UGN-102, a hemoablative mitomycin-containing reverse thermal gel, was associated with maintained health-related quality of life (HRQOL) in patients with low grade non–muscle invasive bladder cancer (NMIBC), according to findings from the single-arm phase 2b Optima II trial (NCT03558503), which were presented during the AUA 2022 Annual Meeting.

Traditionally, low-grade NMIBC is treated by transurethral resection of the bladder (TURBT), which can lead to worsening health-relate quality of life (HRQOL), Angela B. Smith, MD, MS, vice chair of academic affairs, director of urologic oncology, and associate professor of urology at the University of North Carolina School of Medicine in Chapel Hill, noted in a presentation of the findings. Investigators evaluated HRQOL through patient-reported questionnaires 3 months after initiation of the noninvasive study medication. Eleven QOL measures were evaluated including questions concerning urinary symptoms, malaise, future worries, bloating/flatulence, intravesical treatment issues, male sexual problems, sexual intimacy, partner contamination, female sexual problems, sexual function, and sexual enjoyment.

Investigators reported that the gel did not lead to decrements in urinary symptoms, bloating/flatulence, or malaise; further, sexual function mildly worsened. Among patients who completed the questionnaire, 70% (31 of 44) achieved a complete response, defined as having a negative endoscopic examination, cytology, and for-cause biopsy. Demographic and clinical characteristics were not correlated with HRQOL changes, reported the investigators.

Primary outcome measures included complete response rate, and secondary outcome measures included durable complete response, as well as frequency, seriousness, and severity of adverse events. Area under the curve, concentration, and maximum concentration were also measured.

Eligibility requirements included patients with newly diagnosed or historic low-grade NMIBC who are at intermediate risk for progression, defined as having the presence of multiple tumors, recurrence, or a solitary tumor greater than 3 cm. Patients were ineligible if they have received Bacillus Calmette-Guérin treatment for urothelial carcinoma within the past 2 years, if they had a history of neurogenic bladder, active urinary retention, or any condition that would prohibit normal voiding.

A total of 63 patients enrolled in the trial and received 6 weekly doses UGN-102, which has a sustained release time of up to 8 hours. Forty-four patients were designated for the HRQOL cohort and completed the questionnaire. The majority of individuals in the HRQOL cohort were men (61%), over 65 years of age (57%), and non-Hispanic Whites (89%). The Sign test was used to measure longitudinal changes, and demographic and clinical characteristics were evaluated using regression testing.

Investigators reported that 10 patients (23%) were interviewed, and transcripts were double-coded using standard methods. In this subcohort, the majority were female (60%), non-Hispanic White (90%), and had a mean age of 65.6 years (8.4%).

During the interview sessions, patients expressed an appreciation of the nonsurgical treatment option and would recommend the gel to other patients, choosing the gel over TURBT. Additionally, patients noted that the gel did not require a long recovery period. Regarding safety, patients recalled minimal adverse events; however, frequent urination, restricted urethra, and blood in the urine were recorded.

The investigators concluded that a phase 3 trial is warranted.

Smith AB, Basak R, Mueller D, et al. Longitudinal health-related quality of life outcomes in adults with non-muscle-invasive bladder cancer receiving a chemoablative gel as a primary treatment (Optima II: phase 2b, single arm, open-label trial). 

. 2022;207(suppl 5):e928. doi:10.1097/JU.0000000000002633.06

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Investigators reported that mitomycin gel was not associated with decrements in urinary symptoms, bloating and flatulence, or malaise, and that sexual function only mildly worsened.

Patients With Low Grade NMIBC Experience Maintained Quality-of-Life With Mitomycin Gel

Treatment with the CD40 agonist sotigalimab (APX005M) in addition to pembrolizumab (Keytruda) elicited immunologic changes that yielded positive clinical responses in patients with unresectable stage III or IV metastatic melanoma, according to phase 1/2 findings (NCT02706353) presented during the 2022 AACR Annual Meeting.

Furthermore, the agent was found to have a favorable safety profile. Investigators also identified broad immune activity in both local and distant lesions through biomarker analysis.

In addition to evaluating the safety of sotigalimab, investigators determined the maximum-tolerated dose, the recommended phase 2 dose (RP2D), and objective response rate (ORR).

Among the total evaluable patients (n = 30), the ORR was 50% and was comprised of complete (17%) and partial responses (33%). Seventeen percent reported stable disease and 33% reported disease progression. The disease control rate was 67% and the response rate at the RP2D was 55%, said Bentebibel. Responses were also seen across PD-L1 and lactate dehydrogenase (LDH) levels.

By the data cutoff of December 30, 2021, 30 patients had been enrolled, said lead author Salah-Eddine Bentebibel, PhD. In the phase 1 portion of the study, 14 patients who were immune checkpoint inhibitor–naïve received an initial dose of intratumoral sotigalimab (0.1 mg) and intravenous pembrolizumab (2.0 mg/kg). This was followed by 4 increasing doses of sotigalimab at 0.5 mg, 1.0 mg, 3.0 mg, and 10 mg. Pembrolizumab was administered at 2.0 mg/kg across the escalation.

At the conclusion of phase 1, it was determined that the RP2D should be sotigalimab at 10 mg and pembrolizumab at 2 mg/kg. The phase 2 portion of the study is underway and will seek to enroll approximately 20 patients.

Investigators had hypothesized that sotigalimab could harness the CD40 pathway and activate innate and adaptive immunity. This is especially important because “many patients do not respond to [checkpoint inhibitor] therapy or develop resistance after initial tumor regressions, and new combinations are needed to improve the benefit risk profiles,” Bentebibel, an instructor in the Department of Melanoma Medical Oncology–Research at The University of Texas MD Anderson Cancer Center in Houston, Texas, said during the presentation of the data.

The majority of patients were male (n = 26; 87%) and were a median age of 65 years (range, 32-81). ECOG performance status was either 0 (57%) or 1 (43%). Fifty-seven percent had stage IV disease and 54% were 

 negative. Most patients (47%) had low LDH levels but 30% had very high LDH levels. PD-L1 status was unknown or negative in 37% of patients, respectively, and 8 patients (27%) were PD-L1 positive.

Biomarker analysis was conducted using blood and tumor samples obtained from local and distant lesions at baseline and at 24 hours post sotigalimab. Upregulation of genes and CD40 activation were noted by the investigators. “We saw robust upregulation of genes associated with antigen-presenting cells [APCs] and also engagement of MAP kinase and nuclear factor ĸB, a regulator of innate immunity,” Bentebibel said. In addition to the early time points of upregulated APCs, the investigators also reported T-cell response at later time points. “So [taken] together, these data suggest that sotigalimab engages the CD40 pathway,” Bentebibel said.

Further immune activity observed included an increase in macrophage, T cells, CD8+ T, and cytotoxic gene signatures in responding patients and the combination resulted in an increase in T-cell infiltration and clonality in local and distant lesions.

Regarding safety, investigators reported zero study discontinuations or death due to treatment-related adverse events (TRAEs). The most common TRAEs were injection-site reactions and 6 patients (20%) reported grade 3 immune-related AEs. Zero dose-limiting toxicities were observed for any dose level of sotigalimab.

Investigators concluded that the combination of sotigalimab and pembrolizumab showed encouraging antitumor activity and that the combination could induce immune activity in both local and distant lesions.

Bentebibel S-E, Johnson D, Amariae R, et al. Intratumoral CD40 agonist sotigalimab with pembrolizumab induces broad innate and adaptive immune activation in local and distant tumors in metastatic melanoma. Presented at: 2022 AACR Annual Meeting; April 8-13, 2022; New Orleans, LA. Abstract CT039.

The CD40 agonist sotigalimab in combination with pembrolizumab yielded promising outcomes in patients with unresectable stage III or IV metastatic melanoma.

Sotigalimab/Pembrolizumab Jumpstarts Immune Activity, Ignites Clinical Responses in Metastatic Melanoma

Survival rates in T-cell acute lymphoblastic leukemia (T-ALL), although formally inferior to survival rates in B-cell acute lymphoblastic leukemia (B-ALL), are now considered similar to B-cell (B-ALL), with a survival rate close to 90%.

The drastic improvement in T-ALL survival rates over the past half-century has been described as one of the great success stories of modern medicine, said David T. Teachey, MD, attending physician and researcher at Children’s Hospital of Philadelphia. Yet, despite these great advancements, researchers are still striving to reach a 100% survival rate.

To reach this goal, Teachey outlined a few encouraging approaches during his presentation, “Novel Approaches to T-ALL,” presented at the Society of Hematologic Oncology 2021 Annual Conference.

“I think introducing targeted therapies and incorporating immunotherapies are the 2 areas where we continue to make improvements in outcomes and survival in these diseases,” Teachey said during his presentation. In addition, methods to improve risk stratification can lead to optimal benefit.

There are several potential new agents under development that are based on the biology of T-ALL, including signal transduction inhibitors, notch pathway inhibitors, CDK4/6 inhibitors, BCL-2 family inhibitors, epigenetic modulators, next-generation chemotherapeutics, and immunotherapies.

“T-ALL is far more biologically complex than B-ALL, so it’s harder to find a one-size-fits-all [treatment] but you can [stratify] patients with T-ALL into different groups who are more likely to respond to different small molecule inhibitors and other novel therapies based on the biology of leukemic blasts,” Teachey said.

In preclinical models, proteasome inhibitors have demonstrated encouraging activity, especially the ability to synergize with chemotherapeutics that can overcome resistance to steroids and other drugs. Further, these agents have shown promise in relapse trials, said Teachey. A number of relapsed trials are ongoing with a focus on proteasome inhibitors, including first-generation proteasome inhibitor bortezomib (Velcade) and second-generation inhibitors, including carfilzomib (Kyprolis).

The phase 3 AALL1231 trial (NCT02112916) randomized patients with T-ALL or T-cell lymphoblastic lymphoma (T-LL) to receive a modified augmented Berlin-Frankfurt-Münster chemotherapy backbone with or without bortezomib during induction and delayed intensification.

 Patients were stratified as standard, intermediate, or very high risk.

Investigators reported a 3-year overall survival (OS) rate for the control group (Arm A) of 85.5% compared with 88.2% for the treatment arm (Arm B). In patients with T-LL, the 3-year OS rate was 78.0% in Arm A and 89.5% in Arm B. The 3-year OS rate for patients with T-ALL was 88.2% in Arm A compared with 87.7% for patients in Arm B. Overall, bortezomib significantly improved event-free survival for these patient populations. “We found that there was a trend towards improved survival in patients who received bortezomib, but it didn’t rise to statistical significance,” Teachey said. “What we found that was interesting, though, was if you broke out patients on this trial who had T-ALL vs T-LL, we found there was no survival benefit.”

JAK/STAT inhibition is another potential pathway to be explored, Teachey said. This pathway is particularly attractive in patients with early T-cell precursor phenotype where JAK/STAT signaling is commonly dysregulated. Teachey noted several trials evaluating JAK inhibitors including ADVL1011 (NCT01164163), which is a phase 1 trial evaluating ruxolitinib (Jakafi) to determine the maximum tolerated or recommended phase 2 dose, dose-limiting toxicities, pharmacokinetics, and pharmacodynamics in children with recurrent/refractory solid tumors;

 and the phase 2 trial AALL1521 (NCT02723994), which is exploring ruxolitinib in combination with a standard multi-agent chemotherapy regimen in CRLF2/JAK-altered ALL.

Other inhibitors that are undergoing evaluation are CDK4/6 inhibitors. Specifically, the AINV18P1 trial (NCT03792256) is exploring palbociclib (Ibrance) in combination with a standard re-induction regimen.

 In the dose-determination portion of the study (part 1; n = 6), palbociclib was administered orally once daily for 21 consecutive days, first as a single agent (days 1-3) and subsequently in combination with 4-drug re-induction chemotherapy. In the ongoing expansion cohort (part 2; n = 2), patients will undergo further assessment for safety and feasibility of combination therapy.

Another target undergoing evaluation is BCL-2. Chonghaile et al

 found that T-ALL cell lines and primary patient samples are dependent upon BCL-XL, except when the cancer has an early T-cell progenitor (ETP) phenotype, in which case the cancer is BCL-2 dependent. The investigators described a change in antiapoptotic protein dependence that is related to the differentiation stage of the leukemic clone. Teachey said their findings demonstrate that BCL-2 is a potential target for therapeutic intervention and that ETP may be sensitive to venetoclax (Venclexta) monotherapy, as demonstrated by Pullarkat et al.

“Pediatric oncologists found [the venetoclax] data exciting because it included 7 relapsed/refractory pediatric patients and a response rate of 86%. I think we need more data and more patients, but this is a promising pathway,” Teachey said.

Turning to immunotherapies, Teachey said that there are several approaches in B-ALL, but that T-ALL poses some challenges. “The field has lagged a little in T-ALL because it’s more difficult to develop chimeric antigen receptors [CARs] against T-ALL for a number of reasons,” Teachey said. He noted that toxicity and CAR T-cell fratricide add to the difficulty in developing CARs in this setting. Despite the challenges, however, Teachey was encouraged because a few T-cell immunotherapy trials are underway that focus on daratumumab (Darzalex), pembrolizumab (Keytruda), nivolumab (Opdivo), and isatuximab-irfc (Sarclisa).

Teachey DT, Devidas M, Wood BL, et al. Cranial radiation can be eliminated in most children with t-cell acute lymphoblastic leukemia (t-all) and bortezomib potentially improves survival in children with t-cell lymphoblastic lymphoma (t-ll): results of children’s oncology group (COG) trial AALL1231. Presented at: 62nd American Society of Hematology Annual Meeting and Exposition. December 5-8, 2020. Abstract 266. Accessed September 8, 2021. https://bit.ly/3DXViLp

Loh ML, Tasian SK, Rabin KR, et al. A phase 1 dosing study of ruxolitinib in children with relapsed or refractory solid tumors, leukemias, or myeloproliferative neoplasms: A children’s oncology Group phase 1 consortium study (ADVL1011). 

. 2015;62(10):1717-1724. doi:10.1002/pbc.25575

Raetz EA, Teachey DT, Minard C, et al. Safety of Palbociclib in combination with chemotherapy in pediatric and young adult patients with relapsed/refractory acute lymphoblastic leukemia and lymphoma: a children’s oncology group pilot study. Presented at: 62nd American Society of Hematology Annual Meeting and Exposition. December 5-8, 2020. Abstract 1018. Accessed September 8, 2021. https://bit.ly/3yP1TnG

Chonghaile TN, Roderick JE, Glenfield C, et al. Maturation stage of T-cell acute lymphoblastic leukemia determines BCL-2 versus BCL-XL dependence and sensitivity to ABT-199. 

. 2014;4(9):1074-1087. doi:10.1158/2159-8290.CD-14-0353

Pullarkat VA, Lacayo NJ, Jabbour E, et al. Venetoclax and navitoclax in combination with chemotherapy in patients with relapsed or refractory acute lymphoblastic leukemia and lymphoblastic lymphoma. 

. 2021;11(6):1440-1453. doi:10.1158/2159-8290.CD-20-1465

While survival rates in T-cell acute lymphoblastic leukemia remain around 90%, researchers are optimistic that the use of targeted therapies and immunotherapies will continue to improve treatment options.  

Targeted Therapies Continue to Improve OS in T-Cell Acute Lymphoblastic Leukemia

An updated analysis from the phase 1 MonomentTAL-1 trial (NCT03399799) shows that patients with relapsed/refracted multiple myeloma reported high clinical response rates after being treated with Talquetamab (GPRC5D) at the recommended phase 2 dose (RP2D) of 405 µg/kg weekly, according to a presentation at the 2021 ASCO Annual Meeting.

The agent yielded an overall response rate of 70%, when given at the RP2D, with a median time to first confirmed response of 1 month (range, 0.2-3.8). Moreover, 65.2% of patients (n = 15/23) with triple-refractory disease responded to treatment, as did 83.3% of those (n = 5/6) with penta-refractory disease.

“Talquetamab is an off-the-shelf T cell-redirecting agent that requires limited steroid use and has a manageable safety profile,” Jesus G. Berdeja, MD, lead study author and director of myeloma research at Sarah Cannon Cancer Institute, said in a presentation on the data. Talquetamab is a first-in-class antibody that binds to CD3 and GPRC5D to redirect T cells to kill multiple myeloma cells.

Eligible patients with relapsed/refractory disease received talquetamab intravenously (IV, range, 0.5-180 µg/kg) or subcutaneously (SC; range, 5.0-800 µg/kg). Primary objectives of part 1 of the trial was identification of the RP2D whereas safety and tolerability were the objectives of part 2.

In the trial, 184 patients received talquetamab, 102 patients by IV and 82 patients by SC. In patients who received the drug SC there were 6 dose levels tested from 5 µg/kg to 800 µg/kg.

A maximum tolerated dose was not reached and Berdeja noted that safety, efficacy, pharmacokinetic, and pharmacodynamic data supported a weekly SC dose of 405 µg/kg as the RP2D. In the updated analysis, the RP2D of 405 µg/kg was administered SC once weekly to 30 patients with a median follow-up of 6.3 months (range, 1.4-12.0).

In the SC group (n = 82), the median age was 63.0 years (range, 42-80) and in the RP2D group (n = 30) the median age was 61.5 years (range, 46-80). Twenty-two patients (27%) were over 70 years of age in the SC group compared with 7 (23%) in the RP2D group. Twenty patients (24%) in the SC group received prior B-cell maturation antigen (BCMA) therapy compared with 8 (27%) patients in the RP2D group.

In the SC group, 76% of patients were triple-class refractory compared with 77% in the RP2D group. In the SC group, 28% of patients were penta-drug refractory compared with 20% in the RP2D group.

Regarding safety, Berdeja reported that talquetamab had a tolerable safety profile at the RP2D dose with no dose-limiting toxicities (DLTs) reported. Cytopenias were confined to patients who received step-up doses and neutropenias resolved within a week. In general, all grade 1-2 neurotoxicities were observed in 4 patients who received SC dosing and 2 patients who received the RP2D. Skin-related adverse effects (AEs) were reported in 67% of patients in the SC group and 77% in the RP2D group, with the majority being grade 1-2. There were no deaths due to AEs at the RP2D reported.

Overall, the most common nonhematologic AE reported was any grade cytokine release syndrome (CRS) with 67% of patients in the SC group reporting. In this group, 1 patient reported grade 3 CRS. In the RP2D group, 73% of patients reported any grade CRS.

“CRS was confined to step-up and first full doses,” Berdeja explained. “Most patients only required 1 dose of tocilizumab [Actemra] as a supportive measure.”

Of 6 evaluable patients across IV and SC cohorts, 4 had MRD-negative complete responses (CR)/sustained CR at 10-6, including 1 patient in the RP2D group. MRD negativity was sustained 7 months post CR in 1 evaluable patient.

Berdeja noted that responses were durable and deepened over time with 81% of responders in the RP2D group continuing on treatment. He said data from the IV cohort were more mature and that at subtherapeutic doses, responses were ongoing at more than 22 months in patients with longer follow-up.

Regarding immunogenicity, 6 of 50 (12%) patients treated with SC talquetamab had low titer antidrug antibodies, which did not appear to affect safety, pharmacokinetics, or efficacy. Pharmacodynamic analysis revealed that post treatment, PD-1-positive T cells were induced in the periphery, indicative of T-cell activation. Further, cytokine induction was consistent at doses greater than 45 µg/kg SC.

“Findings were encouraging and a phase 2 expansion study of talquetamab at the RB2D [NCT04634552] is currently in progress,” Berjeda concluded.

Berdeja JG, Krishnan A, Oriol A, et al. Updated results of a phase 1, first-in-human study of talquetamab, a G protein-coupled receptor family C group 5 member D (GPRC5D) × CD3 bispecific antibody, in relapsed/refractory multiple myeloma (MM). 

. 2021;39(suppl 15):8008. doi:10.1200/JCO.2021.39.15_suppl.8008

This article was originally published as 

“Talquetamab at RP2D Elicits High Clinical Response Rate in Relapsed/Refractory Multiple Myeloma”

Treating patients with relapsed/refractory multiple myeloma with Talquetamab at RP2D elicits high clinical response rate.

Talquetamab at RP2D Effective in Treating Relapsed/Refractory Multiple Myeloma 

The use of real-time comprehensive profiling provides valuable diagnostic information and identifies potential therapeutic targets in adults with malignancies, but this process remains widely underutilized for pediatric patients and represents a significant unmet need. Investigators in Heidelberg, Germany, using the INFORM (INdividualized therapy FOr Relapsed Malignancies in Childhood) registry demonstrated the feasibility of implementing a large-scale multinational personalized oncology platform to aid in decision-making and improve clinical benefit. INFORM also provided diagnostic refinement and targeted therapy options to pediatric patients.

“This is the first time that such a large precision oncology platform [involving] pediatric patients was assessed for its clinical benefit,” Cornelis M. van Tilburg, MD, PhD, senior physician in Pediatric Oncology and Hematology, and head, Early Phase Clinical Trials at the Hopp Children's Cancer Center, in Heidelberg, Germany, said during a press program ahead of the 2020 American Society of Clinical Oncology (ASCO) Virtual Scientific Program.

Eight countries participated in the study by sending samples from pediatric patients for molecular analysis. The analyses were shared with an online interdisciplinary molecular tumor board that included the patient’s pediatric oncologist. A predefined algorithm using a 7-step scale that ranged from “very high priority” to “very low priority” target labels was implemented and was based on how druggable the target was, the alteration type, and any specific evidence. Treating physicians could access an online database to review the analyses.

“It is important to note that INFORM is not a clinical trial,” Tilburg said. “Treatment decisions made by the patient’s physician encompassed either enrolling the pediatric patient in a clinical trial, prescribing an off-label targeted drug, or treating with conventional therapy.” Any documentation follow-up was included in the online database.

In the analysis presented at ASCO, samples from 526 children were evaluated, of which 149 received a matching targeted drug. Twenty samples were determined to have the highest priority label. Children with higher-level targets more frequently received a matching targeted drug, said Tilburg. Seventeen children (3.2%) enrolled in clinical trials and 40 children (7.6%) with a potential cancer predisposition syndrome were detected, 17 of which were previously unknown. Families of these children were offered genetic counseling. “In approximately 8% of the brain tumors, we were able to provide diagnostic refinement of the original diagnosis,” Tilburg said.

Progression-free survival (PFS) rates in patients who received a matching targeted drug were similar to patients who did not receive a matching targeted drug. The survival curves overlap, said Tilburg.

An analysis of the highest priority level targets, however, reveals that those patients who had a very high priority level target and received a matching targeted drug had a median PFS rate of 204.5 days, compared with all other children, whose PFS rate was 114.0 days. “Children with very high priority level target show longer PFS,” Tilburg said.

In the initial INFORM study, 214 tumor samples of pediatric patients at high-risk were profiled and collected from 47 German centers.

 A breakdown of tumor types revealed that 39% were sarcomas, 30% were brain tumors, 13% were neuroblastomas, and 18% were hematological or other malignancies. On average, the turnaround time from tissue arrival to molecular results was 21 calendar days. In 14 of 214 patients (7%), the investigators identified an underlying germline predisposition syndrome. The investigators detected 1 or more potentially druggable alterations in 69% of samples (147 out of 214). Based on these findings, targeted therapeutics were incorporated into the therapy regimen in one-third of patients.

Tilburg said that pediatric precision oncology in a real-world, multinational setting is feasible. For the subgroup of children with very high priority level targets, the INFORM registry provided therapeutic opportunities and new diagnostic information.

“Looking to future research, there is an urgent need for biomarker-driven pediatric interventional clinical trials,” Tilburg said. “A significant group of patients didn't have very high-level targets and we should put our efforts in adding additional layers of diagnostics to allow them to benefit from new treatments,” he concluded.

1. Van Tilburg CM. The pediatric precision oncology study INFORM: Clinical outcome and benefit for molecular subgroups. J Clin Oncol. 2020;38(suppl; abstr LBA10503). doi: 10.1200/JCO.2020.38.15_suppl.LBA10503           

2. Worst BC, Pfaff E, Van Tilburg CM, et al. The INFORM personalized medicine study for high-risk pediatric cancer patients. J Clin Oncol. 2017;35(suppl 15):10509-10509. doi: 10.1200/JCO.2017.35.15_suppl.10509

This article was originally published on OncLive as, "

Using a Multinational Pediatric Cancer Registry Helps to Improve PFS in High-Risk Patients

Pediatric precision oncology in a real-world, multinational setting is feasible. For the subgroup of children with very high priority level targets, the INFORM registry provided therapeutic opportunities and new diagnostic information.
 

International Pediatric Cancer Registry Can Improve Outcomes

A study by researchers with the US Department of Defense Center for Prostate Disease Research (CPDR) Multicenter National Database has found that for men with positive needle biopsy for prostate cancer, active surveillance (AS) did not negatively impact their quality-of-life compared with men who had a negative prostate needle biopsy.

These findings suggest that a more conservative treatment approach was not a stress point for these individuals with low-risk disease.

“We found that there were really no quality-of-life differences between these two groups of men, which was a nice surprise,” said lead author Jennifer Cullen, PhD, MPH, director of the CPDR Epidemiological Research Program. “We were concerned that those who had cancer would have worse mental health, because of a confirmed cancer diagnosis.”

The findings suggest that AS “is a reasonable option in low-risk patients in terms of promoting and maintaining a high level of quality of life relative to those patients without cancer,” Cullen said.

Data for the years 2007-2014 were evaluated. Of the 1204 individuals who met study eligibility requirements, 420 (35%) had a negative prostate needle biopsy (noncancer group) and 787 (65%) had a positive prostate needle biopsy for cancer. Of the men with a positive finding, 411 (52%) were diagnosed with low-risk prostate cancer, 89 of whom were placed on AS.

Cullen and researchers used two questionnaires with established validity and reliability—EPIC, a prostate cancer specific instrument, and SF-36, a general health assessment test to determine health-related quality-of-life (HRQoL) measures. Findings were assessed at biopsy (baseline) and annually for up to 3 years. The researchers said they undertook the study because it is poorly understood how HRQoL of men who select AS compares with the HRQoL of men at similar risk, but without prostate cancer.

“In our study, we focused on two patient subsets—one group that was biopsied was found to not have cancer. The other group had cancer but was at such low risk that it was a comfortable option for the physician to advise the patient that he was eligible for active surveillance,” said Cullen, a research assistant professor in the department of surgery at the Uniformed Services University of the Health Sciences.

EPIC measures four paired subscales: urinary, sexual, bowel, and hormonal function and bother. SF-36 measures eight subscales that can be combined into physical and mental component summary scores. Both tests offer subscale scores that range from 0 to 100, with higher scores indicating better HRQoL. HRQoL surveys were administered before or after biopsy (baseline), and at 3, 6, 12, 18, 24, 30, and 36 months after a positive biopsy or 12, 24, and 36 months after a negative biopsy. The researchers reported that only baseline surveys and those from 12-, 24-, and 36-month points were included in the analysis.

The researchers found that the only time HRQoL trends differed were for urinary function and mental health subscales, with the group undergoing AS reporting additional decreases of approximately two points per year. Cullen and colleagues attributed this finding as a regression to the mean, particularly with regard to urinary functions, which was higher in the AS group at baseline. They reported that the changes did not result in statistically significant or clinically meaningful differences in adjusted mean scores of these subscales at 3 years.

The decision for a patient to choose active surveillance is a complex one, said Cullen. “A number of factors go into the decision. It could be that the physician strongly recommends it, the patient may have a preference to avoid surgery or radiation therapy, or the patient’s spouse might recommend against surgery or radiation therapy.”

She added that surgery and radiation can result in sexual, urinary, and bowel dysfunction, “so there are serious consequences in pursuing aggressive treatment. A man in his 50s or 60s may want to delay treatment because of those adverse events that affect these core functions,” she said.

The interplay between patient and clinicians is important, and Cullen pointed out that “all of the patients who participated were seen in a multidisciplinary clinic where they have a chance to meet with a radiation oncologist, surgical oncologist, and even a nurse educator.” All the health team members had a chance to meet, and all treatment options were on the table, she said.

However, this setting could have biased the results, she cautioned, because the general population does not always have the same level of access to healthcare facilities and consistency in follow-up care, as in the military population who participated in the study. In addition, armed forces personnel tend to be “very loyal to this health system, so we don’t see the high rates of attrition that might occur outside of this military cohort.”

“We know overwhelmingly that most men with a prostate cancer diagnosis are going to have a positive outcome. I’m confident in saying that their quality of life remains high during the 3-year period after diagnosis,” she said. “But because this is one study that examined one military cohort, more studies should be undertaken to repeat the analysis,” Cullen concluded.

 Pham KN, Cullen J, Hurwitz LM, et al. Prospective quality of life in men choosing active surveillance compared to those biopsied but not diagnosis with prostate cancer. 

For men with positive needle biopsy for prostate cancer, active surveillance (AS) did not negatively impact their quality-of-life compared with men who had a negative prostate needle biopsy.

For Men With Low-Risk Prostate Cancer, Active Surveillance Does Not Cause More Stress

Although use of robotic surgery for prostate cancer has surpassed open surgical procedures, the impact of this approach on patient quality of life has not been well-studied. To address this knowledge gap, a group of researchers compared quality of life (QOL) indicators from two prior studies of patients with prostate cancer who had either robotic or open surgery and found that scores on sexual function were better for those who had the robotic procedure, yet comparative results for urinary function were not as conclusive.

The findings of the analysis were shared in a late-breaking abstract reported at the 2015 American Urological Association (AUA) Annual Meeting May 17, 2015 in New Orleans.

“In our study, we examined urinary and sexuality quality of life outcomes from two large cohort studies that were separated in time and dominated by a single technique,” said Brock O’Neil, MD, of the department of Urologic Surgery at the Vanderbilt University Medical Center. “Our hypothesis was that neither surgical approach would result in superior quality of life over the other.”

Currently most available QOL data on robot-assisted, laparoscopic radical prostatectomy (RALP) and open radical prostatectomy (RRP), are from single surgeon/center reports, lack adequate risk-adjustment, or use limited information on patient-reported outcomes, O’Neil explained.

To gain a better comparative understanding of post-prostatectomy QOL, researchers looked at data from two large, population-based, prospective cohort studies: the Prostate Cancer Outcomes Study (PCOS) conducted from 1994-1995 and the more recent Comparative Effectiveness Analysis of Surgery and Radiation (CEASAR) study which was carried out from 2011-2012. All PCOS patients had open surgery, and QOL was assessed using the UCLA Prostate Cancer Index. The majority of men (78%) in CEASAR had the robotic procedure, and QOL was measured using the Expanded Prostate Cancer Index Composite-26.

In order to account for differences in these tools, researchers identified four common measures of urinary incontinence, three of sexual function, and set modified domain summary scores on a scale of 0-100, with 100 indicating ideal function.

Differences between the groups were assessed at 6 and 12 months after surgery using multivariate linear regression. Covariate adjustment was used to control for sociodemographic and clinical pathologic features, including baseline urinary and sexual function.

Data were analyzed for 2438 men across the two study cohorts, 1505 of whom had RRP, and 933 had RALP. Among the men who underwent RRP, 1243 were from the PCOS study and 262 were from the CEASAR study.

For the 74% of men with excellent urinary function scores (= 100) at baseline, those who underwent RALP had a mean QOL score of 74.1 at 6 months versus 70.4 in the RRP group (a difference of 3.8 points, 95% CI, 1.1-6.4); however, urinary continence scores were not significantly better at 12 months (78.7 vs 77.5, respectively, or a difference of 1.2 points; 95% CI, -1.3- 3.7).

Among the upper quartile of men who had with excellent baseline sexual function, the mean score after 6 months was 55.1 in the RALP group versus 44.9 in the RRP cohort, a difference of 10.2 points (95% CI, 7.5-12.9). Notably, and unlike the urinary continence scores, at 12 months, the sexual function score differential was sustained, with better scores in the robotic surgery group (61.4 vs 51.1, respectively, a 10.3-point difference; 95% CI, 7.5-13.1).

In the lower quartile of men with reduced sexual function at baseline (score = 65) the mean score for those undergoing robotic surgery still had a statistically significant better score (45.9 vs 40.7, respectively (+5.2 [95% CI,2.8-7.6]) which continued at 12 months, where mean scores were 3.3 points higher in the RALP group (49.0 vs 45.7, respectively [95% CI, 0.8-5.8]).

“Sensitivity analysis, which compared robotic CEASAR vs open CEASAR, robotic CEASAR vs open PCOS, and open CEASAR vs open PCOS, provided consistent support for the sexual function outcomes and mixed support for urinary incontinence outcomes,” said O’Neil.

O’Neil noted that the study had a few limitations. QOL measures were used from two different scales, which were not previously psychometrically validated, and PDE5 inhibitors were not available during the PCOS enrollment period.

“Our study, using CEASAR and PCOS, which were performed more than a decade apart but having similar methodology, suggests that robotic surgery performs better than open surgery for sexual function and possibly urinary function, out to at least 12 months,” O’Neil concluded.

Longer follow-up is required to establish whether benefits persist beyond 1 year and to assess for differences in oncologic outcomes.

	O'Neil B, Koyama T, Rudd J, et al. Evidence of superior quality of life after robotic prostatectomy: results from a population-based analysis. Presented at: AUA Annual Meeting; May 15-19, 2015; New Orleans, LA. Abstract PII-LBA5.

Although use of robotic surgery for prostate cancer has surpassed open surgical procedures, the impact of this approach on patient quality of life has not been well-studied. 

Measuring Quality of Life After Robotic Surgery for Prostate Cancer

When the United States Preventive Services Task Force (USPSTF) recommended against routine PSA screening for early detection of prostate cancer in May 2012, it caused a sea change in practice patterns among primary care physicians.

The impact of the recommendations had “a significant chilling effect,” said Sam Chang, MD, a professor of Urology at Vanderbilt University Medical Center, who moderated a panel discussion on the topic at the 2015 American Urological Association (AUA) Annual Meeting.

Data presented by Ryan Werntz, MD, during the panel discussion showed that after the guideline was issued, the overall rate of PSA testing decreased by 50% among primary care physicians at Oregon Health & Science University (OHSU).

In particular, the most significant decrease in PSA use was seen in men aged 50 to 70 years—a cohort most likely to benefit from screening.

“If you look back before PSA was a big part of prostate cancer screening, 20% to 25% of men would often first see a physician with back pain and be subsequently diagnosed with metastatic disease,” said Werntz, a urologic resident at OHSU.

“It’s a little bit unnerving, because if the guidelines for primary care physicians are recommending not to screen for prostate cancer, we could go back to those days when 1 in 5 men are presenting with metastatic disease,” continued Werntz. “Now, only 4% of men are presenting with metastatic disease, and that has to be due to PSA screening.”

Previous research revealed a significant decrease in screening frequency in two cohorts of men studied from June-November 2011 and during the same 6-month period in 2012 after the USPSTF guideline (8.6% vs 7.6%, 

 = .0001; adjusted odds ratio 0.89; 95% CI, 0.83-0.95).

The goals of the study reported at AUA were to identify trends in PSA testing by OHSU primary care physicians before and after the recommendation was issued, to determine which age groups were impacted the most, and to identify the rate of PSA testing in men with lower urinary tract symptoms (LUTS). The USPSTF guideline was largely based on an analysis from the Pacific Northwest Evidence Based Practice Center at OHSU, noted Werntz.

Men aged >40 years who were new patients at the family or internal medicine clinic at OHSU between January 2008 and December 2013 were identified for inclusion in the study using the OHSU electronic database. Those with a history of prostate cancer or who had previously been treated by a urologist were excluded.

Researchers compared PSA testing before and after the USPSTF recommendation, with results stratified by age. They found that PSA testing for men aged 50-59 years fell from 19.2% over the 4 years 2008-2012 before the USPSTF recommendation, to 8.5% after May 2012 when the guideline was issued—a reduction in screening of 56%. Similarly, for men aged 60-69 years, the rate fell by 60%, from 19.3% to 7.2%, respectively.  

The researchers observed no significant difference in the frequency of PSA testing for men aged 40 to 49 years after the recommendation was issued (4.2% vs 4.4%, respectively) and for men 70 years or older (10.2% vs 9.3%, respectively).

Benign prostatic hyperplasia (BPH) or LUTS was a noted diagnosis in 3.6% of new patients examined, yet only 36% of men with this diagnosis were given a PSA test, suggesting underutilization of PSA in this symptomatic group of men. LUTS is a potential symptom of advanced prostate cancer, but current AUA guidelines suggest that PSA testing is optional. AUA guidelines do recommend a digital rectal exam (DRE), but this is often not done, Werntz noted.

Widespread use of PSA testing has contributed to the detection and overtreatment of men with low-risk, non-aggressive prostate cancer. Nevertheless, recognizing the benefits of PSA testing, the AUA updated its guidelines in 2013 to incorporate a man’s health risk, age, race, and family history.

Enhanced education for primary care providers is required to stress that not every prostate cancer needs treated. Screening should include shared decision making with the patient and a restriction of screening and biopsy to high-risk groups of healthy men. For those at low-risk, less frequent PSA screening could be appropriate and newer tests that correlate with cancer aggressiveness could be utilized to lessen the chance of overdiagnosis and overtreatment.

“Urologists are uniquely positioned to monitor PSA test results with their patients, and to know when to biopsy an individual,” concurred Werntz. “Obviously, it should be a shared decision.”

			Werntz R, Martinez-Acevedo AC, Conlin MJ, et al. Trends in PSA utilization by primary care physicians: impact of the USPSTF recommendation. Presented at:  AUA Annual Meeting; May 15-19, 2015; New Orleans, LA. Abstract PD44-02.

			Cohn JA, Wang CE, Lakeman JC, et al. Primary care physician PSA screening practices before and after the final US Preventive Services Task Force recommendation. 

PSA Screening Declines, Especially Among Men Most Likely to Benefit

A new study has found that older, single white males with advanced bladder cancer have the highest suicide risk among those with other cancers of the male genitals and urinary system. 

“The older, white, single male is already at higher risk in the general society for suicide; add on the fact that he has advanced bladder cancer, and this is a high-risk patient,” said Zachary Klaassen, MD, a urology resident at the Medical College of Georgia at Georgia Regents University, the study’s corresponding author. “But this has taught me that we have to look for warning signs in all these patients.”

When compared with the general population, overall suicide risk was 2.7 times higher for bladder cancer patients; rates were 1.86 times higher in kidney cancer patients, 1.27 times higher in prostate cancer, 1.23 times higher in testicular cancer, and 0.96 times higher in penile cancers.

Researchers reviewed the National Cancer Institute’s Surveillance, Epidemiology, and End Results Program, or SEER, database from 1988-2010 to find 1.2 million people with genitourinary cancer, examining variables such as age, sex, race, as well as disease and treatment aggressiveness.

They found that bladder cancer patients across the board, whether or not they had surgery or advanced disease, had a higher suicide risk than patients with other genitourinary cancers. Older patients with bladder, prostate, and testis cancer were generally at an increased risk. When looking specifically at the black population, those with bladder cancer also had the highest suicide rates; however, those with bladder, prostate, and kidney cancer had much lower suicide rates than whites in the group. Prostate cancer patients had an increased suicide risk over time, with the highest rate 15 years or more after their diagnosis.

The review identified suicide in these patients as a public health dilemma that needs physician awareness, particularly in patients who are older, male, and have aggressive disease.

“It’s a tough situation. We have to talk more with our patients about how they are feeling even if it’s uncomfortable for us,” said Martha K. Terris, MD, chief of the section of Urology, chief of Urology at the Charlie Norwood Veterans Affairs Medical Center, and the study’s senior author.

The clinicians recognized the challenging road faced by many of these patients during recovery. Those with bladder cancer, for example, often have surgery to both remove their diseased bladder and divert urine to a collection bag at their side. Recovery from this major procedure takes about 3 months; interferes initially with bowel function; can result in ongoing problems such as leakage and infection; and patients need long term, close follow up for signs of metastasis, so it’s also a very expensive cancer to treat.

Monica Smith, the executive director of the Bladder Cancer Advocacy Network (BCAN) says its important for patients to remember that "cancer is not a death sentence though in the debpths of depression, it may seem like it."

"Most bladder cancer patients, even those with urinary diversion, are able to maintain a full and active lifestyle and BCAN can offer support and resources that can help," she added. 

The average age of diagnosis of bladder cancer is 73, and about nine out of 10 patients with bladder cancer are over age 55, according to the American Cancer Society. Bladder cancer is more common in men and smokers, with about 74,000 new cases annually in this country and more than a half million survivors. Suicide is the 10th leading cause of death in the United States; cancer is number two, according to the Centers for Disease Control and Prevention.

Study Finds Advanced Bladder Cancer Increases Suicide Risk

The continuing contentious debate about screening for prostate cancer remains top of mind among the public and lay press, but, Leonard G. Gomella, MD, told attendees at the 8th International Prostate Cancer Congress, the decision to screen or not to screen boiled down to “using common sense, shared decision making, and choosing the right patients to screen.”

At the heart of the debate is the US Preventive Services Task Force (USPSTF) recommendation against PSA-based screening.

 The task force gave the screening test a grade D back in May 2012, but Gomella, professor and chairman of the Department of Urology at the Sidney Kimmel Cancer Center, Thomas Jefferson University, stressed that a careful reading of the full recommendation is necessary.

“If you read the fine print, the recommendation says to discuss the treatment options with your patient and that screening could be conducted on an every-other-year basis,” he said.

That’s not to say that the recommendation is not without flaws, however. “The recommendation missed some important concepts,” he continued. “It focused on complications of treatment—incontinence, erectile dysfunction, and rectal injury&mdash;but not on the value of screening and the amount it has saved the healthcare system.”

Additionally, the recommendation discussed population screening, “but ignored African Americans, the effect of family history, and morbidity associated with prostate cancer. And most importantly, no one on the task force has actually treated patients with prostate cancer,” Gomella noted. The latter point has spurred the introduction of legislation that could reform the task force by requiring consultation with experts who treat the specific disease in question.

The case for screening is a good one with 5-year relative survival in men diagnosed with prostate cancer approaching 100%, said Gomella.

 Prostate cancer mortality was on the decline before the task force issued its recommendation, but it’s not clear if screening was the sole contributor. Most likely it was “a combination of increased screening and better therapy,” he said.

But recent findings presented at the 2015 Genitourinary Cancers Symposium suggest a deleterious effect of the task force guidelines. Researchers found that between 2011 and 2013, there was a 6% increase in the diagnosis of intermediate or higher risk prostate cancer in men and concluded that many more deaths could result from this disease.

They made no determination whether a decline in PSA screening was the cause.

The results of two large screening trials

 suggest that the ideal candidates for PSA screening are men who are at high risk of prostate cancer, older men, those with a family history, those who are at high risk of suffering morbidity and mortality from the disease, and men who are in good health and are asymptomatic with a life expectancy of 10-15 years.

Other diseases experience conflicting recommendations as well, said Gomella. “Breast, lung, and thyroid cancer recommendations run into similar problems. With prostate cancer, there are many men with false negatives, but few with prostate cancer. This suggests we have to refine our screening efforts: do it smarter, do it better, and avoid overtreatment.”

One emerging tool that might help clinicians are new genomic tests, and several are currently available, including the Genomic Health Oncotype DX prostate cancer test and the Myriad Prolaris test. It is hoped that genomic tests will help stratify patients with localized prostate cancer based on disease aggressiveness. “It will become more important to incorporate these tests in deciding who is at the biggest risk for not treating early prostate cancer,” said Gomella.

Gomella recommended better education for primary care physicians because not all prostate cancer needs treatment when detected, shared decision making with the patient, restricting screening and biopsy to high-risk groups of healthy men, less frequent PSA screening if the patient is at low risk or has a low PSA, and to consider incorporating newer tests that correlate with cancer aggressiveness to lessen the chance of overdiagnosis and overtreatment.

			Moyer VA. Screening for prostate cancer: US Preventive Services Task Force recommendation statement. Ann Intern Med. 2012;157(2):120-134.

			H.R. 1151, The USPSTF Transparency and Accountability Act of 2015. https://www.govtrack.us/congress/bills/114/hr1151. Accessed March 14, 2015. 

			National Cancer Institute. Surveillance, Epidemiology, and End Results Program. http://seer.cancer.gov/statfacts/html/prost.html. Accessed March 14, 2015.

			Hall MD, Schultheiss TE, Farino G, et al. Increase in higher risk prostate cancer cases following new screening recommendation by the US Preventive Services Task Force (USPSTF). 2015 Genitourinary Cancers Symposium. J Clin Oncol. 2015;33 (suppl 7). Abstract number 143. http://meetinglibrary.asco.org/content/140836-159. Accessed March 14, 2015.

			Andriole GL, Crawford ED, Grubb RL 3rd. Mortality results from a randomized prostate-cancer screening trial. N Engl J Med. 2009;360(13):1310-1319.

			Schröder FH, Hugosson J, Roobol MJ, et al. Screening and prostate-cancer mortality in a randomized European study. N Engl J Med. 2009;360(13):1320-1328.

The continuing contentious debate about screening for prostate cancer remains top of mind among the public and lay press, but, Leonard G. Gomella, MD, told attendees at the 8th International Prostate Cancer Congress, the decision to screen or not to screen boiled down to "using common sense, shared decision making, and choosing the right patients to screen."

Tony Berberabe, MPH