Bryony Simcock

Quality of life after total laparoscopic hysterectomy versus total abdominal hysterectomy for stage I endometrial cancer (LACE): a randomised trial

BACKGROUND This two-stage randomised controlled trial, comparing total laparoscopic hysterectomy (TLH) with total abdominal hysterectomy (TAH) for stage I endometrial cancer (LACE), began in 2005. The primary objective of stage 1 was to assess whether TLH results in equivalent or improved quality of life (QoL) up to 6 months after surgery compared with TAH. The primary objective of stage 2 was to test the hypothesis that disease-free survival at 4.5 years is equivalent for TLH and TAH. Here, we present the results of stage 1. METHODS Between Oct 7, 2005, and April 16, 2008, 361 participants were enrolled in the QoL substudy at 19 centres across Australia, New Zealand, and Hong Kong; 332 completed the QoL analysis. Randomisation was done centrally and independently from other study procedures via a computer-generated, web-based system (providing concealment of the next assigned treatment), using stratified permuted blocks of three and six patients. Patients with histologically confirmed stage I endometrioid adenocarcinoma and Eastern Cooperative Oncology Group performance status less than 2 were randomly assigned to TLH (n=190) or TAH (n=142), stratified by histological grade and study centre. Patients and study personnel were not masked to treatment assignment. QoL was measured at baseline, 1 and 4 weeks (early), and 3 and 6 months (late) after surgery, using the Functional Assessment of Cancer Therapy-General (FACT-G) questionnaire. The primary endpoint was the difference between groups in QoL change from baseline at early and late timepoints (a 5% difference was considered clinically significant). Analysis was done according to the intention-to-treat principle. Patients for both stages of the trial have now been recruited and are being followed up for disease-specific outcomes. The LACE trial is registered with ClinicalTrials.gov, number NCT00096408. FINDINGS Eight of 332 patients (2.4%) had treatment conversion-seven from TLH to TAH and one from TAH to TLH (patient preference). In the early phase of recovery, patients who had TLH reported significantly greater improvement in QoL from baseline compared with those who had TAH, in all subscales apart from emotional and social wellbeing. Improvements in QoL up to 6 months after surgery continued to favour TLH, except in the emotional and social wellbeing measures of FACT and the visual analogue scale of the EuroQoL five dimensions (EuroQoL-VAS). Operating time was significantly longer in the TLH group (138 min [SD 43]) than in the TAH group (109 min [34]; p=0.001). Although the proportion of intraoperative adverse events was similar between groups (TAH eight of 142 [5.6%] vs TLH 14 of 190 [7.4%]; p=0.53); postoperatively, twice as many patients in the TAH group experienced adverse events of grade 3 or higher (33 of 142 [23.2%] vs 22 of 190 [11.6%] in the TLH group; p=0.004). Postoperative serious adverse events occurred more in the TAH group (27 of 142 [19.0%]) than in the TLH group (16 of 190 [7.9%]; p=0.002). INTERPRETATION QoL improvements from baseline during early and later phases of recovery, and the adverse event profile, favour TLH compared with TAH for treatment of stage I endometrial cancer. FUNDING Cancer Council Queensland, Cancer Council New South Wales, Cancer Council Victoria, Cancer Council Western Australia; NHMRC project grant 456110; Cancer Australia project grant 631523; The Women and Infants Research Foundation, Western Australia; Royal Brisbane and Womens Hospital Foundation; Wesley Research Institute; Gallipoli Research Foundation; Gynetech; TYCO Healthcare, Australia; Johnson and Johnson Medical, Australia; Hunter New England Centre for Gynaecological Cancer; Genesis Oncology Trust; and Smart Health Research Grant QLD Health.

Improved surgical safety after laparoscopic compared to open surgery for apparent early stage endometrial cancer: Results from a randomised controlled trial

AIM To compare Total Laparoscopic Hysterectomy (TLH) and Total Abdominal Hysterectomy (TAH) with regard to surgical safety. METHODS Between October 2005 and June 2010, 760 patients with apparent early stage endometrial cancer were enroled in a multicentre, randomised clinical trial (LACE) comparing outcomes following TLH or TAH. The main study end points for this analysis were surgical adverse events (AE), hospital length of stay, conversion from laparoscopy to laparotomy, including 753 patients who completed at least 6 weeks of follow-up. Postoperative AEs were graded according to Common Toxicity Criteria (V3), and those immediately life-threatening, requiring inpatient hospitalisation or prolonged hospitalisation, or resulting in persistent or significant disability/incapacity were regarded as serious AEs. RESULTS The incidence of intra-operative AEs was comparable in either group. The incidence of post-operative AE CTC grade 3+ (18.6% in TAH, 12.9% in TLH, p 0.03) and serious AE (14.3% in TAH, 8.2% in TLH, p 0.007) was significantly higher in the TAH group compared to the TLH group. Mean operating time was 132 and 107 min, and median length of hospital stay was 2 and 5 days in the TLH and TAH group, respectively (p<0.0001). The decline of haemoglobin from baseline to day 1 postoperatively was 2g/L less in the TLH group (p 0.006). CONCLUSIONS Compared to TAH, TLH is associated with a significantly decreased risk of major surgical AEs. A laparoscopic surgical approach to early stage endometrial cancer is safe.

Is the treatment of CIN 2 always necessary in women under 25 years old

OBJECTIVE The purpose of this study was to review the outcome of conservatively managed cervical intraepithelial neoplasia (CIN) 2 in women <25 years old. STUDY DESIGN This was a retrospective review that included women who were <25 years old with biopsy proven CIN2 between 2005 and 2009. Analysis was performed that compared women who had immediate treatment with women whose treatment was deferred >4 months. The primary outcome measure was spontaneous regression of CIN2. Secondary outcomes were treatment rates and loss to follow-up evaluation. RESULTS Of the 452 women who were identified, 256 women (57%) received immediate treatment; 157 women (35%) met the definition for conservative management, and 39 women (9%) had unknown subsequent management. Of the 157 women who were managed conservatively, 98 women (62%) showed spontaneous regression, with a median of 8 months observation. No conservatively managed women progressed to cancer. CONCLUSION Based on the 62% regression rate in this study, routine treatment may not be necessary for all women with CIN2 who are <25 years old.

Effect of total laparoscopic hysterectomy vs total abdominal hysterectomy on disease-free survival among women with stage I endometrial cancer. A randomized clinical trial

Importance Standard treatment for endometrial cancer involves removal of the uterus, tubes, ovaries, and lymph nodes. Few randomized trials have compared disease-free survival outcomes for surgical approaches. Objective To investigate whether total laparoscopic hysterectomy (TLH) is equivalent to total abdominal hysterectomy (TAH) in women with treatment-naive endometrial cancer. Design, Setting, and Participants The Laparoscopic Approach to Cancer of the Endometrium (LACE) trial was a multinational, randomized equivalence trial conducted between October 7, 2005, and June 30, 2010, in which 27 surgeons from 20 tertiary gynecological cancer centers in Australia, New Zealand, and Hong Kong randomized 760 women with stage I endometrioid endometrial cancer to either TLH or TAH. Follow-up ended on March 3, 2016. Interventions Patients were randomly assigned to undergo TAH (n = 353) or TLH (n = 407). Main Outcomes and Measures The primary outcome was disease-free survival, which was measured as the interval between surgery and the date of first recurrence, including disease progression or the development of a new primary cancer or death assessed at 4.5 years after randomization. The prespecified equivalence margin was 7% or less. Secondary outcomes included recurrence of endometrial cancer and overall survival. Results Patients were followed up for a median of 4.5 years. Of 760 patients who were randomized (mean age, 63 years), 679 (89%) completed the trial. At 4.5 years of follow-up, disease-free survival was 81.3% in the TAH group and 81.6% in the TLH group. The disease-free survival rate difference was 0.3% (favoring TLH; 95% CI, −5.5% to 6.1%; P = .007), meeting criteria for equivalence. There was no statistically significant between-group difference in recurrence of endometrial cancer (28/353 in TAH group [7.9%] vs 33/407 in TLH group [8.1%]; risk difference, 0.2% [95% CI, −3.7% to 4.0%]; P = .93) or in overall survival (24/353 in TAH group [6.8%] vs 30/407 in TLH group [7.4%]; risk difference, 0.6% [95% CI, −3.0% to 4.2%]; P = .76). Conclusions and Relevance Among women with stage I endometrial cancer, the use of total abdominal hysterectomy compared with total laparoscopic hysterectomy resulted in equivalent disease-free survival at 4.5 years and no difference in overall survival. These findings support the use of laparoscopic hysterectomy for women with stage I endometrial cancer. Trial Registration clinicaltrials.gov Identifier: NCT00096408; Australian New Zealand Clinical Trials Registry: CTRN12606000261516

Risk factors to predict the incidence of surgical adverse events following open or laparoscopic surgery for apparent early stage endometrial cancer: Results from a randomised controlled trial☆

AIMS To identify risk factors for major adverse events (AEs) and to develop a nomogram to predict the probability of such AEs in patients who have surgery for apparent early stage endometrial cancer. METHODS We used data from 753 patients who were randomised to either total laparoscopic hysterectomy or total abdominal hysterectomy in the LACE trial. Serious adverse events that prolonged hospital stay or postoperative adverse events (using common terminology criteria 3+, CTCAE V3) were considered major AEs. We analysed pre-surgical characteristics that were associated with the risk of developing major AEs by multivariate logistic regression. We identified a parsimonious model by backward stepwise logistic regression. The six most significant or clinically important variables were included in the nomogram to predict the risk of major AEs within 6weeks of surgery and the nomogram was internally validated. RESULTS Overall, 132 (17.5%) patients had at least one major AE. An open surgical approach (laparotomy), higher Charlsons medical co-morbidities score, moderately differentiated tumours on curettings, higher baseline Eastern Cooperative Oncology Group (ECOG) score, higher body mass index and low haemoglobin levels were associated with AE and were used in the nomogram. The bootstrap corrected concordance index of the nomogram was 0.63 and it showed good calibration. CONCLUSIONS Six pre-surgical factors independently predicted the risk of major AEs. This research might form the basis to develop risk reduction strategies to minimise the risk of AEs among patients undergoing surgery for apparent early stage endometrial cancer.

Recurrence of high-grade cervical abnormalities following conservative management of cervical intraepithelial neoplasia grade 2

OBJECTIVE Conservative management of cervical intraepithelial neoplasia (CIN) grade 2 in women younger than 25 years may reduce overtreatment. However, long-term efficacy remains uncertain. This retrospective cohort study aimed to determine the rate of recurrence of high-grade abnormalities among young women with a history of CIN 2 that spontaneously regressed within 2 years and compare this with the rate of high-grade abnormality in similar women with an initial diagnosis of CIN 1. STUDY DESIGN We identified all women aged younger than 25 years who were diagnosed with CIN 1 or CIN 2 between January 2005 and August 2009 within 2 colposcopy units. Follow-up data from the National Cervical Screening Programme were obtained to identify those women who developed recurrent high-grade lesions before October 2012. Comparisons were made using Cox proportional hazards regression. RESULTS A total of 683 women were included: 106 with CIN 2 that spontaneously regressed, 299 with treated CIN 2, and 278 with conservatively managed CIN 1. Median follow-up was 4 years. There was no significant difference in the risk of development of high-grade abnormalities after 2 years between the spontaneously regressing CIN 2 and CIN 1 groups (P = .83). Women with treated CIN 2 had a significantly lower risk of recurrence than women with untreated CIN 2 (P = .01). CONCLUSION CIN 2 that has spontaneously regressed appears to behave as a low-grade lesion. This study contributes to the growing body of evidence that careful observation of CIN 2 is an efficacious and appropriate initial management option for women aged younger than 25 years at diagnosis.

The role of positron emission tomography/computed tomography in planning radiotherapy in endometrial cancer.

Objective The optimal method of assessing disease distribution in endometrial cancer is widely debated. Knowledge of disease distribution assists in planning adjuvant radiotherapy; in this study we used positron emission tomography/computed tomography (PET/CT) to assess disease distribution before radiotherapy. Methods Seventy-three consecutive patients referred to the Peter MacCallum Cancer Centre for adjuvant radiotherapy for endometrial cancer, with either high-risk disease after a hysterectomy or recurrent disease, had a PET/CT before treatment. The findings on PET/CT and clinical course were recorded. Results PET/CT found additional disease in 35% of postoperative patients, changing planned treatment in 31%. In the group with known recurrence, additional disease was found in 72%, changing management in 36%. Conclusions PET/CT is a valuable tool for planning radiotherapy in endometrial cancer.

Evidence for lymphatic pathogenesis of endosalpingiosis

Sir, There is recent speculation and early evidence to suggest that acquired endosalpingiosis is at the benign end of a spectrum of müllerian disorders (müllerianoses) of serous differentiation that includes benign and proliferating (borderline) ovarian serous neoplasms, their ‘primary peritoneal’ counterparts and, perhaps most intriguing of all, so-called noninvasive and invasive peritoneal implants (long attributed to accompanying ovarian neoplasms), and all derived from shed tubal epithelium which implants on the visceral and parietal serosal surfaces of the female pelvis and abdomen. No mention is made of lymphatic spread but this must occur. A recently encountered case of florid chronic salpingitis, pseudocarcinomatous epithelial proliferation with lymphatic spread to the adjacent ovary and the presence of a proliferating (borderline) surface serous papillary tumour in the same ovary, supports this additional possible mechanism for development of acquired endosalpingiosis. A 33-year-old otherwise asymptomatic woman presented with secondary infertility. Pelvic ultrasound revealed a complex left adnexal mass which, at laparotomy, proved to be a thickened abnormal left fallopian tube attached by inflammatory adhesions to a multicystic ovarian mass with surface excrescences. Fine peritoneal adhesions and thickwalled cysts were also present in the pouch of Douglas and, to a lesser extent, around the right adnexa, which appeared otherwise normal. Due to the patient’s wish to retain

Observational Management of CIN 2 in Young Women: A Prospective Multicenter Trial.

Objectives We present the rationale and methods for PRINCess—a multicenter prospective trial—which aims to determine outcome and predictors of regression in a large cohort of women younger than 25 years with cervical intraepithelial neoplasia grade 2 (CIN 2) undergoing observational management. Materials and Methods Six hundred women younger than 25 years with newly diagnosed biopsy-proven CIN 2 are being recruited to observational management (i.e., repeat colposcopy, cytology, and cervical biopsy every 6 months for 2 years). Five hundred fifty-two women from throughout New Zealand and 1 site in Australia have been recruited so far. Measures include histology, cytology, human papillomavirus genotyping, and immunohistochemical staining. Women who develop CIN 3 will be treated with large loop excision of the transformation zone. The primary outcomes are rates of clinical regression of CIN 2 (i.e., 2 consecutive colposcopy follow-ups showing CIN 1 or normal), loss to follow-up, and progression to invasion. Conclusions The optimal treatment for young women with a diagnosis of CIN 2 is controversial. Although many undergo surgical treatment, observational management is increasingly recommended. However, there is little evidence from large clinical trials of the safety and practicality of observational management of young women with CIN 2. When completed, we will have adequate evidence by which to counsel women regarding their likely outcomes and to offer advice on clinical follow-up protocols.

Subtypes of stage IV ovarian cancer; response to treatment and patterns of disease recurrence

BACKGROUND To compare three different patterns of stage IV epithelial ovarian cancer; pleural effusion, parenchymal metastases and extra-abdominal lymph node metastases with treatment response and pattern of disease recurrence, and correlate treatment modality with outcome. METHODS Retrospective analysis of FIGO stage IV epithelial ovarian cancer diagnosed between 2008 and 2012 in three gynaecologic oncology centres in New Zealand. RESULTS 124 patients were analysed, 58 had pleural effusions, 38 parenchymal metastases, and 28 extra-abdominal lymph nodes. There was no significant difference in overall survival between these three groups. The most common site of first or any recurrence in all three groups was the abdomen with only a small number of recurrences arising in extra-abdominal sites. When looking at treatment modality, 13% had primary debulking surgery, 47% had neoadjuvant chemotherapy with interval debulking surgery, and 40% never had surgery. Overall survival was highest in patients with no residual abdominal disease after surgery. CONCLUSION The site of extra-abdominal disease did not alter prognosis or pattern of disease recurrence in stage IV epithelial ovarian cancer, with most recurrences in the abdomen suggesting controlling abdominal disease with surgery may be important in all stage IV disease.