Effect of reduced follow-up care on patient satisfaction with care among patients with endometrial cancer: The ENSURE randomized controlled trial.

BACKGROUND: Evidence on the optimal follow-up schedule after endometrial cancer is lacking. The study aim was to compare satisfaction with care between women who received reduced follow-up care and women who received usual guideline-directed follow-up care for three years after surgery. METHODS: The ENSURE (ENdometrial cancer SURvivors' follow-up carE) trial was a non-inferiority randomized controlled multicenter trial in 42 hospitals in the Netherlands. The intervention arm received reduced follow-up care (4 visits/3 years), while the control group received usual follow-up care (8-11 visits/3 years). Primary outcome was overall satisfaction with care, PSQIII score, over three years follow-up, with a non-inferiority margin of 6. Mixed linear regression, intention-to-treat and per-protocol analyses (presented below) were used. RESULTS: Among 316 women included, overall satisfaction with care was not lower in the reduced follow-up (mean 82; SD = 15) compared with the usual follow-up group (mean 80; SD = 15) group (B = 1.80(-2.09;5.68)). At 6, 12 and 36 months, more women (93/94/90%) in the reduced follow-up group were satisfied with their follow-up schedule than in the usual follow-up group (79/79/82%; p < 0.001; p < 0.001; p = 0.050). CONCLUSIONS AND RELEVANCE: Women with low-risk, early-stage endometrial cancer who received reduced follow-up care were no less satisfied with their care than women receiving usual follow-up care. Compared with usual follow-up, women in the reduced follow-up group had fewer clinical visits and, at the same time, more often reported being satisfied with their follow-up schedule. Findings suggest that reduced follow-up care may be the new standard, but should be tailored to meet additional needs where indicated.

Low preoperative skeletal muscle density is predictive for negative postoperative outcomes in older women with ovarian cancer.

OBJECTIVE: To determine the predictive value of lumbar skeletal muscle mass and density for postoperative outcomes in older women with advanced stage ovarian cancer. METHODS: A multicenter, retrospective cohort study was performed in women ≥ 70 years old receiving surgery for primary, advanced stage ovarian cancer. Skeletal muscle mass and density were assessed in axial CT slices on level L3. Low skeletal muscle mass was defined as skeletal muscle index < 38.50 cm2/m2. Low skeletal muscle density was defined as one standard deviation below the mean (muscle attenuation < 22.55 Hounsfield Units). The primary outcome was any postoperative complication ≤ 30 days after surgery. Secondary outcomes included severe complications, infections, delirium, prolonged hospital stay, discharge destination, discontinuation of adjuvant chemotherapy and mortality. RESULTS: In analysis of 213 patients, preoperative low skeletal muscle density was associated with postoperative complications ≤ 30 days after surgery (Odds Ratio (OR) 2.83; 95% Confidence Interval (CI) 1.41-5.67), severe complications (OR 3.01; 95%CI 1.09-8.33), infectious complications (OR 2.79; 95%CI 1.30-5.99) and discharge to a care facility (OR 3.04; 95%CI 1.16-7.93). Preoperative low skeletal muscle mass was only associated with infectious complications (OR 2.32; 95%CI 1.09-4.92). In a multivariable model, low skeletal muscle density was of added predictive value for postoperative complications (OR 2.57; 95%CI 1.21-5.45) to the strongest existing predictor functional impairment (KATZ-ADL ≥ 2). CONCLUSION: Low skeletal muscle density, as a proxy of muscle quality, is associated with poor postoperative outcomes in older patients with advanced stage ovarian cancer. These findings can contribute to postoperative risk assessment and clinical decision making.

Conservative Treatment Seems the Best Choice in Adenocarcinoma In Situ of the Cervix Uteri.

OBJECTIVE: To study diagnostic and therapeutic strategies, outcomes, and follow-up in a large series of women with adenocarcinoma in situ (AIS) of the uterine cervix and investigate if human papillomavirus (HPV) typing among women with negative cytology reports would have helped with early AIS detection. MATERIALS AND METHODS: Records of 132 AIS cases diagnosed between 1989 and 2012 were retrieved. Clinical and pathological data were reviewed and analyzed. RESULTS: Mean age at diagnosis was 37 years. Seventy-two percent (n = 95) of all patients were asymptomatic; diagnosis was established using cytology and biopsy. Primary treatment for 124 patents was cold knife cone or loop electrosurgical excision procedure (LEEP). Positive margins were found in 18% of those women treated with CKC versus 40% in those treated with LEEP. The mean follow-up time was 62 months (range, 2-217 months; median, 46 months). Three recurrences were found after conservative treatment in 86 patients. High-risk HPV (hrHPV) positivity was detected in 115 (96%) of 120 patients, with HPV-18 being the most commonly occurring subtype (51%). CONCLUSIONS: There is a small risk of relapse after conservative therapy with cold knife cone or LEEP when resection margins are negative in women with AIS. Patients should be given the options of hysterectomy or conservative therapy with strict follow-up.

Adenocarcinoma in situ of the uterine cervix--a systematic review.

OBJECTIVE: This study aimed to review literature if therapeutic strategies in adenocarcinoma in situ of the cervix could lead to a more conservative approach. METHODS: A review of the literature was conducted using a Medline search for articles published between 1966 and 2013. RESULTS: Thirty-five studies showed that after a radical cone, 16.5% residual disease in the re-cone or uterus was found. After cone with positive margins, residual abnormalities were found in 49.3%. Thirty-seven studies showed 5% recurrence rate after conservative therapy (large loop excision transformation zone-cold knife conization. After conization with negative margins, the risk of recurrence was 3%. CONCLUSIONS: Adenocarcinoma in situ is a relatively rare premalignant but increasingly frequent lesion of the cervix. Although there is a risk of relapse (3%) with a chance of malignancy (<1%), this risk is so small that conservative treatment with negative margins by large loop excision transformation zone or cold knife conization is justified and justifiable not only for women to have children.

HPV-type has no impact on survival of patients with adenocarcinoma of the uterine cervix.

OBJECTIVE: To review and characterise by clinical evaluation, immunohistochemistry and HPV typing a group of adenocarcinomas initially diagnosed with primary localisation in the cervix. Furthermore, to assess the prevalence and prognostic significance of HPV genotypes in a large series of HPV positive cervical adenocarcinomas (AC). METHODS: One hundred and seventy-one cases of adenocarcinomas (AC) with a primary localisation in the cervix and diagnosed between 1989 and 2008 in the region of Rotterdam, the Netherlands were retrieved. Slides and blocks were reviewed and immunohistochemically stained for CEA and vimentin. HPV testing for high-risk HPV (hrHPV) by PCR (GP5+/6+) and genotyping by reversed line blot were performed. RESULTS: In 113 of 171 patients HPV evaluation was possible. 101 were HPV-positive (89%) and 11 were HPV-negative (11%). The 5-year disease free survival was 80% in the HPV-positive group versus 74% in the HPV-negative group (ns). The distribution of HPV types was type 18 in 55 patients (54%), type 16 in 37 (37%), type 45 in 7 (7%), types 53 and 39 were found in 2 respective patients. 5-year overall-survival in patients with HPV-18 was not significantly worse than in patients with HPV-16 (81 versus 87%). Patients with HPV-45 had a worse 5-year survival, 57%. CONCLUSIONS: AC is hrHPV related in most cases (89%) and HPV-18 is the most frequent type (54%). With the exception of HPV-45, HPV-positivity or type in endocervical AC has no significant influence on survival.

Primary surgery versus primary radiotherapy with or without chemotherapy for early adenocarcinoma of the uterine cervix.

BACKGROUND: For early squamous cell carcinoma of the uterine cervix, the outcome is similar after either primary surgery or primary radiotherapy. There are reports that this is not the case for early adenocarcinoma (AC) of the uterine cervix: some studies have reported that the outcome is better after primary surgery. There are no systematic reviews about surgery versus chemoradiation in the treatment of cervical cancer. This is an updated version of the original Cochrane review published in Cochrane Database of Systematic Reviews 2006, Issue 4. Art. No.: CD006248. DOI: 10.1002/14651858.CD006248. OBJECTIVES: The objectives of this review were to compare the effectiveness and safety of primary surgery for early stage AC of the uterine cervix with primary radiotherapy or chemoradiation. SEARCH METHODS: We searched Cochrane Central Register of Controlled Trials (CENTRAL) Issue 3, 2009, MEDLINE (1950 to July week 5, 2009), EMBASE (1980 to week 32, 2009) and we also searched the related articles feature of PubMed and the Web of Science. We also checked the reference lists of articles. For this update, the searches were re-run in June 2012: MEDLINE 2009 to June week 2, 2012, EMBASE 2009 to 2012 week 24, CENTRAL Issue 6, 2012, Cochrane Gynaecological Specialised Register June 2012. SELECTION CRITERIA: Studies of treatment of patients with early AC of the uterine cervix were included. Treatment included surgery, surgery followed by radiotherapy, radiotherapy and chemoradiation. DATA COLLECTION AND ANALYSIS: Forty-three studies were selected by the search strategy and 30 studies were excluded. Twelve studies were considered for inclusion. Except for one randomised controlled trial (RCT), all other studies were retrospective cohort studies with variable methodological quality and had limitations of a retrospective study. Comparing the results from these retrospective studies was not possible due to diverging treatment strategies. MAIN RESULTS: Analysis of a subgroup of one RCT showed that surgery for early cervical AC was better than radiotherapy. However, the majority of operated patients required adjuvant radiotherapy, which is associated with greater morbidity. Furthermore, the radiotherapy in this study was not optimal, and surgery was not compared to chemoradiation, which is currently recommended in most centres. Finally, modern imaging techniques (i.e. magnetic resonance imaging (MRI) and positive emission tomography - computed tomography (PET-CT) scanning) allow better selection of patients and node-negative patients can now be more easily identified for surgery, thereby reducing the risk of 'double trouble' caused by surgery and adjuvant radiotherapy.   AUTHORS' CONCLUSIONS: We recommend surgery for early-stage AC of the uterine cervix in carefully staged patients. Primary chemoradiation remains a second best alternative for patients unfit for surgery; chemoradiation is probably first choice in patients with (MRI or PET-CT-suspected) positive lymph nodes. Since the last version of this review no new studies were found.

Loss of skeletal muscle density during neoadjuvant chemotherapy in older women with advanced stage ovarian cancer is associated with postoperative complications.

OBJECTIVE: To assess the association between loss of lumbar skeletal muscle mass and density during neoadjuvant chemotherapy (NACT) and postoperative complications after interval cytoreductive surgery (CRS) in older patients with ovarian cancer. MATERIALS AND METHODS: This multicenter, retrospective cohort study included patients aged 70 years and older with primary advanced stage ovarian cancer (International Federation of Gynecology and Obstetrics stage III-IV), treated with NACT and interval CRS. Skeletal muscle mass and density were retrospectively assessed using Skeletal Muscle Index (SMI) and Muscle Attenuation (MA) on routinely made Computed Tomography scans before and after NACT. Loss of skeletal muscle mass or density was defined as >2% decrease per 100 days in SMI or MA during NACT. RESULTS: In total, 111 patients were included. Loss of skeletal muscle density during NACT was associated with developing any postoperative complication ≤30 days after interval CRS both in univariable (Odds Ratio (OR) 3.69; 95% Confidence Interval (CI) 1.57-8.68) and in multivariable analysis adjusted for functional impairment and WHO performance status (OR 3.62; 95%CI 1.27-10.25). Loss of skeletal muscle density was also associated with infectious complications (OR 3.67; 95%CI 1.42-9.52) and unintended discontinuation of adjuvant chemotherapy (OR 5.07; 95%CI 1.41-18.19). Unlike loss of skeletal muscle density, loss of skeletal muscle mass showed no association with postoperative outcomes. CONCLUSION: In older patients with ovarian cancer, loss of skeletal muscle density during NACT is associated with worse postoperative outcomes. These results could add to perioperative risk assessment, guiding the decision to undergo surgery or the need for perioperative interventions.

High-risk human papillomavirus seems not involved in DES-related and of limited importance in nonDES related clear-cell carcinoma of the cervix.

OBJECTIVE: Over 90% of all cervical adenocarcinoma are caused by a transforming infection with a high-risk type human papillomavirus (hrHPV). Previous studies demonstrated that the association between hrHPV positivity and cervical clear-cell adenocarcinoma (CCAC) varies between 0% and 100%. As approximately 60% of all CCAC are associated with intra-uterine diethylstilbestrol (DES) exposure, we determined in a cohort of both DES-exposed and DES-unexposed women the prevalence of hrHPV infections, and the potential etiological role of hrHPV by additional analysis of p16INK4a and p53 expression. METHODS: Representative slides of 28 women diagnosed with CCAC were tested for hrHPV by two PCR methods (the clinically validated GP5+/6+ PCR and the very sensitive SPF(10)PCR/LiPA(25)). Fifteen women were DES-exposed, 10 unexposed and of 3 women DES-exposure was unknown. Twenty-one cases with sufficient material were immuno-histochemically stained for p16INK4a and p53. RESULTS: Seven tumors, of which four DES-exposed and two unexposed tested positive for hrHPV with GP5+/6+ PCR. Thirteen tumors, of which five DES-exposed and seven unexposed, tested positive with SPF(10)PCR/LiPA(25). In one women with unknown exposure, a CCAC tested positive in both assays. Only three cases, none in DES-exposed women, and all positive with both hrHPV assays, revealed diffuse p16INK4a immuno-staining and weak p53 staining as well, supporting indisputable hrHPV involvement. CONCLUSIONS: Although the prevalence of hrHPV was high, only two DES-unrelated CCAC (25%) and one tumor in a woman with unknown exposure could be attributed to hrHPV.

Conservative therapy in microinvasive adenocarcinoma of the uterine cervix is justified: an analysis of 59 cases and a review of the literature.

OBJECTIVE: This study aimed to evaluate the treatment and follow-up in a large series of women with early cervical adenocarcinoma (AC), stages IA1 and IA2, and to perform an extensive review of the literature in an effort to ascertain whether conservative therapy is justified. METHODS: Records of 59 cases of microinvasive AC diagnosed between 1987 and 2006 in the Rotterdam district, the Netherlands, were retrieved. Clinical and pathological data were reviewed and analyzed. A mesh review of all relevant literature concerning stage IA1 and IA2 was performed. RESULTS: Of all patients, 33 had stage IA1 and 26 stage IA2 cervical AC. Also, 42 patients were treated conservatively (ie, conization or simple hysterectomy) and 17 patients were treated radically (ie, radical hysterectomy/trachelectomy with lymph node dissection). Recurrence occurred in 1 patient (1.7%) with stage IA1 disease (grade 1 adenocarcinoma, depth 1.4 mm, and width 3.8 mm, with lymph vascular space involvement [LVSI]) treated by vaginal hysterectomy. The mean follow-up was 79.9 months. From the literature, pooling all data from patients with stage IA1 and IA2 AC, the risk of recurrent disease was 1.5% after conservative therapy and 2.0% after radical therapy. CONCLUSIONS: Extensive treatment such as radical hysterectomy with pelvic lymph node dissection or trachelectomy does not prevent recurrent disease. Patients with microinvasive AC should be treated identically to patients with SCC. In stage IA1 and IA2 AC, we recommend conservative therapy (by conization). In cases with LVSI, an additional lymphadenectomy is advised. For patients with stage IA2 AC with LVSI, a trachelectomy/radical hysterectomy with lymph node dissection should be considered.

Primary surgery versus primary radiation therapy with or without chemotherapy for early adenocarcinoma of the uterine cervix.

BACKGROUND: For early squamous cell carcinoma of the uterine cervix, the outcome is similar after either primary surgery or primary radiotherapy. There are reports that this is not the case for early adenocarcinoma (AC) of the uterine cervix: some studies have reported that the outcome is better after primary surgery. There are no systematic reviews about surgery versus chemoradiation in the treatment of cervical cancer. OBJECTIVES: The objectives of this review were to compare the effectiveness and safety of primary surgery for early stage AC of the uterine cervix with primary radiotherapy or chemoradiation. SEARCH STRATEGY: We searched Cochrane Central Register of Controlled Trials (CENTRAL) Issue 3, 2009, MEDLINE (1950 to July week 5, 2009), EMBASE (1980 to week 32, 2009) and we also searched the related articles feature of PubMed and the Web of Science. We also checked the reference lists of articles. SELECTION CRITERIA: Studies of treatment of patients with early AC of the uterine cervix were included. Treatment included surgery, surgery followed by radiotherapy, radiotherapy and chemoradiation. DATA COLLECTION AND ANALYSIS: Forty-three studies were selected by the search strategy and thirty studies were excluded. Twelve studies were considered for inclusion. Except for one randomised controlled trial (RCT), all other studies were retrospective cohort studies with variable methodological quality and had limitations of a retrospective study. Comparing the results from these retrospective studies was not possible due to diverging treatment strategies. MAIN RESULTS: Analysis of a subgroup of one RCT showed that surgery for early cervical AC was better than RT. However, the majority of operated patients required adjuvant radiotherapy, which is associated with greater morbidity. Furthermore, the radiotherapy in this study was not optimal, and surgery was not compared to chemoradiation, which is currently recommended in most centres. Finally, modern imaging techniques, i.e. MR-imaging and PET-CT-scanning, allow better selection of patients and node negative patients can now be more easily identified for surgery, there by reducing the risk of 'double trouble' caused by surgery and adjuvant radiotherapy. AUTHORS' CONCLUSIONS: We recommend surgery for early stage AC of the uterine cervix in carefully staged patients. Primary chemoradiation remains a second best alternative for patients unfit for surgery; chemoradiation is probably first choice in patients with (MRI or PET-CT-suspected) positive lymph nodes.

Validation and Implementation of BRCA1/2 Variant Screening in Ovarian Tumor Tissue.

BRCA1/2 variant analysis in tumor tissue could streamline the referral of patients with epithelial ovarian, fallopian tube, or primary peritoneal cancer to genetic counselors and select patients who benefit most from targeted treatment. We investigated the sensitivity of BRCA1/2 variant analysis in formalin-fixed, paraffin-embedded tumor tissue using a combination of next-generation sequencing and copy number variant multiplex ligation-dependent probe amplification. After optimization using a training cohort of known BRCA1/2 mutation carriers, validation was performed in a prospective cohort in which screening of BRCA1/2 tumor DNA and leukocyte germline DNA was performed in parallel. BRCA1 promoter hypermethylation and pedigree analysis were also performed. In the training cohort, 45 of 46 germline BRCA1/2 variants were detected (sensitivity, 98%). In the prospective cohort (n = 62), all six germline variants were identified (sensitivity, 100%), together with five somatic BRCA1/2 variants and eight cases with BRCA1 promoter hypermethylation. In four BRCA1/2 variant-negative patients, surveillance or prophylactic management options were offered on the basis of positive family histories. We conclude that BRCA1/2 formalin-fixed, paraffin-embedded tumor tissue analysis reliably detects BRCA1/2 variants. When taking family history of BRCA1/2 variant-negative patients into account, tumor BRCA1/2 variant screening allows more efficient selection of epithelial ovarian cancer patients for genetic counseling and simultaneously selects patients who benefit most from targeted treatment.

Use of genetic testing and prophylactic mastectomy and oophorectomy in women with breast or ovarian cancer from families with a BRCA1 or BRCA2 mutation.

PURPOSE: To analyze the use of genetic testing, prophylactic mastectomy, and oophorectomy among women with breast and/or ovarian cancer from families with a BRCA1 or BRCA2 mutation. PATIENTS AND METHODS: We examined prospectively the use of BRCA1/BRCA2 testing in all women with a primary breast or ovarian cancer from a consecutive series of 112 high-risk families in which a BRCA1/BRCA2 mutation eventually was identified. The rate of prophylactic bilateral and contralateral mastectomy and prophylactic oophorectomy was analyzed in the women who carried a BRCA1/BRCA2 mutation and who had no metastatic disease at the time of the genetic test disclosure. We examined predictors for genetic test uptake and prophylactic surgery using univariate and multivariate analysis. RESULTS: Overall, 192 of 220 women (87%) with primary tumors underwent genetic testing. Eleven of these 192 tested women (6%) appeared not to carry the family-specific BRCA1/BRCA2 mutation. Genetic testing occurred significantly more frequently at ages younger than 50 years (P =.04) and in persons with multiple primary tumors (P =.02). Among eligible women, 35 of 101 (35%) requested bilateral or contralateral mastectomy, and 47 of 95 (49%) requested oophorectomy. Women aged younger than 50 years and women who developed their first tumor after the initial identification of a BRCA1/BRCA2 mutation in the family were significantly (both P =.01) more likely to opt for prophylactic bilateral or contralateral mastectomy. CONCLUSION: In a clinical setting, we show a high demand for BRCA1/BRCA2 testing and for prophylactic surgery by women with breast and/or ovarian cancer from high-risk families.

Prognosis of adenocarcinoma of the uterine cervix: p53 expression correlates with higher incidence of mortality.

We investigated the significance of prognostic markers-estrogen receptor, progesterone receptor, p53, MIB-1 and bcl-2 - in adenocarcinoma of the uterine cervix. In 101 patients with primary cervical adenocarcinoma, treated from 1989 to 2000, we evaluated clinical parameters in relation to these prognostic markers. Mean age of patients was 45 years. Seventy eight percent of the patients were in FIGO stage I, 16% stage II, 7% stage III and IV. estrogen receptor, progesterone receptor, p53 and bcl-2 immunoreactivity was scored as 0 (up to 5% positive cells), 1+ (5-25% of cells positive), 2+ (26-50% of cells positive), 3+ (51-75% of cells positive) or 4+ (>76% of cells positive). MIB-1 was scored in 10 categories: 0-10, 11-20, 21-30, 31-40, 41-50, 51-60, 61-70, 71-80, 81-90, 91-100. The overall survival rate was 67%. Survival was not influenced by estrogen receptor, progesterone receptor, MIB-1, or bcl-2 strongly positive staining. Only p53 showed significant influence on survival, even when adjusted for stage or tumor grade. In conclusion, it does not seems useful to determine estrogen receptor, progesterone receptor, MIB-1 or bcl-2 in cervical adenocarcinomas as an indication of prognosis: survival is not influenced by presence or absence. However, if p53 staining is strongly positive survival is significantly worse than in tumors scored as negative or weak positive.