From National to International Collaboration in Gestational Trophoblastic Disease: Hurdles and Possibilities

Abstract

Background

Today, most women with gestational trophoblastic disease (GTD) can expect to be cured, particularly if they live in middle- to high-income countries with access to GTD centres. In contrast, countries lacking organized GTD care achieve lower survival rates.

Objectives

The aim of the study was to review and consider some of the successes and areas for improvement in GTD care that have been achieved through national and international collaborations.

Methods

The authors searched PubMed and used their own knowledge of working nationally and internationally in GTD to write this review.

Conclusions

The establishment of expert centres and national systems for managing GTD is associated with the best disease outcomes. National and in particular international collaboration is most likely to result in further optimisation of management protocols and outcomes.

Outlook

It remains crucial for countries lacking GTD centres to try to establish such facilities with support from national agencies and international expert societies.

Introduction

Gestational trophoblastic diseases (GTDs) include a spectrum of disorders spanning from the pre-malignant conditions of hydatidiform moles through to the rare malignant disorders called gestational trophoblastic neoplasia (GTN) consisting of invasive mole, choriocarcinoma and, even more rarely, placental site and epithelioid trophoblastic tumours (PSTT/ETT) [1, 2]. The very high rates of survival for GTN patients treated as recommended by national or international guidelines tend to prove the importance of disseminating these recommendations and, at least for certain complicated cases with a very high risk of death [3–5], the importance of centralizing care in dedicated expert centres [6]. The collaboration of experts in trophoblastic diseases is possible and already in place in several but far from all European countries [7], resulting in the highest possible cure rates with the minimum of side effects. The organization in centralized national networks then makes it possible to obtain such results [6]. However, the availability of high-level skills regarding such rare tumours cannot be achieved homogeneously across all EU countries and more generally across all countries in the world [8]. And yet, as an estimate of the burden of this rare disease, it is considered that each year over 20,000 women of childbearing age will develop GTN globally. To improve outcomes, organized international collaborations should make it possible to provide each patient suffering from GTN with the necessary diagnostic and therapeutic resources. An example of this is provided by the European reference network for rare cancers, European Rare Adult Cancer Network (EURACAN), organized by the European Union [9].

National Co-Operation

The optimization of the national management of GTN is primarily based on the possibility of monitoring the evolution of the pre-malignant forms of GTD, namely, hydatidiform moles. The constitution of a national network based on local obstetricians, gynaecologists, and pathologists (histopathology and chemical pathology) working closely with a GTD centre expert in histopathological review [10], hCG reference assays [11], clinical management of GTN, and aided by specialists in molecular genotyping [12], makes it possible to improve the diagnosis and treatment of GTD. This is in part achieved by first sensitizing doctors to the importance of monitoring hCG after evacuation of a hydatidiform mole, knowing that nearly 3 in 4 GTN occur in the aftermath of a mole. This network will then make it possible, by disseminating knowledge of the 2000 FIGO criteria for GTN [13], to reduce the time to diagnosis of GTN, thus enabling simplified chemotherapeutic treatment that may be necessary and also improving the prognosis of the disease. The rise of hCG on at least three consecutive weekly measurements over at least 2 weeks or the plateauing of hCG on at least 4 consecutive weekly measurements are the usual modes of diagnosis of a GTN occurring after a mole. These two criteria illustrate the very usual independence of the diagnosis of GTN from pathological criteria, unlike almost all human malignancies. This specificity, which makes it possible to introduce chemotherapy without histological proof, should not obscure the fact that the diagnosis of GTN can occasionally be made on the pathology of a biopsy from the uterus or from a metastatic site, particularly in the post-partum setting [8]. However, the recognition that biopsies can precipitate life-threatening haemorrhage should not be forgotten, so any attempt to obtain tissue in a woman with suspected GTN should always be discussed with an expert centre. Moreover, such expert centres may now have the ability to diagnose GTN on liquid biopsies [14].

The ability of such national networks, when it is possible to build them, to help practitioners follow up on patients who have had a mole is certainly a major asset for raising the overall level of treatment for GTN. The structuring of this network has the main objective, in addition of allowing an earlier diagnosis of the malignant forms of the disease, of helping to standardize the treatment of these patients. It will thus make it possible to avoid under-treatment or over-treatment with non-adapted chemotherapy regimens, to recommend or avoid hysterectomies in women of childbearing age [15], and sometimes to justify hysterectomies in the rarest forms of GTN, namely, PSTT and ETT. Countries that have achieved national GTD/GTN care networks report improved survival rates [6, 8].

International Collaborations

The proper functioning of such national networks depends on the capacity of a state to finance the necessary staff and technical know-how. The heterogeneity of resources and socio-economic development within the different countries of the European Union, makes it possible to understand that such networks cannot exist in each member state, thus justifying the creation of European reference networks for rare tumours. The EURACAN is such a virtual network connecting patients with such malignant diseases and healthcare providers across Europe. It aims to provide the skills and highly specialized care necessary for the management of these rare tumours on the scale of the European Union and the countries associated with this approach. Thus, 24 countries are affiliated to EURACAN, which is one of the 24 ERNs for tumours or other rare and complex diseases. EURACAN brings together 10 domains of rare tumours including domain G2, which concerns rare cancers of the female genital organs and placenta [9].

Alongside the organized collaboration allowed by the European Union, more global international co-operation is essential for the harmonization of guidelines and for optimal scientific research for diseases whose numbers are too small at a local or regional level. Indeed, international collaborations between GTD centres have already been shown to be important. For example, it was widely thought that patients with low-risk GTN whose FIGO score was 5 or 6 had a relatively low chance of achieving remission with relatively non-toxic single-agent therapies such as methotrexate or actinomycin D [16]. Consequently, some international experts were minded to manage such patients with much more toxic multi-agent chemotherapy [17]. However, by combining patients from GTD centres in Brazil, the USA, and the UK, it was possible to have enough FIGO 5–6 cases treated in a homogenous fashion to demonstrate that 60% could enter remission with methotrexate or sequential actinomycin D, thereby sparing the need for multi-agent chemotherapy [18]. Moreover, this collaboration also identified 3 sub-groups in the remaining 40% of patients who started single-agent therapy but ended up needing combination-agent chemotherapy, where the latter could have been started from the outset [18]. This type of international study with large case numbers, while retrospective is more likely to change practice globally than single-centre studies. Another important international collaboration is now underway involving the European Society of Gynecologic Oncology (ESGO) together with the European Organization for Treatment of Trophoblastic Disease (EOTTD), the International Society for the Study of Trophoblastic Disease (ISSTD), and the Gynecologic Cancer InterGroup (GCIG). This project is updating the practical clinical guidelines of the EOTTD for treatment and referral of GTD/GTN patients [19] to make a global set of consensus guidelines. If successful, this should help facilitate the development of more expert GTD centres serving national networks in many other countries across the globe.

Existing and Future Collaborations

One approach to improving our understanding of GTD and how to manage the resulting tumours has been the establishment of international databases. The first of these was driven by the ISSTD and was focused on registering all cases of PSTT/ETT from as many international centres as possible. This has enabled us to examine the behaviour and prognostic factors of, for example, ETT the rarest form of GTN. The initial findings have shown that this tumour appears to behave like PSTT in that an interval greater than 4 years from the end of the causative pregnancy and advanced stage are independent adverse prognostic factors [20]. This database has now been expanded to include ultra-high-risk GTN, another patient group that can have a worse survival and where more information is needed [4].

It has been previously noted that the FIGO scoring system used to determine the use of single verses combination-agent chemotherapy in non-PSTT/ETT GTN is not as predictive as we would like. Indeed, several studies have looked at trying to improve the accuracy and/or simplify FIGO scoring [21, 22], but to do this well requires very large case numbers. Consequently, the global trophoblastic community under the auspices of the ISSTD are currently collaborating to address this issue and initial retrospective results are expected soon. However, any new proposal will need prospective validation, and again, this can most rapidly be done through international collaboration. One such prospective study called the TITANIUM trial is underway, examining the role of Doppler ultrasound as a potential independent predictor of single-agent chemotherapy resistance in GTN [23] among other questions. This trial is currently open in several EU centres and is about to open in Brazil and some other global sites.

While randomized prospective trials provide a gold standard approach for developing new treatments, they have been particularly challenging to undertake in very rare diseases like GTN. For example, to achieve sufficient numbers for an adequately powered trial, many sites need to be involved. It is important that all sites have a strong interest to ensure completion of the study in an expeditious manner. Where associated laboratory studies are required, there may be difficulties in sharing tissues or fluids with sites in other countries due to very strict rules regarding cross-border movement of samples. Funding to support investigator-led rare cancer studies is often very difficult to achieve, and it may be necessary to open parallel studies in several countries with a prespecified agreement to pool the data on completion.

Consequently, the development of new therapies for GTN has largely been based on single-centre or national experiences that are often retrospective rather than prospective trials. The discovery of checkpoint immunotherapies (CPIs) as valuable agents for salvaging advanced GTN cases that had failed existing therapies is no exception to this. Indeed, there are only limited retrospective series/case reports [24–27] and two small phase II trials to date, one from France [28] and one from China [29] to determine how best to deploy these exciting new therapies. For example, which CPI agent is best, should it be used alone or in combination with chemotherapy or other CPI and when should they be given in the treatment pathway [30]. International collaborations should make it possible to move forward more effectively in determining the exact place of these very promising new therapies.

Despite the early promising results with these CPI agents, a significant number of patients fail to respond and still need salvage treatment. High-dose chemotherapy will only save a small proportion [31], so novel therapies are still needed. Such therapies will likely arise from an improved understanding of disease biology. While some progress is being made [32–36], it is hampered by a lack of fresh frozen material, cell lines, animal models, and patient-derived xenografts. Thus, for choriocarcinoma, there are only 2 cell lines, which are used to derive xenografts and currently there are no patient-derived xenografts. A similar situation exists for ETT/PSTT. International collaboration is clearly required to facilitate the development and sharing of these tools. Once potential novel agents have been identified from an improved biological understanding then further collaboration across major centres will be essential to test whether these treatments will actually be effective in the rare patients who have failed all existing therapies. While these steps are important, we should not lose sight of the crucial need to ensure that women in low- to middle-income countries can access existing treatments that are relatively cheap and simple to administer. Such action will globally save more lives.

Conclusion

It is clear that countries that have a coordinated approach to the management of GTD with established GTD centres achieve better survival results than those lacking such systems. Sadly, however, most countries fail to provide this. To combat these deficiencies in health provision, it does not need to be very expensive and indeed saving the lives of young women who can then contribute much to society is cost-beneficial even in low- to middle-income economies. The ISSTD and EOTTD, together with regional organisations like EURACAN are trying to improve this situation by running out-reach educational programmes, cross-border multi-disciplinary meetings for complex case discussions, and by establishing practical clinical guidelines. However, much more needs to be done to ensure that young women afflicted by GTN can avoid pointlessly dying from easily curable disease.

Statement of Ethics

An ethics statement is not applicable because this study is based exclusively on published literature.

Conflict of Interest Statement

The authors have no conflicts of interest to declare.

Funding Sources

There was no funding to support the development of this manuscript.

Author Contributions

M.J.S. and F.G. contributed equally to the review of literature and writing and editing of this manuscript.

Funding Statement

There was no funding to support the development of this manuscript.

Data Availability Statement

This review is based on published literature and the opinions of the authors, and there are no new data presented that are not already available through existing publications. Further enquiries can be directed to the corresponding author.