title: Phase 1 Trial of Everolimus and Radiation Therapy for Salvage Treatment of Biochemical Recurrence in Prostate Cancer Patients Following Prostatectomy.
abstract: In up to half of patients treated with salvage radiation therapy (SRT) for rising prostate-specific antigen levels, a second biochemical recurrence ultimately develops. Phosphatase and tensin homolog inactivation is implicated in prostate cancer progression, and upregulation of the mammalian target of rapamycin pathway can lead to tumor hypoxia and radioresistance. Everolimus is a mammalian target of rapamycin inhibitor with both antitumor and radiosensitizing effects.
  
  
  
  We performed a phase 1 study using a modified 3 + 3 dose-escalation design to evaluate the safety and tolerability of everolimus in combination with standard SRT for the treatment of biochemical recurrence following prostatectomy. After a 2-week run-in period of everolimus daily therapy, patients received prostate bed irradiation with daily cone beam computed tomography localization in 37 fractions of 1.8 Gy each (total dose, 66.6 Gy). Patients were monitored for both acute (≤90 days) and chronic (>90 days) treatment-related toxicities.
  
  
  
  Eighteen patients received everolimus at dose levels of 5 mg (n=6), 7.5 mg (n=6), or 10 mg (n=6) daily in conjunction with SRT. No dose-limiting toxicities were observed. Common acute treatment-related toxicities included grade 1 or 2 mucositis (55.6%), grade 1 or 2 fatigue (38.9%), grade 1 or 2 rash (61.1%), and grade 1 urinary symptoms (61.1%). A grade 3 acute toxicity occurred in 4 patients (22.2%) (n=1 for rash, anemia, lymphopenia, and neutropenia), and no patients had a chronic toxicity of grade 3 or greater. After a median follow-up time of 17.8 months (range, 1.2-46.0 months), an undetectable prostate-specific antigen nadir was achieved in 9 patients (56.3%) and a second biochemical recurrence developed in 5 patients (31.3%).
  
  
  
  Everolimus at a dose of ≤10 mg daily appears to be safe and tolerable in combination with fractionated post-prostatectomy radiation therapy.
authors.affiliation: Division of Hematology/Oncology, University of Pennsylvania, Philadelphia, Pennsylvania; Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Vivek
authors.initials: V
authors.lastname: Narayan
authors.affiliation: Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania; Department of Radiation Oncology, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Neha
authors.initials: N
authors.lastname: Vapiwala
authors.affiliation: Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania; Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Rosemarie
authors.initials: R
authors.lastname: Mick
authors.affiliation: Division of Hematology/Oncology, University of Pennsylvania, Philadelphia, Pennsylvania; Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Pearl
authors.initials: P
authors.lastname: Subramanian
authors.affiliation: Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania; Department of Radiation Oncology, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: John P
authors.initials: JP
authors.lastname: Christodouleas
authors.affiliation: Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania; Department of Radiation Oncology, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Justin E
authors.initials: JE
authors.lastname: Bekelman
authors.affiliation: Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania; Department of Radiation Oncology, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Curtiland
authors.initials: C
authors.lastname: Deville
authors.affiliation: Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania; Department of Radiation Oncology, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Ramji
authors.initials: R
authors.lastname: Rajendran
authors.affiliation: Division of Hematology/Oncology, University of Pennsylvania, Philadelphia, Pennsylvania; Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania. Electronic address: naomi.haas@uphs.upenn.edu.
authors.forename: Naomi B
authors.initials: NB
authors.lastname: Haas
mesh_terms: D000368:Aged; D018450:Disease Progression; D019583:Dose Fractionation, Radiation; D000068338:Everolimus / Q000009:adverse effects / Q000627:therapeutic use*; D005240:Feasibility Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000097:blood / Q000188:drug therapy* / Q000532:radiotherapy*; D017430:Prostate-Specific Antigen / Q000097:blood; D011468:Prostatectomy; D011471:Prostatic Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000532:radiotherapy*; D011836:Radiation Tolerance; D011838:Radiation-Sensitizing Agents / Q000009:adverse effects / Q000627:therapeutic use*; D050397:Radiotherapy, Intensity-Modulated / Q000009:adverse effects / Q000379:methods*; D016879:Salvage Therapy / Q000009:adverse effects / Q000379:methods*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors
chemical_list: D011838:Radiation-Sensitizing Agents; D000068338:Everolimus; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D017430:Prostate-Specific Antigen