Oncological applications of Raman spectroscopy have been contemplated, pursued, and developed at academic level for at least 25 years. Published studies aim to detect pre-malignant lesions, detect ...cancer in less invasive stages, reduce the number of unnecessary biopsies and guide surgery towards the complete removal of the tumour with adequate tumour resection margins. This review summarizes actual clinical needs in oncology that can be addressed by spontaneous Raman spectroscopy and it provides an overview over the results that have been published between 2007 and 2017. An analysis is made of the current status of translation of these results into clinical practice. Despite many promising results, most of the applications addressed in scientific studies are still far from clinical adoption and commercialization. The main hurdles are identified, which need to be overcome to ensure that in the near future we will see the first Raman spectroscopy-based solutions being used in routine oncologic diagnostic and surgical procedures.
This review summarizes actual clinical needs in oncology that can be addressed by Raman spectroscopy, provides results published in the last 10 years and analyses the current status of translation of these results into clinical practice.
The gastrin-releasing peptide receptor (GRPR) is expressed in high numbers in a variety of human tumors, including the frequently occurring prostate and breast cancers, and therefore provides the ...rationale for directing diagnostic or therapeutic radionuclides on cancer lesions after administration of anti-GRPR peptide analogs. This concept has been initially explored with analogs of the frog 14-peptide bombesin, suitably modified at the N-terminus with a number of radiometal chelates. Radiotracers that were selected for clinical testing revealed inherent problems associated with these GRPR agonists, related to low metabolic stability, unfavorable abdominal accumulation, and adverse effects. A shift toward GRPR antagonists soon followed, with safer analogs becoming available, whereby, metabolic stability and background clearance issues were gradually improved. Clinical testing of three main major antagonist types led to promising outcomes, but at the same time brought to light several limitations of this concept, partly related to the variation of GRPR expression levels across cancer types, stages, previous treatments, and other factors. Currently, these parameters are being rigorously addressed by cell biologists, chemists, nuclear medicine physicians, and other discipline practitioners in a common effort to make available more effective and safe state-of-the-art molecular tools to combat GRPR-positive tumors. In the present review, we present the background, current status, and future perspectives of this endeavor.
Objectives
To review the literature to determine the sensitivity and specificity of gallium‐68 prostate‐specific membrane antigen (68Ga‐PSMA) positron‐emission tomography (PET) for detecting pelvic ...lymph node metastases in patients with primary prostate cancer (PCa), and the positive predictive value in patients with biochemical recurrence (BCR) after initial curative treatment, and, in addition, to determine the detection rate and management impact of 68Ga‐PSMA PET in patients with BCR after radical prostatectomy (RP).
Materials and Methods
We performed a comprehensive literature search. Search terms used in MEDLINE, EMBASE and Science Direct were ‘(PSMA, 68Ga‐PSMA, 68Gallium‐PSMA, Ga‐68‐PSMA or prostate‐specific membrane antigen)’ and ‘(histology, lymph node, staging, sensitivity, specificity, positive predictive value, recurrence, recurrent or detection)’. Relevant s were reviewed and full‐text articles obtained where possible. References to and from obtained articles were searched to identify further relevant articles.
Results
Nine retrospective and two prospective studies described the sensitivity and specificity of 68Ga‐PSMA PET for detecting pelvic lymph node metastases before initial treatment, which ranged from 33.3% to 100% and 80% to 100%, respectively. In eight retrospective studies, the positive predictive value of 68Ga‐PSMA PET in patients with BCR before salvage lymph node dissection ranged from 70% to 100%. The detection rate of 68Ga‐PSMA PET in patients with BCR after RP in the PSA subgroups <0.2 ng/mL, 0.2–0.49 ng/mL and 0.5 to <1.0 ng/mL ranged from 11.3% to 50.0%, 20.0% to 72.7% and 25.0% to 87.5%, respectively.
Conclusion
The review results showed that 68Ga‐PSMA PET had a high specificity for the detection of pelvic lymph node metastases in primary PCa. Furthermore, 68Ga‐PSMA PET had a very high positive predictive value in detecting lymph node metastases in patients with BCR. By contrast, sensitivity was only moderate; therefore, based on the currently available literature, 68Ga‐PSMA PET cannot yet replace pelvic lymph node dissection to exclude lymph node metastases. In the salvage phase, 68Ga‐PSMA PET had both a high detection rate and impact on radiotherapy planning in early BCR after RP.
Aims To investigate the surgical margin status in patients with prostate cancer who underwent robot‐assisted radical prostatectomy (RARP) with intraoperative neurovascular structure‐adjacent ...frozen‐section analysis (NeuroSAFE) and evaluate differences compared to patients who underwent radical prostatectomy without NeuroSAFE. Patients and Methods Between September 2018 and January 2021, 962 patients underwent centralized RARP with NeuroSAFE. A secondary resection was performed in case of a positive surgical margin (PSM) on intraoperative frozen section (IFS) analysis to convert a PSM into a negative surgical margin (NSM). A retrospective cohort consisted of 835 patients who had undergone radical prostatectomy in a tertiary centre without NeuroSAFE between January 2000 and December 2017. We performed multivariable logistic regression to evaluate differences in risk of PSM between cohorts after controlling for clinicopathological variables. Results Patients operated with NeuroSAFE in the centralized clinic had 29% PSM at a definitive pathological RP examination. The median cumulative length of definitive PSM was 1.1 mm (interquartile range: 0.4–3.8). Among 275 men with PSM, 136 (49%) had a cumulative length ≤1 mm and 198 (72%) ≤3 mm. After controlling for PSA, Grade group, cribriform pattern, pT‐stage, and pN‐stage, patients treated in the centralized clinic with NeuroSAFE had significantly lower odds on PSM (odds ratio OR: 0.70, 95% confidence interval CI: 0.56–0.88; P = 0.002), PSM length >1 mm (OR: 0.14, 95% CI: 0.09–0.22; P < 0.001), and >3 mm (OR: 0.21, 95% CI: 0.14–0.30; P < 0.001). Conclusion This study provides a detailed overview of surgical margin status in a centralized RP NeuroSAFE cohort. Centralization with NeuroSAFE was associated with lower PSM rates and significantly shorter PSM cumulative lengths, indicating improved control of surgical margin status.
Objectives
To investigate the impact of intra‐operative neurovascular structure‐adjacent frozen‐section examination (NeuroSAFE) on the rate of nerve‐sparing surgery (NSS) and oncological outcome in a ...large radical prostatectomy (RP) cohort.
Patients and methods
Between January 2016 and December 2020, 1756 prostate cancer patients underwent robot‐assisted RP, of whom 959 (55%) underwent this with NeuroSAFE and 797 (45%) without (control cohort). In cases where NeuroSAFE showed tumour in the margin, a secondary resection was performed. The effect of NeuroSAFE on NSS and positive surgical margin (PSM) status was analysed using logistic regression. Cox regression was used to identify predictors of biochemical recurrence‐free survival (BCRFS).
Results and limitations
Patients in the NeuroSAFE cohort had a higher tumour grade (P < 0.001) and clinical stage (P < 0.001) than those in the control cohort. NeuroSAFE enabled more frequent NSS for both pT2 (93% vs 76%; P < 0.001) and pT3 disease (83% vs 55%; P < 0.001). In adjusted analysis, NeuroSAFE resulted in more frequent unilateral (odds ratio OR 3.90, 95% confidence interval (CI) 2.90–5.30; P < 0.001) and bilateral (OR 5.22, 95% CI 3.90–6.98; P < 0.001) NSS. While the PSM rate decreased from 51% to 42% in patients with pT3 stage disease (P = 0.031), NeuroSAFE was not an independent predictor of PSM status (OR 0.85, 95% CI 0.68–1.06; P = 0.2) in the entire cohort. Patients who underwent NeuroSAFE had better BCRFS compared to the control cohort (hazard ratio 0.62, 95% CI 0.45–0.84; P = 0.002). This study is limited by its comparison with a historical cohort and lack of functional outcomes.
Conclusions
NeuroSAFE enables more unilateral and bilateral NSS without negatively affecting surgical margin status and biochemical recurrence. This validation study provides a comprehensive overview of the implementation, evaluation and intra‐operative decision making associated with NeuroSAFE in clinical practice.
PURPOSEWe developed a model predicting the probability of detecting prostate cancer recurrence outside the prostatic fossa on prostate specific membrane antigen positron emission ...tomography/computerized tomography in patients with biochemical recurrence after radical prostatectomy. MATERIALS AND METHODSWe retrospectively included 419 consecutive patients with biochemical recurrence (prostate specific antigen less than 2.0 ng/ml) after radical prostatectomy who underwent 68Ga-prostate specific membrane antigen-11 positron emission tomography/computerized tomography to guide salvage therapy. Patients receiving androgen deprivation therapy between radical prostatectomy and prostate specific membrane antigen positron emission tomography/computerized tomography were excluded from the study. We used multivariable logistic regression to assess predictors for the detection of prostate cancer recurrence outside the prostatic fossa on prostate specific membrane antigen positron emission tomography/computerized tomography. We minimized overfitting of the model and used decision curve analysis to determine clinical utility. RESULTSMedian prostate specific antigen at scanning was 0.40 ng/ml (IQR 0.30-0.70). Overall 174 (42%) patients had prostate cancer recurrence outside the prostatic fossa. Prostate specific antigen at time of scanning, and grade group, N stage and surgical margin status at radical prostatectomy specimen were significant predictors for detecting prostate cancer recurrence outside the prostatic fossa. The bootstrapped AUC of this model was 0.75 (IQR 0.73-0.77). The decision curve analysis showed a net benefit by a model based probability from 16%. Limitations include the retrospective design and the missing histological correlation of positive lesions. CONCLUSIONSNext to the prostate specific antigen at time of scanning, grade group, N stage and surgical margin status at radical prostatectomy specimen are significant predictors for detecting prostate cancer recurrence outside the prostatic fossa on prostate specific membrane antigen positron emission tomography/computerized tomography. The presented model is implemented in a dashboard to assist clinicians in determining the optimal time to perform 68Ga-prostate specific membrane antigen-11 positron emission tomography/computerized tomography in patients with biochemical recurrence after radical prostatectomy.
A risk-adapted ultrasound-directed pathway detected relevant cancers equally well in comparison to a magnetic resonance imaging (MRI)-directed pathway and suitable for prostate cancer diagnosis if ...prostate MRI is not available. If prostate MRI availability is sufficient, risk assessment should be performed with MRI to minimize overdiagnosis.
European Association of Urology guidelines recommend a risk-adjusted biopsy strategy for early detection of prostate cancer in biopsy-naïve men. It remains unclear which strategy is most effective. Therefore, we evaluated two risk assessment pathways commonly used in clinical practice.
To compare the diagnostic performance of a risk-based ultrasound (US)-directed pathway (Rotterdam Prostate Cancer Risk Calculator RPCRC #3; US volume assessment) and a magnetic resonance imaging (MRI)-directed pathway.
This was a prospective multicenter study (MR-PROPER) with 1:1 allocation among 21 centers (US arm in 11 centers, MRI arm in ten). Biopsy-naïve men with suspicion of prostate cancer (age ≥50 yr, prostate-specific antigen 3.0–50 ng/ml, ± abnormal digital rectal examination) were included.
Biopsy-naïve men with elevated risk of prostate cancer, determined using RPCRC#3 in the US arm and Prostate Imaging Reporting and Data System scores of 3–5 in the MRI arm, underwent systematic biopsies (US arm) or targeted biopsies (MRI arm).
The primary outcome was the proportion of men with grade group (GG) ≥2 cancer. Secondary outcomes were the proportions of biopsies avoided and GG 1 cancers detected. Categorical (nonparametric) data were assessed using the Mann-Whitney U test and χ2 tests.
A total of 1965 men were included in the intention-to-treat population (US arm n = 950, MRI arm n = 1015). The US and MRI pathways detected GG ≥2 cancers equally well (235/950, 25% vs 239/1015, 24%; difference 1.2%, 95% confidence interval CI −2.6% to 5.0%; p = 0.5). The US pathway detected more GG 1 cancers than the MRI pathway (121/950, 13% vs 84/1015, 8.3%; difference 4.5%, 95% CI 1.8–7.2%; p < 0.01). The US pathway avoided fewer biopsies than the MRI pathway (403/950, 42% vs 559/1015, 55%; difference −13%, 95% CI −17% to −8.3%; p < 0.01). Among men with elevated risk, more GG ≥2 cancers were detected in the MRI group than in the US group (52% vs 43%; difference 9.2%, 95% CI 3.0–15%; p < 0.01).
Risk-adapted US-directed and MRI-directed pathways detected GG ≥2 cancers equally well. The risk-adapted US-directed pathway performs well for prostate cancer diagnosis if prostate MRI capacity and expertise are not available. If prostate MRI availability is sufficient, risk assessment should preferably be performed using MRI, as this avoids more biopsies and detects fewer cases of GG 1 cancer.
Among men with suspected prostate cancer, relevant cancers were equally well detected by risk-based pathways using either ultrasound or magnetic resonance imaging (MRI) to guide biopsy of the prostate. If prostate MRI availability is sufficient, risk assessment should be performed with MRI to reduce unnecessary biopsies and detect fewer irrelevant cancers.
Aims
Radical prostatectomy (RP) for prostate cancer is frequently complicated by erectile dysfunction and urinary incontinence. However, sparing of the nerve bundles adjacent to the posterolateral ...sides of the prostate reduces the number of complications at the risk of positive surgical margins. Preoperative selection of men eligible for safe, nerve‐sparing surgery is therefore needed. Our aim was to identify pathological factors associated with positive posterolateral surgical margins in men undergoing bilateral nerve‐sparing RP.
Methods and results
Prostate cancer patients undergoing RP with standardised intra‐operative surgical margin assessment according to the NeuroSAFE technique were included. Preoperative biopsies were reviewed for grade group (GG), cribriform and/or intraductal carcinoma (CR/IDC), perineural invasion (PNI), cumulative tumour length and extraprostatic extension (EPE). Of 624 included patients, 573 (91.8%) received NeuroSAFE bilaterally and 51 (8.2%) unilaterally, resulting in a total of 1197 intraoperative posterolateral surgical margin assessments. Side‐specific biopsy findings were correlated to ipsilateral NeuroSAFE outcome. Higher biopsy GG, CR/IDC, PNI, EPE, number of positive biopsies and cumulative tumour length were all associated with positive posterolateral margins. In multivariable bivariate logistic regression, ipsilateral PNI odds ratio (OR) = 2.98, 95% confidence interval (CI) = 1.62–5.48; P < 0.001 and percentage of positive cores (OR = 1.18, 95% CI = 1.08–1.29; P < 0.001) were significant predictors for a positive posterolateral margin, while GG and CR/IDC were not.
Conclusions
Ipsilateral PNI and percentage of positive cores were significant predictors for a positive posterolateral surgical margin at RP. Biopsy PNI and tumour volume can therefore support clinical decision‐making on the level of nerve‐sparing surgery in prostate cancer patients.
Ipsilateral PNI and percentage of positive biopsies were independent predictors of a positive posterolateral margin and could support decision‐making on level of nerve‐sparing surgery.
We assessed predictors of short-term oncologic outcomes of patients who underwent salvage radiation therapy for biochemical recurrence after robot-assisted laparoscopic radical prostatectomy without ...evidence of metastases on prostate specific membrane antigen positron emission tomography/computerized tomography.
We retrospectively analyzed 194 patients with biochemical recurrence after robot-assisted laparoscopic radical prostatectomy who underwent prostate specific membrane antigen positron emission tomography/computerized tomography prior to salvage radiation therapy. Patients with lymph node or distant metastases on restaging imaging or at the time of extended pelvic lymph node dissection during robot-assisted laparoscopic radical prostatectomy were excluded, as were patients who received androgen deprivation therapy during or prior to salvage radiation therapy. A multivariable logistic regression analysis was performed to assess predictors of treatment response, defined as prostate specific antigen value ≤0.1 ng/ml after salvage radiation therapy.
Overall treatment response after salvage radiation therapy was 75% (146/194 patients). On multivariable analysis, prostate specific antigen value at initiation of salvage radiation therapy (OR 0.42, 95% CI 0.27-0.62, p <0.001), pathological T stage (pT3a vs pT2 OR 0.28, 95% CI 0.11-0.69, p=0.006; pT3b vs pT2 OR 0.26, 95% CI 0.09-0.71, p=0.009) and local recurrent disease on imaging (OR 5.53, 95% CI 1.96-18.52, p=0.003) were predictors of treatment response.
Salvage radiation therapy in patients without evidence of metastases on prostate specific membrane antigen positron emission tomography/computerized tomography showed a good overall treatment response of 75%. Higher treatment response rates were observed in patients with lower prostate specific antigen values at initiation of salvage radiation therapy, those with local recurrent disease on imaging and those with lower pathological T stage (pT2 vs pT3a/b).
The gastrin-releasing peptide receptor (GRPr) is overexpressed in prostate cancer (PCa) cells, making it an excellent tool for targeted imaging. The
Ga-labeled GRPr antagonist SB3 has shown excellent ...results in preclinical and clinical studies and was selected for further clinical investigation. The aims of this phase I study were to investigate
Ga-SB3 PET/CT imaging of primary PCa tumors and assess safety. More aims included an investigation of biodistribution and dosimetry and a comparison with pathology and GRPr expression.
Ten therapy-naïve, biopsy-confirmed PCa patients planned for prostatectomy were included. A 3-h extensive PET/CT imaging protocol was performed within 2 wk before prostatectomy. Prostate tissue was evaluated for tumor localization and Gleason score, and in vitro autoradiography was performed to determine GRPr expression. Available MRI scans performed within 3 mo before the study were matched. For dosimetry, residence times were estimated and effective dose to the body as well as absorbed doses to organs were calculated using the IDAC dose model, version 2.1.
Administration of
Ga-SB3 (187.4 ± 40.0 MBq, 40 ± 5 μg) was well tolerated; no significant changes in vital signs or laboratory results were observed.
Ga-SB3 PET/CT showed lesions in 8 of 10 patients. Pathologic analysis revealed a total of 16 tumor lesions, of which PET/CT showed 14, resulting in a sensitivity of 88%.
Ga-SB3 PET/CT imaging showed uptake in 2 large prostatic intraepithelial neoplasia foci, considered a precursor to PCa, resulting in an 88% specificity. Autoradiography of tumor lesions revealed heterogeneous GRPr expression and was negative in 4 patients. Both PET/CT-negative patients had a GRPr-negative tumor. In autoradiography-positive tumors, the level of GRPr expression showed a significant correlation to tracer uptake on PET/CT. Dosimetry calculations estimated the effective dose to be 0.0144 mSv/MBq, similar to other
Ga-labeled radiopeptides. The highest absorbed dose was detected in the physiologic GRPr-expressing pancreas (0.198 mGy/MBq), followed by the bladder wall and kidneys.
Ga-SB3 PET/CT is a safe imaging method and a promising tool for early PCa imaging.
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