Keywords
imaging - oncology - PET-CT
Principles of PET-CT Scanning
Principles of PET-CT Scanning
Cancer cells proliferate and grow by rapidly metabolizing glucose to lactate. Increased
glucose uptake in cancer cells is the key to positron emission tomography-computed
tomography (PET-CT) imaging.[1]
[2] However, you need to identify a glucose analogue that will follow the same metabolic
pathways as glucose but will render itself to be detected by imaging. The glucose
analogue 18F-fluoro-2-deoxyglucose (FDG) is the most widely used PET-CT radiopharmaceutical
in clinical routine. Its uptake and trapping in cancer cells can be picked up by a
PET-CT scanner as it is unstable. It is an isotope that emits positrons. The positrons
are positively charged and readily combined with a freely available negatively charged
electron. When the positron and electron collide, they both disappear. This process
is called annihilation and it ends in releasing the gamma rays that are detected by
a PET-CT scanner.
Availability and Indications for PET-CT
Availability and Indications for PET-CT
When it comes to high-end imaging studies, particularly PET-CT there are significant
global inequities. The availability and cost of PET-CT remain a major issue. The logistics
for transport of FDG is another bottleneck as it has a half-life of 110 minutes and
needs a cyclotron for its production. Within India most PET-CT scanners are clustered
in big cities with hardly any visible availability in tier-2 and tier-3 cities. While
an affording patient in a big city has easy and quick access to PET-CT, a needy patient
in a remote area may never get one. The referring physicians are over enthusiastic
and quick to order a PET-CT regardless of the evidence in a particular situation.
Since there are no strict guidelines in India, we often find indiscriminate use or
misuse of PET-CT. As most patients pay out of pocket, there is hardly any audit or
control by a regulatory body. It is estimated that 20% of PET-CT scans ordered in
India are not in line with evidence-based practice.
In the United States, insurance coverage for PET-CT was driven by evidence-based data.
The Center for Medicare and Medicaid Services authorized coverage for different cancers
over a period of time based on evidence.[3] Their strategy has been coverage with evidence development. As of now most cancers
are covered for reimbursement. However, it is not covered for screening. Initially
the terminology used for initial scan was for “diagnosis and staging.” For subsequent
scan, the terminology was for “restaging and monitoring response to treatment.” The
current terminology is PET-CT for initial treatment strategy and PET-CT for subsequent
treatment strategy. The cancers that are now covered are colorectal, esophagus, head
and neck (T3,T3 tumors or bulky nodes), lymphoma, non-small cell lung cancer (NSCLC),
ovary, brain, cervix (except for initial treatment strategy), small cell lung cancer
(SCLC), soft tissue sarcoma, pancreas, testes, prostate (not for initial treatment
strategy), thyroid, breast (for distant metastases), melanoma, myeloma, and other
solid tumors in a specific situation. However, there is a limit on the number of PET-CT
scans that can be covered for subsequent management after completion of initial anticancer
therapy. The total number of PET-CT scans to guide subsequent treatment strategy cannot
exceed three.
Preparation before PET-CT Scan
Preparation before PET-CT Scan
Adequate hydration is recommended as it would ensure reduced FDG concentration in
the urine.[4] This will minimize artifacts. Consumption of 1 L of water prior to FDG injection
is helpful. Oral contrast agent is usually not given even for a diagnostic CT scan.
Glucose containing parenteral nutrition and intravenous fluids should be stopped 4 hours
before the FDG injection. After the injection of FDG, the patient should remain seated
or recumbent and silent. Remaining silent will minimize FDG uptake in laryngeal muscles.
The patient should be kept warm to minimize FDG agglomeration in brown fat. Patients
must avoid any exercise or physical activity for minimum 24 hours prior to the PET-CT
examination. Patients should empty the bladder immediately before the study to minimize
urinary bladder activity. The patient should not move during the examination which
will take approximately 20 to 40 minutes.
Serum glucose level prior to FDG administration should be checked. For FDG-PET-CT
study, plasma glucose level has to be below 11 mmol/L (∼200 mg/dL). Levels equal to
or higher than 11 mmol/L (∼200 mg/dL) requires rescheduling of PET-CT.
Breast Cancer
PET-CT is not recommended for routine staging of early-stage breast cancer. National
Comprehensive Cancer Network (NCCN), European Society for Medical Oncology, Spanish
Society of Medical Oncology, and the National Institute for Care Excellence, UK, do
not recommend PET-CT in females having early-stage (I or II) breast cancer or even
in those with operable stage III breast cancer.[5] However, there are situations where a PET- CT can pick up distant metastases in
the bone, soft tissues, or elsewhere thereby changing the initial management strategy,
which can happen in locally advanced breast cancer, breast cancer with extensive axillary
lymphadenopathy, and triple negative breast cancers. Therefore, it appears reasonable
to evaluate such cases with PET-CT which is superior to CT or magnetic resonance imaging
(MRI) for detecting distant metastases.
Head and Neck Cancers
The prevalence of head and neck cancers is high in India.
The usual malignancies in the head and neck region are as follows:
-
Head and neck squamous cell carcinoma (HNSCC).
-
Thyroid cancer, mainly papillary cancer.
-
Nasopharyngeal cancer (NPC)
-
Lymphoma (systemic or confined to the neck glands)
-
Minor salivary gland cancers
-
Rhabdomyosarcoma
-
Retinoblastoma
Unless otherwise stated, this part of the article mainly deals with HNSCC.
Imaging for the malignancies in the head and neck is required for:
CECT or CEMRI is usually performed for follow-up after local and or systemic therapy.
In case of locoregionally advanced disease, PET-CT may be performed for follow-up.
PET-CT should be done minimum 3 to 6 months after radiation therapy as there may be
high false-positives if done within 3 months.
PET-CT is the initial imaging modality of choice if residual disease is suspected
after definitive radiotherapy and where surgery is contemplated.
For lymphoma, as discussed, PET-CT is the best choice in primary staging, interim,
follow-up as well as post-therapy imaging.
Pitfalls
Tuberculous nodes are FDG avid and may cause confusion in a patient with known malignancy
undergoing a staging scan. Many patients develop infection after chemotherapy and
again false-positive findings on PET-CT cause confusions. PET-CTs performed within
3 to 6 months of surgery or radiotherapy are prone to false-positive findings due
to post treatment inflammation.
Recommendation for India
In India, the constraints of widespread use of PET-CT are expense and availability
of scanners and cyclotrons for generation of the isotope. The scan being an outpatient
procedure is not covered by insurance and is, hence, an out-of-pocket expense. Almost
all tier-2 cities are devoid of scanner and it is only of late that all aircrafts
are being allowed to carry isotopes. One must also consider the guidelines that clearly
have no significant role of use of this scan in first-line staging of all patients
as well as for follow-up.
In HNSCC, PET-CT for routine evaluation is justified only if residual/recurrent disease
post-radiotherapy is suspected and surgery is being contemplated. Assessment of response
at least 12 weeks after chemoradiation may be helpful in avoiding unnecessary neck
dissection. Cervical lymph node metastases with unknown primary are another reasonable
indication for doing a PET-CT.[7] It provides value in initial staging of stage III and IV HNSCC. It is not recommended
for routine surveillance after 6 months of completion of therapy.
Colorectal Cancer
Colorectal cancer (CRC) ranks third in males and second in females among most common
cancers and is responsible for 10% of all tumor types globally. In India, colon and
rectal cancers are 9th and 10th most common cancers in males respectively. As far
as females in India are concerned, colon cancer ranks 9th, while rectal cancer does
not figure in the list of top 10 cancers.[8] In the last decade, mortality rate of CRC has significantly reduced due to advancement
in imaging technology and optimization of surgical, neoadjuvant and palliative therapies.
Adenocarcinoma is most common cancer affecting colon or rectum, while other less common
cancers of colon include gastrointestinal stromal tumors lymphoma, carcinoid, neuroendocrine,
and squamous cell carcinoma.[9] Certain hereditary syndromes like familial adenomatosis polyposis, lynch syndrome,
and Peutz-Jeghers syndrome are associated with colonic polyp or cancers and genetic
testing has significant role in such patients.
Coloscopy remains the gold standard for primary evaluation of CRCs. It gives a benefit
to simultaneous biopsy from the lesion and in same sitting also gives an opportunity
for therapeutic polypectomy for small size polyps. Alternative method includes virtual
CT colonoscopy and it is recommended as screening tool in an asymptomatic patient
by American Cancer Society. Imaging in CRCs has significantly evolved over the time
and it has established central role in screening to surveillance of CRC. Various modalities
range from barium enema, multi-detector computed tomography (MDCT), MRI to the development
of novel tracers, and fusion technologies (PET-CT). PET-CT has evolving role in CRC.
Role of PET-CT in Screening
Role of PET-CT in Screening
Many colon cancers develop from preexisting colonic polyps or adenoma and also associated
with many hereditary polyposis syndromes. Screening tool should be safe, accurate,
easily available, and cost-effective. Normal lymphoid tissue in colon may cause focal
or diffuse physiological uptake, and in the same way, inflammatory conditions like
ulcerative colitis and diverticulitis can cause focal uptake on FDG-PET-CT; thus,
PET becomes least suitable modality for screening of colon cancer or premalignant
conditions like polyposis. FDG-PET should not be used as a routine screening or initial
staging of CRC patients.
PET-CT in Diagnosis and Primary Staging
Entire tumor removal and regional lymphadenectomy carry the best prognosis for CRC.
PET-CT is suboptimal for T-staging of the primary tumor due to limited spatial resolution
and failure to differentiate layers of colon and rectum.
Due to better visualization of anatomic details, transrectal ultrasound and MRI are
excellent for T-staging of rectal cancers. MRI is the most reproducible method for
T staging of rectal cancers and for tumors of the anal canal. Post-contrast MDCT is
standard of imaging investigations for cancers of colon cranial to the peritoneal
reflection.
Accurate staging also requires nodal staging and evaluation of distant metastasis
accurately.
PET-CT is invaluable for differentiating benign from malignant nodes at a distant
location from the primary tumor owing to the metabolic activity. However, small nodes
in the proximity to the primary tumor can evade detection owing to FDG uptake of the
primary tumor. PET-CT also has limitations in detection of nodal metastasis from mucinous
CRC as it does not show significant uptake, small size nodes appear false-negative;
while associated inflammatory conditions give false-positive in normal size or in
enlarged nodes.[10]
FDG-PET has increased sensitivity than CT for identifying liver metastasis and mild
peritoneal and omental disease. FDG-PET shows highest accuracy of up to 98% in identification
of hepatic metastases. Early detection of hepatic metastasis in colorectal carcinoma
provides opportunity of neoadjuvant chemotherapy followed by liver resection. FDG-PET,
due to its superiority in identifying extrahepatic metastatic sites, also helps in
management decision making as the treatment plan then changes from localized treatment
to systemic chemotherapy.
PET-CT in Restaging, Recurrence, and Surveillance in CRC
Colon cancer recurs in a different pattern as compared with the rectal cancer. Rectal
cancers recur more locally than colon cancers. For suspected recurrence due to clinical
symptoms or rising tumor marker levels, PET has an established role for recurrence
detection. FDG-PET is also superior in response evaluation post-radiotherapy, chemoradiation,
or local ablative treatment.
On post-treatment scan for response assessment, PET-CT provides useful information
on presence of viable tumor, distinguishes disease from fibrosis/scar, and also helps
in prognostication. PET-CT also add benefits in rectal cancer patients who develop
local recurrence following chemoradiations. PET-CT plays an important role in surgical
planning of patients who develop recurrence in the form of operable hepatic or pulmonary
metastasis. Although PET-CT is an optimal method for restaging and monitoring treatment
response following chemoradiation, many issues like lack of standardization for optimal
timing of imaging, universal criteria for response evaluation, and cost-effectiveness
offer challenges. In India, MDCT is still most commonly used modality for surveillance
and therapeutic monitoring.
PET-CT in Radiation Therapy Planning for CRC
PET-CT guided planning for radiotherapy has been used for CRC patients. Radiation
portal field size can be reduced without omitting macroscopic disease in the vicinity
of primary tumor by using PET-CT for radiotherapy planning. PET-defined gross tumor
volume (GTV) is invaluable for planning the boost volume for adjuvant radiation therapy
post-rectal tumor resection.
The development of PET-CT has a considerable impact in decision making and intention
to treat from curative to palliative in locally advanced CRCs. However, major limitations
of PET-CT include technical, economical, and logistic challenges, as well as lack
of robust evidence for standardization and formal guidance for PET-CT protocols in
staging, restaging, and surveillance at present. Future implications of development
of PET-CT as standard imaging tool for evaluation of CRC will depend upon newer PET-CT
machines with radiation dose reduction, better spatial resolution, latest cost-effective
isotopes having increased specificity, and more importantly oncologist and cancer
imaging specialist jointly working on patient management.
Current Recommendations
-
PET-CT scan is not recommended as a standard screening tool for CRCs or for the evaluation
of premalignant conditions.[10]
-
For staging, PET-CT is not routinely used, unless initial CT study suggestive of hepatic
metastasis or when there is diagnostic dilemma for hepatic or extrahepatic metastases
on CT scan or on MRI. MRI is standard imaging tool for staging of rectal cancers and
MDCT for colon cancer.
-
PET-CT scan is not routinely indicated for restaging after nonsurgical treatment of
metastatic CRC, unless curative resection is considered.
-
PET-CT scans are recommended for staging/restaging in surgical resection of hepatic
or pulmonary metastasis.
Pitfalls and Challenges of PET-CT Scanning
Pitfalls and Challenges of PET-CT Scanning
PET-CT in Lung Cancer
Role of PET-CT in the management of lung cancer has immensely increased in recent
times.[11]
[12]
[13]
[14] Amalgamation of functional and anatomic information has allowed PET-CT to look into
various aspects of lung cancer, allowing more precise disease staging and providing
helpful data during the characterization of indeterminate pulmonary nodules. Moreover,
increased accuracy of PET-CT over conventional modalities in certain situations has
made PET-CT an invaluable noninvasive modality for the investigation of lung cancer.
Common indications for PET-CT with regard to pulmonary nodules or masses are as follows;
-
For TNM staging of the mediastinum and screening for metastases that might not be
detected by CT alone;
-
For radiotherapy planning; and
-
For restaging lung cancer patients following treatment.
In addition, PET-CT can provide some information on the histopathological type of
lung mass. PET-CT is useful for staging and restaging of disease, detecting recurrent
or residual disease, assessing response to therapy, and for prognostication. Prior
studies evaluating preoperative maximum standardized uptake value have shown that
lepidic predominant adenocarcinoma and other well-differentiated tumors have less
FDG-avidity than squamous cell carcinomas.[15] Ninety percent of all lung cancer cases are NSCLC on histological analysis.
As per the NCCN imaging appropriateness criteria, FDG-PET-CT covering skull base to
knees or whole-body FDG-PET-CT is recommended for stage I to stage IV NSCLC.[13]
[16] As per the NCCN guidelines, distant disease detected on PET-CT requires histopathologic
or other imaging confirmation, and FDG uptake detected in mediastinal nodes requires
histopathologic confirmation. Incidental lung nodule more than 8 mm requires FDG-PET-CT
for evaluation as per the NCCN guidelines.
Standardized uptake value more than that of the baseline mediastinal blood pool is
considered as a positive PET result. False-negative results of PET can be seen in
small nodules, generally less than 8 to 10 mm in diameter (T1a), mucinous adenocarcinomas
with a relatively small number of cells, and low-grade malignancies such as carcinoma
in situ (Tis) and minimally invasive adenocarcinoma [T1a(mi)]. Occult metastases detected
on FDG-PET-CT in locally advanced NSCLC can help to reduce the frequency of futile
thoracotomies.
The rates of progression-free survival and overall survival are dismal (p < 0.001) in upstaged disease with PET-CT. There is no recommendation to use bone
scintigraphy for staging NSCLC. FDG-PET-CT can better differentiate tumor from postobstructive
atelectasis than CT, the distinction essential for local tumor staging, deciding biopsy
site, planning radiation therapy, and evaluation of treatment response. Studies have
shown increased FDG uptake in areas of atelectasis as compared with normal lung, and
reduced FDG uptake as compared with tumor tissue. Gross tumor volume assessed using
PET tends to be smaller than CT-measured tumor volume in 13 to 17% of patients. Disadvantage
of FDG-PET-CT lies in the evaluation of chest wall invasion owing to blooming artifact.
Conclusion
PET has high accuracy in detecting lymph nodal as well as extrathoracic metastases.[15] As per the NCCN guidelines, FDG-PET-CT covering skull base to knees or whole-body
FDG-PET-CT is recommended for stage I to stage IV NSCLC.[14] Imaging specialists should be aware of the advantages and disadvantages of FDG-PET-CT
in staging.
Summary and Conclusions
Emergence and availability of PET-CT have transformed the way we stage and manage
cancers. It has a proven role for staging of most cancers, assessing response to therapy,
and in follow-up. Guidelines for the use of PET-CT in oncology vary across countries
and across institutions. In the light of clinical judgement if the possibility of
metastatic disease is high and it will entail a change in management, then advising
a PET-CT appears reasonable regardless of the guidelines. If use of PET-CT for detection
results in change of management, then it is justified. More often the change in management
is from a more aggressive treatment strategy to a less aggressive one, thereby saving
costs and unnecessary intervention.
