Pegylated liposomal doxorubicin for relapsed epithelial ovarian cancer.

BACKGROUND: Cancer of ovarian, fallopian tube and peritoneal origin, referred to collectively as ovarian cancer, is the eighth most common cancer in women and is often diagnosed at an advanced stage. Women with relapsed epithelial ovarian cancer (EOC) are less well and have a limited life expectancy, therefore maintaining quality of life with effective symptom control is an important aim of treatment. However, the unwanted effects of chemotherapy agents may be severe, and optimal treatment regimens are unclear. Pegylated liposomal doxorubicin (PLD), which contains a cytotoxic drug called doxorubicin hydrochloride, is one of several treatment modalities that may be considered for treatment of relapsed EOCs. This is an update of the original Cochrane Review which was published in Issue 7, 2013. OBJECTIVES: To evaluate the efficacy and safety of PLD, with or without other anti-cancer drugs, in women with relapsed high grade epithelial ovarian cancer (EOC). SEARCH METHODS: We searched CENTRAL, MEDLINE (via Ovid) and Embase (via Ovid) from 1990 to January 2022. We also searched online registers of clinical trials, abstracts of scientific meetings and reference lists of included studies. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that evaluated PLD in women diagnosed with relapsed epithelial ovarian cancer. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data to a pre-designed data collection form and assessed the risk of bias according to the Cochrane Handbook for Systematic Reviews of Interventions guidelines. Where possible, we pooled collected data in meta-analyses. MAIN RESULTS: This is an update of a previous review with 12 additional studies, so this updated review includes a total of 26 RCTs with 8277 participants that evaluated the effects of PLD alone or in combination with other drugs in recurrent EOC: seven in platinum-sensitive disease (2872 participants); 11 in platinum-resistant disease (3246 participants); and eight that recruited individuals regardless of platinum sensitivity status (2079 participants). The certainty of the evidence was assessed for the three most clinically relevant comparisons out of eight comparisons identified in the included RCTs. Recurrent platinum-sensitive EOC PLD with conventional chemotherapy agent compared to alternative combination chemotherapy likely results in little to no difference in overall survival (OS) (hazard ratio (HR) 0.93, 95% confidence interval (CI) 0.83 to 1.04; 5 studies, 2006 participants; moderate-certainty evidence) but likely increases progression-free survival (PFS) (HR 0.81, 95% CI 0.74 to 0.89; 5 studies, 2006 participants; moderate-certainty evidence). The combination may slightly improve quality of life at three months post-randomisation, measured using European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (mean difference 4.80, 95% CI 0.92 to 8.68; 1 study, 608 participants; low-certainty evidence), but this may not represent a clinically meaningful difference. PLD in combination with another chemotherapy agent compared to alternative combination chemotherapy likely results in little to no difference in the rate of overall severe adverse events (grade ≥ 3) (risk ratio (RR) 1.11, 95% CI 0.95 to 1.30; 2 studies, 834 participants; moderate-certainty evidence). PLD with chemotherapy likely increases anaemia (grade ≥ 3) (RR 1.37, 95% CI 1.02 to 1.85; 5 studies, 1961 participants; moderate-certainty evidence). The evidence is very uncertain about the effect of PLD with conventional chemotherapy on hand-foot syndrome (HFS)(grade ≥ 3) (RR 4.01, 95% CI 1.00 to 16.01; 2 studies, 1028 participants; very low-certainty evidence) and neurological events (grade ≥ 3) (RR 0.38, 95% CI 0.20 to 0.74; 4 studies, 1900 participants; very low-certainty evidence). Recurrent platinum-resistant EOC PLD alone compared to another conventional chemotherapy likely results in little to no difference in OS (HR 0.96, 95% CI 0.77 to 1.19; 6 studies, 1995 participants; moderate-certainty evidence). The evidence is very uncertain about the effect of PLD on PFS (HR 0.94, 95% CI 0.85 to 1.04; 4 studies, 1803 participants; very low-certainty evidence), overall severe adverse events (grade ≥ 3) (RR ranged from 0.61 to 0.97; 2 studies, 964 participants; very low-certainty evidence), anaemia (grade ≥ 3) (RR ranged from 0.19 to 0.82; 5 studies, 1968 participants; very low-certainty evidence), HFS (grade ≥ 3) (RR ranged from 15.19 to 109.15; 6 studies, 2184 participants; very low-certainty evidence), and the rate of neurological events (grade ≥ 3)(RR ranged from 0.08 to 3.09; 3 studies, 1222 participants; very low-certainty evidence). PLD with conventional chemotherapy compared to PLD alone likely results in little to no difference in OS (HR 0.92, 95% CI 0.70 to 1.21; 1 study, 242 participants; moderate-certainty evidence) and it may result in little to no difference in PFS (HR 0.94, 95% CI 0.73 to 1.22; 2 studies, 353 participants; low-certainty evidence). The combination likely increases overall severe adverse events (grade ≥ 3) (RR 2.48, 95% CI 1.98 to 3.09; 1 study, 663 participants; moderate-certainty evidence) and anaemia (grade ≥ 3) (RR 2.38, 95% CI 1.46 to 3.87; 2 studies, 785 participants; moderate-certainty evidence), but likely results in a large reduction in HFS (grade ≥ 3) (RR 0.24, 95% CI 0.14 to 0.40; 2 studies, 785 participants; moderate-certainty evidence). It may result in little to no difference in neurological events (grade ≥ 3) (RR 1.40, 95% CI 0.85 to 2.31; 1 study, 663 participants; low-certainty evidence). AUTHORS' CONCLUSIONS: In platinum-sensitive relapsed EOC, including PLD in a combination chemotherapy regimen probably makes little to no difference in OS compared to other combinations, but likely improves PFS. Choice of chemotherapy will therefore be guided by symptoms from previous chemotherapy and other patient considerations. Single-agent PLD remains a useful agent for platinum-resistant relapsed EOC and choice of agent at relapse will depend on patient factors, e.g. degree of bone marrow suppression or neurotoxicity from previous treatments. Adding another agent to PLD likely increases overall grade ≥ 3 adverse events with little to no improvement in survival outcomes. The limited evidence relating to PLD in combination with other agents in platinum-resistant relapsed EOC does not indicate a benefit, but there is some evidence of increased side effects.

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.

Quality of life from cytoreductive surgery in advanced ovarian cancer: Investigating the association between disease burden and surgical complexity in the international, prospective, SOCQER-2 cohort study.

OBJECTIVE: To investigate quality of life (QoL) and association with surgical complexity and disease burden after surgical resection for advanced ovarian cancer in centres with variation in surgical approach. DESIGN: Prospective multicentre observational study. SETTING: Gynaecological cancer surgery centres in the UK, Kolkata, India, and Melbourne, Australia. SAMPLE: Patients undergoing surgical resection (with low, intermediate or high surgical complexity score, SCS) for late-stage ovarian cancer. MAIN OUTCOME MEASURES: Primary: change in global score on the European Organisation for Research and Treatment of Cancer (EORTC) core quality-of-life questionnaire (QLQ-C30). Secondary: EORTC ovarian cancer module (OV28), progression-free survival. RESULTS: Patients' preoperative disease burden and SCS varied between centres, confirming differences in surgical ethos. QoL response rates were 90% up to 18 months. Mean change from the pre-surgical baseline in the EORTC QLQ-C30 was 3.4 (SD 1.8, n = 88) in the low, 4.0 (SD 2.1, n = 55) in the intermediate and 4.3 (SD 2.1, n = 52) in the high-SCS group after 6 weeks (p = 0.048), and 4.3 (SD 2.1, n = 51), 5.1 (SD 2.2, n = 41) and 5.1 (SD 2.2, n = 35), respectively, after 12 months (p = 0.133). In a repeated-measures model, there were no clinically or statistically meaningful differences in EORTC QLQ-C30 global scores between the three SCS groups (p = 0.840), but there was a small statistically significant improvement in all groups over time (p < 0.001). The high-SCS group experienced small to moderate decreases in physical (p = 0.004), role (p = 0.016) and emotional (p = 0.001) function at 6 weeks post-surgery, which resolved by 6-12 months. CONCLUSIONS: The global QoL of patients undergoing low-, intermediate- and high-SCS surgery improved at 12 months after surgery and was no worse in patients undergoing extensive surgery. TWEETABLE ABSTRACT: Compared with surgery of lower complexity, extensive surgery does not result in poorer quality of life in patients with advanced ovarian cancer.

British Gynaecological Cancer Society recommendations for women with gynecological cancer who received non-standard care during the COVID-19 pandemic.

During the COVID-19 pandemic, pressures on clinical services required adaptation to how care was prioritised and delivered for women with gynecological cancer. This document discusses potential 'salvage' measures when treatment has deviated from the usual standard of care. The British Gynaecological Cancer Society convened a multidisciplinary working group to develop recommendations for the onward management and follow-up of women with gynecological cancer who have been impacted by a change in treatment during the pandemic. These recommendations are presented for each tumor type and for healthcare systems, and the impact on gynecological services are discussed. It will be important that patient concerns about the impact of COVID-19 on their cancer pathway are acknowledged and addressed for their ongoing care.

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.

Development and implementation of veterinary anesthesia medical quality standards for primary care.

OBJECTIVE: The provision of general anesthesia is common in veterinary hospitals and procedures include some level of risk, up to and including mortality. A quality initiative was introduced with a focus on reducing canine and feline anesthesia mortality. This paper describes the development and implementation of risk-based medical quality standards (MQS) and resultant impacts on anesthesia mortality. STUDY DESIGN: This was a qualitative observational study. MQS focused on the provision of anesthesia were researched, developed and implemented. Anesthesia mortality rates, captured via an automated process based on the electronic medical record, were recorded before and after implementation. Compliance to standards was determined via hospital auditing. ANIMALS: Client-owned dogs and cats presenting to Banfield Pet Hospital (a national network of primary care hospitals) for elective and nonelective general anesthesia procedures. Over the course of the study, 2,038,318 dogs and 350,410 cats had a general anesthesia event. METHODS: Literature reviews and analysis of veterinary patient medical records identified risk factors associated with anesthesia mortality. Risk factors informed the development of MQS. Evidence-based standards focused on the provision of general anesthesia were written, reviewed, evaluated and edited. Implementation occurred over 6 months via a robust communication plan. Anesthesia mortality rates were continuously monitored before, during and after the introduction of standards. Compliance with all quality standards was assessed via hospital-based auditing performed on an annual basis. RESULTS: Prior to quality standards implementation, anesthesia mortality rates for dogs and cats combined was 7.4 deaths/10,000 procedures. At 6 months after implementation, the mortality rate was 6.24 deaths/10,000 procedures, representing a 16% decrease. Compliance with standards improved over time with continued focus and education. CONCLUSIONS AND CLINICAL RELEVANCE: Development, implementation and continued focus on MQS can improve anesthetic safety and reduce anesthesia mortality in primary care veterinary hospitals.

Chemotherapy versus surgery for initial treatment in advanced ovarian epithelial cancer.

BACKGROUND: Epithelial ovarian cancer presents at an advanced stage in the majority of women. These women require surgery and chemotherapy for optimal treatment. Conventional treatment has been to perform surgery first and then give chemotherapy. However, there may be advantages to using chemotherapy before surgery. OBJECTIVES: To assess whether there is an advantage to treating women with advanced epithelial ovarian cancer with chemotherapy before debulking surgery (neoadjuvant chemotherapy (NACT)) compared with conventional treatment where chemotherapy follows debulking surgery (primary debulking surgery (PDS)). SEARCH METHODS: We searched the following databases on 11 February 2019: CENTRAL, Embase via Ovid, MEDLINE (Silver Platter/Ovid), PDQ and MetaRegister. We also checked the reference lists of relevant papers that were identified to search for further studies. The main investigators of relevant trials were contacted for further information. SELECTION CRITERIA: Randomised controlled trials (RCTs) of women with advanced epithelial ovarian cancer (Federation of International Gynaecologists and Obstetricians (FIGO) stage III/IV) who were randomly allocated to treatment groups that compared platinum-based chemotherapy before cytoreductive surgery with platinum-based chemotherapy following cytoreductive surgery. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed risk of bias in each included trial. MAIN RESULTS: We found 1952 potential titles, with a most recent search date of February 2019, of which five RCTs of varying quality and size met the inclusion criteria. These studies assessed a total of 1713 women with stage IIIc/IV ovarian cancer randomised to NACT followed by interval debulking surgery (IDS) or PDS followed by chemotherapy. We pooled results of the three studies where data were available and found little or no difference with regard to overall survival (OS) (1521 women; Hazard Ratio (HR) 0.95, 95% CI 0.84 to 1.07; I2 = 0%; moderate-certainty evidence) or progression-free survival in four trials where we were able to pool data (1631 women; HR 0.97, 95% CI 0.87 to 1.07; I2 = 0%; moderate-certainty evidence). Adverse events, surgical morbidity and quality of life (QoL) outcomes were poorly and incompletely reported across studies. There may be clinically meaningful differences in favour of NACT compared to PDS with regard to serious adverse effects (SAE grade 3+). These data suggest that NACT may reduce the risk of need for blood transfusion (risk ratio (RR) 0.80; 95% CI 0.64 to 0.99; four studies,1085 women; low-certainty evidence), venous thromboembolism (RR 0.28; 95% CI 0.09 to 0.90; four studies, 1490 women; low-certainty evidence), infection (RR 0.30; 95% CI 0.16 to 0.56; four studies, 1490 women; moderate-certainty evidence), compared to PDS. NACT probably reduces the need for stoma formation (RR 0.43, 95% CI 0.26 to 0.72; two studies, 581 women; moderate-certainty evidence) and bowel resection (RR 0.49, 95% CI 0.26 to 0.92; three studies, 1213 women; moderate-certainty evidence), as well as reducing postoperative mortality (RR 0.18; 95% CI 0.06 to 0.54:five studies, 1571 women; moderate-certainty evidence). QoL on the EORTC QLQ-C30 scale produced inconsistent and imprecise results in two studies (MD -1.34, 95% CI -2.36 to -0.32; participants = 307; very low-certainty evidence) and use of the QLQC-30 and QLQC-Ov28 in another study (MD 7.60, 95% CI 1.89 to 13.31; participants = 217; very low-certainty evidence) meant that little could be inferred. AUTHORS' CONCLUSIONS: The available moderate-certainty evidence suggests there is little or no difference in primary survival outcomes between PDS and NACT. NACT may reduce the risk of serious adverse events, especially those around the time of surgery, and the need for bowel resection and stoma formation. These data will inform women and clinicians and allow treatment to be tailored to the person, taking into account surgical resectability, age, histology, stage and performance status. Data from an unpublished study and ongoing studies are awaited.

Neoadjuvant chemotherapy before surgery versus surgery followed by chemotherapy for initial treatment in advanced ovarian epithelial cancer.

BACKGROUND: Epithelial ovarian cancer presents at an advanced stage in the majority of women. These women require a combination of surgery and chemotherapy for optimal treatment. Conventional treatment has been to perform surgery first and then give chemotherapy. However, there may be advantages to using chemotherapy before surgery. OBJECTIVES: To assess whether there is an advantage to treating women with advanced epithelial ovarian cancer with chemotherapy before debulking surgery (neoadjuvant chemotherapy (NACT)) compared with conventional treatment where chemotherapy follows debulking surgery (primary debulking surgery (PDS)). SEARCH METHODS: We searched the following databases up to 9 October 2020: the Cochrane Central Register of Controlled Trials (CENTRAL), Embase via Ovid, MEDLINE (Silver Platter/Ovid), PDQ and MetaRegister. We also checked the reference lists of relevant papers that were identified to search for further studies. The main investigators of relevant trials were contacted for further information. SELECTION CRITERIA: Randomised controlled trials (RCTs) of women with advanced epithelial ovarian cancer (Federation of International Gynaecologists and Obstetricians (FIGO) stage III/IV) who were randomly allocated to treatment groups that compared platinum-based chemotherapy before cytoreductive surgery with platinum-based chemotherapy following cytoreductive surgery. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed risk of bias in each included trial. We extracted data of overall (OS) and progression-free survival (PFS), adverse events, surgically-related mortality and morbidity and quality of life outcomes.  We used GRADE methods to determine the certainty of evidence. MAIN RESULTS: We identified 2227 titles and abstracts through our searches, of which five RCTs of varying quality and size met the inclusion criteria. These studies assessed a total of 1774 women with stage IIIc/IV ovarian cancer randomised to NACT followed by interval debulking surgery (IDS) or PDS followed by chemotherapy. We pooled results of the four studies where data were available and found little or no difference with regard to overall survival (OS) (Hazard Ratio (HR) 0.96, 95% CI 0.86 to 1.08; participants = 1692; studies = 4; high-certainty evidence) or progression-free survival in four trials where we were able to pool data (Hazard Ratio 0.98, 95% CI 0.88 to 1.08; participants = 1692; studies = 4; moderate-certainty evidence). Adverse events, surgical morbidity and quality of life (QoL) outcomes were variably and incompletely reported across studies. There are probably clinically meaningful differences in favour of NACT compared to PDS with regard to overall postoperative serious adverse effects (SAE grade 3+): 6% in NACT group, versus 29% in PDS group, (risk ratio (RR) 0.22, 95% CI 0.13 to 0.38; participants = 435; studies = 2; heterogeneity index (I2) = 0%; moderate-certainty evidence). NACT probably results in a large reduction in the need for stoma formation: 5.9% in NACT group, versus 20.4% in PDS group, (RR 0.29, 95% CI 0.12 to 0.74; participants = 632; studies = 2; I2 = 70%; moderate-certainty evidence), and probably reduces the risk of needing bowel resection at the time of surgery: 13.0% in NACT group versus 26.6% in PDS group (RR 0.49, 95% CI 0.30 to 0.79; participants = 1565; studies = 4; I2 = 79%; moderate-certainty evidence). NACT reduces postoperative mortality: 0.6% in NACT group, versus 3.6% in PDS group, (RR 0.16, 95% CI 0.06 to 0.46; participants = 1623; studies = 5; I2 = 0%; high-certainty evidence). QoL on the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) scale produced inconsistent and imprecise results in three studies (MD -0.29, 95% CI -2.77 to 2.20; participants = 524; studies = 3; I2 = 81%; very low-certainty evidence) but the evidence is very uncertain and should be interpreted with caution. AUTHORS' CONCLUSIONS: The available high to moderate-certainty evidence suggests there is little or no difference in primary survival outcomes between PDS and NACT. NACT probably reduces the risk of serious adverse events, especially those around the time of surgery, and reduces the risk of postoperative mortality and the need for stoma formation. These data will inform women and clinicians (involving specialist gynaecological multidisciplinary teams) and allow treatment to be tailored to the person, taking into account surgical resectability, age, histology, stage and performance status. Data from an unpublished study and ongoing studies are awaited.

Sentinel node biopsy for diagnosis of lymph node involvement in endometrial cancer.

BACKGROUND: Pelvic lymphadenectomy provides prognostic information for those diagnosed with endometrial (womb) cancer and provides information that may influence decisions regarding adjuvant treatment. However, studies have not shown a therapeutic benefit, and lymphadenectomy causes significant morbidity. The technique of sentinel lymph node biopsy (SLNB), allows the first draining node from a cancer to be identified and examined histologically for involvement with cancer cells. SLNB is commonly used in other cancers, including breast and vulval cancer. Different tracers, including colloid labelled with radioactive technetium-99, blue dyes, e.g. patent or methylene blue, and near infra-red fluorescent dyes, e.g. indocyanine green (ICG), have been used singly or in combination for detection of sentinel lymph nodes (SLN). OBJECTIVES: To assess the diagnostic accuracy of sentinel lymph node biopsy (SLNB) in the identification of pelvic lymph node involvement in women with endometrial cancer, presumed to be at an early stage prior to surgery, including consideration of the detection rate. SEARCH METHODS: We searched MEDLINE (1946 to July 2019), Embase (1974 to July 2019) and the relevant Cochrane trial registers. SELECTION CRITERIA: We included studies that evaluated the diagnostic accuracy of tracers for SLN assessment (involving the identification of a SLN plus histological examination) against a reference standard of histological examination of removed pelvic +/- para-aortic lymph nodes following systematic pelvic +/- para-aortic lymphadenectomy (PLND/PPALND) in women with endometrial cancer, where there were sufficient data for the construction of two-by-two tables. DATA COLLECTION AND ANALYSIS: Two review authors (a combination of HN, JM, NW, RG, and WH) independently screened titles and abstracts for relevance, classified studies for inclusion/exclusion and extracted data. We assessed the methodological quality of studies using the QUADAS-2 tool. We calculated the detection rate as the arithmetic mean of the total number of SLNs detected out of the total number of women included in the included studies with the woman as the unit of analysis, used univariate meta-analytical methods to estimate pooled sensitivity estimates, and summarised the results using GRADE. MAIN RESULTS: The search revealed 6259 unique records after removal of duplicates. After screening 232 studies in full text, we found 73 potentially includable records (for 52 studies), although we were only able to extract 2x2 table data for 33 studies, including 2237 women (46 records) for inclusion in the review, despite writing to trial authors for additional information. We found 11 studies that analysed results for blue dye alone, four studies for technetium-99m alone, 12 studies that used a combination of blue dye and technetium-99m, nine studies that used indocyanine green (ICG) and near infra-red immunofluorescence, and one study that used a combination of ICG and technetium-99m. Overall, the methodological reporting in most of the studies was poor, which resulted in a very large proportion of 'unclear risk of bias' ratings. Overall, the mean SLN detection rate was 86.9% (95% CI 82.9% to 90.8%; 2237 women; 33 studies; moderate-certainty evidence). In studies that reported bilateral detection the mean rate was 65.4% (95% CI 57.8% to 73.0%) . When considered according to which tracer was used, the SLN detection rate ranged from 77.8% (95% CI 70.0% to 85.6%) for blue dye alone (559 women; 11 studies; low-certainty evidence) to 100% for ICG and technetium-99m (32 women; 1 study; very low-certainty evidence). The rates of positive lymph nodes ranged from 5.2% to 34.4% with a mean of 20.1% (95% CI 17.7% to 22.3%). The pooled sensitivity of SLNB was 91.8% (95% CI 86.5% to 95.1%; total 2237 women, of whom 409 had SLN involvement; moderate-certainty evidence). The sensitivity for of SLNB for the different tracers were: blue dye alone 95.2% (95% CI 77.2% to 99.2%; 559 women; 11 studies; low-certainty evidence); Technetium-99m alone 90.5% (95% CI 67.7% to 97.7%; 257 women; 4 studies; low-certainty evidence); technetium-99m and blue dye 91.9% (95% CI 74.4% to 97.8%; 548 women; 12 studies; low-certainty evidence); ICG alone 92.5% (95% CI 81.8% to 97.1%; 953 women; 9 studies; moderate-certainty evidence); ICG and blue dye 90.5% (95% CI 63.2.6% to 98.1%; 215 women; 2 studies; low-certainty evidence); and ICG and technetium-99m 100% (95% CI 63% to 100%; 32 women; 1 study; very low-certainty evidence). Meta-regression analyses found that the sensitivities did not differ between the different tracers used, between studies with a majority of women with FIGO stage 1A versus 1B or above; between studies assessing the pelvic lymph node basin alone versus the pelvic and para-aortic lymph node basin; or between studies that used subserosal alone versus subserosal and cervical injection. It should be noted that a false-positive result cannot occur, as the histological examination of the SLN is unchanged by the results from any additional nodes removed at systematic lymphadenectomy. AUTHORS' CONCLUSIONS: The diagnostic test accuracy for SLNB using either ICG alone or a combination of a dye (blue or ICG) and technetium-99m is probably good, with high sensitivity, where a SLN could be detected. Detection rates with ICG or a combination of dye (ICG or blue) and technetium-99m may be higher. The value of a SLNB approach in a treatment pathway, over adjuvant treatment decisions based on uterine factors and molecular profiling, requires examination in a high-quality intervention study.

Patient-initiated follow-up after treatment for low risk endometrial cancer: a prospective audit of outcomes and cost benefits.

OBJECTIVE: Recurrence of low-risk endometrioid endometrial cancer is rare, and traditional hospital follow-up has a cost to both the patient and the healthcare system, without evidence of benefit. We examined the uptake of patient-initiated follow-up, pattern of recurrences, and survival for women following surgical treatment of low-risk endometrial cancer and compared estimated costs with hospital follow-up. METHODS: This study was a prospective audit of outcomes following implementation of a patient-initiated follow-up policy in a UK-based gynecological cancer center for women with low-risk endometrial cancer treated surgically (International Federation of Gynecology and Obstetrics (FIGO) stage 1A, G1-2) from January 2010 to December 2015. Women were identified following multidisciplinary team meetings and data were collected from the electronic cancer register, paper, and electronic clinical records. Health service costs were calculated based on standard tariffs for follow-up appointments; patient costs were estimated from mileage traveled from home postcode and parking charges. Progression-free survival and overall survival were assessed. Estimated financial costs to the health service and patients of hospital follow-up were compared with actual patient-initiated follow-up costs. RESULTS: A total of 129 women were offered patient-initiated follow-up (declined by four; accepted by another 11 after hospital follow-up for 6 months to 3.5 years) with median follow-up of 60.7 months (range 1.4-109.1 months). Ten women recurred: four vaginal vault recurrences (all salvaged), three pelvic recurrences (all salvaged), and three distant metastatic disease (all died). Five-year disease-specific survival was 97.3%. Ten women in the cohort died: three from endometrial cancer and seven from unrelated causes. The cost saving to the health service of patient-initiated follow-up compared with a traditional hospital follow-up regimen was £116 403 (median £988.60 per patient,range £0-£1071). Patients saved an estimated £7122 in transport and parking costs (median £57.22 per patient,range £4.98-£147.70). CONCLUSION: Patient-initiated follow-up for low risk endometrial cancer has cost benefits to both health service and patients. Those with pelvic or vault recurrence had salvageable disease, despite patient-initiated follow-up.

British Gynaecological Cancer Society recommendations and guidance on patient-initiated follow-up (PIFU).

The National Cancer Survivorship Initiative through the National Health Service (NHS) improvement in the UK started the implementation of stratified pathways of patient-initiated follow-up (PIFU) across various tumor types. Now the initiative is continued through the Living With and Beyond Cancer program by NHS England. Evidence from non-randomized studies and systematic reviews does not demonstrate a survival advantage to the long-established practice of hospital-based follow-up regimens, traditionally over 5 years. Evidence shows that patient needs are inadequately met under the traditional follow-up programs and there is therefore an urgent need to adapt pathways to the needs of patients. The assumption that hospital-based follow-up is able to detect cancer recurrences early and hence improve patient prognosis has not been validated. A recent survey demonstrates that follow-up practice across the UK varies widely, with telephone follow-up clinics, nurse-led clinics and PIFU becoming increasingly common. There are currently no completed randomized controlled trials in PIFU in gynecological malignancies, although there is a drive towards implementing PIFU. PIFU aims to individualize patient care, based on risk of recurrence and holistic needs, and optimizing resources. The British Gynaecological Cancer Society wishes to provide the gynecological oncology community with guidance and a recommendations statement regarding the value, indications, and limitations of PIFU in endometrial, cervical, ovarian, and vulvar cancers in an effort to standardize practice and improve patient care.

Management of Malignant Vulval Melanoma: A Retrospective Case Series and Review of the Literature.

OBJECTIVES: The aims of the study were to evaluate clinicopathologic features, management, and outcomes in vulval melanoma and to review the literature. MATERIALS AND METHODS: Data were collected retrospectively on patients with vulval melanoma from 2001 to 2017 in 5 gynecological oncology cancer centers (Bristol, Taunton, Truro, Plymouth, and Cheltenham). SPSS software was used for univariate and multivariate statistical analysis. Disease-specific median survival was calculated using Kaplan-Meier curves. RESULTS: Forty-four patients with vulval melanoma were included, with a median age of 71 years. Forty-three of 44 had wide local excision with full inguinal lymphadenectomy if abnormal lymph nodes. Seven patients had sentinel lymph nodes. However, 2 patients with negative sentinel lymph nodes had distant recurrences within 16 months.On univariate analysis, presence of ulceration (p = .012), perineural invasion (p = .03), and area of lesion (p = .016) were associated with risk of recurrence but only presence of microsatellites (p = .01) was associated with risk of death.There were 31 deaths (70%): 29 (94%) of 31 from melanoma and 28 (64%) of 44 recurrences: 17 local (10 groin, 7 vulval) and 9 distant. Overall median survival was 32.5 months (95% CI, 17.8-46.5 months) and median recurrence-free survival 12.6 months (95% CI, 7.7-17.4 months). CONCLUSIONS: This retrospective multicenter study highlights the high recurrence rate and poor prognosis of vulval melanoma. Lymph node surgery did not make any difference to recurrence-free survival or overall survival. The presence of microsatellites was associated with a statistically increased risk of death.

Chemotherapy versus surgery for initial treatment in advanced ovarian epithelial cancer.

BACKGROUND: Epithelial ovarian cancer presents at an advanced stage in the majority of women. These women require surgery and chemotherapy for optimal treatment. Conventional treatment has been to perform surgery first and then give chemotherapy. However, there may be advantages to using chemotherapy before surgery. OBJECTIVES: To assess whether there is an advantage to treating women with advanced epithelial ovarian cancer with chemotherapy before debulking surgery (neoadjuvant chemotherapy (NACT)) compared with conventional treatment where chemotherapy follows debulking surgery (primary debulking surgery (PDS)). SEARCH METHODS: We searched the following databases on 11 February 2019: CENTRAL, Embase via Ovid, MEDLINE (Silver Platter/Ovid), PDQ and MetaRegister. We also checked the reference lists of relevant papers that were identified to search for further studies. The main investigators of relevant trials were contacted for further information. SELECTION CRITERIA: Randomised controlled trials (RCTs) of women with advanced epithelial ovarian cancer (Federation of International Gynaecologists and Obstetricians (FIGO) stage III/IV) who were randomly allocated to treatment groups that compared platinum-based chemotherapy before cytoreductive surgery with platinum-based chemotherapy following cytoreductive surgery. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed risk of bias in each included trial. MAIN RESULTS: We found 1952 potential titles, with a most recent search date of February 2019, of which five RCTs of varying quality and size met the inclusion criteria. These studies assessed a total of 1713 women with stage IIIc/IV ovarian cancer randomised to NACT followed by interval debulking surgery (IDS) or PDS followed by chemotherapy. We pooled results of the three studies where data were available and found little or no difference with regard to overall survival (OS) (1521 women; hazard ratio (HR) 1.06; 95% confidence interval (CI) 0.94 to 1.19, I2 = 0%; moderate-certainty evidence) or progression-free survival in four trials where we were able to pool data (1631 women; HR 1.02; 95% CI 0.92 to 1.13, I2 = 0%; moderate-certainty evidence). Adverse events, surgical morbidity and quality of life (QoL) outcomes were poorly and incompletely reported across studies. There may be clinically meaningful differences in favour of NACT compared to PDS with regard to serious adverse effects (SAE grade 3+). These data suggest that NACT may reduce the risk of need for blood transfusion (risk ratio (RR) 0.80; 95% CI 0.64 to 0.99; four studies,1085 women; low-certainty evidence), venous thromboembolism (RR 0.28; 95% CI 0.09 to 0.90; four studies, 1490 women; low-certainty evidence), infection (RR 0.30; 95% CI 0.16 to 0.56; four studies, 1490 women; moderate-certainty evidence), compared to PDS. NACT probably reduces the need for stoma formation (RR 0.43, 95% CI 0.26 to 0.72; two studies, 581 women; moderate-certainty evidence) and bowel resection (RR 0.49, 95% CI 0.26 to 0.92; three studies, 1213 women; moderate-certainty evidence), as well as reducing postoperative mortality (RR 0.18; 95% CI 0.06 to 0.54:five studies, 1571 women; moderate-certainty evidence). QoL on the EORTC QLQ-C30 scale produced inconsistent and imprecise results in two studies (MD -1.34, 95% CI -2.36 to -0.32; participants = 307; very low-certainty evidence) and use of the QLQC-30 and QLQC-Ov28 in another study (MD 7.60, 95% CI 1.89 to 13.31; participants = 217; very low-certainty evidence) meant that little could be inferred. AUTHORS' CONCLUSIONS: The available moderate-certainty evidence suggests there is little or no difference in primary survival outcomes between PDS and NACT. NACT may reduce the risk of serious adverse events, especially those around the time of surgery, and the need for bowel resection and stoma formation. These data will inform women and clinicians and allow treatment to be tailored to the person, taking into account surgical resectability, age, histology, stage and performance status. Data from an unpublished study and ongoing studies are awaited.

Epidermal growth factor receptor blockers for the treatment of ovarian cancer.

BACKGROUND: This is an update of a previously published version of the review (Issue 10, 2011).Epithelial ovarian cancer (EOC) is the seventh most common cause of cancer death among women worldwide. Treatment consists of a combination of surgical debulking and platinum-based chemotherapy. Between 55% and 75% of women who respond to first-line therapy experience relapse within two years. Second-line chemotherapy is palliative and aims to reduce symptoms and prolong survival. Improved understanding about the molecular basis of EOC has led to the development of novel agents, such as epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors and anti-EGFR antibodies. OBJECTIVES: To compare the effectiveness and harmful effects of interventions that target the epidermal growth factor receptor in the treatment of epithelial ovarian cancer (EOC). SEARCH METHODS: We searched the Cochrane Gynaecological Cancer Group Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL; 2010, Issue 4), MEDLINE, and Embase up to October 2010. We also searched registers of clinical trials, abstracts of scientific meetings, and reference lists of included studies, and we contacted experts in the field. This update includes further searches up to September 2017. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing anti-EGFR agents with or without conventional chemotherapy versus conventional chemotherapy alone or no treatment in women with histologically proven EOC. DATA COLLECTION AND ANALYSIS: Two review authors independently abstracted data, assessed risk of bias, and performed GRADE assessment. MAIN RESULTS: From 6105 references obtained through the literature search and an additional 15 references derived from grey literature searches, we identified seven RCTs that met our inclusion criteria and included 1725 participants. Trial results show that after first-line chemotherapy is provided, maintenance treatment with erlotinib (EGFR tyrosine kinase inhibitor (TKI)) probably makes little or no difference in overall survival (hazard ratio (HR) 0.99, 95% confidence interval (CI) 0.81 to 1.20; one study; 835 participants; low-certainty evidence) and may make little or no difference in progression-free survival (HR 1.05, 95% CI 0.90 to 1.23; one study; 835 participants; very low-certainty evidence). Less than 50% of participants provided quality of life data, and study authors reported these results incompletely. The certainty of evidence is very low, but treatment may reduce quality of life compared to observation.Treatment with an EGFR TKI (vandetanib) for women with relapsed EOC may make little or no difference in overall survival (HR 1.25, 95% CI 0.80 to 1.95; one study; 129 participants; low-certainty evidence) and may make little or no difference in progression-free survival (HR 0.99, 95% CI 0.69 to 1.42; one study; 129 participants; very low-certainty evidence). In treating patients with relapse, giving EGFR TKI may slightly increase some toxicities, such as severe rash (risk ratio (RR) 13.63, 95% CI 0.78 to 236.87; one study; 125 participants; very low-certainty evidence). Quality of life data were not available for meta-analysis.Anti-EGFR antibody treatment in relapsed EOC may or may not make a difference to overall survival (HR 0.93, 95% CI 0.74 to 1.18; four studies; 658 participants; moderate-certainty evidence) and may or may not have any effect on progression-free survival (HR 0.90, 95% CI 0.70 to 1.16; four studies; 658 participants; low-certainty evidence). Anti-EGFR antibody treatment may or may not increase side effects, including severe nausea and/or vomiting (RR 1.27, 95% CI 0.56 to 2.89; three studies; 503 participants; low-certainty evidence), severe fatigue (RR 1.06, 95% CI 0.66 to 1.73; I² = 0%; four studies; 652 participants; low-certainty evidence), and hypokalaemia (RR 2.01, 95% CI 0.80 to 5.06; I² = 0%; three studies; 522 participants; low-certainty evidence). Severe diarrhoea rates were heterogeneous across studies (RR 2.87, 95% CI 0.59 to 13.89; four studies; 652 participants; low-certainty evidence), and subgroup analysis revealed that severe diarrhoea was more likely with pertuzumab (RR 6.37, 95% CI 1.89 to 21.45; I² = 0%; three studies; 432 participants; low-certainty evidence) than with seribantumab treatment (RR 0.38, 95% CI 0.07 to 2.23; I² = 0%; one study; 220 participants; very low-certainty evidence). Quality of life data were incompletely reported, and we were unable to combine them in a meta-analysis. AUTHORS' CONCLUSIONS: Current evidence suggests that an anti-EGFR single-agent biological treatment (EGFR TKI or anti-EGFR antibody) makes little or no difference to survival, either as maintenance treatment after first-line chemotherapy or in association with chemotherapy in recurrent cancer. Anti-EGFR therapy may increase some side effects and may or may not reduce quality of life.

Lymphadenectomy for the management of endometrial cancer.

BACKGROUND: This is an update of a previous Cochrane review published in Issue 1, 2010 and updated in Issue 9, 2015. The role of lymphadenectomy in surgical management of endometrial cancer remains controversial. Lymph node metastases can be found in approximately 10% of women who before surgery are thought to have cancer confined to the womb. Removal of all pelvic and para-aortic lymph nodes (lymphadenectomy) at initial surgery has been widely advocated, and pelvic and para-aortic lymphadenectomy remains part of the FIGO (International Federation of Gynaecology and Obstetrics) staging system for endometrial cancer. This recommendation is based on data from studies that suggested improvement in survival following pelvic and para-aortic lymphadenectomy. However, these studies were not randomised controlled trials (RCTs), and treatment of pelvic lymph nodes may not confer a direct therapeutic benefit, other than allocating women to poorer prognosis groups. Furthermore, the Cochrane review and meta-analysis of RCTs of routine adjuvant radiotherapy to treat possible lymph node metastases in women with early-stage endometrial cancer found no survival advantage. Surgical removal of pelvic and para-aortic lymph nodes has serious potential short-term and long-term sequelae. Therefore, it is important to investigate the clinical value of this treatment. OBJECTIVES: To evaluate the effectiveness and safety of lymphadenectomy for the management of endometrial cancer. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and Embase to June 2009 for the original review, updated the search to June 2015 for the last updated version and further extended the search to March 2017 for this version of the review. We also searched registers of clinical trials, abstracts of scientific meetings, and reference lists of included studies, and we contacted experts in the field. SELECTION CRITERIA: RCTs and quasi-RCTs that compared lymphadenectomy versus no lymphadenectomy in adult women diagnosed with endometrial cancer. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed risk of bias. Hazard ratios (HRs) for overall and progression-free survival and risk ratios (RRs) comparing adverse events in women who received lymphadenectomy versus those with no lymphadenectomy were pooled in random-effects meta-analyses. We assessed the quality of the evidence using the GRADE (Grades of Recommendation, Assessment, Development and Evaluation) approach. MAIN RESULTS: 978 unique references were identified via the search strategy. All but 50 were excluded by title and abstract screening. Three RCTs met the inclusion criteria; for one small RCT, data were insufficient for inclusion in the meta-analysis. The two RCTs included in the analysis randomly assigned 1945 women, reported HRs for survival adjusted for prognostic factors and based on 1851 women and had an overall low risk of bias, as they satisfied four of the assessment criteria. The third study had an overall unclear risk of bias, as information provided was not adequate concerning random sequence generation, allocation concealment, blinding, or completeness of outcome reporting.Results of the meta-analysis remained unchanged from the previous versions of this review and indicated no differences in overall and recurrence-free survival between women who underwent lymphadenectomy and those who did not undergo lymphadenectomy (pooled hazard ratio (HR) 1.07, 95% confidence interval (CI) 0.81 to 1.43; HR 1.23, 95% CI 0.96 to 1.58 for overall and recurrence-free survival, respectively) (1851 participants, two studies; moderate-quality evidence).We found no difference in risk of direct surgical morbidity between women who underwent lymphadenectomy and those who did not undergo lymphadenectomy. However, women who underwent lymphadenectomy had a significantly higher risk of surgery-related systemic morbidity and lymphoedema/lymphocyst formation than those who did not undergo lymphadenectomy (RR 3.72, 95% CI 1.04 to 13.27; RR 8.39, 95% CI 4.06 to 17.33 for risk of surgery-related systemic morbidity and lymphoedema/lymphocyst formation, respectively) (1922 participants, two studies; high-quality evidence). AUTHORS' CONCLUSIONS: This review found no evidence that lymphadenectomy decreases risk of death or disease recurrence compared with no lymphadenectomy in women with presumed stage I disease. Evidence on serious adverse events suggests that women who undergo lymphadenectomy are more likely to experience surgery-related systemic morbidity or lymphoedema/lymphocyst formation. Currently, no RCT evidence shows the impact of lymphadenectomy in women with higher-stage disease and in those at high risk of disease recurrence.

Working together to shape the endometrial cancer research agenda: The top ten unanswered research questions.

BACKGROUND: Endometrial cancer (EC) is the most common gynaecological cancer in developed nations and its incidence is rising. As a direct consequence, more women are dying from EC despite advances in care and improved survivorship. There is a lack of research activity and funding, as well as public awareness about EC. We sought to engage patients, carers and healthcare professionals to identify the most important unanswered research questions in EC. METHODOLOGY: The priority setting methodology was developed by the James Lind Alliance and involved four key stages: gathering research questions; checking these against existing evidence; interim prioritisation; and a final consensus meeting during which the top ten unanswered research questions were agreed using modified nominal group methodology. RESULTS: Our first online survey yielded 786 individual submissions from 413 respondents, of whom 211 were EC survivors or carers, and from which 202 unique unanswered research questions were generated. 253 individuals, including 108 EC survivors and carers, completed an online interim prioritisation survey. The resulting top 30 questions were ranked in a final consensus meeting. Our top ten spanned the breadth of patient experience of this disease and included developing personalised risk scoring, refining criteria for specialist referral, understanding the underlying biology of different types of EC, developing novel personalised treatment and prevention strategies, prognostic and predictive biomarkers, increasing public awareness and interventions for psychological issues. CONCLUSION: Having established the top ten unanswered research questions in EC, we hope this galvanises researchers, healthcare professionals and the public to collaborate, coordinate and invest in research to improve the lives of women affected by EC.

Lymphadenectomy for the management of endometrial cancer.

BACKGROUND: This is an update of a previous Cochrane review published in Issue 1, 2010. The role of lymphadenectomy in surgical management of endometrial cancer remains controversial. Lymph node metastases can be found in approximately 10% of women who clinically before surgery have cancer confined to the womb. Removal of all pelvic and para-aortic lymph nodes (lymphadenectomy) at initial surgery has been widely advocated, and pelvic and para-aortic lymphadenectomy remains part of the FIGO (International Federation of Gynaecology and Obstetrics) staging system for endometrial cancer. This recommendation is based on data from studies that suggested improvement in survival following pelvic and para-aortic lymphadenectomy. However, these studies were not randomised controlled trials (RCTs), and treatment of pelvic lymph nodes may not confer a direct therapeutic benefit, other than allocating women to poorer prognosis groups. Furthermore, the Cochrane review and meta-analysis of RCTs of routine adjuvant radiotherapy to treat possible lymph node metastases in women with early-stage endometrial cancer found no survival advantage. Surgical removal of pelvic and para-aortic lymph nodes has serious potential short-term and long-term sequelae. Therefore it is important to investigate the clinical value of this treatment. OBJECTIVES: To evaluate the effectiveness and safety of lymphadenectomy for the management of endometrial cancer. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), the Cochrane Gynaecological Cancer Review Group Trials Register, MEDLINE and EMBASE to June 2009 for the original review and extended the search to June 2015 for this version of the review. We also searched registers of clinical trials, abstracts of scientific meetings and reference lists of included studies, and we contacted experts in the field. SELECTION CRITERIA: RCTs and quasi-RCTs that compared lymphadenectomy versus no lymphadenectomy in adult women diagnosed with endometrial cancer. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed risk of bias. Hazard ratios (HRs) for overall and progression-free survival and risk ratios (RRs) comparing adverse events in women who received lymphadenectomy versus those with no lymphadenectomy were pooled in random-effects meta-analyses. We assessed the quality of the evidence using the GRADE (Grades of Recommendation, Assessment, Development and Evaluation) approach. MAIN RESULTS: Three RCTs met the inclusion criteria; for one small RCT, data were insufficient for inclusion in the meta-analysis. The two RCTs included in the analysis randomly assigned 1945 women, reported HRs for survival adjusted for prognostic factors and based on 1851 women and had an overall low risk of bias, as they satisfied four of the assessment criteria. The third study had an overall unclear risk of bias, as information provided was not adequate concerning random sequence generation, allocation concealment, blinding or completeness of outcome reporting.Results of the meta-analysis remain unchanged from the previous version of this review and indicate no differences in overall and recurrence-free survival between women who underwent lymphadenectomy and those who did not undergo lymphadenectomy (pooled HR 1.07, 95% CI 0.81 to 1.43; HR 1.23, 95% CI 0.96 to 1.58 for overall and recurrence-free survival, respectively) (1851 participants, two studies; moderate-quality evidence).We found no difference in risk of direct surgical morbidity between women who underwent lymphadenectomy and those who did not undergo lymphadenectomy. However, women who underwent lymphadenectomy had a significantly higher risk of surgery-related systemic morbidity and lymphoedema/lymphocyst formation than those who did not undergo lymphadenectomy (RR 3.72, 95% CI 1.04 to 13.27; RR 8.39, 95% CI 4.06 to 17.33 for risk of surgery-related systemic morbidity and lymphoedema/lymphocyst formation, respectively) (1922 participants, two studies; high-quality evidence). AUTHORS' CONCLUSIONS: This review found no evidence that lymphadenectomy decreases risk of death or disease recurrence compared with no lymphadenectomy in women with presumed stage I disease. Evidence on serious adverse events suggests that women who undergo lymphadenectomy are more likely to experience surgery-related systemic morbidity or lymphoedema/lymphocyst formation. Currently, no RCT evidence shows the impact of lymphadenectomy in women with higher-stage disease and in those at high risk of disease recurrence.

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

BACKGROUND: Ovarian cancer is the sixth most common cancer and seventh most common cause of cancer death in women world-wide. Three-quarters of women present when the disease has spread throughout the abdomen (stage III or IV) and treatment consists of a combination of debulking surgery and platinum-based chemotherapy. Although initial responses to chemotherapy are good, most women will relapse and require further chemotherapy and will eventually develop resistance to chemotherapy.PARP (poly (ADP-ribose) polymerase) inhibitors, are a novel type of medication that works by preventing cancer cells from repairing their DNA once they have been damaged by other chemotherapy agents. It is not clear how PARP inhibitors compare to conventional chemotherapy regimens for the treatment of ovarian cancer, with respect to survival, side effects and quality of life. OBJECTIVES: To determine the benefits and risks of PARP inhibitors 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 2014, Issue 4), the Cochrane Gynaecological Cancer Group Trial Register, MEDLINE (1990 to May 2014), EMBASE (1990 to May 2014), ongoing trials on www.controlled-trials.com/rct, www.clinicaltrials.gov, www.cancer.gov/clinicaltrials and the National Research Register (NRR), the FDA database and pharmaceutical industry biomedical literature. SELECTION CRITERIA: Women with histologically proven EOC who were randomised to treatment groups in trials that either compared PARP inhibitors with no treatment, or PARP inhibitors versus conventional chemotherapy, or PARP inhibitors 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, where possible. Outcomes included survival, quality of life and toxicity. MAIN RESULTS: We included four RCTs involving 599 women with EOC. Data for veliparib were limited and of low quality, due to small numbers (75 women total). Olaparib, on average, improved progression-free survival (PFS) when added to conventional treatment and when used as maintenance treatment in women with platinum-sensitive disease compared with placebo (hazard ratio (HR) 0.42, 95% confidence interval (CI) 0.29 to 0.60; 426 participants ; two studies), but did not improve overall survival (OS) (HR 1.05, 95% CI 0.79 to 1.39; 426 participants; two studies). We graded this evidence as moderate quality using the GRADE approach. Olaparib was associated with more severe adverse events (G3/4) during the maintenance phase compared with controls (risk ratio (RR) 1.74, 95% CI 1.22 to 2.49; 385 participants, two studies; moderate quality evidence). Quality of life data were insufficient for meta-analysis. We identified four ongoing studies. AUTHORS' CONCLUSIONS: PARP inhibitors appear to improve PFS in women with recurrent platinum-sensitive disease. Ongoing studies are likely to provide more information about whether the improvement in PFS leads to any change in OS in this subgroup of women with EOC. More research is needed to determine whether PARP inhibitors have any role to play in platinum-resistant disease.