A remarkable response to combination chemotherapy with nivolumab and ipilimumab in a patient with primary pulmonary choriocarcinoma: a case report

Introduction

Choriocarcinoma is a subtype of non-seminomatous germ cell tumor; this rare cancer is composed of cytotrophoblasts, intermediate trophoblasts, and syncytiotrophoblast cells (1). It can occur in extragonadal sites including the mediastinum, lung, brain, and digestive tract. Primary pulmonary choriocarcinoma (PPC) accounts for 10% of choriocarcinoma cases (2). Due to its rarity, no standardized treatments for PPC have been established. Cytotoxic chemotherapy regimens based on those used to treat female choriocarcinomas or male germ cell tumors are conventionally adopted for PPC treatment; however, these therapies have limited efficacy. Immune checkpoint inhibitors (ICIs) could potentially be used to treat chemotherapy-resistant choriocarcinoma, as they engender long-term survival benefits and durable responses against multiple tumor types (3).

Based on the result of CheckMate 9LA trial (4), the combination of chemotherapy, nivolumab [anti-programmed cell death protein 1 (PD-1) antibody], and ipilimumab [anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) antibody] is widely used as a first-line treatment for advanced non-small-cell lung cancer (NSCLC). In CheckMate 9LA, the combination therapy engendered longer progression-free survival (PFS) and overall survival (OS) than chemotherapy alone regardless of programmed death-ligand 1 (PD-L1) expression and NSCLC histology. Here we report a patient who underwent surgical resection for PPC but experienced relapse 6 months after the operation. This patient was successfully treated with chemotherapy, nivolumab, and ipilimumab. We present this case report in accordance with the CARE reporting checklist (available at https://tcr.amegroups.com/article/view/10.21037/tcr-23-221/rc).

Case presentation

A 72-year-old man was referred to Nippon Medical School Tamanagayama Hospital with suspected lung cancer. He had no symptoms and no notable past medical history, but 25 pack-years of smoking history. Preoperative ¹⁸F-fluorodeoxyglucose positron emission tomography/computed tomography (¹⁸F-FDG-PET/CT) imaging showed intense uptake in an 18 mm nodule in the left upper lobe of the lung, but the transbronchial biopsy showed no evidence of malignancy. Brain magnetic resonance imaging showed no metastatic lesions. The clinical stage was cT1bN0M0, stage IA2. The patient underwent left upper lobectomy and mediastinal lymphadenectomy and was diagnosed with PPC (Figure 1A-1C). The pathological stage was pT3N0M0, stage IIB.

Figure 1 Pathology of resected PPC. (A) Hematoxylin and eosin staining at an original magnification of ×40: there are large atypical cells with abundant eosinophilic spores resembling intermediate trophoblast and syncytiotrophoblast cells. (B) Rabbit polyclonal anti-hCG antibody staining at an original magnification of ×10: diffusely positive tumor cells are shown in the image. (C) Pan-cytokeratin antibody (AE1/AE3) stain is positive in tumor cells at an original magnification of ×10. PPC, primary pulmonary choriocarcinoma; hCG, human chorionic gonadotropin.

Six months after the operation, he presented with multiple pulmonary nodules and an intracardiac mass following chest CT (Figure 2A-2C). He was diagnosed with postoperative relapse of PPC. The Oncomine^TM Dx target test showed no mutation of cancer-relevant genes, and PD-L1 expression was negative (0%) in the 22C3 assay. The patient’s serum β-human chorionic gonadotropin (β-hCG) level was high, at 688 mIU/mL (normal is <2.0 mIU/mL). He had an Eastern Cooperative Oncology Group performance status score of 0. He was treated with carboplatin [area under the curve (AUC) 5 every 3 weeks for two cycles], paclitaxel (200 mg/m² every 3 weeks for two cycles), nivolumab (360 mg every 3 weeks), and ipilimumab (1 mg/kg every 6 weeks), based on the regimen of CheckMate 9LA. After 2 months of starting therapy, serum β-hCG was undetectable, and a CT scan showed significantly less multiple lung nodules and an intracardiac mass reduction (Figure 2D-2F). There was a partial response (PR) according to the Response Evaluation Criteria in Solid Tumors (RECIST, V1.1). Grade 3 febrile neutropenia and grade 2 rash according to the Common Terminology Criteria for Adverse Events (CTCAE, V5.0) were observed. The rash was manageable with topical steroids and oral antihistamines. The patient has continued to receive nivolumab and ipilimumab maintenance therapy, and a further anti-tumor response was achieved after 7 months of starting therapy (Figure 2G-2I). At the time of writing, this response has been sustained for a further 12 months.

Figure 2 The serum β-hCG level (upper) and chest CT findings (lower). (A,B) Before administering the treatment, the chest CT shows multiple lung nodules. (C) An intracardiac mass is adjacent to the left pulmonary artery (white arrow). (D-F) After 2 months of starting therapy, fewer lung nodules and an intracardiac mass reduction (white arrow) are observed. (G-I) After 7 months of starting therapy, further tumor reduction, including that of the intracardiac mass (white arrow) is observed. CT, computed tomography, β-hCG, β-human chorionic gonadotropin.

All procedures performed in this study were in accordance with the ethical standards of Nippon Medical School Tamanagayama Hospital and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Discussion

To our knowledge, this is the first reported case of a male PPC patient who was successfully treated with chemotherapy, nivolumab, and ipilimumab. Choriocarcinoma is a germ cell tumor that most commonly originates in the gonads and secretes the hormone, hCG. Primary choriocarcinoma (which is also called non-gestational choriocarcinoma) is rare in males. It generally occurs in the testis, mediastinum, retroperitoneum, lung, brain, and digestive tracts. About 10% of primary choriocarcinomas develop in the lung (2), and only 41 cases of PPC have been reported in males up to 2021 (5). The prognosis of PPC is notably poor and the malignancy rapidly progresses to other organs. Treatment options are surgical resection, cytotoxic chemotherapy, or a combination of the two. Radiation therapy is not commonly used as a treatment for PPC due to its low efficacy (6). The 1-year survival rate of male PPC patients ranges from 15% to 31% (5,7). Gender, older age, past smoking history, metastases at presentation, tumors >5 cm, and treatment with chemotherapy or surgery alone are independent factors associated with poor prognosis (7).

There is no standardized chemotherapy for male patients with primary choriocarcinoma, including those with PPC. A regimen of etoposide, methotrexate, dactinomycin, cyclophosphamide, and vincristine (EMA-CO), which is effective in female choriocarcinoma (8), is also conventionally used to treat male primary choriocarcinoma (7,9). Bleomycin, methotrexate, and cisplatin (BEP) and etoposide, ifosfamide, and cisplatin (VIP) regimens for male germ cell tumor are also used (10-12). In contrast to gestational choriocarcinoma, which can be cured with cytotoxic chemotherapy, male primary choriocarcinoma is frequently resistant to cytotoxic chemotherapy, thus leading to poor prognosis (3). There are no clinically available molecular-targeted drugs for patients with primary choriocarcinoma. Oncomine^TM Dx target test, which is a next-generation sequencing panel for NSCLC, showed no genetic alteration in this case. A previous case of PPC reported some mutations, such as fibroblast growth factor receptor, tumor protein p53, and neuroblastoma RAS viral oncogene homolog (NRAS) proto-oncogene mutations (5). However, due to its rarity, the gene mutation profile of patients with PPC is still unclear. In some cases, pembrolizumab and nivolumab have been used to elicit a long-term antitumor response after failure of cytotoxic chemotherapy (Table 1) (9-11,13). Furthermore, a previous case report showed that combining second-line treatment nivolumab with right upper lobe resection achieved long-term survival in a patient with a poorly differentiated adenocarcinoma with choriocarcinomatous features (10). This was the first case in which an ICI was administered to a male patient with pulmonary choriocarcinoma; based on the success of this approach, we decided to use chemotherapy and ICIs to treat our patient.

We administered nivolumab and ipilimumab combined with two cycles of carboplatin and paclitaxel. In CheckMate 9LA, the randomized phase 3 trial evaluating nivolumab plus ipilimumab combined with two cycles of chemotherapy vs. chemotherapy alone in NSCLC, updated treatment data showed durable efficacy over chemotherapy alone (14). This combination therapy has therefore been widely adopted as a first-line treatment for advanced NSCLC. We chose this regimen for three main reasons.

First, male PPC progresses rapidly and has a poor prognosis, so administration of ICIs alone (including a combination of nivolumab with ipilimumab) may be insufficient to provide initial disease control. Indeed, this was indicated by the CheckMate 227 phase 3 trial in NSCLC, where the Kaplan-Meier curves of PFS and OS in the nivolumab and ipilimumab group crossed those in the chemotherapy group in the early stage of initiating treatment. Disease control rate of nivolumab plus ipilimumab was lower than that of chemotherapy (65.5% vs. 77.0%) (15). To improve the initial disease control, two cycles of chemotherapy were added to nivolumab and ipilimumab in CheckMate 9LA. Our patient had an intracardiac mass at presentation, and failure of first-line treatment could be fatal. Initial disease control was therefore as important as long-term efficacy.

Second, PD-L1 expression was absent in our case. The subgroup analysis in CheckMate 9LA showed equivalent survival benefits regardless of PD-L1 expression (4). The combination of anti-CTLA-4 and anti-PD-1 blockade therapy has enhanced survival benefits, but the underlying mechanisms remain unclear. Combining ICIs with different modes of action may have synergistic effects that are not elicited by single-agent treatment. For example, anti-CTLA-4 inhibitors induce the expansion of T helper 1-like cells that express inducible co-stimulator, whereas PD-1 inhibitors do not (16). Also, combining anti-CTLA-4 and anti-PD-1 inhibitors treatment converts dysfunctional CD8 T-cells into activated effector CD8 T-cells and induces more infiltration of CD8 and CD4 T-cells into the tumor than does ICI monotherapy (17,18). These synergistic effects will contribute to long term therapeutic efficacy in PD-L1-negative patients. However, we note that more studies in which the combination of anti-CTLA-4 and anti-PD-1 blockade is tested in male PPC patients are required to formally demonstrate the efficacy and long-term survival benefits of this regimen.

Third, we were concerned about myelosuppression induced by cytotoxic chemotherapies, such as VIP, BEP, and EMA-CO. The VIP and BEP regimens are used to treated testicular germ cell tumors and are associated with high rates of myelosuppression. VIP and BEP cause grade 4 myelosuppression in 34% and 70% of patients, respectively (12). Furthermore, EMA-CO is reported to cause grade 4 myelosuppression in more than 30% of patients (19). On the other hand, the CheckMate 9LA regimen was associated with fewer hematologic toxicities, with grade 4 anemia reported in less than 1% of patients, neutropenia in 3%, thrombocytopenia in 5% (4). VIP, BEP, and EMA-CO are usually administered to patients in their twenties and thirties. In contrast, patients in the CheckMate 9LA trial were mostly in their sixties or seventies (4). Although our patient experienced grade 3 febrile neutropenia, this was manageable. In general, the incidence of severe myelosuppression is higher in older patients treated with cytotoxic chemotherapies, and this can lead to treatment interruption, discontinuation, or even patient death. As our patient was 72 years old, it would have been inappropriate to place him on one of the treatment regimens used for younger patients. In CheckMate 9LA, the most frequently reported grade 3 and 4 immune-related adverse events were gastrointestinal, skin, and hepatic events (4). Our patient had grade 2 rash during his first cycle of therapy, but this adverse event was also manageable.

Conclusions

This is the first reported case of a male PPC patient that has successfully been treated with chemotherapy, nivolumab, and ipilimumab. This therapy may be a promising option for advanced PPC.

Acknowledgments

Funding: None.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://tcr.amegroups.com/article/view/10.21037/tcr-23-221/rc

Peer Review File: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-23-221/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-23-221/coif). MS received honoraria for lectures from Bristol-Meyers Squib, and Ono Pharmaceutical. TH received honoraria for lectures from Bristol-Meyers Squib. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of Nippon Medical School Tamanagayama Hospital and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Rejlekova K, Cursano MC, De Giorgi U, et al. Severe Complications in Testicular Germ Cell Tumors: The Choriocarcinoma Syndrome. Front Endocrinol (Lausanne) 2019;10:218. [Crossref] [PubMed]
2. Jiang F, Xiang Y, Feng FZ, et al. Clinical analysis of 13 males with primary choriocarcinoma and review of the literature. Onco Targets Ther 2014;7:1135-41. [Crossref] [PubMed]
3. Ji YS, Park SH. Clinical Experience of Male Primary Choriocarcinoma at the Samsung Medical Center. Cancer Res Treat 2021;53:874-80. [Crossref] [PubMed]
4. Paz-Ares L, Ciuleanu TE, Cobo M, et al. First-line nivolumab plus ipilimumab combined with two cycles of chemotherapy in patients with non-small-cell lung cancer (CheckMate 9LA): an international, randomised, open-label, phase 3 trial. Lancet Oncol 2021;22:198-211. [Crossref] [PubMed]
5. Zhang X, Ding B, Chen L, et al. Primary pulmonary choriocarcinoma in male: report a case with genetic testing and review of the literature. Transl Cancer Res 2022;11:1844-9. [Crossref] [PubMed]
6. Sridhar KS, Saldana MJ, Thurer RJ, et al. Primary choriocarcinoma of the lung: report of a case treated with intensive multimodality therapy and review of the literature. J Surg Oncol 1989;41:93-7. [Crossref] [PubMed]
7. Snoj Z, Kocijancic I, Skof E. Primary pulmonary choriocarcinoma. Radiol Oncol 2016;51:1-7. [Crossref] [PubMed]
8. Deng L, Zhang J, Wu T, et al. Combination chemotherapy for primary treatment of high-risk gestational trophoblastic tumour. Cochrane Database Syst Rev 2013;CD005196. [Crossref] [PubMed]
9. Han C, Zhou Y, Ma JA, et al. A promising treatment option for refractory male primary choriocarcinoma: report of two cases. Transl Cancer Res 2020;9:3054-60. [Crossref] [PubMed]
10. Ochi M, Miyamoto S, Terada Y, et al. The Significant Antitumor Activity of Nivolumab in Lung Adenocarcinoma with Choriocarcinomatous Features. Intern Med 2018;57:1773-7. [Crossref] [PubMed]
11. Chi EA, Schweizer MT. Durable Response to Immune Checkpoint Blockade in a Platinum-Refractory Patient With Nonseminomatous Germ Cell Tumor. Clin Genitourin Cancer 2017;15:e855-7. [Crossref] [PubMed]
12. Nichols CR, Catalano PJ, Crawford ED, et al. Randomized comparison of cisplatin and etoposide and either bleomycin or ifosfamide in treatment of advanced disseminated germ cell tumors: an Eastern Cooperative Oncology Group, Southwest Oncology Group, and Cancer and Leukemia Group B Study. J Clin Oncol 1998;16:1287-93. [Crossref] [PubMed]
13. Loh KP, Fung C. Novel Therapies in Platinum-refractory Metastatic Germ Cell Tumor: A Case Report with a Focus on a PD-1 Inhibitor. Rare Tumors 2017;9:6867. [Crossref] [PubMed]
14. Paz-Ares LG, Ciuleanu TE, Cobo-Dols M, et al. First-line (1L) nivolumab (NIVO)+ ipilimumab (IPI)+ 2 cycles of chemotherapy (chemo) versus chemo alone (4 cycles) in patients (pts) with metastatic non-small cell lung cancer (NSCLC): 3-year update from CheckMate 9LA. J Clin Oncol 2022;40:LBA9026. [Crossref]
15. Hellmann MD, Paz-Ares L, Bernabe Caro R, et al. Nivolumab plus Ipilimumab in Advanced Non-Small-Cell Lung Cancer. N Engl J Med 2019;381:2020-31. [Crossref] [PubMed]
16. Wei SC, Levine JH, Cogdill AP, et al. Distinct Cellular Mechanisms Underlie Anti-CTLA-4 and Anti-PD-1 Checkpoint Blockade. Cell 2017;170:1120-1133.e17. [Crossref] [PubMed]
17. Wei SC, Anang NAS, Sharma R, et al. Combination anti-CTLA-4 plus anti-PD-1 checkpoint blockade utilizes cellular mechanisms partially distinct from monotherapies. Proc Natl Acad Sci U S A 2019;116:22699-709. [Crossref] [PubMed]
18. Shi LZ, Fu T, Guan B, et al. Interdependent IL-7 and IFN-γ signalling in T-cell controls tumour eradication by combined α-CTLA-4+α-PD-1 therapy. Nat Commun 2016;7:12335. [Crossref] [PubMed]
19. Ji M, Jiang S, Zhao J, et al. Efficacies of FAEV and EMA/CO regimens as primary treatment for gestational trophoblastic neoplasia. Br J Cancer 2022;127:524-30. [Crossref] [PubMed]