Using PET in Cervical 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

Cervical Cancer Problem: Accounts for 6% of all malignancies in women Estimated 16,000 new cases of invasive cancer of the cervix per year with ~ 5,000 annual deaths in the US Overall mortality has decreased due to early detection and treatment of pre-invasive disease Mortality of invasive cervical cancer has not changed in 30 years Prognosis: Determined by extent of disease at time of initial diagnosis Affected by patient age at diagnosis, performance status, primary tumor size, presence of para-aortic & pelvic lymph node metastases

Cervical Cancer Diagnosis and Staging Combination of physical exam Palpation, biopsy, conization, colposcopy, cystoscopy, sigmoidoscopy Conventional radiographic exams Chest and bone radiographs, IVP, barium enema Clinical tools have limited accuracy in more advanced disease 68 – 83% in Stage IB 33 – 50% in Stage II - IV

Cervical Cancer Diagnosis and Staging CT and MRI Useful in assessing tumor size, depth of stromal invasion, stage of disease, presence of lymph node metastasis CT - overall staging accuracy of 58 – 88% Sensitivity of only 44% for detection of nodal mets Unreliable in evaluation of tumor size and identification of early parametrial invasion MRI – most accurate imaging modality for assessing tumor size and level of invasion Accuracy of 80-92% Sensitivity for nodal mets similar to CT – 50%

Cervical Cancer Diagnosis and Staging GYN Oncology Group Study evaluated detection of para-aortic lymph node mets by US, CT and lymphangiography at initial staging. Surgical confirmation of all imaging findings. Lymphangiography – sensitivity 79%, specificity 73% CT – sensitivity 34%, specificity 96% US – sensitivity 19%, specificity 99% Limitations of current imaging techniques - basis for expanded coverage by CMS for initial staging of newly diagnosed cervical cancer patients in whom conventional imaging is negative or equivocal – PET has high sensitivity for detection of nodal disease

Cervical Cancer Key indicators of Prognosis > Staging > Volume of primary tumor > Histopathological grade of primary tumor > Presence of lymph node metastasis Spread of lymph node metastasis- PelvicPara AorticDistal Primary cervical cancer- Squamous cell carcinoma – High FDG avidity in primary and metastases

Cervical Cancer Role for PET and PET/CT Diagnosis / Staging - squamous and non-squamous cell cervical cancers are FDG avid May require modified imaging technique to reduce interference from physiologic activity in the urinary tract (post void images, use of diuretics, in some cases bladder catheterization) Reported sensitivity of 86-91% for detection of primary cervical cancers More accurate detection of lymph node metastasis PET – sensitivity of 86%, specificity of 100% Compared with surgical staging of para-aortic lymph nodes, PET demonstrated sensitivity of 75% and specificity of 92% Sensitivity of PET in identification of pelvic lymph node disease was greater than para-aortic nodes Sagawara Y., et al, J Nucl Med, Vol 40, No 7: p 1125-1131 (1999) Rose P., et al, J of Clin Oncool, Vol 17, No 1: p 41-45 (1999)

Cervical Cancer Role for PET and PET/CT Accurate staging of the para-aortic nodes allows modification of the radiation therapy fields to include the diseased nodes which are not routinely part of the treatment field PET has a distinct advantage for restaging patients with distorted anatomy following surgery and/or radiation therapy Since metabolic changes precede anatomic changes after effective therapies, PET could prove to be an early and reliable marker to assess treatment response CT and MRI have difficulty in assessing treatment response after radiation therapy or radiation implants

Cervical Cancer Staging Primary PET shows higher sensitivity than CT for detection of nodal mets Accuracy of PET in detecting Para aortic node mets with - CT 50 pts with locally advanced Ca Cx & - Abd CT FDG PET compared to surgical exploration FDG PET Sensitivity 85.7% Specificity 94.4% Accuracy 92% Comparison of PET and CT for lymph node metastasis in CA Cervix 101 consecutive pts with Ca Cervix underwent PET and CT and f/up > Pelvic node metastases- PET 67% CT 20% > Para Aortic node mets- PET 21% CT 7% > Supraclavicular mets- PET 8% CT 0% Presence of paraaortic node mets on PET most important prognostic indicator Lin et al Gynecol Oncol 89:73-76 2003 Grigsby et al J Clin Oncol. 2001 Sep 1;19(17):3745-9

Cervical Cancer Staging Lymph node metastasis in patients with clinical early stage Cervical Cancer: Detection with integrated FDG PET/CT 47 consecutive Ca Cervix patients underwent FDG PET/CT before radical hysterectomy with PLND 32% pts had metastatic lymph nodes confirmed by histopathology Sensitivity Specificity PPV NPV Accuracy PET/CT 72% 99.7% 81 % 99.5% 99.3% (for all nodes) PET/CT 100% 99.6% 81% 100% 99.6% (for nodes>0.5cm) PET/CT method of choice in primary staging of Cervical CA especially for pelvic and para-aortic nodal mets Sironi et al Radiology 238 Jan 2006

Cervical Cancer Staging 37 year old with a history of recently diagnosed cervical cancer for staging PET and XRT planning. PET/CT revealed heterogenous uptake in the uterus, intense uptake in the cervix and uptake in the R adnexal area (probable malignant node uptake). Surgical excision of adnexal node showed negative pathology. In view of PET/CT results, subsequent review of pathology taking fine cuts through the lymph node, showed positive for recurrence. Images courtesy of Todd Blodgett, MD, UPMC

Cervical Cancer Restaging Value of FDG PET in local recurrence & nodal metastases 20 pts underwent FDG PET for detection of local recurrence & nodal metastases. PET Sensitivity Specificity Overall 90% 100% Local Recurrence 86% 92% Pelvic node mets 100% 94% Para aortic node mets 100% 100% Distal metastases 100% 100% Sun et al. Anticancer Res. 2001 Jul-Aug;21(4B):2957-61

Cervical Cancer Restaging PET in detection of recurrent cervical CA Recurrence rate of cervical cancer- 6.5% after surgery & 26.2% after RT 60% of recurrences occur within two years of completion of primary therapy 249 pts with no evidence of disease at end of therapy evaluated retrospectively for detection of early recurrence with FDG PET 80 pts (32.1%) showed + lesions with FDG PET, 28 pts (11.2%) were confirmed as having recurrences. FDG PET- Sensitivity 90% Specificity 76% for detection of early recurrence Sensitivity higher for recurrence in spine, liver, mediastinal, hilar and scalene nodes Ryu et al J Nucl Med. 2003 Mar;44(3):347-52. 22 pts of cervical CA evaluated for recurrence with FDG PET Tissue biopsy and clinical follow up indicator of true recurrence PET True + 12 True – 13 PET False + 2 False – 2 PET Sens 85% Spec 86% PPV 85% NPV 86% for detection of recurrence Havrilesky et al. Gynecol Oncol. 2003 Jul;90(1):186-90

Cervical Cancer Restaging PET vs CT in detection of recurrent Cervical CA 36 pts with clinically suspected recurrence underwent PET & CT 18 pts confirmed for recurrence by histopathology & follow up TP FP FN TP Sens Spec Accu CT 14 3 4 15 77.8% 83% 80% PET 18 1 0 17 100% 94% 97% False + CT due to radiation necrosis False – CT due to metastatic nodes smaller than 1 cm Park DH et al. Korean J Radiol. 2000 Jan-Mar;1(1):51-5.

Cervical Cancer Restaging 76 yr old with locally recurrent cervical cancer, CT shows pelvic adenopathy, scheduled for pelvic exenteration. PET positive for disease beyond pelvis.

Cervical Cancer Restaging Recurrent Disease 43 year old female, 9 mos. post hysterectomy for cervical cancer, restage. Enhancing mass with abnormal glucose metabolism in the left pelvis consistent with recurrent cervical cancer involving the left aspect of the vaginal cuff and contiguously involving left ovary. Additional solitary left iliac chain nodal metastasis revealed on FDG PET images. Left iliac chain nodal metastasis Images courtesy of Dr. P. Shreve, Grand Rapids, MI

Cervical Cancer Restaging 42 year old female with a history of cervical cancer, s/p resection, for XRT planning. Staging clinical CT showed few paraaortic nodes. PET/CT showed near complete resolution of the paraaortic nodes and complete resolution of L pelvic sidewall node. Images courtesy of Todd Blodgett, MD, UPMC

Cervical Cancer Prognosis PET in prediction of survival in cervical cancer 76 pt reviewed – all pre and post therapy FDG PET Normal Post therapy FDG PET- 86% progression free 2 yr survival Persistent FDG PET positive lesions – 40% progression free 2 yr survival New hypermetabolic sites on FDG PET- 0% progression free 2 yr survival. Grigsby et al. Int J Radiat Oncol Biol Phys 55:907-913 2003

Cervical Cancer Summary PET increases accuracy for detecting lymph node metastasis in patients with advanced-stage cervical cancer Fusion with anatomic images, CT and/or MRI, ensures accurate localization of increased uptake Predicts both the presence and absence of pelvic and para-aortic nodal metastatic disease Presence of nodal disease alters therapeutic management of patients – surgery, radiation therapy and/or chemotherapy – affects patient outcomes PET uniquely valuable in evaluation of the response of primary cervical cancer and lymph node metastasis to radiation therapy and chemotherapy May have value for surveillance of patients after initial therapy to detect asymptomatic recurrence PET imaging approved 2005 for initial staging of cervical cancer when CI negative. Many commercial insurance companies approve PET for these cancers with documentation of medical necessity.

Cervical Cancer Conclusion PET stages cervical cancer with high diagnostic accuracy PET/CT is superior to any conventional imaging modality for staging and follow up PET or PET/CT should be used to monitor the effects of treatment and the course of the disease PET provides important prognostic information PET/CT impacts patient management cost-effectively

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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