در مرکز پزشکی هسته ای دکتر دباغ – دکتر صادقی در خدمت شما هستیم مشهد، ملاصدرا 11 ، پلاک 1/4 Tel:+98(51) ; +98(51)

Molecular Imaging with PET: A Revolution in Medicine 18 FDG-PET and PET/CT in Lung Cancer V. R. Dabbagh Kakhki, M.D. Nuclear Medicine Specialist Associate Professor DSNMC Nuclear Medicine Research Center (NMRC; MUMS)

18 FDG-PET and PET/CT Whole-body PET: –Quantities metabolic processes in vivo. PET images show functional information, however they provide limited anatomical data PET imaging in oncology-----> PET/CT

Lung cancer

18 FDG-PET: Analysis Qualitative (visual) Quantitative Semi-quantitative: –Standardized uptake value (SUV) is a semi- quantitative index of glucose utilization Obtained by normalizing the accumulation in the abnormal lesion to the injected dose and patient body weight.

Talk Overview Background Statistics Staging Overview Traditional Staging methods –Clinical Exam and history –CXR –CT Chest –Surgical Staging

Background Lung cancer (of all types) is the second most common malignancy and the leading cause of cancer death Survival (and management) are closely correlated to stage

Background Lung cancer Four main histologic types; SCC Adenocarcinoma (BAC) Large Cell Carcinoma Small Cell Carcinoma »Small Cell Carcinoma »NSLC

Stages IT1-2, N0,M0 IIT1-2, N1,M0 T3, N0, M0 IIIAT3, N1,M0 T1-3,N2,M0 IIIBAny T4, Any N3, M0 IVAny M1

AJCC-6 Staging T0No tumor TxTumor by cytology but no lesion found TisCarcinoma in situ T1Smaller than 3cm T2>3cm or Involves the main bronchus, 2 cm or more distal to the carina or invades the visceral pleura, or with atelectasis extending to the hilum T3Extends to chest wall, diaphragm, pericardium, or mediatinal pleura or is a main bronchus tumor <2cm from carina, or causes total atelectasis of the lung T4Invades mediastinal structures, trachea, vertebra, or carina or malignant effusion present Size, Involving main bronchus, pleura, chest wall, diaphragm, pericardium, mediastinal structures, trachea, vertebra, carina or malignant effusion, atelectasis

Nodes NXCannot assess regional nodes N0No regional lymph nodes N1Metastasis to ipsilateral peribronchial and/or ipsilateral hilar lymph nodes, and intrapulmonary nodes (even if directly invaded by primary tumor) N2Metastasis to ipsilateral mediastinal and/or subcarinal lymph nodes N3Metastasis to contralateral mediastinal or hilar nodes, ipsilateral or contralateral scalene, or supraclavicular lymph nodes Ipsilateral or contralateral peribronchial, hilar, intrapulmonary, mediastinal, subcarinal, scalene, or supraclavicular lymph nodes

Management by Stage Stage I & II: Surgical (or definitive XRT) Stage IIIA: being elucidated; –neoadjuvant chemoradiotherapy –Radiotherapy alone –Chemoradiotherapy Stage IIIB –Chemotherapy or chemoradiation Stage IV –Chemotherapy

Traditional Staging PE/ clinical exam/ history CXR CT scan Surgical Methods

CT Scanning Criteria for positivity rely on size (short axis greater than 1 cm) series (by Pieterman, et al) suggest that sensitivity and specificity for detecting lymph node metastases are approximately 75% and 66%; metanalysis by Dwamena is similar

CT scanning All patients should undergo CT scan as an initial staging evaluation Images taken from:

Surgical Staging Possibilities include –Mediastinoscopy –Thoracoscopy –Transbronchial needle aspiration –and endoscopic ultrasound with fine needle aspiration Final surgical stage often differs from initial clinical stage

18 FDG-PET and PET/CT Lung Cancer Solitary pulmonary nodule Diagnosis of primary lung cancer Staging Radiotherapy planning Therapy Planning Monitoring of therapy Detection of recurrence Ideal site for possible tissue diagnosis Prediction of prognosis. PET/CT has the best of both worlds of metabolic and anatomic imaging and may provide optimal disease assessment.

Imaging of Non-small Cell Lung Cancer FDG CT

Lung cancer

18 FDG-PET and PET/CT Solitary Pulmonary Nodule The crucial objective in the evaluation of the SPN is: – The ability to noninvasively differentiate benign from malignant lesions –In cost-effective manner –Minimizing morbidity and mortality FDG-PET has proven an accurate, noninvasive method for the work up patients with SPN Sensitivity; % Specificity: 77%-100%

18 FDG-PET and PET/CT Solitary Pulmonary Nodule Visual analysis of the PET images Semi-quantitative analysis: SUV>2.5 A few lesions of less than 2.5 are malignant

PET in oncology: Solitary pulmonary nodule evaluation A patient with a 1.5 cm left upper lobe nodule. A PET scan was performed but demonstrated no uptake in the lesion (some cardiac activity can be seen more anteriorly). The nodule was resected and found to be a granuloma.

18 FDG-PET and PET/CT Solitary Pulmonary Nodule False-positive results: –Active granulomatous disease (tuberculoma and histoplasmosis) –Certain other inflammatory processes due to increased glycolytic activity within the active macrophages. False-negative results: –Low metabolic activity: Bronchoalveolar carcinoma(BAC), Pulmonary carcinoids –Lesion is less than 5-7 mm in diameter

PET in oncology: Solitary pulmonary nodule evaluation A patient presented for evaluation of an 7 mm right lower lobe pulmonary nodule (white arrow). The PET scan was negative, but because of the lesions small size, the lack of uptake is not definitive for a benign lesion.

18 FDG-PET and PET/CT Solitary Pulmonary Nodule –The negative predictive power of PET is sufficiently high to avoid biopsy. –If FDG-PET is negative for lesions > 7 mm diameter, then the process is most likely benign, and may be followed with serial surveillance. –If the lesion is <7 mm diameter then malignancy cannot be excluded with a negative PET –When FDG-PET is positive then diagnostic and definitive treatment may be instituted

18 FDG-PET and PET/CT Lung Cancer Staging –Survival stage –Stage treatment and prognosis –CT is frequently unable to discriminate between malignant enlarged mediastinal lymph nodes and benign reactive hyperplasia –Conventional imaging limited to the thorax and upper abdomen is unable to detect more distant metastatic disease which can occur in 9% to 11% of all patients with non-small cell lung cancer (NSCLC)

18 FDG-PET and PET/CT Lung Cancer Staging –FDG-PET: Can lead to changes in initial staging and treatment plans for lung cancer when used in combination with conventional work-up –One retrospective study; use of PET has an important impact on stage designation and clinical decision making. PET upstaged 16.2% and downstaged 6.1% of the patients.

18 FDG-PET and PET/CT LC Staging: Primary Tumor (T) –CT: excellent in primary tumor for determining the location anatomic size its relationship to surrounding structures –Compared to CT, ‘‘isolated’’ PET offers little additional information in the T characterization of lung cancer lack of spatial resolution invisibility of all but the grossest anatomical landmarks One exception is its usefulness in distinguishing between tumor and post- obstructive atelectasis In addition, PET can be beneficial in evaluating the cause of pleural effusions. –Accuracy rate of 91% for PET in a study of 35 patients with lung cancer and suspected malignant pleural effusion.

18 FDG-PET and PET/CT LC Staging: Primary Tumor (T) –FDG-PET: metabolic activity of the primary lung cancer (cell turnover rate) – May indicate the biologic aggressiveness of the cancer –SUV has prognostic value independent of conventional clinical TNM staging For example, Higashi et al. demonstrated –A primary tumor SUV greater than 5 was associated with a significant increase in postoperative relapse in early stage lung cancer. –Thereby PET in initial T staging by predicting the likelihood of tumor recurrence after treatment, may help in selecting which patients are likely to respond to induction therapy before surgery and which patients should receive adjuvant chemotherapy/radiotherapy.

18 FDG-PET and PET/CT LC Staging: Primary Tumor (T) –PET/CT :more useful than PET in determining the T stage and in assessing the presence of mediastinal or chest wall invasion Accuracy: PET/CT: 97%, PET only: 67%. Accuracy for T staging with PET/CT: 88% and CT:58% The reasons for this surprising finding were not fully explored, but it is worth reiterating that PET can have a role in T staging by distinguishing between tumor and distal atelectasis. –Remember: CT component of PET/CT is acquired without IV contrast. – Therefore, a diagnostic contrast-enhanced CT scan of the chest, performed as part of the PET/CT study or independently as a separate scan, is still recommended.

Non-small cell lung cancer. PET/CT images show invading the visceral pleura without chest wall invasion while on the CT alone it would be more difficult to determine the chest wall invasion (T2 N0 M0)

18 FDG-PET & PET/CT LC Staging: Nodal Involvement (N) –Mediastinal lymph node staging: Imaging Sampling –Pooled ROC curves analysis: PET was significantly more accurate than CT or MRI in identifying nodal metastasis with –An accuracy of 81% to 96% – A meta-analysis: nodal stage: –PET: Sensitivity of 79% and a specificity of 91% –CT: 60% and 77%, respectively, – Overall, 20% improvement in accuracy of PET over CT imaging for mediastinal staging of NSCLC. –PET/CT : even higher diagnostic accuracy than either CT or PET alone with a sensitivity of 89% and specificity of 94% and an overall diagnostic accuracy of 93%.

PET in oncology: Bronchogenic carcinoma (Staging) A patient with a left lung NSCLC showed a pathologic aorto- pulmonary window node (N2) by CT size criteria (white arrow), and a non-pathologic retrocaval-pretracheal contralateral mediastinal node (N3) (yellow arrow). PET-FDG images revealed increased tracer accumulation within both nodes, consistent with metastases

18 FDG-PET & PET/CT LC Staging: Nodal Involvement (N) –A very well designed prospective study compared CT and PET in the diagnosis of mediastinal lymph node metastases in patients with potentially resectable NSCLC. NPV was very high, at 98%. Conclusion: Both imaging methods are complementary Their strength is powerful NPV. Thus PET/CT may be more helpful from one of these alone.

18 FDG-PET & PET/CT LC Staging: Nodal Involvement (N) False-positive PET results in the mediastinum: –13% to 17% –Mainly due to inflammatory lymph nodes (secondary to pneumonia, postobstructive pneumonitis, or chronic granulomatous infection) –May lead to mistaken up-staging of the primary tumor False-negative rate as high as 8% for the detection of mediastinal metastases by PET imaging.

18 FDG-PET & PET/CT LC Staging: Nodal Involvement (N) It is suggested by some authors that one of the main values of PET is based on its high negative predictive value for nodal disease, (estimated at greater than 90% in several studies)

18 FDG-PET & PET/CT Lung Cancer Staging: Nodal Involvement The implication of this is that eligible patients with negative mediastinal nodes on PET examinations may proceed directly to thoracotomy without the need for mediastinoscopy. False-negatives can occur in this group of patients, with tumour subsequently identified at thoracotomy. These patients are, however, referred to by some as having ‘‘minimal N2 disease’’, which confers a better prognosis.

18 FDG-PET & PET/CT LC Staging: Nodal Involvement (N) De Langen and co-workers have made recommendations based on the fact that the prevalence of nodal disease increases with size on CT. –They concluded that patients with nodes< less than 15 mm on CT and a negative PET examination do not require mediastinoscopy, –whereas those patients with negative PET but large lymph nodes on CT should nevertheless undergo invasive staging. –It is suggested to avoid mediastinoscopy in patients with T1 tumors and negative PET scans.

18 FDG-PET & PET/CT LC Staging: Nodal Involvement (N) –The lower PPV makes cytologic or histologic confirmation necessary in case of a positive mediastinum on PET. –In patients with locally advanced but potentially operable tumors based on conventional clinical staging (stages II– IIIA), PET can detect nodal metastases that are inaccessible by cervical mediastinoscopy and that may be missed by conventional staging methods. It can change the work-up of the patient by indicating the need for a different approach to invasive lymph node sampling.

Non-small cell lung cancer. PET/CT images show a mass involving the right hilum with extension into mediastinum without extension to the contralateral mediastinum but a separable focus in the right superior mediastinum (stage IIIA)

Lung Cancer w/metastasis

18 FDG-PET & PET/CT LC Staging: Distant Metastasis (M) –Advantage: FDG-PET versus CT: whole body can be imaged. –In addition to staging the mediastinum, PET has shown promise for identifying distant metastases. –Ability of PET to detect clinically unsuspected distant metastases in 10% to 29% of patients

18 FDG-PET & PET/CT LC Staging: Distant Metastasis (M) –PET have an accuracy of 96% and bone scanning, 66%, in the evaluation of osseous involvement in patients with NSCLC. –Although these tests were very similar in high sensitivity for bone metastasis, PET had a much higher specificity for disease than bone scan.

18 FDG-PET & PET/CT LC Staging: Distant Metastasis (M) – On PET or PET/CT imaging, the finding of FDG uptake within the adrenal gland greater than that of the liver is a highly sensitive and specific sign of adrenal metastatic disease, with an overall diagnostic accuracy of greater than 92%.

18 FDG-PET & PET/CT LC Staging: Distant Metastasis (M) –In brain and genitourinary system, PET is less accurate in identifying malignancy. –The high metabolic activity the brain and concentration and excretion in the genitourinary system, make it difficult to differentiate metastatic disease from normal activity. –As the brain is common site for metastatic lung cancer, CT or MRI recommended.

PET in oncology: Bronchogenic carcinoma (Staging) A patient had a left lung NSCLC. There was no uptake of tracer within the hila or mediastinum to suggest nodal metastases, however, unsuspected bone metastases were found in the right humerus and right hip (black arrows).

PET in oncology: Bronchogenic carcinoma (Staging) Uptake within the patients primary lung cancer can be seen within the right chest. Uptake within the bilateral adrenal glands (black arrows) confirmed the presence of adrenal metastases.

PET in oncology: Bronchogenic carcinoma (Staging) The bone scan (left) significantly underestimated the extent of skeletal metastases as demonstrated on FDG PET imaging (right) which revealed multiple vertebral body metastases.

PET in oncology: Bronchogenic carcinoma (Staging) A patient felt to have Stage IIIB disease based upon the chest CT findings. FDG PET imaging confirmed ipsi- and contralateral mediastinal adenopathy, but also reveal a left scapular metastasis This resulted in a change in patient stage as the patient was now has Stage IV disease.

18 FDG-PET & PET/CT LC Staging: Distant Metastasis (M) –It is frequently difficult to establish the diagnosis of a malignant pleural effusion, –Because cytology of fluid obtained at thoracentesis is only positive for malignancy in 66% of patients, and more invasive tests such as pleural biopsy or thoracoscopy may be required for confirmation.

18 FDG-PET & PET/CT LC Staging: Distant Metastasis (M) –PET has promising diagnostic accuracy for the diagnosis of pleural metastases, with reported sensitivities of 92% - 100%, specificities of 67% - 71%, NPV of 100%, and PPV 63% - 79% –Interpretation of the PET findings should take into account the results of pleural fluid analysis and the patient’s recent medical history because of false positive uptake of FDG by the pleura secondary to pleural infection or inflammation after talc pleurodesis.

18 FDG-PET & PET/CT LC Staging: Distant Metastasis (M) –Although PET imaging has a higher overall detection rate for metastatic disease than conventional workup, this is not to say that PET can replace conventional imaging modalities, but rather should complement them.

63-year-old male with newly diagnosed lung ca Diagnosis: Lung primary Mediastinal LN Left adrenal metastasis Ileal loop Left vocal cord paralysis From Delbeke D. Diagnostic Imaging 2003

18 FDG-PET & PET/CT Treatment, prognosis and follow-up –Whole-body PET has potential value in treatment planning simultaneously assess for regional and metastatic disease alteration of clinical staging and significantly alter management. –The use of PET: different stage: 60% patient management changes in 41% of the cases –A multivariate analysis; Cut off 5 for SUV in the primary tumor was the strongest prognostic factor for overall survival.

18 FDG-PET & PET/CT Treatment, prognosis and follow-up –Wolfgang et al in a prospective study demonstrate that in patients with advanced NSCLC, effective chemotherapy causes a rapid reduction of tumor glucose use. After one cycle of platinum-based chemotherapy (21 days), a metabolic response in PET imaging was significantly correlated with best response to this chemotherapy regimen. In patients without a metabolic response, the response rate was only 4%, whereas it was 71% in patients with a metabolic response. For patients with a metabolic response, the 1-year survival rate was 44%, whereas it was only 10% in patients with no metabolic response.

18 FDG-PET & PET/CT Treatment, prognosis and follow-up –In another prospective study of 57 patients with locally advanced NSCLC who underwent restaging PET imaging after only 1 cycle of platinum-based chemotherapy, a fall in SUVmax of 20% or greater in the primary tumor was an independent predictor of long-term survival. –

18 FDG-PET & PET/CT Treatment, prognosis and follow-up –Normalization of FDG uptake after treatment appears to be a sensitive indicator of favorable response and good prognosis –Hebert et al. demonstrated that patients with negative PET scans were alive 2 years after treatment, and 50% of patients with residual hypermetabolism on PET had died. –Several studies reported that FDG-PET has sensitivities of 98% -100% and specificities of 62% -92% for the detection of recurrent malignancy after definitive treatment.

PET in oncology: Bronchogenic carcinoma (Response to treatment) 58 year old male with a left upper lobe NSCLC and contralateral right hilar lymphadenopathy (blue arrow). FDG imaging also identified uptake in the inferolateral aspect of the right hemithorax which most likely represented a pleural metastasis with probable chest wall/rib invasion (black arrow). Follow-up PET FDG imaging demonstrated decreased tracer uptake and decreased size of the primary lesion in the left upper lobe (red arrow).

18 FDG-PET & PET/CT Treatment, prognosis and follow-up –Sensitivity, specificity, and accuracy of PET are high in differentiating recurrent malignancy from benign post- treatment changes in patients studied after therapy. –Detection of recurrent disease using radiologic changes is made difficult by the often extensive anatomic abnormalities that exist after definitive treatment, such as parenchymal scarring, distortion of normal bronchovascular architecture, pleural thickening and effusions, and mediastinal fibrosis – A PET evaluation has been shown to be more useful than conventional imaging for diagnosing tumor recurrence

18 FDG-PET & PET/CT Treatment, prognosis and follow-up Specificity of PET for malignant disease is lower than at initial staging because of the often coexisting inflammation secondary to radiotherapy or chemotherapy, which can appear FDG-avid on PET scans.

18 FDG-PET & PET/CT Treatment, prognosis and follow-up –Diagnostic difficulties :recurrent cancer most frequently arise after radiotherapy, which causes low-grade inflammation in the treated lung. –On PET scans, areas of radiation pneumonitis characteristically appear as diffuse areas of mild to moderate FDG uptake that conform to the region of irradiated lung, –whereas tumor recurrence is suspected where a focal site of more intense metabolic activity is seen. –It is advisable to wait for a period of 3 to 6 months after the end of treatment before performing surveillance PET scans –Findings suspicious for tumor recurrence on a post- treatment PET scan should be confirmed by histologic or cytologic evidence to avoid diagnostic errors.

Top images: PET/CT abnormalities secondary to radiation pneumonitis. Bottom images: Resolving radiation changes 5 months later

18 FDG-PET & PET/CT Radiotherapy Planning –FDG-PET can also assist in radiation therapy planning by focusing radiation ports to precise areas of tumor activity, preventing irradiation of uninvolved areas and omission of regions of active tumor from radiation ports. –Different meta-analyses have shown FDG-PET to be superior to conventional mediastinal staging using CT scans and esophageal ultrasound.

18 FDG-PET & PET/CT Radiotherapy Planning –In several studies, incorporation of PET/CT imaging into treatment planning resulted in an alteration of the initial radiotherapy plan in over 50% of patients with NSCLC, compared with the use of CT alone, because of the better differentiation of metabolically active tumor from adjacent atelectasis and by increased sensitivity for nodal metastatic disease.

18 FDG-PET & PET/CT Cost-effectiveness –The general consensus is that PET can reduce needless thoracotomy rates. –Gambhir et al. used a decision analysis model to compare the cost-effectiveness of four strategies for the diagnosis and management of solitary pulmonary nodules. CT-plus- PET was the most cost-effective strategy when an intermediate pretest likelihood of 12% to 69% was present. In addition, CT-plus-PET strategy over CT alone yielded cost savings of $91 to $2200 per patient. –Scott et al. findings supported the use of thoracic PET as an adjunct to thoracic CT for preoperative staging. – Furthermore, several different CT-plus-PET strategies resulted in a greater life expectancy than the CT-only strategy.

18 FDG-PET & PET/CT Cost-effectiveness –A recent French study used a decision tree analysis model to compare various strategies including CT only, PET for patients with negative CT and PET plus CT. They concluded that employing a combination of both PET and CT was the most cost-effective. –

Conclusion –FDG-PET has been approved by the Health Care Finance Administration for Medicare reimbursement for diagnosing, staging, and restaging lung cancer. –FDG-PET and PET/CT provide a noninvasive and cost-effective strategic approach to patient selection for interventional and therapeutic procedures without contributing to increased morbidity. –FDG-PET is the recommended test for evaluation of the solitary pulmonary nodule to as small as 7 mm, mediastinal and extrathoracic staging excluding brain, evaluation of therapy response and restaging following treatment. –

Conclusion –PET/CT has the best of both worlds of metabolic and anatomic imaging and may likely be the first choice in lung cancer imaging of the future. – Currently available data on PET/CT suggests that its superiority to alone PET lies principally in better T staging, but it also provides tangible benefits for N and M staging. –Also PET/CT is useful in prediction of prognosis, follow-up of patients, radiotherapy planning, facilitating image-guided biopsy for definitive diagnosis, as well as differentiating viable tumor from adjacent or necrotic tissue and tumor recurrence from residual scar. –The clinical applications of PET/CT are still evolving, and future research will determine the precise role that metabolic imaging has to play in the management of patients with lung cancer.