Angiogenesis inhibitors for the treatment of epithelial ovarian cancer.

BACKGROUND: Many women, and other females, with epithelial ovarian cancer (EOC) develop resistance to conventional chemotherapy drugs. Drugs that inhibit angiogenesis (development of new blood vessels), essential for tumour growth, control cancer growth by denying blood supply to tumour nodules. OBJECTIVES: To compare the effectiveness and toxicities of angiogenesis inhibitors for treatment of epithelial ovarian cancer (EOC). SEARCH METHODS: We identified randomised controlled trials (RCTs) by searching CENTRAL, MEDLINE and Embase (from 1990 to 30 September 2022). We searched clinical trials registers and contacted investigators of completed and ongoing trials for further information. SELECTION CRITERIA: RCTs comparing angiogenesis inhibitors with standard chemotherapy, other types of anti-cancer treatment, other angiogenesis inhibitors with or without other treatments, or placebo/no treatment in a maintenance setting, in women with EOC.  DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. Our outcomes were overall survival (OS), progression-free survival (PFS), quality of life (QoL), adverse events (grade 3 and above) and hypertension (grade 2 and above). MAIN RESULTS: We identified 50 studies (14,836 participants) for inclusion (including five studies from the previous version of this review): 13 solely in females with newly-diagnosed EOC and 37 in females with recurrent EOC (nine studies in platinum-sensitive EOC; 19 in platinum-resistant EOC; nine with studies with mixed or unclear platinum sensitivity). The main results are presented below.  Newly-diagnosed EOC Bevacizumab, a monoclonal antibody that binds vascular endothelial growth factor (VEGF), given with chemotherapy and continued as maintenance, likely results in little to no difference in OS compared to chemotherapy alone (hazard ratio (HR) 0.97, 95% confidence interval (CI) 0.88 to 1.07; 2 studies, 2776 participants; moderate-certainty evidence). Evidence is very uncertain for PFS (HR 0.82, 95% CI 0.64 to 1.05; 2 studies, 2746 participants; very low-certainty evidence), although the combination results in a slight reduction in global QoL (mean difference (MD) -6.4, 95% CI -8.86 to -3.94; 1 study, 890 participants; high-certainty evidence). The combination likely increases any adverse event (grade ≥ 3) (risk ratio (RR) 1.16, 95% CI 1.07 to 1.26; 1 study, 1485 participants; moderate-certainty evidence) and may result in a large increase in hypertension (grade ≥ 2) (RR 4.27, 95% CI 3.25 to 5.60; 2 studies, 2707 participants; low-certainty evidence). Tyrosine kinase inhibitors (TKIs) to block VEGF receptors (VEGF-R), given with chemotherapy and continued as maintenance, likely result in little to no difference in OS (HR 0.99, 95% CI 0.84 to 1.17; 2 studies, 1451 participants; moderate-certainty evidence) and likely increase PFS slightly (HR 0.88, 95% CI 0.77 to 1.00; 2 studies, 2466 participants; moderate-certainty evidence). The combination likely reduces QoL slightly (MD -1.86, 95% CI -3.46 to -0.26; 1 study, 1340 participants; moderate-certainty evidence), but it increases any adverse event (grade ≥ 3) slightly (RR 1.31, 95% CI 1.11 to 1.55; 1 study, 188 participants; moderate-certainty evidence) and may result in a large increase in hypertension (grade ≥ 3) (RR 6.49, 95% CI 2.02 to 20.87; 1 study, 1352 participants; low-certainty evidence).  Recurrent EOC (platinum-sensitive) Moderate-certainty evidence from three studies (with 1564 participants) indicates that bevacizumab with chemotherapy, and continued as maintenance, likely results in little to no difference in OS (HR 0.90, 95% CI 0.79 to 1.02), but likely improves PFS (HR 0.56, 95% CI 0.50 to 0.63) compared to chemotherapy alone. The combination may result in little to no difference in QoL (MD 0.8, 95% CI -2.11 to 3.71; 1 study, 486 participants; low-certainty evidence), but it increases the rate of any adverse event (grade ≥ 3) slightly (RR 1.11, 1.07 to 1.16; 3 studies, 1538 participants; high-certainty evidence). Hypertension (grade ≥ 3) was more common in arms with bevacizumab (RR 5.82, 95% CI 3.84 to 8.83; 3 studies, 1538 participants).  TKIs with chemotherapy may result in little to no difference in OS (HR 0.86, 95% CI 0.67 to 1.11; 1 study, 282 participants; low-certainty evidence), likely increase PFS (HR 0.56, 95% CI 0.44 to 0.72; 1 study, 282 participants; moderate-certainty evidence), and may have little to no effect on QoL (MD 6.1, 95% CI -0.96 to 13.16; 1 study, 146 participants; low-certainty evidence). Hypertension (grade ≥ 3) was more common with TKIs (RR 3.32, 95% CI 1.21 to 9.10). Recurrent EOC (platinum-resistant) Bevacizumab with chemotherapy and continued as maintenance increases OS (HR 0.73, 95% CI 0.61 to 0.88; 5 studies, 778 participants; high-certainty evidence) and likely results in a large increase in PFS (HR 0.49, 95% CI 0.42 to 0.58; 5 studies, 778 participants; moderate-certainty evidence). The combination may result in a large increase in hypertension (grade ≥ 2) (RR 3.11, 95% CI 1.83 to 5.27; 2 studies, 436 participants; low-certainty evidence). The rate of bowel fistula/perforation (grade ≥ 2) may be slightly higher with bevacizumab (RR 6.89, 95% CI 0.86 to 55.09; 2 studies, 436 participants). Evidence from eight studies suggest TKIs with chemotherapy likely result in little to no difference in OS (HR 0.85, 95% CI 0.68 to 1.08; 940 participants; moderate-certainty evidence), with low-certainty evidence that it may increase PFS (HR 0.70, 95% CI 0.55 to 0.89; 940 participants), and may result in little to no meaningful difference in QoL (MD ranged from -0.19 at 6 weeks to -3.40 at 4 months). The combination increases any adverse event (grade ≥ 3) slightly (RR 1.23, 95% CI 1.02 to 1.49; 3 studies, 402 participants; high-certainty evidence). The effect on bowel fistula/perforation rates is uncertain (RR 2.74, 95% CI 0.77 to 9.75; 5 studies, 557 participants; very low-certainty evidence). AUTHORS' CONCLUSIONS: Bevacizumab likely improves both OS and PFS in platinum-resistant relapsed EOC. In platinum-sensitive relapsed disease, bevacizumab and TKIs probably improve PFS, but may or may not improve OS. The results for TKIs in platinum-resistant relapsed EOC are similar. The effects on OS or PFS in newly-diagnosed EOC are less certain, with a decrease in QoL and increase in adverse events. Overall adverse events and QoL data were more variably reported than were PFS data. There appears to be a role for anti-angiogenesis treatment, but given the additional treatment burden and economic costs of maintenance treatments, benefits and risks of anti-angiogenesis treatments should be carefully considered.

ANTECEDENTES: Muchas mujeres con cáncer de ovario epitelial (COE) desarrollan resistencia a los fármacos de quimioterapia convencional. Los fármacos que inhiben la angiogénesis (desarrollo de vasos sanguíneos de neoformación), esencial para el crecimiento tumoral, controlan el crecimiento del cáncer al impedir el riego sanguíneo a los nódulos tumorales. OBJETIVOS: Comparar la efectividad y los efectos adversos de los inhibidores de la angiogénesis para el tratamiento del cáncer de ovario epitelial (COE). MÉTODOS DE BÚSQUEDA: Se identificaron ensayos controlados aleatorizados (ECA) mediante búsquedas en CENTRAL, MEDLINE y Embase (desde 1990 hasta el 30 de septiembre de 2022). Se realizaron búsquedas en los registros de ensayos clínicos y se estableció contacto con los investigadores de ensayos finalizados y en curso para obtener información adicional. CRITERIOS DE SELECCIÓN: ECA que compararan los inhibidores de la angiogénesis con la quimioterapia estándar, otros tipos de tratamiento anticancerígeno, otros inhibidores de la angiogénesis con o sin otros tratamientos, o placebo/ningún tratamiento en un contexto de mantenimiento, en mujeres con COE. OBTENCIÓN Y ANÁLISIS DE LOS DATOS: Se utilizaron los procedimientos metodológicos estándar previstos por Cochrane. Los desenlaces fueron la supervivencia general (SG), la supervivencia sin progresión (SSP), la calidad de vida (CdV), los eventos adversos (de grado 3 o superior) y la hipertensión (de grado 2 o superior). RESULTADOS PRINCIPALES: Se identificaron 50 estudios (14 836 participantes) para inclusión (incluidos cinco estudios de la versión anterior de esta revisión): 13 únicamente en mujeres con COE recién diagnosticado y 37 en mujeres con COE recidivante (nueve estudios en COE sensible al platino; 19 en COE resistente al platino; nueve con estudios con sensibilidad mixta o incierta al platino). A continuación se presentan los principales resultados. COE recién diagnosticado El bevacizumab, un anticuerpo monoclonal que se une al factor de crecimiento endotelial vascular (VEGF), administrado con quimioterapia y continuado como mantenimiento, probablemente da lugar a poca o ninguna diferencia en la SG en comparación con la quimioterapia sola (cociente de riesgos instantáneos [CRI] 0,97; intervalo de confianza [IC] del 95%: 0,88 a 1,07; dos estudios, 2776 participantes; evidencia de certeza moderada). La evidencia es muy incierta para la SSP (CRI 0,82; IC del 95%: 0,64 a 1,05; dos estudios, 2746 participantes; evidencia de certeza muy baja), aunque la combinación produce una ligera reducción de la CdV global (diferencia de medias [DM] ­6,4; IC del 95%: ­8,86 a ­3,94; un estudio, 890 participantes; evidencia de certeza alta). La combinación probablemente aumenta cualquier evento adverso (grado ≥ 3) (razón de riesgos [RR] 1,16; IC del 95%: 1,07 a 1,26; un estudio, 1485 participantes; evidencia de certeza moderada) y podría dar lugar a un gran aumento de la hipertensión (grado ≥ 2) (RR 4,27; IC del 95%: 3,25 a 5,60; dos estudios, 2707 participantes; evidencia de certeza baja). Los inhibidores de la tirosina cinasa (ITK) para bloquear los receptores del VEGF (VEGF­R), administrados con quimioterapia y continuados como mantenimiento, probablemente den lugar a poca o ninguna diferencia en la SG (CRI 0,99; IC del 95%: 0,84 a 1,17; dos estudios, 1451 participantes; evidencia de certeza moderada) y podrían aumentar ligeramente la SSP (CRI 0,88; IC del 95%: 0,77 a 1,00; dos estudios, 2466 participantes; evidencia de certeza moderada). Es probable que la combinación reduzca ligeramente la CdV (DM ­1,86; IC del 95%: ­3,46 a ­0,26; un estudio, 1340 participantes; evidencia de certeza moderada), pero aumente ligeramente cualquier evento adverso (grado ≥ 3) (RR 1,31; IC del 95%: 1,11 a 1,55; un estudio, 188 participantes; evidencia de certeza moderada) y podría dar lugar a un gran aumento de la hipertensión (grado ≥ 3) (RR 6,49; IC del 95%: 2,02 a 20,87; un estudio, 1352 participantes; evidencia de certeza baja). COE recidivante (sensible al platino) La evidencia de certeza moderada de tres estudios (con 1564 participantes) indica que el bevacizumab con quimioterapia, y continuado como mantenimiento, probablemente da lugar a poca o ninguna diferencia en la SG (CRI 0,90; IC del 95%: 0,79 a 1,02), pero posiblemente mejora la SSP (CRI 0,56; IC del 95%: 0,50 a 0,63) en comparación con la quimioterapia sola. La combinación podría dar lugar a poca o ninguna diferencia en la CdV (DM 0,8; IC del 95%: ­2,11 a 3,71; un estudio, 486 participantes; evidencia de certeza baja), pero aumenta ligeramente la tasa de cualquier evento adverso (grado ≥ 3) (RR 1,11; 1,07 a 1,16; tres estudios, 1538 participantes; evidencia de certeza alta). La hipertensión (grado ≥ 3) fue más frecuente en los grupos con bevacizumab (RR 5,82; IC del 95%: 3,84 a 8,83; tres estudios, 1538 participantes). Los ITK con quimioterapia podrían dar lugar a poca o ninguna diferencia en la SG (CRI 0,86; IC del 95%: 0,67 a 1,11; un estudio, 282 participantes; evidencia de certeza baja), probablemente aumenten la SSP (CRI 0,56; IC del 95%: 0,44 a 0,72; un estudio, 282 participantes; evidencia de certeza moderada) y podrían tener poco o ningún efecto en la CdV (DM 6,1; IC del 95%: ­0,96 a 13,16; un estudio, 146 participantes; evidencia de certeza baja). La hipertensión (grado ≥ 3) fue más frecuente con los ITK (RR 3,32; IC del 95%: 1,21 a 9,10). COE recidivante (resistente al platino) El bevacizumab con quimioterapia y continuado como mantenimiento aumenta la SG (CRI 0,73; IC del 95%: 0,61 a 0,88; cinco estudios, 778 participantes; evidencia de certeza alta) y probablemente da lugar a un gran aumento de la SSP (CRI 0,49; IC del 95%: 0,42 a 0,58; cinco estudios, 778 participantes; evidencia de certeza moderada). La combinación podría dar lugar a un gran aumento de la hipertensión (grado ≥ 2) (RR 3,11; IC del 95%: 1,83 a 5,27; dos estudios, 436 participantes; evidencia de certeza baja). La tasa de fístula/perforación intestinal (grado ≥ 2) podría ser ligeramente superior con bevacizumab (RR 6,89; IC del 95%: 0,86 a 55,09; dos estudios, 436 participantes). La evidencia de ocho estudios indica que es probable que los ITK con quimioterapia den lugar a poca o ninguna diferencia en la SG (CRI 0,85; IC del 95%: 0,68 a 1,08; 940 participantes; evidencia de certeza moderada), con evidencia de certeza baja de que podrían aumentar la SSP (CRI 0,70; IC del 95%: 0,55 a 0,89; 940 participantes), y podrían dar lugar a poca o ninguna diferencia significativa en la CdV (la DM varió de ­0,19 a las seis semanas a ­3,40 a los cuatro meses). La combinación aumenta ligeramente cualquier evento adverso (grado ≥ 3) (RR 1,23; IC del 95%: 1,02 a 1,49; tres estudios, 402 participantes; evidencia de certeza alta). El efecto sobre las tasas de fístula/perforación intestinal es incierto (RR 2,74; IC del 95%: 0,77 a 9,75; cinco estudios, 557 participantes; evidencia de certeza muy baja). CONCLUSIONES DE LOS AUTORES: Es probable que el bevacizumab mejore tanto la SG como la SSP en el COE recidivante resistente al platino. En la enfermedad recidivante sensible al platino, el bevacizumab y los ITK probablemente mejoran la SSP, pero podrían o no mejorar la SG. Los resultados para los ITK en el COE recidivante resistente al platino son similares. Existe menos certeza en cuanto a los efectos sobre la SG o la SSP en el COE recién diagnosticado, con una disminución de la CdV y un aumento de los eventos adversos. Los eventos adversos globales y los datos de CdV se informaron de forma más variable que los datos de SSP. El tratamiento antiangiogénico parece tener una función, pero dada la carga adicional de tratamiento y los costes económicos de los tratamientos de mantenimiento, se deben considerar cuidadosamente sus beneficios y riesgos.

Poly(ADP-ribose) polymerase (PARP) inhibitors for the treatment of ovarian cancer.

BACKGROUND: Ovarian cancer is the sixth most common cancer in women world-wide. Epithelial ovarian cancer (EOC) is the most common; three-quarters of women present when disease has spread outside the pelvis (stage III or IV). Treatment consists of a combination of  surgery and platinum-based chemotherapy. Although initial responses to chemotherapy are good, most women with advanced disease will relapse. PARP (poly (ADP-ribose) polymerase) inhibitors (PARPi), are a type of anticancer treatment that works by preventing cancer cells from repairing DNA damage, especially in those with breast cancer susceptibility gene (BRCA) variants. PARPi offer a different mechanism of anticancer treatment from conventional chemotherapy. OBJECTIVES: To determine the benefits and risks of poly (ADP-ribose) polymerase) inhibitors (PARPi) for the treatment of epithelial ovarian cancer (EOC). SEARCH METHODS: We identified randomised controlled trials (RCTs) by searching the Cochrane Central Register of Controlled Trials (Central 2020, Issue 10), Cochrane Gynaecological Cancer Group Trial Register, MEDLINE (1990 to October 2020), Embase (1990 to October 2020), ongoing trials on www.controlled-trials.com/rct, www.clinicaltrials.gov, www.cancer.gov/clinicaltrials, the National Research Register (NRR), FDA database and pharmaceutical industry biomedical literature. SELECTION CRITERIA: We included trials that randomised women with EOC to PARPi with no treatment, or PARPi versus conventional chemotherapy, or PARPi together with conventional chemotherapy versus conventional chemotherapy alone. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodology. Two review authors independently assessed whether studies met the inclusion criteria. We contacted investigators for additional data. Outcomes included overall survival (OS), objective response rate (ORR), quality of life (QoL) and rate of adverse events. MAIN RESULTS: We included 15 studies (6109 participants); four (3070 participants) with newly-diagnosed, advanced EOC and 11 (3039 participants) with recurrent EOC. The studies varied in types of comparisons and evaluated PARPi. Eight studies were judged as at low risk of bias in most of the domains. Quality of life data were generally poorly reported. Below we present six key comparisons.  The majority of participants had BRCA mutations, either in their tumour (sBRCAmut) and/or germline (gBRCAmut), or homologous recombination deficiencies (HRD) in their tumours. Newly diagnosed EOC Overall, four studies evaluated the effect of PARPi in newly-diagnosed, advanced EOC. Two compared PARPi with chemotherapy and chemotherapy alone. OS data were not reported. The combination of PARPi with chemotherapy may have little to no difference in progression-free survival (PFS) (two studies, 1564 participants; hazard ratio (HR) 0.82, 95% confidence interval (CI 0).49 to 1.38; very low-certainty evidence)(no evidence of disease progression at 12 months' 63% with PARPi versus 69% for placebo).  PARPi with chemotherapy likely increases any severe adverse event (SevAE) (grade 3 or higher) slightly (45%) compared with chemotherapy alone (51%) (two studies, 1549 participants, risk ratio (RR) 1.13, 95% CI 1.07 to 1.20; high-certainty evidence). PARPi combined with chemotherapy compared with chemotherapy alone likely results in little to no difference in the QoL (one study; 744 participants, MD 1.56 95% CI -0.42 to 3.54; moderate-certainty evidence).  Two studies compared PARPi monotherapy with placebo as maintenance after first-line chemotherapy in newly diagnosed EOC. PARPi probably results in little to no difference in OS (two studies, 1124 participants; HR 0.81, 95%CI 0.59 to 1.13; moderate-certainty evidence) (alive at 12 months 68% with PARPi versus 62% for placebo). However, PARPi may increase PFS (two studies, 1124 participants; HR 0.42, 95% CI 0.19 to 0.92; low-certainty evidence) (no evidence of disease progression at 12 months' 55% with PARPi versus 24% for placebo). There may be an increase in the risk of experiencing any SevAE (grade 3 or higher) with PARPi (54%) compared with placebo (19%)(two studies, 1118 participants, RR 2.87, 95% CI 1.65 to 4.99; very low-certainty evidence), but the evidence is very uncertain. There is probably a slight reduction in QoL with PARPi, although this may not be clinically significant (one study, 362 participants; MD -3.00, 95%CI -4.48 to -1.52; moderate-certainty evidence).  Recurrent, platinum-sensitive EOC Overall, 10 studies evaluated the effect of PARPi in recurrent platinum-sensitive EOC. Three studies compared PARPi monotherapy with chemotherapy alone. PARPi may result in little to no difference in OS (two studies, 331 participants; HR 0.95, 95%CI 0.62 to 1.47; low-certainty evidence) (percentage alive at 36 months 18% with PARPi versus 17% for placebo). Evidence is very uncertain about the effect of PARPi on PFS (three studies, 739 participants; HR 0.88, 95%CI 0.56 to 1.38; very low-certainty evidence)(no evidence of disease progression at 12 months 26% with PARPi versus 22% for placebo). There may be little to no difference in rates of any SevAE (grade 3 or higher) with PARPi (50%) than chemotherapy alone (47%) (one study, 254 participants; RR 1.06, 95%CI 0.80 to 1.39; low-certainty evidence). Four studies compared PARPi monotherapy as maintenance with placebo. PARPi may result in little to no difference in OS (two studies, 560 participants; HR 0.88, 95%CI 0.65 to 1.20; moderate-certainty evidence)(percentage alive at 36 months 21% with PARPi versus 17% for placebo). However, evidence suggests that PARPi as maintenance therapy results in a large PFS (four studies, 1677 participants; HR 0.34, 95% CI 0.28 to 0.42; high-certainty evidence)(no evidence of disease progression at 12 months 37% with PARPi versus 5.5% for placebo). PARPi maintenance therapy may result in a large increase in any SevAE (51%) (grade 3 or higher) than placebo (19%)(four studies, 1665 participants, RR 2.62, 95%CI 1.85 to 3.72; low-certainty evidence). PARPi compared with chemotherapy may result in little or no change in QoL (one study, 229 participants, MD 1.20, 95%CI -1.75 to 4.16; low-certainty evidence). Recurrent, platinum-resistant EOC Two studies compared PARPi with chemotherapy. The certainty of evidence in both studies was graded as very low. Overall, there was minimal information on the QoL and adverse events. AUTHORS' CONCLUSIONS: PARPi maintenance treatment after chemotherapy may improve PFS in women with newly-diagnosed and recurrent platinum-sensitive EOC; there may be little to no effect on OS, although OS data are immature. Overall, this is likely at the expense of an increase in SevAE. It is  disappointing that data on quality of life outcomes  are relatively sparse. More research is needed to determine whether PARPi have a role to play in platinum-resistant disease.