University of Groningen Exploring new molecular imaging concepts of prostate cancer Wondergem, Maurits

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University of Groningen

Exploring new molecular imaging concepts of prostate cancer

Wondergem, Maurits

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Conclusions and future

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Few fields in nuclear medicine show such rapid development as imaging of prostate cancer. Increasing interest in prostate cancer imaging is not only driven by the wide availability of Positron Emission Tomography (PET) and PET/Computed Tomography (CT) scanners resulting from the success of PET/CT with 18_{F-fluorodesoxyglucose (FDG) in}

many oncologic, inflammatory and infectious diseases, but also from the development of many tracers that may give insight in the extent of prostate cancer.

In prostate cancer imaging, conventional nuclear medicine imaging techniques using gamma-emitting tracers, such as planar scintigraphy or Single Photon Emission Computed Tomography (SPECT), are increasingly replaced by techniques that use positron emitters, which enable PET. Moreover, there is a shift towards hybrid imaging. While PET/CT is frequently used in clinical practice, PET/MRI is still used primarily for scientific purposes. Also, a trend is observed from the development of tracers that visualise pathways commonly affected in multiple diseases to tracers that visualise pathways that are more specific for a particular disease.

Detection of bone metastases

Trends described in the previous paragraph are seen when it comes to detection of bone metastases of prostate cancer. For decades nuclear medicine played a pivotal role in detection of bone metastases by means of 99m_{Tc-diphosphonates bone scintigraphy}

(BS). However, higher diagnostic accuracies for detection of bone metastases are found with hybrid PET/CT using 18_{F-sodiumfluoride (NaF),}11_{C-choline or}18_{F-fluorocholine}

in literature as reviewed in this thesis, which is underpinned by data in this thesis indicating improved sensitivity and specificity of NaF PET/CT at initial staging of prostate cancer patients as compared to BS. Furthermore it is shown that in comparison to NaF PET/CT, BS yields inconclusive results in a relatively high number of patients; 23% and 3% for BS and NaF PET/CT, respectively while further diagnostic testing is necessary in 16 and 2%, respectively. Therefore to our opinion BS should not be used when NaF PET/CT is available.

Interestingly, studies that compared NaF and/or choline based PET tracers with BS used acquisition protocols for bone scintigraphy, which are probably suboptimal

(1-4). None of the included studies in the literature review used SPECT/CT, while a

prospective diagnostic accuracy study reported a sensitivity and specificity of 98 and 96% for detection of bone metastases, respectively (5). The performance of SPECT/CT in this study with a mixed oncological population was similar to that of NaF PET/CT and

11_{C-choline or}18_{F-fluorocholine PET/CT. Therefore further evaluation of the diagnostic}

accuracy of SPECT/CT with 99m_{Tc-diphosphonates is of interest, especially for those}

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Given the promising results of PET/CT with Prostate Specific Membrane Antigen (PSMA) targeted tracers for detection of prostate cancer lesions, evaluation of the diagnostic accuracy of these tracers for detection of bone metastases is of great interest (6-8). Once an improved accuracy of these tracers for detection of bone metastases has been established, potent new imaging modalities with the ability to detect both bone metastases and metastases in soft tissues will become generally available for clinical use.

Acquisition parameters of 18_{F-fluorocholine}

As mentioned before FDG PET/CT is a successful nuclear medicine imaging technique and is, at present, the cornerstone of PET/CT imaging in most nuclear medicine departments. It is observed that some aspects of FDG PET/CT imaging, including aspects of patient preparation and acquisition timing, are copied to other tracers once they find their way into clinical practice. Choline based tracers were the first tracers enabling visualisation of both bone and soft tissue lesions in prostate cancer patients, which found their way in standard clinical practice and are mentioned in the guidelines (9, 10). In this thesis it is shown that fasting for at least 6 hours, which is a common patient preparation in FDG PET/CT and, which is also frequently proposed for 11_{C-choline or}18_{F-fluorocholine}

PET/CT, does not influence the uptake of 18_{F-fluorocholine in the gastrointestinal tract.}

More specifically, it has been demonstrated that it does not influence tracer uptake in regions of the gastrointestinal tract that may interfere with the detection of lymph node metastases. Therefore, fasting before 11_{C-choline or}18_{F-fluorocholine PET/CT is not}

recommended and can safely be omitted.

For 18_{F-fluorocholine it is shown in this thesis that most lesions are already seen}

on images acquired 4 to 7 minutes after intravenous administration. However, late images acquired 45 to 60 minutes post injection (p.i.) have a higher discriminatory ability between malignant and non-malignant lymph nodes, due to a decrease in

18_{F-fluorocholine activity over time in non-malignant lymph nodes, which results}

in absence of 18_{F-fluorocholine in most of those nodes on late images. According to}

bone lesions both early and late images are able to discriminate malignant from non-malignant lesions with a similar accuracy. However, it must be acknowledged that a minority of malignant bone lesions were missed on late images, due to increased

18_{F-fluorocholine activity in muscle over time, which resulted in diminished contrast}

between bone lesions and physiologic muscle activity. Incidentally bone lesions may also be missed due to imaging of blood flow in the tumour at early images without tracer deposition, resulting in absent activity at the late time point. Therefore, at least a dual time-point acquisition protocol is recommended; consisting of early images, starting the acquisition a few minutes post injection, and late images. If a single time-point acquisition is preferred, for whatever reason, late imaging is recommended over early imaging.

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In contrast to other studies no evidence was found that early images increased the detection rate of local prostate cancer recurrence after prostatectomy. Instead arguments were found that focally increased activity seen near the prostatic fossa corresponded to physiologic activity in the penile bulb.

18_F-DCFPyL

The shift to use of tracers that are more specific for a particular disease is clearly seen since tracers that target the PSMA ligand found their way into clinical practice. Some studies showed better detection rates of PSMA targeted tracers as compared to choline based tracers, and as a result more and more nuclear medicine departments cross over to PSMA targeted tracers (11). Generally, PSMA PET/CT images are acquired at 60 minutes p.i., which is in line with the commonly applied acquisition time point of FDG PET/ CT images. However in this thesis it is shown that image acquisition with 18_F-DCFPyL,

a promising PSMA targeting tracer, at 120 min p.i. detects more lesions in 39% of the patients in comparison with image acquisition at 60 min p.i. and in 9% of patients a change in TNM stage is seen. Therefore it should be recommended to acquire images with 18_{F-DCFPyL 120 min p.i. at the earliest. Given the increasing activity in prostate}

cancer lesions over time, it would be of interest to evaluate whether image acquisition at time points beyond 120 minutes p.i. increases the detection rate of suspicious lesions even further.

Best tracer for imaging of prostate cancer

Although, especially according to the standards for reporting diagnostic accuracy studies (STARD 2015), the currently available evidence for use of PSMA targeted tracers instead of choline based tracers is very limited (12), choline based tracers seem to lose ground in clinical practice from PSMA targeted tracers. Initially PSMA tracers were mainly used for detection of sites accountable for biochemical recurrences since choline based tracers were also indicated at this stage of the disease by the guidelines. However, the clinical experience with PSMA tracers has encouraged clinicians to also use those tracers in primary staging. Although it is well conceivable that this is a sensible approach, it must be noticed that hardly any evidence supports this approach. Therefore, it would be of great interest to elucidate the diagnostic characteristics of PSMA tracers in primary staging of prostate cancer.

The quest for the best tracers for prostate cancer imaging does not end with the tracers that are discussed extensively in this thesis. As mentioned in the introduction of this thesis there are a lot of other potential tracers for imaging of prostate cancer beyond

99m_{Tc-diphosphonates, NaF, choline based tracers and tracers that target PSMA, including} 18_F-FACBC,11_{C-methionine,} 18_F-FDHT,18_F-FLT,18_{F-FMAU and}68_{Ga-bombesin analogues and}

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The reference standard

Interpretation of images is an important aspect of medical imaging especially when it comes to studies that are aimed to position new imaging techniques and compare them to other diagnostic techniques already in use in standard clinical practice. A reference standard (RS) is needed to test whether statements on presence or absence of disease based on imaging techniques match with reality. The RS is defined as the best available method for establishing the presence or absence of the target condition according to STARD 2015 (12). In practice histopathological confirmation is usually accepted as the best RS or gold standard and studies that lack this confirmation are often considered less valuable and the results often remain a matter of debate. In this debate, it is often overlooked that histopathological confirmation in imaging of oncologic patients with a considerable risk of having metastases, which can be considered a systemic disease, is most often practically impossible, nor ethically acceptable, for both per patient and per lesions analysis. A major drawback is the inability to determine the number of false negative and true negative lesions/patients. Another drawback is the possibility of false negative findings in histopathological biopsies, which is certainly a factor if there is no good opportunity for image-guided biopsies of lesions only visible on PET images without correlating anatomical substrate on CT. In oncologic imaging, especially when presence of metastases is likely, determination of a suitable RS is probably more difficult than that for better diagnostic imaging modalities. It can be suggested that a combination of histopathological examination and a follow-up period, including the results of follow-up imaging (including MRI, CT, BS, and PET scans) and biochemically follow-up (PSA), is most suitable to serve as a RS in prostate cancer imaging.

Trends in therapy

There is always an interaction between the ability to diagnose and stage the disease and the therapeutic options. While according to most guidelines bone metastases preclude therapies with curative intent, this perception is shifting maybe as a result of higher sensitivities of newer imaging modalities and the ability to better localise the metastatic lesions. There is growing evidence that an intermediate oligometastatic state has favourable survival outcomes compared to patients with widespread metastatic disease. Some patients may be curable with aggressive multimodality treatments

(13). For oligometastatic bone metastases stereotactic body radiation therapy has

been shown to be safe and well tolerated with high local control rates (14-16). Also for more extensive metastasised disease at initial diagnosis there is a shift toward more aggressive treatment. Long-term hormone therapy has been the standard of care for advanced prostate cancer since the 1940s, however there is evidence that docetaxel treatment should become part of the standard of care for adequately fit patients commencing long-term hormone therapy (17). In these perspectives imaging techniques with higher diagnostic performances, with both high sensitivity and high specificity and the ability to localise metastases become even more important for proper selection of therapy and evaluation of patients with prostate cancer.

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As mentioned before PSMA targeted tracers are increasingly used in clinical practice because of the expected better diagnostic accuracy of those tracers. However, there is another interesting feature according to molecules that target PSMA. Linked to beta- or alpha-emitting isotopes PSMA targeted therapies are feasible. Promising results are reported including a retrospective study cohort study that showed a median survival benefit of approximately 10 weeks (29.4 versus 19.7 weeks) for a cohort that received standard of care plus 177_{Lu-PSMA therapy compared to a cohort that only received}

standard of care, including hormone therapy, docetaxel, cabazitaxel, abiraterone and enzalutamide (18). In the light of those therapies PSMA PET-tracers including 18_F-DCFPyL

may serve as a theranostic and may be used for treatment planning, dosimetric calculations, and treatment follow-up.

PET/MRI

New hybrid imaging techniques that combine Magnetic Resonance Imaging (MRI) with PET may potentially increase accuracy as compared to PET/CT. MRI has superior soft-tissue resolution, while PET is highly specific for diagnosis of particular diseases, especially PET with new highly targeted tracers. Although there are technical challenges including attenuation correction based on MR images, some studies have shown that the performance of PET/MRI for specific indications is at least equivalent to, if not slightly better than that of PET/CT. In patients with biochemically recurrence lesion detection of 11_{C-choline PET/CT and PET/MRI has been shown to be equivalent, however PET/}

MRI allocated lesions better, especially in bone and the pelvis (19). Higher diagnostic accuracy of 68_{Ga-PSMA-HBED-CC PET/MRI in localising prostate cancer than either multi}

parametric MRI or PET alone has been reported on the basis of sextant pathology. Therefore, this technique could be used to guide diagnostic biopsies (20). PET/MRI may also improve the accuracy of detection of bone metastases. Focal bone uptake observed on PET images acquired using NaF, choline based tracers or PSMA targeted tracers is not always accompanied by anatomical substrate on CT. Diffusion weighted MRI is more sensitive for detection of bone metastases as compared with CT (21, 22) and therefore PET/MRI may increase the certainty of the status of bone lesions and decrease the number of equivocal findings. Those first results are cautiously positive, however PET/ MRI in prostate cancer involves a new field to be explored.

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REFERENCES

1. Even-Sapir E, Metser U, Mishani E, Lievshitz G, Lerman H, Leibovitch I. The detection of bone metastases in patients with high-risk prostate cancer: 99mTc-MDP planar bone scintigraphy, single- and multi-field-of-view SPECT, 18F-fluoride PET, and 18F-fluoride PET/CT. J Nucl Med. 2006;47:287-297.

2. Picchio M, Spinapolice EG, Fallanca F, et al. 11C]choline PET/CT detection of bone metastases in patients with PSA progression after primary treatment for prostate cancer: Comparison with bone scintigraphy. Eur J Nucl Med Mol Imaging. 2012;39:13-26.

3. Withofs N, Grayet B, Tancredi T, et al. (1)(8)F-fluoride PET/CT for assessing bone involvement in prostate and breast cancers. Nucl Med Commun. 2011;32:168-176.

4. Iagaru A, Mittra E, Dick DW, Gambhir SS. Prospective evaluation of (99m)tc MDP scintigraphy, (18)F NaF PET/CT, and (18)F FDG PET/CT for detection of skeletal metastases. Mol Imaging Biol. 2012;14:252-259.

5. Zhao Z, Li L, Li F, Zhao L. Single photon emission computed tomography/spiral computed tomography fusion imaging for the diagnosis of bone metastasis in patients with known cancer. Skeletal Radiol. 2010;39:147-153.

6. Afshar-Oromieh A, Malcher A, Eder M, et al. PET imaging with a [68Ga]gallium-labelled PSMA ligand for the diagnosis of prostate cancer: Biodistribution in humans and first evaluation of tumour lesions. Eur J Nucl Med Mol Imaging. 2013;40:486-495.

7. Afshar-Oromieh A, Avtzi E, Giesel FL, et al. The diagnostic value of PET/CT imaging with the (68) ga-labelled PSMA ligand HBED-CC in the diagnosis of recurrent prostate cancer. Eur J Nucl Med

Mol Imaging. 2015;42:197-209.

8. Herlemann A, Wenter V, Kretschmer A, et al. 68Ga-PSMA positron emission tomography/ computed tomography provides accurate staging of lymph node regions prior to lymph node dissection in patients with prostate cancer. Eur Urol. 2016;70:553-557.

9. Heidenreich A, Bastian PJ, Bellmunt J, et al. EAU guidelines on prostate cancer. part 1: Screening, diagnosis, and local treatment with curative intent-update 2013. Eur Urol. 2014;65:124-137. 10. Integraal Kankercentrum Nederland. Richtlijn prostaat carcinoom version 2.1. 2014. Available

at: http://www.oncoline.nl/prostaatcarcinoom, accessed May 11, 2017

11. Afshar-Oromieh A, Zechmann CM, Malcher A, et al. Comparison of PET imaging with a (68)ga-labelled PSMA ligand and (18)F-choline-based PET/CT for the diagnosis of recurrent prostate cancer. Eur J Nucl Med Mol Imaging. 2014;41:11-20.

12. Bossuyt PM, Reitsma JB, Bruns DE, et al. STARD 2015: An updated list of essential items for reporting diagnostic accuracy studies. BMJ. 2015;351:h5527.

13. Broughman JR, Chen RC. Management of node-positive and oligometastatic prostate cancer.

Semin Radiat Oncol. 2017;27:79-86.

14. Muacevic A, Kufeld M, Rist C, Wowra B, Stief C, Staehler M. Safety and feasibility of image-guided robotic radiosurgery for patients with limited bone metastases of prostate cancer. Urol

(11)

172

15. Decaestecker K, De Meerleer G, Lambert B, et al. Repeated stereotactic body radiotherapy for oligometastatic prostate cancer recurrence. Radiat Oncol. 2014;9:135-717X-9-135.

16. Berkovic P, De Meerleer G, Delrue L, et al. Salvage stereotactic body radiotherapy for patients with limited prostate cancer metastases: Deferring androgen deprivation therapy. Clin

Genitourin Cancer. 2013;11:27-32.

17. James ND, Sydes MR, Clarke NW, et al. Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): Survival results from an adaptive, multiarm, multistage, platform randomised controlled trial. Lancet. 2016;387: 1163-1177.

18. Rahbar K, Bode A, Weckesser M, et al. Radioligand therapy with 177Lu-PSMA-617 as A novel therapeutic option in patients with metastatic castration resistant prostate cancer. Clin Nucl

Med. 2016;41:522-528.

19. Souvatzoglou M, Eiber M, Takei T, et al. Comparison of integrated whole-body [11C]choline PET/MR with PET/CT in patients with prostate cancer. Eur J Nucl Med Mol Imaging. 2013;40: 1486-1499.

20. Eiber M, Weirich G, Holzapfel K, et al. Simultaneous 68Ga-PSMA HBED-CC PET/MRI improves the localization of primary prostate cancer. Eur Urol. 2016;70:829-836.

21. Hricak H, Choyke PL, Eberhardt SC, Leibel SA, Scardino PT. Imaging prostate cancer: A multidisciplinary perspective. Radiology. 2007;243:28-53.

22. Luboldt W, Kufer R, Blumstein N, et al. Prostate carcinoma: Diffusion-weighted imaging as potential alternative to conventional MR and 11C-choline PET/CT for detection of bone metastases. Radiology. 2008;249:1017-1025.

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