Risk stratification and prognosis determination using 18F-FDG PET imaging in endometrial cancer patients: A systematic review and meta-analysis

doi:10.1016/j.ygyno.2014.01.039

Gynecologic Oncology

Volume 132, Issue 3, March 2014, Pages 669-676

https://doi.org/10.1016/j.ygyno.2014.01.039 Get rights and content

Research highlights

•
Prognostic importance of 18-F-FDG PET in endometrial cancer is reviewed.
•
Pooled average SUVmax was higher in high risk patients vs. low risk ones.
•
Pooled HR of pre-operative SUVmax for disease free survival was 7.415.

Abstract

Objectives

In the current study, we systematically searched and analyzed the available literature on the prognostic value of semi-quantitative ¹⁸F-FDG PET imaging (SUVmax/mean) in patients with endometrial cancer and presenting the results in a meta-analytic format.

Methods

Pubmed, SCOPUS, and ISI Web of Knowledge were searched using “endometr* AND PET” as the search algorithm. All studies evaluating the ¹⁸F-FDG PET performance in pre-operative risk stratification or its prognostic value in patients with endometrial cancer were included. Statistical pooling of diagnostic accuracy indices was performed using random effects model. Cochrane Q test and I² index were used for heterogeneity evaluation.

Results

Ten studies (771 patients) were included in the systematic review. Pooled average SUVmax values in patients with risk factors [grade III, lymphovascular invasion (LVI), cervical invasion (CI), myometrial invasion (MI) ≥ 50%] were statistically higher than those in patients without risk factors. Pooled HR of pre-operative SUVmax for disease free survival was 7.415 [2.892–19.432] (p = 0.000046).

Conclusion

Despite higher average SUVmax in the high-risk group compared to the low-risk group of patients with endometrial cancer, the usefulness of ¹⁸F-FDG PET SUVmax in classifying patients into pre-defined risk groups seems to be limited. However, pre-operative SUVmax of endometrial tumors seems to be an independent prognostic marker of recurrence and death. Further large multicenter studies with adequate follow-up are needed to confirm our findings.

Introduction

Endometrial cancer is the most common gynecological malignancy in the western countries characterized by favorable prognosis due to its early diagnosis [1]. Surgery is the mainstay of treatment which consists of hysterectomy and bilateral salpingo-oophorectomy. A challenging issue in the surgical management of endometrial cancer is the selection of patients with high-risk cancer who would benefit from a more radical surgery and lymphadenectomy [2]. Many researchers have identified several risk factors which are associated with poor prognosis and extra-uterine involvement in patients with endometrial cancer such as myometrial invasion (MI), pathological grade (G), cervical invasion (CI), lymphovascular invasion (LVI), and histological features. For example high grade tumors and those with more than 50% of MI are associated with higher risk of pelvic lymph node involvement and recurrence [3], [4], [5]. However, these risk factors can only be identified by surgical staging. Alternative methods such as sentinel node mapping [6] and pre-operative radiological risk stratification have been used in order to identify patients who would benefit from a more radical surgery [7].

Fluorine-18-fluorodeoxyglucose positron emission tomography (¹⁸F-FDG PET) is a functional imaging method used in staging or restaging of numerous malignancies including endometrial cancer and uterine tumors [8], [9], [10], [11]. Several studies evaluated the prognostic implication of ¹⁸F-FDG PET imaging and its potential value for risk stratification in patients with endometrial cancer by using semi-quantitative indices [maximal and/or mean standardized uptake values (SUVmax and/or SUVmean)]. In the current study, we systematically searched and analyzed the available literature on the prognostic value of ¹⁸F-FDG PET imaging in patients with endometrial cancer presenting the results in a meta-analytic format.

Section snippets

Material and methods

The PRISMA guidelines were followed for performing the current systematic review and meta-analysis (http://www.prisma-statement.org). We searched Pubmed and SCOPUS database using the following search algorithm: “endometr* AND PET”. The literature search was performed by two authors independently (GH and SR) and it was updated until October 2013 without language or time limit. The reference lists of relevant studies were reviewed for possible missing articles. Articles cited were also searched

Results

PRISMA flowchart of the study is shown in Fig. 1. Three studies were identified as duplicate and were excluded accordingly [19], [20], [21], [22], [23]. Ten studies (771 patients) were included in the systematic review [24], [25], [26], [27], [28], [29], [30], [31], [32], [33]. Characteristics of the included studies are provided in Table 1.

Discussion

In the current systematic review, we can divide our discussion into two parts:

I — Pre-operative risk stratification

The pooled mean differences of SUVmax were statistically significant in all risk categorization (G, MI, LVI, CI). In other words, average SUVmax of the primary tumors was statistically higher in high-risk groups (grade III, patients with CI or LVI and MI ≥ 50%) compared to low-risk groups. These results show that ¹⁸F-FDG uptake is higher in more aggressive endometrial tumors due to their increased glucose metabolism. In fact, Nakamura et al. reported that expression of glucose transporter-1 was

II — Prognostic significance of ¹⁸F-FDG PET imaging

There are few reports on the prognostic value of ¹⁸F-FDG PET imaging in patients with endometrial cancer with somehow contradictory results.

Two studies reported that pre-operative SUVmax of the tumor was the only independent risk factor in predicting the disease free survival and/or the overall survival. Even tumor size, LVI, CI, G, and age were not statistically significant risk factors [28], [30]. Our meta-analysis also showed statistically significant pooled HR (7.41) for disease free

Limitations

Our systematic review has several limitations. The quality of the studies included in our systematic review is often not high. For example only in one study could we ascertain the similarity of the high-risk and low-risk groups regarding confounding variables. Two of the prognostic studies did not recruit patients at a common point of the disease course and this makes their results less reliable. More importantly, the number of studies with prognostic information is low and the results of our

Conclusion

Despite higher average SUVmax in high-risk compared to low-risk patients with endometrial cancer, the usefulness of ¹⁸F-FDG PET SUVmax in classifying patients into pre-defined risk groups seems to be limited. However, pre-operative SUVmax of endometrial tumors seems to be an independent prognostic marker of recurrence and death. Further large multicenter studies with adequate follow-up are needed to confirm our findings.

Although pre-operative ¹⁸F-FDG PET seems to be useful for its prognostic

Conflict of interest

The authors declare no conflict of interest.

Acknowledgments

This study is the result of a residency thesis which was conducted in Women's Health and Nuclear Medicine Research Centers of Mashhad University of Medical Sciences under the approval number of 900786. We sincerely thank Suzuki et al. and Antonsen et al. for providing additional information. We are also grateful to Barbara Muoio for language editing.

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A systematic review about the role of preoperative <sup>18</sup>F-FDG PET/CT for prognosis and risk stratification in patients with endometrial cancer
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Analizar la literatura disponible sobre el valor pronóstico de los parámetros metabólicos de la ¹⁸F-FDG PET/TC preoperatoria y su utilidad en la estratificación de riesgo en pacientes con cáncer de endometrio (CE).
En búsquedas de Pubmed se utilizó «(endometr* OR uter*) AND (PET OR FDG)» como palabras clave desde enero-2000 hasta junio-2020. Se revisaron referencias en los artículos incluidos buscando posibles publicaciones no incluidas en la primera búsqueda. Se incluyeron los estudios que evaluaron el valor pronóstico de la ¹⁸F-FDG PET/TC preoperatoria y su papel para la estratificación del riesgo en pacientes con CE. Los artículos no originales (revisiones, editoriales, cartas, casos legales, entrevistas, informes de casos, etc.) no fueron incluidos.
Veintiséis estudios (1.918 pacientes) fueron elegidos según los criterios de inclusión en esta revisión. Se incluyeron 13 estudios (939 pacientes) relacionados con el papel pronóstico de la ¹⁸F-FDG PET/TC preoperatoria y 14 estudios (1.036 pacientes) relacionados con su papel en la estratificación de riesgo. Parámetros como SUVmáx, volumen tumoral metabólico (VTM) y glicólisis total de lesión (GTL) del tumor primario fueron analizados.
El SUVmáx preoperatorio es útil para realizar diagnósticos no invasivos y decidir la estrategia terapéutica adecuada, ya que podría utilizarse como marcador pronóstico independiente de recurrencia y supervivencia en el CE. Además, tanto VTM como GTL preoperatorios podrían ser factores pronósticos independientes para predecir recurrencia y supervivencia, pero, aun no existe suficiente evidencia científica. La utilidad del SUVmáx para la estratificación del riesgo es limitada (no existe literatura suficiente acerca de que la ¹⁸F-FDG PET/TC pueda sustituir la estadificación quirúrgica), aunque el VTM y la GTL sí que son más precisos y tienen un valioso papel en la estratificación del riesgo del CE. Sin embargo, se necesitan estudios multicéntricos más amplios con un tiempo de seguimiento adecuado para confirmar estos hallazgos.
To analyse the available literature on the prognostic value of preoperative ¹⁸F-FDG PET/CT metabolic parameters and their usefulness in risk stratification in patients with endometrial cancer (EC).
Pubmed searches used «(endometr* OR uter*) AND (PET OR FDG)» as keywords from January-2000 to June-2020. References in included articles were checked for possible publications not included in the first search. Studies evaluating the prognostic value of preoperative ¹⁸F-FDG PET/CT and its role for risk stratification in patients with EC were included. Non-original articles (reviews, editorials, letters, legal cases, interviews, case reports, etc.) were not included.
Twenty-six studies (1918 patients) were selected according to the inclusion criteria in this review. Thirteen studies (939 patients) related to the prognostic role of preoperative ¹⁸F-FDG PET/CT and 14 studies (1036 patients) related to its role in risk stratification were included. Parameters such as SUVmax, metabolic tumour volume (MTV) and total lesion glycolysis (TLG) of the primary tumour were analysed.
Preoperative SUVmax is useful for non-invasive diagnosis and for deciding the appropriate therapeutic strategy, as it could be used as an independent prognostic marker for recurrence and survival in EC. In addition, both preoperative VTM and GTL could be independent prognostic factors for predicting recurrence and survival, but there is still insufficient scientific evidence. The usefulness of SUVmax for risk stratification is limited (there is insufficient literature that ¹⁸F-FDG PET/CT can replace surgical staging), although VTM and GTL are more accurate and have a valuable role in risk stratification of EC. However, larger multicentre studies with adequate follow-up time are needed to confirm these findings.
ESGO/ESTRO/ESP guidelines for the management of patients with endometrial carcinoma
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ESGO/ESTRO/ESP nominated an international multidisciplinary development group consisting of practicing clinicians and researchers who have demonstrated leadership and expertise in the care and research of endometrial carcinoma (27 experts across Europe). To ensure that the guidelines are evidence-based, the literature published since 2014, identified from a systematic search was reviewed and critically appraised. In the absence of any clear scientific evidence, judgment was based on the professional experience and consensus of the development group. The guidelines are thus based on the best available evidence and expert agreement. Prior to publication, the guidelines were reviewed by 191 independent international practitioners in cancer care delivery and patient representatives.
The guidelines comprehensively cover endometrial carcinoma staging, definition of prognostic risk groups integrating molecular markers, pre- and intra-operative work-up, fertility preservation, management for early, advanced, metastatic, and recurrent disease and palliative treatment. Principles of radiotherapy and pathological evaluation are also defined.
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As with other endometrial histologies, preoperative evaluation of gross and/distant extrauterine spread of UCCC can be accurately assessed by imaging including CT of the chest/abdomen and pelvis or PET/CT. Although endometrial cancer shows intense FDG uptake which can be of prognostic significance when PET/CT is utilized, its utility in early endometrial cancer is restricted due to spatial resolution and physiological uptake [25,26]. The sensitivity, specificity and accuracy of PET/CT in detection of lymph node metastases based on increase tracer uptake by the lymph node was reported as 53%, 99%, 98%, respectively and appears superior to MRI [27–29].
Uterine clear cell cancer (UCCC) is a rare but aggressive disease. Due to its rarity, large, prospective studies focused on UCCC are exceedingly difficult therefore available data are generally from small, retrospective studies. There is also pertinent information from subsection analysis of larger studies that include UCCC and other histotypes. In 2009, the clinical practice committee of the Society of Gynecologic Oncology (SGO) published a review on UCCC aimed at guiding management. Since that publication, there have been developments which are relevant to UCCC, these include availability of data from landmark trials regarding adjuvant therapy, increasing utilization of sentinel lymph node approach and availability of immunotherapy as a treatment option.
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The prognostic value of SUV<inf>max</inf> measuring on primary lesion and ALN by <sup>18</sup>F-FDG PET or PET/CT in patients with breast cancer
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That is to say, patients with high SUVmax might benefit from a more aggressively effective treatment with less risk and side effects. Although, primary lesion SUVmax has been found to have significant prognostic value for OS in different kinds of cancers, such as cervical cancer, lung cancer and esophageal cancer [7,17,35,40], we did not find the similar predictive value of SUVmax for OS in BC patients in primary lesion and ALN. This might be affected by insufficient statistical power, since there were only two studies available (Garcia Vicente et al. and Kim et al.).
To evaluate the prognostic value of maximum standardized uptake values (SUV_max) measured in the primary lesion and axillary lymph nodes (ALN) by pretreatment fluorine-18-fluorodeoxyglucose (¹⁸F-FDG) positron emission tomography (PET) or positron emission tomography/computed tomography (PET/CT) in patients with breast cancer.
We systematically searched PubMed, Embase, and the Cochrane Library. The primary prognosis endpoint was event-free survival (EFS), and the secondary endpoint was overall survival (OS). The pooled hazard ratio (HR) was estimated by using random-effects model according to the results of heterogeneity.
Fifteen eligible studies with 3574 breast cancer patients were included. For EFS, patients with higher primary SUV_max showed a poorer survival prognosis with pooled HR of 1.96 (95% confidence interval (CI) 1.40–2.73). The combined HR of high SUV_max in ALN and ALN-to-primary SUV_max ratio (N/T ratio) were 1.89 (95% CI 0.70–5.07) and 2.06 (95% CI 0.59–7.21), respectively. In analyzing invasive ductal carcinoma (IDC) patients, the pooled HR was 1.91 (95% CI 1.40–2.64). For OS, the pooled HR of SUV_max in primary lesion and ALN were 0.64 (95% CI 0.23–1.84) and 1.09 (95% CI 0.07–16.53), respectively.
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ReviewRisk stratification and prognosis determination using 18F-FDG PET imaging in endometrial cancer patients: A systematic review and meta-analysis

Research highlights

Abstract

Objectives

Methods

Results

Conclusion

Introduction

Section snippets

Material and methods

Results

Discussion

I — Pre-operative risk stratification

II — Prognostic significance of 18F-FDG PET imaging

Limitations

Conclusion

Conflict of interest

Acknowledgments

Gynecol Oncol

Gynecol Oncol

J Clin Epidemiol

Control Clin Trials

Gynecol Oncol

Nuklearmedizin

Gynecol Oncol

Gynecol Oncol

Gynecol Oncol

Cancer statistics, 2010

CA Cancer J Clin

Current therapy of patients with endometrial carcinoma. A critical review

Strahlenther Onkol

The incidence of pelvic lymph node metastasis by FIGO staging for patients with adequately surgically staged endometrial adenocarcinoma of endometrioid histology

Int J Gynecol Cancer

Endometrial cancer: prognostic significance of risk classification based on pre-intraoperative findings

Arch Gynecol Obstet

What is the impact of cervical invasion on lymph node metastasis in patients with stage IIIC endometrial cancer?

Arch Gynecol Obstet

Sentinel node biopsy in endometrial cancer: systematic review and meta-analysis of the literature

Eur J Gynaecol Oncol

Accuracy of 18F-FDG PET/CT for diagnosing inguinal lymph node involvement in penile squamous cell carcinoma: systematic review and meta-analysis of the literature

Clin Nucl Med

Review
Risk stratification and prognosis determination using ¹⁸F-FDG PET imaging in endometrial cancer patients: A systematic review and meta-analysis

II — Prognostic significance of ¹⁸F-FDG PET imaging

Accuracy of ¹⁸F-FDG PET/CT for diagnosing inguinal lymph node involvement in penile squamous cell carcinoma: systematic review and meta-analysis of the literature