Kendi, A. Tuba

The aim of this narrative review is to evaluate the current status of 177Lu-PSMA (prostate specific membrane antigen) therapy for metastatic castration-resistant prostate cancer (mCRPC) in the light of the current literature. We also addressed patient preparation, therapy administration and side effect profiles. 177Lu-PSMA therapy efficacy was assessed by using prospective trials, meta-analyses and major retrospective trials. Predictors of efficacy were also mentioned. Although there are some different approaches regarding the use of 177Lu-PSMA therapy in different countries, this type of therapy is generally safe, with a low toxicity profile. From the oncological point of view, a PSA (prostate specific antigen) decline of ≥50% was seen in 10.6–69% of patients with mCRPC; whereas progression-free survival (PFS) was reported to be 3–13.7 months in different studies. Consequently, 177Lu-PSMA therapy is a promising treatment in patients with mCRPC, with good clinical efficacy, even in heavily pretreated patients with multiple lines of systemic therapy. Currently, there are ongoing clinical trials in the United States, including a phase III multicenter FDA registration trial.

Abstract Introduction Recent classification of neuroendocrine neoplasms has defined well-differentiated high-grade neuroendocrine tumors (NET G3) as a distinct entity from poorly differentiated neuroendocrine carcinoma. The optimal treatment for NET G3 has not been well-described. This study aimed to evaluate metastatic NET G3 response to different treatment regimens. Materials and Methods This was a retrospective study of patients with NET G3 within the Mayo Clinic database. Patients’ demographics along with treatment characteristics, responses, and survival were assessed. Primary endpoints were progression-free survival (PFS) and overall survival. Secondary endpoints were objective response rate (ORR) and disease control rate (DCR). Results Treatment data was available in 30 patients with median age of 59.5 years at diagnosis. The primary tumor was mostly pancreatic (73.3%). Ki-67 index was ≥55% in 26.7% of cases. Treatments included capecitabine + temozolomide (CAPTEM) (n = 20), lutetium 177 DOTATATE (PRRT; n = 10), Platinum-etoposide (EP; n = 8), FOLFOX (n = 7), and everolimus (n = 2). CAPTEM exhibited ORR 35%, DCR 65%, and median PFS 9.4 months (95% confidence interval, 2.96–16.07). Both EP and FOLFOX showed similar radiographic response rates with ORR 25.0% and 28.6%; however, median PFS durations were quite distinct at 2.94 and 13.04 months, respectively. PRRT had ORR of 20%, DCR of 70%, and median PFS of 9.13 months. Conclusion Among patients with NET G3, CAPTEM was the most commonly used treatment with clinically meaningful efficacy and disease control. FOLFOX or PRRT are other potentially active treatment options. EP has some activity in NET G3, but responses appear to be short-lived. Prospective studies evaluating different treatments effects in patients with NET G3 are needed to determine an optimal treatment strategy. Implications for Practice High-grade well-differentiated neuroendocrine tumors (NET G3) are considered a different entity from low-grade NET and neuroendocrine carcinoma in terms of prognosis and management. The oral combination of capecitabine and temozolomide is considered a good option in the management of metastatic NET G3 and may be preferred. FOLFOX is another systemic option with reasonable efficacy. Similar to other well-differentiated neuroendocrine tumors, peptide receptor radionuclide therapy seems to have some efficacy in these tumors.

Objective Studies evaluating leptomeningeal disease on whole-body 18F-FDG PET are lacking. The purpose was to evaluate PET imaging of leptomeningeal disease and investigate the incremental utility of newer PET reconstructions in leptomeningeal disease. Methods PET imaging of 56 patients with leptomeningeal disease detected initially on MRI (n = 53) or cytopathology (n = 35) were retrospectively reviewed. Regular 3-dimensional iterative reconstruction (3D IR, n = 56) and advanced reconstruction (AdvRecon, n = 41) PET images were evaluated by readers blinded to clinical and MRI findings for uptake involving cauda equina, posterior fossa and spinal cord. Spinal cord uptake pattern was classified as normal (uptake < liver), uptake = liver, conus uptake > liver, conus and cervical cord uptake > liver and multifocal/diffuse uptake > liver. SUVmax ratios of conus/liver, conus/left atrium and conus/cervical cord were compared between 3D IR and AdvRecon datasets. Results Cauda equina uptake was seen in 64% and 78% on 3D IR and AdvRecon; posterior fossa uptake was seen in 52% and 54% on 3D IR and AdvRecon, respectively. Twelve percent had cauda equina or posterior fossa uptake visible only on AdvRecon. On 3D IR, normal spinal cord uptake was most common (27%); on AdvRecon, conus and cervical cord uptake > liver was most common (32%). Seven of 11 patients with normal spinal cord uptake on 3D IR were upgraded to increased uptake on AdvRecon. AdvRecon showed significantly higher conus/liver, conus/blood pool and conus/cervical cord SUVmax ratios (P < 0.0001). Conclusion Abnormal uptake in cauda equina, posterior fossa and spinal cord uptake are visible on FDG PET in leptomeningeal disease with increased conspicuity advanced PET reconstructions.

e17587 Background: Radium (Ra)-223 has become the cornerstone treatment in patients with metastatic castrate-resistant prostate cancer (mCRPC) with bone metastases. Ra-223 has been shown to suppress abnormal bone formation by inducing DNA double-strand breaks in tumor cells. This can reduce skeletal-related events, as well as improve survival and quality of life. Studies have indicated mutations that regulate DNA damage response in prostate cancer as susceptible to PARP inhibitors and platinum-based therapies. This study aims to evaluate mCRPC response to Ra-223 stratified by tumor genomics. Methods: This is a retrospective study of mCRPC patients who received Ra-223 and genetic testing within the Mayo Clinic database (Arizona, Florida, and Minnesota). Patient demographics, genetic mutations, treatment responses in terms of alkaline phosphatase (ALP) and prostate-specific antigen (PSA), and survival were assessed. Primary end points were progression-free survival (PFS) and overall survival (OS) from time of first radium treatment. Results: 239 mCRPC patients treated with Ra-223 were identified. Germline and/or somatic genetic sequencing was available in 50 patients, who had a median age of 61 years at time of diagnosis and 68 years at time of Ra-223 treatment. Median Gleason score at time of diagnosis was 8.0. 100% of patients received prior androgen deprivation therapy. 72% received prior docetaxel, and 18% received prior cabazitaxel. Notable mutations included TP53 (45.2%), TMPRSS2-ERG (28.6%), PTEN (26.2%), BRCA1/2 (14.3%), ATM (9.3%), CDK12 (7.1%), and Rb (4.9%). TMPRSS2-ERG was the second most commonly found mutation, with median OS 12.7 mo versus 15.4 mo in patients without TMPRSS2-ERG mutations (p = 0.099). In patients with CDK12 mutations (2 of 28 tested positive), PFS was 10.4 mo versus 5.6 mo in patients without CDK12 mutations (p = 0.157). The assessment of ALP and PSA response to radium treatment stratified by genetic mutation did not reach statistical significance. Conclusions: Among mCRPC patients treated with Ra-223 at Mayo Clinic, TMPRSS2-ERG was the second most commonly found genetic mutation and had observed worse survival outcomes that approached statistical significance. Prospective studies and increased sample sizes are needed to determine the impact of genetic mutations in response to Ra-223.

5577 Background: Prostate specific antigen (PSA) has well-recognized limitations as a marker for treatment response and disease progression. A post hoc analysis of the PREVAIL trial reported 24.5% of chemotherapy naïve mCRPC patients on enzalutamide had radiographic progression on conventional imaging with non-rising PSA. In this study, we sought to retrospectively compare PSA levels with C-11 choline positron emission tomography/ computed tomography (PET/CT) images in patients with m-CRPC on 2nd-HT with prior use of chemotherapy. Methods: We identified 123 patients with mCRPC on 2nd-HT following prior use of docetaxel chemotherapy (Abiraterone, n = 106; Enzalutamide, n = 17). Patients underwent serial PSA testing and C-11 choline PET/ CTs every 3–6 months. Disease progression was defined by the increase in blood pool corrected maximum standardized uptake value (SUVmax) of the index lesion on C-11 choline PET/CT scan. Suspicious lesions were confirmed by biopsy and/or conventional imaging. Results: Approximately 43% (n = 53) of patients had radiographic disease progression while on 2nd-HT. At time of radiographic progression, 60.4% of patients showed a parallel rise in PSA (Group-A), while 39.6% showed a paradoxical response; defined as radiographic progression with stable or down-trending PSA (Group-B). Median PSA at time of progression was 3.1 ng/ml for Group-A, and 1.3 ng/ml for Group-B (p-value = 0.0176). Median SUVmax was the same (4.9 Group-A, 4.6 Group-B; p-value = 0.6072). Bone-predominance progression was more significant in Group-B (90%) versus Group-A (65%) (p-value = 0.0309). The median time for radiographic progression was 9.5 months versus 3.9 months for Group-A and Group-B, respectively (Log-Rank = 0.0063). Conclusions: Metabolic imaging is a useful tool that should complement PSA in the evaluation of treatment response and disease progression in mCRPC patients on 2nd-HT, especially considering the paradoxical response observed in our data.

e16691 Background: Recent WHO classification of NET has defined high-grade well-differentiated NET (NET G3) as a distinct entity that is clinically different from neuroendocrine carcinoma. The optimal treatment for NET G3 has not been well-described. This study aims to evaluate NET G3 response to different treatment regimens. Methods: This is a retrospective study of NET G3 patients within the Mayo Clinic database (Arizona, Florida, and Minnesota). Patient demographics along with treatment responses and survival were assessed. Primary end points were progression-free survival (PFS) and objective response rate (ORR) by RECIST 1.1 criteria. Results: 71 patients with NET G3 were identified. Systemic treatment data was available in 30 patients who had a median age of 59.5 years at time of diagnosis. The primary tumor was most commonly pancreatic (73.3%). Ki 67 index was ≥55% in 26.7% of cases. 56.7% of cases had > 1 metastatic site. Treatment regimens included: capecitabine+temozolomide (CAPTEM) (n = 20), somatostatin analog (SSA) (n = 14), carboplatin/cisplatin+etoposide (EP) (n = 7), everolimus (n = 2), FOLFOX (n = 7), and lutetium Lu 177 DOTATATE (PRRT) (n = 10). CAPTEM was the most commonly used regimen (10 first-line, and 10 second-line) with ORR of 35%, disease control rate (DCR) of 65%, and median PFS of 9.4 months. The table summarizes the treatment data and responses rates for the various therapies used. Conclusions: Among NET G3 patients treated at Mayo Clinic, CAPTEM was found to be the most commonly used treatment with reasonable efficacy and disease control. Other treatment options include SSA, PRRT, FOLFOX, and EP. Prospective studies evaluating different treatments effects in NET G3 patients are needed to determine an optimal treatment strategy. [Table: see text]

143 Background: Systemic treatment in the management of metastatic prostate cancer is inevitable. However, there is a growing interest in metastases-directed therapy (MDT). We sought to investigate the efficacy of MDT in treating patients with solitary metastatic prostate cancer and hence, delaying initiation of systemic treatment (i.e., Androgen deprivation therapy or chemotherapy). Methods: We retrospectively identified 61 patients treated with targeted therapy in the form of surgery (n = 30), stereotactic body radiation therapy (SBRT) (n = 25), or cryotherapy (n = 7) for their solitary metastases prostate cancer. Complete response was defined by achieving a PSA value of ≤0.2 ng/ml plus resolution of the solitary metastatic lesion on C-11 choline PET choline scan, while incomplete response was defined by a residual PSA of > 0.2 ng/ml and/or radiographic evidence of disease following metastases-targeted therapy. Results: Mean (±SD) age was 68.4 (±7.8) yrs., median (IQR) primary Gleason Score was 7 (7-9) and median (IQR) pre-MDT PSA was 2 (1.3-3.8) ng/ml. Median (IQR) time from primary treatment of the prostate to MDT was 5.1 (2.7-10.1) years. None of the patients were on hormone therapy at the time of presentation with solitary metastases prostate cancer. 30 patients had bone metastases, 29 patients had lymph node metastases, 1 patient had soft tissue metastasis (pelvic metastatic mass), and another patient had visceral metastasis (to the lung). 42% of the patients (n = 26) achieved complete response to targeted therapy. Median time to initiation of 2nd line systemic treatment following MDT was 17.8 months for the complete responders versus 9.3 months for incomplete responders. 11% of the patients (n = 7) did not require 2nd line therapy after their MDT for a mean (±SD) time of 56.9 (±22.5) months. Conclusions: The use of targeted therapy in the management of patients with solitary metastatic disease or low-volume metastatic disease can provide comparable outcomes to those of systemic treatment. Further studies are warranted.

617 Background: Currently, there is no published data on the efficacy of SSAs for well-differentiated G3 NETs. Randomized trials have demonstrated a progression-free survival (PFS) benefit and limited tumor response for lower grade 1-2 NETs, but the optimal systemic therapy for metastatic/unresectable G3 NETs is unknown. We sought to evaluate the efficacy of SSAs in G3 NETs. Methods: We performed a retrospective analysis of Mayo Clinic patients treated with SSAs for metastatic/unresectable G3 NETs, querying data from 1992 - present. Inclusion criteria were: centrally reviewed pathology confirming well-differentiated morphology, G3 based on WHO classification, SSA monotherapy, and radiological data available to assess response. Patients who had prior lines of treatment were included as long they subsequently were treated with single-agent SSA. Poorly-differentiated tumors were excluded. The primary endpoint was PFS. Best overall response was determined by radiographic regression, stabilization, or progression of tumor size. Results: Ninety patient records were reviewed, with 14 meeting inclusion criteria (diagnosed 2014 – 2018). Median Ki-67 proliferative index was 25%. Two patients (14%) had a partial response to SSA therapy, five (36%) had stable disease, and seven (50%) had progressive disease. The estimated median PFS was 4.4 months (95% CI 2.9 – 24). Of the 7 patients with stable disease or partial response, the median time to progression was 8.7 months. Three patients had stable disease for greater than 9 months (24, 29 and 42 months, respectively). Overall survival was not estimable. There was no association of Ki-67 index with PFS based on a proportional hazards model. Conclusions: This is the first report on the efficacy of SSAs for G3 NETs. Although half of the patients in our series had at least stable disease, the PFS was modest at only 4.4 months. Given their favorable side-effect profile compared to cytotoxic chemotherapy, SSAs may present an attractive option to be further explored in a prospective fashion. We are presently updating this data by reassessing response using RECIST criteria.

AbstractBackgroundPathologic extranodal extension (ENE) has traditionally guided the management of head and neck cancers. The prognostic value of radiographic ENE (rENE) in human papillomavirus (HPV)‐associated oropharyngeal squamous cell carcinoma (HPV + OPX) is uncertain.MethodsPatients with HPV + OPX with adequate pretreatment radiographic nodal evaluation from a single institution were analyzed. rENE status was determined by neuroradiologists' at time of diagnosis. Distant metastasis‐free survival (DMFS), overall survival (OS), and locoregional recurrence‐free survival (LRFS) were estimated using Kaplan‐Meier methods. Cox proportional hazards models were fit to assess the impact of rENE on survival endpoints.ResultsHundred sixty‐eight patients with OPX + squamous cell carcinomas diagnosed between April 2008 and December 2014 were included for analysis with median follow‐up of 3.3 years. Eighty‐eight percent of patients received concurrent chemoradiotherapy. rENE was not prognostic; its presence in patients with HPV + OPX did not significantly impact OS, LRFS, or DMFS.ConclusionsIn patients with HPV + OPX, rENE was not significantly associated with OS, LRFS, or DMFS.