INTRODUCTION

Gestational trophoblastic neoplasia comprises an infrequent group of malignancies encompassing invasive moles, choriocarcinoma, and the exceptionally rare placental site trophoblastic tumors and epithelioid trophoblastic tumors. These all arise from abnormal proliferation of placental trophoblast cells. Gestational trophoblastic neoplasia accounts for less than 1% of all gynecological cancers worldwide, with around 18 000 diagnoses a year.1

Building on the earlier Charing Cross Hospital scoring system, the International Federation of Gynecology and Obstetrics (FIGO) scoring system is used to guide optimal management of patients with newly diagnosed gestational trophoblastic neoplasia (Table 1).2 Those with a score of <7 are considered at low risk of developing drug resistance to single-agent treatment with either methotrexate or actinomycin-D. Those with high-risk scores (≥7) conventionally undergo treatment with combination agent chemotherapy such as EMA/CO, which comprises etoposide, methotrexate, and actinomycin-D alternating weekly with cyclophosphamide and vincristine. Multiagent chemotherapy is intensive by design and thus considerably more toxic both in the short term (nausea/vomiting, alopecia, myelosuppression, neuropathy) and long term (earlier menopause, increased risk of secondary malignancy in prolonged treatment).3

Table 1

FIGO Scoring in gestational trophoblastic neoplasia

The overall 5-year survival rate for gestational trophoblastic neoplasia, excluding placental site and epithelioid trophoblastic tumors, is greater than 98%.4 However, outcomes are different between FIGO risk groups. Patients with low-risk disease can expect an overall survival rate of 100%,5 while patients with high-risk disease have a 5-year survival rate of 94–96%.5 A third group of patients with FIGO scores of ≥13 are defined as having ultra-high-risk disease, characterized by factors including liver and brain metastases, associated with a 5- year survival rate of around 80%.4 6

Patients with placental site and epithelioid trophoblastic tumors are inherently more chemoresistant and are therefore not classified under the FIGO scoring system. Instead, surgery is the mainstay of treatment for localized disease and those with advanced disease require multimodal therapy. The two independent adverse prognostic factors for these tumors are an interval of more than 4 years from the end of the antecedent or causative pregnancy and stage IV disease.7–9 For example, the 5-year overall survival in patients with an interval of less than, versus more than, 4 years was 98% and 0%, respectively, regardless of stage. With the introduction of more aggressive platinum-based therapies, including high-dose chemotherapy, the survival of patients with long-interval disease has improved to 48%.8

Broadly, patients can therefore be considered as those with high vs relatively low probability of cure. For both groups, but in particular those with highly curable disease, reduction of treatment toxicity is a priority. Among those with lower cure probability, new approaches to combat drug resistance and achieve better survival outcomes are necessary, particularly considering the young patient cohort affected by this group of placental cancers.

CHECKPOINT IMMUNOTHERAPY HAS REVOLUTIONIZED CANCER CARE

A major development in cancer therapeutics that may enable us to achieve these goals is the advent of immune checkpoint inhibitors. These are monoclonal antibodies that act by blocking inhibitory ligands expressed by tumors or their receptors, such as programmed-death 1 (PD-1), which is expressed by tumor-infiltrating T cells, thus stimulating anti-cancer immune responses.10 Anti-PD-1 agents such as pembrolizumab and nivolumab have revolutionized the care of patients with multiple cancer types, including melanoma, renal and lung cancer.11 As discussed below, pembrolizumab has emerged as a powerfully effective agent with limited toxicity. This expands the repertoire of therapeutic options for gestational trophoblastic neoplasia in a manner that we argue should prompt a rethink of how both low- and high-risk disease is managed to maximize cure rates and reduce toxicity. Indeed, the frequency of toxicities with immune checkpoint inhibitors is substantially lower than with combination agent chemotherapies, and those that do occur, while very occasionally life threatening, are usually easily managed and reversible. Data analyzing over 14 000 patients in the USA undergoing immune checkpoint inhibitor therapy found that immune-related adverse events requiring treatment or hospitalization occurred in less than 3.5% of cases.12 Patients themselves frequently report how much easier it is to undergo immunotherapy in comparison with chemotherapy.

Use of immune checkpoint inhibitors, and specifically PD-1 pathway blockade, in gestational trophoblastic neoplasia is based on multiple lines of evidence. First, anti-cancer immune responses are partly driven by immune cell recognition of cancer antigens as non-self or foreign. In general, neoantigens arising from mutated proteins are critical targets for anti-cancer immune responses. The burden of neoantigens13 and degree of ‘foreignness’14 shapes the anti-cancer immune response and predicts immunotherapy outcomes.15 Uniquely, gestational trophoblastic neoplasia arises from placental trophoblasts, which are genetically composed of both maternal and paternal DNA, or if derived from a complete hydatidiform mole, then of paternal DNA only.1 Thus, gestational trophoblastic neoplasia represents a semi- or fully allogeneic transplant, predicted to be highly visible to the immune system.

Second, the PD-1 ligand PD-L1 is strongly expressed by trophoblasts in all pathological subtypes of gestational trophoblastic neoplasia, although expression is not thought to be related to FIGO score or drug resistance.16 In normal pregnancy, maternal immune cells recognize fetal tissues as the placental extravillous trophoblast invades into the endometrium and PDL-1 blockade results in fetal loss in miscarriage-prone mice.17 Thus PD-1 signaling is specifically relevant in protecting the semi-allogeneic placenta and fetus from destruction by the maternal immune system. Gestational trophoblastic neoplasia is richly infiltrated by T cells (tumor-infiltrating lymphocytes),18 19 and the degree of infiltration predicts patient outcomes,19 suggesting an active anti-cancer immune response. PD-1 is expressed by tumorinfiltrating lymphocytes -in gestational trophoplastic disease18 20 and in general, the abundance of PD-1 expressing tumor-infiltrating lymphocytes correlates with anti-PD-1 responses in other tumor types.21 22 Consequently, PD-1 signaling probably also protects gestational trophoblastic neoplasia from immune destruction.

Clinically, anti-PD-1 therapy with pembrolizumab is highly effective in patients with chemotherapy-resistant gestational trophoblastic malignancies, yielding durable complete responses and very little toxicity.18 Thus in our original case series of four patients, two presented with high-risk choriocarcinoma and had progressed through multiple lines of chemotherapy, including high-dose chemotherapy, before achieving a sustained response to pembrolizumab, with a normal human chorionic gonadotropin level maintained at 24 and 5 months, respectively. A further patient with a placental site trophoblastic tumor and widespread metastases who had progressed on third-line chemotherapy achieved a complete response with pembrolizumab and remained in remission 15 months after the end of treatment.

All patients in our original report had high PD-L1 expression (>90%). Interestingly the one patient who progressed following pembrolizumab had absent tumor-infiltrating lymphocytes, suggesting the importance of a pre-existing immune response, or a microenvironment capable of supporting T cell infiltration. Multiple case reports supporting the efficacy and low toxicity of pembrolizumab in gestational trophoblastic neoplasia have subsequently been published.23–27 Across these reports, 12 out of 17 patients with multidrug-resistant disease went on to have human chorionic gonadotropin normalization. The majority had PD-L1 expression of >90% and treatment was well tolerated throughout. Our unpublished data on an additional 58 cases, further confirm our initial findings that the majority of drug-resistant patients are cured with pembrolizumab and demonstrate the durability of responses.

LOW-RISK DISEASE: REDUCING EXPOSURE TO MULTIAGENT CHEMOTHERAPY

In selecting a therapeutic approach, there is usually a trade-off between intensity/efficacy and quality of life. Given that our patient cohort are often working or caring for young children, the desire to minimize disruption to daily life is paramount. The FIGO risk stratification tool and further attempts to refine these criteria exemplify this trade-off.28 Thus patients below a certain probability of cure—for instance, those with a FIGO score of ≥7, are routinely managed with more intense multiagent chemotherapy rather than less toxic single-agent therapies. Similarly, patients with a FIGO score <7 who commence on single-agent therapy such as methotrexate or actinomycin-D and then develop resistance or toxicity, receive no more than the alternative single-agent before switching to multiagent regimens such as EMA/CO.

With an increased range of treatment options and confidence that even the most difficult to treat patients have a very good chance of cure, there is now increased space for introducing therapeutic approaches that extend the number of women who can be treated and cured with relatively less toxic single-agent therapy.

For instance, at Charing Cross Hospital we have shown that a proportion of patients with FIGO scores of 7 may be successfully treated with single-agent therapy (presented at the International Society for the Study of Trophoblastic Disease (ISSTD) Sydney meeting in October 2022 and manuscript in preparation). Thus, one approach to reducing exposure to toxic multiagent chemotherapy could be to extend the threshold for offering methotrexate to patients in this group, assuming that those for whom this therapy fails can still expect to be cured with subsequent treatments. Of course, the downside of such a strategy might be to prolong the time it takes to achieve remission and complete therapy.

A second approach could be to combine single-agent chemotherapy with pembrolizumab, as a means of expanding the proportion of patients cured without the need for the more toxic EMA/CO multiagent therapy. This concept is currently being developed in the UK as the AVOCADO study, which will offer combination pembrolizumab and actinomycin-D for patients for whom methotrexate or methotrexate and sequential actinomycin-D fails. In addition, the TROPHAMET study is currently open and evaluating the use of combined methotrexate and the PD-L1 directed monoclonal antibody avelumab in low-risk gestational trophoblastic neoplasia as a first-line treatment (NCT04396223).29 These approaches could be combined with offering single-agent treatment to patients with higher FIGO scores, further increasing the cohort of those likely to benefit and reducing exposure to the more toxic combination agent chemotherapy.

A further possibility to reduce exposure to chemotherapy includes use of immunotherapy in the neoadjuvant setting. In other, less immunogenic cancers, immunotherapy delivered before surgery has been shown to be effective, resulting in pathological complete responses. In non-small cell lung cancer for example, where only a minority of patients are suitable for potentially curative resection, there is a high-risk of post-operative recurrence, estimated to be between 25% and 70%.30 A meta-analysis including nearly 1000 patients from a number of smaller single-arm studies suggests that neoadjuvant immunotherapy or chemoimmunotherapy improved pathological response and downstaging of the tumor compared with neoadjuvant chemotherapy alone (43.5% and 21.9% vs 4%, respectively).31 Given the immunotherapy sensitivity of gestational trophoblastic neoplasia and relatively low cure rates achieved with second evacuation for patients with post-molar disease,32 33 neoadjuvant immunotherapy may significantly boost the cure rate of second evacuation and eliminate the need for chemotherapy in this patient group. To address this, we have developed the RESOLVE study, which is currently being set up by our group.

LIMITING CHEMOTHERAPY EXPOSURE IN HIGH-RISK DISEASE

Two potential treatment approaches could be adopted to limit chemotherapy exposure among high-risk patients: earlier treatment and combination with chemotherapy.

Most straightforwardly, immunotherapy could be offered earlier. Following our initial demonstration that pembrolizumab is effective among highly pre-treated patients, national funding approvals allowed the drug to be offered to patients for whom two lines of multiagent chemotherapy have failed, including first-line EMA/CO.34 During the initial outbreak of COVID-19, this was relaxed to permit access after failure of first-line EMA/CO in order to reduce hospital attendances since pembrolizumab is given less frequently and over a much shorter infusion duration than EMA/CO. Importantly, in unpublished data, we have not observed a reduction in efficacy in second-line versus third-line therapy, although further data will be required to evaluate this. Future studies could thus explore whether first-line pembrolizumab could further reduce the proportion of patients exposed to chemotherapy.

Combination therapy is a second potential approach. Currently, most pembrolizumab data are from patients with multiple drug-resistant disease who are heavily pre-treated . In the CAP01 study of the anti-PD-1 agent camrelizumab plus the tyrosine kinase inhibitor apatinib,35 seven of nine patients whose disease progressed on immunotherapy went on to have a complete response with subsequent salvage chemotherapy (NCT04047017). Interestingly, for five of these seven, chemotherapy regimens had failed prior to enrollment in the trial. This suggests potential effects of immunotherapy on chemoresistance and asks whether earlier introduction of chemoimmunotherapy should be explored more systematically. Chemotherapy can enhance tumor immunogenicity through mechanisms including altered expression of antigens,36 hence the rationale for combined use with immunotherapy. Indeed, combined chemoimmunotherapy is effective in multiple cancer types.37 A potential strategy to enhance the efficacy of multiagent chemotherapy, and thus reduce the duration of exposure required, could therefore be combination with pembrolizumab. To extend this concept, other approaches could include combining immunotherapy with less toxic multiagent regimens such as EMA (etoposide/methotrexate/actinomycin-D) alone, thereby avoiding the neurotoxicity of vincristine contained in the CO arm of standard EMA/CO regimens.

Finally, since chemotherapy may additionally have immunosuppressive properties, the sequential use of immunotherapy may prove more effective. In metastatic urothelial cancer, the KEYNOTE-361 phase III trial showed that standard chemotherapy plus pembrolizumab conferred no survival benefit compared with chemotherapy alone.38 However, the JAVELIN Bladder 100 trial showed that maintenance immunotherapy with avelumab after 4–6 cycles of gemcitabine/cisplatin chemotherapy gave a significant overall survival benefit of 7.1 months.39 Following a similar approach in gestational trophoblastic neoplasia, induction EMA/CO for a limited duration could be followed by maintenance immunotherapy.

ADJUVANT IMMUNOTHERAPY

For patients in poor prognostic groups, including placental site and epithelioid trophoblastic tumors, with a long duration between diagnosis and antecedent pregnancy, we routinely offer adjuvant therapy following surgical resection of the disease. Conventionally, this has been with intense multiagent therapy, including high-dose chemotherapy and autologous stem cell transplantation. This represents a highly toxic strategy with a 5–10% death rate in this population.40

Phase III immunotherapy trials in the adjuvant setting have shown significant benefit in reducing the risk of recurrence. The KEYNOTE-564 study showed improved disease-free survival with pembrolizumab versus placebo following nephrectomy for high-risk renal cell carcinoma, with minimal toxicity.41 In melanoma, several studies including the KEYNOTE-854 and CheckMate 238 studies have also demonstrated significant sustained recurrence-free survival with adjuvant immunotherapy.42

Consequently, we now currently offer pembrolizumab to patients with fully resected, poor prognosis placental site and epithelioid trophoblastic tumors. While early indications suggest this is an effective approach, a longer period of follow-up is required to evaluate this and a multicenter study is warranted given the rarity of this clinical scenario.

Survivorship ImplicationsFertility

Long-term data on fertility outcomes among patients with gestational trophoblastic neoplasia treated with chemotherapy indicate no significant effect from single-agent treatment. Multiagent therapy has been shown to hasten menopause by 3 years, although overall fertility outcomes remain spared.43 Pregnancies are not reported after high-dose chemotherapy. In contrast, long-term fertility data on women treated with immunotherapy are mostly lacking.

In theory, fertility may be impacted by endocrine dysregulation, which is an uncommon complication of PD-1 and PD-L1 inhibition—up to 6% of patients will experience hypothyroidism and <1–3% hypophysitis, both of which disrupt reproductive function. Animal studies assessing pembrolizumab in monkeys reported no effects on female reproductive organs, however, and while high-dose atezolizumab in monkeys was shown to cause irregular menstrual cycles, this effect was reversible.44

Reassuringly, a number of reports indicate that fertility is not impaired following immunotherapy. Thus, in the TROPHIMMUN study of second-line avelumab (NCT03135769), one of eight patients in remission went on to have a normal pregnancy.29 An analysis of patients becoming unexpectedly pregnant during immunotherapy trials revealed that all seven pregnancies were carried to term, resulting in vaginal births of healthy babies.45 There are multiple similar case reports of patients undergoing immune checkpoint inhibitor treatment for melanoma and Hodgkin’s lymphoma.46 47 International collaboration to understand the long-term effects on fertility following use of immunotherapy among women with gestational trophoblastic neoplasia is clearly needed.

Long-term Toxicity

Long-term toxicity from multiagent chemotherapy includes neurotoxicity, with 50% of patients receiving EMA-CO developing some degree of peripheral neuropathy,48 as well as an increased risk of secondary malignancy following administration of etoposide. While an analysis of almost 2000 patients undergoing treatment for gestational trophoblastic neoplasia between 1958 and 2000 at Charing Cross Hospital showed no significantly increased risk of solid tumors, there was an increased risk of developing leukemia linked to etoposide exposure, with six patients developing acute myeloid leukemia within 10 years of their multiagent chemotherapy.3

In contrast, long-term follow-up of immunotherapy-treated patients indicates a relatively low burden of toxicity. Patrinely et al evaluated survivorship following immunotherapy in 217 patients treated with anti-PD-1/PD-L1 for melanoma, renal cell carcinoma, and non-small cell lung carcinoma between 2009 and 2017. It was observed that chronic immune-related adverse events were seen in a minority of patients (10.6% hypothyroidism, 3.2% arthralgia, 2.8% neuropathy, 3.2% adrenal insufficiency), but that patient-reported outcomes were favorable compared with both populations with cancer and general populations.49

ARE ALL IMMUNOTHERAPY AGENTS EQUAL?

While the global experience in gestational trophoblastic neoplasia has mostly been with pembrolizumab, it is unknown whether other immunotherapy agents are equally effective.

In the recent TROPHIMMUN trial,29 patients with chemoresistant gestational trophoblastic disease received avelumab. In cohort A, 15 women with low-risk methotrexate-resistant disease were treated with avelumab. Eight of these went on to have a complete and sustained response. Three of the remaining seven were cured with actinomycin-D, three with multiagent chemotherapy, and one with hysterectomy. Treatment was well tolerated with no treatment delays or dose reductions, and no treatment-related adverse events of greater than grade 2. Thus, five patients avoided the more toxic multiagent chemotherapy with this approach.

TROPHIMMUN cohort B assessed avelumab among patients resistant to multiagent chemotherapy. Among seven patients recruited, one had a treatment response with human chorionic gonadotropin normalization, but resistance developed in the remaining six, and this arm of the trial was stopped for futility. Of note, treatment-related adverse events were experienced in 57.1% of patients at grade 1–2, with fatigue as the most commonly occurring event (42.9%).

Other anti-PD-1 agents have supporting data. Cheng et al assessed the use of camrelizumab plus apatinib in 20 patients with high-risk chemo-resistant or relapsed gestational trophoblastic neoplasia.35 The overall response rate was 55%, with 10 patients achieving complete response. The rationale behind using apatinib as a tyrosine kinase inhibitor was derived from high vascular endothelial growth factor expression seen in choriocarcinoma and placental site trophoblastic tumors. The additional benefit of apatinib over a PD-1 inhibitor alone is unclear, as there was no apatinib alone control arm and no historical data in gestational trophoblastic neoplasia for comparison. Furthermore, the most common treatment-related adverse events of grade 3 hypertension were attributable to apatinib. Further work is required to determine whether camrelizumab alone is equally effective.

Based on experience in multiple cancer types, other immunotherapy agents such as anti-CTLA4 (cytotoxic T lymphocyte-associated antigen) or anti-LAG3 (lymphocyte activation gene-3) drugs could possibly also be targeted, although there currently are no data to support their use in gestational trophoblastic neoplasia.50 Given that those patients with high PD-L1 expression but low tumor-infiltrating lymphocytes demonstrated resistance to pembrolizumab, mechanisms that inhibit immune infiltration, such as expression of transforming growth factor β and indoleamine-pyrrole 2,3-dioxygenase may warrant further exploration for this group and could be targeted in combination with anti-PD-1 therapies.51 52

CONCLUSIONS

Immunotherapy opens opportunities for a re-evaluation of established treatment guidelines to prioritize lower toxicity and promote better quality of life in our young patient cohort undergoing treatment for gestational trophoblastic neoplasia. We present an appraisal of how the future treatment landscape could be shaped in this regard.

While pembrolizumab salvage treatment in multidrug-resistant disease is established, given the efficacy and relatively low toxicity, immunotherapy offers opportunities to avoid or reduce the use of multiagent chemotherapy regimens.

Many questions remain, which will require international collaboration to solve, given the rare nature of this disease and current paucity of phase III data on the use of immune checkpoint inhibitors in gestational trophoblastic neoplasia. Across all cancer types, data on long-term toxicity and fertility are scarce. Given the nature of our cohort, careful evaluation of long-term fertility outcomes, in particular, are required.

As there are a limited number of small immunotherapy trials in gestational trophoblastic neoplasia, and these have used distinct agents, it is unclear whether there are drug-specific differences in efficacy. However, avelumab is unlikely to become a treatment option in the high-risk setting. Clearly, further work is required to better understand this, but given the available literature, pembrolizumab appears to be the agent of choice. Studies including RESOLVE, AVOCADO, and others will address how immunotherapy can be used to cure more patients with less toxicity and should reveal whether there are any longer-term toxicity issues in this young female population.

Ethics statementsPatient consent for publication

Not applicable.

Ethics approval

Not applicable.

Acknowledgments

We are grateful to the UK Department of Health for continued funding of the Gestational Trophoblastic Disease Centre. We acknowledge support from the Harris and Trotter Clients Charitable Trust, the NIHR Biomedical Research Centre, Cancer Research UK (CRUK), and the Imperial College Experimental Cancer Medicine Centre. EG acknowledges support from a CRUK clinician scientist fellowship.