Category: News

Refuting Oncologist’s Doubts About Radioligand Therapy: A Case for Confidence

As ¹⁷⁷Lu-PSMA therapy gains attention for its role in treating metastatic castration-resistant prostate cancer (mCRPC), some oncologists remain hesitant to fully embrace it. Their concerns, while understandable, are often based on regulatory, safety, and patient selection uncertainties. However, a growing body of evidence and clinical experience suggests that many of these doubts are unfounded, and it’s time to address them head-on.

1. Regulatory Approval: Procedural Lag & Geographic Differences

While ¹⁷⁷Lu-PSMA (Pluvicto© by Novartis) was approved by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) as a late-stage treatment for metastatic castration-resistant prostate cancer, one of the most frequent arguments against the widespread adoption of ¹⁷⁷Lu-PSMA therapy is the lack of formal approval at earlier stages. Without regulatory approval, oncologists express concerns over the absence of established inclusion criteria and treatment guidelines. However, this objection overlooks several important factors:

• Precedent from Lutathera: Radioligand therapy (RLT) is not a new concept. ¹⁷⁷Lu-DOTATATE (Lutathera©), a similar radioligand treatment for neuroendocrine tumors, was approved by the EMA in 2017 and by the FDA in 2018 for patients with locally advanced or metastatic disease that is unresectable or progressive. Its success set a clear path for the approval of ¹⁷⁷Lu-PSMA. The PSMA-targeted approach is based on the same theranostic principle, combining diagnosis and therapy, and has benefited from nearly a decade of clinical application in countries like Germany. This track record builds confidence in its therapeutic framework.
• Flexible Access: While the medical regulatory framework in the US is stricter, many countries have developed a more flexible and patient-centred approach, where doctors have greater medical liberty to recommend treatments based on individual patient needs, such as intolerance to chemotherapy or hormonal treatments. This approach has greatly expanded access to ¹⁷⁷Lu-PSMA, even at earlier disease stages. The accumulated experience has been invaluable in refining patient selection criteria and demonstrating safety in real-world clinical settings. Germany, for instance, has led the charge in integrating this therapy into their prostate cancer treatment landscape at various stages with highly promising results.
• Clinical Trials: Rigorous clinical trials, including PSMAfore and UpFrontPSMA, continue to accumulate robust data on the safety and efficacy of ¹⁷⁷Lu-PSMA. These studies are critical to advancing the therapy to earlier stages, and their outcomes support the use of this therapy as a front-line option in patients with high PSMA expression.

2. Adverse Effects: Manageable and Comparable to Conventional Therapies

Concerns over adverse effects, particularly nephrological and haematological toxicities such as microangiopathy or thrombocytopenia, are often cited by oncologists as reasons to hesitate in applying ¹⁷⁷Lu-PSMA therapy. However, the data we have thus far indicates that the side effect profile is not only manageable but, in many cases, far less severe than that associated with conventional treatments like chemotherapy and external radiation. Besides, in such a disease as cancer “it is not reasonable to define absolute contra-indications. In general, the chances to improve should outweigh the risks of harming a patient.” ^[1]

• High Precision: The key advantage of ¹⁷⁷Lu-PSMA, or any radioligand therapy for that matter, is its ability to selectively target cancer cells while sparing healthy tissue, reducing off-target effects. Chemotherapy, on the other hand, has a well-known systemic impact, causing fatigue, nausea, and significant haematologic side effects such as neutropenia and anaemia, which can be far more debilitating. Similarly, external radiation can lead to localized damage to healthy organs surrounding the tumor. In contrast, ¹⁷⁷Lu-PSMA’s targeted approach minimizes these risks and actually improves the quality of life, as demonstrated in multiple trials and compassionate use settings.

The main challenge is the natural presence of PSMA enzymes in other organs like the salivary glands. The name "Prostate" in PSMA (Prostate Specific Membrane Antigen) is to an extent misleading; while this enzyme was indeed first discovered on the surface of normal prostate cells, it is actually present in greater numbers in other organs. The most common side effect after ¹⁷⁷Lu-PSMA therapy is xerostomia or dry mouth. However, studies and experience have shown that this is mostly transient and reversible and is far outweighed by the therapeutic benefits. Moreover, doctors have developed prophylactic precautions to mitigate these expected side-effects by accompanying intravenous saline infusions to maintain sufficient hydration and if needed protective co-medication.

• Unclear Source of Side Effects: Given that most novel therapeutic approaches first involve late-stage, heavily pre-treated patients, it is difficult to definitively attribute some side effects like thrombocytopenia to the therapy itself or to the progression of advanced cancer. In fact, there is growing evidence that administering ¹⁷⁷Lu-PSMA earlier in the disease course — before patients undergo multiple rounds of chemotherapy or hormonal treatment — could reduce the incidence of side effects and further enhance the therapeutic effect, as healthier bone marrow and immune systems are better equipped to tolerate the therapy and even combat the cancer weakened by it.

3.  Patient Selection Criteria: Gaining Consensus

Another area of ongoing debate is how to best select patients for ¹⁷⁷Lu-PSMA therapy. Some oncologists argue that without universal criteria, treatment protocols will remain inconsistent, leading to variable outcomes. However, the selection process for ¹⁷⁷Lu-PSMA therapy is actually clearer than for many other treatments. The field is, after all, called "theranostics" for a reason.

• PSMA PET Imaging: PSMA enzyme first established itself as a diagnostic target. The integration of ⁶⁸Ga-PSMA PET/CT imaging as part of the pre-treatment assessment protocol was a game-changer. It enables the detection of micrometastases that are not “visible” with traditional diagnostic methods such as ¹⁸F-FDG or scintigraphy, ensuring precise staging of the disease. This imaging modality provides a detailed evaluation of PSMA expression, ensuring that only patients with high uptake are considered for therapy. In fact, “PSMA-PET (or PSMA-SPECT) is a strong and relative unique factor for prediction of an individual patient’s response probability to ¹⁷⁷Lu-PSMA-RLT.”¹ As more institutions adopt this tool, patient selection will become more consistent, and variability in treatment outcomes will decrease.
• Experience in Germany and Australia: Countries like Germany and Australia, which have been at the forefront of ¹⁷⁷Lu-PSMA research and application, have accumulated a wealth of experience over the past decade. This experience shows that selecting patients based on PSMA expression and prior treatment history leads to highly effective outcomes. Not for nothing is it called "personalized medicine".

4. The Case for Early Intervention

UpFrontPSMA and PSMAfore trials, have shown that the earlier ¹⁷⁷Lu-PSMA is introduced, the better the outcomes, with a more significant reduction in PSA levels and fewer long-term side effects compared to later-stage applications.

Conclusion: Confidence in a Proven Modality

While concerns about regulatory approval, side effects, and patient selection are valid in any new therapy, the evidence surrounding ¹⁷⁷Lu-PSMA therapy strongly supports its safety and efficacy. With over a decade of experience in several countries, ongoing trials, and the successful application of similar therapies like Lutathera, the case for radioligand therapy as a standard-of-care option is compelling. If your oncologist is still hesitant, feel free to put them in touch with us. Cancer requires an interdisciplinary approach.

Bibliography

¹⁷⁷Lu-PSMA-617 radioligand therapy of metastatic castration-resistant prostate cancer: Initial 254-patient results from a prospective registry (REALITY Study). Khreish F, Ghazal Z, Marlowe RJ, Rosar F, Sabet A, Maus S, Linxweiler J, Bartholomä M, Ezziddin S. Eur J Nucl Med Mol Imaging. 2022 Feb;49(3):1075-1085. doi: 10.1007/s00259-021-05525-7. Epub 2021 Sep 7. PMID: 34494131; PMCID: PMC8803625.

[¹⁷⁷Lu]Lu-PSMA-Radioligand Therapy Efficacy Outcomes in Taxane-Naïve Versus Taxane-Treated Patients with Metastatic Castration-Resistant Prostate Cancer: A Systematic Review and Metaanalysis. Swayamjeet Satapathy, Ranjit K. Sahoo, Chandrasekhar Bal, Journal of Nuclear Medicine May 2023, 265414; DOI: 10.2967/jnumed.123.26541

Comparative Analysis of Morphological and Functional Effects of ²²⁵Ac- and ¹⁷⁷Lu-PSMA Radioligand Therapies (RLTs) on Salivary Glands. Feuerecker, Benedikt & Gafita, Andrei & Langbein, Thomas & Tauber, Robert & Seidl, Christof & Bruchertseifer, Frank & Gschwendt, Jürgen & Weber, Wolfgang & D'Alessandria, Calogero & Morgenstern, Alfred & Eiber, Matthias. (2023). International Journal of Molecular Sciences. 24. 16845. 10.3390/ijms242316845.

Extensive ¹⁷⁷Lu-PSMA Radioligand Therapy Can Lead to Radiation Nephropathy with a Renal Thrombotic Microangiopathy–like Picture. Schäfer, Hannah & Mayr, Sarah & Büttner, Maike & Knorr, Karina & Steinhelfer, Lisa & Böger, Carsten & Gschwend, Jürgen & Heemann, Uwe & Eiber, Matthias & Schmaderer, Christoph & Tauber, Robert. (2022). European Urology. 83. 10.1016/j.eururo.2022.05.025.

Joint EANM/SNMMI procedure guideline for the use of ¹⁷⁷Lu-labeled PSMA-targeted radioligand-therapy (¹⁷⁷Lu-PSMA-RLT). Kratochwil, Clemens & Fendler, Wolfgang & Eiber, Matthias & Hofman, Michael & Emmett, Louise & Calais, Jeremie & Osborne, Joseph & Iravani, Amir & Koo, Phillip & Lindenberg, Liza & Baum, Richard P. & Bozkurt, Murat & Delgado Bolton, Roberto C. & Ezziddin, Samer & Forrer, Flavio & Hicks, Rodney & Hope, Thomas & Kabasakal, Levent & Konijnenberg, Mark & Hermann, Ken. (2023). European Journal of Nuclear Medicine and Molecular Imaging. 50. 10.1007/s00259-023-06255-8.

Long-Term Nephrotoxicity of ¹⁷⁷Lu-PSMA Radioligand Therapy. Steinhelfer, Lisa & Lunger, Lukas & Cala, Lisena & Pfob, Christian & Lapa, Constantin & Hartrampf, Philipp & Buck, Andreas & Schäfer, Hannah & Schmaderer, Christoph & Tauber, Robert & Brosch-Lenz, Julia & Haller, Bernhard & Meissner, Valentin & Knorr, Karina & Weber, Wolfgang & Eiber, Matthias. (2023). Journal of Nuclear Medicine. 65. jnumed.123.265986. 10.2967/jnumed.123.265986.

Safety and Efficacy of [¹⁷⁷Lu]-PSMA-I&T Radioligand Therapy in Octogenarians with Metastatic Castration-Resistant Prostate Cancer: Report on 80 Patients over the Age of 80 Years. Tauber R, Knorr K, Retz M, Rauscher I, Grigorascu S, Hansen K, D'Alessandria C, Wester HJ, Gschwend J, Weber W, Eiber M, Langbein T. J Nucl Med. 2023 Aug;64(8):1244-1251. doi: 10.2967/jnumed.122.265259. Epub 2023 Jun 15. PMID: 37321824.

^[1] Joint EANM/SNMMI procedure guideline for the use of ¹⁷⁷Lu-labeled PSMA-targeted radioligand-therapy

We are proud to announce that we have been accredited as a Theranostics Center of Excellence by the European Association of Nuclear Medicine (EANM). Currently, our facility is the only one in Austria to be awarded the EARL certificate.

You can listen to this article.

The European Association of Nuclear Medicine (EANM) hosted its annual conference, EANM24, from October 19-22, 2024, in Hamburg, Germany. EANM conferences are known for showcasing advancements in nuclear medicine, which can be broadly categorized into key areas:

• New Targets: Identification of novel proteins and enzymes in different cancers and lesions
• Novel Ligands: Development of transport molecules with enhanced binding capabilities
• New Tracers: better more potent radionuclides with a more limited radiation radius to minimize the damage to the surrounding healthy cells
• Expanded Applications of Known Radioligands: discovery of known proteins / enzymes in other cancers and lesions.

As usual during such professional get-togethers, this year’s conference also focused on how to bring theranostics to patients, addressing technical issues such as clinic setups, doctor training, patient flow, and enhancing the “last mile” delivery. Notably, one presentation from Finland examined the feasibility of outpatient theranostic treatment—something our clinic has been a shining example of. ¹

Streamlining and unifying EU-wide regulations would further improve patient access to nuclear medicine therapies, with Austria providing a strong model for efficient practice.

AI and Nuclear Medicine

Artificial intelligence was a prominent topic, with discussions on AI’s potential to enhance nuclear medicine, for example, in interpreting PET scans. AI's ability to improve diagnostics could represent a substantial advancement in accuracy and efficiency.

Applications of PSMA- and DOTATATE-Based Theranostics

PSMA and DOTATATE-based imaging and therapy have become standard-of-care, with over a decade of clinical experience now guiding the development of new tracers and targets, such as FAP. A major theme was expanding PSMA therapy to earlier stages of prostate cancer and addressing resistance issues by shortening treatment intervals — a protocol our clinic has pioneered. Our streamlined protocol consists of three sessions with four-week intervals in contrast to the usual six to eight based on the research of our chief nuclear specialist Prof. Dr. Hartenbach. This regimen reduces cancer’s adaptive potential, yet still remaining tolerable for patients.

The revolutionary impact of PSMA PET/CT in clinical decision-making is being reaffirmed, with numerous studies corroborating its value in improving diagnosis and survival outcomes.²

New research on somatostatin receptors in myelomas and PSMA enzymes in gliomas holds promise for treating these cancers with targeted radionuclide therapy.³

New Targets

Approximately one-third of prostate cancers are PSMA-negative and do not respond to PSMA theranostics, requiring alternative markers. One study revealed high CD13 positivity in PSMA-negative prostate cancer, suggesting the protein CD13 as a viable target for theranostics.⁴

Emerging Radioligands and Radionuclides

New developments in radioligands include the DOTA-LM3, labelled with ¹⁶¹Terbium ([¹⁶¹Tb]Tb-DOTA-LM3), which demonstrated a seven-fold increase in tumor absorption compared to [¹⁷⁷Lu]Lu-DOTATOC due to its superior two binding points.⁵

Terbium-161 as such also emerged as a promising radionuclide alternative to an often scarce Lutetium-177. ¹⁶¹Tb offers more concentrated radiation while maintaining favorable biodistribution. This radionuclide emits β- radiation similar to Lutetium-177, while also emitting therapeutically active very short range effective conversion electrons and auger electrons in combination with its low energy γ-ray emission, allowing for imaging via Single Photon Emission Computed Tomography (SPECT).⁶

Fibroblast Activation Proteins (FAPi)

FAPi warrants special attention. These proteins, characteristic of inflamed fibrous tissues, have been discovered in the microenvironment of most solid tumors, presenting a promising avenue for a universal therapy in stromal cancers. Stroma plays a critical role in cancer proliferation by nurturing tumors and shielding them from the body’s immune response. The oncological reality, however, is vastly more complex and heterogeneous. While FAPi-based imaging has shown success, therapeutic applications continue to face challenges related to suitable ligands.

These highlights only scratch the surface of the knowledge shared at EANM24. We will delve deeper into select topics and studies in upcoming publications, focusing on those most relevant to our patient cohort.

From EANM ’24 Abstract Book

¹ OP-093 “Establishing a ¹⁷⁷Lu-PSMA treatment site in an oncology outpatient day-ward”, T. Noponen, A. Saikkonen, L. Kääriä, M. Seppänen, K. Mattila, A. Ålgars

² OP-423 “PSMA-PET and PROMISE re-define stage and risk in prostate cancer patients”, M. Karpinski, J. Hüsing, K. Claassen, L. Möller, H. Kajüter, F. Oesterling, V. Grünwald, L. Umutlu, H. Lanzafame, T. Telli, A. Merkel-Jens, A. Hüsing, C. Kesch, K. Herrmann, A. Stang, B. Hadaschik, W. P. Fendle

³ OP-359 “Assessing the theranostic potential of SSTR imaging in advanced multiple myeloma patients - the SCARLET trial”, W. Delbart, I. Karfis, M. Vercruyssen, S. Vercauteren, Z. Wimana, N. Meuleman, P. Flamen, E. Woff
OP-514 “First-In-Human Experience of Peptide Receptor Radionuclide Therapy with ¹⁷⁷Lu-DOTATATE in Patients with Advanced Multiple Myeloma”, W. Delbart, I. Karfis, M. Vercruyssen, S. Vercauteren, Z. Wimana, N. Meuleman, P. Flamen, E. Woff
EP-0113 “Diagnostic utility of ⁶⁸Ga-Prostate-Specific Membrane Antigen-11 PET/CT in glioma recurrence - a prospective analysis”, A. Meena, K. Subramanian, R. Kumar, H. Singh, B. Mittal
EP-0653 “⁶⁸Ga/¹⁷⁷Lu-PSMA theranostics in recurrent high-grade glioma - First study results & future perspectives”, A. Karlberg, B. E. Vindstad, E. M. Berntsen, H. Johansen, T.M. Keil, O. Solheim, S. Kjærnes Øen, T. Skeidsvoll Solheim, L.Eikenes

⁴ OP-424 “CD13 as a Potential Membrane Marker in PSMA-Negative Prostate Cancer: A Complementary or Superior Alternative to PSMA”, Y. Tang, L. Xiao, J. Yang, J. Hou, J. Hong, A. Rominger, K. Shi, S. Hu

⁵ OP-252 “Therapy with the somatostatin receptor antagonist DOTA-LM3 labeled with terbium-161: Interim results of the Phase 0 Study in patients with gastroenteropancreatic neuroendocrine tumors”, J. Fricke, F. Westerbergh, L. McDougall, C. Favaretto, E. Christ, G. Nicolas, S. Geistlich, F. Borgna, M. Fani, P. Bernhardt, N. van der Meulen, C. Müller, R. Schibli, D. Wild

⁶ OP-515 “When Lutetium-177 DOTATATE Is Not Available: Insights Into Use of Terbium-161 in the Treatment of Metastatic Paraganglioma”, N. Jacobs, O. Kolade, K. Hlongwa, S. More
OP-529 “Mixed-LET ¹⁶¹Tb-ART-101 radiopharmaceutical enhances therapeutic responses in advanced prostate cancer”, M. Bio Idrissou, J. Tromp, H. Comas Rojas, L. Lambert, A.
Pinchuk, Y. Medina, A. Carston, R. Hernandez
OP-532 “Development of [¹⁶¹Tb]Tb-DOTA-HYNIC-panPSMA for targeted radionuclide therapy of prostate cancer”, C. Morgat, D. Vimont, K. Attia

The results of the UpFrontPSMA trial are in, unveiled during the ESMO 2024 in Barcelona, and they are truly encouraging for the future of prostate cancer treatment. ¹⁷⁷Lu-PSMA radioligand therapy (RLT) has taken a significant leap forward in the treatment protocol, now positioning ahead of docetaxel chemotherapy. Initially introduced after the VISION trial as a last-in-line therapy for advanced metastatic castration-resistant prostate cancer in heavily pre-treated patients, this RLT has shown remarkable efficacy and a favorable safety profile, allowing it to move closer to the forefront of treatment options. In fact, it seems like the earlier, the more effective it is.

Trial Overview

The UpFrontPSMA phase 2 trial evaluated the efficacy of administering ¹⁷⁷Lu-PSMA prior to docetaxel compared to docetaxel alone in patients newly diagnosed with high-volume metastatic hormone-sensitive prostate cancer (mHSPC). The experimental group received two cycles of ¹⁷⁷Lu-PSMA (7.5 GBq each) followed by six cycles of docetaxel, while the control group received only docetaxel. The primary endpoint^[1] was achieving undetectable prostate-specific antigen (PSA) levels after 48 weeks—a high bar for success.

Participant Selection Criteria

The most critical selection criterion for the trial was high PSMA uptake, with patients requiring a SUVmax above 20 based on ⁶⁸Ga-PSMA PET/CT scans. (As researchers reported, some patients had to be excluded despite having initially demonstrated PSMA-avid lesions. This exclusion occurred because androgen deprivation therapy (ADT) prior to treatment led to downregulation of PSMA expression.)

Adverse Events

The combination of ¹⁷⁷Lu-PSMA with docetaxel did not result in increased toxicity. The most common severe adverse events were the same in the two groups:

• febrile neutropenia (11% in the combination experimental group vs. 10% in the docetaxel-alone control group) and
• diarrhoea (6% in the combination group vs. none in the control group).

The only adverse event that was different in the experimental arm was dry mouth, a known common side effect of the ¹⁷⁷Lu-PSMA. But even this one was all grade 1, so very mild.

Being a targeted therapy, ¹⁷⁷Lu-PSMA was well tolerated with fewer side effects, resulting in better quality of life (QoL). Unlike docetaxel, which caused a rapid decline in QoL, patients receiving ¹⁷⁷Lu-PSMA maintained their well-being longer, with QoL dipping only after the introduction of docetaxel.

Protocol Considerations

There were some concerns about whether the experimental arm might have been underdosed, as only two cycles of ¹⁷⁷Lu-PSMA were administered. Typically, three cycles are standard practice. However, the trial's design aimed to avoid delaying conventional docetaxel treatment.

As a side note, our clinic follows a stricter protocol, spacing the cycles four weeks apart and not the usual six to eight based on the research of Prof. Dr. Hartenbach, our leading specialist. In general, German university hospitals, having played a pivotal role in developing PSMA-targeted therapies in the early 2000s, have accumulated significant expertise in this area.

Results

The results of the trial were highly promising. 41% of patients in the ¹⁷⁷Lu-PSMA plus docetaxel group achieved undetectable PSA levels at the 48-week mark, compared to just 16% in the docetaxel-alone group. This significant difference demonstrates the superior antitumor activity of administering ¹⁷⁷Lu-PSMA therapy before docetaxel, without an increase in toxicity. These findings promise to trigger a change in the standard-of-care and introduce ¹⁷⁷Lu-PSMA in the treatment of mHSPC at the very early stage.

^[1] The predefined, primary goal of a clinical study, against which its success is measured

The WARMTH^[*]-initiated multicentre retrospective study investigated the efficacy and safety of ²²⁵Ac-PSMA radioligand therapy (RLT) in treating metastatic castration-resistant prostate cancer (mCRPC). This study included 488 men from Australia, India, Germany, and South Africa, aged between 37 and 90. Most patients had previously undergone multiple treatments, including chemotherapy, androgen-axis-receptor inhibitors, or ¹⁷⁷Lu-PSMA RLT.

The findings show that 73% of the patients experienced some PSA decline after at least one cycle of ²²⁵Ac-PSMA RLT, with 57% showing a decline of 50% or more. Despite common side effects like xerostomia and bone marrow toxicities (with a notable prevalence of impaired bone marrow observed before treatment initiation), the therapy was generally well-tolerated, even in patients with pre-existing conditions.

With the study being retrospective, ²²⁵Ac-PSMA RLT was frequently administered as a last-line intervention when all other options had been exhausted and proven ineffective.

A significant association was found between a PSA decline of at least 50%, absence of prior exposure to specific treatments, lack of certain metastases, and absence of anaemia at the initiation of ²²⁵Ac-PSMA RLT with extended both progression-free and overall survival. However, the number of treatment cycles did not correlate with improved progression-free survival or overall survival.

In conclusion, ²²⁵Ac-PSMA RLT demonstrated significant antitumor effects in mCRPC, even in individuals with compromised bone marrow and renal function. The impact of previous treatment history and metastatic burden on time to death or disease progression suggests that patients with a comparatively lower disease burden may derive greater benefit from ²²⁵Ac-PSMA RLT.

Our clinic has an established practice of offering our patients with a corresponding disease profile a combination therapy of 1 + 2 (one ²²⁵Ac-PSMA + two ¹⁷⁷Lu-PSMA cycles). 

^[*] WARMTH – World Association of Radiopharmaceutical & Molecular THerapy

Recent research has found that somatostatin receptor type 2 (SSTR2) is overexpressed in certain types of breast cancer, particularly in estrogen receptor (ER) positive tumors. This discovery paves the way for the potential use of the well-established DOTATATE theranostics to improve the diagnosis and treatment of this type of breast cancer. A study involving both preclinical and phase 2 clinical trials demonstrated highly promising results.

In the ever-evolving battle against cancer, the field of radiopharmaceuticals has emerged as a potent weapon, and alpha emitters such as actinium-225, astatine-211, and lead-212 are quickly gaining prominence. These alpha-emitting isotopes are revolutionizing cancer treatment, offering targeted therapy with the potential to eradicate malignant cells while minimizing damage to surrounding healthy tissue.

Radioligand therapy (RLT) utilizing ¹⁷⁷Lu-PSMA gained initial approval in the USA as a final recourse once all other treatment options have been exhausted. However, quite a few ongoing trials are exploring the potential for deploying this therapy earlier in the course of the disease due to its demonstrated safety, efficacy, and relatively low incidence of side effects. In fact, radioligand therapy is very safe. A recent study has demonstrated that even 6 sessions are very well tolerated, what makes this treatment a viable option as a recurring therapy in case of recurrence.

Peptide receptor radionuclide therapy (PRRT) has significantly advanced in the last two decades within the realm of neuroendocrine tumours (NETs), leveraging the overexpression of somatostatin receptors characteristic of these tumours. This same receptor profile is also prevalent in nearly all meningiomas, with expression of somatostatin receptor 1 & 2 (SSTR1 / SSTR2), rendering PRRT a viable treatment option. Multiple studies have scrutinized the efficacy of PRRT (¹⁷⁷Lu-DOTATATE) in meningioma patients, consistently demonstrating its effectiveness, particularly in prolonging progression-free survival (PFS).

In the realm of medical diagnostics, the groundbreaking procedure of ⁶⁸Ga-PSMA PET/CT has emerged as a game-changer, offering unprecedented insights into the assessment and management of prostate cancer. Its extraordinary precision enables clinicians to visualize prostate cancer at a molecular level. It has revolutionized the diagnosis, staging, and personalized treatment strategies for prostate cancer, ultimately enhancing patient outcomes and reshaping the landscape of prostate cancer care. Below is the review of just some of the latest studies.

Nuclear medicine is the fastest growing medical field, specifically in cancer treatment. It is extremely effective and low in side effects affording patients a prolonged and higher-quality life compared to conventional treatments like chemotherapy. It is also very versatile and applied in treatment of many cancer types. Our clinic not only provides cutting-edge therapies such as the radioligand PSMA therapy with ¹⁷⁷Lu and ²²⁵Ac, as well as ¹⁷⁷Lu-Dotatate therapy, but also offers the latest diagnostic procedure, ⁶⁸Ga-FAPI PET/CT. Suitable especially well for such cancer types as breast, colon and pancreatic carcinomas, it represents a pioneering approach in diagnostic precision. Here you can learn more about FAPI in diagnostics.

A study evaluating the efficacy and safety of ¹⁷⁷Lu-PSMA radioligand therapy for treating mCRPC in octogenarians demonstrated that radioligand therapy is safe and effective also in elderly patients. Moreover, patients who have not previously undergone chemotherapy had a better and longer-lasting response both in terms of overall and progression-free survival.

The challenge of the radiation therapy in cancer treatment lies in achieving an optimal radiation level within tumours and metastases, effectively eradicating cancer cells while minimizing harm to surrounding healthy tissues. The combination of Stereotactic Body RadioTherapy (SBRT) and internal radioligand therapy (RLT) with ¹⁷⁷Lu-PSMA appears to be precisely the way to maximize the treatment of oligometastatic prostate cancer.

A recent study demonstrated a remarkable increase in the median biologically effective dose (BED) to 159 Gy with the combined ¹⁷⁷Lu-PSMA RLT and SBRT. Importantly, this was achieved without significant side effects, whereas standalone external radiation typically falls short of reaching 70Gy. SBRT, strategically applied post-RLT, precisely targets any remaining PSMA-positive metastases, as verified by a control PSMA PET/CT after RLT.

In collaboration with our partners specializing in Cyberknife, SBRT and proton/C-Ion-therapy, our clinic offers these advanced therapies in a coordinated approach. We are committed to providing our patients with the cutting-edge oncological treatment, ensuring the highest standards of care and precision in their fight against cancer.

Cancer operates insidiously, shaping a distinct microenvironment even before the emergence of actual cancer cells. This inherent challenge makes crucial early detection difficult. Enter the groundbreaking 'tracer,' designed to detect the FAP alpha receptor on cancer-associated fibroblasts (CAF). This innovative approach unveils the early fingerprints of cancer, akin to fingerprint powder, facilitating early diagnosis that significantly enhances therapeutic decision-making, as evidenced by the latest study.

In another noteworthy study, ⁶⁸Ga-FAPI PET/CT proves its superiority over the conventional ¹⁸F-FDG in oncological diagnostics, especially for detecting metastases and local malignancy recurrence in advanced metastatic pancreatic cancer. The scans exhibit higher lesion intensity (SUV), underscoring the effectiveness of FAPI in targeting the microenvironment of solid tumors prevalent in sarcomas, breast, colon, and pancreatic cancers. Precise diagnostics translates to improved therapy decisions. Our clinic offers ⁶⁸Ga-FAPI; contact us for a consultation and appointment.

Explore further details on FAPI diagnostics here.

Radioligand PSMA therapy with the lutetium isotope ¹⁷⁷Lu has proven to be very effective against metastatic prostate cancer. Nevertheless, there is still a share of patients who do not respond to this treatment. A possible reason may be insufficient radiation dose delivered to the cancer cells so that they are able to survive. So scientists are now experimenting with another isotope terbium-161 (¹⁶¹Tb) that emits a wider range of energies, namely conversion and Auger electrons next to beta radiation. It has decay properties similar to 177-Lutetium, half-life of about 7 days, but higher destructive power due to co-emission of conversion and Auger electrons. Their short radiation range allows it to release all their power directly in the cancer cells with almost no damage to the neighbouring healthy cells.

PSMA PET/CT is the current mainstay diagnostic tool to stage prostate cancer, especially valuable if metastatic, and to decide on the right treatment (suitability of radioligand therapy ¹⁷⁷Lu-PSMA). The newest study has established that it can also be used to evaluate the effectiveness of the treatment with Androgen Receptor Pathway Inhibitors (ARPIs).

PSMAfore trial by Novartis (Phase III trial of ¹⁷⁷Lu-PSMA-617 in taxane-naïve patients with mCRPC) has not only met its primary endpoint of radiographic progression-free survival (rPFS) but has shown amazing results with the potential to change the clinical practice, as presented at 2023 ESMO conference. Radioligand therapy (RLT) with ¹⁷⁷Lu-PSMA-617 in pre-chemo patients brought about the median rPFS of 12 months compared to only 5,6 months in the control group under standard care. The radioligand treatment is also better tolerated with fewer grade 3 adverse effects. The results seem to demonstrate – the earlier in the course of the disease the RLT is applied, the more effective it is. Our own clinical practice certainly corroborates this in relevant cases.

Although rare (orphan) and slow growing cancer type, some neuroendocrine tumors (NETs) are associated with rapid progression and poor prognosis. Original authorization for ¹⁷⁷Lu-DOTATATE (Lutathera®) was based on the results of the NETTER-1 trial for inoperable midgut NETs. In the NETTER-2 trial ¹⁷⁷Lu-DOTATATE has now also demonstrated its efficacy in patients with Grade 2 and 3 advanced gastroenteropancreatic NETs (GEP-NETs), and at that - as the first line treatment for newly diagnosed patients.

Fibroblast activation protein (FAP) is overexpressed in the tumor microenvironment or stroma of over 90% of solid tumors, what makes it a promising target for both therapeutic and molecular imaging applications. FAP-targeting molecular imaging has been quickly gaining steam in cancer diagnostics. It is especially useful for tumors with a strong desmoplastic (forming fibrous tissue) reaction, such as breast, colon, and pancreatic cancers.

Since the end of the VISION trial that proved ¹⁷⁷Lu-PSMA to be an effective treatment of metastasized prostate cancer, the next question arose – does it work even better if applied earlier in the course of the disease? An exciting study has now demonstrated that ¹⁷⁷Lu-PSMA applied prior to chemotherapy is indeed more effective.

The metaanalysis was designed to evaluate the impact of prior taxane chemotherapy on response and survival in mCRPC patients after ¹⁷⁷Lu-PSMA RLT.

It pooled together 13 studies comprising 2.068 patients. The results were:

• Taxane-naïve patients had 1,82 times better odds of biochemical response, i.e. 1,8 higher chances of no PSA rise.
• Taxane-naïve status was a predictor of both: significantly better progression-free survival (over 40%) and overall survival (over 46%).

Another clinical trial underway looks at the effectiveness of ¹⁷⁷Lu-PSMA RLT in parallel with the anti-hormonal Androgen Deprivation Therapy. Results are expected in Q3 2024.

Manufacturing radioligands is an extremely complex and time-sensitive process, because radiopharmaceuticals need to be “delivered” directly to the cancer cells within days after being synthesized. This is what personalized targeted radionuclide therapy, a game-changer in oncology, is all about. Having our own laboratory and highly proficient radiochemists helps us serve our patients in-time and with the highest possible flexibility.

Some prostate cancer cases will never develop metastases or any clinical symptoms and are defined as clinically insignificant. Accurate diagnosis able to differentiate between clinically significant and insignificant lesions leads to better disease management. The latest research of our working group has demonstrated that combined hybrid imaging using [¹⁸F] fluoromethylcholine (FMC) PET and [⁶⁸Ga]Ga-PSMA^HBED-CC conjugate 11 (PSMA)-PET achieved higher sensitivity for detecting clinically significant prostate cancer compared to multiparametric MRI alone. The PSMA PET is the leading method in this hybrid approach and is in fact more reliable than MRI alone.

As many trials with ¹⁷⁷Lu-PSMA radioligand therapy (RLT) have demonstrated, a reduction of PSA of over 50% leads to statistically significant increase in overall survival. Our clinic’s results show the reproducibility of this data. After 3 sessions of ¹⁷⁷Lu-PSMA PSA decreases by an average of 68%. Preserving remissions and increasing quality of life of our patients remain our goals.

Following FDA approval in March 2022, European Medicines Agency (EMA) also approved Pluvicto® (lutetium (¹⁷⁷Lu) vipivotide tetraxetan) of Novartis in December 2022 for targeted radioligand treatment of progressive PSMA–positive metastatic castration-resistant prostate cancer. The EMA approval is based on the results from the Phase III VISION trial, in which “radioligand therapy with ¹⁷⁷Lu-PSMA-617 prolonged radiographic progression-free survival and overall survival when added to standard care in patients with advanced PSMA-positive metastatic castration-resistant prostate cancer”^[1]. Pluvicto® is to be used together with androgen deprivation therapy in adults previously treated with androgen receptor pathway inhibitors and taxanes. “The lutetium-177-PSMA was developed by the German Cancer Research Center (DKFZ) in cooperation with Heidelberg University Hospital and Heidelberg University.”^[2]

^[1] https://www.nejm.org/doi/full/10.1056/nejmoa2107322

^[2] https://www.krebsinformationsdienst.de/aktuelles/2022/news059-metastasierter-prostatakrebs-zulassung-pluvicto-lutetium-177-psma-617-europa.php 

We are thrilled and proud to share that our colleague Prof.Dr. Alexander Haug has been awarded The European Awards in Medicine 2022 in the field of nuclear medicine.

The study of FAPi-based lutetium-177 therapy in the All India Institute Of Medical Sciences in New Delhi was meant to investigate the therapeutic efficacy and safety of ¹⁷⁷Lu-DOTAGA.(SA.FAPi)₂ in RR-DTC patients. 15 heavily pre-treated (min 2 lines of prior treatment with lenvatinib and/or sorafenib) patients with the disease progression were selected based on FAPi PET/CT. An average of 3 sessions of 2 GBq each was administered in an 8-week interval.

TheraP, a phase II trial comparing radioligand treatment with ¹⁷⁷Lu-PSMA-617 to the chemotherapy using cabazitaxel was finalized with ¹⁷⁷Lu-PSMA demonstrating a clear advantage over the chemotherapy.

After the conclusion of the Vision trials the urological associations start gradually adjusting their Prostate Cancer guidelines, both in diagnostics and treatment. EAU now strongly recommends:

• PSMA PET/CT (with gallium-68 or fluorine-18) as a more accurate diagnostic method than CT and bone scan for the staging of high-risk prostate cancer (PSA > 20 ng/mL, or GS > 7, or clinically palpable tumour in both lobes (cT2c)), and
• ¹⁷⁷Lu-PSMA as a therapy of choice for pre-treated (ADT) mCRPC patients with one or more metastatic lesions, highly expressing PSMA on the diagnostic radiolabelled PSMA PET/CT scan.

https://uroweb.org/guidelines/prostate-cancer/summary-of-changes

Both are available in our institution. Make your appointment now.

Fluorine-18 is a commonly used isotope utilized for conducting PSMA-PET/CT to stage prostate cancer, due to its longer half-life and higher production capacity as compared to Gallium-68. The latest study, however, has demonstrated superiority of Ga-68, because of the focal unspecific uptake of F-18 in the bones of ribs and pelvis. Without additional follow-up exams or any morphological correlates, this may be misinterpreted as bone metastasis. While nonspecific uptake in other tissues and physiologic uptake in the ganglia can be filtered out, unspecific bone uptake tends to lead to false interpretation and misdiagnosis. Bone metastases do occur in 10% of patients with the newly diagnosed prostate cancer, and 80-90% of patients in the advanced stage. Over-staging the patient may result in inadequate therapy decisions, especially in case of early biochemical recurrence. Read more.

How oft is the Lu-PSMA treatment conducted? The usual cycle consists of 3 sessions with 6 to 8 weeks interval in-between. Our more restrictive treatment regimen of 3 initial cycles with an interval of only 4 weeks in-between demonstrated >80% response rates even in heavily pre-treated patients. This treatment does not care, “where” the metastases are: lymph nodes, bone, lungs, liver or even tumor in the prostate region itself. The usual “victims” of PSMA ligands, the salivary glands and kidneys, are not significantly affected under this regimen. Read more here.

Check other scientific investigations of our team on the topic.

On 23 March 2021 Novartis announced positive results of the phase III trial with radioligand therapy ¹⁷⁷Lu-PSMA-617 in patients with castrate-resistant metastatic prostate cancer (mCRPC) after taxane chemotherapy and several androgen deprivation therapies (ADT).

Frontiers in Urology

Working group headed by Prof. Markus Hartenbach was able to demonstrate the outstanding diagnostic value of PSMA PET / MRI in biopsy-proven prostate cancer. PSMA-PET/MRI can provide an accurate staging of newly diagnosed prostate cancer. In addition, treatment strategies were changed in almost a third of the patients due to the information of this hybrid imaging technique. The scientific paper was published in the Clinical Cancer Research journal.

The working group headed by Prof. Markus Hartenbach MD was able to demonstrate the superiority of PSMA PET in the diagnosis of biochemical recurrence of prostate cancer, even at low PSA levels. Moreover, this diagnostic tool adds significant information to standard CT/MRI, changing treatment strategies in a significant number of patients. PSMA-positive lesions were detected in 85.5% patients, whereas 57.3% had no suspicious correlates according to the MRI or CT reports. Detection rates were 65% for a PSA value of 0.2 to <0.5 ng/ml, 85.7% for 0.5 to <1, 85.7% for 1 to <2 and 100% for ≥2. PSMA-PET changed therapeutic decisions in 74.6% of the patients (p < 0.001), with 86% of them being considered for metastases-directed therapies. The scientific paper was published in the “European Journal of Nuclear Medicine and Molecular Imaging”.

Markus Hartenbach wins Oncology Council's Young Investigator Award of the North American Association of Nuclear Medicine.