APCCC 2019: Pitfalls of PSMA PET-CT in Advanced Prostate Cancer Imaging

[pjoshea13]

This was presented at APCCC 2019 in Switzerland a week or so ago. -Patrick:

Basel, Switzerland (UroToday.com)

"As a follow-up to Dr. Stefano Fanti’s presentation on the advantages of PSMA PET-CT imaging, Dr. Ian Davis from Melbourne discussed some of the pitfalls and disadvantages of PSMA PET-CT in advanced prostate cancer imaging. Admitting that in his opinion, although 68Ga-PSMA PET-CT is great, there is a certain degree of false positives and negatives, inappropriate changes in management, and true positives that may not change management in today’s landscape.

False positives may occur in 68Ga-PSMA PET-CT imaging for prostate cancer because PSMA expression is also evident in non-prostatic tissue, such as the kidney, gut, breast, brain, adrenal, ovary, salivary gland, celiac ganglion, small intestine, NSCLC, neuroendocrine tumors, Paget’s disease of the bone, and reactive lymph nodes. Despite upregulation of PSMA in prostate cancer secondary to AR inhibition, these other organ sites are important to note. Pitfalls of false positives include the misdiagnosis as metastatic prostate cancer, missing another critical diagnosis, and the inappropriate selection of treatment.

False negatives are not as much of an issue in the overt metastatic disease setting. However, there is a low sensitivity for nodal disease at <4mm, and nodes cannot be detected at <2mm. Furthermore, and importantly, 5-10% of prostate cancers do not express PSMA, and thus one must be aware of PSMA-negative, but FDG-positive patients. The pitfalls of false negatives include radical treatment of incurable patients and unnecessary multimodality treatment of “localized” prostate cancer that is actually metastatic.

A recent prospective single-arm trial assessed the accuracy of 68Ga-PSMA-11 PET in localizing recurrent prostate cancer among 635 patients with biochemically recurrent prostate cancer after prostatectomy (n = 262, 41%), radiation therapy (n = 169, 27%), or both (n = 204, 32%).1 The presence of prostate cancer was recorded by 3 blinded readers on a per-patient and per-region base. 68Ga-PSMA-11 PET localized recurrent prostate cancer in 475 of 635 (75%) patients, and detection rates significantly increased with PSA (p<0.001):

38% for <0.5 ng/mL (n = 136)

57% for 0.5 to <1.0 ng/mL (n = 79)

84% for 1.0 to <2.0 ng/mL (n = 89)

86% for 2.0 to <5.0 ng/mL (n = 158)

97% for ≥5.0 ng/mL (n = 173)

For certain patients, there may be true positives, but they are not particularly useful. For example, there is likely no value above conventional imaging for patients with known extensive metastatic disease. Furthermore, clinical utility is low for patients with known likely metastatic disease but who are planning for local therapy (ie. ADT + radiation therapy with high-risk features). Dr. Davis notes that PSMA PET-CT may be useful when trying to find a reason to not give radical local therapy.

Dr. Davis also highlighted some examples of inappropriate changes in management. For patients with high-risk primary disease, PSMA-detected metastases may lead to the decision to not treat the primary tumor. Second, PSMA imaging may lead to unnecessary additional investigations that delay treatment, such as a rib biopsy for a PSMA avid lesion. Finally, PSMA detected lesions may influence decisions on eligibility of trial participation. An Australian study recently assessed the impact of 68Ga-PSMA PET on management intent among 431 patients with primary or recurrent prostate cancer.2 Before undertaking 68Ga-PSMA PET imaging, referring medical specialists completed a questionnaire detailing their proposed management plan. A separate follow-up questionnaire was completed after the 68Ga-PSMA PET/CT scan results were available to determine whether the management plan would change. Overall, 68Ga-PSMA PET/CT scanning led to a change in planned management in 51% of patients. The impact was greater in the group of patients with biochemical failure after definitive surgery or radiation treatment (62% change in management intent) than in patients undergoing primary staging (21% change).

Dr. Davis concluded his presentation by highlighting several additional pitfalls:

Situations exist where PSMA PET is clearly of value, but sometimes there is no added value to the management plan.

PSMA PET sometimes comes with incomplete information, such as decisions made without treatment context, lack of histology/genomic data, no parallel FDG PET, and a CT component without diagnostic quality.

PSMA findings may lead to patient distraction, what Dr. Davis notes as “PSMA neurosis.”

Presented by: Ian D. Davis, MBBS, PhD, FRACP, FAChPM, Eastern Health Clinical School, Monash University, Melbourne, Australia

Written by: Zachary Klaassen, MD, MSc – Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia Twitter: @zklaassen_md at the 2019 Advanced Prostate Cancer Consensus Conference (APCCC) #APCCC19, Aug 29 - 31, 2019 in Basel, Switzerland

References:

Fendler WP, Calais J, Eiber M, et al. Assessment of 68Ga-PSMA-11 PET Accuracy in Localizing Recurrent Prostate Cancer: A Prospective Single-Arm Clinical Trial. JAMA Oncol 2019 Jun 1;5(6):856-863.

Roach PJ, Francis R, Emmett L, et al. The Impact of 68Ga-PSMA PET/CT on Management Intent in Prostate Cancer: Results of an Australian Prospective Multicenter Study. J Nucl Med 2018 Jan;59(1):82-88.

[GP24]

Let me add the PRO talk by Stefano Fanti:

Basel, Switzerland (UroToday.com)

At the Advanced Prostate Cancer Consensus Conference (APCCC) 2019 meeting, Dr. Stefano Fanti from [Bologna] discussed the advantages of PSMA PET-CT in advanced prostate cancer imaging, specifically the role in staging, biochemical recurrence, and therapy planning.

For staging, the updated European Association of Urology guidelines do not explicitly mention PSMA PET-CT, however, do say that “evidence is rapidly evolving, in that choline PET/CT, PSMA PET-CT, and MRI provide a more sensitive detection of lymph node and bone metastases than the classical work-up associating bone scan and abdominopelvic CT”. In a recent study from Australia, Yaxley et al. retrospectively reviewed 1,253 consecutive men referred for 68 Ga-PSMA PET/CT scan for staging at the initial diagnosis.[1] Metastatic disease was identified in 12.1% of men, including 8.2% with a PSA level of <10 ng/mL and 43% with a PSA level of >20 ng/mL. Metastases were identified in 6.4% with ISUP grade 2-3 and 21% with ISUP grade 4-5. Furthermore, lymph node metastases were suspected in 107 men, with 47.7% outside the boundaries of an extended pelvic lymph node dissection. Skeletal metastases were identified in 4.7%. In men with intermediate-risk prostate cancer, metastases were identified in 5.2%, compared to 19.9% with high-risk disease. Based on these results, according to Dr. Fanti, there appears to be a role for PSMA PET-CT in initial staging.

up.picr.de/36680776is.png

For biochemical recurrence, a recent systematic review of 98 studies found that at recurrent PSA levels <0.5ng/ml, detection rates were up to 31.3% using 11C choline PET-CT and up to 65.0% using 68Ga PSMA-11 PET-CT.[2] Furthermore, at recurrent PSA levels <0.2ng/ml, detection rates of 68Ga PSMA-11 PET-CT ranged from 11.3% to as high as 58.3%. The updated European Association of Urology guidelines does recommend using PSMA PET-CT imaging in patients with persistent PSA after radical prostatectomy. However, the strength rating of this recommendation is still “weak” due to lack of knowledge regarding the effect of using this imaging modality on outcomes.

More recently, PSMA PET-CT has also been used in therapy planning. In a study of 100 patients with biochemical failure after radical prostatectomy ± prior radiation therapy who underwent 68 Ga-PSMA PET/CT or PET/MRI, uptake indicative for tumor recurrence in 68 Ga-PSMA-PET was found in 76% of the patients with biochemically recurrent prostate cancer.[3] Taken together, 43% of all patients experienced a change in TNM stage due to 68 Ga-PSMA-PET imaging. Due to the additional knowledge of 68 Ga-PSMA-PET imaging, initially planned radiation therapy planning was adapted in 59% of all cases. Thus, even at low PSA levels, 68 Ga-PSMA-PET imaging may have an important clinical impact on staging and radiation therapy management in patients with biochemically recurrent prostate cancer.

up.picr.de/36680775xs.png

Theranostic

As part of treatment planning, theranostics has also emerged in the past several years.

up.picr.de/36680566mh.png

In a phase two, single-arm, single-center trial assessing the role of 177Lu-PSMA-617 in patients with mCRPC, 50% of patients had more than a 50% PSA response, and 27% of patients had more than an 80% PSA response.[4] These results are quite encouraging, but there is still more room for improvement.

Dr. Fanti concluded noting that PSMA PET-CT is (i) non-invasive, simple, and reproducible, (ii) allows clinicians to study local disease, nodes, bone, and other visceral organs with one imaging modality, (iii) is more sensitive than other imaging methods, and (iv) has rapid diffusion and is easy to implement.

[ up.picr.de/36680613xy.png ]

Presented by: Stefano Fanti, MD, Director of PET Center, Director of Nuclear Medicine Division, Orsola-Malpighi Hospital, Professor of Diagnostic Imaging, University of Bologna, Bologna, Italy

Written by: Zachary Klaassen, MD, MSc – Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia at the 2019 Advanced Prostate Cancer Consensus Conference (APCCC) #APCCC19, Aug 29 - 31, 2019 in Basel, Switzerland

References:

[1] Yaxley JW, Raveenthiran S, Nouhaud FX, et al. Risk of metastatic disease on 68 gallium-prostate-specific membrane antigen positron emission tomography/computed tomography scan for primary staging of 1,253 men at the diagnosis of prostate cancer. BJU Int 2019 Sep;124(3):401-407.

[2] De Visschere PJL, Standaert C, Futterer JJ, et al. A systematic review on the role of imaging in early recurrent prostate cancer. Eur Urol Oncol 2019 Feb;2(1):47-76.

[3] Habl G, Sauter K, Schiller K, et al. 68 Ga-PSMA-PET for radiation treatment planning in prostate cancer recurrences after surgery: Individualized medicine or a new standard of salvage treatment.

[4] Hofman MS, Violet J, Hicks RJ, et al. [177Lu]-PSMA-617 radionuclide treatment in patients with metastatic castration-resistant prostate cancer (LuPSMA trial): a single-centre, single arm, phase 2 study. Lancet Oncol 2018 Jun;19(6):825-833.