Patients Criteria and Study Design:
Prospective study For 46 patients with histologically proven osteosarcoma imaged with PET/CT and MRI before and while they were under treatment at the Children Cancer Hospital,
Egypt,
(CCHE) during the period from Oct,
2014 to Oct,
2016.
The age of patients encountered in the study ranged from five to seventeen years with a median of 13 years,
mean of 12.28 +/-0.49 they included 26 males (56.5%) and 20 females (43.5%).
Pretreatment Evaluation:
Patients underwent conventional evaluation (plain radiography and MRI of the primary tumor,
bone scan and CT scan of the chest) and 18F-FDG PET before neoadjuvant chemotherapy.
Pathological confirmation by open biopsy was performed before the first PET/CT scan.
The histologically proven patients with osteosarcoma were investigated by PET/CT and MRI three times,
the first one was done at initial assessment before starting the neo-adjuvant chemotherapy,
the second one was done after finishing three cycles of chemotherapy,
the last one was done after finishing 6 cycles of Neo-adjuvant chemotherapy and before tumor excision.
Then PET/CT (SUVmax) and MRI (tumor volume) results were compared with the percentage of tumor necrosis and pathological response after surgical resection.
Only 32 patients from 46 underwent the three PET/CT and MRI scans.
Eight patients underwent first and second scans and missed the third one,
and six patients underwent the first and third scans and missed the second one.
F18-FDG PET/CT:
F18-FDG PET/CT study was done using a dedicated PET/CT scanner (Biograph,
True-Point; Siemens).
This machine integrates a PET scanner with a dual-section helical CT scanner (40 slice Emotion; Siemens) and allows the acquisition of co-registered CT and PET images in one session.
Patient preparation
1.
The patients were asked to fast for 4 - 6 hours prior to PET/CT.
2.
Blood sugar levels were checked to ensure that there was no hyperglycemia because FDG uptake in cancer cells is reduced if there are competing unlabeled glucose molecules,
a level of less than 150 mg/dl is desirable.
None of the patient was diabetic.
3.
0.22 mCi/kg body weight of FDG was administered intravenously 1 hour before imaging.
4.
Patients sat quietly in a dimly lit room during the uptake phase and were asked to void just prior to imaging.
The CT and PET scans were obtained with the patient in quiet respiration.
5.
Patients were allowed to drink water during the uptake period.
They were instructed to avoid any kind of strenuous activity 24 hours prior to the examination to avoid physiologic muscle uptake of FDG.
6.
Patients were positioned with the arms above the head.
However,
not all patients could maintain this position comfortably without moving for the entire study (PET and CT),
and arms by the side was an alternative.
7.
Forty five to sixty minutes after FDG injection,
the patients were placed supine on the imaging table acquiring at first the CT portion of the study.
This was applied as whole body scan with application of IV contrast (PET/CECT).
8.
A whole body PET study (totally covering the involved tumor sites) followed an enhanced whole body CT study.
The CT study took approximately 60–70 seconds to be completed and the PET study was done for ~ two minutes per bed position.
Imaging technique
(A) CT imaging Protocol:
For a typical whole body PET/CT study (neck,
chest,
abdomen,
pelvis and lower limbs if needed),
scanning began at the level of the skull base and extended caudally to include the involved tumor site.
Typical scanning parameters would be a collimator width of 3.0 mm,
pitch of 1.5,
gantry rotation time of 0.8 second,
and field of view of 50 cm.
The resulting images from CT reconstructed with a 512 x 512 matrix and a 50 cm field of view,
were converted using equivalent attenuation factors of 511 keV for attenuation correction.
(B) PET imaging:
PET performed on a dedicated PET scanner with approximately six to eight bed positions that planned in the three-dimensional acquisition mode for scanning the entire patient with 2-minute acquisition at each bed position in a caudo-cranial direction.
Each bed position is 15.5 cm long,
and the table moves 11.5 cm following acquisition of data at each bed position,
there is approximately a 4 cm (25%) overlap between table stations.
The maximum length of the patient that can scanned with the current PET/CT scanner is 180 cm.
The PET images were reconstructed with a 128 x 128 matrix,
an ordered subset expectation maximum iterative reconstruction algorithm (2 iterations,
28 subsets),
an 8 mm Gaussian filter,
and a 50 cm field of view.
Then PET,
PET/CT and CT images were reviewed using a dedicated workstation and software (E.soft; Siemens Medical Solutions),
which allowed three-dimensional displays (trans-axial,
coronal and sagittal) to be constructed using CT,
PET and PET/CT images and maximum intensity projection displays of the PET data.
A) Qualitative Image interpretation with PET and PET/CT.
Normal physiologic uptake of 18F-FDG as shown before (Fig.
10):
Accurate interpretation of FDG PET scans requires a thorough knowledge of the normal physiologic distribution of FDG and of normal variants that may reduce the accuracy of PET studies,
thereby significantly affecting patient treatment.
B) Quantitative measurement with PET:
PET provides images of quantitative uptake of the radionuclide injected that can give the concentration of radiotracer activity by normal and pathologic tissues,
such as the standardized uptake value (SUV).
This may be of value,
especially for evaluating changes over time or with therapy.
Standardized uptake value (SUV):
The SUV is a semi-quantitative assessment of the radiotracer uptake from a static PET image.
The SUV of a given tissue is calculated with the following formula:
Tracer activity in tissue
Injected radiotracer dose/patient weight
[SUV = (μCi/gram in tissue)/ (total mCi injected) body weight]
Where tissue tracer activity is in microcuries per gram,
injected radiotracer dose is in millicuries,
and patient weight is in kilograms.
Typically,
malignant tumors have an SUV of greater than 2.5 –3.0,
whereas normal tissues such as the liver,
lungs,
and marrow have SUVs ranging from 0.5-2.5.
Many factors can affect the reliability of SUV,
such as tracer extra-vasation at the site of injection,
the patient's serum glucose levels,
and the time interval between injection and image acquisition.
It is best to use SUV as a guide to interpretation rather than an absolute value,
and to rely more heavily on visual estimation of uptake to indicate whether a process is benign or malignant.
Image interpretation:
Focal FDG uptake was considered abnormal when it was greater than that of hepatic uptake,
regarding the diagnosis of metastatic deposits.
All PET/CT scans were reviewed and interpreted by two experienced nuclear medicine physicians.
Magnetic resonance imaging:
MRI sequences included a standard (spin-echo) T1-weighted sequence (repetition time [ms]/echo time [ms],
400–900/10–20),
with or without gadolinium enhancement,
and an intermediate weighted/T2-weighted sequence (1,500–2,500/70–100),
without fat suppression.
Intramedullary tumor lengths were measured in coronal sections of unenhanced T1-weighted sequences,
and tumor widths and depths were measured in axial enhanced T1- and T2- weighted sequences without fat suppression.
Neoadjuvant chemotherapy:
The treatment plan for osteosarcoma cases at CCHE demonstrated at (Fig.
11),
the red arrows represent the time of initial,
post-Week five and post- Week ten PET/CT and MRI scans.
Histologic Assessments of Response to Preoperative Chemotherapy:
Histologic responses to neo-adjuvant chemotherapy were evaluated in the resected specimen by an experienced pathologist.
Good response was defined as 90% or more tumor necrosis while poor response was defined if less than 90% tumor necrosis was achieved.
Definitions and Calculations of Parameters:
We defined the following definitions:
• Pre-chemotherapy (initial) SUVmax and MRI tumor volume as SUVmax1 and MRTV1.
• Pre-chemotherapy (initial) tumor SUVmax to liver SUVmax ratio defined as TLR1.
• Post week five SUVmax and MRI tumor volume as SUV2 and MRTV2.
• Post week five tumor SUVmax to liver SUVmax ratio defined as TLR2.
• Post week ten SUVmax and MRI tumor volume as SUV3 and MRTV3.
• Post week ten tumor SUVmax to liver SUVmax ratio defined as TLR3.
• SUV change ratio 2/1 = SUV2/SUV1.
• SUV change ratio 3/1 = SUV3/SUV1.
• MRTV change ratio 2/1 = MRTV2/MRTV1.
• MRTV change ratio 3/1 = MRTV3/MRTV1.
• TLR change ratio 2/1 = TLR2/TLR1.
• TLR change ratio 3/1 = TLR3/TLR1.
Statistics:
The Wilcoxon signed rank test was used for paired comparisons between quantitative parameters.
The receiver operating characteristic (ROC) curves for the prediction of a poor histologic response were generated to determine the cutoff values that offered the highest sensitivity and specificity of the PET and MRI parameters which are SUV1,
SUV2,
SUV3,
TLR2,
TLR3,
SUV2/1,
SUV3/1,
MRTV2/1,
MRTV3/1,
TLR2/1 and TLR3/1.
In terms of their abilities to discriminate good responders from poor responders. All calculations were performed using SPSS (version 22.0; SPSS Inc.).
All P values were derived from the 2-sided test,
and values of less than 0.05 were considered significant.
We used related Sample Wilcoxon signed Rank test for testing change in scans at the different time points.