Andrew Nordin

Activity, safety, and feasibility of cidofovir and imiquimod for treatment of vulval intraepithelial neoplasia (RT3VIN): a multicentre, open-label, randomised, phase 2 trial

BACKGROUND Vulval intraepithelial neoplasia is a skin disorder affecting the vulva that, if left untreated, can become cancerous. Currently, the standard treatment for patients with vulval intraepithelial neoplasia is surgery, but this approach does not guarantee cure and can be disfiguring, causing physical and psychological problems, particularly in women of reproductive age. We aimed to assess the activity, safety, and feasibility of two topical treatments--cidofovir and imiquimod--as an alternative to surgery in female patients with vulval intraepithelial neoplasia. METHODS We recruited female patients (age 16 years or older) from 32 centres to an open-label, randomised, phase 2 trial. Eligibility criteria were biopsy-proven vulval intraepithelial neoplasia grade 3 and at least one lesion that could be measured accurately. We randomly allocated patients to topical treatment with either 1% cidofovir (supplied as a gel in a 10 g tube, to last 6 weeks) or 5% imiquimod (one 250 mg sachet for every application), to be self-applied three times a week for a maximum of 24 weeks. Randomisation (1:1) was done by stratified minimisation via a central computerised system, with stratification by hospital, disease focality, and presentation stage. The primary endpoint was a histologically confirmed complete response at the post-treatment assessment visit 6 weeks after the end of treatment (a maximum of 30 weeks after treatment started). Analysis of the primary endpoint was by intention to treat. Secondary outcomes were toxic effects (to assess safety) and adherence to treatment (to assess feasibility). We present results after all patients had reached the primary endpoint assessment point at 6 weeks; 2-year follow-up of complete responders continues. This trial is registered with Current Controlled Trials, ISRCTN 34420460. FINDINGS Between Oct 21, 2009, and Jan 11, 2013, 180 participants were enrolled to the study; 89 patients were randomly allocated cidofovir and 91 were assigned imiquimod. At the post-treatment assessment visit, a complete response had been achieved by 41 (46%; 90% CI 37·0-55·3) patients allocated cidofovir and by 42 (46%; 37·2-55·3) patients assigned imiquimod. After 6 weeks of treatment, 156 (87%) patients (78 in each group) had adhered to the treatment regimen. Five patients in the cidofovir group and seven in the imiquimod group either withdrew or were lost to follow-up before the first 6-week safety assessment. Adverse events of grade 3 or higher were reported in 31 (37%) of 84 patients allocated cidofovir and 39 (46%) of 84 patients assigned imiquimod; the most frequent grade 3 and 4 events were pain in the vulva, pruritus, fatigue, and headache. INTERPRETATION Cidofovir and imiquimod were active, safe, and feasible for treatment of vulval intraepithelial neoplasia and warrant further investigation in a phase 3 setting. Both drugs are effective alternatives to surgery for female patients with vulval intraepithelial neoplasia after exclusion of occult invasive disease. FUNDING Cancer Research UK.

Factors Affecting Short-term Mortality in Women With Ovarian, Tubal, or Primary Peritoneal Cancer Population-Based Cohort Analysis of English National Cancer Registration Data

Objective International studies show lower survival rates in the United Kingdom than other countries with comparable health care systems. We report on factors associated with excess mortality in the first year after diagnosis of primary invasive epithelial ovarian, tubal, and primary peritoneal cancer. Methods Routinely collected national data were used for patients diagnosed in England in 2008 to 2010. A multivariate Poisson model was used to model excess mortality in 3 periods covering the first year after diagnosis, adjusting for various factors including age at diagnosis, route to diagnosis, tumor stage, tumor morphology, and treatment received. Results Of 14,827 women diagnosed as having ovarian cancer, 5296 (36%) died in the first year, with 1673 deaths in the first month after diagnosis. Age older than 70 years, diagnosis after an emergency presentation or by an unknown route, and unspecified or unclassified epithelial morphologies were strongly and independently associated with excess mortality in the first year after diagnosis. Of the 2100 (14%) women who fulfilled all 3 criteria, 1553 (74%) did not receive any treatment and 1774 (85%) died in the first year after diagnosis. In contrast, only 193 (4%) of the 4414 women without any of these characteristics did not receive any treatment, and only 427 (9%) died in the first year after diagnosis. Conclusions Although our results are based on data from England, they are likely to have implications for cancer care pathways worldwide because most of the identified factors are not specific to the UK health care system. Our results suggest the need to increase symptom awareness, promote timely general practitioner referral, and optimize diagnostic and early treatment pathways within secondary care to increase access to treatment for women with advanced-stage invasive epithelial ovarian, tubal, and primary peritoneal cancer. This process should be pursued alongside continued efforts to develop primary prevention and screening strategies.

Which staging system to use for gynecological cancers: recommendations for practice in the United Kingdom.

To The Editor: L uckett et al 1 reported a comparison of Functional Assessment of Chronic Illness and Therapy and European Organization for Research and Treatment of Cancer (EORTC) site-specific gynecologic quality of life (QoL) modules. The authors state that a review of the results of construct and convergent validity is beyond the scope of their review. However, they proceed to claim a notable difference in the Bsuperior quality and quantity of validation data reported for the Functional Assessment of Cancer Treatment Ovarian (FACT-O) and Functional Assessment of Cancer Treatment Vulval (FACT-V) compared with those for the EORTC Ovarian Quality of Life Questionnaire (QLQOV28) and Cervical Quality of Life Questionnaire (QLQ-CX24).[ Evidence to support this claim does not appear to be provided by the authors. As members of the Gynecology Group of the EORTC Quality of Life Group, we believe that the statement cannot be substantiated, particularly with regard to validation data quality. We acknowledge that FACT-O has been used more widely than EORTC QLQ-OV28 in published clinical trials. However, the EORTC module has been used in several actively recruiting or recently closed large scale European clinical trials, and the QoL data from these studies will further validate this module. Both the FACT-V and EORTC QLQ-CX24 instruments are relatively new and thus far have been used in few published clinical trials. The EORTC Quality of Life Group pursues a culture-sensitive approach to develop reliable and valid measurement tools based on principles of test construction. The EORTC QLQ-OV28, QLQCX24, and the new endometrial cancer module Endometrial Quality of Life Questionnaire (QLQ-EN24) (submitted for publication) were developed with strict adherence to the EORTC Quality of Life Group module development guidelines, with rigorous independent peer-reviewed appraisal on 3 occasions during the 4 phases of the module development process. Patients’ involvement was integral throughout this process for all 3 modules. The EORTC gynecologic cancer disease specific quality-of-life modules were developed as an international collaboration in multiple languages, and published validation data support their use in a large range of languages and cultural settings. These validation studies, which demonstrate robust psychometric properties, are published in seminal publications for each module, detailing the developmental process, reliability, and validation data. Lucket et al focused on sensitivity (an instrument’s ability to distinguish among different clinical groups) and responsiveness (ability to register clinically important changes in QoL over time). We are not aware of evidence indicating superior sensitivity or responsiveness of either the EORTC or the FACIT instruments in assessing the QoL of women with gynecologic cancer. The decision to use a particularQoL questionnaire should be based on the validity and reliability with respect to the population studied.

Specialist surgery for ovarian cancer in England

OBJECTIVE The aim of this study is to evaluate the impact of the 1999 national recommendations for ovarian cancer surgery in England to be performed by specialist surgeons in specialist centres. METHODS A retrospective analysis of English cancer registry records, Hospital Episode Statistics (HES) data for all English NHS providers and General Medical Council (GMC) sub-specialty accreditation, to consider changes to the annual proportion of ovarian cancer (ICD10 C56-C57) patients undergoing major gynaecological surgery in gynaecological cancer centres (GCCs) or by specialist gynaecological oncologists (GOs). RESULTS From 2000 to 2009, 2428 consultants were responsible for surgery on 30,753 patients. There were significant increases in the proportions of patients undergoing surgery at GCCs (43% to 76%, P<0.001), by GMC accredited GOs (5% to 36%, P<0.001), and by high ovarian cancer caseload (≥18 cases) surgeons (22% to 56%, P<0.001). CONCLUSION There have been increased centralisation and specialisation of surgery for ovarian cancer patients since the NHS Cancer Plan (2000) and there has also been improved survival. However, by 2009, many ovarian cancer patients were still not receiving specialist surgery; the majority of patients were not operated on by GMC accredited gynaecological oncologists and there was considerable regional variation. Systems of accreditation should be reviewed and trusts should ensure that HES data accurately records clinical activity.

Life After ASTEC International Journal of Gynecological Cancer Forum Submission

Our cancer center championed theAStudy in the Treatment of Endometrial Cancer (ASTEC) trial, topping the patient recruitment league table. However, we continue to perform lymphadenectomy surgical staging for potential high-and/or intermediate-risk histologic cases. The appropriateness of lymphadenectomy cannot be divorced from adjuvant therapy algorithm. We do not administer adjuvant radiotherapy for confirmed nodenegative intermediate-risk cases. Conversely, our guidelines advise pelvic radiotherapy for highand/or intermediate-risk histologic cases where lymphadenectomy has been omitted because of the presumed higher risk of pelvic sidewall recurrence from occult pelvic nodal disease. Although adjuvant external beam pelvic radiotherapy reduces the risk of pelvic recurrence, the meta-analysis of PORTEC, ASTEC + EN.5 and GOG99 confirms that it does not improve survival. However, external beam radiotherapy causes potential morbidity: acute toxicity incidence, 57% versus 27% (ASTEC); late toxicity, 61% versus 45% (ASTEC); and late complications, 25% versus 6% (PORTEC). Radiotherapy is also associated with an increased relative risk of 40% of a second neoplasm at 10 years and has a negative impact on the quality of life for long-term survivors. Conversely, ASTEC also demonstrates morbidity from lymphadenectomy, particularly moderate/severe lymphedema (0.341% vs 0.003%). If one intervention could safely obviate the need for the other, the question is which intervention is likely to cause less debilitating morbidity or harm fewer patients. In ASTEC, highand/or intermediaterisk histologic cases underwent second randomization to avoid differences in postsurgical treatment on the basis of nodal histology, any differences being attributed to lymphadenectomy. The frustrating consequence is that we cannot assess the clinically relevant comparison between highand/ or intermediate-risk node-negative lymphadenectomy without adjuvant therapy and conventional surgery with adjuvant radiotherapy. GOG99 randomized external beam radiotherapy without brachytherapy for intermediate-risk node-negative lymphadenectomy patients. The major difference was the number of vaginal vault recurrences; local recurrence 1.6% radiotherapy versus 7.4% no adjuvant therapy at 2 years. Confirming other trials, there was no survival difference, but the radiotherapy arm reported more frequent and severe toxicities. Vaginal vault recurrences in nonirradiated patients are potentially salvageable with radiotherapy. However, the effectiveness of adjuvant brachytherapy is also high, PORTEC-2 showing a 0.9% vaginal recurrence rate with low morbidity, compared with 19% for a similar cohort without adjuvant treatment in PORTEC. Perhaps lymphadenectomy surgical staging of intermediate-risk cases with adjuvant brachytherapy for node-negative patients may achieve pelvic disease control with minimal morbidity. Women continue to die from distant metastatic disease, particularly associated with high-risk histology. Among conventional treatment modalities, only adjuvant chemotherapy offers hope to prevent distant recurrence. PORTEC 3 will assess the benefit of chemotherapy with radiotherapy for incompletely staged highand/ or intermediate-risk disease, with adjuvant radiotherapy as the control arm. Perhaps, we should evaluate brachytherapy and che motherapy without external beam radiotherapy for lymphadenectomy-staged nodenegative patients at lower risk of pelvic sidewall recurrence. Guidelines should consider the efficacy and morbidity of the complete treatment pathway. Despite the findings of ASTEC, there is arguably a role for lymphadenectomy to assist in triage of patients for adjuvant therapy to minimize the risk of treatment related morbidity without compromise to overall survival. Andrew John Nordin, MBBS, FRCOG East Kent Gynaecological Oncology Centre Queen Elizabeth the Queen Mother Hospital Margate, Kent, England and University College London NHS ImprovementVCancer London, England Andrew.Nordin@ekht.nhs.uk

Variations in Treatment of Cervical Cancer According to Tumor Morphology—Population-Based Cohort Analysis of English National Cancer Registration Data

Objective This study aimed to investigate differences in the treatment of cervical cancer by tumor morphology after accounting for demographic, diagnostic, and tumor factors. Methods Retrospective population-based observational study using linked cancer registration and treatment data from administrative data sources of women diagnosed with cervical cancer (International Classification of Diseases, Tenth Edition C53, malignant behavior) during 2009 and 2010 in England. Descriptive analyses and multinomial regression modeling have been used to consider differences in treatment by morphological subtype. For each morphological subtype, number and percentage of cases are presented by demographic, diagnostic, and tumor factors and treatment modality. Relative risk ratios are provided for each treatment modality by morphological subtype and other specified factors. Results Forty-three percent of women were treated surgically; 36% by clinical oncology and only 8% by combination of surgery and clinical oncology. Compared with squamous cell carcinomas, both adenocarcinomas and adenosquamous carcinomas were more likely to be treated by trachelectomy, hysterectomy, radiotherapy with hysterectomy, or chemoradiotherapy with hysterectomy than by chemoradiotherapy without hysterectomy. These differences were explained mainly by a different stage distribution, but some difference remained after adjustment for other factors including stage. As clinically recommended, neuroendocrine tumors were not treated surgically. Further treatment differences were found by age, route to diagnosis, stage, and grade. Deprivation was not generally associated with treatment differences, with 1 exception that those from more deprived areas were less likely to be treated by trachelectomy. Conclusions Important treatment differences according to tumor morphology remain after adjusting for relevant patient demographic, diagnostic, and tumor factors. In particular, the difference between the treatment of squamous cell carcinoma and adenocarcinoma is notable.

Cervical cancer – does the morphological subtype affect survival rates?

Abstract A retrospective population-based observational study using cancer registration data of women diagnosed with invasive cervical cancer between 2006 and 2010, in England, was carried out to explore how different morphological subtypes affect survival rates. Age-standardised net survival rates by morphological subtype are presented alongside with excess mortality modelling accounting for the impact of demographic, diagnostic and tumour factors. The three main morphological subtypes (squamous cell carcinoma (SCC), adenocarcinoma and adenosquamous carcinoma) have similar one-year net survival rates of approximately 85%. After adjusting for other important determinants of survival, there were no differences at five-years amongst the three main morphological subtypes, with unadjusted survival rates of 55–65%. As expected, women presenting with neuroendocrine tumours had a much poorer outcome than other epithelial cervical malignancies, with 1-year survival of up to 55%, five-year survival of 34% and excess mortality rates compared to SCC varying between 1.9 and 5.9. Impact Statement What is already known on this subject: This is the first study on survival by cervical cancer morphological subtype using national cancer data. What the results of this study add: This study uses excess mortality modelling to investigate the effects of the morphological subtypes whilst adjusting the other factors that affect cervical cancer survival such as stage, age and grade. What the implications are of these findings for clinical practice and/or further research: It is known that cervical neuroendocrine tumours have a poor prognosis and this is confirmed by this study. Squamous cell carcinomas (SCC), adenocarcinomas (AC) and adenosquamous carcinomas (ASC) have the highest net survival and when accounting for other factors there are no differences amongst these morphological subtypes in terms of survival.

Recurrence of vulval intraepithelial neoplasia following treatment with cidofovir or imiquimod: results from a multicentre, randomised, phase II trial (RT3VIN)

To compare the recurrence rates after complete response to topical treatment with either cidofovir or imiquimod for vulval intraepithelial neoplasia (VIN) 3.