Monterrey, 2015

QUIMIOTERAPIA METRONOMICA

Horace Walpole (1717-1797)

Monterrey, 2015

• 1943 – Durante la WWII , soldados y civiles expuestos accidentalmente a Gas Mostaza mostraron una evidente deplección de células linfoides. • Se inicia una investigación militar secreta en la Univ. de Yale. Los farma-

cologos Alfred Gilman y Louis Goodman inducen remisiones en linfomas con mostaza nitrogenada.

Monterrey, 2015

Monterrey, 2015

Fundamentos de QUIMIOTERAPIA • Mecanismo de acción/ Ciclo Celular• Cinetica de Crecimiento (Gompertziano, Norton L- Simon S model)• Cinética Logaritmica de destrucción celular (Skipper-Wilcox model)• Desarrollo de Resistencias y Metástasis (Goldie y Coldman, Delbruck-

Lubria model)• Intensidad de Dosis. MDT

Tipos de Quimioterapia:• Primaria: Qtpa principal modalidad de Ttº. • Adyuvante: Combinada con Rtpa y/o Cirugía• Neoadyuvante: Qtpa prequirúrgica• Concurrente: Simultánea con Rtpa

Monterrey, 2015

Drs. Vincent T. DeVita, C. GordonZubrod, and Paul P. Carbone in 1972

PRINCIPIOS GENERALES

QUIMIOTERAPIA

MOPP

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• Los Tumores, en general ¡No son clonales!. Una mayoría de tumores malignos, son el resultado de múltiples alteraciones genéticas. Contienen subpoblaciones heterogéneas de células con diferentes propiedades cinéticas, angiogénicas, invasivas, y/o metastásicas. Son enfermedades heterogéneas• Requieren estrategias basadas en combinaciones de agentes capaces de actuar

sobre distintas dianas terapéuticas• Tras variables periódos de sensibilidad, las células tumorales desarrollan resistencias

a los agentes citostáticos• La quimioterapia convencional es en general más eficáz frente al tumor primario que

frente a metástasis del mismo

BIOLOGÍA CELULAR TUMORAL Limitaciones de la Qtpa convencional

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ANGIOGENESIS TUMORAL

J. Folkman, in the early 1960s, while working in a Navy lab

Gimbrone MA

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Judah Folkman (1933 – 2008)

Monterrey, 2015

Inhibidores de angiogénesis• TNP-470;Endostatina • Angiostatina • Trombospondina

• Angioarrestin; • Angiostatin (plasminogen fragment) • Antiangiogenic antithrombin III; Arrestin • Chondromodulin; Canstatin • Cartilage-derived inhibitor (CDI) • CD59 complement fragment• Endostatin; Endorepellin; • Fibronectin ; • Heparinases; hCG; • IFN alphagamma; IP-10; IL-12• Kringle 5 ; • Metalloproteinase inhibitors (TIMPs)• 2-Methoxyestradiol; PEX; PEDF; PRI; • PAI; PF4;P16kD; PRP• kringle 2; Retinoids; S-Flt-1; • Targeting fibronectin-binding integrins; • Tetrahydrocortisol-S• Thrombospondin-1 and -2; TGF-b; • Troponin I; Tumstatin• Vasculostatin; Vasostatin (calreticulin fragment).

Judah Folkman (1933 – 2008)

Monterrey, 2015

Monterrey, 2015

Stop

Tumor size

in mice

Endostatin Treatment

0 40 80 120 Days

StartStart

Stop

Large primary tumor

Angiostatin inhibits

Tiny dormant tumor masses

Monterrey, 2015

Modes of resistance to antiangiogenic therapy• Mode I: evasion of anti-angiogenic therapy:

• Upregulation of alternative pro-angiogenic signall circuits.

• Recruitment of vascular progenitor cells and pro-angiogenic monocytes from the bone marrow.

• Increased and tight pericyte coverage protects tumour blood vessels. • Increased capabilities for invasion without angiogenesis.

• Mode 2: indifference to anti-angiogenic therapy • Pre-existing multiplicity of redundant pro-angiogenic signals. • Pre-existing inflammatory cell-mediated vascular protection.• Characteristic hypovascularity and indifference toward angiogenesis inhibitors. • Invasive (and metastatic) co-option of normal vessels without requisite angiogenesis.

Monterrey, 2015

TOXICIDAD DE ANTIANGIOGENICOS

Monterrey, 2015

Bevacizumab

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Douglas Hanahan

Robert S. Kerbel

• Administración frecuente• Dosis Bajas• Niveles persistentes de droga

Monterrey, 2015

MSAT (Metronomic Scheduling of Anticancer Treatment)

Combinaciones de:1. Citostáticos2. Antiangiogénicos3. Otras (Drug repositioning or repurposing)

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+ Celecoxib/ VP-16

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Procedure: 16 patients (median age: 9 years) with recurrent (9 first, 7 multiple) embryonal brain tumors were treated with an anti-angiogenic multidrug combi-nation regimen (bevacizumab, thalidomi-de, celecoxib, fenofibrate, etoposide, and cyclophophamide) and additional intra-ventricular therapy (etoposide and lipo-somal cytarabine). Results: At a median of 33 months, 10/16 pts.are alive. For the 7 patients with MB, OS and EFS after 6 m. was 100%, after 12 m. 85.7 %, and after 24 m. 68.6%

Monterrey, 2015

• These studies are mainly pilot, phase I or II studies. Overall, they are reports on over 200 children. Among these, 32 (14%) achieved complete or partial response and 89 (40%) a stable disease with a clinical benefit of over 50%.

• These studies confirm that the metronomic regimen can be safe and can control refractory disease.

Monterrey, 2015

Procedures: Pts. with metastatic ES were eligible. Therapy consisted of alternating cycles of ifosfamide–etoposide, and vincristine, doxorubicin,cyclophosphamide. Vinblastine and celecoxib were concomitantly administered. Surgical, radiotherapeutic, or combination local control therapy was given per institutional preference. Results: 35 patients were enrolled. 7 of 21 Pts. who received pulmonary irradiation develop grade 2 or greater pulmonary toxicity. 14 of 16 patients with pelvic disease received local irradiation. Hemorrhagic cystitis developed in six patients, five of whom had received pelvic irradiation. The overall 24-month event free survival was 35% (19–51%).

oral maintenance treatment with trofos-famide, idarubicin, and etoposide (O-TIE)

Monterrey, 2015

The treatment consisted of metronomic courses of Rapamycin/Dasatinib (R/S) for 4 days followed by 5 days of Irinotecan and Temozolomide (I/T). 21 pts. with stage IV (n=19) and stage III (n=2) disease, 5 with refractory disease, 8 with 1st and 8 with 2ndand 3rd relapses were included. Results: 90% showed an initial response: CR in 12 (57%), a PR in 3 (14%) and a SD in 4 (19%). The median PFS was 90 weeks. The OS ( 148 w.) was 43% with 7 patients in CR, 1 VGPR and 1 in PR. There were no toxic deaths in this highly pretreated population. Grade III and IV toxicities were thrombocytopenia in 81%, leukopenia in 76%, anemia in 71%, and diarrhea in 71% respectively.

2013 ASCO Annual MeetingAbstract Number: 10017Selim Corbacioglu et al.

Monterrey, 2015

METRONOMIC CHEMOTHERAPY IN LOW-RESOURCE COUNTRIES (LMICs)

• 80% de todos los niños viven en Países en vías de Desarrollo. • 200,000 de ellos son diagnosticados de cáncer cada año. Sólo un 25% sobrevive. • En Paises con elevados ingresos, >75% de los 50,000 niños diagnosticados cada año

de cáncer sobrevive.

• En LMICs la Oncología Pediatrica es es un prioridad sanitaria baja debido a: • Relativo bajo número de casos • Coste de los tratamientos • Eficacia de los tratamientos

• Problemas a resolver: • Disponibilidad de Medicamentos • Costes • Distancias • Compliance del tratamiento • Retrasos en el Diagnóstico • Falta de seguimiento• Medicina Tradicional• Barreras Culturales

Monterrey, 2015

M. C. IN LOW-RESOURCE COUNTRIES

• http://clinicaltrials.gov/ct2/show/NCT00578864?term=NCT00578864&rank=1 (2014).

• http://clinicaltrials.gov/ct2/show/NCT00885326?term=NCT00885326&rank=1 (2014).

• http://clinicaltrials.gov/ct2/show/NCT01192555?term=NCT01192555&rank=1 (2014).

• http://clinicaltrials.gov/ct2/show/NCT00379457?term=NCT00379457&rank=1 (2013).

• http://clinicaltrials.gov/ct2/show/NCT01661400?term=NCT01661400&rank=1 (2014).

• MC se muestra como un abordaje terapéutico atractivo en LMICs:

• Son tratamientos de bajo coste • Pueden administrarse por vía oral • Pueden administrarse en el domicilio • MC presenta un toxicidad moderada

Denis Burkitt (1911-1993)