Introduction
In the United States, the incidence of cervical cancer has decreased significantly over the last 5 decades as a result of effective screening programs and the ability to successfully treat the disease before invasive cancer develops. Furthermore, as future generations of boys and girls undergo vaccination against human papillomavirus (HPV), the incidence should decrease further.[1] In 2015, there were an estimated 12,900 new cases of cervical cancer and 4,100 deaths.[2] The overwhelming majority of these cases (> 98%) were one of the HPV-associated histologies: adenocarcinoma, squamous cell carcinoma, or adenosquamous carcinoma. For these common histologies, treatment paradigms for patients with newly diagnosed and recurrent disease are well established and accepted. For the rare non–HPV-associated subtypes, however, treatment varies widely, particularly in the recurrent setting.
Neuroendocrine carcinomas are a subtype of cervical cancer that does not appear to be associated with HPV exposure. They are exceedingly rare, accounting for only 1% of newly diagnosed cervical cancer cases. This translates to roughly 100 to 150 cases per year in the United States. Although primary carcinoid tumors of the cervix have been reported, most neuroendocrine tumors of the cervix will be either small-cell or large-cell (or mixed). Small- and large-cell cervical cancers are highly aggressive compared with their squamous cell carcinoma or adenocarcinoma counterparts. For example, as many of 40% of clinical stage I small-cell cervical cancer patients have metastatic disease to the lymph nodes at diagnosis, compared with only 10% to 15% of women with adenocarcinoma or squamous lesions.[3-5]
Initial Workup
In a patient newly diagnosed with neuroendocrine carcinoma of the cervix, it is important to conduct a thorough gynecologic examination, including a rectovaginal exam, in order to establish the clinical stage. In addition to the physical examination, chest x-ray, intravenous pyelogram, cystoscopy, and proctoscopy are all part of the official International Federation of Gynecology and Obstetrics (FIGO) clinical staging protocol, although most physicians in the developed world forgo those tests in favor of more advanced radiologic imaging studies, such as computed tomography (CT), magnetic resonance imaging (MRI), and/or positron emission tomography (PET). Because of the tendency for small- and large-cell carcinomas of the cervix to spread early to lymph nodes, liver, and lung, I order a PET/CT scan for initial radiologic staging. Unlike with small-cell carcinoma of the lung, MRI of the brain is not necessary unless patients are symptomatic or have disease that has spread to the liver or lungs.
Primary Treatment
Early-stage disease
Both the Society of Gynecologic Oncology and the Gynecologic Cancer Intergroup recommend multimodal therapy for all stages of neuroendocrine tumors of the cervix,[6,7] and the majority of patients receive some combination of surgery, radiation, and chemotherapy.[8] Typically, I treat early-stage disease (stages IA1–IB1) with a radical hysterectomy, bilateral salpingo-oophorectomy, and pelvic lymphadenectomy, followed by chemoradiation with cisplatin (50 mg/m2 on day 1 every 3 weeks) and etoposide (100 mg/m2 on days 1–3 every 3 weeks), and then an additional 2 or 3 cycles of cisplatin and etoposide at the same dose. Originally, we used single-agent cisplatin with radiation; however, over the last few years we have transitioned to full-dose cisplatin and etoposide with radiation, since that regimen is believed to be more effective than therapy with cisplatin alone and patients are usually able to tolerate it along with definitive pelvic radiation.[5] There are no prospective phase II or phase III clinical trials for patients with small- or large-cell cervical cancers, so chemotherapy drug choices have been based on those drugs deemed active in patients with small-cell lung cancer. In contrast to small-cell lung cancer, however, prophylactic brain irradiation is not recommended for cervical cancer patients at any stage of disease.
Of note, small- and large-cell cervical cancers seem to occur in women younger than those in whom the more common HPV-associated cervical cancers typically develop, and therefore fertility may be a concern for patients and providers. In the past, we have delayed starting treatment for 2 to 3 weeks in order to allow for ovarian stimulation and egg retrieval by our reproductive endocrinology and infertility colleagues. This is our preferred approach to the preservation of fertility in these patients, since it seems more reliable than ovarian transposition, a procedure that, when followed by radiation, leads to ovarian failure in as many as 80% of patients.[9] In addition, there are theoretical concerns that microscopic disease might be left in the ovary and would then be transposed out of the radiation treatment field-although microscopic disease in the ovary in the absence of other sites of metastatic disease is exceedingly rare.
Locally advanced disease
For women with stage IB2–IVA disease, we treat with concurrent chemoradiation, followed by additional chemotherapy with intent to cure. Radiation typically consists of 40–45 Gy of external beam radiation, followed by an additional 40–45 Gy of brachytherapy. Chemotherapy is the same regimen described above, with cisplatin and etoposide given on an every-3-weeks cycle. For patients with a large burden of nodal metastases and no evidence of intraperitoneal spread, we have had some success with neoadjuvant chemotherapy with cisplatin and etoposide followed by consolidation radiation therapy.
Widely metastatic disease
For patients with metastatic disease (stage IVB) or those with disease not amenable to radiation, we typically treat with chemotherapy alone. Our drugs of choice are again cisplatin and etoposide, but dosed a little higher than for patients receiving concurrent radiation. We give cisplatin at 60 mg/m2 on day 1 every 3 weeks and etoposide at 120 mg/m2 on days 1–3 every 3 weeks. We consider this palliative therapy, the intent of which is to prolong life, with little chance of curative effect.
KEY POINTS
Small- and Large-Cell Neuroendocrine Cervical Cancer
- Small-cell and large-cell neuroendocrine tumors of the cervix are exceedingly rare but incredibly aggressive.
- Because no prospective studies have been performed in this patient population, treatment recommendations are based on small clinical experiences and approaches used in small-cell lung cancer.
- For newly diagnosed patients, multimodal therapy with radiation, chemotherapy, and/or surgery should be strongly considered.
- For recurrent disease, we have seen good responses with the combination of topotecan, paclitaxel, and bevacizumab.
- Consideration of molecular testing and targeted therapy in a clinical trial should be strongly considered, since therapeutic options for these patients are few.
Surveillance
For patients with adenocarcinoma, squamous cell carcinoma, or adenosquamous carcinoma, the recommended surveillance consists of a physical examination, including a pelvic exam, every 3 to 6 months for 2 years and then every 6 to 12 months for an additional 3 years. In addition, a Papanicolaou test should be performed annually.[10] We perform a chest x-ray annually but do not follow this with any other radiologic testing unless recurrence is suspected on the basis of the history or physical examination findings. Because of the aggressive nature of cervical neuroendocrine tumors, I see these patients much more frequently in the posttreatment period. Typically, I will perform a physical examination (with a pelvic exam) every 3 months for the first 2 years and then every 4 to 6 months for the next 3 years. In addition, I perform routine radiologic imaging of the chest, abdomen, and pelvis, with either a CT scan or PET/CT scan at every visit.
Treatment of Recurrence
As mentioned, the choice of primary chemotherapy (cisplatin and etoposide) for small- and large-cell cervical cancer has been extrapolated from the small-cell lung cancer literature and is not supported by any phase II or phase III data. Similarly, in the recurrent setting, there are no data to guide treatment decisions, and many physicians will choose single-agent topotecan, irinotecan, or docetaxel for second-line chemotherapy because these regimens are commonly used to treat recurrent small-cell lung cancer. In our experience, however, these single-agent regimens have had very little activity in patients with recurrent neuroendocrine cervical cancer.
For patients with recurrent or progressive small- or large-cell cervical cancer, our regimen of choice is a three-drug combination of topotecan, paclitaxel, and bevacizumab, given in the same manner as in Gynecologic Oncology Group (GOG) 240, a phase III study in patients with recurrent cervical cancer (squamous cell carcinoma, adenocarcinoma, and adenosquamous carcinoma).[11] Although small- and large-cell cancer patients were ineligible for this study and we therefore have no data to support the efficacy of this regimen in this population, we have opted to use it for the following reasons:
1. This regimen is active in women with recurrent cervical cancer.
2. Based on GOG 240, this regimen is tolerable in women who have previously undergone definitive chemoradiation.[11]
3. Single-agent paclitaxel and single-agent topotecan are active and frequently utilized in recurrent small-cell lung cancer, so the combination would presumably be equally as active as-and potentially more active than-the single-agent regimens.
4. Small-cell cervical cancers express the vascular epithelial growth factor receptor over 95% of the time, supporting the addition of bevacizumab as an active agent.[12]
5. All three drugs have been approved by the US Food and Drug Administration for the treatment of recurrent cervical cancer, so reimbursement is usually not a concern.
We have been using this regimen for over 2 years now with encouraging results and are preparing to publish our experience. Based on what we have seen, we will continue to use this regimen and are planning a phase II study.
As part of our strategy for treating patients with recurrent disease, we also order molecular testing at the time of first recurrence, prior to starting topotecan, paclitaxel, and bevacizumab. We use our own institutional platform; however, other outside providers (eg, Foundation Medicine, Caris) offer similar mutational analyses. Because most patients with recurrences will eventually have progressive disease, this testing allows us to triage patients to a targeted therapy either on-protocol or off-label. For example, we recently had a patient with a KRAS mutation who received the MEK inhibitor trametinib. She had a complete response and was disease-free for over 9 months.[13] Unfortunately, her disease has recently recurred. For patients whose disease progresses after treatment with topotecan, paclitaxel, and bevacizumab and subsequent targeted therapy, we recommend a phase I clinical trial or hospice care.
Conclusions
Small- and large-cell neuroendocrine tumors of the cervix are exceedingly rare and exceedingly aggressive. For newly diagnosed patients, we employ a multimodality approach utilizing surgery, radiation, and chemotherapy for those with early-stage disease, and radiation and chemotherapy for those with advanced-stage disease. We usually administer etoposide and cisplatin both concurrently with radiation and after the completion of radiation. These drugs are chosen because of the histologic similarity of neuroendocrine cervical cancer to small-cell lung cancer, since clinical trials in the former disease have not been performed. For recurrent disease, we have had some initial responses with topotecan, paclitaxel, and bevacizumab used in combination, and a prospective phase II study of this regimen is in development. We have also had some success with targeted therapy based on molecular testing results. Future plans include potentially performing “site agnostic” trials that combine patients with small-cell lung, cervical, head and neck, and urologic cancers.
Financial Disclosure: The author has no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.
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