PSMA: A “PET” Detective for

Prostate Cancer

Luyao Shen, MD1; Johannes Czernin, MD2,3; Jeremie Calais, MD3; Ely

Felker, MD1; David Lu, MD1; Steven Raman, MD1.

1UCLA Department of Radiology2UCLA Department of Nuclear Medicine3UCLA Department of Mol & Med Pharmacology

Background

• CT/MRI and bone scan are not recommended for prostate cancer staging until PSA level

has reached 10 or 20 ng/mL because of low accuracy and sensitivity (Wollin et al, BJU Int.

2015).

• CT, MRI, FDG- or choline-based PET/CT are not sensitive for the detection of lymph nodes

metastases smaller than 8-10 mm in short axis (Hovel et al. Clin Radiol 2008).

• 68Ga-PSMA-11 PET/CT has increased accuracy and high specificity for bone, lymph nodes

and visceral organ metastasis.

• It is recommended to stage recurrent prostate cancer especially for low PSA values

between 0.2-10 ng/mL (Fendler et al. Eur J Nucl Med Mol Imaging 2017)

• 68Ga-PSMA-11 PET/CT not yet FDA approved.

DISCLOSURE: NONE

Table of Content

• Limitations of CT, MRI, and multiple based tracer PET for staging prostate cancer

illustrated by cases.

• What is PSMA?

• Normal distribution of PSMA-11 PET, illustrated by case.

• Pitfalls, false positives, and false negatives, illustrated by cases.

• Current literature review

• Current guidelines for Gallium 68-PSMA PET/CT and Clinical Cases:

• Localization in suspected recurrence

• Primary staging

• Restaging after local and systemic therapy

• PSMA PET MRI

• Use of Lutetium 177 PSMA for systemic therapy: Theranostics

Limitations of CT, MRI, and non-PSMA

PET for staging prostate cancerCT/MRI

• Evaluate lymph node based on size and

morphology.

• However, almost 80% of metastatic

lymph nodes in prostate cancer are

smaller than 8 mm size threshold (Maurer

et al, Nat rev Urol 2016).

• MRI: limited field of view

• Meta-analysis for lymph node metastasis

evaluation: Hovel et al. Clin Radiol 2008.

• CT: sensitivity 42%, specificity 82%

• MR: sensitivity 39%, specificity 82%

Non-PSMA PET

• 11C-choline, 18F-choline, 18F-

fluorocholine, 11C-acetate

• Meta-analysis: Evangelista et al,

Eur Urol 2013. Choline PET.

• Moderate pooled sensitivity 39.2%

(range 33-45%)

• High specificity >/= 95%

• Poor sensitivity→ current guideline

does not recommend non-PSMA

PET for lymph node staging

FDA Approved PET for Recurrent Prostate Cancer

18F-Fluciclovine (Axumin) PET and 11C-Acetate PET

• 11C-Acetate PET was approved by FDA in September 2012.

• 18F-Fuciclovine (Axumin) PET was approved by FDA in May 2017.

• Both are approved for patients with suspected biochemical recurrence (BCR).

• 11C-Acetate PET/CT: poor pooled sensitivity for lymph node metastases (Meta-analysis,

Evangelista et al, Eur Urol 2013.)

• 18F-Fuciclovine PET/CT is superior to 11C-Acetate PET/CT in detecting local recurrence

and distant metastases (lymph node and bone) (Nanni et al, Clin Nucl Med 2015).

• A retrospective study of 10 patients with BCR underwent 18F-Fluciclovine PET/CT and

68Ga-PSMA-11 PET/CT (Calais et al, J Nucl Med 2017): 68Ga-PSMA-11 PET/CT may be

better.

• 5/10 patients (50%) were negative on 18FFluciclovine PET/CT had positive 68Ga-PSMA-11 PET/CT.

• 68Ga-PSMA-11 PET/CT detected additional lymph node metastasis.

Negative 11C-Acetate PET vs. Positive 68Ga-PSMA-11 PET

70 year-old male status radical prostatectomy in 2002 with biochemical recurrence treated with

salvage radiation and systemic hormone therapy in 2008. Now PSA 6.5 ng/mL in 2016.

A 2 mm para-aortic lymph node with intense PSMA uptake was morphologically normal on CT

and negative on 11C-Acetate PET/CT only 5 months ago.

11C-Acetate PET/CT fused

July 2016

Axial CT with contrast

Dec 201668Ga-PSMA PET/CT fused

Dec 2016

68Ga-PSMA

PET only

Dec 2016

PSMA (prostate specific membrane antigen)

• PSMA: type II transmembrane protein.

• Similar to transferrin receptor

• PSMA→ truncated→ PSM’ inside cytoplasm.

• Dysplastic and/or neoplastic transformation→ transfers PSMA from apical

membrane to the luminal surface of the ducts.

• Expressed in adenocarcinoma prostate cancer

• Androgen-independent prostate cancer→ leads to further PSMA expression

• PSMA:PSM’ ratio increases as prostate tumor cells increase in Gleason grade.

• Gallium-68 (68Ga) labeling most common for diagnostic imaging.

• 68Ga-PSMA-11 excretion: majority kidney, some hepatobiliary.

Normal Distribution of 68Ga-PSMA-11 PET

• Salivary glands/parotid glands/lacrimal gland

• Liver, spleen

• Small intestine, colon

• Kidneys, ureters, bladder

Coronal 3D reconstruction

PET image demonstrating

normal physiologic

distribution of Ga68-PSMA

Pitfalls, False Negatives and False Positives

• 10% prostate cancer does not express PSMA

• Systemic review and meta-analysis 2016 (Perera et al. Eur Urol 2016):• Sensitivity and specificity of PSMA detection: both 86% per-patient analysis.

• Other cells express PSMA

• For example: astrocytes, jejunum brush border cells

• Liver metastases

• High background uptake. Liver metastases lose PSMA expression.

• False positive: neovasculature of non-prostate cancer

• Colon cancer, esophageal cancer, thyroid cancer, lung cancer, renal cell

cancer, brain tumors

• False positive

• Stellate ganglion, Paget’s bone disease, ribs

False Positive: Paget’s bone disease

Coronal CT (A), Ga68-PSMA PET/CT fusion (B), and bone scan (C). 64 year-old male with recurrent

prostate cancer and Paget’s bone disease. Diffuse mild PSMA activity is seen in the right hemipelvis

correlating to Paget’s bone disease, which was also diffusely active on bone scan (yellow arrows).

CBA

False Positive: Lung adenocarcinoma

Axial PET (A), Ga68-PSMA-11 PET/CT axial fused (B), and axial CT chest (C). 68 year-old male with

recurrent prostate cancer and lung nodule. PSA 7.9 ng/mL. Restaging PSMA-11 PET demonstrated focal

PSMA-11 uptake of a 11 mm right upper lobe nodule (yellow arrows). Percutaneous core biopsy of the right

upper lobe nodule yielded primary lung adenocarcinoma.

CB

A

False Negative: perirectal lymph node recurrence

Axial PET (A), 68Ga-PSMA-11 PET/CT axial fused (B), and axial CT pelvis (C). 65 year-old male with

recurrent prostate cancer. PSA 0.43 ng/mL. PSMA-11 PET/CT demonstrated a round right mesorectal 6-7

mm lymph node without significant PSMA-11 uptake (SUVmax 0.9). CT guided lymph node biopsy yielded

metastatic adenocarcinoma from prostate origin (PSA+, PSMA+, p53+).

BA C

Current Literature ReviewRetrospective Data - Baseline Detection

Maurer et al. J. Urol 2015.• 130 patients with intermediate risk to

high risk prostate cancer who

underwent radical prostatectomy and

pelvic lymph node dissection.

• Lymph node staging before treatment:

sensitivity 65.9%. Specificity 98.8%.

• False negative

• PSMA-negative primary tumors

• Micrometastases in single lymph

node

Perera et al. Euro Urol 2016.• Systemic review and meta-analysis

• 16 articles involving 1309 patients

overall. 2 studies included outcomes of

PSMA-PET performed for primary

staging.

• 40% (95% CI 19-64%) of scans were

positive for primary staging.

• Growing but limited evidence

supporting use of PSMA-PET for

primary staging.

Current Literature ReviewRetrospective Data – Biochemical Recurrence (BCR)

Eiber et al. J Nucl Med 2015.• 248 patients with BCR after radical prostatectomy. 222 (89.5%) patients with positive 68Ga-PSMA

PET

• Median PSA 1.99 ng//mL (0.2-59.4)

Results

• Detection rate correlates with PSA level: 96.8% for PSA >/= 2; 57.9% for PSA 0.2 to <0.5.

• Detection rate correlates with PSA velocity: 81.8% for <1 ng/mL/yr; 100% for >/= 5ng/mL/yr

• No significant correlation with PSA doubling time

• Higher Gleason (>/= 8)→ better detection rate

• 81 patients (32.7%) PET finding only (CT missed)

• 61 patients (24.6%) PET found additional findings

• No significant correlation between putative sensitivity and androgen deprivation therapy

Current Literature ReviewRetrospective Data - Biochemical Recurrence (BCR)

Afshar-Oromieh et al. Eur J Nucl Med Mol Imaging 2015. • 319 patients with BCR. 82.8% with positive 68Ga-PSMA scan results.

Results

• Positively correlated with PSA level

• Positively correlated with the administration of androgen deprivation therapy (ADT)

• Patients with ADT at time of scan→ more frequently positive PET

• Patients with more advanced disease on ADT

• No correlation with Gleason score

• Lesion-based

• Sensitivity 76.6%, Specificity 100%, NPV 91.4%, PPV 100%.

• Patient-based sensitivity 88.1%

Current Literature ReviewSalvage radiotherapy (SRT) planning

Calais et al. J Nucl Med 2017.• Post-hoc analysis, 4 institutions, 270 patients with BCR after prostatectomy without prior radiotherapy at PSA<1 ng/mL.

• Radiation Therapy Oncology Group (RTOG) consensus clinical target volumes (CTV) that included both the prostate bed

and pelvic lymph nodes were contoured on CT.

• 68Ga-PSMA-11 PET/CT images were analyzed by a nuclear medicine physician.

• PSMA-positive lesions not covered by planning volumes on consensus CTV major potential impact on treatment

planning.

Results

• 52/270 (19%): at least one PSMA-positive lesion not covered by the consensus CTV.

• 33/270 (12%): extra-pelvic PSMA-positive lesions.

• 19/270 (7%): PSMA-positive lesions within the pelvis but not covered by consensus CTV.

• Two most common PSMA-positive locations outside the consensus CTV: bone (23/52, 44%) and perirectal lymph nodes

(16/52, 31%).

Conclusion: Post-hoc analysis of 68Ga-PSMA-11 PET/CT implies a major impact on SRT planning in 52/270 patients

(19%) with BCR (PSA < 1.0 ng/mL).

Justifies a randomized imaging trial of SRT with or without 68Ga-PSMA-11 PET/CT investigating its clinical benefit.

Current Guidelines

Localization in recurrence:

• Strong retrospective data

• 68Ga-PSMA recommended: especially patients with low PSA 0.2-10 ng/mL

• Can guide salvage therapy

Primary staging:

• Several retrospective studies

• For high risk disease: Gleason > 7; PSA > 20 ng/mL; T2c-3a.

• 68Ga-PSMA MAY replace CT/MRI/Bone scan for lymph nodes and bone metastasis.

• Local tumor localization: multiparametric prostate MRI cannot be replaced

Localization in recurrence

Axial CT with contrast (A), 68Ga-PSMA-11 PET (only), and fused 68Ga-PSMA-11 PET/CT (C) at the level of

prostatectomy bed.

75 year-old male status post prostatectomy in 2004, now with PSA 0.3 ng/mL, BCR. Subcentimeter soft tissue

along right surgical margin demonstrated significant PSMA-11 uptake. Patient was then treated with additional

radiation.

A CB

Biochemical Recurrence Restaging

Axial CT (A) and 68Ga-PSMA-11

PET/CT fused (B) at the level of

clavicles. Axial CT (C) and 68Ga-

PSMA-11 PET/CT fused (D) at the

inferior aorta. Coronal 68Ga-

PSMA-11 PET 3D (E). 56 year-old

male with recurrent prostate

cancer. 68GA-PSMA-11 PET

demonstrated PSMA positive

subcentimeter lymph nodes in the

left supraclavicular and infrarenal

bilateral paraaortic regions, highly

suspicious for metastatic disease.

BA

C D

E

Oligometastatic Recurrence

Sagittal 68Ga-PSMA-11 PET 3D (A), Axial CT at various lymph node stations in the

pelvis (B-D). 65 year-old male with recurrent prostate cancer status post

prostatectomy in 2014. PSA 0.28 ng/mL. There are four metastatic lymph nodes

demonstrated significant PSMA-11 uptake: left external iliac (5 mm, B), left pelvic

sidewall (10 mm, C), right posterior pelvic (3 mm, D), and right mesorectum (4 mm,

E).

B

A

ED

Primary Staging

Axial 68Ga-PSMA-11 PET/CT fused (A, B, C), Sagittal PET only (D), and

Sagittal PET/CT fused (E).

72 year-old male newly diagnosed PCa with two positive foci on biopsy. Primary

68Ga-PSMA-11 staging scan demonstrated two intense PSMA-11 uptake foci in

the right posterior peripheral apex and right anterior peripheral base (blue

arrows, A, B, D, and E). A small 2 mm right external iliac lymph node with mild to

moderate PSMA-11 uptake is concerning for early metastasis (yellow arrow, C)

B C

E

D

Primary Staging

Axial T2 (A), DCE (B), ADC (C) , and DWI (D) MRI prostate. Axial Ga68-PSMA-11 PET/CT fused (E) and PET only (F). Coronal 3D PET

(G). 68 year-old male with newly diagnosed prostate cancer. PSA 8.6 ng/mL. MRI prostate and Ga68-PSMA-11 PET/CT two weeks apart.

Focal intense PSMA-11 uptake is seen in right posterior peripheral apical gland corresponding to MRI prostate finding for suspicious lesion.

BA

C D

G

E

F

Current Guidelines

Staging before and during PSMA-directed radiotherapy:

• Imaging before PSMA-directed therapy (radioligand therapy) is crucial.

Targeted biopsy after previously negative biopsy:

• Consider for high suspicion even with negative biopsy. May be valuable

• 68Ga-PSMA PET combined with mpMRI for biopsy guidance.

Monitoring of systemic treatment in metastatic patients:

• Potential application

• Is 68Ga-PSMA PET/CT better than bone scan or CT? NO DATA YET.

Restaging after Therapy

3D Coronal 68Ga-PSMA-11 PET

(A & B).

59 year-old male with metastatic

prostate cancer (bone and soft

tissue) underwent 3 rounds of

177Lu-PSMA in Germany. Pre-

and post-therapy 68Ga-PSMA-11

PET/CT (3 months apart)

demonstrated significant overall

improvement in soft tissue and

bone mets (despite a few new

bone mets).B

3 months after 3x 177Lu-PSMA therapy

PSMA PET MRI

•MRI has superior soft tissue resolution compared to CT

•PSMA PET/MRI can better localize primary disease in the prostate.

•Some retrospective data suggests that 68Ga-PSMA-11 PET/CT is more useful for

lymph node metastases and local staging in high-risk prostate cancer (Tulsyan et

al. Nucl Med Commun. 2017).

•Registration/metrics agreement between MRI and PET and halo artifacts around

bladder and kidneys have been some challenging issues that will need to be

addressed with additional research (Domachevsky et al. Clinical Radiology 2017).

•Fusion MRI/PET guided biopsy can be helpful for patients with high clinical

suspicion but with negative biopsy (MRI guided or TRUS guided).

Lutetium-177 PSMA for Systemic Therapy: Theranostics

• Lutetium-177 (177Lu) desirable physical properties

•Shorter range of beta-emitter better irradiation of small tumors

•Emits low-energy gamma rays at 208 and 113 keV: great ex vivo imaging

•Relatively long physical half-life (6.73 days)

•Allow for the delivery of high activities of 177Lu PSMA to prostate cancer cells.

•Easily administered targeted therapy, intravenously injected, renally excreted,

overall safe.

•Effective for tumor cells that express a high density of the PSMA receptor (pre-

treatment PSMA imaging is crucial).

•Limited number of published trials and retrospective studies, but with good results

showing significant treatment response and well tolerated low-grade toxicities.

•Needs prospective analysis of efficacy in randomized trials to evaluate survival

benefit.Emmet L, Willowson K, violet J, et al. Lutetium 177 PSMA radionuclide therapy for men with prostate

cancer: a review of the recurrent literature and discussion of practical aspects of therapy. J Med Radiat Sci.

2017;64(1):52-60.

Weineisen et al. J Nucl Med 2015.

• First-in-human 68Ga-PSMA (Imaging &

Therapy) I&T

• High contrast detection of bone

lesions, lymph node, and liver

metastases

• 2 patients: treated with 177Lu-PSMA

• effective, safe with no detectable

side effects

Yadav et al. Eur J Nucl Med Mol Imaging

2017.• 31 patients hormone- and/or chemo-refractory with

progression

• 68Ga-PSMA PET/CT image first

• Then treat with with 177Lu-DKEZ-617 PSMA (Lu-

PSMA) quarterly

• Results based on biochemical response criteria:

Complete response 2/31

Partial response 20/31

Stable disease 3/31

Progress disease 6/31

• Safe and well tolerated. 2 patients with mild

hemoglobin toxicity.

Lutetium-177 PSMA for Systemic Therapy: Theranostics

Conclusion

• Current recommendation for Gallium 68-PSMA-11 PET, but not FDA

approved.

• Staging for recurrent prostate cancer

• Especially low PSA level: 0.2-10 ng/mL

• More research needed is needed, especially prospective data.

• PSMA PET MRI and Lu177 PSMA will further change our

understanding of diagnosis and therapy for prostate cancer.

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