Nomogram mCSPC

[Optimist1954]

„Identification and Validation of the Prognostic Impact of Metastatic Prostate Cancer Phenotypes“

https://www.clinical-genitourinary-cancer.com/article/S1558-7673(22)00045-3/fulltext

In dieser Datenbankauswertung ging es um Männer, bei denen bereits bei der Diagnose Metastasen festgestellt wurden (mCSPC). Es wurde versucht verschiedene Phänotypen des hormon-sensitiven, metastasierenden Prostatakrebses und deren Auswirkungen auf das Überleben zu finden.

Die Ergebnisse dienten u.a. zur Erstellung eines Nomograms für die Wahrscheinlichkeit des Überlebens (3 und 5 Jahre) von Betroffenen.

https://tinyurl.com/prostate-met

----------------------------------------------------
Anmerkungen:
- Im Nomogram wurden alle visz. Metastasen (Leber, Lunge, Hirn), vielleicht wegen der geringen Zahl der betroffenen Männer zusammengefasst. Die Prognose bei Lebermetastasen ist jedoch meist schlechter als bei Lungenmetastasen.
- Angaben zur unterschiedlichen Metastasenlast fehlen im Nomogram.

Trotz dieser Mängel eine erste Orientierung für die Gruppe der mCSPC-Betroffenen mit ihren sehr unterschiedlichen Diagnosen.

Franz

[Georg_]

Ich sehe diese Nomogramme skeptisch. Sie basieren auf teilweise recht lange zurückliegenden Fällen und es hat sich in den letzten Jahren sehr viel getan in der Behandlung des fortgeschrittenen Prostatakrebses. Die Ergebnisse der PEACE-1 Studie oder dem Abirateron-Arm von Stampede sind hier nicht eingegangen und mit so einer Kombinationstherapie sollten diese Patienten heute behandelt werden. Außerdem gibt es jetzt die Lu177 Therapie.

[barlaus37]

Es ist halt schwierig, den Patienten klar zu machen, dass diese Nomogramme auch nur statistische Durchschnittswerte darstellen. Es gibt auch Nomogramme, die mir 60% Rezidivwahrscheinlichkeit vorhersagen (Zeitraum nächste 10 Jahre), ob ich als Einzelfall davon betroffen bin, weiß keiner. Nomogramme sind Forschungsinstrumente, keine Glaskugeln für Einzelschicksale. Das mir zu vermitteln war schwierig !!

Nomogramme sind eigentlich dafür da, Therapiemethoden miteinander zu vergleichen, wo in der Masse beim grossen Durchschnitt der Patienten eine Methode insgesamt mehr / weniger profitiert.

Ich bin auch der Meinung von Georg, dass diese Nomogramme neuere Entwicklungen nicht berücksichtigen, muss aber auch Franz rechtgeben: Mein Bruder glaubt jetzt mit der intermittierenden ADT seinen Krebs im Griff zu haben, und macht gerade so weiter wie bisher, ist auch beratungsresistent, was auf ihn zukommt. Da würde ich mir manchmal schon etwas mehr Realitätsbewußtsein wünschen.

Und klar, wenn ein Nomogramm nach RPE vorhersagt, dass die Rezidivwahrscheinlichkeit bei 85 % liegt auf 5 Jahre, legt das eine sofortige Bestrahlung (Adjuvante Bestrahlung) oder bei Überschreiten der Nachweisgrenze von 0.01 nahe.

wegen LU177:
die amerikanische Urologengesellschaft Prostate Cancer Guidelines - American Urological Association (auanet.org)
Localized Prostate Cancer Guideline 050922.pdf

da gibt es bei den amerikanischen Richtlinien bei "Future Directions" folgende Aussage



PSMA-based therapeutics are another potential trea​tment currently emerging from the ability to target PSMA expressed on the surface of cancer cells. These aim to use the homing ability of PSMA-targeted antibodies or small molecules coupled to radioligands, such as 177Lutetium, to target prostate cancer cells systemically.162 These are currently under investigation in the advanced, CRPC stages of prostate cancer, but they are likely to move up in clinical trials to mHSPC, biochemical recurrence, and possibly even as neoadjuvant therapy for high-risk localized disease. The durability of these treatments is being evaluated in multiple prospective clinical studies. This is another area in which integrated multidisciplinary care will be important and will require the expertise of multiple specialties (e.g., medical oncology, nuclear medicine, radiation oncology).

Advanced Prostate Cancer: AUA/ASTRO/SUO Guideline (2020) - American Urological Association (auanet.org)



Ich wollte das einfach mal schreiben, weil ich etwas LU177 penetrant bin und das so oft erwähne und vorschlage. Wenn mich mein Englisch nicht völlig täuscht, wird hier in den amerikanischen Leitlinien darüber nachgedacht, die LU177 Therapie schon in früheren Stadien einzusetzen:

These aim to use the homing ability of PSMA-targeted antibodies or small molecules coupled to radioligands, such as 177Lutetium, to target prostate cancer cells systemically.162 These are currently under investigation in the advanced, CRPC stages of prostate cancer, but they are likely to move up in clinical trials to mHSPC, biochemical recurrence, and possibly even as neoadjuvant therapy for high-risk localized disease.


Daher schreibe ich das mit LU177 so oft.

Gruss Barlaus

[barlaus37]

(Der Link in meinem Text zeigt nicht direkt auf "Future Directions", daher hier eine Kopie des Textes)

Future Directions



Several key areas of future research need emphasis to improve clinical care and provide a path to better patient outcomes with advanced prostate cancer.
Integrations of care

It is now more clear than ever that multimodality approaches and integration of care are critical to improving the care for men with prostate cancer. Multidisciplinary clinics and the resulting multimodality treatment approaches can optimize treatment selection, maximize results and minimize overtreatment and side effects.151 Many clinical trials are evaluating the concepts of integrating systemic therapy with radiation and/or surgery, such as optimizing treatment of men with locally advanced primary tumors, assessing the benefit of local therapy in men with metastatic disease, or determine the impact of metastasis-directed therapy in the oligometastatic setting. The results of these studies are likely to substantially impact the standard approaches to newly diagnosed patients with advanced disease.
Currently, surgical resection of the primary tumor in the setting of metastatic prostate cancer is considered experimental. There are several retrospective single-arm studies demonstrating safety and feasibility, and many studies from large population-based registries show that improved survival is associated with local control in metastatic prostate cancer patients.152-154 However, not all studies have found a survival benefit, and all of these reports should be considered hypothesis-generating as they have unknown biases that make it difficult to apply the data to clinical practice. Several single-arm phase I/II trials and four randomized phase II clinical trials have been completed but are yet to be published.155,156 While the data mature, there is a Phase III RCT—SWOG 1802—evaluating standard systemic therapy with or without local control of the primary in men with hormone-sensitive ‘de novo’ metastatic prostate cancer. There are also plans for a surgical treatment arm in the STAMPEDE study (NCT03678025). Local control in the SWOG 1802 study may consist of surgery, radiation, or both, based on physician discretion and patient choice. This study aims to address whether local treatment of the primary in the setting of metastatic prostate cancer provides a benefit, with OS as the primary endpoint. In the absence of prospective data demonstrating that surgery leads to an oncologic benefit in men with metastatic prostate cancer, its use should be restricted to clinical trials.
Advanced PET imaging

Advanced PET imaging and theranostics are likely to revolutionize prostate cancer staging and management. Currently their role in the management of advanced prostate cancer is not entirely clear. These imaging modalities identify sites of recurrent prostate cancer with superior specificity and sensitivity compared to conventional imaging.157-159 These findings are already impacting treatment planning by altering physician decision making, but they have yet to demonstrate a clear benefit specific to patient outcomes.160 Use of these imaging agents will allow for identification of metastatic sites not otherwise seen with conventional imaging. As a result, it will be important to be cognizant of the stage migration that will occur with advanced PET imaging.
Given the ability to identify metastatic sites earlier than was previously possible, there has been renewed interest in the concept of MDT with radiation, surgery, or ablative technologies. Phase II trials have been designed and executed to determine if there is an impact on the biology of disease. Studies such as the STOMP trial have compared men with newly diagnosed metastatic disease detected on 11C-Choline PET and randomized these men to observation versus MDT. This study was negative for its primary endpoint, but it did demonstrate a prolongation of time to initiation of systemic therapy.58 Other trials are underway to evaluate this concept and also evaluate its use with concomitant systemic therapy. To date, there is little prospective randomized data evaluating PET as a staging study for untreated prostate cancer, mHSPC or CRPC.161 While studies are being completed to generate data for FDA registration based on safety and performance, what will ultimately determine the role of these PET agents will be trials demonstrating improved patient outcomes as a direct result of earlier intensification of systemic therapies, MDT, and/or prediction of responses to specific therapies. Until these trials are completed, use of PET imaging beyond identifying visible disease in patients with PSA recurrences is considered experimental.
PSMA-based therapeutics are another potential treatment currently emerging from the ability to target PSMA expressed on the surface of cancer cells. These aim to use the homing ability of PSMA-targeted antibodies or small molecules coupled to radioligands, such as 177Lutetium, to target prostate cancer cells systemically.162 These are currently under investigation in the advanced, CRPC stages of prostate cancer, but they are likely to move up in clinical trials to mHSPC, biochemical recurrence, and possibly even as neoadjuvant therapy for high-risk localized disease. The durability of these treatments is being evaluated in multiple prospective clinical studies. This is another area in which integrated multidisciplinary care will be important and will require the expertise of multiple specialties (e.g., medical oncology, nuclear medicine, radiation oncology).
Biomarkers and other systemic therapies

Given the dramatic increase in available therapies for advanced prostate cancer over the past 10 years, there is a renewed urgency to identify predictive biomarkers that can guide treatment selection. A number of promising molecular approaches continue to be investigated, but as of yet there is no assay that has been prospectively demonstrated to lead to improved oncologic outcomes.
Currently, the most promising markers are the expression levels of AR-V7 and the identification of germline or somatic alterations in DDR genes such as BRCA1, BRCA2, and ATM. The potential value for assessing these markers stems from the possibility that they can serve as predictive—rather than solely prognostic—biomarkers. That is, there is substantial evidence that these tests might predict differential response to specific systemic therapies, with the implication that pairing these tests with changes in treatment selection could lead to improved long-term outcomes. For AR-V7, the initial seminal study by Antonarakis and colleagues showed that high expression of AR-V7 in CTCs was associated with rapid disease progression in men with mCRPC starting enzalutamide or abiraterone acetate.163 Other studies have confirmed these findings using different platforms for measuring AR-V7 expression in circulation and also showed that patients with high AR-V7 expression may still respond well to chemotherapy.164-167 Two CLIA-certified laboratory developed tests are currently commercially available, and the PROPHECY trial prospectively validated these tests in an mCRPC population while also showing that some discrepancies exist in test results between these two assays.168 Importantly, the vast majority of patients were AR-V7-negative by both assays.
The potential importance of germline and somatic tumor testing, covered in guideline statements 13 and 26, largely surrounds their promise for predicting response to PARP inhibitors such as olaparib, rucaparib, niraparib, veliparib, and talozaparib. Because PARP inhibitors target the DNA replication machinery, tumors with deficiencies in homologous recombination repair (e.g., because of BRCA1, BRCA2 mutations) are uniquely sensitive to PARP inhibition, a phenomenon termed synthetic lethality. In the TOPARP-A trial, heavily-treated mCRPC patients treated with olaparib were much more likely to respond in the setting of a DDR alteration.39 The response rate was 88% in biomarker positive patients and 6% in biomarker negative patients. From a biomarker standpoint, it is important to note that circulating cell-free DNA may be a future alternative approach for identifying these DDR alterations, and subsequent reversion mutations could be identified after disease progression.169 In the TOPARP-B study, which assessed 92 patients with DDR aberrations treated with olaparib, 44 patients (48%) demonstrated a confirmed response by imaging, PSA, or CTC criteria.170 Results of multiple prospective RCTs assessing PARP inhibitors in mCRPC patients with DDR alterations are pending.
In addition to PARP inhibitors, immunotherapies have also emerged as a key therapeutic modality in a large number of solid tumors. Aside from sipuleucil-T, these treatments have generally shown less efficacy in advanced prostate cancer compared to other malignancies, in part related to the relatively low tumor mutational burden of most prostate cancers.171 However, as described in guideline statement 34, there is likely to be a subset of prostate cancer patients who are uniquely sensitive to immunotherapy— particularly those patients who have tumors that have a high mutational burden (MSI-high).172 Ongoing trials continue to explore whether immune checkpoint inhibitors, vaccine-based therapies, or oncolytic viruses may have broader utility in men with advanced prostate cancer.
Unmet needs

While dramatic recent advances have been made, there are many unmet needs in prostate cancer management. Personalized care with predictive markers for treatment selection based on tumor and host biology have not yet been achieved. There has been movement toward identification of prognostic markers and identification of molecular markers based on immunohistochemistry and use of genomic signatures, but these have yet to yield predictive results. A recent example of prognostic ability is the finding that patients with combined defects in tumor suppressor genes (P53, Rb, PTEN) demonstrated improved responses to cabazitaxel plus carboplatin versus cabazitaxel alone in CRPC.173 Further prospective phase III trials are planned to evaluate the predictive ability of this combined defect for treatment selection. As we move forward as a field, we need to focus on the biologic make-up of tumors and how these can be better leveraged to identify treatment options for patients.

[Barnold]

Hab meine Daten "spaßeshalber" mal eingegeben. Danach habe ich eine 2% Chance noch diese Weihnachten zu erleben und gehöre zu den 19% Glücklichen, die 3 Jahre geschafft haben. Ist halt Statistik!
Gruß Arnold

[Optimist1954]

... Außerdem gibt es jetzt die Lu177 Therapie.

Lutetium das neue Wundermittel bei Prostatakrebs? Zumindest wenn es nach der massiven Werbung für die Radioligandentherapie geht.
Meist werden retrospektive Auswertungen individueller Heilversuche mit kleinen Fallzahlen präsentiert.

Es gibt bisher wenig Ergebnisse prospektiver randomisierter Studien. Eine davon ist die "Vision-Studie".
Daten zum OS liegen vor aus der „Vision-Studie“. Eine Verbesserung mit Lutetium gegenüber „best standard of care“ um 4 Monate.
4 Monate ! Den großen Durchbruch beim OS kann ich darin wirklich nicht erkennen.

https://www.urotoday.com/conference-highlights/asco-2021/asco-2021-press-releases/129908-phase-iii-vision-study-of-177lu-psma-617-significantly-improves-overall-survival-and-radiographic-progression-free-survival-for-men-with-metastatic-castration-resistant-prostate-cancer-in.html

„Men who received 177Lu-PSMA-617 plus best standard of care had a 38% reduction in risk of death (median OS benefit of 4 months) and a 60% reduction in the risk of radiographic disease progression or death (median rPFS benefit of 5 months) compared to best standard of care alone“

Auch mit Lutetium bleibt metastasierter Prostatakrebs bisher unheilbar.

Franz

[Georg_]

Franz,

ich wollte die Lu177 Therapie nicht als Wundermittel darstellen, mit dem man vom Prostatakrebs geheilt wird. Aber es ist eine zusätzliche Therapie, die bei dem Patientenkollektiv, das dem Nomogramm zugrundeliegt, zu einem verlängerten Gesamtüberleben geführt hätte. Docetaxel wurde übrigens zugelassen, da dabei ein um 2,4 Monate verlängertes Gesamtüberleben nachgewiesen werden konnte.

Georg

[Optimist1954]

[QUOTE=Georg_;142479...ich wollte die Lu177 Therapie nicht als Wundermittel darstellen, mit dem man vom Prostatakrebs geheilt wird. Aber es ist eine zusätzliche Therapie, die bei dem Patientenkollektiv, das dem Nomogramm zugrundeliegt, zu einem verlängerten Gesamtüberleben geführt hätte. Docetaxel wurde übrigens zugelassen, da dabei ein um 2,4 Monate verlängertes Gesamtüberleben nachgewiesen werden konnte.....[/QUOTE]

Georg,
die Bemerkung zum "Wundermittel Lutetium" war ein Hinweis auf die teilweise sehr euphorischen Berichte über die Lutetium-Therapie in Presse und Neuen Medien. An den Zahlen des Nomograms zum OS wäre mit den wenigen Monaten die durch Lutetium gewonnen werden können, wenn der Status mCRPC erreicht wurde, keine große Änderung zu erwarten.

Lutetium vor Erreichen des mCRPC, dazu gibt es interessante, optimistisch stimmende Fallberichte, aber zu diesem Thema stehen aussagekräftige Studien bisher nicht zur Verfügung.

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Zu den 2,4 Monaten die Du beim Docetaxel genannt hast, wäre zu ergänzen, dass es sich um ein Ergebnis der TAX-327-Studie von 2004 handelt. Docetaxel mit Prednisolon vs. Mitoxantron beim mCRPC.

Franz