Mark Heywood

Pegylated Liposomal Doxorubicin and Carboplatin Compared With Paclitaxel and Carboplatin for Patients With Platinum-Sensitive Ovarian Cancer in Late Relapse

PURPOSEnThis randomized, multicenter, phase III noninferiority trial was designed to test the efficacy and safety of the combination of pegylated liposomal doxorubicin (PLD) with carboplatin (CD) compared with standard carboplatin and paclitaxel (CP) in patients with platinum-sensitive relapsed/recurrent ovarian cancer (ROC).nnnPATIENTS AND METHODSnPatients with histologically proven ovarian cancer with recurrence more than 6 months after first- or second-line platinum and taxane-based therapies were randomly assigned by stratified blocks to CD (carboplatin area under the curve [AUC] 5 plus PLD 30 mg/m(2)) every 4 weeks or CP (carboplatin AUC 5 plus paclitaxel 175 mg/m(2)) every 3 weeks for at least 6 cycles. Primary end point was progression-free survival (PFS); secondary end points were toxicity, quality of life, and overall survival.nnnRESULTSnOverall 976 patients were recruited. With median follow-up of 22 months, PFS for the CD arm was statistically superior to the CP arm (hazard ratio, 0.821; 95% CI, 0.72 to 0.94; P = .005); median PFS was 11.3 versus 9.4 months, respectively. Although overall survival data are immature for final analysis, we report here a total of 334 deaths. Overall severe nonhematologic toxicity (36.8% v 28.4%; P < .01) leading to early discontinuation (15% v 6%; P < .001) occurred more frequently in the CP arm. More frequent grade 2 or greater alopecia (83.6% v 7%), hypersensitivity reactions (18.8% v 5.6%), and sensory neuropathy (26.9% v 4.9%) were observed in the CP arm; more hand-foot syndrome (grade 2 to 3, 12.0% v 2.2%), nausea (35.2% v 24.2%), and mucositis (grade 2-3, 13.9% v 7%) in the CD arm.nnnCONCLUSIONnTo our knowledge, this trial is the largest in recurrent ovarian cancer and has demonstrated superiority in PFS and better therapeutic index of CD over standard CP.

A brief mindfulness-based cognitive behavioral intervention improves sexual functioning versus wait-list control in women treated for gynecologic cancer

GOALnThe goal of this study was to evaluate a mindfulness-based cognitive behavioral intervention for sexual dysfunction in gynecologic cancer survivors compared to a wait-list control group.nnnMETHODSnThirty-one survivors of endometrial or cervical cancer (mean age 54.0, range 31-64) who self-reported significant and distressing sexual desire and/or sexual arousal concerns were assigned either to three, 90-minute mindfulness-based cognitive behavior therapy sessions or two months of wait-list control prior to entering the treatment arm. Validated measures of sexual response, sexual distress, and mood, as well as laboratory-evoked physiological and subjective sexual arousal were assessed at pre-, one month post-, and 6-months following treatment.nnnRESULTSnThere were no significant effects of the wait-list condition on any measure. Treatment led to significant improvements in all domains of sexual response, and a trend towards significance for reducing sexual distress. Perception of genital arousal during an erotic film was also significantly increased following the intervention despite no change in physiologically-measured sexual arousal.nnnCONCLUSIONSnA brief mindfulness-based intervention was effective for improving sexual functioning. Geographic restrictions permitted only a select sample of survivors to participate, thus, the generalizability of the findings is limited. Future studies should aim to develop online modalities for treatment administration to overcome this limitation.

Impact of secondary cytoreductive surgery on survival in patients with platinum sensitive recurrent ovarian cancer: Analysis of the CALYPSO trial

OBJECTIVEnThe role of secondary cytoreductive surgery (SCR) in platinum-sensitive recurrent ovarian cancer (ROC) remains controversial. The overall survival (OS) benefits for surgery reported in observational studies may be due to the selection of patients with better prognosis.nnnMETHODSnUsing data from the CALYPSO trial, OS of patients who had SCR was compared to those treated with chemotherapy alone. Multivariate analyses were performed to adjust for prognostic factors. We also tested for an interaction between baseline prognostic groupings and the benefit of surgery.nnnRESULTSnOf the 975 patients randomised in CALYPSO, 19% had SCR and 80% had chemotherapy alone. OS was longer for the SCR group than for chemotherapy alone (median, 49.9 vs. 29.7 months; adjusted hazard ratio (HR), 0.68; P = 0.004). For patients with SCR, the 3-year OS was 72% for those with no measurable disease, and 28% if residual tumour was larger than 5 cm. Patients with good prognostic features benefited the most from SCR (HR 0.43; P < 0.001). The benefit of SCR was less in patients with poorer prognostic features (test of trend P < 0.001).nnnCONCLUSIONnSCR was associated with improved OS in platinum-sensitive ROC, particularly in patients with favourable prognostic characteristics. However, these findings may be due to selection bias, and hence randomised trials are still essential.

The significance of surgical staging in intermediate-risk endometrial cancer

OBJECTIVEnThe objective was to evaluate rates of nodal disease in endometrial cancer within risk groups based on uterine factors, and to estimate the rate of potential undertreatment and impact on survival if nodal status was unknown.nnnMETHODSnThis was a population-based retrospective cohort study of endometrioid-type endometrial cancer in British Columbia from 2005 to 2009. All women with a preoperative grade 2/3 cancer underwent hysterectomy, bilateral salpingo-oophorectomy (HBSO) and lymphadenectomy, and those with intermediate- or high-risk disease based on uterine factors after HBSO alone underwent secondary lymphadenectomy. We compared rates of node-positivity and potential undertreatment in each group if nodal status had been unknown (chi-square test), and estimated the survival benefit from lymphadenectomy.nnnRESULTSnThere were 222 women who underwent primary or secondary lymphadenectomy. Median age was 65 (range 38-86) and median number of lymph nodes was 10 (range 2-39). Of the 66 women with intermediate-risk disease (grade 1 or 2 tumor, deep myometrial invasion), 6 had nodal disease (9.1%) and received adjuvant chemotherapy. They remain disease-free after 24 months (range 8-55). They would not have qualified for chemotherapy based on uterine factors alone, and would have been undertreated compared to other risk groups (chi-square p=0.071). A 1% survival benefit was estimated from lymphadenectomy.nnnCONCLUSIONnWomen with a grade 1 or 2 tumor and deep myometrial invasion have a 9% risk of nodal disease. Lymphadenectomy is significant for this subgroup as they would have been undertreated based on uterine risk factors alone, although the survival benefit is limited.

Prevention and Treatment of Thrombo-embolic Disease in Gynaecological Surgery

Abstract Objective: to identify pre-operative risk factors for venous thrombo-embolism (VTE) and to provide guidelines for risk assessment and for thrombo-prophylactic measures for VTE in women undergoing gynaecological surgery. Guidelines for diagnostic testing and for acute and long-term treatment of VTE are also provided. Options: low, moderate and high-risk groups of patients are defined and appropriate prophylactic measures are outlined. Alternative measures to low-dose unfractionated heparin (LDUH), for example low molecular weight heparin (LMWH), leg stockings, dextran 70 and acetylsalicylic acid are discussed. Alternative methods for acute treatment of VTE are also provided. Outcomes: venous thrombo-embolism remains a major cause of morbidity and mortality following gynaecological surgery. Adequate prophylaxis can decrease the incidence of VTE. Evidence: evidence was gathered using MEDLINE (National Library of Medicine) to identify pertinent studies and from bibliographies of articles thus identified. Recommendations: prophylactic measures for VTE decrease its incidence (Level 1 evidence). Based on risk assessment, more patients should be considered for prophylaxis (Grade A recommendation). The occurrence of VTE is effectively reduced by the use of LDUH and maybe more soby the use of LMWH (Level 1 evidence). For treatment of VTE, unfractionated heparin (UH) has been standard, although LMWH has now been proven to be at least as effective and safe (Level 1 evidence). Based on this evidence, LDUH or LMWH should be used in prophylaxis when feasible and UH or LMWH in treatment of VTE (Grade A recommendation). Following initial heparinization for treatment of VTE, patients should receive oral anticoagulation for at least three months (Grade A recommendation). Consideration could be given to extending prophylaxis beyond hospital discharge in high-risk patients.

The strong prognostic value of KELIM, a model-based parameter from CA 125 kinetics in ovarian cancer: Data from CALYPSO trial (a GINECO-GCIG study)

BACKGROUNDnUnexpected results were recently reported about the poor surrogacy of Gynecologic Cancer Intergroup (GCIG) defined CA-125 response in recurrent ovarian cancer (ROC) patients. Mathematical modeling may help describe CA-125 decline dynamically and discriminate prognostic kinetic parameters.nnnMETHODSnData from CALYPSO phase III trial comparing 2 carboplatin-based regimens in ROC patients were analyzed. Based on population kinetic approach, serum [CA-125] concentration-time profiles during first 50 treatment days were fit to a semi-mechanistic model with following parameters: d[CA-125]/dt=(KPROD∗exp (BETA∗t))∗Effect-KELIM∗[CA-125] with time, t; tumor growth rate, BETA; CA-125 tumor production rate, KPROD; CA-125 elimination rate, KELIM and K-dependent treatment indirect Effect. The predictive values of kinetic parameters were tested regarding progression-free survival (PFS) against other reported prognostic factors.nnnRESULTSnIndividual CA-125 kinetic profiles from 895 patients were modeled. Three kinetic parameters categorized by medians had predictive values using univariate analyses: K; KPROD and KELIM (all P<0.001). Using Cox multivariate analysis, 5 independent predictors of PFS remained significant: GCIG CA-125 response (favoring carboplatin-paclitaxel arm), treatment arm, platinum free-interval, measurable lesions and KELIM (HR=0.53; 95% CI 0.45-0.61; P<0.001).nnnCONCLUSIONSnMathematical modeling of CA-125 kinetics in ROC patients enables understanding of the time-change components during chemotherapy. The contradictory surrogacy of GCIG-defined CA-125 response was confirmed. The modeled CA-125 elimination rate KELIM, potentially assessable in routine, may have promising predictive value regarding PFS. Further validation of this predictive marker is warranted.

Prévention et traitement de la thromboembolie en chirurgie gynécologique

Resume Objectif : identifier les facteurs de risque preoperatoires de thromboembolie veineuse (TEV) et fournir des lignes directrices pour levaluation du risque, pour les mesures thrombo-prophylactiques contre la TEV chez les femmes subissant une intervention chirurgicale gynecologique ainsi que pour les tests diagnostiques et le traitement aigu a long terme de la TEV. Options : apres avoir defini trois groupes de risque, a savoir, faible, modere et eleve, on presente des mesures prophylactiques appropriees. On examine des solutions de rechange a lheparine non fractionnee a faible dose (HNFFD) telles que lheparine de bas poids moleculaire (HBPM), les bas elastiques, la dextrane 70 et lacide acetylsalicylique. On presente aussi quelques options pour le traitement de la TEV aigue. Resultats : la thromboembolic veineuse demeure une cause majeure de morbidite et de mortalite a la suite dune intervention chirurgicale gynecologique. Une prophylaxie appropriee peut reduire lincidence de TEV. Evidence : levidence a ete accumulee a partir de MEDLINE ( National Library of Medicine ) pour identifier les etudes pertinentes et a partir des bibliographies des articles ainsi identifies. Recommandations : les mesures prophylactiques contre la TEV reduisent son incidence (niveau 1 devidence). Levaluation des risques permet de recommander quon offre une prophylaxie a plus de patientes (recommandation du niveau A). Lincidence de TEV est reduite dune maniere efficace par lheparine non fractionnee a faible dose, et il se peut quelle le soit davantage par lHBPM (niveau 1 devidence). Jusquici, lheparine non fractionnee (HNF) a ete le traitement de reference contre la TEV, mais il est maintenant prouve que lHBPM est au moins aussi efficace et securitaire (niveau 1 devidence). Etant donne cette evidence, on devrait utiliser, si possible, lHNFFD ou lHBPM pour la prophylaxie et lHNF ou lHBPM pour le traitement de la TEV (recommandation du niveau A). A la suite dun traitement initial a lheparine contre la TEV, les patientes devraient prendre un anticoagulant oral pendant au moins trois mois (recommandation du niveau A). On pourrait aussi envisager la possibilite de prolonger la prophylaxie au-dela de la sortie de lhopital pour les patientes a risque eleve.

Lignes Directrices sur L’adénocarcinome in situ du Col Utérin: Caractéristiques Cliniques et Revue du Traitement

Resume Les lesions glandulaires intraepitheliales du col uterin ont un spectre morphologique (apparente au cancer pavimenteux) allant des alterations benignes aux anomalies graves. On se refere a lensemble de ce continuum comme etant «neoplasie glandulaire intraepitheliale du col uterin». Les abreviations sont: NGIC ou NGL Le diagnostic de ladenoarcinome in situ (ACIS) se fait au moyen dune methode dexerese. Le prelevement, de preference de forme cylindrique, doit avoir des marges laterales et superieures negatives (sans evidence de maladie). Le ratio de ladenocarcinome in situ a lepithelioma a la dysplasie pavimenteuse severe/carcinoma in situ est, en moyenne, de 1:50 (ce qui indique que la forme glandulaire comprend environ 2% des cas in situ) alors que les lesions glandulaires malignes constituent entre 6 et 18 pour cent de tous les cancers du col invasifs. Aux deux stades, de 46 a 72 pour cent des lesions glandulaire contiennent une composante pavimenteuse (ce qui indique donc quelles sont de type mixte). Les methodes de depistage et de detection utilisees pour lidentification des lesions et pour determiner la presence dune maladie persistante ou recurrente (cytologie, colposcopie, biopsie et curetage endocervical) ne sont ni precises ni fiables. Cela sexplique parfois par un prelevement cytologique inadequat, par lexistence de diverses «mimiques» colposcopiques (les plus frequentes etant la metaplasie, les condylomes, ladenocarcinome invasif, le cancer pavimenteux invasif et lhyperplasie microglandulaire), par le peu dexperience des colposcopistes en ce qui concerne ces lesions (etant donnee leur rarete) et, dans certains cas, par limperfection du curetage endocervical. Normalement, ladenocarcinome in situ ne depasse pas les 15 mm de longueur (la distance a la surface des tissus entre les bords inferieurs et superieurs et lenvahissement des cryptes des ou glandes endocervicales sous-jacentes) ne depasse generalement pas les 4 mm. Bien que lACIS prenne plusieurs formes architecturales et histologiques, celles-ci naffectent pas le traitement. Le traitement de lACIS demeure controverse. On propose lexerese cervicale (comme la «conisation» fractionnelle, mais avec un prelevement de forme cylindrique) comme traitement conservateur des patientes desireuses de preserver leur fertilite. Le prelevement doit avoir des marges negatives, ce qui veut dire que les bords exterieurs et superieurs sont sans evidence de maladie et que la maladie est entierement contenue a linterieur du tissu preleve. La cytologie de suivi, la colposcopie et le curetage endocervical peuvent manquer de precision pour lidentification dune maladie persistante ou la detection dune maladie recurrente. Si la question de fertilite ne se pose pas, on recommande une hysterectomie simple meme si le prelevement contient des marges negatives bien que la maladie puisse etre quand meme presente dans le specimen dhysterectomie, il sagit normalement dACIS et rarement dun adenoarcinome invasif. Si les marges sont positives, cest-a-dire que la maladie est presente sur la surface superieure ou exterieure de la conisation, la probabilite de trouver une lesion invasive dans la piece dhysterectomie prelevee est accrue. Les patientes qui choisissent le traitement conservateur doivent etre informees de limportance des suivis et des risques possibles dune maladie glandulaire persistante ou recurrente precoce non detectee en depit dun depistage negatif et de lutilisation de methodes de detection invasives. En effet, quelque cas de maladie glandulaire persistante ou recurrente apres exerese ont ete rapportes, malgre des marges negatives dans le specimen de conisation.

Guidelines on Adenocarcinoma in situ of the Cervix: Clinical Features and Review of Management: These guidelines have been prepared by the SOGC/GOC/SCC Policy and Practice Guideline Committee and were approved by the Council of the SOGC

Abstract Cervical intra-epithelial glandular lesions have a morphological spectrum (akin to squamous) that ranges from mild changes to severe abnormalities. The entire spectrum is referred to as cervical intra-epethilial glandular neoplasia and is abbreviated as CIGN, CGIN or GIN. The diagnosis of adenocarcinoma in situ (ACIS) is made by some method of excision. The specimen, preferably cylindrical in shape, must have negative (disease free) lateral and upper margins. The ratio of adenocarcinoma in situ to severe squamous dysplasia/carcinoma in situ averages 1:50 (meaning that glandular comprises roughly 2% of in situ cases) whereas the malignant glandular lesions make up six to 18 percent of all invasive cervical cancers. In both stages, 46 to 72 percent of lesions contain a counterpart squamous component (being, therefore, of mixed type). Screening and invasive detection methods used to identify lesions and determine the presence of persistent or recurrent disease (cytology, colposcopy, biopsy and endocervical curettage) are inaccurate and unreliable. This is because of inadequate cytologic sampling in some cases, the existence of various colposcopic mimics (the most commonly encountered being metaplasia, condylomata, invasive adenocarcinoma, invasive squamous cancer and microglandular hyperplasia), most colposcopists lack of experience with these lesions (due to their rarity) and the inadequacy of endocervical curettage in some cases. Adenocardnoma in situ has a length (the distance over the tissue surface between caudal and cephalad edges) not usually exceeding 15 mm. The underlying cervical crypt (gland) involvement does not usually exceed four millimetres. Although ACIS has many architectural and histological patterns, management is not influenced by these patterns. The management of ACIS continues to be controversial. Cervical excision (like the traditional conization but with the specimen cylindrical in shape) is proposed as conservative management for patients desirous of future fertility. The excised specimen must have negative margins, meaning that the outer and upper margins of the specimen are free of disease and that the disease is completely contained within the excised tissue. Follow-up cytology, colposcopy and endocervical curettage may not be accurate in identifying persistent disease and/or detecting recurrent disease. If fertility is not an issue, simple routine hysterectomy is advocated, even though the specimen contains negative margins. Although disease can still be present in the hysterectomy specimen, it is usually ACIS and rarely an invasive adenocarcinoma. In the case of positive margins, meaning disease is noted at the upper and/or outer surface of the excised specimen, the probability of finding an invasive lesion in the extirpated specimen is enhanced. Patients who choose conservative management must be counselled about the importance of compliance and the potential risks of early undetected persistent or recurrent glandular disease, despite negative screening and invasive detection methods. This is because some cases of persistent or recurrent glandular disease have been reported after excision, despite negative specimen margins.

Déclaration de Principe *: Directives Concernant La Laparoscope De La Masse Annexielle

Resume nDepuis quelques annees, la prise en charge de la masse annexielle a evolue grâce aux progres realises dans le domaine de la chirurgie, peu inva-sive. Les interventions chirurgicales par laparoscopie presentent des avantages par rapport a la laparotomie classique, avantages aussi interessants pour la patiente que pour la societe: cicatrice minime, attenuation de la douleur, raccourcissement du sejour a l’hopital et retablissement plus rapide. C’est pourquoi cette approche a de plus en plus gagne en popularite. Plus recemment, des rapports ont decrit les consequences malheureuses de cancers ovariens non diagnostiques, traites par laparoscopie, cas qui ont necessite une reevaluation de la prise en charge de la masse annexielle. Quoique la masse annexielle soit benigne dans la plupart des cas et puisse etre soignee par laparoscopie, le defi reside dans l’identification des masses qu’il serait preferable de traiter par laparotomie. La presente directive a pour but d’etablir les parametres cliniques et chirurgicaux susceptibles de faciliter la distinction entre une masse annexielle a faible risque et une autre a risque eleve, a partir des donnees existantes. La masse annexielle est evaluee en deux temps: avant et pendant l’operation. Nous analyserons chaque etape en detail. En respectant des criteres severes et en faisant appel a des techniques chirurgicales rigoureuses, on reussira a prendre correctement en charge la plupart des masses annexielles.