Efficacy of radical doses of pelvic radiotherapy for primary tumor treatment in patients with newly diagnosed organ metastatic cervical cancer

Newly diagnosed organ metastatic cervical cancer is defined as a cervical carcinoma that has extended to distant organs such as the lung, bone, liver or brain. Approximately 3% of patients have the International Federation of Gynecology and Obstetrics (FIGO) stage IVB cervical cancer, and patients with organ metastasis account for only a small proportion of these [1].

For locally advanced cervical cancer, definitive pelvic radiotherapy combined with concurrent chemotherapy has been employed as a standard treatment modality [2]. However, the role of definitive pelvic radiotherapy for primary tumor treatment in patients with organ metastatic cervical cancer at presentation is unclear. Systemic treatment based on combination chemotherapy is recommended by the guidelines of the National Comprehensive Cancer Network (NCCN) and the European Society of Gynecological Oncology (ESGO) [3, 4]. Currently, combination chemotherapy alone is widely used as a treatment for cervical cancer patients with organ metastasis, but with limited benefit and poor response outcomes [5‐7].

Increasing evidence suggests that local radiotherapy may be related to improved survival in patients with some specific types of metastatic cancers [8‐10]. Therefore, we performed a retrospective study to evaluate the efficacy of definitive pelvic radiotherapy based on chemotherapy in patients with newly diagnosed organ metastatic cervical cancer.

In this study, we have attempted to assess the efficacy of definitive pelvic radiotherapy combined with chemotherapy in patients with organ metastatic cervical cancer. Our results demonstrated that chemotherapy combined with definitive pelvic radiotherapy improved survival outcome compare with chemotherapy with/without palliative pelvic radiotherapy. The pelvic local control rate was high for patients receiving the definitive pelvic radiotherapy combined with chemotherapy. However, 75% of patients still experienced failure with distant metastatic lesion progression.

Patients with newly diagnosed organ metastatic cervical cancer experienced a poor prognosis [11‐13]. At present, the generally accepted treatment is combinational chemotherapy-based systemic therapy, whereas the role of definitive pelvic radiotherapy for primary tumor as a local treatment is unclear. In the ESGO guideline, combination chemotherapy (cisplatin/paclitaxel and carboplatin/paclitaxel) is recommended while the central role of radiotherapy is palliative, to control pain and bleeding in patients with organ metastasis at diagnosis [4]. In the NCCN guidelines, depending on whether the disease is amenable to local treatment, two treatment modalities have been recommended. However, the criteria for local treatment adaptation have not yet been clearly defined [3]. For patients with organ metastatic cervical cancer, it is still unclear as to the benefits of active local treatment combined with chemotherapy.

As methods for local treatment, surgery and radiotherapy are all recommended in the 2019 NCCN guideline for distant metastatic cervical cancer [3]. Surgical resection treatment can be a useful treatment for lesions of distant metastases [14]. However, as far as primary uterine cervical tumors are concerned, radiotherapy is more suitable than surgical treatment, as most patients with organ metastatic cervical cancer have locally advanced disease.

In our study, most of the treatment failures due to distant progress; people wondered whether definitive pelvic radiotherapy as a local treatment method is a reasonable choice for women with organ metastatic cervical cancer. At present, there is a growing body of evidence supporting a beneficial role for definitive radiotherapy in the sites of primary or metastatic tumors. A large-sample (3169 patients) retrospective study on newly diagnosed metastatic cervical cancer showed that patients who received chemotherapy alone, EBRT alone plus chemotherapy, or EBRT/BT plus chemotherapy had a median survival time 10.1, 12.9, and 27.5 months, respectively; of note, chemoradiotherapy was associated with improved survival than chemotherapy alone for patients with organ metastasis by subgroup analyses (p < 0.05) [15]. Another significant (6382 cases) retrospective study of newly diagnosed metastatic prostate cancer found that patients undergoing prostate radiotherapy and androgen deprivation survived substantially longer than patients receiving androgen deprivation alone; meanwhile, improved overall survival was observed for higher-dose radiotherapy (≥ 65Gy) when compared with lower-dose radiation therapy (< 65 Gy) by subgroup analyses [9]. In addition, some studies showed chemotherapy combined with definitive radiotherapy to sites of oligometastatic diseases achieved favorable survival rates, and the toxicity of radiotherapy-related was minimal and well tolerated [8, 10]. A similar trend was identified in our study, patients with organ metastatic cervical cancer receiving systemic chemotherapy combined with definitive pelvic radiotherapy had increased survival rates when compared with patients receiving systemic chemotherapy with/without palliative pelvic radiotherapy. All these evidence support the use of systemic chemotherapy combined with definitive pelvic radiotherapy for certain women with organ metastatic cervical cancer in good performance status.

In addition to survival benefits, there have been some reports of chemoradiotherapy for cervical cancer with organ metastases giving potential insights into the patient selection. A retrospective study of 24 patients with stage IVB cervical cancer (87.5% with organ metastases) receiving radiotherapy and multiagent chemotherapy found that improved 5-year OS rates (22%) were observed among patients with good performance status [16]. An additional retrospective study looking at prognosis factors from 111 patients with stage IVB cervical cancer has indicated that performance status is one of the independent prognostic factors [13]. In our study, all patients with a good ECOG performance status score had a good tolerance potential for radiotherapy and chemotherapy and showed a 5-year OS rate of 20.2%.

Although high pelvic local control rates were achieved for patients receiving definitive pelvic radiotherapy, distant metastatic lesion progression was the main reason for treatment failure. Our study showed that in group A, 27 patients, representing 75% achieved local complete remission from pelvic primary tumors utilizing definitive pelvic radiotherapy combined with chemotherapy, yet 27 patients (75%) developed treatment failure for distant lesion progression. This result was supported by findings of an earlier study retrospectively analysing 50 patients diagnosed with disseminated cervical cancer with distant lymph nodal or visceral organ metastasis and found that the primary reason for treatment failure was the systemic progression in 32 patients (64%) [17]. Therefore, systemic therapy for organ metastatic cervical cancer is still the most important treatment.

A phase III Gynecologic Oncology Group (GOG) study found that chemotherapy combined with bevacizumab treatment compare with chemotherapy alone significant improved OS (16.8 vs 13.3 months) for patients with recurrent/persistent/metastatic cervical cancer [18]. Therefore, standard chemotherapy (cisplatin/paclitaxel and carboplatin/paclitaxel) combined with bevacizumab is recommended for patients with a good performance status [4]. Recently, an immune checkpoint inhibitor, programmed cell death protein-1 (PD-1), and programmed cell death ligand-1 (PD-L1), showed potential for the treatment of advanced cervical cancer [19]. These new drugs also bring new hope and new research directions for the systemic treatment of organ metastatic cervical cancer.

For patients with organ metastatic cervical cancer in good performance status, systemic treatment (chemotherapy, molecular targeting therapy, and immunotherapy) should be administered first. When systemic treatment is effective, radiotherapy should be considered for local treatment. For some patients with good prognostic factors, such as a limited number of metastases, a definitive radiation dose (EBRT plus BT) for the primary cervical tumor should be considered. Although a few patients with favorable prognostic factors might be completely cured by chemoradiotherapy, some patients may achieve long-term survival with neoplasm. For patients with unfavorable prognostic factors, the aim of definitive pelvic radiotherapy may be to gain good local control, improve quality of life and further delay the progression.

The major limitations of this study are the following: firstly, the inherent bias in a single-institution retrospective study, the small sample size, and covering a long period. Secondly, heterogeneity within patient groups and treatments might represent confounding factors that may influence the outcome. Thirdly, the decision of which treatment regimen should be adopted for a patient may be influenced by a variety of factors, including the opinions from doctor’s team and the decision from patient’s own; furthermore, doctor’s judgment may be affected by patient’s tolerability and efficacy of previous treatment. Fourthly, although survival was the only endpoint assessed here, information on other factors such as quality of life, and symptom control are also important, but these are not found in the database. To eliminate these potential biases, we should conduct prospective multicenter clinical studies in the future.

Despite the inherent drawbacks of retrospective analyses, our data indicate that patients with newly diagnosed organ metastatic cervical cancer, but in good performance status may benefit from definitive pelvic radiotherapy combined with chemotherapy to improve overall survival, especially for some patients with favorable prognostic factors. Prospective multicenter clinical trials to further validate the findings of this study are warranted.