PUOWG Open Meeting Minutes

Wednesday, October 21, 2015

Location: Prague, Czech Republic

Attendees: ??

1. Dr. Cost opened the meeting and asked everyone to introduce themselves and provide updated contact information. He noted that a membership survey will be distributed by Jonathan Ross via email after this meeting, and announced the results of the Executive Committee Elections (offiecs to take effect in Spring 2016): President will be Ferd Ferrer, President-Elect will be Armando Lorenzo, Secretary will be Nick Cost, and at-large members will be Patricio Gargollo, Kathleen Kieran, Jonathan Routh, and Kristina Suson.
2. Dr. Kieran provided an update on Coordinating council meeting:
   • The purpose of PUOWG is to support pediatric urological involvement in the Children’s Oncology Group and in providing pediatric urological oncology educational opportunities to the larger pediatric urology community. Membership is open to all interested SPU members and currently stands at 54 people. Ferd Ferrer will be the president beginning at AUA 2016.
   • The SPU Pediatric Urologic Oncology Working Group will hold its 5th meeting on Thursday, October 15 in SALON 2.2 of the Prague Congress Centre, following the conclusion of the scientific session. We will be discussing ongoing projects, recommendations and updates from the COG meeting last week, and soliciting new project ideas and case presentations from attendees.
   • We have several projects underway. In addition, we will be presenting a session on “The role of partial nephrectomy for Wilms tumor in North America and Europe” at this meeting. We have also just completed a survey of pediatric urologists’ participation in the care of patients with GU tumors and anticipate that this will be presented at the Spring AUA/SPU meeting. New project proposals will be discussed at the Thursday meeting.
   • We have also formed a committee that focuses on the current status of oncofertility in both male and female children undergoing oncologic treatment.
   • SPU Coordinating Council was receptive to and supportive of the update provided.
   • Members provided an update of the recent Children’s Oncology Group meeting.
3. Dr. Cost provided an update on Testis/Germ Cell Tumors
   1. Intermediate Risk on AGCT 0132 – PEB x 3 (Compressed)
      • Included: Stage II-IV testicular, Stage II-III ovarian GCTs, Stage I-II non-gonadal extracranial malignant GCTs=
      • 3yr EFS = 88.7%, 3 yr OS = 97.3%
      • EFS by age: <11y = 93.0% vs. ≥11y = 85.0%
      • 97% EFS for those who started as low risk and relapsed and were transferred to intermediate risk stratum
      • Stage IV testis determined not to be appropriate for IR
      • Stage IV Testis (all >11yr) had a 54% 3 year EFS
      • Compared to a historic cohort with 4 cycles of PEB at 90% EFS
      • Overall Stage III and IV Testis did better with historic 4 cycles of PEB
      • Conclusions:
        • 3 x PEB probably ok for <11yr
        • Stage IV Testis is not appropriate as Intermediate Risk:
        • Need 4 x PEB and may need weekly Bleomycin
   2. New Study – AGCT 1531: Intermediate Risk Groups 1 and 2
      • New Risk Stratification
        • Low Risk – Stage I, all sites
          • Will now include Immature Teratoma
        • Intermediate Risk 1 (IR1)
          • 0-10yr All Sites Stage II-IV
        • Intermediate Risk 2 (IR2)
          • Testis = ≥11yr, Stage II-IV (Good Risk by IGCCCG)
          • Ovarian = ≥11yr, Stage II-III
          • Extragonadal Stage II
        • Poor Risk
          • Testis = ≥11yr, Stage II-IV (Intermediate or Poor Risk by IGCCCG)
          • Ovarian = ≥11yr, Stage IV
          • EGCT = ≥11yr, Stage IV
      • Logistics – will be intergroup with adults (NRG Oncology)
      • Objectives
        • Observation for Stage I, all sites, <50yrs old – include EGCT
        • Intermediate Risk: Carboplatin vs.Cisplatin
        • IR1
        • randomize CEb x 4 vs. PEb x 4 (b = day 1 Bleo)
        • Weekly Bleomycin for IR2
        • randomize CEB x 3 vs. BEP x 3 (B = weekly Bleo)
   3. New Poor Risk Trial (Already ongoing ANZUP)
      • Accelerated BEP for Poor Risk
   4. Dysgerminoma/seminoma study with UK group
      • Likely to be 3 x BEP vs. Single-agent Carbo (AUC>10) x 3-4 cycles
      • Some to get 4 cycles of Carbo if not a good response to 1st cycle
4. Dr. Kieran provided an update on renal tumors
   1. AREN03B2 (only open study)
      • Only study currently open to enrollment (classification of patients with renal tumors by known prognostic factors)—therapeutic studies are closed but tissue banking component still open. Evaluation found a 10% discrepancy between institutional and central review (e.g. histology). Most patients with LOH were stage III (decreased incidence in Stage 1). This is because local (and ultimately, central) review impacts risk stratification and can be used to direct therapy; real-time central review is not feasible but would be ideal. Outcomes in selected groups are discussed below.
      • Stage III FH tumors: OS after relapse (even with alkylator-intense chemotherapy or BMT) is only 40-50% (EFS/OS reported by intention to treat). LOH1p had poorer 4 year EFS than LOH 16q (74% vs 83%) versus neither (92%)
      • VLR, LR, SR treatment for WT: VLR patients had recurrence rate (0.86%); lung and abdomen most common sites. 1q gain did not predict relapse; WT1 mutation (most common 11pLOH), 1p and 16q LOH did not predict relapse. 11p15 status remains important; retention of imprinting is associated with a low (3%) risk of relapse, while LOI, LOH were associated with 20-25% risk of relapse. Current debate: how to use biomarkers, and whether salvage therapy doses should be reduced? Also, in light of these biologic findings, there is consideration of eliminating the weight limit for tumors (e.g. 550 g for children <2 years of age).
      • Current projects within renal committee:
        • CT detection of preoperative rupture
        • CT vs MRI
        • Image based feasibility of NSS
        • Primary nx, intraoperative skills
        • DICER1 mutations
   2. AREN 0532
      • Very Low Risk WT Treated with surgery alone
      • 116 patients, 12 relapses, no deaths
        • 4yr EFS – 90%, OS – 100%
        • Median time to relapse 4.2mo (2.2 – 43mo)
      • Only 1 relapse was contralateral kidney
        • 5 lung, 2 abdomen, 4 tumor bed, 1 contralateral kidney
      • Current Recommended Options for these patients:
        • 1. Observation, 2) Vincristine only x 8wks (UK), 3) EE4a x 18wks
      • HAVE TO HAVE NODES PATHOLOGICALLY ASSESSED TO BE CONSIDERED FOR OBSERVATION.
      • Future plans: likely expand to <4yr and no weight restrictions
        • May also reduce salvage at relapse, withhold Dox (EE4a)?
   3. AREN0533
      • Current focus on newly diagnosed, higher risk FH WT. Using Regimen M, 48.7% have grade 3 or higher toxicity, but primarily hematologic and well managed. ( SIR [slow incomplete responders]: get regimen M.)
      • Saw significantly fewer adverse events than expected (allows conclusion that results are statistically significantly better than the null hypothesis): 3 year EFS 88%, 3 year OS 92%. Regimen M also compares favorably to NWTS5 (74.5% 5 year EFS) and is superior to Regimen D. However, potential for late effects (especially infertility) associated with Regimen M—especially cyclophosphamide.
      • Considering biologic information:
        • LOH: 74.9% 5 year EFS for LOH 1p, 16q compared with 92% for neither in Stage I/II (in Stage III/IV, 65.9% vs 83%)
        • Giving DD4A and Regimen M to patients with LOH 1p and 16q: similar EFS for Stages 1 and 2; for Stages 3 and 4, significantly increased EFS (also clinically significant)
        • Advocated LOH testing for patients with FH WT, especially if high stage disease, to help direct therapy based on stratified risk
   4. AREN0534
      • Current goals:
        • Improve 4 year EFS to 73%
        • Prevent complete nephrectomy in at least 50% of patients by using preoperative chemo
        • To facilitate partial nx
      • Renal Tumor Biology in this group
        • Genetics/epigenetics of BWT (Toronto group—Dr. Lorenzo): are there molecular differences in patients with BWT and metachronous BWT?
   5. TARGET Initiative
      • Most markers regulate renal development and transcription
      • Increased mi-R-200 expression (mesenchymal-epithelial transition)
   6. Trials in development
      • Hypoxia-activated alkylator
      • Lorvotusumab: IgG1 kappa monoclonal ab, links to CD56 Abs
      • Irinotecan: induces replication arrest (MK-1775)
      • Eribulin: antimitotic analog of halichondrin B (active in anaplastic WT xenografts)
   7. Next high-risk renal tumor studies
      • Not CCSK—too few patients for meaningful trial enrollment
      • AnaplastichHistology WT (revised UH-1=regimen I + carboplatin; doses reduced because of high grade toxicity); very high objective response rate in chemonaive patients with DAWT; therapeutic intensification seems helpful in DAWT; increasing XRT has decreased rate of abdominal recurrences. Adding VI seems to add time and may improve outcomes—overall worthwhile.
      • RTK
      • Relapsed WT
      • UH-3 regimen=UH-2 + biologics (AKT 1775, eribulin, MLN8239, PD1i, epigenetic, others)
   8. Design for diffuse AHWT study
      • For stage 1 DAWT and 1-4 FAWT: validate AREN0321 findings
      • For stage 2-3: UH-2/3 vs UH-1/2 (power analogous to AREN0321)
      • For stage 4: VI windows plus additional therapies (none [UH-2] vs biologic agent [UH-3])
      • Possible omission of carboplatin with X weeks of XRT (TBD)
   9. Relapsed WT: harmonizing risk stratification with SIOP
      • UH-2 vs ICE +VI trading renal outcomes and fertility issues; UH-2 gives doxorubicin again (? Worthwhile)
      • Allows combined efficacy signals and toxicity data
   10. RTK: OS 23%, primarily stage 1-2
       • VI and UH-1 studied; all patients progressed immediately therefore abandoned
       • Biologic targets are next step (not alone)—need to evaluate backbone, novel drug, protocol design
       • Looking for early endpoints (18-24 week PFS)
   11. Predictors of early relapse (e.g. while on treatment)
   • Tumor in metastatic sites vs in nodes
   • What makes people stage 3—does this matter??
   • Comparison of histology in synchronous and metachronous BWT—treatment as well as surgical considerations
   • Prenatal findings and maternal/paternal factors in WT development
   11. Future RCC study
       • New age independent TFE+ RCC study near opening – will be intergroup with NRG/ECOG
       • Will use COG Central Review and Resources
       • Randomized Phase 2 Trial of Axitinib vs Pembrolizumab for the treatment of TFE/Translocation Renal Cell Carcinoma across all age groups
         • Axitinib – anti-VEGF small molecule inhibitor
         • Pembrolizumab (Keytruda) – anti PD1 - a humanized monocolonal antibody with potent and selective inhibition of PD1
         • A cross-over design enabling an estimate of clinical benefit of single-agent axitinib and single-agent pembrolizmub in most patients enrolled
         • Will have central pathologic review as part of the study
         • Only open to patients with evaluable (i.e., non-resected metastases) disease
         • Will have surgical question involving impact of LND or Metastectectomy and protocol guidelines will encourage LND and Metastectomy
5. Drs. Kieran and Routh provided an update on RMS
   • Post treatment imaging in RMS. Recently published in Ped Blood and Cancer. Basic question is whether there is value to surveillance imaging for patients with RMS? Do patients whose relapse was detected radiographically do better than those whose relapse is detected clinically? In this group, two-thirds had symptomatic relapse but no other demographic differences between patients with symptomatic and radiographic relapses. OS 14% at 3 years, median time to death 7.2 months. Since screening tests (WHO criteria): treatment capable of reducing morbidity/mortality, disease can be treated, tests are acceptable (safe and relatively inexpensive). If there is no difference in the first two, one can argue that there is really no benefit to screening in patients who are off therapy. One other issue is patient compliance: they are really not getting the imaging done at the proposed intervals, but imaging does get patients in to see physicians rather than falling off the radar altogether.
   • VAC vs VI for Intermediate-Risk RMS. Equivalent failure-free survival in two groups, so performed cost-minimization analysis, looking at direct medical costs (no parent/family/societal perspective). Cost: average wholesale price from Micromedex, CMS reimbursement. VI—chemotherapy itself is less expensive but increased cost of ppx abx and G-CSF.
   • XRT for RMS. Only 40% of patients with metastases have the metastases treated with XRT (opportunity for quality improvement).
   • Secondary neoplasms after RMS. Many secondary malignancies are associated with Li-Fraumeni syndrome (9% have germline mutations, particularly in young patients <3 yo, lower in Europe, ~5%). In patients who received XRT, 55% of secondary malignancies were within radiation field; the types of SMN were consistent with Li-Fraumeni syndrome. In primary RMS, there was an overall 5-fold increased risk of SMN, independent of XRT treatment to primary tumor, and higher for children in whom RMS was diagnosed before 2 years of age and for those with embryonal or pleomorphic subtypes (in patients older than 10, no increased risk in patients with embryonal subtype). This suggests that a subset of young children with embryonal/pleomorphic histology have a constitutional cancer predisposition.
   • Fusion Status in RMS with high risk RMS. FOXO1 fusion status known in low and intermediate risk patients, now looking at high-risk patients. Stage 2-3 patients analyzed based on fusion status. PAX3, PAX7 patients did worse than those who were fusion negative. 9% 5 year EFS for FOXO1 fusion status +; low Oberlin scores: better prognosis. FOXO1 fusion status is predictive only when Oberlin 0-1.
   • Paratesticular RMS
     • Two major issues for urologists regarding upcoming research: 1) get most important aspects from urologists to be sure that they are included in the study design (long term oncologic outcomes); 2) support from institutions/leadership for research (in particular statistical analysis)
     • Current projects
       • International collaborative (800 cases)—captured fields related to surgical outcomes domestically and internationally. Very striking differences between European and American tumor management (especially RPLNDs—90% were done in US versus internationally)—question now is what template is being used for RPLND, and what are the post-RPLND complication rates? Now there is some effort to compare PET scans and RPLND pathology.
       • Quality improvement initiative: were RMS protocols actually followed?
       • Hemiscrotectomy vs WLE rates/outcomes after scrotal incision for orchiectomy
6. Dr. Shnorhavorian gave an update on COG protocol ALTE12C1 (approved by scientific council but not opening pending funding). This study evaluates the effects of modern chemo on spermatogenesis and steroidogenesis in survivors of osteosarcoma. More information will be forthcoming once the study is open for enrollment.
7. Dr. Cost reviewed the status of current PUOWG projects:
   1. Current Work Force Survey Study Completed
      • Awaiting time from Hillary Copp at AUA/SPU 2016 to present
   2. Preoperative Risk Factors in Loco-Regional Wilms Tumor (contact Nick Cost if interested in participation)
      • Open at Denver, Dallas, Cincinnati
      • Nick can re-send details if interested
   3. Testicular Microlithiasis Survey on Management:
      • Developed and Pilot Tested
      • Ready for circulation
      • ESPU and SPU have agreed to distribute
   4. Stone study in patients on chemotherapy
      • Kristina Suson is the lead person on this, please contact if interested
   5. ABU Case Logs Study: abstract written and sent to coauthors for approval. Anticipated presentation at AUA 2016.
      • 281 submitted case logs meeting the study criteria
      • 266 oncology cases were logged
      • 131 (46.6%) of logs reported ≥1 oncology case, 150 (53.4%) reported no oncology cases
      • Only 11 (3.9%) logs accounted for nearly a third (29.3%) of all oncology cases reported
      • The most common oncology cases logged were:
        • Orchiectomy (radical and partial): reported in 83 (29.5%) logs.
        • Nephrectomy (radical and partial): reported in 32 (11.4%) logs
        • RPLND: reported in 27 (9.6%) logs
        • Endoscopic biopsy of bladder, prostate or pelvic malignancy: reported in 18 (6.4%) logs
8. Dr. Cost noted that oncofertility was a focus of PUOWG this year, and opened the floor to discussion regarding ideas to promote oncofertility. Although some centers (e.g. Toronto) have urologists actively involved in fertility preservation, most centers do not. Dr. Shnorhavorian also noted the recent publication indicating that discussion of options for fertility preservation is not universal when a child is newly diagnosed with cancer, and in particular there are socioeconomic barriers to and disparities in whether fertility preservation is discussed or can be accomplished. The group agreed that collaboration among centers in order to have protocols available and to involve other specialties (e.g. oncology, gynecology, endocrinology) will be necessary for success.
9. Dr. Wehbi discussed the status of the website creation project.
   • He called on members to make recommendations for what would be most useful on the website.
   • Dr. Shnorhavorian suggested posting links, as many of these data are already available.
   • Dr. Khoury asked if a website link/listserv would be available to gather the opinions of others, which should be feasible. He also recommended that protocol assistance (e.g. informed consent form, standardized IRB applications) be made available on the website for PUOWG-initiated studies.
10. Dr. Cost adjourned the meeting.