Radiation dosimetry and first therapy results with a 124I/131I-labeled small molecule (MIP-1095) targeting PSMA for prostate cancer therapy

Zechmann, Christian M.; Afshar‐Oromieh, Ali; Armor, Tom; Stubbs, James B.; Mier, Walter; Hadaschik, Boris; Joyal, John L.; Kopka, Klaus; Debus, Jürgen; Babich, John W.; Haberkorn, Uwe

doi:10.1007/s00259-014-2713-y

Cited by 327 publications

(297 citation statements)

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“…However, the used treatment activities are remarkably lower than the projected maximum tolerable dose according to dosimetry estimates, exploiting only 0.2 Gy red-marrow dose (6 GBq x 0.03 Gy/GBq). Simultaneously, the PSA response rates are lower in comparison to the older 131 I-PSMA-RLT data exploiting the full 1 Gy red-marrow tolerance limit (10,16). Surprisingly, none of the authors (22)(23)(24)(25)(26)(27)(28) discussed the possibility that escalation of 177 Lu treatment activity to an estimated redmarrow absorbed dose between 0.2-1.0 Gy should still be well tolerable but offers the chance to further improve anti-tumor-activity because a positive dose/responserelationship is normally expected in radiotherapy.…”

Section: Responsementioning

confidence: 85%

Repeated ¹⁷⁷Lu-Labeled PSMA-617 Radioligand Therapy Using Treatment Activities of Up to 9.3 GBq

et al. 2017

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Current treatment protocols for 177Lu-PSMA-617 therapies were cautiously derived from dosimetry data, but their practical appropriateness have not yet been proven clinically.We retrospectively report our clinical observations using four different treatment activities. Methods: Forty patients with advanced prostate cancer and positive uptake in PSMA-imaging were treated in fractions of 4 GBq / 80 nmol, 6 GBq / 120 nmol, 7.4 GBq / 150 nmol or 9.3 GBq / 150 nmol 177 Lu-activity / precursor-amount (n=10, respectively) every 2 months. Safety lab was checked every 2 weeks, PSA-response every 4 weeks; other effects were assessed per anamnesis. Results: Initial PSA response presented no correlation to treatment activity. However, 2/10, 4/10, 4/10 and 7/10 patients with doses of 4, 6, 7.4 and 9.3 GBq were in partial remission 8 weeks after completing all 3 cycles;This would be in line with, but due to low patient numbers not proving, a positive doseresponse-relationship. Acute hematological toxicity was also irrespective of treatment activity and no more than one grade-3/4 toxicity was observed in each group.Nevertheless, in contrast to the other groups the mean platelet count in the 9. (8,12). Nevertheless, tolerance limits for normal organs reported in the literature are based on external beam radiotherapy and have only been extrapolated to RLT using radiobiological models, which themselves have manifold limitations as reviewed recently (13). Thus, dosimetry in nuclear medicine can only approximate a guidance level for dosing RLT but the optimal treatment regime has still to be refined clinically.In this retrospective analysis we report our clinical experience with fractions of 4 GBq, 6GBq, 7.4 GBq or 9.3 GBq 177 Lu-PSMA-617 repeated every 2 months.by on May 10, 2018. For personal use only. jnm.snmjournals.org Downloaded from MATERIALS AND METHODS Patients 177Lu-PSMA-RLT was performed under the conditions of the updated declaration of Helsinki, § 37 (Unproven interventions in clinical practice) and in accordance to the German Pharmaceuticals Law §13(2b) as a salvage therapy for patients with mCRPC, which had to be resistant against or ineligible for approved options and presented with progressive disease. Patient selection is outlined in Fig. 1. For patients stratified to 177 Lu-PSMA-617, each dose level was administered to 10 consecutive patients. If toxicities were comparable to the placebo group of the ALSYMPCA-trial (14), individual dose escalations for non-responders were considered ethically justified, resulting in a short learning-phase using heterogeneous dosing regimens between respective dose escalation groups. Data of these heterogeneous interim patients were not suitable for this kind of systematical evaluation, nevertheless some have been made public available within other publications (8,15). The chronology how this dose escalation was embedded into clinical practice is summarized in Fig. 2. Patient characteristics were summarized in (Table 1). All patients were informed about the experime...

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Section: Responsementioning

confidence: 85%

Repeated ¹⁷⁷Lu-Labeled PSMA-617 Radioligand Therapy Using Treatment Activities of Up to 9.3 GBq

et al. 2017

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“…Those men with progressive disease who do not respond to 177 Lu PSMA therapy range from 10% to 32%. One of the larger studies, with 56 men enrolled, had 80% of all men enrolled had a PSA response to therapy3 All currently published studies with 177 Lu PSMA therapy in prostate cancer are retrospective, mostly single arm, and involve a variety of treatment regimens, both in terms of dose given (ranging from 3.5 to 8.0 Gbq/injection of Lu PSMA) and the number of doses administered (ranges from a single injection up to 4–6 injections 6 weeks apart) 2, 3, 4, 5, 6, 8, 9, 27, 39. This makes interpretation of the efficacy of the treatment difficult at this stage.…”

Section: Treatment Efficacymentioning

confidence: 99%

Lutetium ¹⁷⁷ PSMA radionuclide therapy for men with prostate cancer: a review of the current literature and discussion of practical aspects of therapy

Emmett

Willowson

Violet

et al. 2017

J of Medical Radiation Sci

255

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Prostate‐specific membrane antigen (PSMA) is a receptor on the surface of prostate cancer cells that is revolutionising the way we image and treat men with prostate cancer. New small molecule peptides with high‐binding affinity for the PSMA receptor have allowed high quality, highly specific PET imaging, in addition to the development of targeted radionuclide therapy for men with prostate cancer. This targeted therapy for prostate cancer has, to date, predominately used Lutetium 177 (Lu) labelled PSMA peptides. Early clinical studies evaluating the safety and efficacy of Lu PSMA therapy have demonstrated promising results with a significant proportion of men with metastatic prostate cancer, who have already failed other therapies, responding clinically to Lu PSMA. This review discusses the practical issues of administering Lu PSMA, and gives an overview of the findings from currently published trials in regards to treatment response rates, expected toxicities and safety.

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“…The past decade witnessed an unprecedented expansion of radioligands for prostate cancer. Milestones include the first a-emitter for treatment of symptomatic bone metastases (2) and theranostic vectors directed at the prostate-specific membrane antigen (PSMA) or bombesin receptor (3)(4)(5). However, current radionuclide therapies are applied at a late stage of the disease aiming at palliation.…”

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confidence: 99%

More α Than β for Prostate Cancer?

Fendler

Cutler

2017

J Nucl Med

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Radi onuclide therapy for prostate cancer started more than 70 y ago (1). Nuclear medicine has since evolved considerably to provide a multitude of new imaging and therapy options. The past decade witnessed an unprecedented expansion of radioligands for prostate cancer. Milestones include the first a-emitter for treatment of symptomatic bone metastases (2) and theranostic vectors directed at the prostate-specific membrane antigen (PSMA) or bombesin receptor (3-5). However, current radionuclide therapies are applied at a late stage of the disease aiming at palliation. Despite recent advances for treatment of metastatic prostate cancer, cure remains an unmet need of the 21st century. Cancer spreads early and develops slowly as submillimeter occult lesions. Lesions grow at distant sites and become detectable only when significant morphologic or metabolic alterations have formed, often years to decades after the initial spread (6). Effective ablation of small metastases is critical for cure and presents a specific challenge for b-emitting radionuclide therapy. Millimeter-range b-particles deliver insufficient amounts of radiation to millimetersize tumor lesions, as energy deposition extends and dilutes beyond lesion boundaries (Fig. 1). a-radiation, because of its micrometer range, targets millimeter-size tumor volumes at higher relative yield (Fig. 1). Further evidence points to a superior biologic effectiveness for a-therapy based on high-linear-energy transfer resulting in frequent double-strand DNA breaks (7). However, are basic advantages of a-therapy associated with a clinical benefit? 223 Ra was the first a-emitter, approved for survival benefit in patients with symptomatic bone metastatic castration-resistant prostate cancer (mCRPC) (2). 223 Ra therapy comes with a low rate of serious adverse events (2) thought to be based on sparing of healthy red marrow by the short-range a-particles. On the contrary, b-emitting bone-seeking 153 Sm and 89 Sr effectively reduce bone pain, however, without evidence for survival benefit and at higher rates for hematologic toxicity (8,9).223 Ra a-therapy has become an important option in the management of mCRPC. However, bone-targeting is of limited value in patients with extraosseous disease (10). Effective targeting of skeletal and extraskeletal disease is achieved by intravenous administration of radiolabeled small ligands for the PSMA (11). 177 Lu-labeled PSMA617 induced a prostate-specific antigen drop of more than 50% in about half of mCRPC patients with bone, lymph node, or soft-tissue metastases (12). Significant tumor shrinkage occurred, and in a few patients even complete response was achieved after PSMA-directed radioligand therapy (12-14). However, disease inevitably recurs. Kratochwil et al. were able to salvage 9 of 11 patients with 177 Lu-PSMA617-recurrent mCRPC by switching to 225 Ac-PSMA617 a-therapy (15). A high response rate was achieved by repeated application of 100 kBq of 225 Ac-PSMA617 per kilogram, an a-therapy protocol with acceptable toxicity for sal...

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Radiation dosimetry and first therapy results with a 124I/131I-labeled small molecule (MIP-1095) targeting PSMA for prostate cancer therapy

Cited by 327 publications

References 17 publications

Repeated ¹⁷⁷Lu-Labeled PSMA-617 Radioligand Therapy Using Treatment Activities of Up to 9.3 GBq

Repeated ¹⁷⁷Lu-Labeled PSMA-617 Radioligand Therapy Using Treatment Activities of Up to 9.3 GBq

Lutetium ¹⁷⁷ PSMA radionuclide therapy for men with prostate cancer: a review of the current literature and discussion of practical aspects of therapy

More α Than β for Prostate Cancer?

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Radiation dosimetry and first therapy results with a 124I/131I-labeled small molecule (MIP-1095) targeting PSMA for prostate cancer therapy

Cited by 327 publications

References 17 publications

Repeated 177Lu-Labeled PSMA-617 Radioligand Therapy Using Treatment Activities of Up to 9.3 GBq

Repeated 177Lu-Labeled PSMA-617 Radioligand Therapy Using Treatment Activities of Up to 9.3 GBq

Lutetium 177 PSMA radionuclide therapy for men with prostate cancer: a review of the current literature and discussion of practical aspects of therapy

More α Than β for Prostate Cancer?

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Repeated ¹⁷⁷Lu-Labeled PSMA-617 Radioligand Therapy Using Treatment Activities of Up to 9.3 GBq

Repeated ¹⁷⁷Lu-Labeled PSMA-617 Radioligand Therapy Using Treatment Activities of Up to 9.3 GBq

Lutetium ¹⁷⁷ PSMA radionuclide therapy for men with prostate cancer: a review of the current literature and discussion of practical aspects of therapy