Sinecatechins ointment as a potential novel treatment for usual type vulval intraepithelial neoplasia: a single-centre double-blind randomised control study.

OBJECTIVE: To compare the safety and efficacy of 10% sinecatechins (Veregen® ) ointment against placebo in the treatment of usual type vulvar intraepithelial neoplasia (uVIN). DESIGN: A Phase II double-blind randomised control trial. SETTING: A tertiary gynaecological oncology referral centre. POPULATION: All women diagnosed with primary and recurrent uVIN. METHODS: Eligible patients were randomised 1:1 to receive either sinecatechins or placebo ointment (applied three times daily for 16 weeks) and were followed up at 2, 4, 8, 16, 32 and 52 weeks. MAIN OUTCOME MEASURES: The primary outcome measure, recorded at 16 and 32 weeks, was histological response (HR). Secondary outcome measures included clinical (CR) response, toxicity, quality of life and pain scores. RESULTS: There was no observed difference in HR between the two arms. However, of the 26 patients who were randomised, all 13 patients who received sinecatechins showed either complete (n = 5) or partial (n = 8) CR, when best CR was evaluated. In placebo group, three patients had complete CR, two had partial CR, six had stable disease and two were lost to follow up. Patients in the sinecatechins group showed a statistically significant improvement in best observed CR as compared with the placebo group (P = 0.002). There was no difference in toxicity reported in either group. CONCLUSION: Although we did not observe a difference in HR between the two treatment arms, we found that 10% sinecatechins application is safe and shows promise in inducing clinical resolution of uVIN lesions and symptom improvement, thus warranting further investigation in a larger multicentre study. TWEETABLE ABSTRACT: A randomised control study indicating that sinecatechins ointment may be a novel treatment for uVIN.

Current insights into the aetiology, pathobiology, and management of local disease recurrence in squamous cell carcinoma of the vulva.

Squamous cell carcinoma of the vulva is predominantly a disease of the elderly, where the mainstay of treatment is radical surgery. Local vulval recurrence (LVR) is a significant problem for these patients, and the rates of recurrence have not improved over the last three decades. Disappointingly, we still lack an understanding of how LVRs develop, and the best approach to prevent and manage the condition. This review discusses recent insights into the key prognostic factors that influence the risk of recurrence, focusing on the role of tumour-adjacent non-neoplastic epithelial disorders, which are thought to play a causative role. TWEETABLE ABSTRACT: A review that discusses the key prognostic factors that influence local recurrence in vulval cancer.

Adjacent Lichen Sclerosis predicts local recurrence and second field tumour in women with vulvar squamous cell carcinoma.

OBJECTIVE: In this study, we investigated if the presence of histologically abnormal epithelium adjacent to the primary tumour influenced the frequency, timing, and topography of local vulvar recurrences (LVR) following treatment for squamous cell carcinoma of the vulva (VSCC). METHODS: The study population comprised a cohort of 201 consecutive cases with incident VSCC. LVR were categorised as local relapses (LR) if they occurred <2cm from the tumour margins, and as second field tumours (SFT) when ≥2cm from these margins. Univariable and multivariable competing risk modelling was performed to identify the prognostic factors associated with local disease recurrence. RESULTS: The characterization of the epithelium adjacent to the invasive component was possible for 199 (99.0%) patients. Of these, 171 (85.9%) were found to have intraepithelial abnormalities found adjacent to the surgical specimen. Multivariable analyses revealed that, following adjustment, Lichen Sclerosis (LS) was associated with an increase in the incidence of LVR, LR and SFT (SHRs: 3.4, 2.7 and 4.4, respectively). Although the incidence of LR and SFT in women with LS associated VSCC was similar, the peak incidence of SFT occurred more than two years before that of LR. CONCLUSIONS: Women with VSCC arising in a field of LS may continue to have an increased risk of developing LR and SFT for many years after resection of their primary tumour. Our study suggests that these women should be followed up more regularly so that LVR can be detected earlier; unless a more robust surveillance programme or chemopreventative treatments become available.

The role of regional anaesthesia in the surgical management of vulval malignancy.

Abstract Surgical excision is the management of choice in vulval cancer however, the patient population are typically elderly and comorbid, for whom general anaesthesia (GA) carries considerable risk. The outcome of 107 procedures were reviewed in order investigate the postoperative complication rates associated with general and regional anaesthesia for the surgical management of vulval cancer. GA was used in 78 (72.9%) cases; 27 (22.9%) had a regional anaesthetic (spinal/epidural/ileoinguinal) and two women had a GA following a failed spinal anaesthetic. Women having a regional anaesthetic were significantly older (p = 0.0198), had a higher ACE (p = 0.0001) and ASA score (p < 0.0001) than those having a GA. There was an association between GA and grade II+ complications, compared with regional techniques (odds ratio, OR 2.72) but this was not significant due to the small number of events. Regional anaesthetic techniques are safe, well-tolerated alternatives to GA for the surgical management of vulval cancer, especially in an elderly and comorbid population.

The use of sentinel node sampling in vulval cancer.

Between March 2007 and December 2009, 38 patients underwent sentinel lymph node biopsy (SLNB) sampling, along with vulvectomy, in their management of vulval cancer. A review has been conducted to establish the reliability and accuracy of the new procedure compared with the traditional total inguinofemoral lymphadenectomy. We also aimed to establish both the short- and long-term morbidities of both total inguinofemoral lymphadenectomy and SLNB and to assess the duration of hospital stay in both groups. Our data have shown a reduced short- and long-term morbidity and reduced length of hospital stay for the SLNB procedure. We conclude that it is a reliable and safe procedure, however it should only be conducted in cancer centres.

Impact of improving outcome guidance in gynaecological cancer on squamous cell carcinoma of the vulva in the West Midlands, UK.

This study aimed to assess the benefits and outcomes of squamous cell carcinoma (SCC) of the vulva managed in a cancer centre post-centralisation of cancer care in the UK. A retrospective study was performed to evaluate the demography and management outcomes of SCC of the vulva in a regional gynaecological cancer centre. The results were then compared with the Rhodes et al. (1998) population-based study. Over the years, disease demography remained largely unchanged. However, centralisation of cancer care has resulted in significant changes in the pattern of care. The number of cases managed has increased by 1.7 times and the permutation of surgeries have reduced from 15 to 4. There is also a significant increased in the number of lymphadenectomies performed (p = 0.003). These changes were accompanied by improvement in 5-year cause-specific survival (p = 0.055).

Long-term follow-up of cervical disease in women screened by cytology and HPV testing: results from the HART study.

BACKGROUND: Several studies have shown that testing for high-risk human papillomavirus (HPV) types results in an improved sensitivity for CIN2+, compared with cytology, although with a somewhat lower specificity. METHODS: We obtained follow-up results, with at least one smear after participation in the HART study, which compared HPV testing (HC-II) with cytology as a primary screening modality. RESULTS: With a median follow-up of 6 years, 42 additional cases of CIN2+ were identified; women who were HPV positive at baseline were more likely to develop CIN2+ than those who were HPV negative (hazard ratio (HR) 17.2; 95% confidence interval (CI) (9.3-31.6)) and the risk increased with increasing viral load. Compared with HPV-negative women (relative light unit (RLU) <1), the HR (95% CI) was 5.4 (1.6, 18.2) for 1-10 RLU and 25.5 (13.6, 47.9) for RLU > or = 10. Positive cytology (borderline or worse compared with negative) was also predictive of developing CIN2, although to a lesser extent (HR 8.7; 95% CI (4.5-17.1)). Only one case of CIN3 and three cases of CIN2 were found in women who showed a positive cytology result but were HPV negative at baseline. CONCLUSION: After 5 years of follow-up, CIN2+ occurred in 0.23% of women who were HPV negative at baseline compared with 0.48% of women who showed a negative cytology result, indicating a much longer low-risk interval for CIN2+ after HPV testing.

Anaesthetic choice in the colposcopy clinic: a retrospective analysis of routinely collected data.

OBJECTIVES: Current guidelines recommend that less than 20% of treatments in colposcopy clinics should be under general anaesthetic. The objective of this study was to increase the evidence base for guidelines by establishing the proportion of women receiving general anaesthesia for treatment, determining the predictors of and reasons recorded for general anaesthetic use. DESIGN: Retrospective analysis of routinely collected data. SETTING: NHS Trust in the West Midlands. PARTICIPANTS: Colposcopy patients; January 2003 to March 2005. METHODS: Logistic regression of factors associated with general anaesthetic choice. MAIN OUTCOME MEASURES: Proportion of women treated under general anaesthesia, factors associated with anaesthetic choice and reasons recorded for general anaesthetic use. RESULTS: About 5.4% (204/3777) of new appointments for colposcopy received treatment under general anaesthetic. Of women requiring treatment, 20% (204/1003) received general anaesthetic. General anaesthetic was more likely to be used when the woman required loop excision (OR = 3.63, 95% CI 2.11-6.24) and less likely when directed biopsy was performed (OR = 0.11, 95% CI 0.01-0.80), when the patient appointment date was after introduction of new guidelines (OR = 0.37, 95% CI 0.24-0.56) or when the assessment visit was with a nonconsultant status doctor rather than nurse or consultant (OR = 0.70, 95% CI 0.50-0.97). General anaesthetic use varied between colposcopists ranging from 0 to 16.5% of new patients seen. Woman's choice was the most commonly specified reason for the use of general anaesthetic. CONCLUSIONS: The proportion of colposcopy patients treated under general anaesthetic is 20%, within guideline limits. Substantial variation in general anaesthetic rates between colposcopists was observed, and further investigation is required to discover the reason for this.

Identifying the performance criteria for appraisal of colposcopists: benchmarking Delphi.

BACKGROUND: Colposcopy forms an essential part of National Health Service Cervical Screening Programme (NHSCSP). With an increased emphasis on accountability and improved performance, there is a need to identify the performance criteria that are essential to be satisfied by the colposcopists at the time of appraisal. OBJECTIVE: To identify the performance criteria essential for appraisal of colposcopists by two-generational Delphi survey. DESIGN: Delphi survey. SETTING: Annual British Society for Colposcopy and Cervical Pathology conference (BSCCP 2005, Edinburgh, UK). POPULATION: Four hundred and ninety-nine delegates attending the above conference. METHOD: A two-generational Delphi survey was undertaken to identify the criteria needed for appraisal. The participants were asked to rate the relevance of quality items that might be considered necessary for appraisal of performance of colposcopists. After the first round, the results were presented, and the respondents were given the chance to reflect on their response and change it if necessary. MAIN OUTCOME MEASURES: Criteria considered to be essential for appraisal of colposcopists in areas of training, diagnostic and therapeutic aspects and communication. RESULTS: In the first round, 306/499 (61%) participants returned the completed questionnaire. Sixty percent (187/306) of participants returned their questionnaire in the second round. In addition to BSCCP certification, four other criteria were identified, which were quality of recorded findings, biopsy rate when atypia noted, proportion of biopsies histologically adequate and proportion of normal initial posttreatment follow-up smears. CONCLUSION: This Delphi survey has been the first to identify criteria to be used in the annual appraisal of professionals. It has resulted in a number of criteria that could be considered for the appraisal and possible revalidation of colposcopists practising in UK.

Combination bleomycin, ifosfamide, and cisplatin chemotherapy in cervical cancer.

We report a phase II study of bleomycin, ifosfamide, and cisplatin (BIP) in cervical cancer. Our aims were to assess response rate, toxicity, and survival in women treated with this combination. Among 49 patients, 34 objective responses (69%) were seen, with 10 complete responses (20%). Toxic effects were assessed in 186 treatment cycles. All patients had alopecia and nausea and vomiting. Other effects included myelosuppression, infection, reduction in renal function, and disturbance of consciousness. These data indicate that BIP is highly active against advanced and recurrent cervical cancer.

Management of women who test positive for high-risk types of human papillomavirus: the HART study.

BACKGROUND: Certain types of human papillomavirus (HPV) are the primary cause of almost all cervical cancers. HPV testing of cervical smears is more sensitive but less specific than cytology for detecting high-grade cervical intraepithelial neoplasia (CIN2+). HPV testing as a primary screening approach requires efficient management of HPV-positive women with negative or borderline cytology. We aimed to compare the detection rate and positive predictive values of HPV assay with cytology and to determine the best management strategy for HPV-positive women. METHODS: We did a multicentre screening study of 11085 women aged 30-60 years. Women with borderline cytology and women positive for high-risk HPV with negative cytology were randomised to immediate colposcopy or to surveillance by repeat HPV testing, cytology, and colposcopy at 12 months. FINDINGS: HPV testing was more sensitive than borderline or worse cytology (97.1% vs 76.6%, p=0.002) but less specific (93.3% vs 95.8%, p<0.0001) for detecting CIN2+. Of 825 randomised women, surveillance at 12 months was as effective as immediate colposcopy. In women positive for HPV at baseline, who had surveillance, 73 (45%) of 164 women with negative cytology and eight (35%) of 23 women with borderline cytology were HPV negative at 6-12 months. No CIN2+ was found in these women, nor in women with an initial negative HPV test with borderline (n=211) or mild (32) cytology. INTERPRETATION: HPV testing could be used for primary screening in women older than 30 years, with cytology used to triage HPV-positive women. HPV-positive women with normal or borderline cytology (about 6% of screened women) could be managed by repeat testing after 12 months. This approach could potentially improve detection rates of CIN2+ without increasing the colposcopy referral rate.

Early serum CA125 response and outcome in epithelial ovarian cancer.

The prognostic value of serum CA125 levels before and after two courses of chemotherapy was assessed in 50 patients with advanced epithelial ovarian cancer. Patients with serum CA125 values below 35 U/ml after two courses were significantly more likely to achieve complete remission and had a significantly longer median survival. In multivariate analysis, serum CA125 levels after two courses were the most important independent prognostic factor: it was possible to predict survival status at 12 months with an overall accuracy of 93%. Serum CA125 can be used to evaluate quantitatively chemotherapeutic response and at an early stage classify patients into good and poor risk groups. Such an approach would facilitate the selection of appropriate therapy and could reduce toxicity.

Glycoprotein patterns in normal and malignant cervical tissue.

Glycoproteins from normal and malignant human cervix were studied using an organ culture system and compared by gel electrophoresis and autoradiography. Five glycoproteins of 178 kDa, 95 kDa, 93 kDa, 82 kDa and 38 kDa and 1 glycolipid (46 kDa) were detected more frequently in squamous carcinomas. Certain glycoproteins were shown to be oncofoetal and some had affinity for Concanavalin A (Con A). The 82 kDa glycoprotein was present in 16/17 squamous carcinomas but in only 1/13 normal cervices. This band represented a glycoprotein containing glucosamine, mannose, small quantities of methionine and no fucose. These preliminary results suggest that these glycoproteins and in particular the 82-kDa glycoprotein are worthy of further investigation and characterisation.

Neoadjuvant (cytoreductive) chemotherapy combined with intervention debulking surgery in advanced, unresected epithelial ovarian cancer.

Thirty-six patients with epithelial ovarian cancer, incompletely resected at primary laparotomy, were treated with one of two intensive cis-platinum-based combination chemotherapy regimens. The intention was to perform further surgical debulking (intervention debulking surgery) after three cycles in patients responding to treatment. Intervention debulking surgery was carried out in 28 of 36 patients (78%) at a median interval of 12.7 weeks from primary diagnosis. Omentectomy and total abdominal hysterectomy were the most commonly performed procedures at intervention debulking. As a result of such surgery, 16 of the 28 women (57%) were left with no macroscopic residual disease, five (18%) had less than 1 cm, four (14%) less than 2 cm residuum, and three (11%) remained with more extensive disease. Post-intervention debulking surgical complications were few, with a median postoperative hospital stay of 10 days and a median interval of 21 days from debulking surgery to resumption of chemotherapy. Neoadjuvant (cytoreductive) chemotherapy combined with early secondary surgical debulking is feasible, with little severe morbidity, and can leave a high proportion of patients free of macroscopic disease. The effect of such a program on patient survival is now being tested in a randomized study.

Residual disease after cone biopsy: completeness of excision and follow-up cytology as predictive factors.

Residual disease was identified in the hysterectomy specimen in 19 of 65 patients (29%) previously found to have cervical intraepithelial neoplasia and in four of 19 (21%) found to have early stromal invasion on histologic examination of a cone biopsy. Residual disease was found in six of 34 cases (18%) of cervical intraepithelial neoplasia and zero of 12 cases of early stromal invasion after complete excision, and in 13 of 31 cases (42%) of cervical intraepithelial neoplasia and four of seven cases (57%) of early stromal invasion after incomplete excision by cone biopsy. Sixteen of 28 women (57%) with abnormal cytology after cone biopsy were found to have residual disease at the time of hysterectomy. In contrast, no residual disease was found in 35 patients who had no evidence of cytologic abnormality after the initial treatment. The finding of abnormal cytology after cone biopsy is shown to be a more useful prognostic indicator than histologic examination of excision margins. Therefore, we believe that a policy of expectant management, based on regular cytologic examination, is justified when histologic assessment has shown the lesion to extend to the line of excision.

Management of postconization cervical stenosis by laser vaporization.

In 18 patients with symptomatic cervical stenosis after conization, laser vaporization of the stenotic segment was performed. Total relief of symptoms was achieved in 12 patients and partial relief in four. In seven cases there was no evidence of stenosis at follow-up, and in a further nine cases the degree of stenosis was less. In seven cases it was possible to visualize the squamocolumnar junction at follow-up. This had not been possible in any cases before the procedure. Vaporization using the carbon dioxide laser provides a useful conservative management technique for postconization stenosis.

Second-look laparotomy in the management of epithelial ovarian carcinoma: an evaluation of fifty cases.

Fifty patients with ovarian cancer had a second-look laparotomy performed after chemotherapy. Complete histologic response was confirmed in 12 patients, microscopic disease was found in 12 patients, and macroscopic disease was found in 26 patients. Fifteen patients with macroscopic disease had total tumor clearance at second look. Surgical response to chemotherapy was found to correlate well with disease volume at the onset of chemotherapy. The operation is a safe, accurate technique for assessing the ovarian cancer patient. The findings and outcome probably depend upon the timing of the procedure. Any survival benefit from the operation remains to be proved.