Immunotherapy in the treatment of chemoresistant gestational trophoblastic neoplasia - systematic review with a presentation of the first 4 Brazilian cases

Braga, Antonio; Balthar, Elaine; Souza, Laís Cristhine Santos; Samora, Michelle; Rech, Matheus; Madi, José Mauro; Amim Junior, Joffre; Rezende Filho, Jorge; Elias, Kevin M.; Horowitz, Neil S.; Sun, Sue Yazaki; Berkowitz, Ross S.

doi:10.1016/j.clinsp.2023.100260

Acessibilidade / Reportar erro

Brasil

Español English

sumário « anterior atual seguinte »

Sumário

Original articles • Clinics 78 • 2023 • https://doi.org/10.1016/j.clinsp.2023.100260 copy

Immunotherapy in the treatment of chemoresistant gestational trophoblastic neoplasia - systematic review with a presentation of the first 4 Brazilian cases

Authorship SCIMAGO INSTITUTIONS RANKINGS

Highlights

Gestational trophoblastic neoplasia responds to anti-PD-1 or anti-PD-L1 immunotherapy.
Multi-drug resistant gestational trophoblastic neoplasia may achieve remission with pembrolizumab.

Abstract

Objective

To evaluate the efficacy of immunotherapy for GTN treatment after methotrexate-resistance or in cases of multiresistant disease, through a systematic review, as well as to present the first 4 Brazilian cases of immunotherapy for GTN treatment.

Methods

Three independent researchers searched five electronic databases (EMBASE, LILACS, Medline, CENTRAL and Web of Science), for relevant articles up to February/2023 (PROSPERO CRD42023401453). The quality assessment was performed using the Newcastle Ottawa scale for case series and case reports. The primary outcome of this study was the occurrence of complete remission. The presentation of the case reports was approved by the Institutional Review Board.

Results

Of the 4 cases presented, the first was a low-risk GTN with methotrexate resistance unsuccessfully treated with avelumab, which achieved remission with sequential multiagent chemotherapy. The remaining 3 cases were high-risk multiagent-resistant GTN that were successfully treated with pembrolizumab, among which there were two subsequent gestations, one of them with normal pregnancy and healthy conceptus. Regarding the systematic review, 12 studies were included, only one of them on avelumab, showing a 46.7% complete remission rate. The remaining 11 studies were on pembrolizumab, showing an 86.7% complete remission rate, regardless of tumor histology. Both immunotherapies showed good tolerability, with two healthy pregnancies being recorded: one after avelumb and another after pembrolizumab.

Conclusion

Immunotherapy showed effectiveness for GTN treatment and may be especially useful in cases of high-risk disease, where pembrolizumab achieves a high therapeutic response, regardless of the histological type, and despite prior chemoresistance to multiple lines of treatment.

Keywords
Gestational trophoblastic neoplasia; Immunotherapy; PD-1/PD-L1 inhibitors; Pembrolizumab; Avelumab

Immunotherapy	Authors	Year	Type	Journal	Country	Number of case(s)
Avelumab	You et al.	2020	Clinical trial	Journal of Clinical Oncology	France	15
Pembrolizumab	Ghorani et al.	2017	Case series / Correspondence	Lancet	UK	4
	Huang et al.	2017	Case report / Correspondence	Journal of Clinical Oncology	US	1
	Choi et al.	2019	Case report	European Journal of Cancer	South Korea	2
	Clair et al.	2020	Case report	Gynecologic Oncology Reports	US	1
	Goldfarb et al.	2020	Case report / Correspondence	Gynecologic Oncology Reports	US	1
	Pisani et al.	2021	Case report	Current Oncology	Malta	1
	Bell et al.	2021	Case report	Gynecologic Oncology Reports	US	1
	Porter et al.	2021	Case report	Gynecologic Oncology Reports	US/UK	1
	Polnaszek et al.	2021	Case report	Obstetrics & Gynecology	US	1
	Paspalj et al.	2022	Case report	Gynecologic Oncology Reports	Austria	1
	Wong et al.	2022	Case report	Gynecologic Oncology Reports	US	1

Immunotherapy	Authors	Age	Histology	Number of cycles to remission	Number of consolidation cycles	Toxicity of (CTCAE grade)	Oncologic Outcome	Relapse after immunotherapy^# # Between parentheses, the follow-up time, in months, after remission is presented, using the median for the study by You et al. CTCAE, Common Terminology Criteria for Adverse Events (reference 16); CC, Choriocarcinoma; PSTT, Placental site trophoblastic tumor; ETT, Epithelioid trophoblastic tumor; TAH, Underwent Total Abdominal Hysterectomy before pembrolizumab.	Reproductive outcomes
Avelumab	You et al.^a a Clinical trial with 15 patients treated with avelumab.	34^b b Median.	All GTN cases are post CHM	8 (median) range 2‒11	3 (per protocol)	^d d Two cases hyperthyroidism (13.3%), one case of hypothyroidism (6.7%); and one case of a grade 2 ovarian cyst (6.7%) and another case of a grade 3 uterine bleeding (6.7%), which were both unrelated to treatment.	Remission in 8/15 (53.3%)	No cases reported (29 months)	^e e One case of healthy baby born vaginally at 39 weeks of gestation.
Pembrolizumab	Ghorani et al.	39	CC	4	5	Arthralgia (G1)	Remission	No relpase after 24 months	Not reported
		44	Mixed PSTTand ETT	5	‒	Pruritis (G1)	Death	‒	TAH
		47	PSTT	8	5	Synovitis (G2) Rash (G1)	Remission	No relpase after 15 months	Not reported
		37	CC	2	5	Neutropaenia (G2) Synovitis (G1)	Remission	No relpase after 5 months	Not reported
	Huang et al.	26	CC	2	2	Hepatotoxicity (G3)	Remission	No relpase after 2 months	Not reported
	Choi et al.	39	PSTT	1	13	Not reported	Remission	No relpase after 29 months	TAH
	Choi et al.	26	ETT	11	4**	Rash (G2)	Remission	***	TAH
	Clair et al.	30	CC	10	Not reported	Not reported	Remission	No relpase after 31 months	TAH
	Goldfarb et al.	50	CC	3	3	Peripheral neuropathy (G3)	Progression¹ 1 . Relapse after 8 months. She was followed up with hCG monitoring and imaging exams until reinitiating pembrolizumab after 14 months from the relapse.	Under treatment	TAH
	Pisani et al.	49	ETT	Not reported	Not reported	Not reported	Remission	No relpase after 12 months	TAH
	Bell et al.	47	ETT	29 cycles ***	‒	Not reported	Remission	***	Not reported
	Porter et al.	34	PSTT	3	Not reported² 2 . Although the number of consolidation chemotherapy cycles with pembrolizumab was not reported, the authors reported that they used, in addition to pembrolizumab, 5 consolidation cycles with the EP/EMA regimen, replacing cisplatin to carboplatin in the last cycle due to toxicity (thrombocytopenia, ototoxicity and tinnitus). Finally, the authors reported that she is still on consolidation treatment with pembrolizumab.	Inflammatory thyroiditis (no grade reported)	Remission	***	TAH
	Polnaszek et al.	23	PSTT	3	‒	Not reported	Remission	No relpase after 12 months	³ 3 . Since the diagnosis of PSTT, the patient has refused to undergo hysterectomy or even conventional chemotherapy for PSTT, accepting only treatment with pembrolizumab. The patient achieved remission with immunotherapy and became pregnant during consolidation chemotherapy with pembrolizumab, which was immediately discontinued. The pregnancy progressed uneventfully with a delivery of a healthy baby born vaginally at 39 weeks of gestation.
	Paspalj et al.	31	CC	4	3	Not reported	Remission	No relpase after 24 months	TAH
	Wong et al.	44	CC	****	****	Arthralgia (G1)	Remission	Relpase after 6 months*****	Not reported

* Need to reduce the dosage of the 2 consolidation cycles of pembrolizumab in 50% due to toxicity.

** The institution's tumor board decided to continue treatment with pembrolizumab, even after remission.

*** The patient was still undergoing consolidation chemotherapy at the time of publication of the case report.

**** The patient achieves remission after 2 cycles of pembrolizumab (followed by 5 consolidation cycles). However, she relapsed after 6 months and was again treated with pembrolizumab. The report was unclear but suggested that the patient achieved remission after 4 further cycles of pembrolizumab, followed by 21 consolidation cycles.

***** After GTN relapse notwithstanding the treatment with pembrolizumab, the patient was rescued with pembrolizumab and achieved remission again, with no evidence of disease and with normal hCG levels after 24 months of the end of immunotherapy.

^#
Between parentheses, the follow-up time, in months, after remission is presented, using the median for the study by You et al.

CTCAE, Common Terminology Criteria for Adverse Events (reference 16); CC, Choriocarcinoma; PSTT, Placental site trophoblastic tumor; ETT, Epithelioid trophoblastic tumor; TAH, Underwent Total Abdominal Hysterectomy before pembrolizumab.
^a
Clinical trial with 15 patients treated with avelumab.
^b
Median.
^d
Two cases hyperthyroidism (13.3%), one case of hypothyroidism (6.7%); and one case of a grade 2 ovarian cyst (6.7%) and another case of a grade 3 uterine bleeding (6.7%), which were both unrelated to treatment.
^e
One case of healthy baby born vaginally at 39 weeks of gestation.
¹
. Relapse after 8 months. She was followed up with hCG monitoring and imaging exams until reinitiating pembrolizumab after 14 months from the relapse.
²
. Although the number of consolidation chemotherapy cycles with pembrolizumab was not reported, the authors reported that they used, in addition to pembrolizumab, 5 consolidation cycles with the EP/EMA regimen, replacing cisplatin to carboplatin in the last cycle due to toxicity (thrombocytopenia, ototoxicity and tinnitus). Finally, the authors reported that she is still on consolidation treatment with pembrolizumab.
³
. Since the diagnosis of PSTT, the patient has refused to undergo hysterectomy or even conventional chemotherapy for PSTT, accepting only treatment with pembrolizumab. The patient achieved remission with immunotherapy and became pregnant during consolidation chemotherapy with pembrolizumab, which was immediately discontinued. The pregnancy progressed uneventfully with a delivery of a healthy baby born vaginally at 39 weeks of gestation.

Faculdade de Medicina / USP Rua Dr Ovídio Pires de Campos, 225 - 6 and., 05403-010 São Paulo SP - Brazil, Tel.: (55 11) 2661-6235 - São Paulo - SP - Brazil
E-mail: clinics@hc.fm.usp.br

Acompanhe os números deste periódico no seu leitor de RSS

[1] * Corresponding author at: Rio de Janeiro Trophoblastic Disease Center, Maternidade Escola da Universidade Federal do Rio de Janeiro, RJ, Rio de Janeiro, Brazil. Rio de Janeiro Trophoblastic Disease Center, Maternidade Escola da Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil. E-mail address:antonio.braga@ufrj.br (A. Braga).