Trends in Surgeon Burnout in the US and Canada: Systematic Review and Meta-Regression Analysis.

BACKGROUND: Burnout among surgeons is increasingly recognized as a crisis. However, little is known about changes in burnout prevalence over time. We evaluated temporal trends in burnout among surgeons and surgical trainees of all specialties in the US and Canada. STUDY DESIGN: We systematically reviewed MEDLINE, Embase, and PsycINFO for studies assessing surgeon burnout from January 1981 through September 2021. Changes in dichotomized Maslach Burnout Inventory scores and mean subscale scores over time were assessed using multivariable random-effects meta-regression. RESULTS: Of 3,575 studies screened, 103 studies representing 63,587 individuals met inclusion criteria. Publication dates ranged from 1996 through 2021. Overall, 41% of surgeons met criteria for burnout. Trainees were more affected than attending surgeons (46% vs 36%, p = 0.012). Prevalence remained stable over the study period (-4.8% per decade, 95% CI -13.2% to 3.5%). Mean scores for emotional exhaustion declined and depersonalization declined over time (-4.1 per decade, 95% CI -7.4 to -0.8 and -1.4 per decade, 95% CI -3.0 to -0.2). Personal accomplishment scores remained unchanged. A high degree of heterogeneity was noted in all analyses despite adjustment for training status, specialty, practice setting, and study quality. CONCLUSIONS: Contrary to popular perceptions, we found no evidence of rising surgeon burnout in published literature. Rather, emotional exhaustion and depersonalization may be decreasing. Nonetheless, burnout levels remain unacceptably high, indicating a need for meaningful interventions across training levels and specialties. Future research should be deliberately designed to support longitudinal integration through prospective meta-regression to facilitate monitoring of trends in surgeon burnout.

Fertility-sparing surgery for diffuse adenomyosis: a narrated, stepwise approach to the Osada procedure.

OBJECTIVE: To equip reproductive surgeons with an approach to the Osada procedure and critical prophylactic hemostatic measures that optimize perioperative outcomes. DESIGN: Stepwise demonstration of the Osada procedure with narrated video footage. SETTING: Definitive management of symptomatic adenomyosis requires hysterectomy. However, adenomyomectomy can improve symptoms and restore anatomy while maintaining fertility potential. Limited but comparable perioperative outcomes exist for minimally invasive methods of adenomyomectomy, and most involve resection of focal, not diffuse, adenomyosis. Among the literature involving resection of diffuse adenomyosis using minimally invasive methods, relatively small volumes of resected tissue are reported and none include obstetric outcomes. Most published reports for excision of diffuse adenomyosis involve laparotomic resection, likely because of specific intraoperative challenges curtailed by this approach. In response, a laparoscopic-assisted laparotomic approach was developed in 2011 by Dr. Hisao Osada, a reproductive surgeon in Japan. This procedure involves aggressive excision of adenomyotic tissue with prophylactic hemostatic techniques and subsequent uterine wall reconstruction using a triple-flap method. Compared with other excisional methods for diffuse adenomyomectomy, the Osada procedure has the best reported obstetric outcomes. PATIENT(S): A 37-year-old nulliparous female presented with pelvic pain, bulk symptoms, abnormal uterine bleeding, and infertility. Physical examination demonstrated a 20-week, bulky uterus with limited bimanual mobility. Her endometrial cavity was inaccessible because of marked anatomic distortion. Magnetic resonance imaging revealed marked abnormality of her endometrial contour because of a 15 cm adenomyoma with diffuse adenomyomatous tissue in the posterior uterine compartment. Prior interventions included a trial of combined hormonal contraceptive, leuprolide acetate, and tranexamic acid. She was interested in fertility-sparing adenomyomectomy to address symptoms and fertility potential and chose to proceed with the Osada procedure. She was optimized medically with oral and parenteral iron therapy to bring her hemoglobin from 55-111 g/L preoperatively. Institutional review board approval and informed consent from the patient were obtained. INTERVENTION(S): The Osada procedure was performed using the following 8 surgical steps: Systemic administration of tranexamic acid was also administered intraoperatively. MAIN OUTCOME MEASURE(S): Perioperative blood loss, anatomic normalization, symptom remediation, and maintenance of fertility potential. RESULTS: Perioperative blood loss was minimal, 469 g of adenomyotic tissue was extracted, and discharge was on postoperative day 2 without any complications. Three months later, cyclic pain and bleeding had improved markedly, ultrasound confirmed Doppler flow throughout the uterus, hysterosalpingogram demonstrated a nonobliterated endometrial cavity and tubal patency, and magnetic resonance imaging confirmed normalized uterine dimensions measuring 11 × 7 cm from 19 × 10 cm. Most literature supports waiting at least 6-12 months and until demonstration of normalized uterine blood flow in the operated area before attempting conception. CONCLUSION: Fertility-sparing excision of diffuse adenomyosis can be achieved safely using the Osada procedure, following the 8 discrete steps demonstrated in this video. Reproductive surgeons can reference this video to teach and maintain this important procedure.

Impact of Minimally Invasive Gynaecology Fellowship Training on Quality Performance Metrics for Hysterectomy.

OBJECTIVE: To evaluate differences in quality metrics between hysterectomies performed by fellowship-trained surgeons and those performed by generalists. METHODS: Retrospective review of 2845 consecutive hysterectomies by 75 surgeons (23 fellowship-trained, 52 generalists) at 7 hospitals in Ontario, Canada. The primary outcome was a composite of any complication or return to the emergency department (ED) within 30 days of hysterectomy. Secondary outcomes were 2 quality outcome measures (grade of complication and return to ED within 30 days) and 4 quality process measures (minimally invasive hysterectomy rate, rate of preoperative anemia, same-day discharge for laparoscopic hysterectomy [LH], and performing cystoscopy at LH). RESULTS: Fellowship-trained surgeons were more likely to perform concurrent resection of endometriosis, bilateral ureterolysis, lysis of adhesions, uterine/internal iliac artery ligation, and morcellation (all P < 0.001). Generalists performed more vaginal procedures, including vaginal repair, vault suspension, and insertion of mid-urethral sling (all P < 0.001). After controlling for patient and surgical factors, there was no difference in the primary outcome (adjusted odds ratio [aOR] 1.07; 95% CI 0.79-1.45, P = 0.667). Fellowship-trained surgeons were more likely to perform minimally invasive hysterectomy (aOR 2.38; 95% CI 1.15-4.93, P = 0.020), had higher rates of same-day discharge for LH (aOR 2.23; 95% CI 1.31-3.81, P = 0.003), and were more likely to perform cystoscopy (unadjusted OR 2.94; 95% CI 2.30-3.85, P < 0.001). There were no differences in the rates of preoperative anemia, surgical complications, and ED visits. CONCLUSION: Differences exist between fellowship-trained surgeons and generalists regarding case mix and process quality metrics. Postoperative complications and readmissions were comparable for both groups of surgeons.

Ulipristal Acetate Prior to Surgery for Endometriosis.

Selective progesterone receptor modulators may have a role in the treatment of endometriosis. The aim of this report is to review the effect of ulipristal acetate (UPA) on endometriosis lesions and symptoms in women treated prior to surgery. A pathology review of eutopic endometrium and endometriotic lesions was conducted by two gynecologic pathologists. The main outcome measures reported are pain reduction, amenorrhea, and pathologic progesterone receptor modulator-associated endometrial changes (PAECs). Overall, fifteen women with endometriosis received UPA over a 27-month study period. UPA was administered in an intermittent fashion in the majority of patients while 27% of patients had continuous treatment, between 6 and 24 months. Eleven (73%) patients reported amenorrhea on UPA and 11 (92%) of 12 patients with pain reported pain reduction or resolution. Fourteen patients (93%) proceeded with surgical management. Thirteen (93%) patients underwent excision of suspected endometriosis at surgery. Twelve cases (86%) had concurrent eutopic endometrium specimens and PAEC was identified in 58% (n = 7). Among the 14 cases that underwent surgery, a total of 49 extraovarian sites were sampled. Endometriosis was definitively identified in 31 (63%) of these sites. Three cases (21%) showed morphologic features similar to PAEC within foci of endometriosis. All cases of PAEC-like features in endometriosis also had PAEC in the endometrium. These patients had all noted pain reduction and amenorrhea preoperatively. In conclusion, PAECs may be found in endometriosis lesions in patients treated with UPA. Further prospective investigation is required to evaluate the efficacy and safety of SPRMs in women with endometriosis.

No. 385-Indications for Pelvic Examination.

OBJECTIVE: The primary objective of this document is to clarify the indications for pelvic examination. INTENDED USERS: Physicians, including gynaecologists, obstetricians, family physicians, and emergency physicians; nurses, including registered nurses and nurse practitioners; midwives, including midwives in clinical practice and midwifery trainees; medical trainees, including medical students, residents, and fellows; and all other health care providers who care for women. TARGET POPULATION: This publication provides evidence and expert-based recommendations for pelvic examination in adult women (18 years and older) both with and without gynaecologic symptoms. OUTCOMES: This publication clarifies indications for pelvic examination in the context of recently published national task force statements on the utility of pelvic examination. We aim to ensure that women who have clinical indications for examination receive proper clinical investigation with minimal delays to diagnosis of treatable disease. EVIDENCE: For this committee opinion, relevant studies were identified in PubMed and Medline using the following terms, either alone or in combination, with the search limited to English-language materials and human subjects and no publication date cut-off: pelvic examination, bimanual examination, speculum examination, rectovaginal examination, ovarian cancer screening, asymptomatic women, periodic health examination. The search was performed in May and June 2018. Relevant evidence was selected for inclusion in the following order: meta-analyses, systematic reviews, guidelines and national task force statements, randomized controlled trials, prospective cohort studies, observational studies, non-systematic reviews, case series, and reports. Additional articles were identified by cross-referencing the identified publications. A formal systematic review was not conducted for all topics discussed due to the paucity of evidence and number of different subtopics discussed. The total number of publications included in this review was 66. VALIDATION METHODS: The content and recommendations were drafted and agreed upon by the principal authors. The Boards of the Society of Gynecologic Oncology of Canada (GOC), the College of Family Physicians of Canada (CFPC), and the Society of Obstetricians and Gynaecologists of Canada (SOGC) approved the final draft for publication after review by their respective representative committees. The quality of evidence was rated using the criteria described in the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology framework (Tables 1 and 2). The Summary of Findings is available upon request. BENEFITS, HARMS, AND COSTS: This committee opinion should benefit all women with and without gynaecologic symptoms who present to gynaecologists and primary care practitioners. It will help guide practitioners in identifying indications for pelvic examination to reduce unnecessary examination with related potential harm while also increasing indicated examination to reduce delays in diagnosis of treatable gynaecologic conditions. GUIDELINE UPDATE: This SOGC Committee Opinion will be automatically reviewed 5 years after publication to determine if all or part of the committee opinion should be updated. However, this review may be performed earlier if new high-impact research is published in the interim. SUMMARY STATEMENTS: 1. National and international statements and guidelines on pelvic examination should not be interpreted to suggest that the pelvic examination is irrelevant or noncontributory to physical assessment or that the pelvic examination in symptomatic women should be omitted. 2. Pelvic examination may include visual inspection, speculum examination, bimanual examination, single digit examination, and/or rectovaginal examination depending on the indication for examination. 3. No study published to date has adequately evaluated any component of the pelvic examination as a screening method for any type of malignant gynaecologic disease, except for the speculum examination for cervical cancer cytology screening. As such, any universal recommendations for or against pelvic examinations for other indications can only be made based on expert opinion and low-quality evidence. 4. In asymptomatic women at average risk for cervical cancer, cervical cytology screening reduces both the incidence of, and mortality from, cervical cancer by detecting pre-invasive, treatable lesions. 5. In asymptomatic women at average risk of malignancy, a visual and bimanual examination at the time of obtaining cervical cytology samples may add value to this screening manoeuvre: Women might not raise certain gynaecologic concerns until the time of pelvic examination; the examination provides an opportunity for patient education and practitioner skill maintenance; and, although inadequately studied to date, there may be positive effects on ovarian and vulvar malignancy that require further investigation. These potential benefits should be weighed against potential harms like patient discomfort and false positives/negatives that may result in inappropriate reassurance or unnecessary investigations/interventions. RECOMMENDATIONS: Symptomatic Women. 1) Any woman with gynaecologic complaints including, but not limited to, vulvar complaints, vaginal discharge, abnormal premenopausal bleeding, postmenopausal bleeding, infertility, pelvic organ prolapse symptoms, urinary incontinence, new and unexplained gastrointestinal symptoms (abdominal pain, increased abdominal size/bloating, and difficulty eating/early satiety), pelvic pain, or dyspareunia should undergo appropriate components of the pelvic examination to identify benign or malignant disease (strong, low). 2) Health care providers may consider discussing the risks and benefits of performing a baseline pelvic examination including visual and bimanual examination prior to prescribing hormonal replacement therapy/menopausal hormonal treatment (weak, very low). Asymptomatic Women. 3) Health care practitioners should perform cervical cytology cancer screening in accordance with provincial/territorial guidelines (strong, strong). 4) There is insufficient evidence to guide recommendations on screening pelvic examination for noncervical gynaecologic malignancy or any benign gynaecologic disease in healthy, asymptomatic women with average risk of malignancy. However, health care practitioners may consider performing a screening pelvic examination including visual, speculum, and bimanual examinations in concert with cervical cytology sampling intervals as recommended by provincial/territorial guidelines. This practice may identify clinically important benign or malignant disease not recognized or reported by the patient (weak, very low). 5) In women over age 70 who no longer require screening with cervical cytology, health care practitioners should consider continuing periodic screening of asymptomatic women for vulvar disease with inspection of the vulva, perineum, and anus to identify benign or malignant disease unrecognized by this population. There is insufficient evidence to guide recommendations on frequency of this examination (weak, low). 6) Women with a personal history of gynaecologic malignancy, a genetic diagnosis that increases gynaecologic malignancy risk, or a history of in utero diethylstilbestrol exposure may benefit from more frequent screening pelvic examinations to identify early primary, recurrent, or metastatic malignancy in the absence of symptoms. Because there is inadequate evidence to define these screening intervals, they should be in accordance with provincial/territorial guidelines and expert opinion (weak, very low). 7. Non-invasive and self-collection screening options for chlamydia and gonorrhea are acceptable in asymptomatic women, but pelvic examination, including visual inspection, speculum examination, and bimanual examination, is required in the presence of symptoms to rule out pelvic inflammatory disease or tubo-ovarian abscess (strong, low). 8) No pelvic examination is required prior to prescription of hormonal contraception in a healthy woman with no gynaecologic symptoms (strong, low).

No 385 - Indications de l'examen pelvien.

OBJECTIF: L'objectif principal du présent document est de clarifier les indications de l'examen pelvien. UTILISATEURS CONCERNéS: Médecins, y compris les gynécologues, obstétriciens, médecins de famille, urgentologues; infirmières, y compris les infirmières autorisées et les infirmières praticiennes; sages-femmes, y compris les sages-femmes en pratique clinique et les apprenties sages-femmes et les apprentis en médecine, y compris les étudiants de médecine, résidents, stagiaires (fellows); et tous les autres fournisseurs de soins de santé qui prodiguent des soins aux femmes. POPULATION CIBLE: La présente publication fournit des données probantes et des recommandations fondées sur des avis d'experts sur l'examen pelvien chez les femmes adultes (18 ans et plus) avec et sans symptômes gynécologiques. ISSUES: La présente publication clarifie les indications de l'examen pelvien dans le contexte des déclarations de groupes d'étude nationaux récemment publiées sur l'utilité de l'examen pelvien. L'objectif est de veiller à ce que les femmes qui présentent des indications cliniques d'examen fassent rapidement l'objet d'une évaluation clinique adéquate pour diagnostiquer les maladies traitables. DONNéES PROBANTES: Pour la présente opinion de comité, les études pertinentes ont été repérées dans PubMed et Medline à l'aide des termes suivants, seuls ou combinés, et les recherches ont été limitées aux publications en anglais portant sur des humains sans date limite de publication : pelvic examination, bimanual examination, speculum examination, rectovaginal examination, ovarian cancer screening, asymptomatic women, periodic health examination. La recherche a été effectuée en mai et en juin 2018. Les données probantes pertinentes ont été retenues dans l'ordre suivant : méta-analyses, revues systématiques, lignes directrices et déclarations des groupes d'étude nationaux, essais cliniques randomisés, études de cohorte prospective, études observationnelles, revues non systématiques, études de série de cas et rapports. Des articles supplémentaires ont été repérés en consultant les notices bibliographiques des publications sélectionnées. Une revue systématique officielle n'a pas été menée pour tous les sujets discutés en raison du manque de données probantes et du nombre de différents sous-thèmes abordés. Le nombre total de publications examinées dans le cadre de cette revue était de 66. MéTHODES DE VALIDATION: Les auteurs principaux ont rédigé le contenu et les recommandations et ils se sont entendus sur ces derniers. Les conseils d'administration de la Society of Gynecologic Oncology of Canada (GOC), de Collège des médecins de famille du Canada (CMFC) et de la Société des obstétriciens et gynécologues du Canada (SOGC) ont approuvé la version définitive aux fins de publication après que leurs comités représentatifs respectifs l'aient passée en revue. La qualité des données probantes utilisées dans le présent document a été évaluée au moyen des critères du cadre méthodologique GRADE (Grading of Recommendations, Assessment, Development, and Evaluation). (Tableaux 1 et 2) Le résumé des conclusions est disponible sur demande. AVANTAGES, PRéJUDICE ET COûTS: La présente opinion de comité devrait aider toutes les femmes qui souffrent ou non de symptômes gynécologiques qui se présentent chez le gynécologue et un fournisseur de soins primaires. Elle aidera les praticiens à déterminer les indications d'examen pelvien afin de réduire le nombre d'examens inutiles et susceptibles de porter préjudice tout en augmentant le nombre d'examens indiqués afin de réduire les retards de diagnostic des affections gynécologiques traitables. MISE à JOUR DE LA DIRECTIVE CLINIQUE: La présente opinion de comité de la SOGC sera automatiquement passée en revue cinq ans après sa publication pour déterminer si une partie ou l'ensemble de l'opinion de comité devrait être mis à jour. Cependant, cette revue peut être effectuée plus tôt si de nouvelles recherches révolutionnaires sont publiées entre-temps. DÉCLARATIONS SOMMAIRES: 1) Les déclarations et les directives nationales et internationales sur l'examen pelvien ne devraient pas être interprétées comme si l'examen pelvien est superflu, qu'il ne contribue pas à l'évaluation physique ou que l'examen pelvien chez les femmes symptomatiques devrait être omis. 2) L'examen pelvien peut comprendre les examens visuels, au spéculum, bimanuel, à un doigt ou rectovaginal selon l'indication d'examen. 3) Aucune étude publiée à ce jour n'a évalué adéquatement quelque composante que ce soit de l'examen pelvien comme méthode de dépistage pour quelconque type de maladie gynécologique maligne, à l'exception de l'examen au spéculum pour le dépistage cytologique du cancer du col de l'utérus. Ainsi, toute recommandation universelle, pour ou contre les examens pelviens pour d'autres indications ne peut qu'être faite selon l'opinion des spécialistes et des données probantes de faible qualité. 4) Chez les femmes asymptomatiques dont le risque de cancer du col de l'utérus est moyen, le dépistage cytologique du cancer du col de l'utérus réduit à la fois son incidence et son taux de mortalité en détectant les lésions préinvasives traitables. 5) Chez les femmes asymptomatiques dont le risque de tumeur ou affection maligne est moyen, un examen visuel et bimanuel au moment d'obtenir des échantillons cytologiques cervicaux peut apporter une valeur ajoutée à cette méthode de dépistage. Les femmes peuvent ne pas soulever certaines inquiétudes sur le plan gynécologique jusqu'au moment de l'examen pelvien; l'examen offre une occasion de sensibiliser les patientes et de maintenir les compétences du praticien; de plus, même si le sujet n'a pas encore été étudié adéquatement, il pourrait comporter des effets positifs sur les tumeurs ou affections malignes ovariennes et vulvaires qui nécessiteraient des analyses plus poussées. Ces avantages potentiels devraient être soupesés par rapport aux préjudices potentiels comme l'inconfort de la patiente et les faux positifs ou négatifs qui pourraient la rassurer à tort ou entraîner des analyses et des interventions non justifiées. RECOMMANDATIONS: Femmes symptomatiques 1) Toute femme qui exprime des plaintes de nature gynécologique, y compris, mais sans s'y limiter, des plaintes concernant la vulve, des pertes vaginales, des saignements préménopausiques anormaux, des saignements postménopausiques, l'infertilité, des symptômes de prolapsus des organes pelviens, l'incontinence urinaire, de nouveaux symptômes gastro-intestinaux inexpliqués (douleur abdominale, distension abdominale ou ballonnement et difficulté à manger ou satiété précoce), la douleur pelvienne ou la dyspareunie, devrait subir des composantes pertinentes de l'examen pelvien afin de détecter les maladies bénignes ou malignes (forte, basse). 2) Les fournisseurs de soins de santé peuvent envisager de discuter des risques et avantages de l'exécution d'un examen pelvien de base qui comprend un examen visuel et un examen bimanuel avant de prescrire une hormonothérapie substitutive ou un traitement hormonal de la ménopause (faible, très basse). Femmes asymptomatiques 3) Les professionnels de la santé devraient faire le dépistage cytologique du cancer du col de l'utérus conformément aux lignes directrices provinciales ou territoriales (forte, forte). 4) Les données sont insuffisantes pour orienter les recommandations sur l'examen pelvien aux fins de dépistage de tumeurs ou affections malignes de nature gynécologique non cervicales ou de toute maladie gynécologique bénigne chez les femmes asymptomatiques en santé dont le risque de tumeur ou affection maligne est moyen. Cependant, les professionnels de la santé peuvent envisager d'effectuer un examen pelvien aux fins de dépistage comprenant les examens visuel, bimanuel et au spéculum conjointement avec le prélèvement d'échantillons cytologiques cervicaux selon les intervalles recommandés dans les lignes directrices provinciales ou territoriales. Cette pratique pourrait permettre de détecter d'importantes maladies bénignes ou malignes non reconnues ou signalées par la patiente (faible, très basse). 5) Chez les femmes âgées de plus de 70 ans qui n'ont plus à subir de dépistage cytologique cervical, les professionnels de la santé devraient envisager de continuer chez les femmes asymptomatiques le dépistage périodique des maladies vulvaires en examinant la vulve, le périnée et l'anus afin de détecter les maladies bénignes ou malignes méconnues de cette population. Les données sont insuffisantes pour déterminer des recommandations sur la fréquence de cet examen (faible, basse). 6) Des examens pelviens de dépistage plus fréquents pour déceler les signes précoces de tumeurs ou affections malignes primitives, récidivantes ou métastatiques en l'absence de symptômes pourraient s'avérer bénéfiques pour les femmes qui ont des antécédents personnels de tumeurs malignes de nature gynécologique, un diagnostic génétique qui augmente le risque de tumeurs ou affections malignes gynécologiques ou des antécédents d'exposition in utero au diéthylstilbestrol. Puisque les données pour déterminer ces intervalles de dépistage sont inadéquates, on devrait les déterminer en fonction des lignes directrices provinciales ou territoriales et de l'opinion des spécialistes (faible, très basse). 7) Les options non effractives et par auto-prélèvement de dépistage de la chlamydia et de la gonorrhée sont acceptables chez les femmes asymptomatiques, mais l'examen pelvien, qui comprend les examens visuel, bimanuel et au spéculum, est requis en présence de symptômes pour écarter la possibilité d'une maladie inflammatoire pelvienne ou d'un abcès tubo-ovarien (forte, basse). 8) Aucun examen pelvien n'est requis avant la prescription de contraception hormonale chez une femme en santé qui ne présente aucun symptôme gynécologique (forte, basse).

PPX and Concurrent Radiation for Newly Diagnosed Glioblastoma Without MGMT Methylation: A Randomized Phase II Study: BrUOG 244.

PURPOSE: Efficacy signals but substantial myelosuppression were demonstrated in a single arm phase II study of paclitaxel poliglumex (PPX) in combination with temozolomide (TMZ) and radiation therapy (RT) for first-line treatment of glioblastoma. The objective of this randomized phase II trial was to assess the efficacy and safety of single-agent PPX with RT (PPX/RT) versus TMZ with RT (TMZ/RT) for glioblastoma without O-methylguanine-DNA methyltransferase (MGMT) methylation. MATERIALS AND METHODS: Patients with glioblastoma with unmethylated MGMT without prior chemotherapy or RT were eligible. Patients were randomly assigned 2:1 to PPX, 50 mg/m/wk for 6 weeks, or standard TMZ, with concurrent 60.0 Gy RT. One month after completion of chemoradiation all patients received standard maintenance TMZ. The primary endpoint was progression-free survival (PFS). RESULTS: Of the 164 patients enrolled, 86 were MGMT unmethylated. Of these, 63 patients were randomized (42 to PPX/RT and 21 to TMZ/RT). Fifty-nine patients could be analyzed. The median PFS was 9 months in the PPX/RT group and 9.5 months in the TMZ/RT group (hazard ratio in the PPX/RT group, 1.10; 95% confidence interval, 0.79-2.08; P=0.75). Median overall survival was 16 versus 14.8 months for PPX/RT and TMZ/RT groups, respectively (hazard ratio, 1.44; 95% confidence interval, 0.75-2.77; P=0.27). In the PPX and TMZ groups 44% versus 22% of patients, respectively, experienced one or more grade 3 or higher toxicities during chemoradiation. CONCLUSIONS: PPX/RT did not improve PFS or overall survival. This study provides an effective trial design for screening RT sensitizers in glioblastoma.

Paclitaxel poliglumex, temozolomide, and radiation for newly diagnosed high-grade glioma: a Brown University Oncology Group Study.

OBJECTIVES: Paclitaxel poliglumex (PPX), a drug conjugate that links paclitaxel to poly-L-glutamic acid, is a potent radiation sensitizer. Prior studies in esophageal cancer have demonstrated that PPX (50 mg/m/wk) can be administered with concurrent radiation with acceptable toxicity. The primary objective of this study was to determine the safety of the combination of PPX with temozolomide and concurrent radiation for high-grade gliomas. METHODS: Eligible patients were required to have WHO grade 3 or 4 gliomas. Patients received weekly PPX (50 mg/m/wk) combined with standard daily temozolomide (75 mg/m) for 6 weeks with concomitant radiation (2.0 Gy, 5 d/wk for a total dose of 60 Gy). RESULTS: Twenty-five patients were enrolled, 17 with glioblastoma and 8 with grade 3 gliomas. Seven of 25 patients had grade 4 myelosuppression. Hematologic toxicity lasted up to 5 months suggesting a drug interaction between PPX and temozolomide. For patients with glioblastoma, the median progression-free survival was 11.5 months and the median overall survival was 18 months. CONCLUSIONS: PPX could not be safely combined with temozolomide due to grade 4 hematologic toxicity. However, the favorable progression-free and overall survival suggest that PPX may enhance radiation for glioblastoma. A randomized study of single agent PPX/radiation versus temozolomide/radiation for glioblastoma without MGMT methylation is underway.

Lapatinib/gemcitabine and lapatinib/gemcitabine/oxaliplatin: a phase I study for advanced pancreaticobiliary cancer.

OBJECTIVE: To evaluate the safety/tolerability and potential antitumor activity of lapatinib, at dose ranges of 1000 to 1500 mg/d, in combination with gemcitabine and gemcitabine/oxaliplatin (GEMOX) in patients with advanced pancreaticobiliary cancer. MATERIALS AND METHODS: Patients with advanced pancreaticobiliary cancer were assigned to 1 of 4 cohorts of lapatinib administered once daily. Toxicities, response, and survival were assessed. RESULTS: Twenty-five patients were enrolled, 18 with pancreatic cancer and 7 with biliary cancer. Lapatinib, 1500 mg/d, was successfully administered with weekly gemcitabine. Dose limiting toxicities of nausea and anorexia occurred in 2 of 5 patients receiving 1500 mg/d lapatinib with GEMOX. The median survival of all patients was 11 months and the 1-year survival was 48%. CONCLUSION: Lapatinib, 1500 mg/d, can be administered with weekly gemcitabine. The maximum tolerated dose of lapatinib is 1000 mg/d with GEMOX. A phase II study of lapatinib and gemcitabine for metastatic pancreatic cancer will be initiated.

Cetuximab with concurrent chemoradiation for esophagogastric cancer: assessment of toxicity.

PURPOSE: To determine the feasibility and toxicity of the addition of cetuximab with paclitaxel, carboplatin, and radiation for patients with esophagogastric cancer on a Phase II study. METHODS AND MATERIALS: Patients with locoregional esophageal and proximal gastric cancer without distant organ metastases were eligible. All patients received cetuximab, paclitaxel, and carboplatin weekly for 6 weeks with 50.4 Gy radiation. RESULTS: Sixty patients were enrolled, 57 with esophageal cancer and 3 with gastric cancer. Forty-eight had adenocarcinoma and 12 had squamous cell cancer. Fourteen of 60 patients (23%) had Grade 3 dermatologic toxicity consisting of a painful, pruritic acneiform rash on the face outside of the radiation field. The rates of Grades 3 and 4 esophagitis were 12% and 3%, respectively. Three patients had Grade 3/4 cetuximab hypersensitivity reactions and were not assessable for response. Forty of 57 patients (70%) had a complete clinical response after chemoradiation. CONCLUSION: Cetuximab can be safely administered with chemoradiation for esophageal cancer. Dermatologic toxicity and hypersensitivity reactions were associated with the addition of cetuximab. There was no increase in esophagitis or other radiation-enhanced toxicity.

Docetaxel, capecitabine and carboplatin in metastatic esophagogastric cancer: a phase II study.

PURPOSE: A Phase I investigation of docetaxel, carboplatin, and capecitabine at our institution demonstrated the safety and tolerability of this regimen in patients with metastatic esophagogastric cancer. The objectives of this Phase II study were to determine the response rate, toxicity, and survival for patients with metastatic esophagogastric cancer treated with this regimen. MATERIALS AND METHODS: Chemotherapy naïve patients with metastatic esophageal or gastric cancer received a regimen comprised of docetaxel 40 mg/m(2), days 1 and 8, carboplatin AUC = 2, Days 1 and 8, and capecitabine 2000 mg/m(2), Days 1-10 in 21-Day cycles. Patients were treated until disease progression or unacceptable toxicity. RESULTS: Twenty-five patients were treated with a median of 4 cycles of chemotherapy. Twelve of 25 patients (48 percent) had a Grade 3/4 toxicity. There were no Grade 4 nonhematologic toxicities, and 1 patient (4 percent) had neutropenic fever. There were 3 complete responses, and 9 partial responses, for an overall response rate of 48 percent. The median survival was 8 months (95% confidence interval, 5.5-13 months), and the 1-year survival was 36 percent. CONCLUSIONS: Weekly docetaxel and carboplatin with capecitabine was an easily administered outpatient regimen. The response rate and 1-year survival were similar to more complex regimens. Future trials may investigate the substitution of carboplatin with more active agents.

A phase I study of docetaxel, oxaliplatin, and capecitabine in patients with metastatic gastroesophageal cancer.

OBJECTIVES: Docetaxel, capecitabine, and oxaliplatin are important new agents in esophagogastric cancer. The Brown University Oncology Group initiated a phase I study to determine the maximum tolerated dose of weekly docetaxel, oxaliplatin, and capecitabine. METHODS: Patients with metastatic esophageal and gastric cancers received docetaxel and oxaliplatin on days 1 and 8 and capecitabine in divided doses, twice daily, on days 1 to 10, with each cycle repeated every 21 days. Patients were enrolled in cohorts of 3 at escalating dose levels. The docetaxel dose ranged from 30 to 35 mg/m2, the oxaliplatin dose from 40 to 50 mg/m2, and the capecitabine dose from 750 to 850 mg/m2 BID. RESULTS: Sixteen patients were enrolled over 4 dose levels. The median age was 59 years. Eight patients had esophageal cancer and 9 had gastric cancer. Grade 3/4 dose-limiting toxicities of diarrhea, nausea, fatigue, and febrile neutropenia occurred in 3 of 4 patients at dose level 3. An intermediate dose level was added (2A), reducing the capecitabine dose to 750 mg/m2. One of 6 patients had a dose-limiting toxicity at level 2A. CONCLUSIONS: Oxaliplatin 50 mg/m2 and docetaxel 30 mg/m2 day 1 and 8 with capecitabine 750 mg/m2 BID for 10 days in 21-day cycles may represent a promising, easily administered regimen for metastatic esophageal and gastric cancer. A phase II study will be initiated.

Phase I/II study of trastuzumab, paclitaxel, cisplatin and radiation for locally advanced, HER2 overexpressing, esophageal adenocarcinoma.

PURPOSE: To determine the overall survival for patients with locally advanced, HER2 overexpressing, esophageal adenocarcinoma receiving trastuzumab, paclitaxel, cisplatin, and radiation on a Phase I-II study. METHODS AND MATERIALS: Patients with adenocarcinoma of the esophagus without distant organ metastases and 2+/3+ HER2 overexpression by immunohistochemistry (IHC) were eligible. All patients received cisplatin 25 mg/m2 and paclitaxel 50 mg/m2 weekly for 6 weeks with radiation therapy (RT) 50.4 Gy. Patients received trastuzumab at dose levels of 1, 1.5, or 2 mg/kg weekly for 5 weeks after an initial bolus of 2, 3, or 4 mg/kg. RESULTS: Nineteen patients were entered: 7 (37%) had celiac adenopathy, and 7 (37%) had retroperitoneal, portal adenopathy, or scalene adenopathy. Fourteen of 19 patients (74%) had either 3+ HER2 expression by immunohistochemistry, or an increase in HER2 gene copy number by HER2 gene amplification or high polysomy by fluorescence in situ hybridization. The median survival of all patients was 24 months and the 2-year survival was 50%. CONCLUSIONS: Assessment of the effect of trastuzumab in the treatment of patients with esophageal adenocarcinoma overexpressing HER2 is limited by the small number of patients in this study. Overall survival, however, was similar to prior studies without an increase in toxicity. Evaluation of HER2 status should be performed in future trials for patients with adenocarcinoma of the esophagus that investigate therapies targeting the HER family.

Paclitaxel poliglumex (PPX-Xyotax) and concurrent radiation for esophageal and gastric cancer: a phase I study.

OBJECTIVES: To determine the maximal tolerated dose (MTD) and dose limiting toxicities of poly(l-glutamic acid)-paclitaxel (PPX) and concurrent radiation (PPX/RT) for patients with esophageal and gastric cancer. METHODS: Patients with esophageal or gastric cancer receiving chemoradiation for loco-regional, adjuvant, or palliative intent were eligible. The initial dose of PPX was 40 mg/m2/wk, for 6 weeks with 50.4 Gy radiation. Dose levels were increased in increments of 10 mg/m2/wk of PPX. RESULTS: Twenty-one patients were enrolled over 5 dose levels. Sixteen patients had esophageal cancer and 5 had gastric cancer. Twelve patients received PPX/RT as definitive loco-regional therapy, 4 patients had undergone resection and received adjuvant PPX/RT, and 5 patients had metastatic disease and received PPX/RT for palliation of dysphagia. Dose limiting toxicities of gastritis, esophagitis, neutropenia, and dehydration developed in 3 of 4 patients treated at the 80 mg/m2 dose level. Four of 12 patients (33%) with loco-regional disease had a complete clinical response. CONCLUSIONS: The maximally tolerated dose of PPX with concurrent radiotherapy is 70 mg/m2/wk for patients with esophageal and gastric cancer.

Breast enlargement in 13 men who were seropositive for human immunodeficiency virus.

Breast enlargement, a condition that was rarely reported in the era before highly active antiretroviral therapy, is emerging as a problem in the treatment of male human immunodeficiency virus (HIV)-infected patients. Evaluation of this condition must distinguish between gynecomastia (proliferation of ducts and periductal stroma), lipomastia (adipose-tissue deposition), and malignancy. We describe 13 HIV-infected men, all of whom had exposure to antiretroviral therapy, who presented with breast enlargement. Nine of these patients had gynecomastia, only 1 had lipomastia, and 3 had lymphoma (2 had non-Hodgkin lymphoma and 1 had Hodgkin disease). Gynecomastia was unilateral in all but a single case. In addition, all but 1 of our patients with gynecomastia had prolonged exposure to protease inhibitors. Six patients had potential causes of gynecomastia other than antiretroviral therapy, including liver disease (in 2 patients), mild hypogonadism (in 1), long-term marijuana use (in 2), and use of medications that have known associations with gynecomastia (in 3). Although most causes of breast enlargement in HIV-infected men are likely to be benign, malignancies other than carcinoma are of concern.