Classification systems in Gestational trophoblastic neoplasia - Sentiment or evidenced based?

Accepted Manuscript Controversy Classification Systems in Gestational Trophoblastic Neoplasia - Sentiment or Evidenced Based? V.L. Parker, A.A. Pacey, J.E. Palmer, J.A. Tidy, M.C. Winter, B.W. Hancock PII: DOI: Reference:

S0305-7372(17)30053-1 http://dx.doi.org/10.1016/j.ctrv.2017.04.004 YCTRV 1628

To appear in:

Cancer Treatment Reviews Cancer Treatment Reviews

Received Date: Revised Date: Accepted Date:

30 December 2016 7 April 2017 8 April 2017

Please cite this article as: Parker, V.L., Pacey, A.A., Palmer, J.E., Tidy, J.A., Winter, M.C., Hancock, B.W., Classification Systems in Gestational Trophoblastic Neoplasia - Sentiment or Evidenced Based?, Cancer Treatment Reviews Cancer Treatment Reviews (2017), doi: http://dx.doi.org/10.1016/j.ctrv.2017.04.004

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Classification Systems in Gestational Trophoblastic Neoplasia - Sentiment or Evidenced Based? V.L. Parkera, A.A. Paceya, J.E. Palmerb, J.A. Tidyb,c, M.C WinterC, and B.W. Hancockd. aAcademic

Unit of Reproductive and Developmental Medicine, Department of Oncology and Metabolism, The University of Sheffield, Level 4, The Jessop Wing, Tree Root Walk, Sheffield, S10 2SF; bDepartment

of Gynaecological Oncology, G18, Sheffield Teaching Hospitals NHS Foundation Trust, Royal Hallamshire Hospital, Glossop Road, Sheffield, S10 2JF; cSheffield

Centre for Trophoblastic Disease, Weston Park Hospital, Sheffield Teaching Hospitals NHS Foundation Trust, Whitham Road, Sheffield, S10 2SJ. dAcademic

Unit of Clinical Oncology, University of Sheffield, Weston Park Hospital, Whitham Road, Sheffield, S10 2SJ.

Keywords: Gestational Trophoblastic Disease Gestational Trophoblastic Neoplasia Classification System Prognosis Evidence

Corresponding author: Victoria Parker; [email protected]

Manuscript word count: 6151 Abstract word count: 194 Tables: 6

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Classification Systems in Gestational Trophoblastic Neoplasia - Sentiment or Evidenced Based?

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Abstract The classification system for Gestational Trophoblastic Neoplasia (GTN) has proved a controversial topic for over 100 years. Numerous systems simultaneously existed in different countries, with three main

rival

classifications gaining popularity, namely histological, anatomical and clinical prognostic systems. Until 2000, prior to the combination of the FIGO and WHO classifications, there was no worldwide consensus on the optimal classification system, largely due to a lack of high quality data proving the merit of one system over another. Remarkably, a validated, prospectively tested classification system is yet to be conducted. Over time, increasing criticisms have emerged regarding the currently adopted combined FIGO/WHO classification system, and its ability to identify patients most likely to develop primary chemotherapy resistance or disease relapse. This is particularly pertinent for patients with low-risk disease, whereby one in three patients are resistant to first line therapy, rising to four out of five women who score 5 or 6. This review aims to examine the historical basis of the GTN classification systems and critically appraise the evidence on which they were based. This culminates in a critique of the current FIGO/WHO prognostic system and discussion surrounding clinical preference versus evidence based practice.

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Introduction The main factor that has driven the development of a classification system for GTN is to identify, at the point of diagnosis, which patients will not respond to single-agent chemotherapy treatment. This is extremely important to guide subsequent management, and ensure that patients are treated with the most appropriate first line regimen, highlighting those who are likely to need more intensive therapy [1]. However, the classification of GTN has historically proven highly controversial, and prior to the combination of the FIGO and WHO classification system in 2000, multiple classification systems were used throughout the world [2]. Each comprised different combinations of prognostic risk factors for GTN (e.g. maternal age, blood group, smoking status) and attributed varying weighting to their clinical significance in terms of remission or primary cure. This variability renders attempts to compare the merit of each classification system extremely difficult, if not impossible, as depending on country of diagnosis, patients with the same risk factors would have a different prognostic assessment and receive different chemotherapy regimens (i.e. some would receive single-agent low-risk treatment whereas others would have highrisk combination chemotherapy). Therefore, it is not possible to compare time to primary remission, the percentage of patients cured by primary chemotherapy, and rates of relapse with any accuracy or validity. Even today, despite attempts to standardise the classification system worldwide, countries such as Japan continue to develop and utilise their own [3]. One of the main difficulties in generating a unifying classification system arises from the fact that GTN incorporates three distinct pathological diagnoses: (i) post-molar GTN; (ii) choriocarcinoma; and (iii) Placental Site (PSTT) and Epithelioid Trophoblastic Tumour (ETT). These heterogeneous subtypes differ in terms of incidence, clinical presentation and prognostic risk factors including antecedent pregnancy and interval, pathological, immunohistochemical and genetic characteristics [4]. Accommodating these differences within a single classification system is extremely difficult, and one of the reasons why the current FIGO/WHO scoring system is not validated for use in patients diagnosed with PSTT and ETT. CS Review Version 1.7.5 07/04/2017

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Despite difficulties concerning sample size given the rare nature of GTN, the literature on which classification systems and current management of GTN patients are based is frequently of low methodological quality and reproducibility. Conducting robust clinical trials that are not skewed by bias is problematic, an issue which was identified by the latest Cochrane review investigating first line chemotherapy in low-risk GTN, highlighting that the findings of several studies were influenced by selection, detection or reporting bias [5]. Further problems arise given that worldwide there is little standardisation in the management of GTN, with different centres using varying chemotherapy regimens, doses and administration schedules. Given the extremely high cure rate in trophoblastic disease, conducting clinical trials is also fraught with ethical dilemmas and anxiety in changing proven chemotherapeutic regimens, reducing the enthusiasm of clinicians and patients alike to engage in such research. These problems contributed to the early closure of a recent Gynecologic Oncology Group trial (GOG275) in low risk GTN. Furthermore, with the advent of national centralised registries for GTN patients, it has become increasingly evident that the current FIGO/WHO classification system is imperfect, with a significant proportion of patients being resistant to primary chemotherapy, which occurs in 25-35% patients classified as low-risk (WHO score ≤6) and 70-80 % of those with a WHO score of 5 or 6 [1, 5-14]. Suggested predictors of resistance to single-agent chemotherapy include a high pre-treatment hCG level [15], metastatic disease at diagnosis [8, 16] and a histological diagnosis of choriocarcinoma [17]. However, within the low-risk group, a more robust system is required to more accurately identify the 25-35% patients who are likely to require second line or more intensive treatment, after failing to respond to first line single-agent chemotherapy. This would enable tailored and more accurate counselling of patients from the outset, and potentially mediate the damaging psychological consequences to both the patient and their family of ‘failing’ to respond to treatment. Ultimately, this may also influence the selection of chemotherapy regimen (single-agent versus multiagent) offered to patients as first line treatment. Based upon this, several authors

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have called for a revision of the current FIGO/WHO classification system to more accurately predict from the outset, which patients will be resistant to primary chemotherapy to enable targeted, more efficacious treatment [9, 18-20].

Anatomical, histological and clinical classifications Histological classification Historically, the classification system for GTN has taken three rival approaches; an anatomical, histological or clinical prognostic score, with different research groups maintaining that each is superior to the other. The first histological classification of GTN dates back to Sänger in 1893 [21], who described the condition as a uterine sarcoma, subdivided into three morphological groups: (a) decidual sarcoma with chorionic elements (diffuse ulcerated, nodular nonulcerated and mixed nodular-ulcerative sub-types); (b) decidual sarcoma with chorionic elements following hydatidiform mole; and (c) interstitial, destructive hydatidiform mole. Subsequently in 1895, Marchand pioneered the introduction of a histological classification that was also guided by prognostic features; dividing patients into typical and atypical forms depending upon their clinical behaviour and outcome [22]. However, a competing system was born fifteen years later when Ewing classified

patients

according

to

their

histological

sub-type:

syncytial

endometritis, chorioadenoma destruens (invasive mole) and choriocarcinoma [23], which formed the basis of the histological GTN subgroups used in current practice. The main difficulty with a histological classification system was that it could not be used prospectively to predict prognosis and guide management, which led to significant delays in patient care and management. Furthermore, it required primary surgical management (hysterectomy), which was not routinely practiced or indeed indicated in such young women who wished to conserve their fertility. Increasing observational data also suggested that tumour type and the degree of trophoblast differentiation was not significantly associated with CS Review Version 1.7.5 07/04/2017

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prognostic outcome and chemotherapeutic response [18, 24]. It is clear that these histological classification systems were entirely based upon individual clinicians’ experience, with no robust validation studies on large patient populations. Despite these concerns, several years later in the 1960s, Japan developed a morphological classification system for GTN [18, 25]. Compared to previous histological classifications, this system more closely approximates the GTN subtypes that are used in current practice. However, if the histological diagnosis was unavailable, patients were classified as having a ‘clinically invasive mole’ or ‘clinical choriocarcinoma’ using a choriocarcinoma risk score developed in 1982, of which is still used today (Table 1: Japanese Morphological Classification and Risk Score for Trophoblastic Disease). Anatomical classification Inspired by the classification of other malignancies, a Beijing group developed an anatomical staging system endorsed by FIGO in 1982, which divided patients into Stage I-IV. Stage I involved disease confined to the uterine corpus, whereas stage IV was defined by distant metastases (Table 2: The Song classification system for GTN) [26]. This system was soon refuted as patient prognosis was found to vary considerably within each stage, indicating that other factors were more influential [18, 24]. Despite this, some units in China still use this classification system, highlighting the inconsistency with which GTN patients are risk stratified and managed, and the dominance of clinical preference and individual units’ experience rather than evidence based data. Clinical classification Evidence gradually mounted that clinical factors strongly influenced GTN prognosis, such as the presence of metastases or large tumour bulk. Following a conference in 1965, The International Union Against Cancer (UICC) produced the first combined anatomical and clinical classification system, including clinical factors such as the presence of metastases, antecedent pregnancy and history of previous treatment (Table 3: The UICC 1967 Classification for GTN) [16]. This

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followed a study in 1965, which was one of the first papers to identify clinical factors as important prognostic determinants [27]. The study involved a retrospective, single unit review of fifty patients with metastatic GTN who were sequentially treated with methotrexate and dactinomycin, of which 74% (thirtyseven out of fifty) achieved remission. Irrespective of the histopathological subtype or duration of disease, patients with hCG levels <1x106 mouse uterine units (MUU) had significantly higher remission rates (p<0.001). Furthermore, an interval of ≥4 months before starting chemotherapy was associated with reduced remission rates (p<0.025), irrespective of the hCG titre or histopathological diagnosis. The presence of cerebral metastases was also deemed a negative prognostic indicator. Histological sub-type, age, gravidity, antecedent pregnancy or history of previous hysterectomy ± oophorectomy did not significantly affect prognosis, yet statistical analysis was not provided within the paper. Unfortunately the number of patients receiving each regimen was not equally divided (methotrexate n=38, dactinomycin n=14), whilst the data suggests that the remission rates were higher amongst the group receiving primary dactinomycin (57% compared to 47% for methotrexate) or dactinomycin followed by methotrexate (60% compared to 47% for methotrexate followed by dactinomycin), this was not noted within the paper and statistical assessment was not provided. This may have distorted the interpretation of the importance of clinical prognostic factors, given that the data was pooled for this analysis, to include all remissions irrespective of the treatment administered. The study only involved metastatic GTN patients and a single unit’s experience, which combined with the above discussion, questions the study validity and generalisability. This is of particular concern given this paper has been influential in the development of subsequent prognostic classification systems, including the UICC 1967 classification for GTN. At the same time, The Japan Society of Obstetrics and Gynecology developed a rival classification system, which more closely approximates the modern-day FIGO/WHO prognostic classification system. The system combines anatomical criteria such as tumour location and metastatic site, with key clinical factors CS Review Version 1.7.5 07/04/2017

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including antecedent pregnancy, interval to commencing treatment and hCG titre, and is still used in Japan today in preference to the FIGO/WHO system [25]. A recent analysis re-classified 443 GTN patients according to the 2000 FIGO/WHO classification, who were initially scored using the Japanese Choriocarcinoma system [2, 18, 25, 28]. FIGO low-risk and high-risk disease tended to correlate with clinical invasive mole and clinical choriocarcinoma groups respectively within the Japanese system. Regarding drug resistance, primary remission and relapse rates, no significant difference was observed between patients classified as FIGO low-risk and clinical invasive mole on the Japanese score, or FIGO high-risk and clinical choriocarcinoma. Significantly higher relapse and resistance rates existed between the FIGO high-risk and lowrisk group (p=0.001) and Japanese choriocarcinoma versus invasive mole group (p=0.001), despite giving combination chemotherapy to the FIGO high-risk and clinical choriocarcinoma groups. The significant degree of chemotherapy resistance amongst patients with a FIGO score of 5-6 was evidenced by a separate sub-group analysis. Out of the fifty-two patients with a FIGO score of 5 or 6, seventeen were classified as clinical choriocarcinoma within the Japanese system and received combination chemotherapy, despite which, 25% patients experienced disease relapse. The remaining thirty-five patients were categorised as having a clinical invasive mole and were given single-agent first line treatment according to the Japanese classification, and has a statistically lower relapse rate of 5.7% (p=0.001). Interestingly, in patients with a FIGO score of 5-6, the rates of drug resistance were not significantly different amongst patients with a clinically invasive mole or choriocarcinoma based upon the Japanese classification system, despite administering combination chemotherapy to the choriocarcinoma group. This analysis prompted the authors to recommend using the Japanese classification system for patients with a FIGO score of 5-6; to facilitate the choice of chemotherapeutic agent; minimising unsuccessful treatment and disease relapse [28]. The validity of these conclusions is questionable however, given the method of re-classifying patients, which involved a significant proportion of patients given

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different first line treatment. In the FIGO/WHO classification, low-risk patients score 0-6 and are given single-agent chemotherapy, whereas high-risk patients score ≥7 and are given first line combination chemotherapy. However, twentyseven patients (25.7%) in the clinical choriocarcinoma group had a score <7 and three patients (0.9%) with a clinical invasive mole had a score ≥7, potentially distorting the findings. In 1973, the Southeastern Trophoblastic Disease Centre developed a competing clinical classification that paved the way for the current WHO classification system, dividing patients into good and poor prognostic groups based on features such as hCG level at diagnosis, duration of symptoms, antecedent pregnancy and previous chemotherapy treatment (Table 4: Hammond’s Southeastern Trophoblastic Disease Centre Clinical classification for GTN) [29]. This classification system was widely adopted throughout the USA. The classification was based upon a single unit, retrospective (1966 to 1971) analysis of eighty-eight patients with metastatic GTN, of which seventy-one patients (79%) were classified as having ‘good prognosis’ and seventeen (19%) had ‘poor prognosis’. Similar to the aforementioned studies [16, 18, 27], this analysis only included patients with metastatic disease. It is apparent that modern day GTN classification systems have been developed from a subset of patients that are not comparable to the current patient population, where the vast majority (75% (Author’s unpublished data)) do not have metastatic disease at presentation. Overall the classification is based upon the authors’ findings [30], a study involving sixty-two patients with metastatic GTN [31] and the aforementioned 1965 paper, whose methodology we have critiqued earlier in this review [27]. The clinical risk factors included in this classification system were entirely based upon relatively low quality, observational, single unit studies with small patient numbers and the use of varying treatment regimens, which is likely to confound the results. The study quality is additionally reduced by the inclusion of unequally sized prognostic groups (seventy-one versus seventeen patients). It is likely that PSTT and ETT patients, not yet characterised at this time, were

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erroneously incorporated into these analyses, particularly considering that a large proportion of these cases present with metastatic disease. PSTT and ETT should not be included in prognostic classification systems due to their differing biological behaviour. A rival and improved system was simultaneously underway in England in 1976, whereby a seminal paper identified twelve clinical risk factors to formulate the first weighted classification system (Table 5a: Bagshawe prognostic classification system (1976)), which indicated the relative prognostic importance of each factor and undoubtedly formed the foundations of today’s combined FIGO and WHO prognostic classification (Table 5b: The Combined FIGO/WHO prognostic classification system (2000)) [14, 32]. The system was based upon a retrospective analysis of 314 patients treated at a single unit (Charing Cross Hospital, London, UK) between 1958 and 1973 and found that chemotherapeutic response was definitively influenced by multiple factors, including antecedent pregnancy, interval between antecedent pregnancy and start of chemotherapy, parents’ blood group, maternal age, tumour burden as indicated by hCG level, extent of mononuclear infiltration in the tumour, patients’ immunological status, size of the tumour mass and the size and location of metastases [32]. The classification system divided patients into low, medium and high-risk groups, yet its widespread use was limited due to substantial variations in the score allocated to the same risk factors by different clinicians, and the fact that risk factors were often missed out due to a lack of clinical information or unavailability of some tests in developing countries [33]. Critically appraising this paper, the quality of the results may be reduced by the retrospective analysis, as prospective data are more accurate to prevent opportunistic analysis of multiple factors. The study is also limited by its use of data from only one unit, considering that the numbers in some groups (e.g. race, metastatic sites) were too small to statistically assess. Furthermore, statistical analyses were not applied to all risk factors, hence statistical significance is dubious; whilst in some cases, there was insufficient tissue for the research centre to validate the histological sub-type and diagnosis of GTN.

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Nevertheless, this system was adopted by the WHO in 1983, who simplified the classification system to contain only nine risk factors and adjusted the attributed weighting to 0-4 compared with 0-40 [34]. The WHO classification system classified patients into three prognostic groups to guide chemotherapeutic management; score ≤4 low-risk, 5-7 medium risk and ≥8 high-risk. Many centres worldwide used this system, yet the lack of evidence to support a specific, unified classification system was again revealed by the two UK Centres for Trophoblastic Disease (Weston Park Hospital in Sheffield, UK and Charing Cross Hospital in London, UK) using slightly different classification systems. Sheffield used the same nine risk factors but divided patients into only two treatment groups; score 0-7 low-risk, score >7 high-risk. In 1992, FIGO proposed a final update to the anatomical classification system, combining anatomical staging with two clinical risk factors; specifically hCG levels >100,000U/l and time to diagnosis >6 months [35]. However, through multivariate analyses, it was widely accepted that the WHO clinical classification system more reliably predicted outcome, due to the inclusion of multiple clinical risk factors influential in the development of GTN [24, 33, 36-41]. For several years, there was no worldwide consensus on the optimal classification system for GTN, largely due to a lack of high quality data proving the merit of one system over another. In 2000, the International Society for the Study of Trophoblastic Disease (ISSTD) gathered the leading experts in GTN and aimed to resolve the confusion and ambiguity surrounding the various classification systems, which reflects the weaknesses in them all [33]. The group decided to combine the FIGO anatomical and WHO clinical prognostic classification system: classifying patients with both metastatic and nonmetastatic disease into only two groups (low-risk 0-6 and high-risk ≥7), thus culminating in the FIGO 2000 guidelines [2]. The intermediate category was therefore removed; a decision predominantly based on data from one study, yet many experts agreed with this decision [14, 41]. In addition, the combined system removed blood group as a risk factor due to a lack of evidence regarding its influence on outcome, with several studies proving this on both univariate

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and multivariate analyses [36, 42-45]. Furthermore, blood group details were often lacking within clinical data and thus ‘missed out’ of the classification process. The weighting of risk factors was also changed to 0 to 4, liver metastases were deemed high-risk, scoring 4, and PSTT and ETT patients were excluded from the classification system due to the differing behavior of these sub-types. These recommendations were largely based upon six retrospective studies [38, 41, 42, 45-47] combined with the historical papers discussed previously, all of which have significant methodological flaws. Only one paper [41] investigated the impact of the new combined FIGO/WHO classification system by retrospectively re-scoring 201 patients treated for persistent GTN according to the original WHO classification system of 1983 [34], revised FIGO system of 1992 [35], and the proposed combined FIGO/WHO classification. With respect to chemotherapy resistance and outcome, all classification systems were largely similar, yet the FIGO/WHO classification system would have caused sixteen patients to receive different treatment. Of concern, four out of eight patients reclassified as low-risk by the FIGO/WHO system, who were originally classified as high-risk by the Sheffield system, were resistant to first line high-risk treatment, three of which were cured by second line chemotherapy. The paper also referenced unpublished data from Charing Cross in London, whereby a retrospective re-classification of 367 patients according to the combined system, would have changed the initial treatment in only three cases. The combined system increased the number of low-risk patients from 40-50% to 86%, which was suggested to minimise patient exposure to toxic high-risk chemotherapy regimens without compromising outcome [41]. Potential criticisms of this study include the retrospective analysis, yet the study involved a relatively large sample number considering the rare nature of the condition, and excluded patients with PSTT or atypical histology, which increased the accuracy of the results. The remaining studies on which the ISSTD based their decision to change the GTN classification system are highly variable in methodology, treatment

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administered to patients, and results generated, questioning the validity and robustness of the data upon which such fundamental changes were made (Table 6: Summary of articles on which ISTTD recommendations to combine the FIGO and WHO prognostic classification systems were based). None of the studies analysed the proposed impact of the new combined classification system, even by retrospective analysis. Instead, the studies jointly analysed patients who had previously failed primary treatment (often following inadequate regimens at non-specialist centres) with those who were treatment naïve, despite these being very different GTN groups. This confounded overall prognostic data and the interpretation of which risk factors influenced outcome [36, 38, 42, 45]. The recommended treatment regimens for patients with low versus high-risk, metastatic versus non-metastatic disease have changed significantly over time, leading studies to compile a retrospective group of patients who have had very different treatments, rendering the data incomparable for analysis of prognostic risk factors. Some studies only recruited patients with certain histological subtypes [38] or metastatic GTN [36], whilst others contained a combination [38, 42, 45]. As most GTN papers included patients with metastatic disease, clinicians have suggested that the combined classification should only include these patients. Those with non-metastatic disease could be over-treated if classified as high-risk [39]. It is not therefore surprising that these studies each identified different key prognostic markers on uni- and multivariate analysis (Table 6: Summary of articles on which ISTTD recommendations to combine the FIGO and WHO prognostic classification systems were based), yet the studies concurred that there was no evidence that several risk factors incorporated in the WHO system actually influenced prognosis. Remarkably, in the sixteen years since introducing the combined FIGO/WHO classification system, there has never been a prospective, validation study to test this classification system, despite the concerns raised by authors regarding the inclusion of risk factors that do not appear to influence outcome [18, 20, 36, 38, 42, 45]. This is particularly pertinent considering that over time, issues have emerged with the classification system. Some clinicians believe that it is a mistake not to include hydatidiform mole patients as Stage 0 within the

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classification system, to facilitate the monitoring of these patients given that 15% of complete hydatidiform moles develop GTN [1, 13, 18]. The optimal management of patients with a FIGO score of 5-6 remains one of the key challenges amongst trophoblastic disease specialists worldwide. Since the removal of the intermediate prognostic group a significant proportion of lowrisk patients (25-35%) are resistant to primary, single-agent chemotherapy. Amongst patients with a WHO score of 6, primary chemotherapy resistance can reach 80% [1, 5-14, 47]. These patients then require second line or more intensive chemotherapy regimens, with potential adverse psychological consequences for the patient and her family [13]. In Europe and Northern America, intramuscular methotrexate is generally favoured for managing low-risk patients with a score of 5-6, however an alternative therapy is dactinomycin, which is also used as a salvage regimen following first line methotrexate resistance. In many countries, methotrexate remains the treatment of choice in low resource areas, particularly considering its feasibility of administration as a more straightforward outpatient treatment [5, 48]. Dactinomycin requires intravenous administration, likely hospital admission if being given as a five-day regimen, and is associated with much higher treatment costs [49]. The recently updated Cochrane review included a total of 667 women in seven randomized control trials to compare the efficacy of methotrexate with dactinomycin inpatients diagnosed with low risk GTN. The group concluded with a moderate degree of certainty that dactinomycin was more likely to lead to primary remission and less likely to result in treatment failure compared to methotrexate. Evidence concerning the comparative side effect profile was more limited, yet dactinomycin, particularly the five-day regimen, was suggested to be associated with more adverse side effects [5]. On the other hand, it is equally problematic to administer more intensive, toxic combination chemotherapy regimens unnecessarily to patients who would have been cured by single agent therapy. Combination treatment is associated with a significant increase in more serious short-term effects including alopecia and

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myelosuppression, whilst long-term side effects include earlier menopause (brought forward by three years) and a 1.5 fold increase in the rate of secondary malignancies, particularly leukaemia [6, 50-55]. Etoposide has been reported to increase the risk of secondary breast, thyroid, colorectal cancer and melanomas [55, 56]. However, more recent data from Charing Cross in London involving 1903 patients followed up for an average of 16.9 years, concluded that the risk of a secondary malignancy was not increased following single agent methotrexate or combination therapy with EMA/CO (etoposide, methotrexate, dactinomycin, cyclophosphamide, vincristine). In fact, the risk of subsequent malignancy was equivalent to the general population [55-57]. Despite this, there remains an increased risk of secondary leukaemia in patients treated with combination chemotherapy, with 6 cases seen compared with 1.3 expected (Standard Incidence Ratio 4.5, 95% CI 2.0–10.1, p<0.01), with the risk increasing with higher alkylating agent and etoposide exposure [57]. For this reason, efforts are made to limit the duration of therapy to less than six months [11, 54-56]. Combination chemotherapy additionally accelerates the age of menopause. A recent study found that 13% women treated with combination chemotherapy (EMA-CO) had reached the menopause by age 40 years, rising to 36% by age 45 years. The rates of menopause were significantly higher (cumulative risk by age 35 years =0.09, p<0.01, cumulative risk by age 40 years = 0.28, p<0.05) in women who started treatment aged ≥30 years, compared to those treated at younger ages (<30 years) [57]. Fortunately, aside from accelerating the menopause, combination therapy does not otherwise effect fertility and evidence suggests that there is no increase in the rates of congenital abnormalities, miscarriage, ectopic pregnancy or stillbirth in future pregnancies compared to the general population [50, 58, 59]. Given the potential significant toxicity profile of combination chemotherapy, it is essential to optimise methods to identify patients most likely to be resistant to first line chemotherapy, to avoid under- or over-treatment and adverse short and longerterm consequences.

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As a strategy to reduce the use of multi-agent chemotherapy in low risk GTN patients who develop methotrexate resistance, carboplatin has recently been proposed as an alternative second line agent to combination chemotherapy. In this patient group, prior standard practice at our centre in Sheffield, recommended dactinomycin (intravenous bolus at a dose of 1.25 mg/m 2 every two weeks) if the hCG is <300IU/L or combination chemotherapy (EA (etoposide/dactinomycin [EA (E:100 mg/m 2 given intravenous, days 1–3, A:0.5 mg intravenous, days 1–3)], involving a two night hospital stay for patients every 10-days] if the hCG level exceeds 300IU/L at the time of treatment failure [55]. Using carboplatin AUC6 on a 3-weekly basis, instead of EA combination treatment, 81% (17/21 patients) achieved a complete hCG response, with four patients needing third line EA. Eleven of the 21 patients (52%) treated with carboplatin following first line treatment failure had a FIGO risk score of 5 or 6. Overall carboplatin was well tolerated, with the main side effect being myelosuppression. The regimen was suggested as a promising alternative regimen to combination chemotherapy in patients resistant to first line methotrexate, avoiding alopecia and in-patient treatment, and minimising exposure to combination regimens that are also associated with an increased risk of premature menopause and leukaemia [55]. A ’regression’ back to an intermediate prognostic group may not necessarily be the answer. However, patients more accurately identified to be at the highest risk of non-response to single-agent methotrexate could be offered alternative, most likely multi-agent, chemotherapy from the outset, which may limit the psychological consequences of ‘failing’ first line treatment. Ultimately, the aim would be to reduce the need for sequential lines of chemotherapy and shorten treatment duration. However, in the UK using the current scoring classifications, and given that the survival rate in low-risk disease is 100%, the current consensus is that patients should be treated with the least toxic, single-agent therapy first line to avoid exposure to more toxic multi-agent regimens if at all possible [1, 15, 18, 60]. Furthermore, it appears that non-response to first line single-agent chemotherapy does not significantly increase the length of treatment [15]. Some clinicians recommend counselling patients with their

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treatment options; allowing them to make an informed choice between first line single or combination chemotherapy [17]. Such practice is carried out at Charing Cross Hospital, where patients with poor prognostic markers; FIGO score of 5-6 or hCG level >100,000IU/L) are offered either low risk single agent methotrexate or combination therapy with EMA/CO [15].

Future perspectives In light of the issues raised with the current FIGO/WHO scoring system in more accurately identifying first line chemotherapy resistance, several novel approaches have been proposed including hCG regression; hyperglycosylated hCG; ultrasound features; microRNA and cell free DNA. These will be discussed briefly below. hCG regression The pattern and fall of hCG following uterine evacuation has been proposed as a useful indicator for predicting the development of GTN, but also for the early identification of first line, single agent chemotherapy resistance. By comparing the regression of hCG in benign moles whose hCG levels spontaneously resolve, to those who ultimately develop GTN, linear regression lines and area under the curve calculations have been generated to predict over half of GTN patients with a high specificity (97.5%) [61]. Crucially, these calculations can identify GTN earlier than is currently possible. Further preliminary work on the regression of hCG has revealed that hCG measurements before the fourth and sixth course of single agent chemotherapy (approximately seven weeks into treatment) can accurately identify primary treatment resistance [62]. Studying 800 patients with low risk GTN, a modeled kinetic parameter called hCGres can be calculated after only three cycles of methotrexate to identify patients with chemotherapy resistance. The study purported hCGres with a cut off value of 420.44 IU/L as a more accurate predictor of methotrexate resistance than other factors [63], and was recently validated in 210 patients by the Gynecologic Oncology Group-174 Phase III trial (GOG-174) having a sensitivity of 88.9% and specificity of 73.1% [64]. Further prospective validation is now required.

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Hyperglycosylated hCG (hCG-H) Lawrence Cole has pioneered the role of hCG-H, recommending its use as a highly sensitive and specific tumour marker that can differentiate between premalignant and malignant disease and predict the need for chemotherapy. Cole describes two distinct clinical entities of ‘quiescent’ and ‘minimally aggressive GTD’. ‘Quiescent’ GTD is characterised by the absence of hyperglycosylated hCG, representing a group of pre-malignant cases who will ultimately transform, whereas ‘minimally aggressive GTD’ is an in-between state between highly aggressive disease (with a high proportion of hCG-H in the total hCG count) and quiescent disease. In minimally aggressive GTD, hCG-H levels are typically <40% of total hCG, representing a gradually progressive condition that is characterised by slow hCG doubling times and is believed to represent the group who are resistant to primary chemotherapy [65-67]. However, Cole’s work has been critiqued by numerous trophoblastic disease experts worldwide, who feel the conclusions are misleading due to absent clinical data and inadequate follow up. Prospective or validation upon a larger patient population is recommended prior to the introduction of this marker into routine clinical practice [68-70].

Ultrasound features The ultrasonographic features of trophoblastic disease have recently been suggested as a marker for the early differentiation between benign and malignant disease and a predictor of first-line chemotherapy resistance. Significant differences were identified between healthy controls and patients diagnosed with trophoblastic disease (benign and malignant subtypes), using ultrasound parameters including the resistance (RI), flow (FI), pulsatility (PI), vascularisation (VI) and vascularisation-flow indices (VFI). Moreover, low RI, high VI, FI and VFI appeared to characterise malignant compared to benign trophoblastic disease, while the VI, FI and VFI fell concurrently with hCG levels in keeping with an effective chemotherapeutic response [71]. Ultrasound has additionally been used to denote chemotherapy response and disease resistance amongst patients with low-risk, stage I GTN. Reduced echogenicity of myometrial lesions, decrease in Doppler signal or size were indicative of a radiological response to chemotherapy. In three cases of methotrexate resistance CS Review Version 1.7.5 07/04/2017

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as denoted by a refractory hCG response, ultrasound features could be successfully used to guide ongoing therapy, recommending that methotrexate should be continued in the presence of an ultrasound response. All three of these patients achieved a complete response and avoided unnecessary combination chemotherapy [72]. Finally, a group from Charing Cross has investigated the role of Doppler ultrasound, specifically uterine artery pulsatility index (UAPI) in predicting first line chemotherapy resistance. UAPI is inversely proportional to the vascularity of the tumour; therefore a larger uterine tumour with more vascular, abnormal angiogenesis would have a lower UAPI. Specifically, patients with a FIGO score of 5-6 have been studied; identifying vascular uterine tumours with a UAPI ≤1 to be an independent risk factor for resistance to first line methotrexate [11, 73, 74]. Specifically, in patients with a UAPI ≤1 and a FIGO score of 5 or 6, 81% and 100% respectively were resistant to first line methotrexate. Pending the outcome of a larger validation study, the group advocates a role for UAPI in guiding clinical management; suggesting that patients with a FIGO score of 5-6 and a UAPI ≤1 should be offered first line combination chemotherapy, due to the very high rates of methotrexate resistance [74].

Biomarkers The most novel and exciting future direction for GTN is the identification of reliable biomarkers to predict disease resistance or even malignant conversion much earlier than is currently possible. Currently, the role of microRNA and cell free DNA is under exploration. microRNA is one of the most rapidly expanding scientific fields and is certainly an area for further investigation with respect to trophoblastic disease. In a small patient cohort, specific circulating microRNAs (hsa-miR-520b, hsa-miR-520f and hsa-miR-520c-3p) have been identified in patients diagnosed with complete hydatidiform moles that either spontaneously resolve or develop into GTN [75, 76]. These biomarkers may ultimately prove useful as an adjunct to hCG in the monitoring of GTN and chemotherapeutic response. In addition, using formalin foxed trophoblastic tissues, a specific microRNA (miR-21) has been found to be CS Review Version 1.7.5 07/04/2017

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significantly upregulated in patients with hydatidiform moles compared to normal, healthy placentas. Using quantitative real time PCR and Western Blotting, miR-21 had an important role in the dysregulation of normal cellular mechanisms in choriocarcinoma, and therefore plays a role in the aggressive nature of this condition [77].

Currently, there is one published article detailing the role of plasma derived cell free DNA (cfDNA) in diagnosing trophoblastic disease. Circulating tumour DNA was successfully identified in twelve out of twenty GTN patients, with potential future applications for earlier diagnosis. Furthermore, circulating tumour DNA proved helpful to confirm cases of GTN in patients of diagnostic uncertainty/inconclusive histology [78].

Discussion Critically appraising the criteria by which prognostic risk factors have historically been included within the classification systems leaves significant questions regarding the accuracy and reliability of the currently used FIGO/WHO classification system. Researchers from different countries have developed their own classification systems based on individual, single unit experience, involving relatively small patient numbers and observational data with little scientific rigor. Key statistics are often absent or involve wide confidence intervals, raising questions regarding the reliability and precision of the findings. Conclusions are often based on factors that ‘appear’ to be significant, reliant only upon the clinician’s clinical experience. Remarkably, despite being in existence for over a decade, the currently adopted FIGO/WHO classification system has never been tested prospectively. There is no statistical proof that the included risk factors do indeed influence prognosis, and no evidence base for the attributed weighting to each risk factor. Put simply, it seems that clinicians have continued to use this system based on sentiment and familiarity, rather than true evidenced based medicine.

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Worldwide, GTN continues to be managed in small hospitals by clinicians who have limited experience of the condition. Therefore, one of the major challenges to introducing a new classification system will arise from its global dissemination and widespread adoption. Potential dissemination strategies include adoption of the updated classification system by the International Society for the Study of Trophoblastic Diseases (ISSTD) and the European Organisation for Treatment of Trophoblastic Diseases (EOTTD). In addition, FIGO and WHO should distribute knowledge, standardise management and generate comparable data suitable for multi-centre clinical trials. Moreover, it is known that outcome and survival rate is much higher amongst patients treated by specialist, experienced clinicians in designated centres, highlighting the importance of a globally adopted system [79]. The need for an updated classification system is particularly pertinent given the high rates of primary chemotherapy resistance amongst low-risk patients scoring 5 or 6, who subsequently need a change in systemic therapy to potentially more intensive chemotherapy regimens, which has a significant physical and psychological impact upon these women and their families. In addition, a prognostic classification system is urgently needed for patients diagnosed with PSTT and ETT who are currently excluded from the FIGO/WHO system due to the differing tumour characteristics and behaviour [13]. There are several exciting approaches under investigation that may prove useful as an adjunct, or even as an improved prognostic marker, in future practice. Based upon exiting work in other malignancies [80]; the authors believe a particularly promising future lies with microRNA. Whilst the inherently rare nature of GTN may lend itself to studies with relatively small sample sizes and low power, this must be countered by large, multi-site studies including several accredited GTN centres worldwide. Only this way can clinicians rigorously test the classification system and ensure that GTN patients are managed using truly evidenced based medicine.

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Table 1: Japanese Morphological Classification and Risk Score for Trophoblastic Disease) [18, 25]. Copyright 1982, with permission from John Wiley and Sons. (a) Morphological Classification for trophoblastic disease 1. Total (or complete) hydatidiform mole 2. Partial hydatidiform mole 3. Invasive (or destructive) hydatidiform mole 4. Choriocarcinoma a) Post-molar persistantly high hCG level 5. Persistant trophoblastic disease b) Clinically invasive (or destructive) mole c) Clinical choriocarcinoma

(b) Japanese Choriocarcinoma Risk Score Score Parameter Preceding pregnancy

0

1 3 Probability of choriocarcinoma (%) <50 50-60 70-80 Hydatidiform Abortion mole

4

5

80-90 −

>90 Delivery

Interval time

<6 months

-

−

6 months to 3 years

≥3 years

Primary tumour

Corpus/ parametrium/ vagina

-

Tube/ovary

Cervix

Extra-pelvic

None/lung/ pelvis

-

-

−

Extra pelvic (except lung)

<20

-

20 to 30

-

b) Size

Uniform

-

-

Variety in size

c) Number Urinary hCG (mIU/mL) Menstrual cycles

≤ 20 < 106

-

-

-

106 to 107

≥107

-

-

-

−

Metastatic site Lung metastases a) Diameter (mm)

Monophasic (irregular)

≥30 Variety in size ≥21 Biphasic (regular)

Score ≤4 = Clinical invasive mole, recommend first-line single-agent chemotherapy Score ≥5 = Clinical choriocarcinoma, recommend first-line combination chemotherapy

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Table 2: The Song classification system for GTN [26]. Copyright 1981, with permission from Publisher. Stage I II III

Description A B A B

IV

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Disease confined to the uterus Disease extends to the adnexa and parametria Disease extends to the vagina Disease extends to lung and metastases are <3cm in diameter or mottling in less than half of one lung. Disease extends to lung and metastases are >3cm in diameter or mottling in more than half of one lung. Disease extends to other organs e.g. brain, liver, kidney and bowel.

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Table 3: The UICC 1967 Classification for GTN [16]. Copyright 1967, with permission from Springer. A B

Gestational Non-gestational

I. CLINICAL DIAGNOSIS 1) Non-metastatic 2) Metastatic 3) Other required information

a) Local (pelvic) b) Extrapelvic (specify location) a) Evidence i) Morphological ii)Non-morphological b) Antecedent pregnancy – specify duration i) Normal ii) Abnormal iii)Molar c) Previous treatment i) Untreated ii)Treated, specify

II. MORPHOLOGICAL DIAGNOSIS 1. Hydatidiform mole 2. Choriocarcinoma 3. Uncertain 4. Other required information

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a) Non-invasive b) Invasive

a) Diagnostic basis – specify i) C =curettage ii) U = excised uterus iii) N= necropsy iv) O= other b) Date of diagnosis (with respect to date of onset of treatment) c) Subsequent change in morphological diagnosis – specify diagnosis as in II.4a

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Table 4: Hammond’s Southeastern Trophoblastic Disease Centre Clinical classification for GTN [29]. Copyright 1973, with permission from Elsevier. I II A 1. 2. 3. 4. 5. B 1. 2. 3. 4. 5.

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Non-metastatic GTN Metastatic GTN Good Prognosis Urinary hCG < 100,000 IU/24hr urine or < 40,000 IU/L serum Symptoms present for less than 4 months No brain or liver metastases No prior chemotherapy Pregnancy event is not term delivery (i.e.. mole, ectopic or spontaneous abortion Poor prognosis Urinary hCG > 100,000 IU/24hr urine or > 40,000 IU/L serum Symptoms present for more than 4 months Brain or liver metastases Prior chemotherapeutic failure Antecedent term pregnancy

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Table 5: Weighted prognostic classification systems. (a) Bagshawe prognostic classification system (1976) [32]. Copyright 1976, with permission from John Wiley and Sons. Score

0

10

20

40

Age (years) Parity Antecedent pregnancy Histological diagnosis

<39 1,2, >4 Mole Invasive mole

≥39 3 or 4 Abortion Not known

– – – –

Interval (AP to start of chemotherapy) (months) hCG (plasma IU/L or urine IU/day) ABO groups (patient x husband)

<4

4–7

– – Term Choriocarcinom a 7–12

103–104

<103

104–105

>105

AxA O or A x B O or A x AB None Not detected Lung, vagina 3

O x O, A x O O x A, B x B AB x B 1-4 Spleen Kidney 3–5

BxOxA AB x O x A

–

4-8 Gastrointestinal tract, liver 5

>8 Brain

Marked

Moderate or unknown Unknown –

Slight

–

Unreactive Yes

– –

Number of metastases Site of metastases Largest tumor mass diameter (cm) Lymphocytic infiltration of tumour Immune status Relapse after previous chemotherapy

Reactive –

>12

–

(b) The Combined FIGO/WHO prognostic classification system (2000) [14]. Copyright 2000, with permission from Elsevier. FIGO Anatomical Stage Stage I II

Disease confined to the uterus GTN extends outside of the uterus but is limited to the genital structures (adnexae, vagina, broad ligament) GTN extends to the lungs, with or without known genital tract involvement All other metastatic sites

III IV

Modified WHO Prognostic Classification System, as adapted by FIGO Score

0

1

2

4

Age (years) Antecedent pregnancy Interval months from index pregnancy Pre-treatment hCG (IU/L) Largest tumor size including uterus (cm) Site of metastases Number of metastases Previous failed chemotherapy

<40 Mole <4

≥40 Abortion 4–6

– Term 7–12

– – >12

<103

103–104

104–105

>105

<3

3–4

≥5

–

Lung – –

Spleen, kidney 1–4 –

Gastrointestinal 5–8 Single drug

Liver, brain >8 ≥2 drugs

Score 0-6 = Low-risk, Score ≥7 = High-risk.

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Table 6: Summary of articles on which ISTTD recommendations to combine the FIGO and WHO prognostic classification systems were based Author, Year

Methodology

Kim et al., 1998 [45]

 Retrospective analysis, 1982-1995  2 main centres, 2 smaller units  165 GTN patients treated with EMA/CO first line (high-risk patients, WHO score ≥8, n= 96) or after 1st (n=61) or 2nd line (n=8) treatment failure with a variety of agents including MTX, MAC, CHAMOCA). FIGO stages Ib to IVc.  Overall 136 (83.6%) survived, 27 (16.4% died)

Ngan et al., 1994 [36]

 Retrospective review, 1976-1988, 2 centres  2 centres  55 patients with metastatic GTN, all treated with CHAMOCA, FIGO stages II-IV.  16 patients received 1st line treatment prior to this with poor response.  Overall 39 (71%) survived, 16 (29%) died.

Results -univariate analysis Significant prognostic determinants: Tumour age (p=0.002), initial hCG level (p=0.021), metastatic site (p=0.001), number of metastatic organs (p=0.001), unplanned operation (p=0.003), gravidity (p=0.034) and inadequate previous chemotherapy (p=0.012)

Comments

Stepwise-Cox Proportional Hazards Regression, significant factors related to survival:

 Combined analysis of patients who had failed previous chemotherapy and those who were treatment naïve.  Only performed multivariate analysis on factors significant on univariate analysis.  Many factors in WHO classification system were not significant determinants of prognosis.  Conclude that the WHO score is not accurate at predicting outcome due to the wide range of predicted survival probabilities.  No improvements to prognostic classification system suggested.

Tumour age (p=0.0029), number of metastatic organs (p=0.0002), metastatic site (p=0.00249), inadequate previous chemotherapy (p=0.0312).

Other factors within the WHO classification system were not significant; age (p=0.242), antecedent pregnancy (p=0.086), blood type (p=0.290), largest tumour size (p=0.159) and number of metastases (p=0.715).

Significant factors in the WHO classification system on stepwise logistic regression:

Significant prognostic determinants:

Cox multiple regression analysis:

Interval between antecedent pregnancy and GTN diagnosis (p=0.004), urinary hCG at presentation (p=0.02), number of metastatic sites (p=0.046).

Intervals from antecedent pregnancy to diagnosis and hCG level were the two main factors significantly related to survival.

WHO score >8 associated with a higher probability of death (p=0.003). FIGO stage II-III no significant difference in probability of dying compared to stage IV patients (p=1.0). Other factors within the WHO classification system were not significant; age (p=0.32), antecedent

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Results – multivariate analysis

Tumour age (p=0.0029), number of metastatic sites (p=0.0002).

 Combined analysis of patients who had failed previous chemotherapy and those who were treatment naïve. Type of first line chemotherapy not described.  Statistics for multivariate regression not provided within the paper.  Concluded that the WHO classification system was not precise in predicting patient prognosis, due to the range of predicted survival probabilities.  WHO system deemed more predictive of outcome than the FIGO classification.  WHO system contains many factors that do not significantly influence prognosis.  Recommend a prospective trial with a simpler classification system including

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Soper et al., 1994 [42]

 Retrospective review, 1968-1992, single centre  454 patients with metastatic and nonmetastatic GTN; 385 for primary therapy, 69 for second line treatment.  Overall 90% survival, 96.3% for those having primary chemotherapy, 60% for those receiving second line treatment (p<0.0001).  Range of FIGO stages Ia-IVc.

pregnancy (p=0.13) blood group (p=1.0), lesion size (p=1.0), number of metastases (p=0.33), site of metastases (p=0.48), previous chemotherapy (p=0.72). Significant prognostic determinants: For all factors, p< 0.0001: Duration of disease, type of antecedent pregnancy, clinicopathological diagnosis, anatomic site of highest risk metastases, number of metastatic sites or foci, maximum extrauterine tumour size and type of prior therapy. Maternal age was also significant (p<0.02) hCG level, year of diagnosis and type of chemotherapy used were not significant (p<0.1).

Hancock et al., 2000 [41]

 Retrospective review, 1986-1996, single centre  201 patients with GTN  Overall 198 (99%) survived, 3 patients (1%) died.  Histology: 85% complete hydatidiform mole, 9% choriocarcinoma, 6% partial mole.  Stages I-IV disease

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Patients retrospectively scored according to the Charing Cross, FIGO 1992, WHO 1983 and modified combined FIGO/WHO classification system. With respect to chemotherapy resistance and outcome, the classification systems were similar. New combined system generated a higher proportion of low-risk patients (86%) compared to 46% with WHO system and 51% using FIGO classification.

only significant risk factors highlighted in this study. Significant prognostic determinants: Prior therapy (p<0.004), antecedent pregnancy (p<0.05), number of metastatic sites (p<0.0001) and duration of disease (p<0.006) Clinicopathological diagnosis (p<0.07) and pre-treatment hCG level (p<0.04) were borderline risk factors, but not independent risk factors when patients with metastatic disease and primary therapy were analysed separately.

Sixteen patients would have received different treatment according to the new FIGO/WHO classification system: 8 patients were low-risk on the Sheffield classification system and high-risk on the combined FIGO/WHO system, of which 3 were resistant to primary single-agent chemotherapy. 8 patients high-risk on the Sheffield system were classified as low-risk by the combined FIGO/WHO system, of which 4 were resistant to first line high-risk chemotherapy.

 Compared several classification systems; FIGO anatomic system of 1992, WHO clinical prognostic system of 1983 and the historical clinical classification system.  Patients were divided into primary and second line therapy for the analysis; all systems stratified patients into low or high-risk groups with equal efficacy with statistical significance reached.  State benefits of the more complex WHO system are unclear.  However, no comment on whether one classification system deemed superior to the others in predicting survival.  First paper to statistically prove that FIFO score is associated with outcome.  Claim no classification system accurately predicts outcome.  New FIGO/WHO classification system means that fewer patients are exposed to aggressive high-risk chemotherapy regimens, with reduced early and late toxicity.  Suggest that the proposal to combine the modified FIGO/WHO classification and divide patients into two prognostic groups (low-risk and high-risk) is realistic and practicable.  Recommend a prospective study to validate the new classification system.

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Lurain et al., 1991 [38]

 Retrospective review, 1969-1988, single centre  391 patients with GTN (invasive mole and choriocarcinoma)  223 (57%) had non-metastatic disease, 168 (43%) had metastatic disease.  Overall 363 (93%) cured; 223 (100%) patients with non-metastatic disease and 139 (83%) with metastatic disease.  Stages I-IV disease

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Significant prognostic determinants:

Significant prognostic determinants:

hCG level (p=0.05), duration of disease (p=0.0003), antecedent pregnancy (p=0.001), site of metastases (p<0.0001), number of metastases (p<0.0001), number of metastatic sites (p<0.0001), tumour size (p<0.0001), clinicopathological classification (p=0.0001) and previous chemotherapy (P=0.0005).

Number of metastases (p<0.0001), metastases to sites outside the lung or vagina (P=0.0002) and previous failed chemotherapy (p=0.0014). Compared the FIGO 1982, WHO 1983, Hammond and UICC classification system, all 4 significantly predicted outcome (p<0.0001), but the UICC score was the strongest overall predictor of survival (highest χ2 score).

 Combined analysis of patients who had

failed previous chemotherapy and those who were treatment naïve.  Authors excluded presence of metastases and clinicopathological diagnosis from multivariate analysis as noted only patients with metastatic choriocarcinoma died. This may have confounded the data.  Concluded WHO score was an important predictor of treatment outcome but UICC score had higher χ2 score.

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Highlights for manuscript entitled: Classification Systems in Gestational Trophoblastic Neoplasia- Sentiment or Evidenced Based?    

Critically appraising the classification systems for Gestational Trophoblastic Neoplasia Are they based on evidence or sentiment? Patients with a WHO score of 5-6 have high rates of primary chemotherapy resistance. Is it time for an updated classification system to help identify this patient group?

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