Sudha Sundar

Positron emission tomography/computerised tomography imaging in detecting and managing recurrent cervical cancer: systematic review of evidence, elicitation of subjective probabilities and economic modelling

BACKGROUNDnCancer of the uterine cervix is a common cause of mortality in women. After initial treatment women may be symptom free, but the cancer may recur within a few years. It is uncertain whether it is more clinically effective to survey asymptomatic women for signs of recurrence or to await symptoms or signs before using imaging.nnnOBJECTIVESnThis project compared the diagnostic accuracy of imaging using positron emission tomography/computerised tomography (PET-CT) with that of imaging using CT or magnetic resonance imaging (MRI) alone and evaluated the cost-effectiveness of adding PET-CT as an adjunct to standard practice.nnnDATA SOURCESnStandard systematic review methods were used to obtain and evaluate relevant test accuracy and effectiveness studies. Databases searched included MEDLINE, EMBASE, Science Citation Index and The Cochrane Library. All databases were searched from inception to May 2010.nnnREVIEW METHODSnStudy quality was assessed using appropriately modified Quality Assessment of Diagnostic Accuracy Studies (QUADAS) criteria. Included were any studies of PET-CT, MRI or CT compared with the reference standard of histopathological findings or clinical follow-up in symptomatic women suspected of having recurrent or persistent cervical cancer and in asymptomatic women a minimum of 3 months after completion of primary treatment. Subjective elicitation of expert opinion was used to supplement diagnostic information needed for the economic evaluation. The effectiveness of treatment with chemotherapy, radiotherapy, chemoradiotherapy, radical hysterectomy and pelvic exenteration was systematically reviewed. Meta-analysis was carried out in RevMan 5.1 (The Cochrane Collaboration, The Nordic Cochrane Centre, Copenhagen, Denmark) and Stata version 11 (StataCorp LP, College Station, Texas, USA). A Markov model was developed to compare the relative cost-effectiveness using TreeAge Pro software version 2011 (TreeAge Software Inc., Evanston, IL, USA).nnnRESULTSnFor the diagnostic review, a total of 7524 citations were identified, of which 12 test accuracy studies were included in the review: six studies evaluated PET-CT, two evaluated MRI, three evaluated CT and one evaluated both MRI and CT. All studies were small and the majority evaluated imaging in women in whom recurrence was suspected on the basis of symptoms. The PET-CT studies evaluated local and distant recurrence and most used methods similar to current practice, whereas five of the six CT and MRI studies evaluated local recurrence only and not all employed currently used methods. Meta-analysis of PET-CT studies gave a sensitivity of 92.2% [95% confidence interval (CI) 85.1% to 96.0%] and a specificity of 88.1% (95% CI 77.9% to 93.9%). MRI sensitivities and specificities varied between 82% and 100% and between 78% and 100%, respectively, and CT sensitivities and specificities varied between 78% and 93% and between 0% and 95%, respectively. One small study directly compared PET-CT with older imaging methods and showed more true-positives and fewer false-negatives with PET-CT. The subjective elicitation from 21 clinical experts gave test accuracy results for asymptomatic and symptomatic women and the results for symptomatic women were similar to those from the published literature. Their combined opinions also suggested that the mean elicited increase in accuracy from the addition of PET-CT to MRI and/or CT was less than the elicited minimum important difference in accuracy required to justify the routine addition of PET-CT for the investigation of women after completion of primary treatment. For the effectiveness review, a total of 24,943 citations were identified, of which 62 studies were included (chemotherapy, 19 randomised controlled trials; radiotherapy or chemoradiotherapy, 16 case series; radical hysterectomy and pelvic exenteration, 27 case series). None provided the effectiveness of cisplatin monotherapy, the most commonly used chemotherapeutic agent in the NHS, compared with supportive care in a background of other treatment such as radiotherapy in recurrent and persistent cervical cancer. The model results showed that adding PET-CT to the current treatment strategy of clinical examination, MRI and/or CT scan was significantly more costly with only a minimal increase in effectiveness, with incremental cost-effectiveness ratios for all models being > £1M per quality-adjusted life-year (QALY) and the additional cost per additional case of recurrence being in the region of £600,000.nnnLIMITATIONSnThere was considerable uncertainty in many of the parameters used because of a lack of good-quality evidence in recurrent or persistent cervical cancer. The evidence on diagnostic and therapeutic impact incorporated in the economic model was poor and there was little information on surveillance of asymptomatic women.nnnCONCLUSIONSnGiven the current evidence available, the addition of PET-CT to standard practice was not found to be cost-effective in the diagnosis of recurrent or persistent cervical cancer. However, although probabilistic sensitivity analysis showed that the main conclusion about cost-ineffectiveness of PET-CT was firm given the range of assumptions made, should more reliable information become available on accuracy, therapeutic impact and effectiveness, and the cost of PET-CT reduce, this conclusion may need revision. Current guidelines recommending imaging for diagnosis using expensive methods such as PET-CT need to be reconsidered in the light of the above.nnnFUNDINGnThe National Institute for Health Research Health Technology Assessment programme.

Role of lymphangiogenesis in cancer

Regional lymph node metastasis is a common event in solid tumors and is considered a marker for dissemination, increased stage, and worse prognosis. Despite rapid advances in tumor biology, the molecular processes that underpin lymphatic invasion and lymph node metastasis remain poorly understood. However, exciting discoveries have been made in the field of lymphangiogenesis in recent years. The identification of vascular endothelial growth factor ligands and cognate receptors involved in lymphangiogenesis, an understanding of the embryology of the mammalian lymphatic system, the recent isolation of pure populations of lymphatic endothelial cells, the investigation of lymphatic metastases in animal models, and the identification of markers that discriminate lymphatics from blood vessels at immunohistochemistry are current advances in the field of lymphangiogenesis, and as such are the main focus of this article. This review also evaluates evidence for lymphangiogenesis (ie, new lymphatic vessel formation in cancer) and critically reviews current data on the prognostic significance of lymphatic vascular density in tumors. A targeted approach to block pathways of lymphangiogenesis seems to be an attractive anticancer treatment strategy. Conversely, promotion of lymphangiogenesis may be a promising approach to the management of treatment-induced lymphedema in cancer survivors. Finally, the implications of these developments in cancer therapeutics and directions for future research are discussed.

Should grade 3 endometrioid endometrial carcinoma be considered a type 2 cancer—A clinical and pathological evaluation

OBJECTIVEnEndometrial cancer is classified into: Type I estrogen-dependent endometrioid adenocarcinoma, with good prognosis and type 2 non-estrogen-dependent cancer with serous or clear cell histology and poor prognosis. Grade 3 endometrioid cancers (G3 EEC), share features of type 1 and type 2 cancer and have not been classified as either. This study compares immunohistochemistry and survival in G3 EEC and type 2 cancers.nnnMETHODSnClinicopathological data compared with immunohistochemistry and survival in 156 consecutive patients with poor prognosis cancer-G3 EEC, uterine papillary serous (UPSC) and clear cell carcinoma (CC), sarcoma, carcinosarcoma and endometrial tumors of mixed histology. 131 (84%) datasets were complete, 25 tumors comprising sarcoma, carcinosarcoma or mixed histologies were excluded. Tissue microarray constructed and tested for estrogen receptor (ER), progesterone receptor (PR), p53 and human epidermal growth factor receptor-2 (Her-2).nnnRESULTSnThere was no significant difference in the mean age for G3 EEC (n=68) and USPC + CC (n=38), (68.01 and 67.08 respectively, p=0.697) or stage at diagnosis (p=0.384). For ER, PR, p53 and Her-2, there was no significant difference in marker positivity between G3 EEC and UPSC + CC (p=0.612, 0.132, 0.16 and 0.132 respectively). With a mean follow-up time 148 months Disease specific and recurrence-free survival between G3 EEC and USPC + CC was similar (p=0.842 and 0.863).nnnCONCLUSIONnG3 EEC and UPSC + CC share similar clinical, immunohistochemistry and poor survival. G3 EEC is better characterised as type 2 cancer and should be treated with similar adjuvant therapy to UPSC/CC.

Differential trends in the rising incidence of endometrial cancer by type: data from a UK population-based registry from 1994 to 2006.

Background:Endometrial cancer is the most common gynaecological cancer in the western world, the incidence increasing in the United Kingdom by over 40% since 1993. Two types of endometrial cancer exist – oestrogen-dependent type 1 with good prognosis and non-oestrogen-dependent type 2 with poor prognosis. The histopathological distribution of the increase in endometrial cancer is unknown. This study investigates the observed incidence trends of the two types, the age, stage, and socioeconomic distribution of this increase and survival outcome.Methods:Data were analysed from 6867 women with endometrial cancer registered between 1994 and 2006, at a UK population-based cancer registry.Results:Increased endometrial cancer incidence is confined to type 1 cancers with a significant increase in age standardised incidence rate (ASR) from 12.0 per 100u2009000 (confidence interval (CI) 10.7–13.2) in 1994 to 16.3 per 100u2009000 (CI 14.9–17.7), P<0.001 in 2006, while ASR of type 2 cancer changed from 2.5 per 100u2009000 (CI 2.0–3.1) in 1994 to 2.2 per 100u2009000 (CI 1.7–2.7) in 2006, which was not statistically significant P>0.05. Increase in type 1 cancer is most marked in age groups 60–69 years (P<0.001) and 70–79 years (P<0.001) and distributed equally among socioeconomic quintiles. While outcome for type 1 cancer has improved, 1-year survival in type 2 cancer is unchanged from 73.1% in 1994 to 74.3%, P=0.089 and 5-year survival decreased from 55.1% to 40.9%, P=0.001.Conclusion:Increased incidence in endometrial cancer is confined to type 1 cancers, seen most in the 60–79 age groups and across all socioeconomic quintiles. Survival in type 2 cancer has decreased significantly. Urgent research is needed to investigate prevention strategies in type 1 and improve therapy in type 2 cancers.

Tetraspanin CD151 is a novel prognostic marker in poor outcome endometrial cancer

Background:Type II cancers account for 10% of endometrial cancers but 50% of recurrence. Response rates to chemotherapy at recurrence are poor and better prognostic markers are needed to guide therapy. CD151 is a small transmembrane protein that regulates cell migration and facilitates cancer metastasis. High CD151 expression confers poor prognosis in breast, pancreatic and colorectal cancer. The prognostic significance of tetraspanin CD151 expression in poor outcome endometrial cancers was evaluated, along with oestrogen receptor (ER), progesterone receptor (PR), p53, human epidermal growth factor receptor -2 (HER-2), and CD 151 staining compared with α6β1, α3β1 integrins, and E-cadherin.Methods:Tissue microarray constructed from 156 poor outcome endometrial cancers, tested with immunohistochemistry and staining correlated with clinicopathological data were used. A total of 131 data sets were complete for analysis.Results:Expression of CD151 was significantly higher in uterine papillary serous and clear cell carcinoma than in grade 3 endometrioid carcinoma, sarcoma or carcinosarcoma (P<0.001). In univariate analysis, age, stage, histology type and CD151 were significant for both recurrence free (RFS) and disease specific survival (DSS). In multivariate analyses, CD151 was significant for RFS and DSS (P=0.036 and 0.033, respectively) in triple negative (ER, PR and HER-2 negative) tumours (88/131). The HER-2, p53, ER and PR were not prognostic for survival. There was strong concordance of CD151 with E-cadherin (98%), but not with α6β1 (35%), α3β1 staining (60%).Conclusion:The CD151 is a novel marker in type 2 cancers that can guide therapeutic decisions. CD151 may have an important role in tumourigenesis in some histology types.

Diagnosis of ovarian cancer

#### The bottom linennOvarian cancer is the seventh most common cancer in women worldwide, with 239u2009000 new cases diagnosed in 2012.1 As with many other types of cancer, geographical variation in the incidence of and mortality from ovarian cancer is substantial, with a higher incidence in economically developed regions of the world.2 Incidence is highest in the 50-70 year old age group, with 75% of cases diagnosed in women aged more than 55 years.3 In 80% of women the disease will be advanced at presentation, with a low five year survival rate; the all stage five year survival in the United Kingdom is 46%.4 This low survival rate in the UK has been recognised in the International Cancer Benchmarking Partnership and has been attributed at least partly to less timely diagnosis.5 This review summarises the presenting features, diagnostic tests, risk factors, and groups at high risk of ovarian cancer and is aimed at primary care practitioners and hospital doctors in other specialties.nn#### Sources and selection criteriannWe carried out an electronic search of PubMed, Medline, Embase, the Cochrane Library, and the Cochrane database of systematic …

Role of lymphangiogenesis in epithelial ovarian cancer

We investigated the significance of lymphatic count, vascular count and angiogenic growth factors using immunohistochemistry in 108 tumour specimens of epithelial ovarian cancer with antibodies to lymphatic vessel endothelial hyaluronan receptor (LYVE-1), platelet endothelial cell adhesion molecule CD31, vascular endothelial growth factor (VEGF) and thymidine phosphorylase (TP) in epithelial ovarian cancer to understand the pathogenesis of metastasis in ovarian cancer. The effect of prognostic variables on progression-free and overall survival was assessed. On multivariate analysis, bulky residual disease after surgery was the best prognostic indicator (P<0.001) for progression-free and overall survival (P<0.001). Lymphatic count was statistically significant as a prognostic factor for progression-free (P=0.05) and overall survival (P=0.04). However, lymphatic count did not impact on survival curves. No correlation was found between lymphatic count and age, histological subtype, FIGO stage or residual disease. Vascular count, VEGF or TP expressions were not significant in either analysis. Lymphatic spread may be significant in aiding metastases in ovarian cancer but requires other biological factors to act in conjunction, as it does not have clearcut prognostic significance. Dissemination of ovarian cancer does not occur primarily through vascular or lymphatic routes but may occur through direct intraperitoneal spread of disease.

Evaluating PET-CT in the detection and management of recurrent cervical cancer: Systematic reviews of diagnostic accuracy and subjective elicitation

Positron emission tomography–computed tomography (PET‐CT) is recommended to triage women for exenterative surgery and surveillance after treatment for advanced cervical cancer.

Sentinel lymph node biopsy in vulval cancer: systematic review and meta-analysis.

Background:The purpose of this study was to determine the accuracy of sentinel lymph node (SLN) biopsy with technetium 99 (99mTc) and/or blue dye-enhanced lymphoscintigraphy in vulval cancer.Methods:Sensitive searches of databases were performed upto October 2013. Studies with at least 75% of women with FIGO stage IB or II vulval cancer evaluating SLN biopsy with 99mTc, blue dye or both with reference standard of inguinofemoral lymphadenectomy (IFL) or clinical follow-up were included. Meta-analyses were performed using Meta-Disc version 1.4.Results:Of the 2950 references, 29 studies (1779 women) were included; most of them evaluated 99mTc combined with blue dye. Of these, 24 studies reported results for SLN followed by IFL, and 5 reported clinical follow-up only for SLN negatives. Pooling of all studies was inappropriate because of heterogeneity. Mean SLN detection rates were 94.0% for 99mTc, 68.7% for blue dye and 97.7% for both. SLN biopsy had pooled sensitivity of 95% (95% CI 92–98%) with negative predictive value (NPV) of 97.9% in studies using 99mTc/blue dye, ultrastaging and immunohistochemistry with IFL as reference. Pooled sensitivity for SLN with clinical follow-up for SLN-negatives was 91% (85–95%) with NPV 95.6%. Patients undergoing SLN biopsy experienced less morbidity than those undergoing IFL.Conclusions:Sentinel lymph node biopsy using 99mTC, blue dye and ultrastaging with immunohistochemistry is highly accurate when restricted to carefully selected patients, within a rigorous protocol, with close follow-up and where sufficient numbers for learning curve optimisation exist. Patients must make an informed choice between the slightly higher groin recurrence rates of SLN biopsy vs the greater morbidity of IFL.

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

OBJECTIVEnAlthough 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.nnnMETHODSnA 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.nnnRESULTSnThirty-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 survivalnnnCONCLUSIONnIf 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.