Using PET in Breast Cancer Place your logo here

Oncology Imaging Computed Tomography (CT) Photon attenuation Anatomy Magnetic Resonance (MR) Spin flip time Anatomy (blood flow) Ultrasound (US) Sound attenuation Anatomy Conventional Nuclear Radioactive tracer Function Medicine (NM) uptake Positron Emission Radioactive tracer Function Tomography (PET) uptake Function

18F-FDG Pharmacokinetics Plasma Cell Glucose FDG Glucose-6-P FDG-6-P FDG participates in the first step of glucose metabolism, but cannot be further metabolized and is trapped inside the cell where it is retained in proportion to the rate of glycolosis.

Normal distribution pattern of 18F-FDG After IV injection, FDG is distributed to all organs of the body in proportion to cellular glucose metabolism. Normal biodistribution will demonstrate uptake in the brain, evidence of excretion via the urinary and GI systems, faint hepatic uptake, some bone & soft tissue uptake, and variable cardiac uptake Cancer cells are highly metabolic and utilize glucose at 3-5x the rate of normal cells.

Oncology Imaging Clinical Applications of PET Characterization of radiographic abnormalities Detection of radiographically occult lesions Staging – initial evaluation of the extent of disease Restaging - evaluation of the extent of recurrent disease (resectability) Evaluation of response to therapy 3

Characterization of Radiographic Abnormalities 66 yr old w/ ovarian cancer & brain mets treated w/stereotactic radiosurgery & chemotherapy; developed right hemiplegia 2 wks prior to PET. Treated w/steroids, symptoms resolved. A new mass or nodule is identified by conventional imaging (x-ray, CT, MRI, US) and the physician needs to determine what it is.

Characterization of Radiographic Abnormalities 61 year old woman with ovarian cancer and brain metastases treated with whole brain and stereotactic radiation

Characterization of Radiographic Abnormalities 66 year old man with pancoast tumor of the right lung – new adrenal mass. CT shows enlargement of the right adrenal gland, adenoma vs metastasis.

Accuracy of PET in characterizing adrenal masses Differentiation of Benign from Malignant Adrenal Masses Sensitivity Specificity Yun 2001 100% (18/18) 94% (30/32) J Nucl Med 2001;42:1795 Erasmus 1997 100% (23/23) 80% (8/10) Am J Roentgenol 1997;168:1361 Maurea 1996 100% (7/7) 100% (6/6) Radiol Med 1996;92:782 Boland 1995 100% (14/14) 100% (10/10) Radiology 1995;194:131 3

Detection of a radiographically occult lesion 61 yr old man s/p partial colectomy for sigmoid cancer, rising CEA level to 44.8. Negative CT, CEA scan, bone scan, colonoscopy. PET demonstrates FDG uptake; biopsy = adenocarcinoma. Abnormal lab values or physical symptoms indicate possible cancer or cancer spread, but conventional imaging is normal

Staging after initial diagnosis of cancer To determine extent of disease and select the most appropriate treatment course Surgery Induction chemo and/or radiation therapy prior to surgery Systemic therapy Palliative therapy Images courtesy of Macapinlac, UT MD Anderson Cancer Center

Restaging a known or suspected recurrence 76 yr old with locally recurrent cervical cancer, CT shows pelvic adenopathy, scheduled for pelvic exenteration. PET positive for disease beyond pelvis. To determine extent of disease, particularly if planned treatment is local/regional surgery or radiation therapy to confirm suspicion of recurrence

Restaging a known recurrence Repeat positive right breast excisional biopsy. Conventional imaging negative and pt scheduled for right mastectomy PET results: Widespread liver metastases 7 cm abdominal mass (!) Unsuspected left breast tumor Bone metastases, left acetabulum Impact: Mastectomy cancelled and chemotherapy initiated Restaging a Known Recurrence In this case, a patient with a history of Rt. Breast cancer, post wedge resection, chemo and radiation therapy, presented with elevated tumor markers and a new right breast mass. The excisional breast biopsy was positive for metastatic breast cancer. Restaging by conventional imaging was negative and she was scheduled for a mastectomy. Tumor markers remained elevated after the excisional biopsy (should have returned to zero if that were the sole metastatic lesion). PET was performed to confirm extent of disease prior to surgery. PET demonstrated widespread liver metastases, a 7 cm abdominal mass, unsuspected Lt breast tumor, and a bone lesion on the left acetabulum. Her mastectomy was cancelled and she received high dose chemotherapy. Images courtesy of Landis K. Griffeth, MD, PhD, North Texas Clinical PET Institute

Restaging a known recurrence Restaging at completion of therapy The post treatment scan demonstrated complete resolution of her metastatic disease and confirmed the effectiveness of the chemotherapy. Images courtesy of Landis K. Griffeth, MD, PhD, North Texas Clinical PET Institute

Evaluating response to therapy To determine effectiveness of treatment and whether additional treatment is necessary Testicular cancer patient with apparent complete response to chemotherapy Images: Northern California PET Imaging Center

Using PET in Breast Cancer

Breast Cancer Role for PET and PETCT Staging patients at initial diagnosis when distant metastases are suspected based on symptoms, labs or radiographic findings (staging a loco-regional advanced breast cancer) Determining extent of disease at time of local recurrence, if information would affect choice of therapy (restaging a known recurrence) Monitoring patients in chemotherapy or radiation therapy protocols (restaging at the completion of therapy, or response to therapy)

Breast Cancer Role for PET and PETCT Increased use of breast conserving surgery requires Close follow-up exams for early detection of recurrence: Mammography has difficulty w/ implants or surgical scarring And…only images breasts Case example – recurrent breast cancer in lumpectomy scar, axillary & mediastinal mets, lung mets Images courtesy of Macapinlac, UT MD Anderson Cancer Center

Breast Cancer Role for PET and PETCT Restaging, evaluating extent of recurrent disease 39 yr old woman with Rt breast cancer (stage 2B ductal CA) Treated w/ lumpectomy, chemo & XRT 10 months prior PET performed to evaluate new palpable abnormality in surgical scar discovered by patient

Breast Cancer Role for PET and PETCT Comparison of PET and conventional imaging in the evaluation of suspected recurrent breast cancer Conventional imaging (combination of radiography, nm bone scan, CT, MRI, mammography & US – selected for each patient based on routine clinical management parameters) PET sensitivity = 93% specificity = 84% CI sensitivity = 79% specificity = 68% PET NPV = 80% versus 59% for CI PET also was a better predictor of disease free survival Source: Vranjesevic, D. JNM 2002 43:325-329

Breast Cancer Restaging Suspected Recurrence Case Study: Clinical History 50 year old with a history of infiltrating duct carcinoma of the left breast diagnosed 2001 Lumpectomy and left axillary dissection --thirteen lymph nodes were sampled, and none of them were involved with metastatic disease Underwent adjuvant chemotherapy then adjuvant radiotherapy to the left breast. Recently diagnosed with recurrent disease by a biopsy of a left supraclavicular node. CT scan staging does not reveal any other areas of metastatic disease elsewhere. Recommended radiation therapy to the left supraclavicular area.

Images courtesy of Todd Blodgett, MD, UPMC Breast Cancer Restaging Suspected Recurrence PET/CT Findings: Focal lesion posterior to the brachiocephalic vein consistent with mets. Intense area of focal FDG uptake in the left illiac crest. CT negative in correlative area. Consistent with metastatic bone disease. Images courtesy of Todd Blodgett, MD, UPMC

Breast Cancer Restaging Suspected Recurrence Management Change: Her treatment was ultimately changed from local radiation to the supraclavicular area to systemic chemotherapy. Added benefits of PET/CT: Subtle abnormality detected posterior to the brachiocephalic vein that is barely visible on CT, but is certainly very compelling on the fused PET/CT image. Large lesion in the right iliac crest that is not visible on the CT portion of the exam. It is not uncommon to find a lesion on PET, localize it to bone using PET/CT, but realize there is no bony destruction yet.

Breast Cancer Restaging Suspected Recurrence Case Study: Clinical History B mastectomies for breast CA Treated with chemotherapy, tamoxifen, and radiation Some shoulder pain but the bone scan does not show any uptake Appears to be localized disease, parasternal nodal mass. Her oncologist has recommended local radiation, is not recommending any additional chemotherapy aside from the hormonal therapy that she is receiving. She is NOT a candidate for standard radiation due to prior radiation to this area. Plan: stereotactic radio-surgery Risk: damage to the aorta or the lung

Images courtesy of Todd Blodgett, MD, UPMC Breast Cancer Restaging Suspected Recurrence PET/CT identified a number of internal mammary lymph nodes that, although not enlarged, were involved with tumor. Images courtesy of Todd Blodgett, MD, UPMC

Breast Cancer Restaging Suspected Recurrence Management Change: Therapy plan changed from local stereotactic radiosurgery to systemic chemo therapy. Added benefits of PET/CT: One of the benefits of combined PET/CT is the accurate identification of normal sized malignant lymph nodes.

Breast Cancer Response to Therapy Neoadjuvant chemotherapy improves management of patients w/ locally advanced disease Studies have shown that metabolic changes in breast cancer can be detected with PET as early as after the first cycle of chemotherapy, prior to any noticeable change in anatomic tumor size Prediction of response supports the decision to continue dose-intensive preoperative or systemic therapies Early recognition of ineffective therapy allows A change to an alternative, more effective chemotherapy regime Prevents prolonged treatment with ineffective drugs that have potent side effects

Breast Cancer Response to Therapy 22 patients studied – PET exam after first and second course of chemotherapy FDG PET correctly identified all of the responders after the first course of chemotherapy. Response determined by 55% decrease in SUV (semi-quantified measure of uptake) Sensitivity = 100% Specificity = 85% PET findings predicted histopathologic response Accuracy of 88% s/p first course Accuracy of 91% s/p second course Source: Schelling M, el al, J Clin Oncology 2000; 18(8):1689-95

RTP and Breast Cancer

Why PET/CT in RTP? More precise anatomic localization PET benefits from the anatomic framework provided by CT Hypermetabolic lesions can be assigned to specific structures Facilitate biopsy guidelines Improves patient throughput – eliminates transmission scan for AC Improves PET specificity Improves interpretative confidence More accurate staging results in: More appropriate patient selection More appropriate treatment course Images courtesy of Todd Blodgett, UPMC

RTx Applications & Impact of PET Imaging Radiation therapy plays an essential role in the interdisciplinary management of patients with breast malignancies Accurate tumor staging is critical to determine appropriate treatment strategy (may not receive invasive surgical staging) Curative radiation therapy requires Absence of distant metastases Locoregional lymph node metastases must be included in the radiation field Optimized target volume & dose are critical when RT is main strategy for local or regional tumor control RT will be futile if all tumors are not included within high-dose volume

Conventional anatomic imaging and RTP Limitations of conventional imaging: Requires a structural or morphologic change Inability to identify disease in “normal” size lymph nodes Evaluates a limited field of view, not entire body

Role of PET▪CT in RTP Improves accuracy of oncology staging More appropriate patient selection for RTx Fusion of PET & CT provides superior definition of the primary GTV, of nodal involvement & of distant metastases Used to design more conformal radiation dose distributions based on functional tumor volumes Ensure better dose delivery to gross tumor volume while avoiding critical normal tissues

Why PET▪CT for RTP? Change in GTV (>25%) PET/CT vs. CT 56% of cases, GTV was changed significantly if information from PET▪CT was used in RTP (202 patients) Modification in GTV altered PTV (by > 20%) in 46% of cases PET▪CT revealed distant mets in 16% of cases changing treatment from curative to palliative Target volume PTV CTV GTV GTV: Gross tumor volume CTV: Clinical target volume is the GTV and margin to include local sub clinical tumor spread. PTV: planning target = CTV+ margin to ensure that CTV receives the prescribed dose. Source: Ciernik, Dizendorf, et al, RTP w/ Integrated PET/CT. Int J. Rad Onc Biol Phys 2003;57(1):853

Impact of Whole Body FDG PET on Staging & Managing Patients for RTx 202 consecutive patients intended for RRT Variety of malignant tumors Radiation oncologists determined clinical stage of each patient’s tumor, proposed & documented initial management plan based on CI, surgical staging, clinical findings Lymph nodes were considered positive if > 1cm FDG PET scans were performed in all patients All patients were assigned a post-PET tumor stage, discrepancies were biopsied or confirmed by additional imaging modalities Radiation oncologists compared pre-PET and post PET tumor stages & determined changes in patient management Source: Dizendorf et al, JNM 2003; 44(1):24-28

Impact of Whole Body FDG PET on Staging & Managing Patients for RTx Diagnosis Patients (N) Patients with N RX changes % Head & Neck 55 18 33 GYN tumors 28 9 32 Breast CA 7 25 Lung CA 26 8 31 Lymphoma 24 5 21 GI tumors 4 22 Unknown 10 3 75 Melanoma 2 1 50 TOTAL 202 27 Source: Dizendorf et al, JNM 2003; 44(1):24-28

Impact of Whole Body FDG PET on Staging & Managing Patients for RTx Pathologic Findings by PET in 202 patients Over a broad range of clinical indications PET altered therapy planning in 55/202 patients (27%) PET detected unknown nodal metastases in 25% of patients PET detected unsuspected distant metastases in 12% of patients Pathologic findings by PET Newly detected disease by PET Tumor N = 120 25 12% Lymph node metastases 50 Distant metastases 24 Source: Dizendorf et al, JNM 2003; 44(1):24-28

Proof Statements Source: Ciernik, Dizendorf, et al, RTP with Integrated PET/CT. Int J. Rad Onc Biol Phys 2003;57(1):853

Breast Cancer PET/CT for RTP Case Study: Clinical History 75 year old woman with a history of breast cancer 11 years ago and partial R mastectomy and ALND Txd with initial XRT, Tamoxifen times five years 2002, she noticed what she describes as a parasternal lump CT scan was done by her primary physician, that noted a nodular distention surrounding the sternun with soft tissue infiltrate Patient underwent a needle biopsy which verified recurrence of breast cancer. PET/CT done for RTP

Breast Cancer PET/CT for RTP PET/CT Findings: Intense uptake within the R supraclavicular node, parasternal masses, R adrenal, posterior L thoracic rib, consistent with metastatic disease. Images courtesy of Todd Blodgett, MD, UPMC

Breast Cancer PET/CT for RTP Management Change: Her treatment was ultimately changed from local radiation to the supraclavicular area to systemic chemotherapy. Added benefits of PET/CT: Identified several additional areas in the region not identified on CT. Alters target volume for RT Many radiation oncologists have been incorporating both the PET and CT data into their planning software to use both the metabolic and anatomic data to do their contouring.

Breast Cancer Conclusion: PET/CT for RTP Metabolic imaging with FDG PET/CT improves accuracy of oncology staging/restaging over conventional imaging FDG PET can be used to improve GTV calculations for radiation treatment planning PET/CT can demonstrate changes to conventional treatment strategy resulting in improved cancer outcomes with pre- and post-RTx utilization

Breast Cancer Summary: Role of PET/CT At initial staging when there is a high suspicion of advanced locoregional disease At initial staging to clarify inconclusive findings on conventional imaging Restaging – evaluation of suspicious or known recurrence (40% change in patient management) Restaging – completion of therapy Evaluation of treatment response

Problems and Pitfalls False negative: Size less than 10 mm Diabetes fasting blood glucose level >150 mg/dl Histology low grade glioma low grade lymphoma bronchoalveolar carcinoma mucinous adenocarcinoma thyroid, liver, kidney, prostate CA

Problems and Pitfalls Non-Malignant (false) positives: Infection granuloma, abscess, pneumonia Inflammation pneumonitis, wounds, arthritis, reactive nodes Uncertain sarcoid Benign tumors thyroid, parathyroid, carcinoid, colon Autoimmune rheumatoid nodules, thyroiditis Miscellaneous fractures, Paget’s disease

PET in Oncology - Summary Clinical Applications of PET Characterization of radiographic abnormalities Detection of radiographically occult lesions Staging – initial evaluation of the extent of disease Restaging - evaluation of the extent of recurrent disease (resectability) Evaluation of response to therapy Benefits of PET Imaging Impact on patient mgmt (identifies most appropriate course of treatment for a specific patient) Avoid unnecessary biopsies or surgeries Reduce patient risk, improves patient outcome Determine patient response to therapy

PET in Oncology Conclusions Every patient does not need PET, but many will benefit from the addition of PET into their staging/restaging work up The information provided by PET and CT is complementary PET is not perfect - there are false negative and false positive results PET often changes the treatment plan, usually by avoiding futile surgery

PET in Oncology Conclusions A negative PET scan usually eliminates the need for biopsy or surgery – avoid complications associated with unnecessary invasive procedures A negative PET scan rules out cancer with a high degree of confidence A positive PET scan usually indicates malignancy, but should be confirmed with biopsy PET should be used to determine the extent of malignancy any time surgery or local radiation therapy is considered as the definitive treatment The predictive or prognositic power of PET following therapy is greater than CT

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