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 Table of Contents  
ORIGINAL ARTICLE
Year : 2020  |  Volume : 4  |  Issue : 2  |  Page : 54-59

Clinical prognostic factors and treatment outcomes in patients with small cell carcinoma of the cervix: A single institution-based retrospective study


Department of Radiation Oncology, Gujarat Cancer and Research Institute, Ahmedabad, Gujarat, India

Date of Submission05-Apr-2020
Date of Decision25-May-2020
Date of Acceptance04-Jul-2020
Date of Web Publication17-Aug-2020

Correspondence Address:
Niketa Thakur
Department of Radiation Oncology, Gujarat Cancer and Research Institute, New Civil Hospital Campus, Asarwa, Ahmedabad, Gujarat
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/oji.oji_18_20

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  Abstract 


Introduction: Small cell carcinoma of the cervix (SCCC) is relatively uncommon among cervical malignancies and is more likely to develop lymph node and distant metastasis compared to the common squamous histological variant. There is a lack of knowledge about potential prognostic factors, optimal treatment modalities, and survival outcome of SCCC. Aim: The aim of this study is to correlate clinicopathologic parameters and different treatment schedules with survival outcomes of SCCC as progression-free survival (PFS) and overall survival (OS). Materials and Methods: A retrospective study was conducted on diagnosed SCCC patients taking treatment from January 2005 to December 2014. Results: A total of 21 patients were analyzed. The median age of presentation was 47 years. All the patients presented at an advanced stage (IIB-IVB) with high-grade histological differentiation. The median PFS and OS were 5 and 6 months, respectively. The patient receiving multi-agent platinum- and etoposide-based radical concurrent chemoradiotherapy (CCRT) plus brachytherapy had significantly better PFS (P = 0.028) and a trend toward better OS versus other treatment modalities. The median OS was found to be significantly poor in SCCC patients having an additional neuroendocrine component, not receiving brachytherapy after CCRT, and not receiving prophylactic cranial irradiation after radical radiotherapy (P < 0.05). Cisplatinum- plus etoposide-based CCRT schedule had a trend toward better PFS and OS than that of only cisplatinum-based CCRT (P > 0.05). Furthermore, a trend toward better OS was seen for age >40 years, tumor size ≤4 cm, and lymph node-negative status. Relapse was seen in 42.9% of the cases over a 7-month median follow-up. Conclusions: CCRT using multi-agent platinum- plus etoposide-based chemotherapy followed by brachytherapy remains the mainstay of treatment in locally advanced SCCC. The prognostic factors should be considered for customizing treatment.

Keywords: Cervix, prognostic factors, small cell carcinoma, survival outcomes


How to cite this article:
Thakur N, Patel S. Clinical prognostic factors and treatment outcomes in patients with small cell carcinoma of the cervix: A single institution-based retrospective study. Oncol J India 2020;4:54-9

How to cite this URL:
Thakur N, Patel S. Clinical prognostic factors and treatment outcomes in patients with small cell carcinoma of the cervix: A single institution-based retrospective study. Oncol J India [serial online] 2020 [cited 2020 Oct 31];4:54-9. Available from: https://www.ojionline.org/text.asp?2020/4/2/54/291901




  Introduction Top


Small cell carcinoma of the cervix (SCCC) is a relatively rare entity among different subtypes of cervical malignancies and accounts for <5% of all cervical malignancies.[1] The histology and biologic behavior of such variant is similar to that of small cell lung carcinoma, which is highly aggressive. The prognosis of SCCC is poor in comparison to that of other histological types of cervical carcinoma.[2],[3] Several potential prognostic factors including the International Federation of Gynaecology and Obstetrics (FIGO) stage, age, tumor size, lymphovascular space involvement (LVSI), lymph node metastases (LNM), depth of stromal invasion, parametrical involvement, distant metastases, and treatment modality have been found to influence survival in some studies.[2],[3],[4],[5],[6],[7],[8],[9],[10] The 5-year survival rates for early-stage SCCC range from 31.6% to 46.6% and for advanced-stage disease ranges from 0% to 14%.[4],[8]

It is important to have knowledge of possible prognostic factors for the optimal selection of treatment modalities, response assessment, and follow-up schedule. There is a large body of literature on prognostic factors for cervical cancer have been published. However, studies examining the magnitude of prognostic factors, according to histological subtypes, are few. Keeping this in the background, we aimed to conduct this study.


  Materials and Methods Top


A retrospective analysis of 21 patients of diagnosed SCCC treated in a tertiary care institute from January 2005 to December 2014 was conducted to assess the associations of the clinical prognostic and some treatment factors with survival. The study was approved by the institutional ethics committee. The staging of SCCC patients was done using the FIGO staging system. Contrast-enhanced computed tomography scan of the thorax, abdomen, and pelvis was done for staging evaluation. Magnetic resonance imaging of brain, examination under anesthesia or ultrasonography of the abdomen was performed based on individual physician discretion.

The different treatment schedules were radical concurrent chemoradiation (CCRT) with brachytherapy and prophylactic cranial irradiation (PCI), CCRT with brachytherapy only, neo-adjuvant chemotherapy followed by surgery followed by external beam radiotherapy (EBRT), palliative radiotherapy, and palliative chemotherapy. Standard chemotherapy protocol for CCRT consisted of doublet chemotherapy with intravenous cisplatin 40 mg/m2 on days 1, 8, 29, 36, and intravenous etoposide 50 mg/m2 on day 1–5 and 29–33 or single-agent chemotherapy with weekly intravenous cisplatin 40 mg/m2. In the neo-adjuvant setting, chemotherapy was given as intravenous cisplatin 75 mg/m2 on day 1 and intravenous etoposide 100 mg/m2 on day 1–3 every 21 days for three cycles. After three cycles, the patient underwent a radical hysterectomy. The palliative chemotherapy schedule consisted of intravenous carboplatin AUC 6 on day 1 and intravenous etoposide 100 mg/m2 day 1–3 repeated every 28 days.

For EBRT, target volume was defined by the whole pelvis, which included primary tumor and pelvic lymph node stations, i.e., obturator, internal, external and common iliac, and upper presacral nodes. In selective cases, para-aortic nodal basin included along with the whole pelvis as target volume. Total EBRT dose ranged from 45 to 50 Gy in 25 fractions delivered over 4–5 weeks. For the majority of the patients, 3D conformal radiotherapy was used to design the pelvic fields. Brachytherapy was delivered by remote after-loading high-dose-rate technique using iridium 192 over two sessions with 7.5 Gy to point A in each session. PCI was given at the physician's discretion. It was delivered at a dose-fraction schedule of 25 Gy in 10 fractions over 2 weeks after the completion of EBRT and brachytherapy.

The recorded frequencies of clinical characteristics, prognostic factors, and treatment modalities were presented in absolute and percentage figures and were calculated using descriptive statistics. The Chi-square test was used for categorical data. The significance level was set at P < 0.05. The period from the date of diagnosis to the date of progression or last follow-up was defined as the progression-free survival (PFS), while the period from the date of diagnosis to death or last follow-up was defined as the overall survival (OS). Survival curves were constructed using the Kaplan–Meier method. The log-rank test was used to study the association of prognostic factors with survival. The statistical analysis was performed using IBM SPSS v. 25.0. (Armonk, NY: IBM Corp.).


  Results Top


The demographic characteristics of the patients are shown in [Table 1]. A total of 21 patients was included in the study. The median age of presentation for the patients was 47 years within the age range of 34–77 years. Sixteen out of 21 patients (76.2%) had a pure small-cell carcinoma histological type, and rest 5 patients (23.8%) had an additional neuroendocrine component. In our study, all the patients presented at advanced stage IIB-IVB with the FIGO stage IIIB being the most common, accounting for 8 (38.1%) cases.
Table 1: Patient characteristics

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All the patients had high-grade carcinoma. A total of 11 (52.4%) patients had pelvic LNM, among which 1 patient also had para-arotic LNM. Seventeen (81%) of 21 patients received EBRT to the pelvis and 1 of these 17 patients received EBRT to both pelvis and para-arotic region. Ten out of these 17 patients received radical CCRT followed by brachytherapy and thus completed full course of RT schedule. These 10 cases were the only patients who received brachytherapy in our study. Of these 10 patients, 6 patients received double agent etoposide plus cisplatinum-based CCRT (ETO + CIS-CCRT), while the rest 4 received single-agent cisplatinum-based CCRT (CIS-CCRT). 3 (14.3%) patients received only palliative EBRT in view of poor general condition. 4 (19.0%) patients received only palliative chemotherapy as they had been detected with distant metastasis at presentation. PCI was used in 4 (19.0%) patients after the completion of locoregional EBRT and brachytherapy.

The median OS and PFS were 6 months and 5 months, respectively. The association of various clinicopathologic variables with OS and PFS was mentioned in [Table 2]. On univariate analysis, we found that patients with radiological node-negative had a trend toward better median OS (9 months vs. 4 months; P = 0.289) and PFS (8 months vs. 4 months; P = 0.998) [Figure 1]. Patients having tumor size ≤4 cm had a trend toward better OS (10 months vs. 5 months; P = 0.154) and a significantly prolonged PFS (9 months vs. 4 months; P = 0.044) compared to those with tumor size >4 cm. ETO + CIS-CCRT schedule was associated with a trend toward better median OS (11 months vs. 5 months; P = 0.800) and PFS (11 months vs. 4 months; P = 0.077) compared to the use of CIS-CCRT schedule [Figure 2] and [Figure 3]. Patients who received brachytherapy along with EBRT had significantly better median OS (10 months vs. 4 months; P = 0.049) and PFS (10 months vs. 4 months; P = 0.007) compared to those who did not receive brachytherapy [Figure 4].
Table 2: Survival outcome based on some prognostic factors

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Figure 1: Impact of nodal involvement on overall survival

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Figure 2: Comparison of progression free survival in patients receiving single-agent versus double-agent concurrent chemotherapy

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Figure 3: Comparison of overall survival in patients receiving single agent versus double-agent concurrent chemotherapy

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Figure 4: Comparison of overall survival in patients receiving brachytherapy versus no brachytherapy

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Patients with age ≤40 years had a trend toward poor median OS (4 months vs. 7 months; P = 0.272) and PFS (4 months vs. 5 months; P = 0.920) compared to those with age >40 years [Table 2]. Patients with the presence of neuroendocrine components were found to have a significantly shorter median OS (P = 0.049) and PFS (P = 0.046) compared to those with pure small cell histology [Table 2]. Patients treated with PCI had significantly prolonged median OS (8 months vs. 5 months; P = 0.03) and a trend toward better PFS (7 months vs. 4 months; P = 0.902) compared to those who were not given PCI [Table 2].

We also studied the survival outcomes among different treatment modalities. The median overall OS in patients who received radical ETO + CIS-CCRT followed by brachytherapy, radical CIS-CCRT followed by brachytherapy, neo-adjuvant chemotherapy followed by surgery followed by EBRT, chemotherapy followed by palliative EBRT, palliative chemotherapy, and palliative EBRT was 11 months, 5 months, 6 months, 4 months, 3 months, and 3 months, respectively. The median overall PFS in patients who received radical ETO + CIS-CCRT followed by brachytherapy, radical CIS-CCRT followed by brachytherapy, neo-adjuvant chemotherapy followed by surgery followed by EBRT, chemotherapy followed by palliative EBRT, palliative chemotherapy and palliative EBRT was 11 months, 4 months, 4 months, 3 months, 3 months, and 3 months, respectively. The patient receiving ETO + CIS-CCRT followed by brachytherapy had significantly better PFS (P = 0.028) and a trend toward better OS versus other treatment modalities (P = 0.091).

After a median follow-up of 7 months (range: 3–15 months), 9 out of 21 (42.9%) patients had disease progression. Isolated distant relapse was seen in 4/21 (19.0%) patients. Out of these 4 patients, two patients had metastasis in the brain at the time of presentation and had received palliative RT to brain initially. However, metastasis in the brain progressed despite previous brain RT. Rest 2 patients had initially received curative chemoradiotherapy followed by brachytherapy. One patient relapsed in the bone and the other relapsed in the liver. Isolated local and isolated nodal metastasis were identified in 2 (9.5%) and 3 (14.3%) patients, respectively. Two out of 3 patients with nodal relapse initially had distant metastasis in lung and liver, respectively, and had received only chemotherapy as their primary treatment. Rest 1 patient received chemotherapy, followed by palliative radiotherapy to pelvis initially. Out of 2 local relapsed cases, one patient initially received chemotherapy, followed by palliative RT to the pelvis and the other one received neoadjuvant chemotherapy followed by surgery followed by external beam radiotherapy. Both the locally relapsed cases did not receive brachytherapy in their initial treatment course.


  Discussion Top


The study describes the outcomes of a cohort of SCCC patients treated at our center. SCCC is an aggressive malignant tumor with a poor prognosis.[11],[12] Clinicopathologic factors, such as stage, age, tumor size, LVSI, surgical margins, and parametrial invasion, are frequently used to evaluate the prognosis of cervical cancer in common histologic types such as squamous cell carcinoma, adenocarcinoma, and adenosquamous carcinoma.[10],[13],[14],[15] We determined the association of these clinicopathologic and some treatment factors with survival in patients of SCCC. Our findings among the clinical group of 21 patients demonstrated that larger tumor size (>4 cm), age ≤40 years, LNM, use of single-agent concurrent chemotherapy, neuroendocrine component were associated with poor survival outcomes.

Few studies analyzed the prognostic value of lymph node involvement in SCCC with the controversial result from not a prognostic factor to an independent prognostic factor for patients' survival. An analysis of 21 patients in our study detected 52.38% nodal metastases. These patients had a trend toward inferior median PFS and OS compared to the patients without LNM though statistically insignificant. Xie et al. and Chan et al. found lymph node status as an independent prognostic factor for patients' survival.[9],[10] A study by Chen et al. on the FIGO stage I-II SCCC found that patients with histological LNM performed worse 5-year OS than that of negative node patients.[11] However, some studies revealed that lymph node status was not a prognostic factor in SCCC.[16],[17],[18] The possible explanation of such variation among lymph node status on prognosis is due to the limited number of patients and lower incidence of the histology.

Radiation therapy plays an important role in the management of SCCC. The survival outcome of our patients treated with curative chemoradiation, particularly etoposide-and cisplatin-based followed by brachytherapy, was significantly better in terms of PFS (P = 0.028) and also with an increasing trend of median OS (P = 0.091) than those who were treated with other modalities. This indicates the importance of EBRT as a loco-regional treatment modality for SCCC. A large Taiwanese Gynecologic Oncology Group (TGOG) study by Wang et al. on small-cell neuroendocrine carcinoma of the uterine cervix has established the efficacy of CCRT treatment in terms of 5-year failure-free interval and cancer-specific survival supporting our data.[19] Chen et al. conducted a retrospective study on the FIGO stage I-II SCCC patients of TGOG, in which 110 patients underwent primary surgery and 34 patients underwent primary radiotherapy. They had shown that in comparison to primary surgery, primary radiotherapy combined with platinum-based chemotherapy seemed to be associated with a better 5-year OS (P = 0.046) and lower locoregional failure rate (P = 0.009).[11] However, we were unable to compare the survival outcome between primary surgery and primary chemoradiation as initial surgery was not performed in our study.

In our study, ten patients received brachytherapy after completion of CCRT, showing a numerically significant better median PFS and OS than those not receiving brachytherapy with the P = 0.007 and 0.049, respectively. We suggested brachytherapy as an essential component of definitive chemoradiation for locally advanced SCCC. Robin et al. conducted a study regarding the efficacy of the addition of brachytherapy to definitive chemoradiation in locally advanced nonmetastatic neuroendocrine cancer of the cervix by using the National Cancer Database and identified 100 patients for analysis. They found an improvement in median survival of 48.6 months on the addition of brachytherapy compared to 21.6 months for EBRT alone (P = 0.019) supporting our data.[20]

Chemotherapy is important for improved OS in SCCC. Chemotherapy regimens of cisplatin or carboplatin along with etoposide had been used in adjuvant settings for SCCC as similar to the treatment of small-cell lung.[21] Wang et al. in a study on 179 patients of SCCC found better 5-year disease-free survival and cancer-specific survival with platinum and etoposide based CCRT treatment schedule.[19] Data published in several literature revealed improved OS and PFS on the inclusion of platinum-based chemotherapy in the preoperative or postoperative setting.[22],[23],[24] In our study, we found a survival benefit in terms of OS and PFS for the use of CCRT based on platinum and etoposide combination regimen in locally advanced SCCC.

In our study, PCI was administered in only 4 out of 21 patients. We found a better median OS for the patients receiving PCI compared to those not receiving PCI (8 months versus 5 months; P = 0.030). However, no patients developed intracranial metastasis over a median follow-up of 7 months. Hence, we suggested not in favor of PCI treatment for SCCC. However, underlying confounding factors exist in our study, such as the retrospective nature of the study, limited sample size with less duration of follow-up. A study by Naidoo et al. on 280 patients of extrapulmonary small-cell carcinoma had shown the development of brain metastasis in 18 patients (6.4%) over a median OS of 10.1 months and only 2 patients (0.17%) received PCI. They also suggested not in favor of PCI treatment for extrapulmonary small cell carcinoma due to low incidence of brain metastases, and differences in disease biology and metastatic spread between extrapulmonary small cell carcinoma and small-cell lung carcinoma supporting our data.[25] De Caluwé et al., in a large retrospective series on extrapulmonary small-cell carcinoma, estimated the overall rate of symptomatic brain metastasis of 12.5% at 3-years. In PCI eligible patients, they found the 3-year cumulative incidence of new brain metastases of 5.5% for nonmetastatic disease and of 26.3% for M1 disease. They suggest a relatively low rate of intra-cranial metastasis in extrapulmonary small-cell carcinoma.[26] Furthermore, several studies reported the long-term neurocognitive effect of PCI, including a significant decline in both immediate and delayed recall memory in patients with lung cancer.[27],[28] However, a recent study by Roy et al. in 2019, over 25 patients of SCCC found improved distant control and a numerically superior OS with PCI.[29] Although PCI may be helpful in primary SCCC, currently no guidelines recommend the routine use of PCI in extrapulmonary small cell carcinoma.

SCCC has a propensity for rapid distant metastases to various sites such as liver, lung, brain, bone, and lymph node resulting in treatment failure in most of the cases.[29],[30] At a median follow-up of 7 months, we found disease progression in 42.9% (9/21) of cases. Roy et al., in their study, had disease progression in 60% of SCCC over a long period of median follow-up of 54 months.[29] Huang et al. found disease recurrence in 43.1% of cases over a mean follow-up period of 23.6 months, and 29.5% of patients died due to disease.[30] The follow-up duration in our study was less in comparison to Roy et al. and Huang et al. for which we were unable to detect appropriate recurrence rate.

The limitations of this study are retrospective nature, the limited number of patients enrolled in the study and less duration of follow-up. Moreover, the study lacks information relating to the treatment-related toxicities, including the neurocognitive effects of PCI in the patients.


  Conclusions Top


Multi-agent platinum- and etoposide-based concurrent chemoradiation followed by brachytherapy should be the treatment of choice in locally advanced SCCC. The role of PCI is still unclear due to the limited sample size. The different prognostic factors should be evaluated for individualized treatment. Future prospective studies are imperative in this field to evaluate survival outcomes. Our study will provide a platform for designing future prospective studies on SCCC.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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