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Case presentation
A 30-year-old Caucasian woman gravida 4, para 3, presented with vaginal bleeding at 30 weeks of gestation. Her most recent Papanicolaou test had been performed at 13 weeks of gestation at an outside facility and was normal despite the visualization of a small 1 cm lesion in the anterior cervix described as an ectropion. On admission, pelvic examination revealed an 8 cm, pedunculated, tan, friable mass arising from the anterior lip of the cervix with suspicion of left parametrial invasion. Biopsies revealed a high-grade, large-cell carcinoma with neuroendocrine differentiation that stained positive for chromogranin, synaptophysin, and p16 (Figure 1).
Tumor showing medium-sized tumor cells with moderate to severe cytologic atypia. There is increased mitotic activities with mitotic count of 10 per 10 high power fields. (H&E, 400X).
A pelvic and abdominal MRI scan showed an 8×6×5 cm enhancing mass in the anterior lip of the cervix with intermediate T2 signal and associated restricted diffusion corresponding to the known primary malignancy (Figure 2). There was no vaginal or parametrial extension. Ovaries were unremarkable. There was no pelvic or para-aortic nodal disease and no evidence of metastatic disease. Chest X-ray results with fetal protection were normal. The tumor was classified as an International Federation of Gynecology and Obstetrics (FIGO stage IB3 neuroendocrine cervical cancer.
Pelvic MRI. sagittal T2 sequence shows a mass in the anterior cervix and the fetal head.
Obstetrical ultrasound demonstrated a single fetus with no anomalies, in vertex presentation. The patient was admitted and received a course of intramuscular corticosteroids to achieve fetal pulmonary maturity.
Dr Plante
Based on this diagnosis of cervix cancer at the third trimester of pregnancy, what would you consider the ideal management?
Accounting for 10% of all malignancies during pregnancy with an estimated incidence of 0.8 to 1.5 cases per 10 000 births, 1 cervix cancer represents the third most common cancer in pregnancy.2 Patients with cervical cancer who are pregnant or post partum at the time of diagnosis represent 1 to 3% of women with cervical cancer.3 Given the lack of large retrospective studies and the absence of randomized trials on which to base recommendations for the treatment of pregnant patients with cervical cancer, management is generally based on four parameters: the patient’s choice to continue the pregnancy, the stage of cancer, the gestational age, and the risks of modifying or delaying therapy during pregnancy.
In our specific situation, at 30 2/7 weeks of gestation with a locally advanced tumor with no evidence of metastatic disease and no active bleeding, the decision was made to postpone delivery to 32 weeks to avoid severe prematurity. As for all patients with cervix cancer during pregnancy, a Cesarean section should be performed, and some experts recommend a classic incision to minimize blood loss and avoid the large tumor vessels. A low transverse Cesarean delivery should be avoided, particularly in patients with large tumor volume, to decrease the risk of cutting or tearing into tumor tissue.4 After delivery, total body imaging should be performed (CT scan or PET-CT) to rule out metastatic disease.
Dr Touhami
The patient underwent a classical Cesarean section at 32 weeks of gestation with the delivery of a viable female infant weighting 1800 g. The lower uterine segment and both parametria were palpably normal and there was no gross disease in the abdomen or pelvis. The following day, positron emission tomography (PET/CT) confirmed no evidence of metastatic disease with an area of femoral dysplasia of the left femoral head (Figure 3).
PET-CT scan performed the following day after C-section showing no evidence of metastatic disease. Arrow points to an area of femoral dysplasia of the left femoral head.
Dr Plante
a) The tumor is now confirmed as a FIGO IB3 neuroendocrine cervical cancer. What would you propose for the treatment?
b) Are there specificities considering this rare histology (neuroendocrine cancer)?
In a case of a FIGO stage IB3 cervical cancer, the standard treatment would be concurrent chemoradiation with cisplatin, followed by brachytherapy. However, with this specific histology, the most commonly used chemotherapy regimen is based on the combination of platinum and etoposide, as in the management of small-cell lung cancer.5 For locally advanced disease, chemoradiation with cisplatin and etoposide with the addition of brachytherapy followed by additional chemotherapy with cisplatin and etoposide for a total of four to six cycles (two cycles with radiation and two to four cycles after radiation completed) with a goal to reach six cycles is the standard treatment. Another option would be neoadjuvant chemotherapy followed by hysterectomy. However, this management is controversial as there have been only small studies looking at this option, with two suggesting a benefit, 6 7 and a third one showing worse survival.8
Dr Touhami
The patient started chemotherapy 2 days after the Cesarean section with a combination of cisplatin 60 mg/m2 intravenously (IV) on day 1 and etoposide 100 mg/m2 IV on days 1, 2, and 3. She received two cycles of chemotherapy as concurrent chemoradiation, and four additional cycles after radiation was completed. Radiation therapy consisted of 45 Gy to the pelvis followed by brachytherapy to a dose of 30 Gy.
One month after the end of the treatment, the patient developed a pelvic abscess with uterine scar dehiscence and a suspicion of an ileo-uterine fistula. She was treated with a combination of IV antibiotics and percutaneous drainage followed by oral antibiotics, with good evolution. Analyses of the drainage revealed no cancer cells. Five months after the end of chemotherapy the patient developed multiple liver metastases with a malignant mass at the junction of the duodenum and the pancreas (Figure 4). A brain scan revealed no abnormalities.
PET-CT showing multiple liver metastases with a malignant mass at the junction of the duodenum and the pancreas.
Dr St Gelais
What is the ideal management for recurrent neuroendocrine cancer of the cervix?
Due to its rarity, the management of recurrent NECC is mainly based on the management of recurrent small-cell lung cancer where the combination of paclitaxel and topotecan is active with relatively low toxicity. 9 Both agents are also used in combination in the management of patients with non-NECC (squamous cell carcinoma, adenocarcinoma, and adenosquamous carcinoma). 10
In Gynecologic Oncology Group (GOG) 240, the combination of paclitaxel and topotecan induced a response rate of 27% in recurrent, persistent, or metastatic cervical cancer, and this regimen is tolerable in women who have previously received definitive chemoradiation.11 The addition of bevacizumab led to a response rate of 47%. Considering that small-cell neuroendocrine carcinomas of the cervix express the vascular epithelial growth factor receptor in over 95% of the cases, it would make sense to add bevacizumab to the chemotherapy regimen.12
In a study published by Frumovitz et al, the authors retrospectively analyzed patients with recurrent small cell neuroendocrine carcinoma of the cervix.13 Sixty-two patients received the combination of topotecan, paclitaxel, and bevacizumab and 56 received other regimens, mainly platinum with or without a taxane. Median progression-free survival was 8.7 months for the first group and 3.7 months for the second group. Median overall survival was 16.8 months in the first group compared with 14.0 months in the second group, with a HR for death of 0.87 (95% CI 0.55 to 1.37). Overall, 44 (71%) of 62 patients receiving the combination of topotecan, paclitaxel, and bevacizumab experienced a clinical benefit for progression-free survival, 33 (53%) had a partial response or stable disease and 11 patients (18%) achieved a complete response to all disease outside of the brain.
In the specific situation of our patient, bevacizumab was omitted because of the suspicion of the ileo-uterine fistula.
Dr Touhami
Chemotherapy was started with topotecan (0,75 mg/m2 on days 1–3) and paclitaxel (175 mg/m2 on day 1). After three cycles of topotecan and paclitaxel, a CT scan showed progression of the disease with an increase in the size and number of liver metastasis.
Dr Frumovitz
What would be your management after this disease progression?
Therapeutic options in the management of metastatic neuroendocrine carcinoma of the cervix are lacking. In a case of disease progression on topotecan and paclitaxel, the prognosis is generally very poor. The 5-year overall survival rates range from 0% to 7% for stages III–IV.14 One option could be re-treating with platinum and etoposide. In our patient, platinum-based chemotherapy was last used over 6 months prior and I might consider re-challenging with that doublet. At this point, exploring new therapeutic options based on molecular profiling should be considered. In fact, treatment regimens using targeted therapy based on the immunohistochemical expression of pertinent biomarkers have been identified in high-grade neuroendocrine carcinoma of extracervical sites.15
Dr Touhami
The patient received carboplatin and etoposide. After initial stabilization with four cycles of chemotherapy, a CT scan performed after the fifth cycle showed progression of the disease with an increase in the size and number of liver metastases. The patient’s condition was deteriorating rapidly. In the meantime, molecular profiling was performed and revealed a tumor mismatch repair proficient, programed cell death ligand 1 (PD-L1) negative, EGFR negative, BRAF negative, and KRAS negative.
Dr Frumovitz
What would you offer this patient at this time?
What is the role of targeted therapies in the management of neuroendocrine cancer of the cervix?
The molecular findings are not surprising or inconsistent with the literature. In a manuscript published by our team, we used immunohistochemistry to identify immune and molecular targets for potential therapeutic strategies in the treatment of 40 patients with recurrent neuroendocrine cervical carcinoma.16 All samples tested stained for mismatch repair proteins demonstrated intact expression, suggesting they were microsatellite-stable tumors. Of the samples tested for PD-L1 expression, only two (8%) of the 25 pure neuroendocrine carcinomas were positive. Of the 11 small cell specimens tested for PARP-1, 10 (91%) showed PARP expression, with six (55%) demonstrating high expression and four (36%) showing moderate expression. Finally, somatostatin staining was negative in almost all small-cell cases (95%).
While tumor PD-L1 expression is the factor which correlates best with response to immune therapy, data from a study on small cell lung cancer (Checkate-032) support nivolumab as an active agent despite the lack of PD-L1 expression.17 Other factors in the tumor microenvironment, including tumor mutational burden and neoantigen expression, seem to play an important a role in predicting the efficacy of these agents.18 The combination of anti-PD-1 or PD-L1 therapy with other agents, such as ionizing radiation and DNA damage-inducing chemotherapeutics, may upregulate PD-L1 expression, which, in turn, may offer an opportunity for immunotherapies in neuroendocrine tumors.19
The literature is limited in the setting of successful target therapies in the management of neuroendocrine carcinoma of the cervix. Paraghamian et al presented a patient with recurrent, metastatic, PD-L1-negative small-cell neuroendocrine carcinoma of the cervix who experienced a complete response to nivolumab.20 Sharabi et al reported an exceptional response to nivolumab and stereotactic body radiation therapy in a patient with a metastatic neuroendocrine cervical carcinoma with high tumor mutational burden. The patient had a near-complete systemic resolution of disease, ongoing at 10 months.21 Finally, in a patient with recurrent small-cell neuroendocrine carcinoma of the cervix whose tumor was found to have a KRAS mutation, Lyons et al used the mitogen-activated protein kinase 1 inhibitor, trametinib, and had a complete radiologic response after three cycles.22 In our patient, having already used all standard of care options, the off-label use of nivolumab and niraparib was offered.
Dr Touhami
Therapy was initiated with the association of nivolumab and niraparib. After three cycles of treatment, the patient’s condition rapidly improved with a decrease in the size of the liver metastasis and a complete response in duodeno-pancreatic metastasis. After six cycles of treatment, PET-CT showed no evidence of disease (Figure 5). One year after the end of treatment, the patient remains free of disease.
PET-CT showing complete resolution of all lesions.
Dr Frumovitz
What is the rationale behind the association of nivolumab and niraparib in the management of neuroendocrine cancer of the cervix?
High-grade neuroendocrine carcinoma of the cervix are microsatellite stable without significant expression of PD-L1, raising concerns for potential lack of activity with PD-1/PD-L1 inhibitors in these tumors.16 In contrast, significant PARP expression was noted in the majority of neuroendocrine carcinoma of the cervix samples, making PARP inhibitors a potentially good candidate for the management of women with this disease. 16 Molecular studies in recurrent high-grade neuroendocrine carcinomas of the prostate and lung have shown overexpression of PARP and inhibition of tumor growth with PARP inhibitors. 23 PARP-1 has been shown to have a role in DNA repair and in DNA methylation as well as influencing transcription factors.24
PARP inhibitor also upregulates PD-L1 expression through a variety of mechanisms, including interferon γ stimulation, STING pathway activation, or inactivation of glycogen synthase kinase-3b (GSK3b) in solid tumor pre-clinical models.25 The rationale for PARP inhibitor in combination with PD-1/PD-L1 inhibitors involves other mechanisms beside upregulation of PD-L1, such as increasing tumor-infiltrating lymphocytes, production of tumor neoantigen, and enhancing antigen presentation.26 Therefore, the combination of PD-1/PD-L1 inhibitors and PARP inhibitors could work synergistically, improving efficacy over either therapy alone.
Several ongoing trials are based on this potential synergistic association in the management of gynecological cancers, and some small studies have already demonstrated promising results in non-gynecologic sites. For instance, Jiao et al found that treatment with PARP inhibitors led to increased PD-L1 expression in breast cancer cell lines and xenograft tumors.27 Similarly, Sen et al showed that PARP inhibition significantly potentiates the effectiveness of PD-L1 inhibitors in small-cell lung cancer cell lines.28
Conclusion
In an ultra-rare cancer such as high-grade neuroendocrine cervical carcinoma, there are virtually no standard of care options beyond platinum and etoposide as first-line therapy, and paclitaxel, topotecan with bevacizumab for recurrence. This lack of standard options allows providers to be thoughtful and creative in their approach to prescribing chemotherapy for these patients. Large randomized trials will never be performed in a tumor that has an incidence of 0.6 per 100 000 women. We recommend molecular testing to potentially inform clinical trials and would strongly advocate a trial if a good match exists. In the absence of a study, basing therapeutic recommendations on molecular testing, scientific rationale, personal experience/case reports, and active regimens from similar tumors from other tumor sites (small-cell lung cancer) may be the best next option for patients and providers.
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References
Footnotes
Twitter @frumovitz
Contributors OT: presenter; JS-G: hematologist-oncologist; MP: gynecologic-oncologist; MF: discussant.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Provenance and peer review Not commissioned; internally peer reviewed.
© IGCS and ESGO 2023. No commercial re-use. See rights and permissions. Published by BMJ.