Nuclear medicine theranostics comes of age Herrmann, Ken; Krause, Bernd Joachim; Hadaschik, Boris ...
The lancet oncology,
November 2021, 2021-11-00, 20211101, Letnik:
22, Številka:
11
Journal Article
Recenzirano
...that a significant benefit of 177Lu-PSMA has been shown in patients with advanced PSMA-positive metastatic castration-resistant prostate cancer, with a median overall survival of 15·3 months ...versus 11·3 months for standard care (HR 0·62; 95% CI 0·52–0·74; p<0·001),2 the tone of the discussions around treatment has changed, with some advocating the disruption of the molecular imaging theranostic concept by discarding 68Ga-PSMA-PET/CT for patient selection. Despite PSMA expression in the majority of patients with advanced metastatic castration-resistant prostate cancer, 126 (12·6%) of 1003 patients did not meet the criteria for PSMA-radioligand therapy (no PSMA-positive lesions or ≥1 exclusionary PSMA-negative lesion) in the VISION trial.2 Exposing patients with inadequate PSMA expression on their tumours to a high dose of radiation without therapeutic benefit due to paucity or even total absence of the target violates the concept of primum non nocere (first do no harm) and conflicts with the rules set by national and international regulations regarding radiation exposure and safety. The patients treated with PSMA-radioligand therapy showed even higher prostate-specific antigen response rates than those in the VISION trial (decrease in prostate-specific antigen of 50% or more in 66% vs 46%), but the overall objective response rate was similar (49% vs 51%).4 More sophisticated dosimetric approaches might be developed in the future, but these methods could require multiple single-photon emission computed tomography in combination with CT scans, blood sampling, and calculations intending to secure a minimum tumour dose while staying below critical doses to normal organs.
Prostate cancer is the second most common cause of cancer‐related deaths in men, representing a major source of morbidity and mortality. Androgen deprivation therapy is the primary treatment for ...patients with advanced prostate cancer at disease presentation, which can be achieved either with surgical or chemical castration. The development of gonadotropin‐releasing hormone agonists revolutionized the treatment of advanced prostate cancer, replacing the need for surgical castration. Agonists downregulate gonadotropin‐releasing hormone agonist receptors in the pituitary gland, and thus decrease the release of luteinizing hormone and testosterone. Although agonists are a common therapeutic option to date, their use is associated with testosterone surges, metabolic dysfunction and an increase in the risk of cardiovascular disease; they might contribute to tumor flares and potentially an increase in non‐cancer mortality. More recently, gonadotropin‐releasing hormone antagonists have entered the prostate cancer treatment landscape. Unlike agonists, antagonists directly inhibit the androgen receptor in the pituitary gland, and thus do not cause initial testosterone surges. In this article, we provide a concise review of the mechanism of actions, safety and efficacy of the approved agonists and antagonists for prostate cancer treatment.
Abstract Context Prostate cancer (PCa) recurrence following definitive radiation therapy (RT) remains a vexing challenge for the practicing physician. Salvage radical prostatectomy (SRP) has not been ...recognized yet as a valuable therapeutic option. Objective We critically analyzed the currently available evidence on SRP as to patient selection, predictive oncologic factors, surgical technique, cancer control, surgical complications, functional outcomes, and comparison to other salvage therapies. Evidence acquisition A systematic review of the literature was performed in June 2011 using the Medline, Embase, and Web of Science databases, limiting the review to English-language articles published between January 1980 and June 2011. All authors reviewed the list of references and added papers relevant to the topic of the review prior to the analysis. The panel selected 40 articles according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria. Evidence synthesis Positive surgical margins in SRP varied from 43% to 70% in earlier publications versus 0–36% in recent publications, and pathologic organ-confined disease (OCD) was found in 22–53% versus 44–73% in earlier versus recent publications. Biochemical recurrence–free probability after SRP ranged from 47% to 82% at 5 yr and from 28% to 53% at 10 yr. Cancer-specific survival (CSS) and overall survival varied from 70% to 83% and 54% to 89% at 10 yr. Pre-SRP prostate-specific antigen value and prostate biopsy Gleason score were the strongest prognostic risk factors for progression-free survival, OCD, and CSS. Open, laparoscopic, and robotic techniques were shown to be feasible in the hands of experienced surgeons. The most frequent complications included anastomotic stricture (7–41%) followed by rectal injury (0–28%). Major complications (modified Clavien classification grade 3–5) varied from 0% to 25%. Most complications were less frequent in more recent series, except for anastomotic stricture. The majority of patients had erectile dysfunction prior to SRP (50–91%) and 80–100% after SRP. Urinary continence ranged from 21% to 90% after surgery. Limitations of this review include the absence of prospective studies and lack of comparative analyses between SRP and other therapies. Conclusions In selected patients with confirmed, localized, radiation-recurrent PCa, SRP may effectively promote durable cancer control with acceptable associated surgical morbidity and variable functional recovery.
Abstract Background In the European Organization for Research and Treatment of Cancer (EORTC) randomized trial 30904, nephron-sparing surgery (NSS) was associated with reduced overall survival ...compared with radical nephrectomy (RN) over a median follow-up of 9.3 yr (hazard ratio: 1.50; 95% confidence interval CI, 1.03–2.16). Objective To examine the impact of NSS relative to RN on kidney function in EORTC 30904. Design, setting, and participants This phase 3 international randomized trial was conducted in patients with a small (≤5 cm) renal mass and normal contralateral kidney who were enrolled from March 1992 to January 2003. Intervention Patients were randomized to RN ( n = 273) or NSS ( n = 268). Outcome measurements and statistical analysis Follow-up estimated glomerular filtration rates (eGFR; milliliters per minute per 1.73 m2 ) were recorded for 259 subjects in the RN arm and 255 subjects in the NSS arm. Percentages of subjects developing at least moderate renal dysfunction (eGFR <60), advanced kidney disease (eGFR <30), or kidney failure (eGFR <15) were calculated for each treatment arm based on the lowest recorded follow-up eGFR (intent-to-treat analysis). Results and limitations With a median follow-up of 6.7 yr, eGFR <60 was reached by 85.7% with RN and 64.7% with NSS, with a difference of 21.0% (95% CI, 13.8–28.3); eGFR <30 was reached by 10.0% with RN and 6.3% with NSS, with a difference of 3.7% (95% CI, –1.0 to 8.5); and eGFR <15 was reached by 1.5% with RN and 1.6% with NSS, with a difference of –0.1% (95% CI, –2.2 to 2.1). Lack of longer follow-up for eGFR is a limitation of these analyses. Conclusions Compared with RN, NSS substantially reduced the incidence of at least moderate renal dysfunction (eGFR <60), although with available follow-up the incidence of advanced kidney disease (eGFR <30) was relatively similar in the two treatment arms, and the incidence of kidney failure (eGFR <15) was nearly identical. The beneficial impact of NSS on eGFR did not result in improved survival in this study population. Registration EORTC trial 30904; ClinicalTrials.gov identifier NCT00002473.
Abstract Context The role of lymph node dissection (LND) in patients treated with radical nephroureterectomy (RNU) for upper tract urothelial cancer (UTUC) is still controversial. Objective To ...analyze the impact of lymph node invasion on the outcome of patients, the staging, and the possible therapeutic role of LND in UTUC. Evidence acquisition A Medline search was conducted to identify original articles, review articles, and editorials addressing the role of LND in UTUC. Keywords included upper tract urothelial neoplasms, lymphadenectomy, lymph node excision, lymphatic metastases, nephroureterectomy, imaging , and survival. Evidence synthesis Regional nodes are frequently involved in UTUC and represent the most common metastatic site. Regional nodal status is a significant predictor of patient outcomes, especially in invasive disease. Therefore, select patients treated with RNU at high risk for regional nodal metastases should undergo LND to improve disease staging, which would identify those who could benefit from adjuvant systemic therapy. Several retrospective studies suggested the potential therapeutic role of LND in UTUC. An accurate LND could remove some nodal micrometastases not identified on routine pathologic examination, thus improving local control and cancer-specific survival. Radical surgery and LND might be curative in a subpopulation with limited nodal disease, as described in bladder cancer. A clear knowledge of the limits of LND and a template of LND for UTUC are still needed. Conclusions An extended LND can provide better disease staging and may be curative in patients with limited nodal disease. However, current evidence is based on retrospective studies, which limits the ability to standardize either the indication or the extent of LND. Prospective trials are required to determine the impact of LND on survival in patients with UTUC and identify patients for a risk-adapted approach such as close follow-up or adjuvant chemotherapy.
Abstract Context Little is known on the natural history of positive surgical margins (PSMs) in partial nephrectomy (PN). Accumulating data suggest that secondary nephrectomy might not be necessary in ...all patients with PSMs after PN. Objective Provide an overview on incidence and risk factors for PSMs after partial nephrectomy and on the rate of local and distant disease recurrence related to PSMs. We also provide recommendations on how to avoid and how to treat PSMs after PN. Evidence acquisition A nonsystematic literature research was based on Medline, Scopus, and Web of Science queries on these keywords: nephron-sparing surgery, partial nephrectomy/ies, and margin . Only human studies (original research) published in English were included. Evidence synthesis PSMs are present in 0–7% of patients after open PN, in 0.7–4% after laparoscopic PN, and in 3.9–5.7% after robot-assisted PN. The thickness of healthy parenchyma surrounding the tumour is irrelevant as long as complete tumour removal is achieved. The coincidence of a highly malignant tumour and PSM increases the risk of local recurrence. Intermediate follow-up data indicate that the vast majority of patients with PSMs will not experience local or distant tumour recurrence. Frozen-section analysis for evaluation of resection margins during PN is of minor clinical significance, as the surgeon's gross assessment of macroscopically negative margins provides reliable results. Conclusions PSMs in PN are rare. As indicated by intermediate follow-up data, the majority of patients with PSMs after PN remain without disease recurrence, and a surveillance strategy seems preferable to surgical reintervention.
Summary Background Bone metastases are a major cause of morbidity and mortality in men with prostate cancer. Preclinical studies suggest that osteoclast inhibition might prevent bone metastases. We ...assessed denosumab, a fully human anti-RANKL monoclonal antibody, for prevention of bone metastasis or death in non-metastatic castration-resistant prostate cancer. Methods In this phase 3, double-blind, randomised, placebo-controlled study, men with non-metastatic castration-resistant prostate cancer at high risk of bone metastasis (prostate-specific antigen PSA ≥8·0 μg/L or PSA doubling time ≤10·0 months, or both) were enrolled at 319 centres from 30 countries. Patients were randomly assigned (1:1) via an interactive voice response system to receive subcutaneous denosumab 120 mg or subcutaneous placebo every 4 weeks. Randomisation was stratified by PSA eligibility criteria and previous or ongoing chemotherapy for prostate cancer. Patients, investigators, and all people involved in study conduct were masked to treatment allocation. The primary endpoint was bone-metastasis-free survival, a composite endpoint determined by time to first occurrence of bone metastasis (symptomatic or asymptomatic) or death from any cause. Efficacy analysis was by intention to treat. The masked treatment phase of the trial has been completed. This trial was registered at ClinicalTrials.gov , number NCT00286091. Findings 1432 patients were randomly assigned to treatment groups (716 denosumab, 716 placebo). Denosumab significantly increased bone-metastasis-free survival by a median of 4·2 months compared with placebo (median 29·5 95% CI 25·4–33·3 vs 25·2 22·2–29·5 months; hazard ratio HR 0·85, 95% CI 0·73–0·98, p=0·028). Denosumab also significantly delayed time to first bone metastasis (33·2 95% CI 29·5–38·0 vs 29·5 22·4–33·1 months; HR 0·84, 95% CI 0·71–0·98, p=0·032). Overall survival did not differ between groups (denosumab, 43·9 95% CI 40·1–not estimable months vs placebo, 44·8 40·1–not estimable months; HR 1·01, 95% CI 0·85–1·20, p=0·91). Rates of adverse events and serious adverse events were similar in both groups, except for osteonecrosis of the jaw and hypocalcaemia. 33 (5%) patients on denosumab developed osteonecrosis of the jaw versus none on placebo. Hypocalcaemia occurred in 12 (2%) patients on denosumab and two (<1%) on placebo. Interpretation This large randomised study shows that targeting of the bone microenvironment can delay bone metastasis in men with prostate cancer. Funding Amgen Inc.
Recommendations against prostate-specific antigen (PSA) testing in 2012 have increased advanced-stage diagnosis and prostate cancer–specific mortality rates.
To present the position of the European ...Association of Urology (EAU) in 2021 and provide recommendations for the use of PSA testing as part of a risk-adapted strategy for the early detection of prostate cancer.
The authors combined their review of relevant literature, including the EAU prostate cancer guidelines 2021 update, with their own knowledge to provide an expert opinion, representing the EAU’s position in 2021.
The EAU has developed a risk-adapted early prostate cancer detection strategy for well-informed men based on PSA testing, risk calculators, and multiparametric magnetic resonance imaging, which can differentiate significant from insignificant prostate cancer. This approach largely avoids the overdiagnosis/overtreatment of men unlikely to experience disease-related symptoms during their lifetime and facilitates an early diagnosis of men with significant cancer to receive active treatment. It also reduces advanced-stage diagnosis, thereby potentially reducing prostate cancer–specific mortality and improving quality of life. Education is required among urologists, general practitioners, radiologists, policy makers, and healthy men, including endorsement by the European Commission to adapt the European Council’s screening recommendations in its 2022 plan and requests to individual countries for its incorporation into national cancer plans.
This risk-adapted approach for the early detection of prostate cancer will reverse current unfavourable trends and ultimately save lives.
The European Association of Urology has developed a patient information leaflet and algorithm for the early diagnosis of prostate cancer. It can identify men who do not need magnetic resonance imaging or a biopsy and those who would not show any symptoms versus those with more aggressive disease who require further tests/treatment. We need to raise awareness of this algorithm to ensure that all well-informed men at risk of significant prostate cancer are offered a prostate-specific antigen test.
A risk-adapted early prostate cancer detection strategy, incorporating prostate-specific antigen testing, multiparametric magnetic resonance imaging, risk calculators, and biomarkers, will avoid overdiagnosis/overtreatment of insignificant cancers and ensure early detection and treatment of significant cancers, thereby improving quality of life and reducing prostate cancer–related deaths.
Patients with high-risk prostate cancer treated with curative intent are at an increased risk of biochemical recurrence, metastatic progression and cancer-related death compared with patients treated ...for low-risk or intermediate-risk disease. Thus, these patients often need multimodal therapy to achieve complete disease control. Over the past two decades, multiple studies on the use of neoadjuvant treatment have been performed using conventional androgen deprivation therapy, which comprises luteinizing hormone-releasing hormone agonists or antagonists and/or first-line anti-androgens. However, despite results from these studies demonstrating a reduction in positive surgical margins and tumour volume, no benefit has been observed in hard oncological end points, such as cancer-related death. The introduction of potent androgen receptor signalling inhibitors (ARSIs), such as abiraterone, apalutamide, enzalutamide and darolutamide, has led to a renewed interest in using neoadjuvant hormonal treatment in high-risk prostate cancer. The addition of ARSIs to androgen deprivation therapy has demonstrated substantial survival benefits in the metastatic castration-resistant, non-metastatic castration-resistant and metastatic hormone-sensitive settings. Intuitively, a similar survival effect can be expected when applying ARSIs as a neoadjuvant strategy in high-risk prostate cancer. Most studies on neoadjuvant ARSIs use a pathological end point as a surrogate for long-term oncological outcome. However, no consensus yet exists regarding the ideal definition of pathological response following neoadjuvant hormonal therapy and pathologists might encounter difficulties in determining pathological response in hormonally treated prostate specimens. The neoadjuvant setting also provides opportunities to gain insight into resistance mechanisms against neoadjuvant hormonal therapy and, consequently, to guide personalized therapy.
chris.booth@chaps.uk.com Bradley and colleagues’ editorial1 reiterates outdated uncertainties around prostate specific antigen (PSA) based screening for prostate cancer and fails to highlight ...advances in UK clinical practice.2 The editorial correctly points out that national guidance needs updating but cites recommendations from the UK National Screening Committee (NSC) and the United States Preventive Services Task Force (USPSTF). ...the USPSTF had to amend its advice in 2018 and this now parallels that of the NSC—a shared decision based on informed choice. Audit of PSA requesting practices in primary care compared to guidelines established by the Prostate Cancer Risk Management programme in the Avon region of the South West of England.
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