Jason Yap

Regression, relapse, and live birth rates with fertility-sparing therapy for endometrial cancer and atypical complex endometrial hyperplasia: a systematic review and metaanalysis

OBJECTIVE The objective of the study was to evaluate the regression, relapse, and live birth rates of early-stage endometrial cancer (EC) and atypical complex hyperplasia (ACH) with fertility-sparing treatment. STUDY DESIGN This was a metaanalysis of the proportions from observational studies with a random-effects model and a meta-regression to explore for heterogeneity. RESULTS Thirty-four observational studies, evaluating the regression, relapse, and live birth rates of early-stage EC (408 women) and ACH (151 women) with fertility-sparing treatment. Fertility-sparing treatment for EC achieved a pooled regression rate of 76.2%, a relapse rate of 40.6%, and a live birth rate of 28%. For ACH the pooled regression rate was 85.6%, a relapse rate of 26%, and a live birth rate of 26.3%. Twenty women were diagnosed with ovarian cancer (concurrent or metastatic) during follow-up (3.6%) and 10 progressed to higher than stage I EC (1.9%) from which 2 women died. CONCLUSION Fertility-sparing treatment of EC and ACH is feasible and selected women can satisfy their reproductive wishes.

Fertility preservation in female cancer survivors

Summary The advancement of cancer therapies over the last few decades has significantly improved long-term survival of cancer patients, especially children and adolescents. As many of the therapeutic agents used are highly cytotoxic, cancer survivors have to pay the price of enduring various immediate and long-term side-effects. Unfortunately, gonadal failure and infertility are among the most common long-term side-effects, resulting in distress, lowered self-esteem and quality of life. Three modalities of fertility preservation can be offered to female patients prior to commencing their cancer treatment: embryo, oocyte and ovarian tissue cryopreservation. This paper reviews the outcomes for female patients who underwent fertility preservation in University College Hospital between 1995 and 2005, and post-therapeutic use of their frozen specimens. In addition, the effects of cytotoxic agents on fertility and ovarian function, and the range of fertility preservation available for female cancer sufferers are also discussed.

A systematic review evaluating the relationship between progression free survival and post progression survival in advanced ovarian cancer.

OBJECTIVE Although overall survival is the ultimate goal of cancer therapy, many clinical and health economic decisions are taken when only progression free survival (PFS) data are available. This study evaluates the relationship between PFS and post progression survival (i.e. the time between disease progression and death) to estimate how many months a new drug for ovarian cancer might add to overall survival if the number of months the drug added to PFS (relative to a standard drug) was already known. METHODS A literature search was conducted over Medline for randomised controlled trials published between January 1990 and July 2010 that evaluated the effect of a drug treatment in comparison to alternative drug treatment in patients with either advanced stage primary or recurrent ovarian cancer. A systematic review of progression free and post progression survival (PPS) was performed. The relationship between PFS and PPS was evaluated by a graphical method and standard statistical tests. RESULTS Thirty-seven trials involving 15,850 patients met the inclusion criteria. The review found that increases in median PFS generally lead to little change in post-progression survival. Percentage gains in PFS are generally associated with no percentage gains or with very slight percentage gains or losses in post-progression survival CONCLUSION If the effect of a new drug treatment for ovarian cancer is to extend median PFS by x months, then it is reasonable to estimate that the treatment will also extend median overall survival by x months. This information will be useful for individual and collective decision making.

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.

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 12 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).

Over-expression of DNMT3A predicts the risk of recurrent vulvar squamous cell carcinomas

OBJECTIVE Cancer initiation and progression has been linked to aberrant expression of the DNA methyltransferases (DNMT), the enzymes which establish and maintain DNA methylation patterns throughout the genome. In this study, we investigated if DNMT expression in vulvar squamous cell carcinomas (VSCC) was related to clinical outcome. METHODS DNMT1, DNMT3A and DNMT3B expression was measured in a subset of cases drawn from a cohort of consecutive women treated for primary VSCC at the Pan Birmingham Gynaecological Cancer Centre between 2001 and 2008. Univariable and multivariable competing risk modelling was performed to identify whether DNMT expression was associated with local disease recurrence or disease morbidity. RESULTS Over-expression of DNMT3A in the invasive component of the tumour was seen in 44% of tumours and was associated with an increased risk of local vulvar recurrence (LVR) (HR=4.51, p=0.012). This risk was found to increase further after adjustment for disease stage (HR=6.00, p=0.003) and groin node metastasis (HR=4.81, p=0.008). Over-expression of DNMT3B was associated with an increased risk of LVR (HR=5.69 p=0.03), however this ceased to be significant after adjustment for groin node metastasis. In a subset analysis, over-expression of DNMT3A was found to be significantly more common in VSCCs that stained negative for CDKN2A. CONCLUSIONS These observations are consistent with the possibility that epigenetic changes contribute to vulvar neoplasia and DNMT3A over-expression may be useful in predicting local disease recurrence.

Patient-Reported Outcomes After Extensive (Ultraradical) Surgery for Ovarian Cancer: Results From a Prospective Longitudinal Feasibility Study.

Background Extensive (ultraradical) surgery may facilitate complete cytoreduction in ovarian cancer with potential survival benefit but with greater morbidity. Currently, patient-reported outcomes (PROs) from such surgery are unknown. We conducted the Surgery in Ovarian Cancer Quality of life Evaluation Research study (SOCQER 1), a prospective study investigating the feasibility of collection of serial PROs in patients who had extensive surgery and standard surgery for ovarian cancer. Methods Ninety-three patients were recruited for 33 months to complete serial PRO assessments using the validated EORTC QLQ-C30 and the ovarian cancer–specific QLQ-OV28 questionnaires preoperatively, at 6 weeks, and at 3, 6, and 9 months postoperatively. Aletti Surgical Complexity Score of 3 or lower was considered standard surgery; a Surgical Complexity Score of 4 or higher was considered extensive surgery. Prospective data collection was obtained from the hospital electronic database, including patient demographics, American Society of Anaesthesiologists grade, preoperative serum CA125 and albumin levels, chemotherapy regimen, and surgical morbidity. Results Three cohorts of patients—32 benign, 32 undergoing standard surgery, and 24 undergoing extensive surgery—completed the questionnaires. Median questionnaire completion rate in this study was 64%, demonstrating the feasibility of longitudinal quality of life (QoL) assessment after surgery. Patient-reported outcomes revealed a falling trend in QoL in the short-term (6 weeks-3 months) after surgery, which gradually returned to baseline at 6 to 9 months; this trend was more marked after extensive surgery. Conclusions This study provides useful insight into the impact of extensive surgery on patients. Further multicenter studies are needed to evaluate the impact of extensive surgery on patient’s QoL and survival.

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.

A survey on the use of topical steroids in patients treated for lichen sclerosus-associated vulval squamous cell carcinoma

Abstract Evidence suggests that lichen sclerosus (LS) is the primary aetiological factor for local vulval recurrence (LVR) in vulval squamous cell carcinoma (VSCC). The long-term application of topical corticosteroids is believed to prevent LVR. Patients treated for LS-associated VSCC at a gynaecological cancer centre were invited to complete a questionnaire to evaluate whether they are receiving corticosteroids. 55 of the 95 eligible patients (58%) completed the questionnaire; LS was treated in 69%, with steroids given to 84.2%. Most received steroids >3 months, but discontinued treatment once asymptomatic. An online survey was distributed to 313 British Gynaecological Cancer Society members to determine whether gynaecological oncologists prescribe corticosteroids for LS following VSCC surgery. 41 consultants (13.1%) completed the survey; 70.7% prescribe topical corticosteroids (potent/very potent in 79.3%), and 58.6% treat >1 year. Our findings demonstrate that patients are more likely to be given topical corticosteroids if symptomatic of LS. Furthermore, although treatment regimens vary, the majority of respondents advocate the use of very potent steroids and would support a tertiary chemopreventative trial. Impact statement What is already known on this subject: Local vulval recurrence (LVR) affects approximately one in four women who have received surgery for vulval squamous cell carcinoma (VSCC). What the results of this study add: Lichen sclerosus (LS), an inflammatory dermatosis, is recognised as the likely primary aetiological factor for LVR. Although there is evidence to suggest that long-term topical corticosteroid use in patients with residual LS may prevent LVR, the extent to which women were given topical steroids following surgery remains unclear. Our patient questionnaire evaluates if these patients are already receiving topical steroids, along with the strength of such steroids and duration of treatment. The consultant survey determines whether clinicians currently prescribe topical steroids following VSCC surgery, as well as the strength and duration of steroid therapy. What the implications are of these findings for clinical practice and/or further research: We aim to establish whether the gynaecological oncology community believe that long-term steroids may prevent LVR in women with LS-associated VSCC and whether they would support and recruit to a multicentre tertiary chemopreventative trial. These findings could influence a future clinical trial and may alter the ongoing management of these women.

The effectiveness of epigallocathechin-3-gallate for treatment of human papillomavirus-driven epithelial neoplasms: a preclinical study

Abstract Background Epigallocathechin-3-gallate (EGCG), the major bioactive polyphenol in green tea, has anticarcinogenic properties in vitro and in vivo. Several recent reports have shown that EGCG affects the expression of human papillomavirus (HPV)-encoded E6 and E7, two oncoproteins required for HPV-driven oncogenesis. Here, we aimed to explore the effects of EGCG on keratinocyte proliferation and differentiation, in addition to HPV18 replication, in a three-dimensional organotypic raft culture system. Methods Organotypic raft cultures of HPV18-infected keratinocytes cultured at the air–liquid interface for 10 days were treated with EGCG for an additional 10 days before fixation and processing. Raft sections were stained with antibodies specific for various cell proliferation and keratinocyte differentiation markers in addition to tumour suppressor genes. Western blotting was performed on EGCG-treated cells to measure the level of HPV18 E6 and E7 protein expression. Findings EGCG treatment blocked the ability of HPV18-positive keratinocytes to generate hyperplastic epithelium in raft culture. EGCG reduced cell proliferation as assessed by bromodeoxyuridine label incorporation and Ki67 staining; it upregulated expression of several tumour suppressor genes ( p53 [TP53], p21, pRb ), and impaired productive viral replication (as assessed by HPV18 E4 protein expression), but did not have an effect on keratinocyte differentiation. In culture, EGCG treatment promoted degradation of the E6 and E7 proteins and restored tumour suppressor gene expression. Interpretation The results of our preclinical study suggest that EGCG inhibits the proliferation of HPV18-infected keratinocytes by enhancing the turnover and degradation of the E6 and E7 proteins, resulting in re-expression of several key tumour suppressor genes. These findings suggest that EGCG could potentially reverse the dysplastic changes induced by oncogenic HPV strains and could be used clinically to treat HPV-induced neoplasia. Funding Cancer Research UK.