title: A patient-specific therapeutic approach for tumour cell population extinction and drug toxicity reduction using control systems-based dose-profile design.
abstract: BACKGROUND
  When anti-tumour therapy is administered to a tumour-host environment, an asymptotic tapering extremity of the tumour cell distribution is noticed. This extremity harbors a small number of residual tumour cells that later lead to secondary malignances. Thus, a method is needed that would enable the malignant population to be completely eliminated within a desired time-frame, negating the possibility of recurrence and drug-induced toxicity.
  
  
  METHODS
  In this study, we delineate a computational procedure using the inverse input-reconstruction approach to calculate the unknown drug stimulus input, when one desires a known output tissue-response (full tumour cell elimination, no excess toxicity). The asymptotic extremity is taken care of using a bias shift of tumour-cell distribution and guided control of drug administration, with toxicity limits enforced, during mutually-synchronized chemotherapy (as Temozolomide) and immunotherapy (Interleukin-2 and Cytotoxic T-lymphocyte).
  
  
  RESULTS
  Quantitative modeling is done using representative characteristics of rapidly and slowly-growing tumours. Both were fully eliminated within 2 months with checks for recurrence and toxicity over a two-year time-line. The dose-time profile of the therapeutic agents has similar features across tumours: biphasic (lymphocytes), monophasic (chemotherapy) and stationary (interleukin), with terminal pulses of the three agents together ensuring elimination of all malignant cells. The model is then justified with clinical case studies and animal models of different neurooncological tumours like glioma, meningioma and glioblastoma.
  
  
  CONCLUSIONS
  The conflicting oncological objectives of tumour-cell extinction and host protection can be simultaneously accommodated using the techniques of drug input reconstruction by enforcing a bias shift and guided control over the drug dose-time profile. For translational applicability, the procedure can be adapted to accommodate varying patient parameters, and for corrective clinical monitoring, to implement full tumour extinction, while maintaining the health profile of the patient.
authors.forename: Suhela
authors.initials: S
authors.lastname: Kapoor
authors.forename: V P Subramanyam
authors.initials: VP
authors.lastname: Rallabandi
authors.forename: Chandrashekhar
authors.initials: C
authors.lastname: Sakode
authors.affiliation: National Brain Research Centre, Manesar, Haryana 122050, India. prasunkumarroy@gmail.com.
authors.forename: Radhakant
authors.initials: R
authors.lastname: Padhi
authors.forename: Prasun K
authors.initials: PK
authors.lastname: Roy
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects* / Q000627:therapeutic use; D003131:Combined Modality Therapy; D003198:Computer Simulation; D003606:Dacarbazine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D005910:Glioma / Q000188:drug therapy / Q000276:immunology / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D007167:Immunotherapy; D008279:Magnetic Resonance Imaging; D060787:Neoplasm Grading; D009369:Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000473:pathology* / Q000503:physiopathology; D057285:Precision Medicine; D012074:Remission Induction; D000077204:Temozolomide; D057170:Translational Research, Biomedical
chemical_list: D000970:Antineoplastic Agents; D003606:Dacarbazine; D000077204:Temozolomide