Report About Prostate Cancer: PET in Radiotherapy Planning

Introduction:

[bookmark: _Hlk3485638]Imaging modality plays a great role in treatment planning. Positron emission tomography PET has been used in treatment planning in the delineation of Gross target volume GTV which is considered as the most important component in treatment planning. Also, PET Accuracy in the delineation of GTV impact on dose delivery to tumor tissue while delivering a low dose rate to healthy tissue or critical structure surrounding the tumor. PET has great sensitivity and specificity in the delineation of Gross target volume more than other imaging modality that has been used in treatment planning. because PET uses FDG and these an advantage that reduces the uncertainty in defining tumor margin in radiotherapy treatment planning. [1]

PET-based treatment planning:

Recently PET imaging or molecular imaging has been used in treatment planning for cancer patients. By using PET radiotracer 18F-FDG which allow viewing the molecular pathways for the target (tumor), metabolism, proliferation, oxygen delivery, and consumption many receptors or gene expression. Using PET images in treatment planning can give us information about tumor response to radiotherapy, can localize the reoccurring tumors in an early stage. The most important function of PET imaging in treatment planning is Delineation of tumor or target and organ at risk OAR. [9] Positron emission tomography PET, has an advantage in cancer patient management by using 18F-FDG as a tracer helps in the delineation of the target volume in non-small cell lung cancer NSCLC patients, head and neck squamous cell carcinoma HNSCC, and rectal carcinomas.[9] There is another PET radiotracers differ in their sensitivity and specificity which impact the image and the treatment planning. FDG it has non-specific uptake in tumor and high uptake in other areas such as infection or inflammation sites.[9][10] hypoxia imaging with PET a useful tool to know tumor response during radiotherapy treatment or identify the resistant tumor cells, and to deliver the higher radiation dose to the parts that radio-resistant which have a higher chance of tumor reoccurrence. [4] the best PET tracer should have these properties high uptake values in the tumor, high sensitivity and specificity in tumor site, low production cost, and availability.[5]

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Why PET used in treatment planning:

• Provide molecular information about the tumor.
• Higher sensitivity, specificity, and accuracy due to PET tracers.
• Provides accurate information about tumor stage.
• Give information about tumor response and resistant to radiotherapy.
• Accurate delineation of GTV.
• Dose painting with hypoxia tracers (FMISO, FAZA, CU-ATSM) and FLT.
• dose painting by numbers DPBN, shape the dose depending on the voxel intensity.
• Accurate diagnosis of NSCLC and high contrast images.
• Enhance the main aim of radiotherapy treatment by concentrated the radiation dose to the target and lower dose for surrounding tissue or OAR. [5][12][7]

PET Tracers (agents):

· FDG

The first use of PET-FDG was with non-small cancer lung cells NSCLC by accurate delineation for nodal and distant metastases. FDG-PET has been used with CT images due to the poor spatial resolution of FDG-PET.[9] FDG-PET more accurate than CT in localizing mediastinal nodal in SCLC, also FDG-PET helps to reduce the isolated nodal failures outside the clinical target volume CTV.[9] The resolution limits for PET 5-7mm, any object lower than this limit will have a weak signal which affects the resulting image.[9] Due to this limitation, there is the uncertainty of estimating the real tumor size. PET images may contain a signal noise. [12] FDG used as a guide through the segmentation process, then these segments combined to form the large target region. The main objective of segmentation to determine which part of the target will receive the primary dose and which one will have the higher dose GTV.[10] PET-avid delivery of a nonhomogeneous dose of FDG-PET to the target region, by concerted the higher dose to the avid region and lower dose to the OAR or keep the dose below the threshold of deterministic effects.[10] the disadvantage of FDG is non-specific uptakes values for tumor due to the high activity of glucose. [5]

· 18F-FDG PET/CT:

[bookmark: _Hlk3558885][bookmark: _Hlk3558888]Using FDG-PET with CT handle the limitation of low spatial resolution of PET. [9] Fusing PET images with CT images improve the accuracy of delineation, and high sensitivity, and specificity (96.6%) of tumor detection and contributed in treatment decision based on the changing of GTV. [11] since CT provides electron density data that improve the dose calculation in treatment planning. [12] Using two imaging modalities enhance the detection of reoccurrence tumors especially colorectal cancers.[11] Fusing techniques: (1) Hybrid PET/CT fusing the images in the system by RTP and (2) Fusing PET and CT images separately and two registration methods: (1) rigid and (2) deformable. In PET/CT it is important that the immobilization device fits with PET/CT, immobilization device such as masks and shoulder in head and neck cancer easily fits with PET/CT. PET/CT has been used in gate acquisition of lung and thoracic and excellent bowel preparation of abdominopelvic malignancies. Both PET and CT have artifacts due to patient motion especially respiratory motion which lead to the wrong estimation of SUV and tumor size. Inaccurate SUV due to a mismatch between PET and CT because of the difference in time acquisition. PET has superior sensitivity and specificity over CT in lung cancer helps to improve the therapeutic ratio by increasing the dose in the target site and minimize the dose in OAR and normal tissue. There is two correction techniques of respiratory motion 4D PET/CT, DIBH PET/CT. [12]

The uptake process 18F-FDG PET/CT:

1. Before the examination, the patient had to be fasting for at least 6 hours.
2. Then injects the patient with FDG, the amount of FDG calculated by [w×4+20] MBq.
3. Then after 60 min, the PET and CT images obtained. [9]

· 18F-FLT

18F-fluorothymidine FLT it is cellular proliferation, phosphorylated by thymidine kinase inactive cells and trapped in the cell but does not marker DNA.[9][10] FLT is excellent image for tumor volume changes due to radiotherapy. [13] FLT can give information about the tumor response during the treatment course. After 15 to 18 fractioned doses ( chances in GTV is detectable. The uptake values of FLT decrease due to the reduction of tumor cell density during the treatment and this is impacting on the FLT signal.[14]

The uptake process of FLT-PET/CT:

1. The patient fast for at least 6 hours before the examination.
2. Rest for 15 min before the injection of 300-400MBq of FLT.
3. The images were obtained in 60 min after injection.[13]

Comparison between FLT and FDG PET tracers in treatment planning:

FLT

FDG

esophageal cancer

Has a low dose to the lung and cardiac

Higher dose to lung and cardiac

rectal cancer

The same GTV for both

brain tumors

Superior in defining the target in the brain

Has high uptake value in cortical

reactive lymph nodes

May have some uptake value in reactive lymph nodes which increases the difficulty to distinguish active tumors.

specificity

excellent

Good

accuracy for nodal staging

excellent

Good

Primary tumors

Lower sensitivity to detect primary tumors

higher sensitivity to detect primary tumors

[9][10]

· 11C-methionine

The sensitivity of 11C-methionine PET in brain tumor is higher than FDG-PET due to the high activity of glucose in normal brain tissue. This is making 11C-methionine the best PET tracer for brain tumor delineation. [5] 11C-methionine provides biological information about the tumor and the response to treatment. 11C-methionine helps in diagnosis identify the tumor activity with primary and recurrent gliomas patients.[15] tumor grading may be estimated incorrectly in brain tumor especially gliomas kind because it is formed of heterogeneous and microscopic areas of necrosis. so, the biopsy may represent a small part of the primary tumor and underestimate the tumor grading. 11C-methionine shows that are a useful biomarker in gliomas patients and has a higher sensitivity of detection and delineation of the tumor. In contrast with FDG-PET, 11C-methionine can detect tumors with (hypometabolism or is metabolism). 11C-methionine can be used as guidance during the biopsy process.[16] 11C-methionine shows a high uptake value in the pituitary gland and can distinguish between pituitary adenoma and other normal tissue in the brain. These increasing the reduction of GTV and the radiation dose to the normal tissue and the parotid glands, lacrimal glands and inner ears. The drawback of 11C-methionine it has a shorter half-life 20 min, also there is uptake values in other sites such as lacrimal glands, parotid glands, nasopharynx, bone marrow, and normal pituitary gland. [17]

The uptake process of 11C-methionine:

1. Injection the patient with 11C-methionine 210MBq.
2. After 20 min PET image obtained in 3D for 5min /bed position. [15]

· 11C-Choline

11C-Choline can distinguish between curable diseases from metastatic diseases. [18]11C-Choline has been used for prostate cancer and contributed to choosing the best treatment strategy. 11C-Choline helps to improve the therapeutic ratio by high-precision radiation to the target and minimum dose to the normal tissue. It is not recommended using 11C-Choline in early diagnosis or tumor staging. The advantage of using 11C-Choline with prostate cancer that detects the target that localizes beyond the prostate bed so unnecessary radiation dose for prostate bed will be avoided.[19] 11C-Choline has sensitivity and specificity of 85%and 88% inpatient prostate-specific antigen (PSA). The limitation of 11C-Choline is cannot detect small lesions or low activity lesions. [20] other limitation of 11C-Choline cannot distinguish between tumor and non-tumor tissue in the prostate. [21]

The uptake process of 11C-Choline:

1. The patient fast at least for 6 hours before 11C-Choline PET/CT scan.

2. Then patient drink diluted oral contras 300 mg.

3. A rectal filling negative contract agent 100-200mL.

4. Then injected the patient of 691 ±70MBq of 11C-Choline.

5. Then after 5 min, the PET/CT images were obtained.[22]

· 68Ga-PSMA-PET 21

68Ga-PSMA-PET has high sensitivity and specificity in diagnosing prostate cancer. [23]68Ga-PSMA-PET can diagnosis the reoccurrence primary prostate cancer PCA.[21] 68Ga-PSMA helps to eliminate 35.7% Lymph nodes LNs out of CTV which enhances the therapeutic ratio by minimizing the dose to LNs. [23]

The uptake process of 68Ga-PSMA-PET:

1. Patient fasts for at least 4 hours before injection.
2. Then injected the patient 172±34 MBq of 68Ga-PSMA.
3. Then after one-hour PET scan performed. [21]

· 18F-fluciclovine PET/CT

18F-fluciclovine has been used in postprostatectomy to delineate the volume target (prostate bed) and the changes that may affect the OAR. 18F-fluciclovine a non-physiologic uptake in prostate bed, lymph nodes, or bone. [24]

The uptake process of 18F-fluciclovine:

1. The patient must fast at least for 4 hours.
2. Then the patient injected with (371.6±12.4 MBq) over 2 min.
3. The acquisitions of the pelvis to diaphragm obtained at 5-15.5min and at 16-27.5min. [24]

· Hypoxia Tracers:

Hypoxia traces have a great role in treatment planning provides a lot of information by Identify the resistant cells in the tumor. The target/background activity is less than FDG-PET. [10] Hypoxia traces is a nitroimidazole compound. [25] hypoxia tracer it is common to use in solid tumors such as head and neck squamous cell carcinomas (HNSCC). [26]

1. (18F-MISO) the first hypoxia PET tracer can increase the dose to hypoxic tumor up to 105Gy, can detect different tumor sites in one patient.[26]
2. (18F-FAZA) has the same uptake values and biodistribution as 18F-MISO, but the lower concentration in the tumor, that mean lower sensitivity in detection hypoxic sites.[26]

The importance of hypoxia tracer:

1. Prediction of failure of radiotherapy.
2. Prediction of chemotherapy-resistant (ꜜproliferation ꜜdrugs concentration).[26]

PET tracer

Cancer type

Sensitivity-specificity

In GTV delineation

FDG-PET

· Nonsmall cancer lung cells NSCLC

80-90%

85-100%

· Head and neck

50-96%

88-100%

· Cervical carcinoma

75-91%

92-100%

· Esophageal

30-78%

86-98%

· Prostate cancer

67%

83%

11C-Choline PET

· Prostate cancer

80%

96%

11C-Acetate PET

· Prostate cancer

80%

29%

[25][27]

FDG-PET in brachytherapy:

FDG-PET images have been used in brachytherapy for the cervix cancer patient. FDG-PET give significant information in 3D of the tumor or disease spread. The advantage from use FDG-PET image in treatment planning of cervix cancer patient is to reduce the dose to bladder and rectum due to the accurate dose coverage to the target volume. [28]

New PET tracer 18Ffluoroethyl-L-tyrosine FET:

The new PET tracer FET has used in the detection of glioma and has excellent sensitivity and specificity improving the detection. also, have been used with Highly malignant or high-grade glioma. FET-PET used with MRI-based plans to shows the contrast. A mismatch between FET-PET and MRI-based in target volume contour, which improve treatment planning. Also, FET-FDG shows other sites that CT-based did not cover.[29] FET-PET id better than FDG-PET in the detection of a brain tumor but have the same performance in grade glioma. FET-PET mean, and maximum target/background ratio only can distinguish between tumor tissues and nontumor tissues. FET-PET helps to identify the tumor response to radiotherapy and delineation of target volume before radiotherapy which helps in estimating the effect of radiotherapy and chemotherapy in the tumor.[30]

Nonsmall cancer lung cells NSCLC:

In intensity modulated radiotherapy IMRT PET and CT scan improve the treatment planning for NSCLC patients. [31] 18F-FDG PET/CT has the ability to distinguish between tumor tissues and healthy tissues with 93% sensitivity and 88% specificity. the sensitivity, accuracy, and positive predictive value in the detection of primary lung tumors are 94%,94%, and 100% respectively. 18F-FDG PET/CT contributed to changing the treatment planning during the treatment course.[32]

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