title: Addition of rapamycin and hydroxychloroquine to metronomic chemotherapy as a second line treatment results in high salvage rates for refractory metastatic solid tumors: a pilot safety and effectiveness analysis in a small patient cohort.
abstract: BACKGROUND
  Autophagy is an important oncotarget that can be modulated during anti-cancer therapy. Enhancing autophagy using chemotherapy and rapamycin (Rapa) treatment and then inhibiting it using hydroxychloroquine (HCQ) could synergistically improve therapy outcome in cancer patients. It is still unclear whether addition of Rapa and HCQ to chemotherapy could be used for reversing drug resistance.
  
  
  METHODS
  Twenty-five stage IV cancer patients were identified. They had no clinical response to first-line metronomic chemotherapy; the patients were salvaged by adding an autophagy inducer (Rapa, 2 mg/day) and an autophagosome inhibitor (HCQ, 400 mg/day) to their current metronomic chemotherapy for at least 3 months. Patients included 4 prostate, 4 bladder, 4 lung, 4 breast, 2 colon, and 3 head and neck cancer patients as well as 4 sarcoma patients.
  
  
  RESULTS
  Chemotherapy was administered for a total of 137 months. The median duration of chemotherapy cycles per patient was 4 months (95% confidence interval, 3-7 months). The overall response rate to this treatment was of 40%, with an 84% disease control rate. The most frequent and clinically significant toxicities were myelotoxicities. Grade ≥3 leucopenia occurred in 6 patients (24%), grade ≥3 thrombocytopenia in 8 (32%), and anemia in 3 (12%). None of them developed febrile neutropenia. Non-hematologic toxicities were fatigue (total 32%, with 1 patient developing grade 3 fatigue), diarrhea (total 20%, 1 patient developed grade 3 fatigue), reversible grade 3 cardiotoxicity (1 patient), and grade V liver toxicity from hepatitis B reactivation (1 patient).
  
  
  CONCLUSIONS
  Our results of Rapa, HCQ and chemotherapy triplet combination suggest autophagy is a promising oncotarget and warrants further investigation in phase II studies.
authors.affiliation: Department of Radiation Therapy and Oncology, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan.|School of Medicine and Institute of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Kwan-Hwa
authors.initials: KH
authors.lastname: Chi
authors.affiliation: Department of Radiation Therapy and Oncology, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan.
authors.forename: Hui-Ling
authors.initials: HL
authors.lastname: Ko
authors.affiliation: Department of Radiation Therapy and Oncology, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan.
authors.forename: Kai-Lin
authors.initials: KL
authors.lastname: Yang
authors.affiliation: Department of Radiation Therapy and Oncology, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan.
authors.forename: Cheng-Yen
authors.initials: CY
authors.lastname: Lee
authors.affiliation: Department of Radiation Therapy and Oncology, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan.
authors.forename: Mau-Shin
authors.initials: MS
authors.lastname: Chi
authors.affiliation: Division of Chest Medicine, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan.
authors.forename: Shang-Jyh
authors.initials: SJ
authors.lastname: Kao
mesh_terms: D059250:Administration, Metronomic; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001343:Autophagy / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D006886:Hydroxychloroquine / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis / Q000188:drug therapy / Q000473:pathology; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D010865:Pilot Projects; D016879:Salvage Therapy; D020123:Sirolimus / Q000009:adverse effects / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D006886:Hydroxychloroquine; D020123:Sirolimus
keywords: autophagy; hydroxychloroquine; metronomic chemotherapy; rapamycin