following surgery. However, it may be potentially cured if it is early detected, and the curative measures are taken [1,2].
Metastatic disease in colorectal carcinoma can occur anywhere in the body, but it often has nodal, hepatic, and pulmonary predilection; thus, the whole-body screening for the metastatic disease is considered a critical step for the staging of the primary disease and restaging of the recurrent one. Still, according to [3,4], there is an immense debate over the modality of choice for imaging the primary colorectal cancer.
Recently, several diagnostic tools have been implemented for the follow-up of the treated colorectal cancers to assess the recurrent and the metastatic diseases: these include laboratory investigation (e.g., tumor markers and optical colonoscopy) and the conventional diagnostic imaging modalities (e.g., ultrasound, computed tomography (CT) and magnetic resonance imaging (MRI).However, these modalities lack high sensitivity and specificity [3,4].
Through the assessment of the metabolic activity of the tumor tissues, functional imaging is considered a well-established imaging technique using the glucose analogue [18 F] fluorodeoxyglucose-positron emission tomography (FDG-PET) for detection of colorectal cancers and the distant metastatic deposits, yet the poor spatial resolution of FDG-PET was a limitation. To overcome this limitation, hybrid imaging techniques have emerged to provide more enhanced, anatomical details and integrated imaging modalities that may improve the detection of tumor recurrences in treated colorectal cancers and distant metastases [5][6][7][8][9][10][11][12]. The literature has presented the fused PET\CT as both cost-effective and accurate diagnostic modality for detection of the colorectal cancer recurrence [13][14][15]. 4 The current study aims to investigate the diagnostic performance of fused Positron Emission Tomography/ Computed Tomography (PET/CT) compared to contrast-enhanced computed tomography (CECT) in the follow-up assessment and restaging of the patients with treated colorectal cancers through measurements of the sensitivity, specificity, positive predictive value, negative predictive value, and overall accuracy.

Participants
Inclusion criteria: Cases of colorectal malignancies who had curative (surgical or endoscopic) resection, chemotherapy, radiotherapy or any combination of them were included in the current study. However, the patients who had a benign colorectal neoplasm or had colorectal malignancy without any previous treatment were also excluded.
Accordingly, 84 patients were enrolled in the period from November 2017 till July 2019; they were cases of treated colorectal cancers. They were referred to a private imaging center for their assessment by fused PET/CT and the evaluation of their treatment response. The patients' ages ranged from 35 to 80 years with a mean age (58.73± 11.29 years). They were 26 females (31% of cases) and 58 males (69% of cases) (as shown in tables 1 and 2).Participants received one or more of the following treatment methods: the curative (endoscopic or surgical) resections, chemotherapy, and radiotherapy (See Table   5).

Procedure
The patients were instructed to fast for 6 hours before the examination and they were well-hydrated. Blood glucose level was measured before the examination in all patients and was within normal ranges (a maximum limit was 150 mg\dl) before [fluorine -18] fluoro-2-deoxy-d-glucose (FDG) injection.0.22 mCi/kg (18F-FDG) was injected and then the patients relaxed for 45 minutes (considered as the uptake period).The PET/CT system using a multi-detector (sixteen detectors) CT machine (GE, Discovery IQ, USA) was employed to examine the patients. For the sake of attenuation correction and image fusion, a low dose of non-contrast enhanced CT images were taken. The examination levels were extending from the nose to the mid-thigh levels for PET scans. Before contrast media administration for the CECT examination, the serum, urea, and the creatinine levels were measured routinely in all patients. Helical CECT axial images were obtained for the head, neck, thorax, abdomen, and pelvis at intervals of 2mm after intravenous injection of the nonionic contrast media in all patients after they had completed the PET/CT examination. The total acquisition time for the integrated PET/CT scan was nearly 30 minutes.

Statistical Methods
Data management and analysis were performed using the Statistical Package for Social Sciences (SPSS) vs. 21. Numerical data were summarized using means, standard deviations, and ranges, as appropriate. Categorical data were summarized as numbers and percentages. The data were collected, analyzed and tabulated. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of the PET\CT in the diagnosis of recurrent colorectal cancers were calculated using the standard definitions [16].

Data Analysis
Through special workstations, the reconstruction of PET image data sets and using the CT data for attenuation correction and co-registered multiplanar images were obtained using special software. An experienced radiologist (5 years of experience in the PET/CT imaging), the CECT, PET, and the fused PET/CT images were interrogated by visual assessment that considered the hepatic parenchyma as a standard reference for the same 6 patient, and by measuring the standardized uptake value (SUV), a semi-quantitative assessment was conducted. The histopathology reports with a correlation to the clinical and the follow-up examinations for the patients as well as the tumor markers levels (CEA) had served as the reference gold standard.SUV was then automatically calculated using the equation for SUV measurement SUV = (dose in tissue/injected dose) x patient weight, where tissue tracer activity was in microcuries per gram, injected radiotracer dose was in microcuries, and the patient weight was in kilograms [17].

CECT Data Analysis:
Depictions of colonic soft-tissue masses or mural thickening with or without signs of the infiltration of the surrounding peri-colonic tissues were considered as signs of malignancy.
A size-based threshold of 10 mm (short axis) for the malignant lymph glands was considered. The central breaking down (necrosis) was used as a sign of malignancy; however, a preserved fatty hilum and matrix calcification of a lymph gland was considered as signs of benignity. Malignant hepatic focal lesions were reported when hypodense lesions were seen either with or without marginal contrast enhancement. For pulmonary nodules, calcification was used discriminator of benignity, where a calcified pulmonary nodule was considered as a benign nodule.

PET/CT Data Analysis
The colonic soft tissue masses or mural thickenings were considered as a positive recurrence if their FDG uptake was higher than the background activity. The positive hepatic focal lesions were considered if their FDG uptake was more than or equal to that of the rest of the hepatic parenchyma, whereas negative lesions were reported if their FDG uptake was lower than that of the rest of the liver parenchyma. The pulmonary nodules that had a size of 5 mm were considered as positive for malignancy if their FDG uptake was exceeding the mediastinal blood pool, yet a metastatic disease could not be 7 completely ruled out in the pulmonary nodules that were less than 5 mm. If the bone marrow exhibited an obvious multifocal FDG avidity, it was considered as positive for infiltration. However, a diffuse uptake pattern in reactive bone marrow hyperplasia after chemotherapy could simulate or mask a diffuse marrow infiltration; in such case, an appropriate correlation to the patient history was needed. A Few weeks (3-4 weeks) after completion of the chemotherapy were enough for the physiological marrow activity to abate. The positivity of the peritoneal seeding or masses was considered when their FDG uptake was more than that of the background activity.

Discussion
Colorectal cancer is the third leading cause of death worldwide with a relatively high recurrence rate that has been reported in up to one-third of the treated cases; nevertheless, the recurrence patterns could be a loco-regional, nodal or distant metastatic disease. As the recurrent disease is potentially curable in certain cases, the restaging of the recurrence was mandated, and a highly sensitive imaging modality was chosen [18][19][20].
The follow-up methods are quite variable including laboratory studies (tumor markers), endoscopy, and the conventional imaging studies like CT and MRI; however, the lack of a standardized imaging protocol and the reported low sensitivity in the differentiation between the tumor tissue and the postoperative sequelae of intervention has greatly limited the use of such modalities. Moreover, a certain size of the tumor recurrence is required to be assessable and measurable by using these modalities [21,22].
As the conventional CECT may provide useful data about the anatomical and the morphological aspects of the tumor recurrence, the metabolic activity of the tumor cells could also be assessed by FDG PET, thus an integration of their images as fused PET\CT system allows an optimum co-registration of the images with more accurate results than side by side interpretation [5][6][7][8][9][10][11][12]23].
In line with the findings of previous studies [24][25][26], we have reported tumor recurrences in the operative bed; nodal metastases, distant organ metastases, and peritoneal seeding as shown in table 3 (See Figs. 1, 4 &6). Ries et al described the rectosigmoid region as the commonest location for operative bed recurrence [27], which matches our findings where the rectosigmoid region being affected in 31patients (36.9%).As we have reported the disease recurrence in three categories, the operative bed recurrence is present in 60 patients (71.4%), nodal metastases present in 30 patients (35.7%), and distant metastases in 26 patients (30.9%); these findings match those of studies conducted by Chiewvit et al and Hussein and Nassef, who documented a recurrence rate of over 70% [26,28].
In reference to the histopathology results, clinical and radiological follow-up assessments and the tumor markers (if available), the accuracy measures in our study are in a concordance with those by the studies [25,26,29,30].
The false-positive results given by the CECT may lead to a clinical conflict, especially if the patient's laboratory findings are discordant, necessitating a biopsy for the suspicious soft tissue masses. In this way, the fused PET\CT adds great value in this regard and could mitigate the issue (the negative predictive value was 83.33%in our study) as it assesses the metabolic activity in the soft tissue masses for detection of the viable tumor cells with high metabolic activity and the sterile masses with no tumor activity that may represent otherwise scar or operative bed granulation tissues (See Fig. 4).
We had false-positive results by fused PET\CT for operative bed recurrent tissues in four of our cases (4.7%) as negative for tumor cells by the histopathology examination (the gold standard reference in the study for the operative bed recurrence); however, the tumor markers and the follow-up studies for these cases supported the pathology results in terms of the decline in the tumor marker levels, and the metabolic activity in the suspected lesion was no longer seen in the follow-up imaging; these findings align with those by Rodríguez-Vigil et al and other studies, which indicate that the 18F-FDG could be taken up by both malignant and inflammatory cells [31][32][33].
However, the accuracy measures for the detection of the nodal and the distant metastases were not conducted in the current study as the histopathology reference was not available for the nodal and the metastatic lesions, and therefore their assessment was based on the morphological and the metabolic activity for any suspicious lesion as well as its therapeutic response on the follow-up studies and the decline in the CEA levels. The reference standard for the nodal and distant metastatic lesions were the clinical, radiological follow-up and the tumor marker levels as the need for a biopsy from a metastatic lesion is not accepted in the clinical practice except if there was an absolute indication [25,26].
For the nodal metastasis, our study has revealed that nodal affection by PET\CT in 30 cases (35.7%) that were predominantly abdominal in location (22 cases; 26.2%) followed by the mediastinal nodes (6 cases; 7.14%) then by the cervical nodes (3 patients; 3.6%) (See Fig. 4). Such findings agree with those from Hussein and Nassef's study as well as those from Taha Ali's study regarding the detection of the metabolically active lymph glands (as shown by follow-up and by the tumor markers) as malignant nodes with a therapeutic response to the chemotherapy. Hence, the fused PET\CT adds a diagnostic value for detection of the metabolically active lymph glands with a better anatomical localization than the size-based CT detection when used solely.
Regarding the distant metastases, they were ordered sequentially as hepatic, pulmonary, peritoneal, bone, and atypical site metastasis (22, 11, 3, 2& 1 cases respectively) (See being considered as the route of tumor spread as well [34]. Regarding the detection of the distant metastatic lesions and the peritoneal seeding by the PET\CT, a concordance with the findings from Chen et al and Choi et al studies is present [35,36], those from Hussein and Nassef [25] as well as Taha Ali [26]. Through the assessment of the FDG avidity, hepatic metastases were excluded in some of the cases as well as the pulmonary nodules (See Figs. 3& 5) and a detection of such FDG avidity may show a metastatic affection (See Figs. 1, 4& 6),which was correlated to the clinical, radiological follow-up studies and to the tumor marker levels as well. This finding matches those from [25, 26, 35, and 36] that have highlighted a high sensitivity of the fused PET\CT for depiction of distant metastatic diseases and peritoneal seeding. Still, one caveat is that false-positive nodal affection could occur due to inflammatory process.
The atypical distant metastasis was present in only one case (1.2%) of our study, seen in the left adrenal gland (As shown in Fig. 4). This finding concurs with those from Ouchi et al who describe atypical sites of metastases that are infrequently depicted like metastases to the spleen, biliary system, pancreatic, peripancreatic LN, adrenals, mammary, gonadal, cutaneous, umbilical, oral and the vagina cavities [36].

Conclusion
In summary, the current study has shown that fused PET\CT may be more effective than

Declarations
Ethics approval &Consent to participate -The protocol was reviewed and approved by the local ethics committee of the radiology department, Kasr Aliny hospital, Cairo University.
-The reference number was not applicable All patients had given their written consents to participate in this work

-Consent for publication
All patients had given their written consents for publication of this work

-Availability of data and material
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request -Competing Interest: The authors declare that they have no competing interests

-Funding
All authors had no fund for this research and had no competing interests.         Coronal and axial CECT and fused PET-CT images for a 50-year old male patient 28 diagnosed with colonic hepatic flexure infiltrating adenocarcinoma for which he had a right hemicolectomy followed by chemotherapy. Images A and B showed a clear operative bed with no gross hypermetabolic mass lesions (red arrows).
Images C and D showed a right hepatic lobe (segment VIII) hypodense focal lesion that was noted in CT but showed no FDG uptake denoting the absence of tumor activity (yellow arrows). Images E and F showed a left lung pulmonary nodule that was noted in CT but showed no FDG uptake denoting the absence of tumor activity (green arrows).