Positron-Emission Tomography and Assessment of Cancer Therapy Malik E. Juweid, M.D., and Bruce D. Cheson, M.D. N Engl J Med 2006; 354:496-507, Feb 2, 2006

Positron-Emission Tomography Positron-Emission Tomography and Assessment of Cancer and Assessment of Cancer

TherapyTherapy

Malik E. Juweid, M.D., and Bruce D. Cheson, M.D. Malik E. Juweid, M.D., and Bruce D. Cheson, M.D.

N Engl J Med 2006; 354:496-507, Feb 2, 2006. N Engl J Med 2006; 354:496-507, Feb 2, 2006. Review ArticlesReview Articles

報告者報告者 / Int / Int 李瑞翎李瑞翎

Concepts of PETConcepts of PET

1. a noninvasive imaging technique 1. a noninvasive imaging technique

2. positron-emitting isotopes (2. positron-emitting isotopes (1111C, C, 1313N, N, 1515O, O, 1818F) F)

3. provide a 3. provide a functionalfunctional or or metabolicmetabolic

assessment of normal tissues or disease assessment of normal tissues or disease

conditions conditions

4. Clinical applications in oncology : 4. Clinical applications in oncology :

diagnosis, staging, restaging, monitoring diagnosis, staging, restaging, monitoring

response response

Oncologic PET Tracers-Oncologic PET Tracers- 1818F-FDGF-FDG

most commonly usedmost commonly used in oncologic PET in oncologic PET the onlythe only oncologic PET tracer approved oncologic PET tracer approved

by the Food and Drug Administration (FDA) by the Food and Drug Administration (FDA)

for routine clinical use for routine clinical use


Increased uptake of Increased uptake of 1818F-FDG F-FDG

-> reflects elevated glucose consumption -> reflects elevated glucose consumption

-> evidenced by -> evidenced by

(1) the overexpression of (1) the overexpression of glucose glucose

transporter proteinstransporter proteins at the tumor at the tumor

cells‘ surfacecells‘ surface

(2) increased levels of (2) increased levels of active active

hexokinasehexokinase demonstrated in many demonstrated in many

tumors tumors


www.petscanonline.comwww.petscanonline.com/ / faq/faq_fr.aspfaq/faq_fr.asp

hexokinase

Oncologic PET Tracers-Oncologic PET Tracers- 1818F-FDGF-FDG Increased uptake of Increased uptake of 1818F-FDG F-FDG 1. 1. moderate-to-high uptakemoderate-to-high uptake -> most -> most lunglung, , colorectalcolorectal, , esophagealesophageal, stomach, , stomach, headhead and neckand neck, , cervical,cervical, ovarian, and ovarian, and breastbreast cancers and cancers and

in in melanomamelanoma and most types of and most types of lymphomalymphoma ->infectious and inflammatory processes, inflammatory->infectious and inflammatory processes, inflammatory changes after surgery or irradiation, and thymic orchanges after surgery or irradiation, and thymic or bone marrow hyperplasia after treatment bone marrow hyperplasia after treatment

2. 2. variable and unpredictablevariable and unpredictable -> prostate cancer -> prostate cancer

PETPET vsvs

Conventional Radiologic ImagingConventional Radiologic Imaging conventional radiologic imaging techniques, conventional radiologic imaging techniques, such as such as CTCT and and MRIMRI -> tumor's -> tumor's anatomicalanatomical or or morphologicmorphologic features, for features, for example — density, size, and shapeexample — density, size, and shape PETPET -> assesses -> assesses functionalfunctional or or metabolicmetabolic characteristics of the characteristics of the tumor tumor -> detects clinically relevant changes even when no -> detects clinically relevant changes even when no changes or minimal ones are detected by morphologic changes or minimal ones are detected by morphologic imaging (imaging (early detectionearly detection)) -> -> differentiation between malignant and benigndifferentiation between malignant and benign processes processes

Applications in Assessment of Applications in Assessment of Cancer after TherapyCancer after Therapy

widespread use in oncology recently due towidespread use in oncology recently due to

1. 1. Second-generation PET scannersSecond-generation PET scanners : a larger : a larger

field of view, improved resolution and field of view, improved resolution and

sensitivity sensitivity

2. 2. PET–CT PET–CT

3. Centers for Medicare and Medicaid Services3. Centers for Medicare and Medicaid Services

(CMS)(CMS)


CMS to approve reimbursement for CMS to approve reimbursement for

1. the 1. the staging staging and and restagingrestaging of of non–small-cell non–small-cell

lung, esophageal, colorectal, breast, lung, esophageal, colorectal, breast, andand

head and neck cancers, head and neck cancers, as well asas well as lymphoma lymphoma

andand melanoma melanoma

2. the monitoring of the 2. the monitoring of the response to treatmentresponse to treatment of of

breast cancerbreast cancer

3. the 3. the stagingstaging of of cervical cancercervical cancer (recently) (recently)

PETPET 健保給付適應症健保給付適應症 (( 台灣台灣 ))

1. 1. 乳癌分期及治療後評估乳癌分期及治療後評估2. 2. 大腸癌、直腸癌、食道癌、頭頸部癌大腸癌、直腸癌、食道癌、頭頸部癌 ((不包含腦瘤及甲狀不包含腦瘤及甲狀腺癌腺癌 ))、肺癌、肺癌 ((非小細胞性非小細胞性 ))、淋巴癌及黑色素癌之診斷，、淋巴癌及黑色素癌之診斷，分期及復發後之再分期分期及復發後之再分期

3. 3. 存活心肌偵測　存活心肌偵測　4. 4. 癲癇病灶術前評估癲癇病灶術前評估5. 5. 肺癌肺癌 (SPN)(SPN)6. 6. 甲狀腺癌復發後之再分期甲狀腺癌復發後之再分期7. 7. 以電腦斷層或磁振造影無法分期或診斷者以電腦斷層或磁振造影無法分期或診斷者8. 8. 配合腫瘤治療計畫及療效評估者。配合腫瘤治療計畫及療效評估者。

http://www3.vghtc.gov.tw/nm/PET/PAGE5.HTMhttp://www3.vghtc.gov.tw/nm/PET/PAGE5.HTM


一 . Monitoring Response to Treatment二 . Restaging 三 . Requirement for Pretreatment PET before Restaging PET四 . Appropriate Time Point for Restaging with PET五 . Viable Tumor vs. Necrosis or Fibrosis in Residual Masses六 . Detection of Recurrence in Asymptomatic Patients七 . False Positive Findings on Restaging with PET八 . Effect of Restaging with PET on Quality of Life in Cancer九 . Cost-Effectiveness of Restaging with PET 十 . Radiation Dose from PET Scans


一一 . . Monitoring Response to TreatmentMonitoring Response to Treatment1. 1. breast cancerbreast cancer : the only currently : the only currently approved clinical indicationapproved clinical indication2. 2. lymphomas lymphomas andand esophageal, stomach, esophageal, stomach, colorectal, head and neck, colorectal, head and neck, andand non– non– small-cell lung cancerssmall-cell lung cancers : : nono published published reports have clearly demonstrated that reports have clearly demonstrated that PET results were used to alter treatment PET results were used to alter treatment


二二 . . RestagingRestaging 1. Clinical approved : 1. Clinical approved : (1) (1) breast, colorectal, esophageal, head and breast, colorectal, esophageal, head and neck, neck, andand non–small-cell lung cancers, non–small-cell lung cancers, as as well aswell as melanoma and lymphoma melanoma and lymphoma (2) (2) suspected recurrent thyroid cancer of suspected recurrent thyroid cancer of follicular-cell originfollicular-cell origin after thyroidectomy and after thyroidectomy and radioiodine ablation in patients with a radioiodine ablation in patients with a negative 131I whole-body scan and an negative 131I whole-body scan and an elevated level of serum thyroglobulinelevated level of serum thyroglobulin


二二 . . RestagingRestaging 2. review of studies reported from 1993 to 22. review of studies reported from 1993 to 2

000 000 (1) (1) sensitivitysensitivity : : 80 to 95 percent80 to 95 percent (2) (2) specificityspecificity : : 75 to 90 percent75 to 90 percent (3) (3) accuracy accuracy : : 80 to 90 percent80 to 90 percent PS. More recent studies : more PS. More recent studies : more accurate accurate

(owing to use of (owing to use of higher-resolutionhigher-resolution PET sca PET scanners and nners and PET–CT systemsPET–CT systems) )

Detection of Detection of Recurrent Breast CarcinomaRecurrent Breast Carcinoma on PET-CT with 18 F-FDG on PET-CT with 18 F-FDG

The 74-year-old woman in tThe 74-year-old woman in this image had stage IV inflahis image had stage IV inflammatory breast cancer and mmatory breast cancer and had had completedcompleted six cycles of six cycles of doxorubicin and cyclophospdoxorubicin and cyclophosphamide in hamide in October 2004October 2004. . PPET–CTET–CT and and contrast-enhancontrast-enhanced CT scansced CT scans obtained at th obtained at that time were at time were negativenegative. The . The patient was then given trastpatient was then given trastuzumab and was doing well uzumab and was doing well clinically. PET–CT was perfclinically. PET–CT was performed for ormed for restagingrestaging in in AuguAugust 2005st 2005. Coronal, sagittal, a. Coronal, sagittal, and axial views on nd axial views on PETPET (Pan (Panel A) and on integrated el A) and on integrated PETPET–CT–CT (Panel B) show (Panel B) show diseasdisease recurrence with widespree recurrence with widespread bony metastases ad bony metastases

Detection of Recurrent Cervical Carcinoma on PET-CT with 18 F-FDG

The 36-year-old woman in this image uThe 36-year-old woman in this image underwent concurrent radiation therapy nderwent concurrent radiation therapy and chemotherapy for stage IIB squamand chemotherapy for stage IIB squamous-cell cervical carcinoma in ous-cell cervical carcinoma in NovembNovember 2003er 2003. A para-aortic nodal recurrenc. A para-aortic nodal recurrence was found and treated with additionae was found and treated with additional radiation therapy and chemotherapy il radiation therapy and chemotherapy in n July 2004July 2004, and a cervical recurrence , and a cervical recurrence was found and treated with additional cwas found and treated with additional chemotherapy in hemotherapy in November 2004November 2004. PET. PET–CT was performed for –CT was performed for restagingrestaging in in JaJanuary 2005nuary 2005. A sagittal view (Panel A) a. A sagittal view (Panel A) and coronal view (Panel B) on nd coronal view (Panel B) on PET–CTPET–CT, , as well as as well as axial CTaxial CT (Panel C) and (Panel C) and PET PET (Panel D) images, show (Panel D) images, show increased uptincreased uptake of 18F-FDG in a nonpalpableake of 18F-FDG in a nonpalpable, , left left supraclavicular lymph nodesupraclavicular lymph node of under 1 of under 1 cm (arrows). cm (arrows). Metastasis was confirmeMetastasis was confirmed by biopsyd by biopsy. (Images are courtesy of M. (Images are courtesy of Mallinckrodt Institute of Radiology, St. Loallinckrodt Institute of Radiology, St. Louis.)uis.)


三三 . . Requirement for Pretreatment PET before RestaginRequirement for Pretreatment PET before Restaging g

PETPET The majority of patients undergoing restaging with PET dThe majority of patients undergoing restaging with PET d

id not undergo PET before treatment, because : id not undergo PET before treatment, because : (1) cost (1) cost (2) not thought to contribute to the initial diagnosis or (2) not thought to contribute to the initial diagnosis or staging staging (3) a very high percentage of the tumor types that are (3) a very high percentage of the tumor types that are approved by the CMS for restaging with PET are approved by the CMS for restaging with PET are consistently consistently 18F-FDG–avid18F-FDG–avid PS. PS. baseline PETbaseline PET might be considered only for might be considered only for tumor types with less predictable avidity, such tumor types with less predictable avidity, such as as marginal-zone lymphomamarginal-zone lymphoma


四四 . . Appropriate Time Point for Restaging Appropriate Time Point for Restaging with PETwith PET detection of residual or recurrent tumors varies detection of residual or recurrent tumors varies

with the type of therapy with the type of therapy 1. completion of 1. completion of chemotherapy, chemotherapy, chemoimmunotherapy, chemoimmunotherapy, oror chemohormonal chemohormonal therapytherapy : after : after four weeksfour weeks 2. 2. radiation radiation oror chemoradiation chemoradiation : after : after two to three two to three monthsmonths 3. 3. surgerysurgery : after : after one to two monthsone to two months (at the site (at the site of the recent surgery )of the recent surgery )


五五 . . Viable Tumor vs. Necrosis or Fibrosis Viable Tumor vs. Necrosis or Fibrosis in Residual Masses after treatmentin Residual Masses after treatment 1. 1. most relevantmost relevant in in lymphomalymphoma or or testicular testicular cancercancer2. 2. avoidavoid unnecessary toxic therapy to a unnecessary toxic therapy to a nonviable massnonviable mass3. 3. allowsallows the early administration of salvage the early administration of salvage therapy persistent tumors (after been confirmed therapy persistent tumors (after been confirmed by by biopsybiopsy))

CT before and after Therapy and PET after Therapy in a Patient with Diffuse Large-Cell Lymphoma

CTCT performed performed beforebefore the start of the start of therapytherapy s shows a hows a tumor mass in the splenic hilumtumor mass in the splenic hilum (P (Panel A, arrow). The patient also had enlarganel A, arrow). The patient also had enlarged celiac nodes (not shown). ed celiac nodes (not shown). After After six cyclesix cycles of therapy with rituximab plus cyclophosps of therapy with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednhamide, doxorubicin, vincristine, and prednisone, isone, CTCT showed a showed a 5.1-by-6.6 cm residual 5.1-by-6.6 cm residual mass in the splenic hilummass in the splenic hilum (Panel B, arrow). (Panel B, arrow). PETPET that was performed after the terminati that was performed after the termination of therapy shows on of therapy shows no evidence of increano evidence of increased uptake in the residual masssed uptake in the residual mass (Panel C, (Panel C, arrow), indicating that the mass shown on arrow), indicating that the mass shown on CT is CT is fibrosisfibrosis and not residual lymphoma. and not residual lymphoma. The patient had The patient had no evidence of disease at no evidence of disease at 29.5 months of follow-up29.5 months of follow-up. (Images are repri. (Images are reprinted from Juweid et al with the permission nted from Juweid et al with the permission of the publisher.)of the publisher.)


六六 . . Detection of Recurrence in Asymptomatic Detection of Recurrence in Asymptomatic

PatientsPatients Several studies : among patients who Several studies : among patients who

1. have 1. have nono symptoms or only mild ones symptoms or only mild ones

2. but who have an 2. but who have an elevated tumor marker levelelevated tumor marker level

-> tumor restaging with PET can detect-> tumor restaging with PET can detect

and localize and localize disease recurrencedisease recurrence

-> whether the detected disease is -> whether the detected disease is resectable resectable

Detection of Occult Recurrent Colon Cancer by PET-CT with 18 F-FDG

The 82-year-old man in this image The 82-year-old man in this image presented with a presented with a slightly elevated lslightly elevated level of evel of carcinoembryonic antigencarcinoembryonic antigen (3.4 ng per milliliter) (3.4 ng per milliliter) one year after one year after the completion of adjuvant chemotthe completion of adjuvant chemotherapyherapy for right-sided colon cancer. for right-sided colon cancer. Coronal, sagittal, and axial views oCoronal, sagittal, and axial views on n PETPET, which was performed one , which was performed one month later with the use of a month later with the use of a PET–PET–CT CT scanner, show a scanner, show a focal area of ifocal area of increased uptake just below the infencreased uptake just below the inferior portion of the right lobe of the lirior portion of the right lobe of the liverver (Panel A, arrows). This mass c (Panel A, arrows). This mass corresponds to a orresponds to a new 1.2-cm soft-tisnew 1.2-cm soft-tissue densitysue density on on CT CT (Panel B, arrow (Panel B, arrows), as is clearly shown on the fused s), as is clearly shown on the fused PET–CT images (Panel C, arrows). PET–CT images (Panel C, arrows). Three months later, the patient undThree months later, the patient underwent laparotomy, which confirmeerwent laparotomy, which confirmed that this d that this omental massomental mass was recur was recurrent colonrent colon adenocarcinoma.adenocarcinoma. The tu The tumor was successfully resected withmor was successfully resected without complications out complications


七七 . . False Positive Findings on Restaging with False Positive Findings on Restaging with PETPET1. 1. physiologic processesphysiologic processes : : brown fat and cyclic brown fat and cyclic gynecologic activitygynecologic activity 2. 2. infectious and inflammatory processesinfectious and inflammatory processes : such as : such as pneumonia, histoplasmosis, pneumonia, histoplasmosis, andand sarcoidosis sarcoidosis -> Careful history taking !-> Careful history taking !3. 3. rebound thymic hyperplasiarebound thymic hyperplasia in children and in children and young adults young adults


八八 . . Effect of Restaging with PET on Quality of Effect of Restaging with PET on Quality of Life in CancerLife in Cancer ->->unawareunaware ->Recent literature ->Recent literature Porceddu SV, Jarmolowski E, Hicks RJ, et al. Utility of positron emisPorceddu SV, Jarmolowski E, Hicks RJ, et al. Utility of positron emis

sion tomography for the detection of disease in residual neck nodes sion tomography for the detection of disease in residual neck nodes after (chemo)radiotherapy in head and neck cancer. Head Neck 200after (chemo)radiotherapy in head and neck cancer. Head Neck 2005;27:175-181.5;27:175-181.

Yao M, Graham MM, Smith RB, et al. Value of FDG PET in assessYao M, Graham MM, Smith RB, et al. Value of FDG PET in assessment of treatment response and surveillance in head-and-neck cancment of treatment response and surveillance in head-and-neck cancer patients after intensity modulated radiation treatment: a preliminarer patients after intensity modulated radiation treatment: a preliminary report. Int J Radiat Oncol Biol Phys 2004;60:1410-1418y report. Int J Radiat Oncol Biol Phys 2004;60:1410-1418


八八 . . Effect of Restaging with PET on Quality of Effect of Restaging with PET on Quality of Life in CancerLife in Cancer Porceddu SV, Jarmolowski E, Hicks RJ, et al. Utility of Porceddu SV, Jarmolowski E, Hicks RJ, et al. Utility of positron emission tomographypositron emission tomography

for the for the detection ofdetection of disease in residual neck nodes after (chemo)radiotherapy in head disease in residual neck nodes after (chemo)radiotherapy in head and neck cancerand neck cancer. Head Neck 2005;27:175-181.. Head Neck 2005;27:175-181.

-> Patients who (1) achieving a -> Patients who (1) achieving a complete complete response at the primary siteresponse at the primary site (2) having a (2) having a residual abnormality in the neckresidual abnormality in the neck (3)being (3)being PET PET negativenegative -> approximately -> approximately 12 weeks after treatment12 weeks after treatment do do not require neck dissectionnot require neck dissection and can be and can be safely safely observed observed

PET and Contrast-Enhanced CT before and after Therapy in a Patient with Base-of-Tongue Cancer (Stage I with Nodal Involvement [T1N3])

Both Both PET PET and and CT CT scans perforscans performed med beforebefore the start of the start of therapy therapy show show bilateral cervical lymphabilateral cervical lymphadenopathydenopathy (Panel A, arrows). (Panel A, arrows). CTCT performed eight weeks performed eight weeks afteafter chemoradiationr chemoradiation shows a resi shows a residual soft-tissue mass in the rigdual soft-tissue mass in the right neck (Panel B, arrow). The ht neck (Panel B, arrow). The post-therapy post-therapy PET PET performed at performed at that time was that time was negativenegative. The pa. The patient did tient did not undergo neck dissnot undergo neck dissection and had no evidence of ection and had no evidence of disease at follow-up 30 months disease at follow-up 30 months after therapy after therapy

Porceddu SV, Jarmolowski E, Hicks RJ, et al. Utility of positron emisPorceddu SV, Jarmolowski E, Hicks RJ, et al. Utility of positron emission tomography for the detection of disease in residual neck nsion tomography for the detection of disease in residual neck nodes after (chemo)radiotherapy in head and neck cancer. Heaodes after (chemo)radiotherapy in head and neck cancer. Hea

d Neck 2005;27:175-181d Neck 2005;27:175-181


八八 . . Effect of Restaging with PET on Quality of Effect of Restaging with PET on Quality of Life in CancerLife in Cancer Yao M, Graham MM, Smith RB, et al. Value of FDG PET in assessment of treatment response anYao M, Graham MM, Smith RB, et al. Value of FDG PET in assessment of treatment response an

d surveillance in head-and-neck cancer patients after intensity modulated radiation treatment: a pd surveillance in head-and-neck cancer patients after intensity modulated radiation treatment: a p

reliminary report. Int J Radiat Oncol Biol Phys 2004;60:1410-1418reliminary report. Int J Radiat Oncol Biol Phys 2004;60:1410-1418 -> -> FDG PETFDG PET is useful in the is useful in the posttreatment managementposttreatment management of head-and-neck cancer patients treated with IMRTof head-and-neck cancer patients treated with IMRT -> highly accurate in the -> highly accurate in the detection of persistent and detection of persistent and recurrent disease after treatmentrecurrent disease after treatment and allows salvage and allows salvage treatment to be initiated in a timely mannertreatment to be initiated in a timely manner -> -> provides prognostic informationprovides prognostic information concerning the risk concerning the risk of recurrence after curative therapy. of recurrence after curative therapy.


九九 . . Cost-Effectiveness of Restaging with PETCost-Effectiveness of Restaging with PET 1. per scan in the United States : 1. per scan in the United States : $1,800 to $1,900 $1,800 to $1,900 2. Studies : restaging of colorectal cancer as well as head 2. Studies : restaging of colorectal cancer as well as head and neck cancersand neck cancers -> -> cost savingscost savings because of changes in management because of changes in management -> -> avoidance of inappropriate, costly treatmentsavoidance of inappropriate, costly treatments (unresectable)(unresectable)3. periodic PET scanning in patients with 3. periodic PET scanning in patients with nono clinical or clinical or biochemical evidence of disease biochemical evidence of disease -> should be -> should be avoided avoided


十十 . . Radiation Dose from PET ScansRadiation Dose from PET Scans 1. 1. a single PET scana single PET scan : : 10 mSv10 mSv PS. a chest CT : 8 mSv PS. a chest CT : 8 mSv 2. 2. a single PET–CTa single PET–CT : : 20 mSv20 mSv

PS. The potential benefit from restaging with PS. The potential benefit from restaging with

PET usually PET usually far exceedsfar exceeds any potential any potential risk risk

ConclusionsConclusions powerful imaging tools in clinical oncology for powerful imaging tools in clinical oncology for (1) the accurate (1) the accurate restaging restaging of established diseaseof established disease (2) the detection of (2) the detection of occult tumorsoccult tumors (3) the reliable prediction of the (3) the reliable prediction of the nature of residual nature of residual massesmasses that are difficult to evaluate with conventional that are difficult to evaluate with conventional imaging after therapyimaging after therapy (4) evaluating for (4) evaluating for response response or lack of response at a very or lack of response at a very early stage in the course early stage in the course of treatmentof treatment -> shorten the time required to evaluate the efficacy -> shorten the time required to evaluate the efficacy of drugs or to determine the optimal therapeutic of drugs or to determine the optimal therapeutic intervention intervention

Thanks for your attention Thanks for your attention

Documents

Positron-Emission Tomography and Assessment of Cancer Therapy Malik E. Juweid, M.D., and Bruce D. Cheson, M.D. N Engl J Med 2006; 354:496-507, Feb 2, 2006